Semi-final exam questions

A/41. Rejection of transplants

A major barrier to transplantation is the process of rejection in which the recipient's immune system recognizes the graft as foreign and attacks it. Rejection is a process in which T lymphocytes and antibodies produced against graft antigens react against and destroy the grafts RECOGNITION OF ALLOGRAFT: The major antigenic differences between a donor and recipient that results in rejection of transplants are differences in HLA alleles. Grafts exchanged between two individuals of the same species are called allografts. They are either recognized directly or indirectly: Directly= host T cells recognize the foreign HLA antigens of the graft directly on APCs on the graft = ACUTE REJECTION, or indirectly = CHRONIC REJECTION by the graft antigens first being picked up by the APCs, and then presented to the host T cells after. Both of these recognition pathways lead to the activation of CD8+ T cells, which develop into cytotoxic T lymphocytes and Cd4+ helper cells (Th1). These then become cytokine-producing effector cells. The direct pathway is the most important when talking about CTL-mediated acute rejection, while the indirect pathway is the most important in chronic rejections. MORPHOLOGY OF THE DIFFERENT MECHANISMS OF REJECTION: Graft rejections are classified into hyperacute, acute and chronic based on their clinical or pathological features. Hyperacute:Performed by recipient's antibodies that bind to the graft endithelium immediately after transplantation, leading to thrombosis, ischemic damage and rapid graft failure. Hyperacute rejection is not a common problem, due to cross-match testing, where we test the blood of the recipient and the donor to try to diminish this phenomenon. Morphology: Rejected graft becomes cyanotic, mottled, and flaccid. It does not function like a proper organ should. d. Histologically: widespread acute arteritis and arteriolitis, vessel thrombosis and ischemic necrosis. This is all due to preformed antibodies binding to graft epithelium. i. The vessels show characteristic fibrinoid necrosis in the walls → narrowing / occlusion of lumen due to fibrin and cellular debris. Acute: T cells destroy graft parenchyma (and vessels) by cytotoxicity and inflammatory reactions. It occurs within days or weeks after a transplant and is the principal cause of early graft failure. Based on the role of the T cell or antibodies, acute reactions can be divided into two types, although in most rejecting grafts, both patterns are present: -In ACUTE CELLULAR REJECTION: CD8+ and cytotoxic T lymphocytes may directly destroy the graft cells, or CD4+ cells will secrete cytokines and in this way induce inflammation --> damage of graft. --> Type 1= caused by lymphocyte infiltration around tubules --> mainly by T cells, causing tubulitis. Type II = humerola rejection causing vasculitis. (The acute cellular rejection may produce two different types of injury: In the tubulointerstitial pattern/ type I there is interstitial and tubular inflammation associated with focal tubular injury. In type II/cascular pattern shows inflammation of vessels and sometimes even necrosis of the vessel wall. ) -In acute humoral rejection, antibodies bind to the vascular endothelium and activates the compliment system via the classical pathway. The resultant inflammation and endothelial damage cause graft failure. --> The morphology of this type of rejection is manifested mainly by damage to the glomeruli and small blood vessels. Typically, there is inflammation in the kidney due to deposition of complement products, which activates the compliment system through the antibody-dependent classical pathway. Chronic: Is dominated by arteriosclerosis, this type is caused by T cell activation and antibodies. The T cells may secrete cytokines that induce proliferation of vascular smooth muscle cells, and the antibodies cause endothelial injury. The vascular lesions and T cell reactions cause parenchymal fibrosis. --> Chrnoic rejection is dominated by vascular changes, often with intimal thickening and vascular occlusion. Occurs late (months to years) after transplantation. Occurs with an increase in serum creatinine levels (with renal transplants). Seen: vascular changes, interstitial fibrosis and loss of (renal) parenchyma. METHODS OF IMPROVING GRAFT SURVIVAL: Better HLA matching of target to donor is the main way to improve survival. Survival is better, the more loci that match. ii. Another way is immunosuppressive drugs, which can allow for transplants without any HLA matching for e.g. heart, lung, liver and islet transplantation. Usually the transplant is urgent, and anatomical size compatibility is more important -Target supression of CD3 or of CD28 (T) +B7 (B)which are co-stimulators of T cell activation. 1. Immunosuppression should be done in all transplant patients except in identical twins. 2. Global immunosuppression has side effects: increased susceptibility to infections (fungal, viral, etc.). Increased risk for EPV‐induced lymphomas, HPV‐induced squamous cell carcinomas and Kaposi sarcoma. IMMUNEDEFICIENCY: Transplantation of hematopoetic stem cells (HSCs) requires careful matching of donor and recipient and is often complicated by graft-vs-host disease (GVHD) and immune deficiency. GVHD: Source: bone marrow donors, peripheral blood harvest after hematopoietic growth factor administration, or umbilical cord blood of newborns.Recipient gets chemotherapy / radiotherapy to destroy malignant cells and to create a graft bed → HSCs are infused into the peripheral blood → home into their bone marrow niche. iv. Rejection of HSCs is by a combination of host T cells and NK cells that are resistant to the therapies. In the disease, T cells from the graft perceive the host as 'foreign' → react by activation of both types of T cells → inflammation and death of host cells. Prevention: i. GVHD is potentially lethal → can be minimized by HLA matching (but not eliminated). ii. Donor T cells can be depleted before marrow transplant, which can decrease the risk of GVHD, but it increases the risk of graft failure and recurrence of leukemia. Immune Deficiency a. Usually present for a long time in HSC transplant recipients. b. Due to slow reconstitution of the recipient's adaptive immune system (it is destroyed or suppressed to allow the graft to take). It takes many months to recover. c. During this time, recipients are susceptible to many infections (especially viral EVB and CMV).

A/05. Colliquative necrosis and its organ manifestation

ALSO CALLED LIQUEFACTIVE NECROSIS! Is seen in focal bacterial and occasionally, fungal infections because microbes stimulate rapid accumulation of inflammatory cells. The enzymes of leukocytes digest and liquifies the tissue. This is typical for hypoxic death of cells within the CNS. The dead cells will eventually be completely digested, transforming the tissue into a vicious liquid that will eventually be removed by phagocytes, like the microglia - the macrophages of the CNS. If the process is initiated by acute inflammation, as in bacterial infection, the material is frequently creamy, yellow and is called pus.

A/08. Acute myocardial infarction

AMI definition: necrosis of the myocardium as a direct result of myocardial ischemia. The ischemia is due to an obstruction of blood supply. --> Infarction definition: an area of necrosis due to lack of oxygen due to obstruction of the blood supply to that area. Usually results in a pyramidal shape. -Myocaridal infarcts can occur at any age, but frequency rises progressively with an increase in age (and other risk factors, e.g. hypertension, smoking, DM, etc). The major risk factor for ischemic heart disease is atherosclerosis. PATHOGENESIS: Myocardial infarction patients demonstrates coronary thrombosis in 90% of the cases. In most patients, unstable angina, infarction, and sudden cardiac death occur because of abrupt plaque change followed by thrombosis - hence the term acute coronary syndrome. (Initiated by atherosclerosis). The initiating event is typically a sudden disruption (ranging from erosion to rupture) of a partially occlusive plaque. These mechanisms expose highly thrombogenic constituents and the underlying subendothelial tissue, which leads to rapid thrombosis. In addition, hemorrhage into the lumen of the vessel can further occlude the vessel. Anginal symptoms typically occur with fixed lesions in patients with >70% occlusion. Dynamic lesions are caused by for example coronary spasms that will expose the blood to highly thrombogenic constituents --> rapid thrombosis!!! TYPICAL AMI PROGRESSION (coronary artery occlusion, fixed lesion): 1. Sudden disruption (hemorrhage, mechanical force) of an atherosclerotic plaque exposes subendothelial collagen and necrotic plaque contents to the blood. These are thrombogenic. 2. Platelets adhere, aggregate, activate and release secondary aggregators (TXA‐2, ADP, and serotonin). These cause further platelet aggregation and vasospasm. 3. Other mediators activate the extrinsic (tissue factor) pathway of coagulation, adding to the bulk of the thrombus. 4. Within minutes the thrombus can evolve to completely occlude the coronary lumen of coronary vessel MYOCARDIAL RESPONSE TO ISCHEMIA: Within seconds of vascular obstruction to the heart, aerobic metabolism ceases, leading to a drop in ATP and accumulation of potentially harmful substances in the myocytes. THIS CAN BE REVERSED UP UNTIL A POINT OF 30 MINUTES. TIME LAPSED FURTHER THAN 30 MIN WILL LEAD TO IRREVERSIBLE DAMAGE. The functional consequences is a rapid loss of contractability, occuring within a minute or so of ischemia. Irreversible injury of schemic myocytes first occurs in the subendocardial zone, as this area is the last to receive blood delivered by epicardial vessels, as well as being exposed to relatively high intramural pressures, thus making it the most sensitive to ischemia. With more prolonged ischemia, a WAVEFRONT OF CELL DEATH moves through other regions of the myocardium. An infarct usually achieves it's full extent within 3-6hrs. A transmural infarct occurs when the WHOLE myocardial wall is affected in the waveform theory fashion mentioned above. GROSS AND MICROSCOPIC MORPHOLOGY: The gross and microscopic appearance of an MI depends on the age of injury. Myocardial infarcts less than 12 hrs old usually are not grossly apparent. This is the evolution of morphological changes in MI: >= 30 min: Cagulative necrosis starts, which can be REVERSED up until 30 minutes. 0,5 - 4hrs: Diaphorase test can be done in infarcts mores than 3hrs old, exposing myocardium to vital stains to visualize substrates for lactate dehydrogenase. Because this enzymes is depleted in the area of ischemic necrosis (it leaks out of damaged cells) the infarcted area is UNSTAINED (pale) while old scars appear white and glistening. 4-12hrs: Edema, hemorrhage. Beginning of coag. necrosis signs on light microscope. Gross: occasionally dark spots. 12-24 hrs: The necrosis is ongoing; pyknosis of nuclei, hypereosinophilic (Eosin is an acidic dye; thus, the structure being stained is basic and as a corollary, is acidophilic.) appearance, contraction band (=specific for cardio myoccytes, which indicates that the MI is recent, and was tried to salvage with partial reperfusion!!!), beginning of neutrophilic infiltrate. It first now, after 12 hrs that the infarct can be grossly identified by a red-blue discoloration caused by stagnant, trapped blood 1-3 DAYS: Mottling with yellow-tan infarct center. Will have a hyperemic (darker) border around the yellow border as neutrophiles and macrophages are recruited to the area, releasing enzymes which digest the dead cells and debris. Healing period starts now. 7-10 DAYS: Gross: maximal yellow tan, soft red tan margin. Light Microscope: phagocytosis of dead cells. Formation of granulated tissue at margins. 10-14 days: Gross: red-grey depressed border. Light microscope: full granulation, capillirzation, fibroblasts. Collagen deposition. 14- 30 days: Scar formation will progressively form, and once an MI is completely healed, it is impossible to distinguish it's age. Whether present for 8 weeks or 10 years, fibrous scars look the same. Moreover, malnutrition, size of the infarct, poor vasculature or exogenous anti-inflammatory steroids can impede infarct scarring. CONSEQUENCES OF MI: -Cardiac failure due to pump dysfunction: Blood stays in the lung as it is not pumped, increasing the pressure in the lung causing pulmonary edema, some degree of left ventricular failure. -Arrhythmia: MI's lead to myocardial irritability and conduction disturbances. 90% of patients develop some form of rhythm disturbance with the incident being higher in STEMI's, then NSTEMI's. The risk for serious arrhythmia is greatest in the 1 hour and decreases thereafter --> Can develop SCD due to this! -Myocardial rupture: This isn't a common consequence, however, when it occurs, it is fatal. Rupture occurs most commonly after 3-7 days after infarction since this is the time during the healing process when lysis of necrotic myocardium is maximal, thus the myocytes are very weak.(myomalasia --> blood in pericardium --> hemopericardium that compresses the right ventricle --> r. sided tampenade) -Aneurysm: usually a late complication as the muscle wall is weak and dilates (typically the ventricular wall) -Pericarditis: Transmural infarcts can elicit a fibrinohemorrhagic pericarditis develop within 2‐3 days of a transmural MI. It will resolve with time. -Right ventricular infarction -Reinfarction: Thromboembolism from aneurysm → coronary arteries → another MI, or due to progressive heart failure → another MI. -Chronic ischemic heart disease --> Healthy myocardium has to compensate for the non‐working fibrotic myocardium. This increased workload → hypertrophy → increased oxygen demand without subsequent increase of blood perfusion → progressive heart failure. CLINICAL ASPECTS/SYMPTOMS: The classic MI symptom is severe, crushing substernal chest pain or pressure called angina pectoralis. This can radiate to the left arm, neck, jaw and epigastrium (infarcts that radiate to the belly are typical for posterior MI's). Patients are often diaphoretic (sweating) and nauseous (also common for posterior MI's). Dyspnea is also common resulting in impaired myocardial contractability and dysfunction of the mitral valve, resulting in pulmonary edema. MI's can also be "silent" meaning that the patient doesn't experience any symptoms, which can be very typical for diabetic patients, in which autonomic neuropathy prevents their perception of pain. ST elevation is typical for transmural infarcts (STEMI = ST ELEVATED MYOCARDIAL INFARCTS) The lab evaluation of MI's is based on measuring the blood levels of the macromolecules that leak out of the injured myocardial cells through damaged cell membranes. These include: Troponin I, Troponin T and myocardial specific creatine kinase. Therapy: -thromoblysis by thrombolytic enzyme infusion like for ex heparin -baloon catheter to open -stent opens to reperfuse -arterial bypass Drugs like aspirin, beta blockers(decreases heart rate) and nitrates (vasodilates coronaries)

A/16. Anthracosis, lipofuscin and hemosiderin accumulation

ANTHRACOSIS: Refers to the most common exogenous pigment; carbon, and it's deposition in the lungs as blackish pigment. This is a result of the carbon being inhaled, phagocytosed by alveolar macrophages and transported through the lymphatic channels to the regional tracheobronchial lymph nodes. Aggregates of the pigment colours the draining lymph nodes and pulmonary paranchyma black, and this is called anthracosis!!!! LIPOFUSCIN: Is an insoluble brownish-yellow granular i.c pigment that accumulates in different tissues, especially the heart, liver and brain with aging or atrophy. Can be seen in tissues with high turn-over, like the hepatocytes as they turn over all of their organelles in less than a week). The lipofuscin represents complexes produced by the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It, itself is not harmful to the cells, but its presence does work as a marker for past free radical injury. When lipofuscin is present in large amounts, it causes a change to the apperance of the tissue called BROWN ATROPHY! A good example of this is the brown atrophy heart: This occurs with old patients over 80‐90 or patients with cancer disease or very severe long standing inflammatory disease. The heart becomes round because of accumulation of lipofuscin. HEMOSIEDERIN: Is a hbg-derived granular pigment that is golden yellow to brown and acc. in tissues when there is a local or systemic EXCESS OF IRON. iron cannot be stored alone because it is a toxic substance. It makes peroxidation (cell degradation by the use of oxygen from ROS) and cell death. The organs pack iron with apoferritin, so a protein covers the irons. These are called ferritin micelles. We use PRUSSIAN BLUE staining to identify the iron in histological slides. Accumulation of hemosiderin is usually pthological, it can also be found physiologically in tissues that are related to breakdown of RBC's. Excessive deposition of hemosiderin is called hemosiderosis. There is a difference between hemosiderin deposition, which is an active process, where metabolic degradation of hbg is needed, due to for example bleeding before death. Hematin is a black pigment deposited after death. Local diseases related to accumulation of hemosiderin: -Bruising = The extravasated RBC's are phagocytosed and degraded by macrophages explaining the color changing of a bruise from it's red-blue color (enzymatic conversion of hemoglobin), to blue-green (when hbg is converted to bilirubin), and eventually it's golden-brown color due to the pigment hemosiderin. -Induratio brunea pulmoris: Caused by mitral stenosis or left-sided heart failure. In both cases, pressure increases in the capillaries in the lungs. The lung vessels are congested with blood and this leads to pulmonary edema when plasma escapes in alveolar spaces. Rupture of congested capillaries leads to release of hemosiderin from damaged red blood cells. When alveolar macrophages engulf hemosiderin they are called heart failure cells. Death of heart failure cells in their journey back to lung tissue with subsequent hemosiderin release leads to lung fibrosis Systemic diseases: Usually related to hemolysis in which all organs become brown. -Intravascular hemolysis -Hemochromatosis: Is a heridatory iron storage disease. Pathogenesis (1) It regulates hepcidin. Hepcidin is called the iron hormone. It regulates uptake and blockage of iron. (2) Iron is taken up in the small intestine. If the hepcidin level decreases, iron is taken up. If hepcidin level increases, it blocks the iron uptake. (3) This is generated by the HFE gene. If the gene is mutated, hepcidin levels are decreased and therefore there is uncontrolled iron uptake. This uncontrolled uptake of iron leads to macrophages saturation, and the free iron leaks into the body. As iron is toxic, the iron generates necrosis. This can lead to: (1) Pancreatitis (2) Fibrosis of the intestine (3) Brown colored fibrotic skin (4) Liver cirrhosis (5) Liver failure

A/50. Autosomal recessive and X-linked inheritance disorders

AUTOSOMAL RECESSIVE DISORDERS: -The biggest group mendalian disorders. -Both alleles of a given gene locus are mutant -Features: *Trait does not affect parents, but siblings can be affected *Sibling have 1/4 (25%) chance of being affected --> per birth *If the mutant gene has low population frequency, it is likely that the affected person is a product of marriage within the family -Expression of the disease is more uniform than AD disorders -Compelte penetrance is common -Onset is often early in life -New mutations are rarely detected, since the affected asymptomatic heterozygote needs to mate with other heterozygotes to produce affected offspring (often generations later). -The mutations often affect enzymes! CYSTIC FIBROSIS: -Mutation in the CFTR gene (cystic fibrosis transmembrane conductance regulator gene.) , that codes for chloride transport out of cells. -Disorder of epithelial transport affecting fluid secretion in exocrine glands and epithelial lining of the respiratory, GI and reproductive tracts. a. Results usually in recurrent and chronic pulmonary infections and pancreatic insufficiency. b. Often find high levels of NaCl in the sweat, although the exocrine sweat glands are structurally normal. RESULTS IN: -Sweat ducts: decreased reabsorption of sodium chloride and production of hypertonic sweat - Respiratory and GI tracts: loss of chloride secretion into the lumen → passive water reabsorption from the lumen → decreased water content of the surface mucus layer → isotonic but low‐volume surface fluid layer (dehydration). (1) Lungs: defective mucociliary clearance and accumulation of viscous secretions that obstructed the passages and increase the risk of recurring pulmonary infections. -THE MOST SERIOUS COMPLICATION IS THE ONE WITH THE LUNGS IN WHICH OBSTRUCTION AND INFECTION OF THE ARIWAYS DEVELOP, AS WELL AS INCREASED MUCOUS THICKENING. -Mutations can range from mild to severe, depending on how much of the CFTR protein function is lost. -Azoospermia and infertility is very common. Bilateral absence of the vas deferens is also common. PHENYLKETONURIA (PKU) Homozygotes have a severe lack of phenylalanine hydroxylase (PAH) enzyme →hyperphenylalaninemia and PKU. a. Infants are normal at birth, but within a few weeks the show increasing serum phenylalanine level (can impair brain development). b. Severe mental retardation can occur by 6 months of age. c. Seizures, neurological abnormalities, decreased pigmentation of skin and hair and eczema are also commonly seen. -This disorder can be avoided by restricting consumption of phenylalanine early in life. The mother should already restrict before conception and throughout pregnancy to prevent fetal abnormal development. -Is screened in all fetuses post-partum! -As phe--> tyrosine cannot happen, it also means, since tyrosine is a precursor of melanin, that the baby will have a very light pigmentation of the skin GALACTOSEMIA: -GALT (galactose‐1‐phosphate uridyltransferase) is missing due to homozygous mutations in the GALT gene. Galactose from mothers milk (lactose = glucose + galactose) cannot be properly metabolized. --> Results in accumulation of GALT in tissues. -See early‐onset hepatomegaly due to fatty change. This can lead to cirrhosis. Cataracts. Nonspecific changes in the CNS (loss of nerve cells, gliosis, and edema). -From birth the baby will have diarrhea and vomit after ingestion of breast milk. First week shows jaundice and hepatomegaly. --> Removing galactose from the diet for the first 2 years of life will prevent the changes seen. LYSOSOMAL STORAGE DISEASES: -Usually affects infants and small children. -Storage of insoluble intermediates in the mononuclear phagocyte system leads to hepatosplenomegaly. -Often see CNS involvement and neuronal damage. -Cell destruction due to storage of undigested material, macrophage activation and cytokine release. -Very rare condition. TAY-SACHS DISEASE: -Tay-Sachs disease is a genetic disorder that results in the destruction of nerve cells in the brain and spinal cord. The most common type, known as infantile Tay-Sachs disease, becomes apparent around three to six months of age with the baby losing the ability to turn over, sit, or crawl. -A defective gene on chromosome 15 (HEX-A) causes Tay-Sachs disease. This defective gene causes the body to not make a protein called hexosaminidase A. Without this protein, chemicals called gangliosides build up in nerve cells in the brain, destroying brain cells (-Gangliosidosis: accumulation of gangliosides, especially in the brain, due to a deficiency of a catabolic lysosomal enzyme. -Deficiency of hexosaminidase β subunit (ganglioside) which is needed to degrade the GM2 ganglioside. -Affected cells are swollen / foamy (neurons, axon cylindedrs of nerves, glial cells, all in CNS). - See severe mental retardation, blindness, motor weakness and death by age 2 / 3.) GLYCOGEN STORAGE DISEASES: Due to deficiency of any of the enzymes needed for glycogen synthesis or degradation → accumulation of glycogen or abnormal form of glycogen in tissues. We have different forms: -Hepatic type = Von Gierke disease due to lack of glucose‐6‐phosphatase , leads to liver enlargement due to storage of glycogen and hypoglycemia due to failure of glucose production. -Myopathic type= McArdle's disease (type V) is a deficiency of muscle phosphorylase. -Miscellaneous type: Pompe disease (type II): subtype of lysosomal storage disease; deficiency of lysosomal acid maltase → deposition of glycogen into every organ, but especially cardiomegaly. X-LINKED DISORDERS: -There are no known Y-linked disorders -Most X-linked disorders are recessive -Transmitted by heterozygous female carrier only to sons, who are hemizygous for the X chromosome. i. Sons have a 1 in 2 chance of receiving the mutant gene. -Heterozygous females have the paired normal allele, which is enough with the random X‐ inactivation to account for low amount of phenotypical change. e) Affected males do not transmit disorders to sons, but all daughters are carriers. HEMOPHELIA A -Factor VIII is defective DUCHENNE/BECKER MUSCULAR DYSTROPHY -Defect in dystrophin. If it is a frame-shift mutation then it is more severe and develops into duchenne which have a worse prognosis and symptoms, if it is a in-frame mutation then it is becker which is a milder form of the disease FRAGILE X-SYNDROME: -Repeat of 3 nucleotides (CGG) in the FMR1 gene -Loss of function mutation -Causes mental retardation and abnormal facial features.

B/38. Pericardial disease

Almost always associated with diseases in other positions of the heart or surrounding tissues, typically are secondary to systemic diseases! NORMALLY, the pericardial sac contains less than 50ml of thin, clear, straw-colored fluid. Under various circumstances, the pericardial sac can be distended due to increased serous fluid (=pericardial effusion), blood (hemopericardium) or pus (purulent hemocardium). PERICARDIAL EFFUSION: Is normally 30-50ml of serous fluid into the pericardiac cavity, and we call effusion any secretion above this amount. -Serous: CHF, nyeoproteinemia -serousanguinous = blood and serum!: Malignancy, ruptured MI, aortic dissection, bunt trauma to the chest -Chylous: mediastinal lymphatic obstruction It is important to note that slowly accumulating fluid, usually with long-standing cardiac enlargement, leaves the pericardium time to dilate. This permits pericardial effusions to become quite large without interfering with cardiac function. Thus, if the chronic effusions are less than 500ml in Vm the only clinical significance is a characteristic globular enlargement of the heart shadow on chest radiograph! IN CONTRAST, rapidly developing fluid accumulation of as little as 200-300ml (often due to hemopericardium due to ruptured MI or aortic dissection), can produce clinically devastating compression of the thin walled atriua and venae cavae, or even the ventricles themselves= cardiac filling is therefore restricted, producing POTENTIALLY FATAL CARDIAC TAMPONADE! PRIMARY PERICARDITIS: is very uncommon and is typically caused by viral infections, however bacteria and fungi can also be involved. SECONDARY PERICARDITIS: following an AMI, cardiac surgery, uremia = most common cause to secondary paricarditisa (Matolcsy loves this!), SLE or RF = what they call DRESSLER'S SYNDROME ( believed to be an immune system response after damage to heart tissue or to the pericardium, from events such as a heart attack, surgery or traumatic injury.) This can cause immediate hemodynamic consequences or it can resolve itself without consequences or progress to chronic fibrosis! ACUTE PERICARDITIS: depends on the cause, for example: 1) Acute viral pericarditis or uremia = exaduate is typically fibrinous, creating an irregular, shaggy appearance to the peric surface called "bread&butter" pericarditis. 2)Acute bacterial pericarditis: the exudate is fibrinopurpulent often with areas of frank pus. --> Tuberculous pericarditis can exhibit areas of caseation! 3) Malignant pericarditis: Is associated with a shaggy, fibrinous exaduate, and bloody effusion! CHRONIC FIBROSIS: happens with extensive fibrinopurulent secretion or casaution, in which the healing of these leads to fibrosis! Once chronic pericarditis stage is reached, one can see delicate adhesions or dense, fibrotic scars that OBLITERATE THE PERICARDIAL SPACE. In extreme cases, the heart can become completely encapsulated and thus be restricted in such a way that it cannot expand normally. This condition is called CONSTRICTIVE PERICARDITIS and the fate of it is similar to restrictive cardiomyopathy SYMTPOMS: chest pain (atypical, also at rest) and cardiac tamponade, which leads to declining CO and consequent cardiogenic shock!

B/21. Effects of tumor on host (cancer cachexia, paraneoplastic syndromes)

Although malignant tumors of course are more threatening than benign tumors, morbidity and mortality may be associated with any tumor, even a benign one. Both malignant and benign tumors may cause problems due to 1) location and impingement of surrounding structures, 2) functional activity such as hormone synthesis or the dev of paraneoplastic syndromes, 3) bleeding and infections when the tumor ulcerates through adjacent surfaces, 4) symptoms that result from rupture or infarction, 5) cachexia or wasting. LOCATION: Location is crucial in both benign and malignant tumors. A small, 1cm pituitary adenoma can compress and destroy the surrounding normal gland, giving rise to hypopituitaridism. A 0,5cm leiomyoma in the wall of the renal artery is enough to cause ischemia and hypertension of the kidney. Similarly, a carcinoma in the common bile duct may induce fatal biliary tract obstruction! FUNCTIONAL ACTIVITY: Signs and symptoms related to hormone production is often seen in patients with benign and malignant neoplasms arising in endocrine glands! Hormonal producing tumors are more likely to be due to a well-differentiated benign tumor than with a corresponding carcinoma! Ex: adenoma or carcinoma of the beta cells in the pancreas may produce fatal hyperinsulinism. Adenomas or carcenomas of the adrenal gland may disrupt steroid hormone levels and cause Na+ retention, hypertension, hypokalemia etc. ULCERATION: A tumor may ulcerate througha surface, with consequent bleeding or secondary infection. Neoplasms that protrude into the lumen of the GI may be caught in the peristaltic movement of the gut, causing intestinal obstruction and infarction CANCER CACHEXIA: Many cancer patients suffer from progressive loss of body fat and lean body mass, accompanied by profound weakness, anorexia and anemia - a condition referred to as cachexia. This is not due to the increased nutritional demands of the tumor, but rather results from the action of soluble factors such as cytokines produced by the tumor and the host, rather than reduced food intake.It is suspected that TNF and other cytokines produced by the macrophages in response to tumor cells/or the tumor cells themselves mediate cachexia. TNF suppresses appetite and inhibits the action of lipprotein lipase, preventing the relase of FFA's. Another theory is that Alteration of control loop. Adipocytes secrete leptin which blocks neuropeptide (NPY) release (most potent feeding‐stimulatory peptide). This leads to decreased food intake even though the metabolic demand is big. In patients with cancer, calorie expendature remains high, and BMR is increased, despite the reduced food intake. The body does not go into low metabolic rate as in starvation. THERE IS NO SATISFACTORY TREATMENT FOR CANCER CACHEXIA OTHER THAN REMOVAL OF THE UNDERLYING CAUSE = REMOVAL OF THE TUMOR!!! PARANEOPLASTIC SYNDROMES: =symptom complexes that occur in patients with cancer thaat cannot readily be explained by local or distant spread if the tumor or by the elaboration of hormones indigenous to the tissue of origin of the tumor. they appear in 10-15% of patient's with cancer, their clinical recognition is important for several reasons: -Such syndromes may represent the earliest manifestation of an occult neoplasm -In already affected people, the pathological changes may be associated with significant clinical illness and may even be lethal -The symptom complex may mimic metastatic disease, thereby confounding treatment! The most common paraneoplastic syndromes are hypercalcemia due to PTH-related protein produced by tumor cells ( or due to the widespread osteolytic metastatic disease of bone), Cushing syndrome due to ACTH-like polypeptides produced by cancer cells (occurs in small cell carcinoma of lung), and nonbacterial endocarditis (hypercoagulability states).

A/46. AIDS

AIDS is a retroviral disease caused by the human immunodeficiency virus (HIV). Its characterized by infection and depletion of CD4+ T-cells, and by severe immunosuppression which can lead to opportunistic infections, secondary neoplasms and neurologic manifestations that wouldn't have happened in a healthy person. There are about 33 million people living with HIV worldwide, and the majority is in Africa. AIDS is the second leading cause of death in men between ages 25 and 44 years. Let's look at the groups of people who has greater risk of getting it: -Homosexual or bisexual men, Like Freddie Mercury Heterosexuals have also a risk but are better at using protection because of pregnancy risks.HIV spreads more easily in the anus, apparently. -Intravenous drug abusersSharing needles -People with haemophilia. Before 1985, they received factor concentrates from others blood. -Recipients of blood and blood componentsIf the blood giver has not been screened for blood borne infections properly, which is rarely a problem nowadays. -Mother-child transmissionHIV can travel through the placenta, infect during delivery or breast feeding. HIV belongs to the lentivirus family that is non-transforming and exists in two types; HIV-I and HIV-II. HIV-I is the most common type, while the second is pretty rare and is found in West Africa and India. Since HIV-II is so rare, we will consider only the pathogenesis of HIV-I. PATHOGENESIS: The major targets of HIV are the immune system and the CNS, but since we know more about how it attacks the immune system, we will discuss this in detail. We have to look at the structure of the virus. Its surrounded by a lipid envelope containing glycoproteins gp120 and gp41 which are attached to each other. These have a crucial role in the process of binding and entering into a host cell. The virus is able to get through the cell membrane of CD4+ T-cells, macrophages and dendritic cells by binding to their CD4 molecule. However, that's not enough to enter the host cell. HIV must also bind to the chemokine coreceptors, CCR5 or CXCR4 of the CD4+ cells! Note that the latter coreceptor is only found on T-cells. The virus uses its gp120 to bind to CD4, which will make gp120 change its confirmation, giving it a new binding site. Gp120 then binds to the chemokine coreceptors, which induces gp41 to fuse with the cell membrane of the cell, making the virus able to enter the immune cell of the host! When inside the cell, the virus releases its reverse transcriptase, to transcript its RNA genome into the DNA of the host, making a complementary DNA, cDNA. In resting cells, the cDNA will be episomal, meaning that it will lay extrachromosomal, and not enter the genome of the host cell yet. However, as soon as the T-cell gets activated by cytokines or antigens, the viral DNA gets incorporated into the genome of the cell. The transcription of this cDNA will result in completely new HIV particles that bud from the cell membrane. The cell can actually fill up so much with HIV particles that the excessive budding kills it. The virus will spread further, however, repeating the process on new T-cells. Most of the times, the infection stays latent in the T-cells, and it can remain non-transcribed for months or years! MORPHOLOGY: Changes in the tissues (except the brain) are neither specific nor diagnostic. We know that the virus targets monocytes and microglial cells in the brain as they are CD4+. The virus is carried into the brain by infected monocytes, and it believed that the neurons take damage from soluble factors produced by infected microglia, like IL-1, IL-6 and TNF. Neurons also take damage from NO induced by gp41 on the HIV envelope, but the neurons themselves never get infected since they lack the CD4 molecule! Biopsy from lymph nodes show hyperplasia of B-cell follicles which reflects the polyclonal B cell activation and hypergammaglobulinemia seen in HIV-infected individuals. With progression of the disease, the B cell prolif gives rise to the severe lymphoid involutions which may eventually lead to germinal centrs becoming hyalinized and atrophy of the lymph nodes. In severe cases of the disease, lymphoid involution is not only confined to the nodes, but eventually the spleen and thymus are converted to "wastelands" that are devoid of lymphocytes. CLINICAL FEATURES OF AIDS: Acute retroviral infection This stage is in the very beginning. Infected T-cells die on the mucosal surfaces. The immune system of the host develops a response against this virus, while the viral replication takes place in the lymph nodes. This leads to flu-like symptoms: -Sore throat -Myalgias -Fever -Weight loss -Fatique 2. Middle, chronic phase This stage is usually asymptomatic. The lymph nodes and the spleen will have continuous HIV replication and more T-cells die. In this phase, minor opportunistic infections may appear, like oral and vaginal candidiasis, herpes zoster and tuberculosis. 3. Clinical AIDS The host defence is broken down, and the number of CD4+ T cells is minimal in blood, while plasma virus levels are high! If no treatment is given, the patient in this stage will not live longer than 7-10 years. Now, more severe opportunistic infections can develop since the immune system barely works in the host. Usually, they are just latent since the body of a patient with HIV can't get rid of them, and in this stage, they are enough to kill them. The infections can be: -Pneumonia: Bronchopneumonia killed Freddie Mercury -Candidiasis, especially oral (fungal infection) -Colitis -Tuberculosis, both classical and avium -Encephalitis by toxoplasma gondii -Salmonella TREATMENT: There is no cure for AIDS, however, there is medication for slowing down its progress. Antiretroviral drugs target the viral reverse transcriptase and integrase. Medication improve decrease the death rate dramatically as well as they decrease the incidences of pneumocystis and Kaposi sarcoma.

B/40. Aneurysms and Aortic Dissection

Aneurysm: outpouching of the vessel wall which is either congenital or acquired True aneurysm: all 3 layers (intima, media and adventitia) Pseudo aneurysm: 1 or 2 layers only, creating an extravascular hematoma that communicates with the intravascular space, a so called: "pulsating hematoma" -We can also classify them by shape: Saccular aneurysm: are discrete outpouchings ranging from 5-20cm in diameter, often with a contained thrombus! Bare én av sidene av vessel wall bulger ut i convex form! Fusifrom aneurysm: are circumferential dilations up to 20cm in diameter, these most often involve the aortic arch, the abdominal aorta or the iliac arteries! (Basically tenk at begge sider av vessel bulger ut i en convex form PATHOGENESIS OF ANEURYSM FORMATION IN GENERAL: Aneurysms occur when there are alterations in SMC's or ECM that compromise the structural integrity of the arterial media! 1)Inadequate or abnormal CT synthesis: We know that TGF-beta regulates SMC proliferation and matrix synthesis, thus mutations in it's receptor and downstream signalling pathways result in defective elastin and collagen synthesis; in these indiciduals, aneurysms tend to rupture, even when small! Ex: Marfan syndrome, mutation of fibrillin-1, and Ehlers-Danlos syndrome, mutation in collagen type III synthesis! 2)Excessive CT degradation: When we have increased matrix metalloprotease expression by macrophages in atherosclerotic plaques! 3)Loss of SMC's or change in it's phenotype: Atherosclerotic thickening of the intima can cause ischemia of the inner media by increasing the diffusion distance from the lumen. THE TWO MOST IMPORTANT PREDISPOSING CONDITIONS FOR AORTIC ANEURYSMS ARE ATHEROSCLEROSIS AND HYPERTENSION! 1) ABDOMINAL AORTIC ANEURYSM: -Normally between the renal artery and common iliac artery! -The atherosclerotic plaque compresses tunica media causing degeneration and necrosis, thus dialation as the wall of the aorta is broken down due to the necrosis! -The consequences are mural thrombosis, ischemia of lower limb, bleeding into peritoneal cavity. 2) SYPHILIC ANEURYSM, DUE TO SYPHILLUS INFECTION BY TREPONEMA PALLIDUM BACTERIUM: -Dilation of thoracic aorta -Granulomatous reaction of vasa vasorum --> ischemia of wall --> dilation --> insuff of aortic valve and pulsation BERRY ANEURYSM: -Frequent in cerebral arteries, in the branching ones -Patient is predisposed if they have a collagen deficiency, hypertension -Rupture leads to suarachnoid pbleeding -SOL´N= Clip it or insert spiral to slow down BF to aneurysm = stasis = dissolved aneurysm NB! MOST ANEURYSM ARE ASYMPTOMATIC, THUS THIS CANNOT NECESSARILY SAVE THE PATIENT! AORTIC DISSECTION (IS A TYPE OF PSEUDOANEURYSM): -occurs when an injury to the innermost layer of the aorta allows blood to flow between the layers of the aortic wall, forcing the layers apart -Classification, 3 types of aortic dissections: --->DeBakey, I and II - affects the ascending part --->DeBakey III- affects the descending part -Predisposition: collagen deficiency, hypertension, atherosclerosis CONSEQUENCES: -creates a false channel -compresses branching arteries, causing ischemia to different organs -bleeding --> hemothorax, hemopericardium osv -Can have severe cardiac consequences like cardiac tamponade DIAGNOSIS: -Similar symptoms to MI, must make sure by doing an angiography! TREATMENT: Surgery to replace affected segment

A/03. Mechanisms of apoptosis and its pathological characteristics

Apoptosis is a programmed way of cell death and suicide eventually leading to phagocytosis of cells and its fragments NECROSIS VS APOPTOSIS: -Necrosis doesn't require E, apoptosis does -Necrosis induces inflammation, apoptosis does not -In necrosis, membrane integrity is compromised and usually lost, in apoptosis it's not -Necrosis = unspecified enzyme activity, with apoptosis it requires specific caspases -Swelling= necrosis, shrinking =apoptosis -Necrotic nuclei eventually undergoes pyknosis, while apoptotic nuclei undergo fragmentation -Necrosis is purely pathological, while apoptosis can be both CAUSES OF APOPTOSIS: Physiological: Serves to eliminate cells that are no longer needed for the body's physiological function. Examples include: -Embryological development -Removal of tumor cells -Death of cells to reduce and maintain cell nr -Removal of hormone dependant tissue after hormone inactivation -Death of cells with DNA damage Pathological: Excessive apoptosis causes atrophy which can be caused by -ER stress due to misfolded proteins -lack of o2 and nutrients -growth factor deprivation -Viral infections in which virus integrate into the cell to cause cell cycle arrest Insufficient apoptosis leads to cell proliferation and can cause tumors. MORPHOLOGY OF APOPTOSIS: -apoptotic bodies appear -eosinophilic cytoplasm -nuclear changes: pyknosis (condensation) and karyorrhexis (fragmentation) -no inflammation so phagocytosis of antibodies? MECHANISM OF APOPTOSIS: Apoptosis is a process driven by caspases (cystine proteases that cleave proteins after aspartic acid residues). These enzymes can be activated through two different pathways: the extrinsic and intrinsic one. Extrinsic pathway --> MEDIATED BY DEATH RECEPTORS Many cells express death receptors on their surface, that trigger apoptosis. Most of these are member of the TNF (tumor necrosis factor) receptor family, where the cytoplasmic part of the receptor contains a "death domain". Fas ligand is mainly expressed on activated lymphocytes and it is this that is crosslinked with TNF and the death domain to recruit and activate the caspeses. Either caspase-9 or -8 is activated first, eventually activating downstream caspases. Intrinsic pathway --> MEDIATED BY THE MITOCHONDRIA Most physiological and pathological situations are handled with this mechanism. When mitochondrial membranes become permeable, cytochrome c (a protein able to induce apoptosis) leaks out into the the cytoplasm, triggering caspase activation. It is the Bcl-2 which controls the permeability of the mitochondrial membrane. It does so by holding Bak and Bax in check by interacting with growth factors etc. When cells are deprived of growth factors and survival signals, accumulate misfolded proteins or are exposed to damaged DNA, BH3 sensors are activated causing Bak-Bax to dimerize. This dimerization move into the mitochondrial membrane, forming pores in which cytochrome C can leak out. After the protein cyt-c enters the cytosol, it activates caspase-9, leading to more activation of other caspases.

B/05. Promotion mechanisms of oncogenes and role in carcinogenesis

Cancer is a multistep process involving gene mutations, telomerase activation, angiogenesis, invasion and metastasis. TYPES OF GENE MUTATIONS CAUSING CANCER: -Point mutations (most common) -Balanced translocations (like CML, burkitt lymphoma) -Insertion of a viral genome -Other mutations like deletions, overexpression, gene amplification etc 4 classes of normal regulatory genes are the target for genetic damage. i. Growth‐promoting proto‐oncogenes ii. Growth‐inhibiting tumor suppressor genes iii. Genes that regulate programmed cell death iv. Genes involved in DNA repair PROTOONCOGENES: Proto-oncogenes are involved in normal growth and repair usually be secreting and producing growth factors, nuclear transcribers and signal transducers. When these genes are mutated, it leads to SUSTAINED ACTIVITY OF THESE GENES, and overexpression of growth inducing signals. They need only one mutated allele to include cell transformation, aka cancer, whilst tumor supressor genes usually require two! (Anti-oncogenes protect against uregulated cell proliferation by supressing it). PROTOONCOGENIC FACTORS: GROWTH FACTORS: Are normally secreted in paracrine fashion, so normalt cells do not have receptors for their of GF's, but as tumor cells have autocrine receptors, the GF's can act on them, in an autocrine fashion. RECEPTOR TYROSINE KINASE (GROWTH FACTOR RECEPTORS): tumors result from overexpression or mutation in growth factor receptors. These receptors can stimulate growth even if there is no growth factor present. This can lead to hypersensitivity (extreme growth) if growth factor is present in even very low levels. Blocking these receptors can be used as an anti‐ tumor therapy. EXAMPLES: -ERBB1 is a gene for another growth factor receptor. The growth factor in this case is epidermal growth factor (EGF). ERBB1 is overexpressed in: 80% of lung squamous cell carcinomas >50% of glioblastomas 80-100% of head and neck carcinomas -ERBB2, also called HER2, is another tyrosine kinase receptor, however we still don't know its physiological ligand. HER2 is overexpressed in: 15-25% of breast carcinomas Adenocarcinomas of ovary, lung, stomach and salivary glands Biological treatment for HER2 positive breast carcinoma is a monoclonal antibody called herceptine. These antibodies cause the breast carcinoma cells to internalize the HER2 receptor, limiting its harmful potential and effectively treating the cancer. DOWNSTREAM SIGNAL TRANSDUCTION: tumor cells become autonomous (a cancer cell's independence from normal cellular controls) by acquiring gene mutations that couple growth factor receptors and their nuclear targets via signaling molecules. EXAMPLES: -RAS protein: most common mutated proto‐oncogene - 30% of all human tumors. a. Member of small G proteins family: inactive when bound to GDP, but with receptor activation → binds to GTP → becomes active via conformational change. Short‐lived activation due to high intrinsic enzyme activity. b. RAS wills stimulate downstream regulators found in the nucleus → cause cell proliferation. GEF (guanine nucleotide exchange factor) will activate it, and GAP (GTPase activating protein) will inactivate it! c. With mutation activation of RAS (usually point mutations affecting GTP hydrolysis / inactivation) or downstream regulators (BRAF, P13K, AKT), there is trapping of regulators in an activated state → cell is forced into continuous proliferative state. -ABL (Abelson murine leukemia viral oncogene): non‐receptor‐associated / cytoplasmic tyrosine kinase. It regulates processes of cell differentiation, cell division, and cell adhesion. Translocation between chromosome 9 and 22, creates a hybrid called PHILIDELPHIA CHROMOSOME that will put the ABL of the 9q on the BCR gene of 22p, thus creating tyrosine kinase activity and downstream signal transduction --> lead to CML in 90% of cases!! NUCLEAR TRANSCRIPTION FACTORS: Mutations in genes that regulate DNA transcription in the nucleus can also lead to growth autonomy. An example, is MYC which is seen mutated in many different cancers like cervix, colon, breast, lung etc. One specific example is the BURKITT LYMPHOMA, where there is a translocation between cs 8 and 14, that leads to the immunoglobulin gene being overly expressed as MYC, a proto-oncogene that drives cell proliferation is placed in front of it. CYTPLASMIC SERONINE/THREONINE REGULATION: Cancers can become autonomous if there are mutations or amplifications of genes that drive the cell cycle (cyclins, cyclin‐dependent kinases, etc.) *All cancers have gene lesions that disable the G1‐S checkpoint which causes uncontrolled entry into the S phase. EXAMPLE: Increased expression of cyclin‐D‐CDK4 is common in many tumors: esophageal‐, breast‐, liver cancers, lymphomas and plasma cell tumors for cyclin D amplification. CDK4 amplification is seen in melanomas, sarcomas and glioblastomas.

A/40. Type III. and Type IV. Hypersensitivity reactions and their pathological presentations

HYPERSENSITIVITY RXN III: PATHOGENSIS: Is called immune complex disease, as the whole premise of the disease is that so-called immune complexes deposit in vessels, causing inflammation. An immune complex is a complex that is formed when antibodies bind to antigens to form large complexes. The antigens in this case may be exogenous, like microbial proteins, or endogenous proteins as in autoimmune diseases. The antibodies are usually IgG but can be IgM as well. Large immune complexes are easily removed by the spleen and the liver, meaning that the medium or small sized immune complexes are the most pathogenic. Hypersensitivity reactions occur when smaller immune complexes are produced in so large amounts that the body can't get rid of them, causing them to deposit. If they are formed in the circulation will inflammation be systemic, but if they form in organs will the inflammation be local. The most frequent sites of deposition are kidneys, joints and small blood vessels, which is why common symptoms of type III hypersensitivity reactions are glomerulonephritis, arthritis and vasculitis. Deposited immune complexes activate the complement system and neutrophils. The complement system causes inflammation with resulting tissue damage, recruitment of neutrophils and monocytes and increased vascular permeability. Neutrophils release lysosomal enzymes and reactive oxygen species, which damage the tissues. iii. Complexes can form 1. In the circulation → deposition in blood vessels. 2. At sites where antigen has been planted. iv. Injury is 1. Systemic, if complexes are formed in the circulation and deposited in many organs. 2. Localized to particular organs, if the complexes are deposited in specific sites, e.g. kidneys, joints, skin). Systemic immune complex disease begins when immune complexes form in the circulation. These complexes eventually deposit in tissues, which causes an acute necrotizing vasculitis in these tissues. A prime example of this is serum sickness, which occurs when patients are administered serum from healthy people (these usually contains antibodies that are beneficial to the patients). After 5 days has the patient produced antibodies against the antigens in the foreign serum. Immune complexes form and deposit. Serum sickness doesn't occur often nowadays, however the disease progression is similar in all systemic immune complex diseases. Local immune complex disease means that symptoms occur only where the antigen was planted. A model of this is the Arthus reaction, where we inject an antigen under the skin of a previously immunized animal. At the site of injection will an inflammatory reaction develop, and after some hours will there be oedema, haemorrhage and possibly ulceration. EXAMPLES: -systemic lupus erythematosus -Poststreptococcal glomerulonephritis -Serum sickness -Reactive arthritis HYPERSENSITIVTY IV: PATHOGENESIS: The other types of hypersensitivity have been mediated by antibodies; however type IV is mediated by cells and not antibodies. It is therefore also known as T-cell mediated hypersensitivity. Both CD4+ TH cells and CD8+ TC are involved in T-cell mediated hypersensitivity. Of the TH cells are the TH1 and TH17 subtypes most important, as they secrete pro-inflammatory cytokines that recruit and activate macrophages and other cells. TC cells are involved as they exert cytotoxicity, killing host cells and causing tissue damage. TH cell mediated type IV hypersensitivities are often called delayed-type hypersensitivity, or DTH. DELAYED TYPE HYPERSENSITIVITY (DTH): Delayed-type hypersensitivity begins when antigen-presenting cells first meet and phagocytose an antigen, either self-antigen or microbial antigen. The APCs then present this antigen to the TH cells. The APCs also produce cytokines, the types of which decide whether the TH cell will differentiate into TH1 or TH17 subtypes. The person is now sensitized, and nothing more happens, however the TH1 and TH17 cells will "remember the antigen" until the next time it appears. Upon subsequent exposure to the antigen will the previously differentiated TH1 and TH17 be recruited to the site of the antigen and immediately secrete pro-inflammatory cytokines that recruit and activate neutrophils, macrophages and monocytes. Activated (M1) macrophages will continue to phagocytose antigens and continue to present them to T-cells and continue to produce cytokines which stimulate TH1 and TH17-cells, producing a positive feedback loop between activated macrophages and TH cells. However, note that so far has nothing pathogenic happened. This is part of the normal immune response against pathogens. Tissue injury (and therefore hypersensitivity) occurs when the pathogen can't be eliminated. That is when the positive feedback loop becomes an inflammatory machine with no brakes. In some DTH reactions will granulomas develop. Over a period of weeks will the TH cells in the tissues be replaced by activated macrophages. These macrophages accumulate and take on a special morphology where they become large, flat and eosinophilic. At this point they're known as epithelioid cells (due to their resemblance to epithelial cells). Under the influence of IFN-γ, produced by TH1 cells, will epithelioid cells fuse with each other and form multinucleated giant cells. The microscopic accumulation of giant and epithelioid cells, surrounded by lymphocytes, is called a granuloma. Note that granulomatous inflammation doesn't always require a DTH reaction, and not all DTH reactions results in granuloma formation. Delayed-type hypersensitivity is delayed because it takes 12-48 hours for TH1 and TH17 cells to arrive at the site of the antigen and to start producing cytokines. The classic example used to show the characteristic delay and symptoms of a DTH reaction is the tuberculin test. It is a test used to test patients whether they've been exposed to m. tuberculosis. Tuberculin is a mixture of proteins that are injected under the skin of the patient. If the patient has been exposed to m. tuberculosis will the patient already have tuberculosis-sensitized TH1 that will travel to the site of injection and cause inflammation. The resulting erythema and induration are a positive result, meaning that the patient has previously been exposed to m. tuberculosis. EXAMPLES: -MS -Rheumatoid arthritis -Tuberculosis -Type 1 DM -Autoimmune myocarditis

B/13. Inherited cancer syndromes (autosomal dominant, recessive and familiar)

Individuals with inherited mutations of genes involved in DNA repair systems are at greatly increased risk for the development of cancer! Although, we are aware that environmental factors can be mutagenic (chemicals, radiation, Uv light), cancers are relatively rare outcomes of these encounters. Defects in 3 types of DNA repair systems -mismatch, nucleotide excision repair and recombination repair -are important in heridatary cancers! AD inactivation of tumor suppressor genes a) Mutation → uncontrolled cell proliferation and growth. b) Need a double hit: i. 1st allele is generally silenced due to point mutation ii. 2nd allele is usually inactivated later in live → then cancer develops. c) Genes: i. RB gene → retinoblastoma - 40% is familial. 1. Small, round cell tumor in the retina, usually bilaterally. 2. Small children (3‐6 years old). 3. Aggressive, penetrating, infiltrating cancer. 4. Sarcoma can be a secondary cancer. ii. APC gene → adenomatous polyposis coli 1. DNT (β‐catenin) pathway is mutated → deletion of APC gene. a. There is no degradation of β‐catenin→ continuous transcription of growth promoting factors / genes (e.g. cyclin D, myc) → continuous proliferation. 2. Patient has multiple polyps in the colon. 3. By age 15‐20, at least one will have transformed to cancer of the colon / rectum. iii. p53 gene → LiFraumani syndrome 1. Child has 50x more risk for developing malignant tumor by age 50. 2. Wide spectrum of cancers can develop: sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal cortex. iv. Hereditary non‐polyposis colon cancer syndrome (HNPCC) 1. Familial carcinoma of the colon due to defects in DNA repair system (mismatch repair). v. Neurofibromatosis 1. Type 1: brain, sarcoma - NF1 gene 2. Type 2: schwannoma - NF2 gene vi. Multiple endocrine neoplasia 1. Multiple endocrine tumors due to MEN1, RET genes. -Patients with hereditary nonpolyposis colon carcinoma (HNPCC) syndrome dramatically illustrates the role of defect mismatch repair genes in the development of cancer. The disorder, characterized by familial carcinomas of the colon affecting predominately the cecum and proximal colon! Without the mismatch repair genes that "proofreads" the DNA, errors accumulate at an increased rate. Mutations in at least 4 mismatch repair genes have been found to underlie HNPCC! These patients' genome show a characteristic microsatellite instability (MSI) characterized by changes in length of short tandem repeating sequences throughout the genome. In normal healthy individuals, these MS lengths are constant! It is an AD disorder, meaning that the patient inherits one defective copy of mismatch repair genes, and rhen acquires the second "hit" in colonic epithelial cells! Another example of oncogenic AD is retinoblastoma of RB mutation!!! -Patients with Xerodoma pigmentosum, an AR inherited disorder, have defects in the nucleotide excision repair pathway! They are at increased risk for the development of skin cancers in sites exposed to sunlight because of an inability to repair pyrimidine dimers induced by UV light -Another example is ataxia telanga...? -Syndromes involving defects in the homologous recombination DNA repair system constitute a group of disorders - Bloom syndrome, ataxia-telangiectasia and Fanconi anemia - that are characterized by hypersensitivity to DNA-damaging agents such as ionizing radiation. BRCA1 and BRCA2, which are mutated in familial breast cancers, also are involved in homol. DNA repair. These mutations account for 50% of cases of familial breast cancer!!! (However, they are, in contrast to other tumor supressor genes, not inactivated in SPORADIC EVENTS OF BREAST CANCER) Women with BRCA1 mutations have a higher risk for developing epithelial ovarian cancers, and men have a slightly higher risk for developing prostate cancer!

B/27. Congenital heart diseases

Congenital heart disease represents defects of cardiac chambers of the great vessels. These either result in shunting of blood between the right-and - left-sided circulation or cause outflow obstructions. Lesions range from relatively asymptomatic to rapidly fatal. Environmental (toxic or infectious) and genetic causes both contribute. CAUSES: GENETIC: -Trisomy 13, 15, 18, 21 -Turner syndrome -Down's syndrome (trisomy 21) is the most common cause of CHD ENVIRONMENTAL: -Rubella -Teratogens -Alcohol TYPES OF CONGENITAL HEART DISEASES THAT EXIST: CHDs with left-to-right shunts -Ventricular septal defects (VSD) -Atrial septal defects (ASD) -Patent ductus arteriosus (PDA) -Atrioventricular septal defect (AVSD) CHDs with right-to-left shunts -Tetralogy of Fallot -Transposition of the great vessels -Truncus arteriosus communis -Tricuspid atresia -Total anomalous pulmonary venous connection Obstructive CHD -Coarctation aortae -Pulmonary stenosis -Aortic stenosis PATHOGENESIS OG LEFT-TO-RIGHT SHUNTS: (summary from book: These are the most common malformations and they include ASDs, VSDs and PDA. Shunting results in right-sided volume overload that eventually causes pulmonary hypertension and, with reversal of flow and right-to-left shunting, cyanosis (EISENMENGER SYNDROME) Left-to-right shunts range from asymptomatic to complete heart failure. Sometimes can asymptomatic left-to-right shunts develop into fatal conditions, so it's important to screen for them. Especially ASDs tend to be asymptomatic, so in most places are infants screened for ASDs. Left-to-right shunts aren't as dangerous as right-to-left shunts from an oxygenation perspective. The system blood isn't less oxygenated when blood flows from the left side of the heart to the right side. However, the shunt causes blood that have already passed through the pulmonary circulation once to do so again, so the pulmonary blood flow and pressure is increased. This damages the pulmonary circulation, causing fibrosis, which leads to pulmonary hypertension. In any kind of left-to-right shunt, but especially in VSDs Eisenmenger syndrome can develop. Recall that the pressure inside the left ventricle is much higher than in the right ventricle. With a shunt between the two (or between the atria) will blood flow from the LV into the RV during systole with high pressure. This exposes the right ventricle to high levels of stress, to which it responds by hypertrophying. After this process has worked over a long period of time can the right ventricle hypertrophy so much that the pressure inside the right ventricle exceeds that of the left ventricle. This effectively reverses the shunt from left-to-right to right-to-left! When the shunt reverses is the patient said to have Eisenmenger syndrome. Now, as with any right-to-left shunt, is deoxygenated blood shunted from the right ventricle into the left ventricle and into the systemic circulation, causing cyanosis and hypoxic organ damage. The kidney senses the hypoxia and produces erythropoietin, which causes polycythaemia which increases the viscosity of the blood. At this point is the lung damage so significant that even if the CHD is surgically corrected is the only treatment for the patient a lung transplant. Atrial septal defects exist in multiple types. Recall from embryology that the atrial septum is made up of two tissue flaps, septum primum and septum secundum. 90% of all ASDs occur due to the septum secundum not properly closing the ostium secundum. These ASDs are called septum secundum ASDs. The two other types of ASDs are septum primum ASDs and sinus vensosus ASD, together account for just 10% of all ASDs. Septum secundum ASD - 90% of cases In 20% (!) of the population the foramen ovale never closes during embryonic development and stays open forever. This condition is called patent foramen ovale (PFO) and can be seen as an ASD. PFO is mostly asymptomatic, however it does allow for something called paradoxical embolization, where venous emboli can enter the systemic circulation by passing through the PFO instead of going into the pulmonary circulation. ASDs are mostly asymptomatic until the age of 30. Hypertrophy of the right ventricle and dilatation of the right atrium may occur to compensate for the increased right-sided circulation. Ventricular septal defects exist in just two types. Recall again from embryology that the ventricular septum is made up of two types of septa, the membranous septum and the muscular septum. Defects in the membranous septum is called Roger disease and account for 90% of all VSDs, while defects in the muscular septum accounts for just 10% and don't have a cool name. VSDs are the most common type of CHD. It occurs isolated in 30% of cases but is most commonly associated with other CHDs, such as Tetralogy of Fallot. VSDs are rarely asymptomatic, only small ones are, but the larger ones result in severe left-to-right shunting, which can cause pulmonary hypertension, congestive heart failure and Eisenmenger syndrome. Small or medium VSDs don't shunt as much blood as large ones, however they "jet" a small beam of blood onto the wall of the right ventricle with each heartbeat, which can damage the endothelial lining of the RV. This can increase the risk for development of infective endocarditis. Patent ductus arteriosus (= ductus Botalli persistens as the pathology department wants to call it), occurs when the ductus arteriosus between the pulmonary trunk or artery and aorta never closes. It usually closes within one week after birth. Because the pressure inside the aorta is much higher than in the pulmonary circulation the blood will flow from the aorta into the pulmonary circulation, so this is also a left-to-right shunt. In 90% of cases it occurs isolated, and in only 10% is it associated with other CHDs. They can be small enough to be asymptomatic, or they can lead to Eisenmenger syndrome. Atrioventricular septal defect (AVSD) occurs when there is no atrioventricular septum at all. It occurs when the superior and inferior endocardial cushions fail to fuse. Two types exist: incomplete AVSD, which is actually a septum primum ASD with abnormal anterior mitral cusp, and complete AVSD, where all four chambers communicate freely. RIGHT-TO-LEFT SHUNTS: Include tetralogy of Fallot (is a combination of 4 congenital heart abnormalities; VSD, pulmonary valve stenosis, misplaced aorta and RVH) and transposition of the great arteries. These lesions cause early-onset cyanosis and are associated with polycythemia, hypertrophic osteoarthropathy, and paradoxical embolization. OBSTRUCTIVE LESIONS: Include forms of aortic coarctation, the clinical severity of these lesions depends on the degree of stenosis and the patency of the ductus arteriosus.

B/12. Epigenectic changes (DNA methylaton, MicroRNAs) and role in carcinogenesis

Epigenetics: heritable, reversible changes in gene expression not due to DNA sequence changes. Includes post‐translational DNA methylation and histone modification. DNA METHYLATION: a) Process where methyl group (CH3) is added to cytosine or adenine DNA nucleotides, DNA methylation of CpG rich islands of promoters which allow us to inactivate transcription!!! b) Important regulator of normal cells: suppresses expression of harmful genes. c) Genes with high levels of methylation (hypermethylation) in promoter regions are transcriptionally silent. This is a way to control gene transcription. i. Hypermethylation of tumor suppressor genes. 1. E.g. ARFT → colon and stomach cancer. 2. MLH1 → mismatch repair gene in colorectal cancer. ii. Hypomethylation of oncogenes. Important in oncogenesis. d) Methyl groups are not transferred with DNA replication, so the DNA methyltransferases maintain continuous methylation. e) In carcinogenesis: DNA methyltransferases can be produced by tumor cells to silence promoter regions of tumor suppressor genes. i. CDKN2A is a locus that encodes two tumor suppressor genes: p14 and p16. 1. p14 is suppressed by hypermethylation in colon and gastric cancers. 2. p16 is suppressed in a variety of other cancers. ii. Since p14/p16 affects both p53 and RB pathways, this is an effective way for the cancer to remove both at once. HISTONE MODIFICATION: a) The histone N‐terminal tails are important in maintaining chromatin stability. This part is especially susceptible for modifications, and thus has potential to be oncogenic if it is not regulated. b) Post translational histone modification is done by: i. Acetylation will open up the chromatin structure. The activator is histone acetyltransferase (HAT); the repressor is histone deacetylase (HDAC). 1. The p300 HAT gene is mutated in a many GI tumors. ii. Methylation: lysine methylators of histone N‐terminal tails target SET domain proteins. 1. If there is a translocation in the genes that encode Suv39 family of enzymes (catalyze methylation of this SET domain), the susceptibility for B cell lymphoma increases. iii. Phosphorylation: Some parts of the histones (anti‐histone H3) are phosphorylated at mitosis → misregulation in this phosphorylation often implicates cancer. 1. Often related to misregulation of the Aurora kinase (controls chromatid segregation). An elevation in the enzyme is often found in many cancers (increased cell proliferation). MICRO-RNAs= post-transcriptional: a) Non‐coding single‐stranded RNAs: function as negative gene regulators (inhibit gene expression). b) Approximately 22 nucleotides in length. c) Process: i. Pre‐miRNA is transcribed and exported from nucleus → cut by Dicer in cytoplasm → no mature miRNA (double‐stranded) → unwound → each single strand is incorporated into multiprotein complex: RISC complex. ii. Base pairing between mRNA and miRNA directs RISC complex to cleave mRNA or to repress mRNA translation. d) Carcinogenesis i. When mutated, miRNA can no longer suppress the expression of oncogenes → increases expression of oncogenes. 1. Reduction of miRNA quantity can lead to overexpression of oncogenes. 2. E.g. deletion of miRNA gene in leukemia → overexpression of BCL‐2 genes. ii. Over‐activity of miRNA can lead to repression of tumor suppressor genes. 1. Some leukemia and lymphomas: with downregulation of miRNA → increase BCL2 → anti‐apoptotic protein increase.

A/48. Autosomal dominant disorders

MENDALIAN INHERITANCE DISORDERS: -Are caused by single gene mutations, and these defected genes can be pleiotropic (one gene causes lots of different disorders) and show genetic heterogenity ( mutations at many different loci can lead to the same trait/disorders) -Heterozygous inheritance: both males and females are affected and can transmit the condition. -The disorder can be due to inheritance from the parents, or new mutations in the egg or the sperm. - If affected person marries unaffected on, their child has a 1 in 2 chance of having the disease. - Siblings are not affected. -Clinical features can be modified by i. Reduced penetrance: people who inherit the mutant gene but are phenotypically normal. ii. Variable expressivity: the mutated gene is expressed different among people carrying it. --> Often the age of onset is delayed and symptoms don't appear until adulthood. -Usually the mutation affect enzymes and loss of enzyme activity. MARFAN SYNDROME: (ABE LINCOLN, JULIUS CEASAR) Is a connective tissue disorder, where the protein fibrillin is mutated. a. Fibrillin is secreted by fibroblasts. b. It is a major component of microfibrils of the ECM. c. Microfibrils are scaffolding for the deposition of elastic fibers. d. Microfibrils are all over the body, but more so in the aorta, ligaments and ciliary zuonules → these tissues are mostly affected. e. Also results in excessive activation of TGF‐β → overgrowth of bones. MORPHOLOGY: Skeletal: long, slender body, long fingers, high-arched palate, long face. Hyperflexible joints. Ocular: Due to weakness of suspensory ligaments, there will be bilateral disolaction of the lens Cardiovascular: fragmentation of elastic fibers of the tunica media of the aorta → predisposition to aneurysmal dilation and aortic dissection= cystic medionecrosis. --> The valves, especially the MITRAL VALVE will be distendable, regurgitation = FLOPPY VALVE SYNDROME! --> AORTIC VALVE RUPTURE IS THE MOST COMMON CAUSE OF DEATH!!!!!! EHLERS-DANLOS SYNDROMES: Group of diseases that feature collagen synthesis / structure defects. Inheritance pattern is both AD and AR. There are more than 30 different types of collagen, leading to a variety of diseases. Tissues rich in collagen are often affected: skin, ligaments, and joints. a. Skin is hyperextensible, joints are hypermobile and prone to dislocation. b. Can lead to severe internal complications: rupture of the colon and large arteries, ocular fragility with corneal rupture and retinal detachment, and diaphragmatic hernias. Deficiency of lysyl hydroxylase enzyme (AR inheritance) → no cross‐link formation. b. Deficiency of type III collagen synthesis due to mutations of COL3A1 gene. (AD inheritance) → weakness of tissues (blood vessels, bowel walls).

B/22. Tumors of childhood and their characteristics (neuroblastoma, retinoblastoma, Wilms tumor)

Malignant neoplasms constitute the second most common cause of death in children between the ages of 4 and 14 years old! Benign tumors are even more common than cancers! BENIGN TUMORS OF CHILDHOOD: -Hemangiomas are the most common neoplasms of infancy -Lymphangiomas are the lymphatic counterparts to hemangiomas -Teratomas may occur as benign, well-differentiated cystic lesions (mature teratomas), as lesions of indeterminate potential (immature teratomas), or simply malignant teratomas (usually mixed with another germ cell tumor component such a an endodermal sinus tumor). MALIGNANT TUMORS OF CHILDHOOD: -The organ systems involved most commonly by malignant neoplasms in infancy and childhood are the hematopoetic system, neural tissue and soft tissues. -Because of their primitive histologic appearance, many childhood tumors have been collectively reffered to as small, round, blue-cell tumors. NEUROBLASTOMA: Neuroblastoma and related tumors arise from neural crest-derived cells in the SY ganglia and adrenal medulla. In childhood, about 40% oof neuroblastomas arise in the adrenal medulla. The remainder occur anywhere along the SY chain, most commonly in paravertebral region in abdomen (25%) and posterior mediastinum (15%). Neuroblastomas are undifferentiated, whereas ganglioneuroblastomas and ganglioneuromas demonstrate evidence of differentiation. Homer-Wright pseudorosettes are characterstic of neuroblastomas, in which the tumor cells are concentrically arranged about a central space filled with neuropil. Age, stage and MYCN amplification (located on the 2p arm) and ploidy are the most important prognostic features; children younger than 18 months usually have a better prognosisthan older childrenm wheras children with higher-stage tumors or MYCN amplification fare worse. A high frequency of relapsed neuroblastomas have mutations in the RAS-MAP kinase pathway. Neuroblastomas secrete catecholamines, whose metabolites (VMA/HVA) can be used for screening patients. RB - RETINOBLASTOMA GENE, GOVERNOR OF THE CELL CYCLE: -Was the first tumor suppressor gene to be discovered and is said to be the prototype of this family of genes. It was Knudson that discovered it in 1975 in a uncommon childhood tumor disease called retinoblastoma. It is the most common primary intraocular malignancy of children. -In 60% of the cases, retinoblastoma are sporadic, while in the rest it occurs due to familial causes! Two mutations are required to produce retinoblastoma. These mutations involve the Rb gene that has been mapped to chromosome 13q14. Both of the alleles of the RB locus must be inactivated for the development of the blastoma. In familial cases, children inherit one defective copy of the RB gene, while the other copy is normal. This means however, that only one somatic mutation is needed for the retinoblastoma to develop! The trait is said to have an AD inheritance pattern. Retinoblastomas tend to be nodular masses, in microscopic findings, these masses consists of small round cells resembling undifferentiated retinoblasts. Some differentiated structures called Flexner-Wintersteiner rosettes consists of cuboidal or short columnar cells arranged around a central lumen. Retinoblastomas can metastase, most commonly to CNS, skull distal bones, and lymph nodes. CLINICAL FEATURES: -Poor vision, and whitish pupil called "cat's eye reflex" catched on pictures taken with blitz. Untreated, the tumors are fatal, but when treated with chemo, radiation or enucleation, survival is normal. Patients with familial retinoblastoma are in increased risk of the development of osteosarcoma and other soft tissue tumors. WILMS TUMOR: Wilms tumor, or nephroblastoma, is the most common primary tumor of the kidney in children, with most cases presenting itself in patients between 2-5 years of age. Three groups of congenital malformations are associated with an increased risk for Wilms tumor. These are: -Denys-Drash, have approx 90% chance of developing Wilms tumor. People with this disorder, have a dominant negative inactivating mutation in WT1 that interferes with the function of the normal WT1 protein made from the other WT1 allele. WT1 is critical to normal renal and gonadal development. Thus, in this disorder there will be gonadal dysgenesis and early onset nephropathy leading to renal failure. -WAGR syndrome (Wilms tumor, aniridia, genital abnormalities, and mental retardation)., People with this syndrome also show inactiviation of WT1 through the loss of genetic material -Beckwith-Wiedemann arises through imprinting abnormalities at the WT2 locus, principally involving the IGF2 gene. Patients with the syndrome show enlargement of individual body organs like the tongue, kidneys or liver, OR entire body segments, and enlargement of adrenal cortical cells. MORPHOLOGY OF WILMS TUMOR: The morphologic components of Wilms tumor include blastema (small, round blue cells) and epithelial and stromal elements. -Macroscopically, it is a large, well-circumscribed mass, that when cut show a CHARACTERISTIC tan-to-gray, soft inside. -Microscopically, the classic triphase combination of blastemal, stromal and epithelial cell types is observed in most lesions. NEPHROGENIC NESTS: are precursor lesions of Wilms tumors!

B/14. Viral and microbal oncogenesis

Many DNA and RNA viruses have proven to be oncogenic in animals , only a few viruses have been linked with human cancer. VIRAL ONCOGENESIS: ONCOGENIC RNA VIRUSES: HTLV-I (HUMAN T-CELL LEUKEMIA VIRUS TYPE I) is a retrovirus that causes T cell leukemia which is an endemic in Japan and the Caribbean! The HTLV-I genome encodes a viral protein called Tax, which stimulates proliferation, enhances cell survival and interferes with cell cycle controls. Although this proliferation initially is polyclonal, the proliferating T cells are at increased risk for secondary mutations that may lead to the outgrowth of a monoclonal leukemia! ONCOGENIC DNA VIRUSES: MECHANISM IN GENERAL: -Integrating and implanting an oncogene into host DNA - Integrating into hosts DNA → up‐ or down‐regulating its genes (e.g. silencing TSGs or transforming proto‐oncogenes into oncogenes). - Non‐integration of the virus: it is epizomal (just in the cell). This doesn't directly affect the DNA, but might have oncogenes or regulatory genes that can act. Human papillomavirus: HPV is associated with benign warts (type 1, 2, 4 and 7), as well as cervical cancer (type 16 and 18). The oncogenicity of HPV is related to the expression of 2 viral oncoproteins, E6 and E7, which bind to the p53 adn RB tumor supressors, respectively, neutralizing their function. E6 and E7 from high-risk strains of HPV (those that gives rise to cancer), have higher affinity for their targets than do the oncoproteins from low-risk strains of HPV. EPSTEIN BARR VIRUS: EBV, a member of the herpesvirus family, was the first virus linked to human tumor, Burkitt lymphoma. The oncogenic role played by EBV is more direct in EBV-positive B-cell ly,ohomas in immunosupressed patients! EBV is also implicated in the pathogenesis of Hodgkin ly,phoma, uncommon T-cell and NK-cell tumors, nasopharyngeal carcinoma, a subset of gastric carcinoma and rarely sarcomas! EBV uses a complement receptor CD21 to attach and infect B cells. EBV encodes for latent membrane protein (LMP‐1), which acts as the oncogene which promotes cell proliferation. -Certain EBV gene products contribute to oncogenesis by stimulating normal B-cell proliferation pathways. Another compromise of immune competence allows sustained B-cell proliferation, leading eventually to development of lymphoma! MICROBIAL ONCOGENESIS: HEPATITIS B AND C VIRUSES: Between 70-80% of hepatocellular carcinomas worldwide are due to infection with HBV or HCV. The oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation with hepatocellular injury, stimulation of hepatocyte proliferation and production of ROS that can damage DNA. The HBx protein of HBV and the HCV core protein can activate a variety of signal transduction pathways that also may contribute to carcinogenesis. HELICOBACTER PYLORI: H. Pylori has been implicated in both gastric adenocarcinoma and MALT lymphoma. The mechanism of H. pylori-induced gastric cancers is multifactorial, inducing immunologically mediated chronic inflammation, stimulation of gastric cell proliferation, and production of ROS that damage DNA. Can eventually lead to gastric atrophy and metaplasia of the stratified squamous epithelium → columnar cells with goblet cells. This is a long‐term adaptation to low pH (like Barret's esophagus). In the presence of metaplasia, dysplasia can occur → cancer. Cancer will develop in 3% of patients. H. Pylori pathogenicity genes, such as CagA, also may contribute by stim GF pathways. It is thought that H. pylori infection leads to polyclonal B-cell prolif and that eventually a monoclonal B-cell tumor (MALT lymphoma) emerges as a result of accumulation of mutations! These patients usually have a genetic polymorphism in promoters of inflammatory cytokines. H. pylori gives an antigenic stimulus → activates T cells → formation of polyclonal B cells. ii. B cells proliferate due to cytokine presence → increased likelihood of mutation accumulation, including monoclonal B cell tumor formation.

B/41. Arteritis and Phlebitis

Pathogenesis of vasculitis (vessel wall inflammation): The two most common pathogeneic mechanisms of vasculitis are immune-mediated inflammation and direct vascular invasion by infectious pathogens. In any given patient, it is critical to distinguish between infectious and immunologic mechanisms because immunosuppressive therapy is appropriate for immune-mediated vasculitis but could excerbate infectious vasculitis! NON-INFECTIOUS VASCULITIS: as seen in disorders like SLE that are associated with autoantibody production: Can be caused by different drugs as a result of hypersensitivity reactions in which our body to for example penicillin! Or it can be causes as a secondary response to infection, like in PAN! CIRCULATING IMMUNECOMPLEXES: may attach to the vessel wall, cause inflammation and thus vasculitis ANCAs (=ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODIES): -Basically refers to autoantibodies vs neutrophils. -ANCAs can activate nautrophils and thus cause inflammation --> P-ANCA = perinculear localisation, associated with microscopic polyangiitis --> C-ANCA = cytoplasmic labelling, is associated with granulomatosis with polyangiitis ANCAs are important as they can directly activate neurtophils, stimulate the release of ROS' and proteolytic enzymes, in vascular beds this may lead to endothelial cell injury! When ANCAs stimulate inflammatory cells like neutrophils, these release cytokines to further upregulate the surface expression of neutrophils needed for ANCAs to activate them + causing further nutrophils chemotaxis! AB AGAINST ENDOTHELIAL CELLS: have a toxic effect on them = Kawasaki disease LARGE VESSEL VASCULITIS: 1) GIANT CELL (TEMPORAL) ARTERITIS: Primary affected are the arteries in the head, like vertebral and opthalmic arteries, causing chronic granulomatous reaction thus narrowing the vessels. Disease involves segments so a biopsy must be done to make diagnosis, the sample should be large. The older population and women are especially affected. Symptoms include: fever, weight loss and blindness. Treatment= corticosteroids or anti-TNF therapies. Histologically, these large vessels loose their internal elastic membrane due to the GRANULOMATOUS INFLAMMATION. 2)TAKAYASHU ARTHRITIS: -Is a granulomatous vasculitis characterized principally by ocular changes and marked weakenings of the pulse in the upper extremeties!!! Severe luminal narrowing of major branch vessels. Affected is the ascending aortic arch --> narrowing so decr BP, thus the peripheral pulse is lowered and this can lead to blindness! The histo between giant cell and takayashu arthritis is very similar, we only distinguish them based on the age of the patient! Typically, if the patient is older than 50 years of age at the onset of the disease= Giant cell, if younger = Takayashu! T. Arthritis is associated with japanese ethnicity and certain HLA haplotypes, and is believed to autoimmune etiology! MIDDLE SIZED VESSEL VASCULITIS: 3) PAN (polyarteritis nodosa) - HAVE IN A DIFFERENT TOPIC PAN is a systemic vasculitis of small- or medium sized arteries, it typically involves the renal and visceral vessels and spares the pulmonary circulation. 1/3rd of patients have hepatitis B infection and thus the immune complexes deposits in the affected vessels. 4) KAWASAKI SYNDROME: Resmbles vasculitis seen in PAN! Approx 80% of patients are under 4 years old, and the clinical significance stems from the involvement of the coronaries, which, due to the arthritis may rupture and cause MI! Kawasaki syndrome manifests with conjunctival and oral erythma and blisteringm edema of hands and feet; is therefore also called "mucocutaneous lymph node syndrome" SMALL SIZED ARTERIES VASCULITIS: 5) LEUKOCYTOCLASTIC VASCULITIS: Is a necrotizing vasculitis that generally affects capillaries, as well as small arterioles and venules. Is called a hypersensitivity vasculitis. The skin, mucous membranes, lungs, brain, heart, kidneys (90% affected), muscle and GI all can be involved!!! Relates to P-anca, and refers to PMN with fragmented nuclei. Clinical course includes hemoptsys, hematouria, proteinuria. Can be caused by drugs, tumors and viruses. The most effective treatement is removal of the offending agent. 6)WEGENER'S GRANULOMATOSIS: -Relates to C-ANCA, and titers against this can be used as disease markers. Is a necrotizing vasculitis that is characterized by a triad of the following: --> necr vasculitis in the upper resp tract, lower tract or BOTH! --> Necr/ granulomatous vasculitis in capillaries, venules, arterioles of lungs --> Focal necrotizing, often crescentic, glomerulanephritis leading to kidney failure 7) THROMBOANGITIS OBLITERANS (BUERGER'S DISEASE): Occurs almost exclusively in smokers! An abcess from in the vessel wall, thrombosis in lumen, leading to ischemia of tissues. Pathogenesis includes: direct toxicity of tobacco to endothelium, hypersens rxn to tobacco and genetic background! INFECTIOUS VASCULITIS: Localized arthritis may be caused by the direct invasion of arteries by infectious agents like bacteria and fungi. Could either be due to a nearby abcesses or local infections, or less commonly, due to microbial embolization spread in infective endocarditis! Vascular infections may weaken arterial walls and culminate in MYCOTIC ANEURYSMS, or results in thrombosis and infarction

B/08. RB, p53 and APC genes and their roles in tumor development

RB - RETINOBLASTOMA GENE, GOVERNOR OF THE CELL CYCLE: -Was the first tumor suppressor gene to be discovered and is said to be the prototype of this family of genes. It was Knudson that discovered it in 1975 in a uncommon childhood tumor disease called retinoblastoma. -In 60% of the cases, retinoblastoma are sporadic, while in the rest it occurs due to familial causes! Two mutations are required to produce retinoblastoma. These mutations involve the Rb gene that has been mapped to chromosome 13q14. Both of the alleles of the RB locus must be inactivated for the development of the blastoma. In familial cases, children inherit one defective copy of the RB gene, while the other copy is normal. This means however, that only one somatic mutation is needed for the retinoblastoma to develop! The trait is said to have an AD inheritance pattern. In sporadic cases, Both normal RB alleles are lost by somatic mutation in one of the retinoblasts. ALTHOUGH THE LOSS OF NORMAL RB GENES INITIALLY WAS DISCOVERED IN RETINOBLASTOMAS, IT IS NOW EVIDENT THAT BIALLELIC LOSS OF THIS GENE IS FAIRLY COMMON IS SEVERAL CANCERS, INCLUDING BREAST, LUNG (SMALL CELL) AND BLADDER CANCERS, + risk of developing other types of cancers increase! MECHANISM: -Rb exerts anti-prliferatice effects by controlling the G1-to-S transition of the cell cycle. In its active form, RB is hypophosphorylated and binds to E2F transcription factors. This interaction prevents cyclin E to bind which is important for DNA replication, thus THE CELLS ARE ARRESTED IN G1! -GF signalling leads to inactivaton of RB, due to the increased cyclin D expression that will bind to CDK4/6 and phosphorylate RB leading to its inactivation. Loss of cell cycle control is fundamental to malignant transformation. Almost ALL cancers have a disabled G1 checkpoint due to mut in either RB directly or other proteins that affect RB function, exampels of these include cyclin D, CDK4, CDK inhibtors. -MANY ONCOGENIC DNA VIRUSES, LIKE HPV, ENCODE PROTEINS THAT BIND RB AND RENDER IT DYSFUNCTIONAL! TP53 - THE GUARDIAN OF THE GENOME: -The p53-encoding tumor supressor gene, TP53, is the most commonly mutated gene in human cancer and monitors stress of the cell. It can be activated by: anoxia, inappropriate oncogene signalling or DNA damage. -Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNA repair, cellular senscence and apoptosis. -It is activated through the process of phosphorylation, usually due to DNA damage. The activated p53 then drives transcription of p21, which will prevent phosph of RB (keeping it activated), thereby causing a G1-to-S cell cycle block. This pause allows the cell to repair DNA damage -If DNA damage cannot be repaired, p52 induces cellular senescence or apoptosis -Of human tumors, 70% demonstarte biallelic mut in tP53. Patients with the rare LI-FRAUMENI SYNDROME inherit one defective copy of TP53, so that only one somatic mutation is enough to lose normal p53 function. These patients are prone to develop a wide variety of tumors -p53 activates BAX which will drive the intrinsic mechanism of apoptosis, which will stop the inhibitatory function of BCL-2 (which normally inhibits apopotosis by inhibiting release of Cytochrome C in the mitochondria). -As with RB, p53 can be incapacitated when bound by proteins encoded by oncogenic DNA viruses such as HPV! APC GENES - ADENOMATOUS POLYPOSIS COLI DISEASE: Although much is known about the circuitry that applies brakes to the cell cycle, the molecules that transmit antiproliferative signals to cells are less well recognized but also important. -TGF-beta inhibits prolferation of many cell types by activation of growth-inhibting genes such as CDK inhibitors and supression of growht promoting genes such as MYC and encoding cyclins. -It's function is compromised in many tumors by mutations of its receptors (examples include colon, stomach and endometrium) or by mutational inactivation of SMAD genes that transduce TGF-beta signaling (pancreas). -E-cadherin maintains contact inhibition, which is lost in malignant cells -The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein beta-catenin. With the loss of APC, beta-catenin is NOT DESTROYED, but is rather translocated into the nucleus where it acts as a growth-promoting TF that make cells behave as if they are under constant stimulation by the WNT pathway -In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APC gene and sporadic loss of teh sole normal allele causes the development of hundreds of colonic polyps at a young age. These will inevitably develop into colonic cancer! somatic loss of both alleles are seen in 70% of sporadic colon cancers!

A/20. Stone formation; kidney and gallbladder stones

KIDNEY STONES (UROLITHIASIS) PATHOGENESIS: --> Men are at higher risk of getting kidney stones than women, and the risk increases with age. There are three major types of kidney stones: -80% of the stones are composed of either calcium oxalate or calcium oxalate mixed together with calcium phosphate. -10% of the stones are composed of magnesium ammonium phosphate. -the rest are composed of either uric acid or cystine stones. The causes of the stone formation can be many and varied. The most important cause is increased urinary concentration of the stone's constituents, so that it exceeds their solubility in the urine and crystallises (called supersaturation) Meaning that a person that develops calcium stones does not have hypercalcemia, but supersaturation of calcium in the urine causing the stone formation, thus being called hypercalceriuria. Another cause can be increased calcium reabsorption in the gut called absorptive hypercalciuria. The causes of the magnesium ammonium phosphate composed stones is usually a persistant alkaline urine resulting from UTIs. In particular, urea-splitting bacgeria's like staphylococcus predispose a patient to urolithiasis. Gout and disorders involving rapid cell turnover, such as leukemias lead to high uric acid levels in the urine or low pH urine. Cystine stones are usually caused by genetically factors. MORPHOLOGY: Stones are usually unilateral in about 80% of patients. The most common sites of formation is the renal pelvis and calyces and the bladder. The average stone diameter is about 2-3mm and they may be smooth or jagged. CINICAL FEATURES: Stones can be present without producing any symptoms, which is typically true for large stones. Smaller stones however, may pass into the ureter and lodge and cause intense pain often localized to the flank and radiating down to the groin. Often at this time there is gross hematuria. When a patient has kidney stones, they are predisposed to bacterial infections and the diagnosis of the stones are usually done radiologically. GALL STONES: PATHOGENESIS: Women are at much higher risk of developing gallstones than men as estrogens increase hepatic cholesterol uptake and synthesis, leading to excess biliary secrtion of cholesterol. The risk increases in women with oral contraceptive use and pregnancy. Other risk factors include genetics, ethnicity and age. We have two types of stones: cholesterol stones and pigment stones. Bile formation is the only significant pathway for elimination of excess cholesterol from the body (either as free cholesterol or as bile salts). When cholesterol concentrations exceed the solubiliing capacity of bile (supersaturation), cholesterol can no longer remain dispersed and crystallizes out of solution. Cholesterol gallstone formation is enhanced by hypomobilization of the gallbladder (stasis). Pigment stones form when the bile contains high concentration of unconjugated bilirubin in the biliary tree. MORPHOLOGY: Cholesterol stones ARISE EXCLUSIVELY in the gallbladder and consist somewhere between 50-100% of cholesterol. The more cholesterol is present in the stone, the more pale yellow they appear. They appear more gray-white to black depending on other substances within them. They are ovoid and firm, the can occur singly, but are usually several. Pigment stones:MAY ARISE ANYWHERE IN THE BILIARY TREE and are classified into black or brown stones. Black stones are usually found in the sterile gallbladder bile, and the brown ones in infected intrahepatic or extraheptic ducts. Black stones are usually numerous, small and fragile. Brown stones are more commonly just a few, soft, greasy and soaplike in consistency. BLACK STONES ARE RADIOPAQUE (THEY ARE DENSE AND THUS RESIST THE PASSAGE OF X-RAYS), WHILE BROWN STONES ARE RADIOLUCENT (they are not dense and permit passage of rays through them) CLINICAL FEATURES: Gallstones may be present for decades without producing any symptoms. When they do however, usually in smaller stones which can enter the biliary tract (cystic or common ducts) and resultingly initiate excruciating, right-upper quadrant/ epigastric pain. The most dangerous stones are the small, "gravel" like ones. It can also occur that a large stone may erode directly into an adjacent loop of small bowel, generating intestional obstruction (GALLSTONE ILEUS)

B/31. Rheumatic fever and rheumatic myocarditis

Rheumatic fever is an acute, immunological mediated, multisystem inflammatory disease that occurs after GROUP A BETA-HEMOLYTIC STREPTOCOCCAL INFECTIONS (usually pharyngitis). Rheumatic heart disease/myocarditis is the cardiac manifistations of RF. It is associated with inflammation of ALL parts of the heart, but valvular inflammation and scarring produce the most important clinical features. <-- CAUSES PATHOGENESIS: Acute RF is a hypersensitivity reaction clasically done by antidoies against group S. pyogenes has a cell wall containing M protein, a virulence factor that is highly antigenic. The antibodies which the immune system generates against the M protein may cross-react with heart muscle cell protein myosin, heart muscle glycogen and smooth muscle cells of arteries, inducing cytokine release and tissue destruction. CD4+ T cells recognize them and promote a cytokine storm. THEREFORE, THERE IS A CHARACTERISTIC 2-3 WEEK DELAY IN SYMPTOM ONSET AFTER INFECTION , AS THIS IS EXPLAINED BY THE TIME NEEDED TO GENERATE AN IMMUNE RESPONSE! MORPHOLOGY: ACUTE RF: Is characterized by inflammatory foci. The myocardial inflammatory lesions are called ASCHOFF BODIES. They consist of T cells, scattered plasma cells and plump activated macrophages called ANITSCHKOW CELLS associated with zones of fibrinoid necrosis! The anitschkow cells have a characteristic centraly condensed chromatin in a slender, wavy ribbon formation (=thus, they are called CATARPILLAR CELLS). During acute RF, aschoff bodies can be found in any of the three layers of the heart; epicardium, myocardium and endocardium (including valves). CHRONIC RHEUMATIC HEART DISEASE: Is characterized by organization of acute inflammation and subsequent scarring. The aschoff bodies will be replaced by fibrous scars, so the lesions are not usually visible in chronic RF. Most characteristically, the valves and leaflets will become permanently thickened and fusion of chordae tendineae may occur. Calcification can cause "fishmouth"/"buttonhole" stenoses. NB! The most important complication of rheumatic heart disease is VALVULAR STENOSIS AND REGURGITATION; however stenosis tend to dominate. The mitral valve alone is involved in 70% of the cases. CONSEQUENCES: With tight mitral stenosis, the left atrium progressively dilates owing to pressure overload, causing atrial fibrillation. Long standing passive venous congestion gives rise to pulmonar, vascular and parenchymal changes typical of LEFT-SIDED-HEART FAILURE. In time, it leads to LV hypertrophy and failure. CLINICAL FEATURES: -The incidence of RF has declined remarkably in part of the western wolrd over the last decades, both due to improved socioeconomic conditions and rapid diagnosis and treatment of strep pharyngitis. -Acute RF most often develops in children. The symptoms include: -Fever and MIGRATORY POLYARTHRITIS (one joint after the other is affected, and then suddenly is better without explanation) -The cultures for streptococcal strain will be negative at the time of symptom manifistation, but the antibody titer against them will be elivated!!!

B/42. Varices, varicosities and disorders of the lymphatic vessles

VARICOSE VEINS: Accounts for 90% of clinically relevant venous diseases =Abnormally dilated, snake-like veins due to increased intraluminal pressure and loss of vessel wall support. Most commonly, the superficial veins of the legs are involved, and it is more prominent in female, which is believed to be due to the prolonged elevation of venous pressure caused by the compression of the IVC by a pregnant uterus. Other risk factors include obesity, as well as it being a familial tendency toward premature varicosities. -Varicose dilation causes valve incompetence; leading to stasis of the blood, that will lead to: --> LL stasis --> edema of the extremeties -->ischemic skin changes --> stasis dermatitis --> ulcerations --> varicose ulcers (as a consequence of poor wound healing and infections) -->emboli from these superficial veins is very rare compared to DVT embolization! VARICOSITIES AT OTHER LOCATIONS: Varicosities at other sites can occur in case of for example liver cirrhosis (or less frequently portal vein obstruction) where there will be portal vein hypertension and thus, opening of the porto-systemic shunts to try and increase blood flow into veins, leading to esophageal varicoses, hemmoroids (rectum) and caput medusae (periumbilical veins). The most important of these are esophageal varicoses as they are prone to rupturing, causing massive upper GI bleeding, that can be fatal! THROMBOPHLEBITIS AND PHLEBOTHROMBOSIS: Refers to venous thrombosis and inflammation -In 90% of the cases, deep vein thrombosis results in thrombopheblitis, but other locations includes periprostatic veins (in males) and pelvic veins in females, as well as the large veins in the skull and the dural sinuses. CAUSES OF DVT: -Congestive heart failure -prolonged bed rest/immobilization -neoplasia -pregnancy -hypercoagulative state, causing stasis of blood, thus increased risk of thrombus formation. If these thrombi develop in different vasculatory beds = Trousseau's syndrome is a medical sign involving episodes of vessel inflammation due to blood clot (thrombophlebitis) which are recurrent or appearing in different locations over time (thrombophlebitis migrans or migratory thrombophlebitis). -->The biggest complication of DVT is pulmonary embolism! ONE DIAGNOSTIC SIGN THE PHYSICIAN CAN DO TO CHECK FOR DVT IS: HOMAN SIGN! In which the doctor holds the patients thigh, and pushes foot in a dorsiflexion position that will cause pain in the calf for the patient = POSITIVE FOR DVT! SVC AND IVC SYNDROMES: SVC SYNDROME: Compression, or invasion of neoplasm (typically bronchogenic carcinoma or medistinal lymphoma) leads to characteristic dilation of veins of the upper body, head and neck with cyanosis. Pulmonary vessels can also be compressed causing respiratory distress! IVC SYNDROME: compression by neoplastic mass or thrombus from hepatic, renal, LL veins causes edema of the lower extremeties! (NB! Certain neoplasms - particularly hepatocellular carcinoma and renal cell carcinoma have a striking ability to grow WITHIN veins, and thus, these tumors may ultimately obstruct the IVC! LYMPHATIC DISEASES: -Primary diseases of the lymphatics are EXTREMELY uncommon!, They are almost always secondary involved in inflammation, infectious and malignant processes! LYMPHANGITIS: Acute inflammation due to bacterial spread in lymphatics that can cause painful subcutaneous streaks (which basically are just inflamed lymphatics) Causes bacteremia and sepsis LYMPHEDEMA: Localized edema and tissue swelling. -Primary: due to congenital defect or familial cause (= MILROY DISEASE resulting from agenesis or hypoplasia of lymphatics) -Secondary: due to obstruction/compression of lymphatics Regardsless of the cause, lymphedema increases the hydrostatic pressure in the lymphatics distal to the obstruction and causes of edema. Chronic edema leads to deposition of ECM and fibrosis --> peau d´orange (orange skin) of the skin overlying the lymphatics (may also occur in the skin of breast cancer). Due to inadequate perfusion, ulcerations may oppstå. Milky accumulation in body cavities may occur if the lymphatic vessels rupture following for ex obstruction or tumor mass!

A/25. Pathomechanism of cardiac insufficiency

CARDIAC INSUFFICIENCY = HEART FAILURE!!! Heart failure, often referred to as congestive heart failure (CHF), is the common end point for many forms of vardiac disease and typically is a progressive condition with poor prognosis! Roughly 50% of patients die within 5 years of getting the CHF diagnosis. Heart failure may result from systolic or diastoic dysfunction! -Systolic dysfunction results from inadequate myocardial contractile function, usually as a consequence of ischemic heart disease, or hypertension. Ex: DCM -Diastolic dysfunction refers to an inability of the heat to adequately relax and fill, which may be a consequence of massive left ventricular hypertophy, myocardial fibrosis, amyloid deposition or constrictive pericarditis. Ex: HCM. NB! Heart failure may also be caused by valve dysfunction (endocarditis) or may occur following rapid increases in blood volume or blood pressure, even if the heart is normal!! PATHOGENESIS: When the failing heart can no longer efficiently pump blood, there is an increase in end-diastolic ventricular volumes, increased end-diastolic pressures and elevated venous pressures. Thus, inadequate CO is almost always accompanied by increased congestion of the venous circulation. Even though the heart is mainly affected, virtually all other organs will be affected too! The cardiovascular system attempts to compensate for reduced myocardial contractability through several processes: -The FRANK-STERLING MECHANISM: In which the increasing EDV's causes stretch within the heart, that makes the myocytes contract more forcefully, thereby increasing the CO. If the heart is able to compensate for this it is called compensated heart failure. However, this compensation comes at a price as the o2 requirements increase for the already-compromised myocardium. With time, the heart will not be able to propel sufficient blood to the body and this has now developed into decompensated heart failure. -ACTIVATION OF NEUROHUMERAL SYSTEMS: The release of NE increases HR, activation of RAS system augmentate the circulatory volume, and release of ANP balances the RAS system through diuresis and vascular smooth muscle relaxation! -MYOCARDIAL STRUCTURAL CHANGES: like hypertrophy, both concentric and eccentric can occur. However, the compensatory hypertrophy always comes at a cost, since the capillary bed does not expand in step with the myocardium and thus, the myocardium becomes vulnerable to ischemic injury!!! LEFT-SIDED HEART FAILURE CAUSES: -Ischemic heart disease -systemic hypertension -mitral or aortic valve disease -primary diseases of the myocardium like amyloidosis. MORPHOLOGY: -The left ventricule is hypertrophied, and might be dilated, with accompanying atrial dilation and mitral insuffciency = risk of A fib -The lungs will be heavy and boggy as the rising pressures in the pulmonary veins lead to congestion and edema, as well as pleural effusion due to the increased hydrostatic pressure. Edema fluid will accumulate in the alveolar spaces!!! ---> In chronic heart failure, breakdown of RBC's and hemoglobin leads to the apperance of hemosiderin-laden alveolar macrophages called HEART FAILURE CELLS that reflects prev. episodes of pulmonary edema! CLINICAL FEATURES OF LS HEART FAILURE SYMPTOMS: -The earliest and most significant symptom is dyspnoe on exertion, as well as coughing due to the accumulated edema in the alveolar spaces. This will eventually develop into orthopnea, where shortness of breath is experienced even when lying down, which is why patient's with this symptom usually sleep in a half-upright position. -Cardiomegaly, tachycardia, a third heart sound and crackling of the lungs -Diminshed CO leads to decreased renal perfusion that in turn triggers RAS to increase intravasc V + P -In severe CHF, diminished perfusion of the brain may lead to HYPOXIC ENCEPHALOPATHY in which the patient is irritable, has diminshed cognition and feels restless. TREATMENT: The treatment of CHF is often focues on correcting the underlying cause. The clinical approach includes: -Salt restriction -Diuretics -Positive inotropes (increase contractability) -reduce afterload with adrenergic blockers or inhibitors of RAS. These inhibitors also help by limiting hypertrophy!!! RIGHT-SIDED HEART FAILURE CAUSES: Right sides heart failure is usually the consequence of left-sided heart failure, since ANY pressure increases in the pulmonary circulation inevitably produces an increased burden on the right side of the heart. -Isolated right sides heart failure is often referred to COR PULMONALE as it typically occurs due to lung disorders, however the symptoms do not have to do with bad respiration!!! -It's main cause is increased pulmonary hypertension! MORPHOLOGY: -congestive hepatomegaly --> nutmeg liver. When left-sided heart failure also is present, severe central hypoxia produces CENTRILOLOBULAR NECROSIS, with long standing right-sided heart failure, these areas become fibrotic and are called CARDIAC CIRRHOSIS! -Portal hypertension -Splenomegaly -Pleural, pericardial and peritoneal effusion! -Subcutaneous edema of feet and lower legs are said to be a hallmark for right-sided heart failure. CLINICAL FEATURES OF RS HEART FAILURE: SYMPTOMS: Not respiratory related! But related to systemic and portal venous congestion, ascites, hepatic and splenic enlargement etc. as CHF progresses, patients may become frankly cyanotic and acidotic, as a consequence of decreased tissue perfusion resulting from diminshed CO and increased congestion!

B/36. Myocarditis and Cardiomyopathies

CARDIOMYOPATHIES = refers to a group of cardiac diseases that are due to intrinsic myocardial dysfunction. They can be primary; principally confined to the myocardium, or secondary presenting as the cardiac manifestation of a systemic disorder. They are thus a diverse group that includes inflammatory disorders (myocarditis), immunologic disorders (sarcoidosis), systemic metabolic disorders (hemocrhomatosis), msuclar dystrophies, and genetic disorders of myocardial fibers. In many cases, the etiology of the disorders are unknown, and they are therefore termed idiopathic! TYPES OF CARDIOMYOPATHIES: -Dilated cardiomyopathy (DCM) (including arrhythmogenic right ventricular cardiomyopathy) is the most common type, with 90% of the cardiomyopathies being in this category! -Hypertrophic cardiomyopathy (HCM) -Restrictive cardiomyopathy DILATED CARDIOMYOPATHY: CAUSES: -20-50% is genetic in which over 50 various proteins can be mutated (cell membrane, cytoskeleton, sarcomere, nuclear envelope or mitochondrial) -Non-genetic causes include myocarditis, peripartum (pregnancy), toxic (e.g alcohol), iron overload, idiopathic --> leads to defects in force generations, transmission and myocyte signalling MORPHOLOGY: Heart will be enlarged, all 4 chambers, with thinner walls than expected. Hypertrophy has occured though, and the mass of the heart will be greater than normal. There is also variable interstitial and endocardial fibrosis, marking previous necrosis, or missed myocarditis. Mural thrombi are often present. If the DCM is secondary to iron overload, there will be an accumulation of intramyocardial hemosiderin, stained by Prussian blue! CLINICAL FEATURES: -The fundamental defect of DCM is the INEFFECTIVE CONTRACTION! The cardiac ejection fraction which normally is around 50-65% is now as low as 25%!!!! -Secondary mitral regurgitation and cardiac rhytms are common, as well as the mural thrombi and it's complications -DCM typically manifests with signs of slowly progressive CHF TREATMENT: 50% of patients die within 2 years and only 25% survive longer than 5 years. -The only definitive treatment at the moment is heart transplantation, however they are experimenting with implantation of long-term ventricular assist devices more and more. ARRHYTHMIC RIGHT VENTRICULAR CARDIOMYOPATHY IS AN AD DISORDER, WHICH CAN LEAD TO SUDDEN CARDIAC DEATH! Morphologically, the RV wall is significantly thinned owing to myocyte replacement by fatty infiltration and lesser amounts of fibrosis. Many of the causative mutations involve genes encoding desmosomal junctional proteins at the intercalated disc or proteins that communicate with the desmosome! HYPERTROPHIC CARDIOMYOPATHY: Is characterized by myocardial hypertrophy, defective diastolic filling, and - 1/3 of the cases, ventricular outflow obstruction. The heart is the opposite of DCM, it is thick-walled, heavy and hypercontracile. Systolic function is preserved, but the myocardium exhibits primary diastolic dysfunction. CAUSES: -100% genetic causes, usually due to a missense mutations inone of several genes encoding proteins that form the contractile aparatus MORPHOLOGY: -Hypertrophy, without dilation. Myofiber disarray, fibrosis replacement and interstitial, LV outflow tract plaque, thickened septal wall --> oval "banana"-shaped CLINICAL FEATURES: -Typically manifests during postpubertal growth spurt. -There will be a harsh systolic ejection murmur -The consequences are similar to those of DCM -In almost 1/3 of young adults that die of SCD under the age of 35, have underlying HCM! TREATMENT: Patients usually improve when given therapy to force ventricular relaxation, they can be: -Partial surgical excision -controlled alcohol-induced infarction of septal muscle to relieve the outflow tract obstruction RESTRICTIVE CARDIOMYOPATHY: -Is characterized by a primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole (simply put, the wall is stiffer) -Heterogeneous -fibrotic endocardium = like melted sugar -Cause= Bush tea (africa!) -Eosinophelia --> granules release MAJOR BASIC PROTEIN --> fibrosis --> LOEFFLER ENDOMYOCARDITIS! MYOCARDITIS: Inflammation of myocardium leading to myocardial injury! CAUSES: Viral infections, bacterial, protozoa, drugs, immune reaction like allergies! MORPHOLOGY: -Heart may appear normal or dialted during active myocarditis -Microscopically interstitial inflammation with focal necrosis is ssen next to inflammatory cells: --> lymphocytic myocarditis -->Giant cell myocarditis -->hypersensitivity myocarditis CONSEQUENCES: Heart failure, sudden cardiac death and arrhythmias!

A/47. Diagnostics of genetic disorders

DEFINITIONS OF GENETIC DISEASES: -Heriditary: Derived from parents ant transmitted to the children via gametes. -Familial: Genetic disorders found in many generations -Congenital: Disorders that are present at birth. Some of them are not genetic, while others doesn't appear before later in life, even though the person is born with the mutation -Mutation= a perminant change in the DNA --Somatic cell mutations are not transmitted via the familial route, but can cause cancers and some congenital malformations. --POINT/ MISSENSE MUTATION: substitution of one single nucleotide that leads to change in an aa. For example beta-hemaglobin mutation that leads to sickle cell anemia --NONSENSE MUTATION: if the point mutation results in stop codon --> no proton formation --FRAMSHIFT MUTATION: insertion or deletion of 1 or 2 base pairs changes the reading frame of the DNA strand. --TRINUCLEOTIDE REPEAT MUTATION: E.g. Fragile X syndrome: 200‐4000 tandem repeats of CGG in the FMR1 gene → prevents normal FMR1 gene expression. OTHER ALTERATIONS IN CODING DNA: POLYMORPHISMS: SNPs: single nucleotide polymorphisms: -Over 6 million SNPs exist -can appear anywhere in the genome, both coding and non-coding parts of the DNA -Some are inherited with other diseases, and thus can be used as markers CNVs: copy number variations: different forms of large neighboring stretches of DNA from 1000 base pairs to millions of base pairs. -50% are found in coding genes, which is probably why humans have such phenotypical differences. - These changes are often found in genes involved with the immune system and the nervous system. EPIGENETIC CHANGES = Changes in gene / protein expression WITHOUT DNA changes -Regulation is very important during development and in homeostasis. --Alterations of methylation of cytosine residues at gene promoter regions i. If they are strongly methylated, then they cannot be seen by the RNA polymerase → gene silencing. ii. Silencing of tumor suppressor genes due to promoter methylation is seen in many cancers. b. Histone proteins often undergo reversible modifications (e.g. methylation, acetylation) that can affect 2nd and 3rd DNA structure → effect gene transcription. Abnormalities in these modifications results in e.g. cancer. -Imprinting: physiological silencing during development. NON-CODING RNA CHANGES: -ncRNA has a strong regulatory function. -Micro RNAs: inhibit translation of target mRNAs; thus posttranscriptional silencing of gene expression. -Long non‐coding RNAs: modulate gene expression in many ways: e.g. can restrict access of RNA polymerase to chromatin; plays a role in X‐inactivation. GENETIC DISORDERS: -Mendelian disorders: mutant genes of large effect; due to single gene mutations. -Diseases with complex, multigenic inheritance: most common human disorders; genetic and environmental background. -Chromosomal abnormalities: numerical or structural DIAGNOSIS: -2 aspects to take into consideration: 1) Physical characteristics and family history 2)Lab tests TYPES OF LAB TESTS: Molecular: sequencing of specific genes Chromosomal: looks at the karyotype. Usually use FISH Biochemical: looks at levels of enzyme activities to determine if there is a mutation present. -Tests are done on blood, hair, skin, amniotic fluid, buccal smear etc TYPES OF GENETIC TESTS THAT EXIST: Newborn screening: Just after birth to identify disorders that can be treated early in life. E.g. phenylketonuria, congenital hypothyroidism Diagnostic testing: To identify or rule out specific genetic / chromosomal conditions; often used to confirm a diagnosis. Can be performed before birth or any time during life. Carrier testing: To identify if someone carries a copy of a gene mutation that can cause a genetic disorder when present with 2 copies. -Often used on people who have a family history of a genetic disorder or in a risk group for a disorder (e.g. certain ethnicities). Prenatal testing: To identify any changes in a fetus's genes / chromosomes before birth; usually done if there is increased risk for disorder development. -This cannot identify all possible inherited disorders and birth defects. Preimplantation testing: A technique used to reduce the risk of having a child with a particular genetic or chromosomal disorder. -Used with fetus's that were created using assisted reproductive techniques (e.g. in vitro fertilization). The embryos are tested before implantation into the uterus. Predictive and presymptomatic testing: To detect gene mutations associated with disorders that appear after birth, especially for those with a family history of a certain disorder, but have no features of the disorder at the time of testing. Forensic testing: Used to identify a person for legal purposes. This is not used to detect gene mutations associated with disease, but rather for crime / catastrophe victims, to rule out suspects or to establish biological relationships. RISKS AND LIMITATIONS OF GENETIC TESTING: RISKS: -For most people the physical risks are incredibly small. -For fetus's, it can result in miscarriage, due to the tissue / amniotic fluid collected. -Most risks involve emotional, social or financial consequences. LIMITATIONS: -Genetic tests can only give limited information about an inherited condition. It does not give info about: 1) If a person will show symptoms of a disorder 2) How severe these symptoms will be 3) If the disorder will progress over time -There is also a lack of treatment strategies if a disorder is diagnosed.

A/28. Causes and types of edema

Edema results from the movement of fluid from the vasculature into the interstitial spaces; the fluid may be protein poor (transudate) or protein rich (exudate)!!!! Edema may be caused by: *Increased hydrostatic pressure of vessels (like in heart failure) *Increased vascular permeability (e.g inflammation) *Decreased colloid osmotic pressure resulting from reduced plasma albumin (Either decreased proteins synth (liver disease or protein malnutrition) or increased loss of protein like in nephrotic syndrome)). *Lymphatic obstruction (e.g inflammation and neoplasia) *Na+ retention (e.g renal failure) PHYSIOLOGICAL FORMS OF EDEMA: LOCAL: This is due to the increased intravascular pressure due to impaired venous return. --> DUE TO DISTURBED VENOUS RETURN: Can be either due to: -Venous blockage due to venous thrombus -Ascites due to liver cirrhosis causing Venous outflow blockage via portal vein → fluid stays in abdominal cavity → ascites -Due to lymph nodes or benign tumor blocking SVC →outflow blocked → massive swelling of face, neck, shoulders -Pulmonary edema (1) Usually due to increased pressure in pulmonary capillaries, due to acute left sided heart failure (2) Lungs are wet and heavy; fluid comes out when squeezed (3) Histologically: pinkish fluid in alveolar spaces -->DISTURBED LYMPHATIC DRAINAGE: Usually due to breast cancer → metastases to axillary lymph nodes → need to remove both tumor and lymph nodes → lymph blocked in arm (a) Local irradiation results in increased connective tissue (fibrosis of lymphatic channels) (2) E.g. inguinal lymph nodes blocked (by e.g. parasite) or removal (a) Results in lymphedema in the leg (3) Generally connective tissue amount increases in edema tissues → lymphedema becomes inundated → elephant‐ like skin with massive thickening -->INFLAMMATION -->ALLERGIES SYSTEMIC: The whole body is edematic. This is due to increased venous pressure that occurs mostly in congestive heart failure. a. Hypoproteinemia / hypoalbuminemia i. First seen in the face, around the eyes ii. Usually due to massive protein loss into urine due to severe kidney damage (nephrotic syndrome → protein loss) or due to decreased albumin synthesis (liver cirrhosis or protein malnutrition) (1) Will decrease the vascular oncotic pressure → net fluid movement into interstitium → fluid accumulates all over the body (2) Then hypercholesterolemia develops due to increased protein synthesis (also includes Apo B → increased LDL → increased cholesterol) iii. Will be exacerbated by secondary salt and fluid retention. Right sided heart failure (congestive) i. Right side of the heart is weak, usually due to chronic cor pulmonale (1) Later on it becomes dilated ii. Consequences (1) Pericardial sac accumulates fluid → hydropericardium (a) Especially dangerous if slow accumulation (normal ~300ml space, but with slow accumulation it can be up to 1L) (2) Hydrothorax → usually bilateral (3) Ascites (4) Anascara: lower legs contain a huge amount of fluid (cause pitting edema) = severe systemic edema iii. Mix of increased venous hydrostatic pressure and reduced cardiac output Rh (ABO) incompatibility (sometimes infections in babies) i. At first there is just a small amount ii. Without Rh protection → becomes more severe iii. 3rd month of pregnancy → fetal hydrops → intrauterine death iv. Today it is very rare v. Can also come from intrauterine infections MORPHOLOGY: Subcutaneous edema 1. Can be diffuse a. Generally hypoproteinemia type edemas → loose connective tissue i. E.g. periorbital ii. Seen as pitting edema: finger pressure displaces fluid and leaves adepression; not painful. 2. Or occur at spot of greatest hydrostatic pressure → dependent edema (moves to legs when standing, pelvis when lying down) a. Typical for congestive heart failure 3. Anasarca = severe systemic edema iii. Edema of solid organs 1. Results in increased size and weight iv. Pulmonary edema. 1. Related to left ventricular failure, renal failure, adult respiratory distress syndrome, pulmonary infections, and hypersensitivity reactions. 2. Lungs are 2‐3 times their normal weight with a frothy, blood‐tinged fluid 3. Pathogenesis a. Alveolar spaces are filled up → lack of proper gas exchange → hypoxia → heavy lung (2‐3 x normal weight) → clear fluid leaks when squeezed → impaired gas exchange 4. Favorable environment for bacterial infection. v. Cerebral edema. 1. May be localized to site of injury (e.g. abscess, neoplasm) or may be generalized (e.g. encephalitis, hypertensive crises, obstruction to venous outflow). 2. Increased brain weight: Normal weight is 1,200g. Can increase to 1,300‐1,400g. 3. Potentially increased intracranial pressure 4. Narrowed sulci, distended gyri, softening of brain tissue.

A/29. Causes and types of thrombosis

Hemostasis is coagulation of blood in an injured vessel or injured tissue to protect against bleeding. The pathological form is called thrombosis. STEPS OF THROMBOSIS: -Vasoconstriction: occurs as the endothelial cells of the vessel, if damaged, will release endothelin and vasoconstrict the vessel as a first step in hemostasis. -Primary hemostasis: ECM is released which proves as an area for platelet aggregation. -Secondary hemostasis: Tissue factor is released and fibrin and coagluation factors are deposited. -Thrombomodulation: Thrombomodulin is released to inhibit further modulation of thrombus. FACTORS THAT PLAY A ROLE IN THROMBUS FORMATION: Virchow's triangle demonstrates the relationship between the 3 main contributing factors of thrombosis formation. Endothelial integrity is the most important one. Abnormalities of procagulants and anti-coagulants can tip the balance in favor of thrombosis. Abnormal blood flow (stasis or turbulence) can lead to hypercoagulability directly and also indircetly through endothelial dysfunction. (LOOK AT PIC MUST KNOW THIS) ENDOTHELIAL DYSFUNCTION: May produce a thrombus alone as the single factor. Endothel cells normally block exposure to subendothelial collagen and tissue factors. They produce both procoagluative and anticoagulative factors: -Pro-coag: platelet-activating factor (PAF), Von Willebrand factor, plasminogen-activator inhibitor-1, factor VIII -Anti-coag: thrombomudulants, heparin sulfate, prostacyclin, uPA/tPA -They also produce NO (vasorelaxant), ADP(?), endothelin (vasoconstrictor), ACE ((vasoconstrictor)) Effects of endothelial dysfunction: -The direct effect of endothelial dysfunction is that a thrombus may be formed solely from disruption of the endothelial lining of the vessel. -Endothel disruption may lead to altered blood flow, which plays a role in thrombus formation - Endothel damage can also cause hypercoagulity. Causes of endothelial injury: a) Denuding causes: refers to loss of/death of endothel cells on the surface. Causes can be ulcerating atherosclerotic plaque, endocarditis and vasculitis. b)Non-denuding causes: refers to endothel dysfunction. Causes include: hypercholesteremia, irraditation and increased levels of homocysteine (in B12 deficiency)! STASIS/ HEMODYNAMIC CHANGES: This altered blood flow may mean a change from a laminar to a turbulent blood flow, or may result in a stasis. Stasis is the slowing down of circulation. This altered flow itself may cause a thrombus. It can do this by three ways: Effects: a)Direct effect. Altered blood flow may directly promote a thrombus. b). Altered blood flow may cause endothelial damage. c.) Hypercoagulability due to altered blood flow. Laminar flow is a protection for thrombus. Causes of hemodynamic changes: -Altered blood flow like stasis or turbulent flow (during turbulent flow, the platelets get close to the endothel surface -Atherosclerotic plaque (in front of plaque=turbulent, behind plaque=stasis of flow) -Aneurism = stasis of flow -Mitral stenosis = blood stasis in auricles -Atrial fibrillation: produces atrial thrombus -Hyperviscosity: when patient for ex have too many RBC's. HYPERCOAGULABILITY: The blood can coagulate better (due to increased procoagulant or decreased anticoagulant proteins) and can therefore promote generation of a thrombus. Causes: -Primary hypercoagulability: This means that it is a genetic defect on the side of the factors which protect the thrombosis or side which generates the thrombosis. i) Leiden mutation: there is a mutation in factor 5 in the pro-coagulation system ii)Prothrombin mutation: iii) Protein c/ protein S deficiency -Secondary hypercoagulability: are aquired i) Oral contraceptives: this is the most common one ii)smoking iii) obesity iv) Old age MORPHOLOGY: -White: characteristic for atrial thrombi. They are also called sedimentation thrombus. There is endothel damage, so the platelets aggregate on the endothel surface causing a white thrombus typical for the arteries or heart chambers -Red: also called a stagnation thrombi and is characteristic for venous thrombus. -Composite: head is white and tail is red. At the first site, we have sedimentation (white thrombus). In front of the white thrombus there is stasis and where the blood coagulates which makes it red. -Laminated: Typical for aneurisms in the heart and aorta. The process starts again and there are alternating layers of white and red (lines of Zahn), depending which factors dominate at the moment. LOCALIZATION: -Arterial thrombus:White thrombus due to atherosclerosis or vasculitis that rupture, and can be occlusive and block an artery, or mural and attach to wall. Grow in size towards the heart. -Venous thrombus: Red thrombus due to stasis. They are occlusive and grow towards the heart. -Cardiac/Mural Thrombus: This category includes thrombus of the auricle, atrial ball thrombus and of heart aneurysm and vegetation (bacterial growth on the heart valves, leading to a mass). -Micro/ fibrin thrombi: Occur in capillaries and are red. FATE OF THROMBUS: Propagation - the thrombus enlarges by adding more platelets and fibrin, increasing the risk of occlusion or embolization. Dissolution: dissolution by fibrinolytic factors can completely dissolve it. However, this doesn't work with older thrombi because of their extensive fibrin polymerization. Organization or recanalization - Endothelial cells, smooth muscle cells and fibroblasts can grow into older thrombi, and with time, even capillaries can recanalize in the thrombus. This can actually reestablish the continuity of the original lumen. Inflammatory cells come and digest the coagulated blood. Embolization - Some part or the whole thrombus loosens from the vessel wall and moves in the circulation. . CLINICAL SIGNS: Migratory thrombophlebitis (Trousseau's Syndrome). This is a medical sign found in certain cancers that is associated with venous thrombosis and hypercoagulability. Thrombi form in different sites and go away. It generally suggests hypercoagulability due to cancer or polycythemia (incr RBC's).

A/45. Inherited and Acquired immunodeficiencies

Immunedeficiencies can be divided into primary (or congenital) which are often genetically determined or secondary (aquired) which may arise as complications of cancers, infections, malnutritions, or side effects of immunosupression, chemotherapy for cancer etc. The most common aquired imm. def is AIDS that will be discussed in a later topic and these are way more common than primary def. Immunodeficiencies are manifested clinically by increased infections, which may be newly acquired or reactivated of latent infections. PRIMARY/INHERITED IMMUNODEFICIENCIES: Primary immunodeficiencies are inherited genetic disorders that impair mechanisms of innate immunity (phagocytosis, NK cells, or complement) or the humoral arms of adaptive immunity (mediated by B and T cells respecitvely). These primary imm. def. are usually detected in infancy, between 6mths - 2 yrs of age, where the telltale signs is that the child will be more susceptible to recurrent infections. SEVERE COMBINED IMMUNODEFICIENCY (SCID): Many genetically distinct syndromes with same defects in humoral and cell‐mediated immunity.Infants are more susceptible to infections → can be lethal. Affected infants will show thrush (oral candidiasis), severe diaper rash and failure to thrive. Children with SCID are extremely susceptible to recurrent, severe infections by a wide range of pathogens. Without HSC transplant, death occurs within the first year of life. (However, gene therapy has been succesful in X-linked SCID, but other complications are at high risk of occuring.) Two major forms of SCID exists: 1) X-linked SCID: approx 50% of SCID cases is X-linked. These are caused by mutations in the gene encoding for the gamma chain shared among many interleukins. Especially important for the pathogenesis of the disease, is the defective IL-7 signalling due to the mutation in the gamma chain of it's receptor. 2)Autosomal recessive SCID: the remaining half of the cases follow an AR pattern of inheritance, where of half of these again are due to mutations in adenosine deaminase (ADA), an enzyme in the purine metabolism. In both of these forms of SCID, the thymus is small and devoid of lymphoid cells. In X-linked SCID, the thymus contains lobules of undiff epithelial cells resembling a fetal thymus, while in AR SCID, remnants of Hassal corpuscles can be found. X-LINKED AGAMMAGLOBULINEMIA: XLA or Bruton disease, is characterized by the failure of pre-B cells to differentiate into mature B cells, which then results in the absence of antibodies (gamme globulins) in the blood. During normal B-cell maturation, Ig heavy chain genes are rearranged first, followed by light chain genes. In XLA, B-cell maturation stops after the initial heavy chain gene rearr. because of mutations in a inase called Bruton tyrosine kinase (BTK). When BTK is nonfunctional, the pre-B cell receptor cannot signal the cells to proceed along the maturation pathways. As a result, the Ig light chains are not produced, and the complete Ig molecule with both heavy and light chains cannot be assembled. Because the BTK gene is on the X chromosome, the disorder is only seen in males. Clasically, the disease is characterized by a profound reduction in the number of B cells in the blood and secondary lymphoid organs, showcasing an absence of germinal centers and plasma cells in these organs. T-cell numbers are normal. The disease, usually does not become apparent until 6 month of age, as maternal ab's that were transported via the placenta is depleted. The symptoms are recurrent bacterial pharyngitits, sinusitis, otitis media, bronchitis, pneumonia. The causative bacteria strep. pneumoniae or staph. auerus are organsims that normally, would be opsonized by ab's and cleared by phagocytosis. The treatment, is replacement therapy with intravenous immunoglobulins (IVIG) from pooled human blood. DIGEORGE SYNDROME (THYMIC HYPOPLASIA) Is a syndrome caused by a congenital defect in thymic developemtn, resulting in deficient T-cell maturation. T cells will be absent in the lymph nodes, spleen, and periph blood, and infants with this defect are extremely vulnerable to viral, fungal and protozoal infections. The disorder is a consequence of a developemental malformation affecting the 3rd and 4th pharyngeal pouches, structures that give rise to the thymus, parathyroid glands and portions of the face and aortic arch. In addition to the thymus problems, there might be parathyroid gland hypoplasia, resulting in hypocalcemic tetany. Transplantation of thymic tissue has successfully treated some affected infants. HYPER-IGM SYNDROME: The disease is characterized by production of normal/overproduction of IgM antibodies, and decreased levels of IgG, IgA and IgE isotypes; making the underlying defect the inability of T cells to activate B cells. The mechanism involves the CD40L on antigen-activated T cells that, for the CD4+ helper T cell to be activated must bind to CD40 on B cells. This binding triggers Ig class switching. Disease develops when there is a mutation in the CD40L, like in the X-linked version of Hyper IgM syndrome, or if the CD40L experience a loss of function mutation like in the AR inherited type of the syndrome. Patients present with recurrent pyogenic infections because of low levels of opsonizing IgG ab's, and in certain cases, the IgM ab's can react with blood cells, giving rise to autoimmune hemolytic anemia, thrombocytopenia and neutropenia. ISOLATED IGA DEFICIENCY: This is the most common primary immune def, affecting about 1:700 whites. IgA is the major ig in mucosal secretions and is thus involved in defencing the airways and the GI. The weakened mucosal defenses due to IgA def predispose patients to recurrent sinupulmonary infections and diarrhea. COMMON VARIABLE IMMUNODEFICIENCY: Umbrella term for disorders that have hypogammaglobulinemia, impaired antibody response to infections and increased susceptibility to infections. -Clinical symptoms are similar to XLA. - Males and females are equally affected. - Onset is much later, 20‐30 years old. - Diagnosis is one of exclusion. Patients have normal amount of mature B cells, but no plasma cells → block in antigen‐stimulated B cell differentiation. - Defective antibody production is probably due to intrinsic B cell defects, deficient T cell help or excessive T cell suppression activity. -These patients will develop many autoimmune disorders and lymphoid tumors. Immune Deficiency with Thrombocytopenia and Eczema: Wiskott‐Aldrich Syndrome 1. X‐linked recessive 2. Clinical features: thrombocytopenia, eczema, increased risk for recurrent infections, early death 3. Gene encodes a protein → links different membrane receptors to cytoskeleton 4. Underlying faults: a. Thymus is initially normal → progressive age‐related depletion of T cells (peripheral blood and lymph nodes) → loss of cellular immunity. b. Patients have no response to polysaccharide antigens → increased risk of encapsulated, pyogenic bacterial infections. c. Will be more prone to malignant lymphoma development. 5. Treatment: only bone marrow transplant

A/57. How microorganisms cause disease

Infectious agents establish infection and damage tissues by any of three mechanisms: -They can contact or enter host cells and directly cause death of infected cells -The can release toxins that kill cells at a distance, release enzymes that degrade tissue components, or damage blood vessels and cause ischemic necrosis. -They can induce host immune responses that, although directed against the invader, cause additional tissue damage. Thus, the defensive responses of the host can be a mixed blessing, helping to overcome the infection but also contributing to tissue damage. MECHANISMS OF VIRAL INJURY: (Viruses can directly damage host cells by entering them and replicating at the host's expense. Tropoism (Viral tropism can be defined by the ability of different viral strains or isolates to infect different cell types or tissues and to induce syncytia formation and/or acute or chronic infectious virus production as a result of infection) is determined by several factors: -HOST RECEPTOR FOR VIRUSES: Viruses are coated with surface proteins that bind with high specificity to particular host cell surface proteins. Entry of many viruses into cells commences with binding to normal host cell receptors. An example includes the HIV virus has a glycoprotein, gp120 that binds to the CD4 on T cells. -SPECIFICITY OF TRANSCRIPTION FACTORS: The ability of the virus to replicate inside particular cell types depend on presence of transcription factors. -PHYSCIAL CHARACTERSTICS OF TISSUES: Host environment and temperature can contribute to virus tropism. An example is the enteroviruses that can replicate in the intestine in part because they resist inactivation by acids, bile, and digestize enzymes. ) Once the viruses are inside the host cells, they can damage or kill the cells by a number of mechanisms: -DIRECT CYTOPATHIC EFFECTS: Viruses can kill cells by preventing synthesis of critical host macromolecules by producing degradative enzymes and toxic proteins, or by inducing apoptosis -ANTI-VIRAL IMMUNE RESPONSES: Viral proteins on the surface og host cells may be recognized by the immune system, and lymphocytes may attack virus-infected cells. An example is hepatitis B infection, which causes the CTLmediated destruction of infected hepatocytes, a normal response that is attempting to clear the infection. -TRANSFORMATION OF INFECTED CELLS: Different oncogenic viruses (epstein-barr for example) can stimulate cell growth and surviival by a variety of mechanisms, including hijacking the control of cell cycle machinery. MECHANISMS OF BACTERIAL INJURY: Endotoxins: components of the bacterial cell - A.k.a. lipopolysaccharide (LPS) - Found in the outer membrane of gram‐negative bacteria. - Made of long‐chain fatty acid anchor (lipid A) + core sugar chain + sometimes a variable carbohydrate chain (O antigen). --> O antigen can be used to serotype the bacteria. --> Lipid A binds to CD14 on leukocytes → complex binds to toll‐like receptor 4. - Response to LPS can be beneficial and harmful. -->Beneficial: LPS activates protective immunity in many ways --> Detrimental: high levels of LPS can lead to septic shock, DIC and ARDS; usually due to high levels of cytokines (e.g. TNF). 2. Exotoxins: proteins secreted by the bacterium; classified by mechanism and site of action. - Enzymes. E.g. proteases, hyaluronidases, coagulases, fibrinolysins. E.g. S. aureus exfoliative toxin is a protease that acts on keratinocytes. - Toxins that change intracellular signaling or regulatory pathways. Most of these have 2 components: A (active) and B (binding). A has enzymatic activity. B allows the surface receptors binding and delivery of A. Made by e.g. B. anthracis, V. cholerae, C. diphtheria. - Superantigens. Stimulate a lot of T cells by binding to conserved parts of the T cell receptor → massive T cell proliferation and cytokine release →capillary leak → shock. By e.g. S. aureus and S. pyogenes to cause toxic shock syndrome (TSS). -Neurotoxins. By e.g. C. botulinum and C. tetani. These cause paralysis. They do not kill neurons, but rather the A domain cleaves proteins needed for secretion of neurotransmitters at the synaptic junction. -Enterotoxins. Many effects on the GI tract, including nausea, vomiting (S. aureus), much watery diarrhea (V. cholera) or bloody diarrhea (C. difficile). INJURIOUS EFFECTS OF HOST IMMUNE RESPONSES: The host immune response to microbes can sometimes be the cause of tissue injury. A few examples include: -Granulomatous inflammation: Infection with M. Tuberculosis results i a delayed hypersensitivity response and the formation of granulomas, which traps the bacilli and prevents it spreading, but it will also cause tissue damage and fibrosis. -T.cell mediated inflammation: en example is the damage to the hepatocytes done by HBV and HCV -Innate immune inflammation: PCR's bind to PAMPs and DAMPs to activate the immune system and leading to inflammation -Humeral immunity: Exmple: poststreptococcal glomerulonephritis can develop after infection with S. pyogenes. It is caused by ab-ag complexes that deposits in the renal glomeruli and produces nephritis. -Chronic inflammatory disease -Cancer: H- pylori for example is known as an oncogenic microbe, presumably because it triggers chronic inflammation with subsequent tissue regen, which provides a fertile ground for the dev. of cancer.

B/33. Infective endocarditis (acute and subacute)

Infective endocarditis is a microbial infection of the heart valves or the mural endocardium that leads to the fomartion of vegetations composed of thrombotic debris and organisms, often associated with destruction of the underlying cardiac tissues! The aorta, aneurysmal sacs and blood vessles may also become infected! We classify IE into two categories; acute and subacute. ACUTE: turbulent, destructive infections, frequently caused by a highly virulent organism attacking a PREVIOUSLY NORMAL VALVE. It is associated with high mortality rates, even with appropriate antibiotic therapy. SUBACUTE: refers to infections of organisms with lower virulence, affecting a previously abnormal heart, especially scarred or deformed valves. Most patients recover after appropriate antibiotic treatment! PATHOGENESIS: IE can develop in previsouly normal valves, but damaged ones do predispose to such infections like, RF, mitral valve prolapse, bicupsid aortic valves, calcific valvular stenosis, PROSTHETIC HEART VALVES. Vascular catheters and sterile pacemaker lines are foci of bacterial growth. CAUSES: The causative organism is in the vast majority of cases, extracellular bacteria. -Acute: staph. aureus (IV. users), enterococcus -Subacute: strep. viridans attacks already damaged valves. These bacteria's entry into the blood, since they are usualy found in our oral cavity, or skin, may be due to an infection elsewhere, or other entries such as those caused by dental or surgical procedures that will cause a transient bacteremia. IV drug users are prone to develop IE as they inject material directly into their blood, thus the entry of the bacteria is through the skin in this way. Other causes could be occult source in the gut or oral cav, or other trivial injuries. MORPHOLOGY: Of both acute and subacute, is the presence of friable, bulky, potentially destructive vegetations on the heart valves containing fibrin, inflammatory cells and microorganisms. The aortic and mitral valves are the most common sites of infection (for IV users, the tricuspid is most freq affected). The vegetations may be single or multiple, may involve more than one valve, and may actually erode into the myocardium creating an abcess called ring abcess. It is important to note that these vegetations may create fragmented embolisms, consisting of the microorganisms that infected the patient, which may lead to septic infarcts and aneurysms resulting in bacterial infection of the arterial wall (=mycotic aneuryisms). Suvacute endocarditis typically cause less valvular destruction than acute, and when looked at histologically, granulation tissue suggest chornic inflammation in subacute endocarditis. CLINICAL FEATURES: -Fever is the most consistent sign of IE, however, in subacute cases, fever may be absent, and the patient may only present with nonspecific fatigue, weight loss, flulike symptoms, as well as splenomegaly. -Acute symptoms include, rapidly developing fever, chills, weakness and lack of E. -In those who are not treated promptly, the above-mentioned microembolisms may be formed, which can give rise to new symptoms: --> petechia --> nail bed hemorrhages (splinter) --> retinal hemorrhages (ROTH SPOTS) -->painless palm or sole erythematous lesions (JANEWAY LESIONS) --> painful fingertip nodules (OSLER NODES) -A diagnosis must be made by taking a positive blood culture + ECG. -Left untreated, IE is fatal, however, with the appropriate antibiotic treatment (6 weeks or more) and/or valve replacement , mortality is decreased.

A/34. Caracteristics of acute inflammation (cellular events, chemical mediators, systemic effects)

Inflammation is a response of vascularized tissues to infections and tissue damage that brings cells and molecules of host defense from the circulation to the sites where they are needed, to eliminate the offending agents. Inflammation is a process essential for survival. The inflammatory reaction usually develops as follows and can be remembered by the 5 r's: -Recognition of the injurious agent -Recruitment of leukocytes -Removal of the agent -Regulation (control) of the response -resolution (Repair). Characteristics of acute inflammation is: -Rapid onset, short duration -It's purpose is exaduation = delivering cellular and humoral agent to the site of injury -The main cells are neutrophiles and platelets -Arises as a result of infection or necrosis -External manifistations include: 1. Calor (heat) 2. Tumor (swelling) 3. Rubor (redness) 4. Dolor (pain) 5. Function laesa (loss of function) Stimulus for acute inflammation i. Infections, from bacterial, fungal, viral, parasitic. ii. Trauma, from thermal injury (burns, frostbite), irradiation, chemical toxins. iii. Tissue necrosis, from ischemia, physical or chemical injury. iv. Foreign bodies, from splinters, dirt, sutures, crystal deposits. v. Hypersensitivity reactions, against environmental‐ or self‐substances. MÅ NOK FORENKLE DEN DELEN HER LITT: VASCULAR REACTIONS IN ACUTE INFLAMMATION: Vasodilation is induced by inflammatory mediators such as histamine and is the cause of erythema (redness of skin) and stasis of blood flow. Increased vascular permeability is induced by histamine, kinins and other mediators that produce gaps between endothelial cells by direct or leukocyte-induced endothelial injury, and by increased passage of fluids through the endothelium. Increased vascular permeability allows plasma proteins and leukocytes, the mediators of host defense, to enter sites of infection or tissue damage. Fluid leak from blood vessels (called exudation) resulting in edema. CELLULAR EVENTS: LEUKOCYTE RECRUITMENT TO SITES OF INFLAMMATION: Leukocytes are recruited from the blood into the extravascular tissue where infectious pathogens or damaged tissues may be located, migrate to the site of infection or tissue injury, and are activated to perform their functions. Leukocyte recruitment is a multistep process consisting of loose attachment to and rolling on endothelium (mediated by selectins), firm attachment to endothelium (mediated by integrins) and migration through interendothelial gaps. Verious cytokines promote the expression of selectins and integrin ligands on endothelium (TNF, IL-1), increase the avidity of integrins for their ligans (chemokines) and promote directional migration of leukocytes (chemokines). Tissue macrophages and other cells responding to the pathogens or damaged tissues produce many of these cytokines. Neutrophils predominate in the EARLY STAGES OF AN INFLAMMATORY RESPONSE and is later replaced by macrophages and monocytes. CELLULAR EVENTS: LEUKOCYTE ACTIVATION AND REMOVAL OF THE OFFENDING AGENTS: Leukocytes can eliminate microbes and dead cells by phagocytosis , followed by their destruction in phagolysosomes. Destruction is caused by free radicals (ROS and NO) generated in activated leukocytes and by granule enzymes. Neutrophiles can extrude their nuclear contents to form extracellular nets that trap and destroy microbes. Remember that the physiological role of inflammation in eliminating microbes may also damage normal tissues and thus have a pathological consequence. Anti-inflammatory mediators terminate the acute inflammatory reaction when it is no longer needed. CHEMICAL MEDIATORS: -Vasoactive amines, mainly histamine cause vasodilation and increased vascular permeability -Arachidonnic acid metabolites (prostaglandins and leukotrines) are involved in vascular reactions, leukocyte chemotaxis and are antagonized by lipoxins -Cytokines are proteins produced by many cell types: they usually act at short range, mediate multiple effects, mainly in leukocyte recruitment and migration, principal ones in acute inflammation are TNF,IL-1, and chemokines. -Activation of the complement system by microbes or ab's leads to the generation of multiple breakdown priducts, which are responsible for leukocyte chemotaxis, opsonization and phagocytosis of microbes and other particles, and cell killing. -Kinins produced by proteolytic cleavage of precursors mediate vascular reactions and pain. SYSTEMIC EFFECTS OF INFLAMMATION= acute phase reaction: -Fever, cytokines like TNF and IL-1 stimulate production of prostaglandins in the hypothalamus -Production of acute-phase proteins; like C-ractive protein (CRP). Their synthesis is stimulated by cytokines like IL-6 which act on liver cells to upregulate their production -Cytokines stimulate production of leukocytes from their precursors in the bone marrow -In some severe infections, septic shock may occur. There will be a fall in blood pressure, DIC, matabolic abnormalities which again will induce high levels of TNF and other cytokines.

B/04. Invasion and metastasis of neoplasms

LOCAL INVASION: Benign and malignant tumors differ considerably in how they "treat" the tissue they grow in. Benign tumors have a well circumscribed, expansile border, meaning that they don't grow "into" the surrounding tissue but instead pushes it away as they expand. They have no ability to infiltrate, invade or metastasize to other tissues. They often form capsules, which separates them from the surrounding tissue. These properties mean that surgical removal is easy. One exception is leiomyomas in the uterus where there is no border, but the tumor is demarcated by the surrounding muscle tissue. Malignant tumors are not well circumscribed, and they have an infiltrative border instead of an expansile one. Malignant tumors don't push away the surrounding tissues but instead grow into them. They cross borders like basement membranes, enter vessels and penetrates whole walls of organs like the colon, uterus and bladder. They can even break through to the surface of the skin, as seen in the breast carcinoma preparation METASTASIS CASCADE: Definition= development of secondary implants (metastases), which are discontinuous with the primary tumor. - This is an indication for a malignant tumor (in addition to invasiveness). -Metastatic spread is more likely with more anaplasia and larger primary neoplasms. PHASE 1; INVASION OF THE ECM: -(loosening of cell-cell contacts, degradation of ECM, attachment to novel ECM components and migration of tumor cells are the 4 steps of this phase!) 1) Cell-cell contacts are lost by inactivation of E-cadherin through a variety of pathways. This mechanism of tumors is called EMT= endothelial to mesenchymal transformation. 2)Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes secreted by tumor cells and stromal cells, such as MMPs (matrix metalloproteinases) and cathepsins 3)Change in attachment of tumor cells to ECM proteins - Normally loss of adhesion → apoptosis, but tumor cells are resistant. -Also, matrix is modified to promote invasion and metastasis. 4)Migration of tumor cells through degraded basement membrane and zones of matrix proteolysis --> Movement is directed by tumor‐derived cytokines and growth factors. PHASE 2; vascular (hematogenous) dissemination and homing of tumor cells More typical for sarcomas, so thyroid, renal, prostate etc! This step occurs through the veins are arteries are more resistant to invasion: --> Portal‐type metastasis: neoplasm of the intestine → portal vein → liver metastasis. --> Vena cava: via the IVC and SVC → lung metastasis. -->Paravertebral plexus: thyroid and prostate → paravertebral plexus → vertebral column metastasis. --> Bronchogenic carcinoma → adrenal and brain --> Neuroblastoma → liver and bones --> Renal cell carcinoma likes to invade the renal vein to grow up the IVC. -Typically tumor cells are transported by platelets (sometimes leukocytes) in the blood. *Extravasation: vascular endothelium adhesion → traversing basememnt membrane → organ parenchyma. - Tumor cells usually stop in the first capillary bed they encounter. *** MET occurs after extravasation. (Mesenchymal to epithelial transformation) -Helps to establish and stabilize distant metastases. -Helps cancer cells to regain epithelial properties and integrate into distant organs. OTHER ROUTES OF DISSEMINATION: 1)Spreading of body cavities: When a neoplasm invades natural body cavities. Ex: Especially seen with ovarian cancer → peritoneal surface; lung cancer → pleura space; CNS neoplasms (medulloblastoma / ependymoma) → penetration of cerebral ventricles → carried in CSF to reimplanation on meningeal surface. 2)Lymphogenic spread: Typical for carcinomas (lung, breast, etc.). -Pattern of lymph node involvement depends on the site of primary neoplasm and its natural lymphatic drainage. -Ex: lung carcinomas in respiratory tract: 1st metastasis: regional bronchial lymph nodes → 2nd metastasis: tracheobronchial lymph nodes → 3rd: hilar lymph nodes. -Ex: breast carcinoma in upper outer quadrant → 1st: axillary lymph nodes. -Skipped metastases: one lymph node is involved, but the next is not due to alternate channels (3% of cases). -Sentinel lymph node: first lymph node that receives lymph flow from the primary tumor; detectable with injection of blue dye or radiolabelled traces → biopsy is taken to asses spreading extent. Metastases with uncommon routes: i. Prostatic carcinoma - usually spreads to the bone. ii. Bronchial carcinoma - usually spreads to adrenals and brain. iii. Neuroblastomas - spreads to liver and bones. iv. Stomach cancer - metastasizes to ovaries in women (called Krukenberg tumor).

B/20. Grading and staging of cancer

Methods to quantify the probable clinical aggressiveness of a given neoplasm and its apparent extent and spread in the individual patient are necessary for arriving at an accurate prognosis and for comparing end results of various treatment protocols. Systems have been developed to express, at least in semiquantitative terms, level of differentiation, or grade, and extent of spread if a cancer within the patient, or stage, as parameters of the clinical gravity of the disease. When compared with grading, staging has proved to be of greater clinical value! GRADING: Grading of tumors is determined by cytologic appearabce and is based on the idea that behaviour and differentiation are related, with poorly differentiated tumors having more agressive behaviour! The grading scheme has been evolved for every single type of malignancy, and generally range from two categories (low-grade and high-grade) to 4 categories! STAGING: Staging, the extent of the tumor, is deteremined by surgical exploration or imaging, is based in the size, local or regional lymph node spread and distant metastases. Stages is as mentioned, of GREATER CLINICAL VALUE! The system used for classification is TNM system: T for primary: T1-T4 based on increasing size. T0 is used to indicate an in situ lesion (=A group of abnormal cells that remain in the place where they first formed. They have not spread.) N for regional lymph node involvement: N1-N3 would denote involvement of increasing number and range if nodes. N0 would mean no nodal involvement! M for metastasis: M1 or sometimes M2 reflects the presence and estimated number of metastases. M0 signifies no distant metastases.

A/54. Disorders associated with prematurity (IRDS, NEC, Sudden Infant Death)

Prematurity = gestational age of less than 37 weeks or weight less than 2,5kg!!!!! Prematurity is the second most common cause of neonatal mortality! CAUSES OF PREMATURITY: FETAL FACTORS: -Chromosomal disorders -congenital disorders -Congenital infections (TORCH hsuekregel ) PLACENTAL FACTORS: -Placental previa (placenta lies too low and thus may sep. from the wall during labour as the cervix dilates and opens) -Placental abruption (plaecnta sep from the uterus wall too early) -PlAcental infarction MATERNAL FACTORS: -Preeclampsia (high BP during pregnancy) -Chronic hypertension (not due to prgnancy, but all the time) IRDS (INFANT RESPIRATORY DISTRESS SYNDROME): -Is a type of hyaline membrane disease, hyaline= A clear, eosinophilic, homogeneous substance occurring in cellular degeneration!!! -There is an insufficiency in the surfactant normally produced by type II pneumocytes, thus leading to failure of the lungs to inflate --> hypoxia, causing endothel and epithelial camage. There will be formation of hyaline membrane in the alveoli. Low mortality, however long-term consequences can lead to retinopathy and bronchopulmonary dysplasia. The retinopathy develops as the hypoxiic state of the patient decreases levels of VEGF. During therapy, vascular endothelial growth factor levels rebound and this causes neurovascularization in the retina creating the lesions responsible for retinopathy!! TREATMENT: prophylactic administration of steroids, surfactant therapy, and by improved ventilation techniques, like giving O2 decreases the mortality of the disorder, as well as the complications that can occur due to it. NEC (NECROTIZING ENTEROCOLITIS): -This disease usually affects very low weight infants (>1,5kg) -No bacterial infection has been linked to this disease -The involved segment is distended, friable and congested -Gangrenous and intestinal perforations leads to peritonitis and sepsis --> HIGH PERINATAL MORTALITY! But can try to resect the affected bowel segment, and infants who survive this often develop fibrosis due to the healing process. SIDS (SUDDEN INFANT DEATH SYNDROME): -UNEXPLAINED, sudden death of an infant before the age of 1 year -Death usually occurs during sleep, and the disease is of unknown origin, but there is research supporting thaat the arcuate nucleus could be involved leading to defective arousal and cardiorespiratory regulation -This most frequently occurs between 2 -4 months -Risk factors: --> prone sleeping position aka on the stomach!!!!

A/59. Sepsis and perinatal infections

SEPSIS: Sepsis is a whole body inflammation due to infection. The symptoms include: -fever -increased HR -incr resp. rate -confusion -or other, more specific infection related symptoms Septic shock: low blood pressure due to sepsis that does not resolve after IV fluid is given. The cause is usually an immune response reaction to an infection in the lungs, abdomen or urinary tract Risk factors: Lowered immune competence -Very young or very old age -cancer -DM -AIDS -Major trauma or burns -Third trimester pregnancy To diagnose sepsis we need at least 2 systemic response syndrome (SIRS) criteria with presumed infection. -SIRS= inflammatory state affecting the whole body, not necessarily due to infection. - SIRS criteria: (different in children): 1. Body temperature < 36°C or > 38°C 2. Heart rate > 90 bpm 3. Tachypnea > 20 bpm or paCO2 < 32 mmHg 4. WBC count < 4x109 cells / L or > 12x109 cells/L Differential diagnosis: anaphylaxis, adrenal insufficiency, low blood volume, heart failure and pulmonary embolism, etc. Treatment: Blood cultures should be done before treatment with antibiotics. (infection of the blood is not necessary for diagnosis). -->Main treatment is with IV fluids and antibiotics. If this cannot raise blood pressure, drugs are given to increase BP. --> If necessary mechanical ventilation and dialysis can be given to support failing lungs and kidneys. PERINATAL INFECTIONS: These include vertically transmitted infections so from mother to fetus during week 22-28. These are usually infections from bacteria and viruses, not parasites. Usually includes the TORCH complex i. T - Toxoplasma gondii ii. O - Other infections= 1. Coxsackievirus 2. Varicella zoster virus 3. Chlamydia 4. HIV 5. Human T‐lymphotropic virus 6. Syphilis iii. R - Rubella iv. C - Cytomegalovirus v. H - Herpes simplex virus‐2 or neonatal herpes simplex Now used is CHEAPTORCHES i. C - Chickenpox and shingles ii. H - Hepatitis B, C, (D), E iii. E - Enteroviruses iv. A - AIDS (HIV infection) v. P - Parvovirus B19 (produces Hydrops faetalis secondary to aplastic anemia) vi. T - Toxoplasmosis vii. O - Other (Group B Streptococcus, Listeria, Candida, Lyme disease) viii. R - Rubella ix. C - Cytomegalovirus x. H - Herpes simplex xi. E - Everything else sexually transmitted (gonorrhea, Chlamydia infection, Ureaplasma urealyticum, human papillomavirus) xii. S - Syphilis Signs and symptoms depend on the individual pathogen. But they often include fever, poor feeding, newborn is small for the gestational age, possibly petechial rash on skin, hepatosplenomegaly and jaundice. The mother often has mild infections with few to no symptoms. ROUTE OF TRANSMISSION IS TRANSPLACENTAL.

A/44. Sjögren Syndrome, Scleroderma, Polyarteritis Nodosa

SJØGREN SYNDROME: Is a chronic disease characterized by DRY EYES and DRY mouth resulting from immunologically mediated destruction of the lacrimal and salivary glands. It can occur as an isolated disease (primary form) or, more often than not, in association with another autoimmune disorder. This is most commonly associated with RA. It is a type IV hypersensitivity lymphocyte-mediated reaction. The syndrome most frequently affects women between 50-60 years of age. PATHOGENESIS: It is believed to be caused by autoimmune T cells that react against an unknown self antigen expressed in these glands, or immune reactions against the antigens of a virus that infects the tissues. MORPHOLOGY: The lacrimal and salivary glands are the major targets for this disease, however other exocrine glands, including those lining the respiratory and GI tracts, vagina can also be affected. The earliest histologic findings of the syndrome is periductal and perivascular infiltration of lymphocytes in the major and minor glands. Eventually, the lymphoid infiltrate becomes so extensive that we can see lymphoid follicles with germinal centers. The epithelial cells lining the ducts can be seen as hyperplastic and might obstruct the ducts. Later there will be atrophy of the acini, fibrosis and hyalinization, that will be replaced with fat. These patients are in high risk of developing B-cell lymphomas of the salivary glands. Macroscopically, one can see the atrophy of oral mucosa, with inflammatory fissuring and ulceration, as well as a dryness and crusting of the nose. Perforation of the nasal septum might occur as well. CLINICAL FEATURES: The patient will present with: -Blurred vision, burning, itching and thick excretions from the eyes due to keratoconjunctivitis (dry eyes). -Xerostomia (dry mouth) results in difficulty swallowing solid food, a decrease in taste, cracks and fissures of mouth and dryness of buccal mucosa. -Parotid enlargement is prsent in half of the patients -Bronchitis and pharnygitis. --> In contrast to SLE, glomerular lesions are rare in sjøgren, but defects of tubular function however, including renal tubular acidosis, uricosuria and phosphaturia are often seen, and are associated with tubulointerstitial nephritis. SYSTEMIC SCLEROSIS/ SCLERODERMA: Systemic sclerosis is an immunologic disorder characterized by excessive fibrosis in multiple tissues, obliterative vascular disease and evidence of autoimmunity, mainly the production of multiple autoantibodies. It is divided into diffused and localized types. Diffuse type exhibit skin and early visceral involvement. Almost any organ can be involved and most frequently, the esophagus is affected and looses it's flexability and mobility. It is characterized by ANA and anti-DNA topisomerase I (scl-70) anitbody. The localized type exhibits local skin and late visceral involvement. Prototype is CREST syndrome: Calcinosis(anti-centromere antibodies)/ Raynaud phenomenon/ Esophageal dismobility/ Sclerodactyly/ Telangiectasis of skin. PATHOGENESIS: The cause is not known, but it likely results from 3 interrelated processes: -Autoimmune responses: CD4+ T cells release cytokines which activate immune cells and fibroblasts. Il-13 and TGF-beta stimulate synthesis of collagen and ECM in fibroblasts. -Vascular damage: Microvascular disease, by the result of widespread narrowing of the microvasculature is commonly seen in the early stages of the disease. This leads to ischemic injury and scarring. The pulmonary vasculature is frequently involved, thus leading to pulmonary hypertension and right-sided hypertrophy --> corpulmonale. -Fibrosis: Occurs in multiple organs and a suggestion was made about an intrinsic abnormality in the cells making them produce excessive amounts of collagen. MORPHOLOGY: The most prominent changes occur in the skin, esophagus, MS system and kidney, however lesions can be present on blood vessels, heart, lungs and peripheral nerves as well. Skin: Most patients have diffuse fibrosis of the skin and associated atrophy, which typically begins in the fingers and distal regions of the upper extremeties. Edema and perivascular CD4+ infiltrates are seen. Microvasculature may show thickening and even occlusion. In advanced conditions, the fingers take on a claw-like, tapered appearance with limited joint mobility, and the face becomes a brown mask. Loss of blood supply may lead to autoamputation of the terminal phalanges. GI tract: Is affected in 90% of the cases. Progressive atrophy and fibrous replacement of the muscularis may develop at any level of the gut, but is most severe in the esophagus. Resulting in the patient's developing gastroesophageal reflux symtpoms and Barret's metaplasia. Loss of villi and microvilli in the small bowel leads to malabsorption syndrome and might be encountered. Kidney: Renal abnormalities occur in 2/3rds of patients and most prominent are the vascular lesions. Lungs and heart: Lungs are affected in half of the cases due to the pulmonary hypertension leading to right sided hypertrophy and might lead to corpulmonale. CLINICAL FEATURES: -Women are affected 3x more than men. - Peak incidence is 50‐70 years old. -There is much overlap between SS, RA, SLE and dermatomyositis, whereby SS shows much more skin involvement. - Almost all patients have Raynaud phenomenon: vascular disorder featuring reversible vasospam of the arteries. Hands will turn white with cold exposure (vasospasm) → then blue (cyanosis) → finally red (reactive vasodilation). - Atrophy of the hands → immobilization of the joints due to increasing collagen deposition. - Esophageal fibrosis → hypomotility → difficulty swallowing. Destruction of the esophageal wall → atony and dilatation. - Submucosal and muscular atrophy and fibrosis of the SI → malabsorption. - Lung changes → dyspnea and chronic cough. Advanced → secondary pulmonary hypertension → right‐sided heart failure. - Clinical course is variable: most patients have a steady, slow, down‐hill course over years. 1. 10 year survival is from 35‐70%. 2. Chances of survival are better for patients with localized scleroderma. POLYARTERITIS NODOSA: PAN is a systemic vasculitis of small- or medium sized arteries, it typically involves the renal and visceral vessels and spares the pulmonary circulation. 1/3rd of patients have hepatitis B infection and thus the immune complexes deposits in the affected vessels. MORPHOLOGY: Classic PAN is a segmental transmural necrotizing inflammation of small- to medium-sized arteries, often with superimposed thrombosis. Impaired perfusion may lead to ulcerations,infarcts, ischemic atrophy, hemorrhages in the distributed affected arteries. The inflammatory processes also weakens the arterial wall, leading to aneurysms and rupture. Fibrinoid necrosis is also seen in the acute phase. CLINICAL FEATURES: PAN is primarily a disease of young adults but can occur in any all age group. Typically, the symptoms are episodic, with long symptom-free intervals. The symptoms include malaise, fever, weight loss. A classic example of the symptoms include rapidly accelerating hypertension due to renal artery involvement; abdominal pain and bloody stools caused by GI lesions, diffuse muscular pains, predom. affecting motor nerves. Renal involvement is prominent and a major cause of death. Untreated PAN is typically fatal, however with immunosupression, 5 year survival is close to 80%. Relapse can occur in 25% of the cases, more often than not in patient's without the Hep B vaccine.

A/43. Systemic Lupus Erythematodes, Rheumatoid Arthritis

SYSTEMIC LUPUS ERYTHEMATODES: Lupus is a systemic autoimmune disease that is caused by damage done by antibodies against the host which hurt multiple tissues via type II and type III hypersensitivity rxn. Most of the lesions causing symptoms in SLE are caused by immune complex deposition, however autoantibodies of different specificities contribute to the pathology and clinical manifistations of SLE. It is a disease that is way more common in women than in men, especially african-american women. CLINICAL FEATURES: -fever and weight loss -a characteristic butterfly rash in face -arthritis -pleuritis, pericarditis -RENAL DAMAGE: diffuse proliferative glomerulonephritis -Endocarditis --> Libman-sacks endocarditis is a classical finding and is characterozed by small, sterile, deposits on both sides of the mitral valve. -Anemia, thrombocytopenia, leukopenia -Will result in deep vein thrombosis, hepatic vein thrombosis etc. DIAGNOSIS: -It is characterized by anti-nuclear antibodies (ANA) and anti-dsDNA antibodies PATHOGENESIS: GENETIC FACTORS: -Some HLA variations are more common in people with SLE than the general popluation, example= HLA-A1 -Some inherited deficiencies of certain parts of the complement system increases the risk in developing SLE. Example= C2 deficiency! ENVIRONMENTAL TRIGGERS: -Infectious agents -UV -estrogen -medications (ex: hydralazine, procainamide = drug-induced SLE) MORPHOLOGY: -The symptoms above^ -The kidney is heavily affected in SLE and is classified into 6 patterns of glomerular disease, where type I is the least common, and type IV is the most common: 1) Minimal mesangial lupus nephritis/type I: immune complex deposition in the mesangium identified by immunofluorescence 2)Mesangial proliferative lupus nephritis/ type II: mesangial cell prolif accompanied by accumulation of mesangial matrix with deposition og IG's and complement, without the involvement of the glom cap! 3) Focal lupus nephritis/type III: involvement by fewer of 50% of all glomeruli. Affected glomeruli exhibit swelling, leukocyte accumulation, capillary necrosis and hyaline thrombi 4) DIFFUSE LUPUS NEPHRITIS/TYPE IV (most common), is the same lesions as type III, but now over half of the glomeruli are affected! Patients show hematouria and proteinuria, and mild-severe renal insufficiency! 5) Membranous lupus nephritis/class V: diffuse thickening of the cap walls due to dep imm complexes. This is also accompanied by a increased prod of basement membrane-like material 6) Advanced sclerosing lupus nephritis/ class VI: sclerosis of more than 90% of the glomeruli and represents end-stage renal disease. DRUG-INDUCED SLE: SLE may develop in patients being given drugs, like hydralazine and procainamide which are associated with the development of ANAs, especially ab's specific for histones! The disease does go away after the withdrawel of the offending drug! Surprisingly, anti-TNF therapy used in RA and other autoimm diseases, can actually cause DRUG-INDUCED SLE! RHEUMATOID ATHRITIS: RA is a chronic inflammatory disorder of autoimmune origin that principally attacks the joints producing a NONSUPPORTIVE PROLIFERATIVE and inflammatory synovitis. RA often progresses to the destruction of the articular cartilage and, extracellular lesions include the skin, heart, blood vessels and lungs, though this is not as common. PATHOGENESIS: Like in other autoimmune diseases, genetic predisposition and environmental factors contribute to the development, progression and chronicity of RA. The disease is mediated by antibodies against self-antigens and inflammation caused by cytokines secreted by CD4+ T cells. These cells may initiate the autoimmune response of RA by reacting with an arthritogen, perhaps microbial or a chemically modified self-antigen. --> IFN-gamma from Th1 cells activate macrophages and synovial cells --> IL-17 from Th17 cells recruit neutrophils and monocytes --> RANK ligand expressed in activated T cells stimulates osteoclasts and bone resorption. --> TNF and IL-1 from macrophages stimulate resident synovial cells to secrete proteases that destory hyaline cartilage. Anti-citrullinated protein antibodies (ACPA) in combination with T cell response to the citrullinated proteins contribute to disease chonicity. 80% of patients wtih RA have IgM or IgA autoantibodies in their serum that we call rheumatoid factors. It is estimated that 50% of the risk of developing RA is related to inherited genetic susceptibility. The HLA-class II locus is associated with ACPA-positive RA. MORPHOLOGY: RA typically manifests as symetrical arthirits affacting most commonly small joints in hands and feet. Grossly, the joint becomes edematous, thickened, and hyperplastic. The histological features include: 1)synovial cell hyperplasia and proliferation 2)dense inflammatory inflitrates of CD4+, B cells, plasma, dendritic and macrophages 3)increased vascularity as a result of angiogenesis 4)neutrophils and aggregation of fibrin on joint surfaces 5)osteoclastic activity in underlying bone, allowing the synovium to penetrate the bone. This causes a pannus, which can bridge the bones to form a fibrous ankylosis which may ossify to form a bony ankylosis. One can also see rhematoid nodules in subcutaneous tissue, that histologically resemble necrotizing granulomas. CLINICAL COURSE: Ra begins slowly with malaise, fatigue, and genarlized musculoskeletal pain. Joint pain may present itself in the hands, feet, ankles, wrists, knees, elbows, but normally the patient feel the pain in the metacarpophalangeal and prox interphalangeal joints. The joints are swollen, warm and painful. In contrast to OA, the joints feel stiff after a period of inactivity. Radiographic hallmarks are joint effusions and juxtaarticular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage. TREATMENT: The treatment for RA includes corticosteroids, and other immunosuppresants. A characteristic drug is TNF antagonists, as TNF is a big cause of the pathogenesis of RA. However, TNF antagonists, if used for a long time, carries a risk of ibcreased infections with organisms such as tuberculosis bacteria etc.

A/27. Causes and types of shock

Shock is a state in which diminshed cardiac output or reduced effective cirxulating blood volume impairs tissue perfusion and leads to cellular hypoxia, which leads to multiorgan failure. So, in other words, a shock is a whole-body circulatory failure. It is in theory reversible, but prolonged shock leads to irreversible tissue injury and is often fatal. STAGES OF SHOCK: 1) NON-PROGRESSIVE STAGE For different reasons the cardiac output will be severely reduced. This causes a sympathetic activation. The sympathetic activation will try to increase the cardiac output as compensation, and there will be a release of epinephrine, norepinephrine, ADH and angiotensin II, leading to peripheral vasoconstriction, tachycardia and renal fluid retention. Because of vasoconstriction in skin will the skin be cool and pallor, which is characteristic for shock (but not septic shock, where the opposite happens). The vasoconstriction causes blood to be directed from non-vital organs to vital organs such as the brain and heart, because the coronaries and cerebral arteries aren't affected by the sympathetic vasoconstriction. 2) PROGRESSIVE STAGE: If the underlying cause isn't corrected the shock passes into the progressive phase. The vasoconstriction persists, the tissue perfusion is still too low, making the cells switch to anaerob glycolysis and yielding lactate. This accumulation of lactate in blood will give a metabolic acidosis. Metabolic acidosis causes vasodilation of the arterioles (vasomotor response), which causes blood to pool in the microcirculation and flow very slowly. This worsens the cardiac output even further. Vital organs start to fail. 2) IRREVERSIBLE STAGE: Without appropriate intervention will shock enter the irreversible phase. At this stage, not much can be done. The hypoxic damage on cells will be so big in this stage that lysosomal enzymes will leak from the cells. The ischaemia of the bowel wall will allow bacterial flora from faeces to enter the blood stream. Myocardial contractile function worsens because of synthesis of nitric oxide (NO). All this together will superimpose the shock, and the increased necrosis of tissues will lead to failure of organs and death. CLINICAL FEATURES: In hypovolemic and cardiogenic shock, the patient exhibit hypotension, a weak rapid pulse, tachypnea, and cool, clammy, cynaotic skin. In septic shock, the skin may be warm and flushed owing to the peripheral vasodilation. TYPES OF SHOCK: i)Hypovolemic shock: results from low CO due to loss of blood or plasma volume ii) Cardiogenic shock: results from low CO as a result from myocardial pump failure caused by for example MI, ventricular arrhythmia, cardiac tamponade, or pulmonary embolism. We say that endocrinologic shock is a form of cardiogenic shock as it refers to patient's with hypothyroidism that will have reduced CO and thus hypotension. (iii) Obstructive shock: Due to obstruction of blood flow outside of the heart. 1. Cardiac tamponade. Fluid in pericardium prevents inflow of blood into the heart. 2. Constrictive pericarditis in which the pericardium shrinks and hardens. 3. Tension pneumothorax. Increased intrathoracic pressure leads to blood flow to the heart being prevented. 4. Aortic stenosis.) iv) Distributive a) Septic shock: is triggered by microbial infections (usually gram neg bacteria, but can also be gram positive or fungal infections) and is associated with severe systemic inflammatory response syndrome (SIRS). SIRS can also be triggered by pancreatitis, severe burns and trauma. --> Pathomechanism: i. Pathogen endo/exotoxin release → released cytokines → tissue factor expression and fibrin deposition increase → DIC, vasodilation, fluid shift -endothelial damage --> LPS and other PAMPs are regonized by TLR which leads to release of TNFalpha and vasoactive substances which leads to increased adhesion, pro-coagulation and compliment activation. Leads to DIC --> hypovolemia and edema -Metabolic effects: insulin decrease, increase insulin resistance, hypoglycemic stage, decreased neuro activity --> favors bacterial growth -Hypoperfusion of organs: multisystem organ failure --> death b)anaphylatic shock: Caused by severe anaphylactic reaction to an allergen, antigen, drug or foreign protein causing the release of histamine from mast cells which causes widespread vasodilation. c) Neurogenic shock: Spinal lesion may result in loss of vessel tone and further result in vasodilation and slow heart rate due to loss of cardiac sympathetic tone → ↓ VR and ↓ CO.

B/03. Caracteristics of neoplasms rate growth

THE RATE OF TUMOR GROWTH DEPENDS ON 3 FACTORS: - The time it takes for the cells to double in number = doubling time of the tumor cells -The fraction of the tumor cells that are actively proliferating -How quickly the tumor cells die = their death rate. Doubling time of tumors differ between tumors, but the biggest determinant for how fast cancers grow is the proliferative fraction. Not all tumor cells in a tumor is currently replicating, only a fraction of them. This fraction changes considerably in the development of the tumor. In the very early stages of cancer are the majority of cells proliferative, but this fraction decreases when the tumor grows. ---> At the time where cancers become clinically detectable are only approx. 20% of the tumor cells proliferating. Benign tumors are well differentiated and have a slow growth rate, (exception: leiomyoma in the uterus), so does semi-maligant and borderline tumors. Malignant tumors are less differentiated and thus grow much faster APPROXIMATE GROWTH CHARACTERISTICS: -One tumor that is about 10 micrometers in diameter will generate a 1 mg tumor (border of detectable tumor) in approximately 30 cell cycles. EX: 10 μm → 30 cycles → 1 mg → 10 cycles → 1 kg -Less than 1 mg is difficult to detect with recent technology. - About 40 cycles are needed to generate a tumor of 1kg in size. At this point, it is incompatible with life! Chemotherapeutic drugs act on proliferating cancers cells, meaning that the proliferative fraction of the tumor is very important for whether these drugs will have an effect or not. Neuroblastoma and Burkitt lymphoma are both cancers with very high proliferative fractions, and both responds relatively well to chemotherapy. THEORIES: i. Monoclonal theory of neoplasms. This means one cell has a genetic positive hit in which it has become neoplastic and all neoplastic cells are daughter cells of this cell. When they divide, they proliferate. The monoclonal origin of neoplasms has been shown by studying glucose-6-phosphatedehydrogenase (G6PD) isoenzymes A and B in selected neoplasms (e.g., leiomyoma of the uterus).All the neoplastic smooth muscle cells in uterine leiomyomas have either the A or the B G6PDisoenzyme. Nonneoplastic smooth muscle proliferations in the uterus (e.g., pregnant uterus) havesome cells with the A isoenzyme and others with the B isoenzyme, indicating their polyclonalorigin. ii. Cancer stem cell hypothesis. Some of the tumor‐forming cells have stem cell characteristics: they form one daughter cell that has self‐renewal (proliferative fraction) and another daughter cell that can differentiate (non‐proliferative fraction). This theory explains cancer persistence. TREATMENT: i. Debulking. Surgery is made to remove the tumor and this pushes the cells back to the proliferative phase. ii. Chemotherapy. The chemotherapy can now reach the cells. RATE OG GROWTH DEPENDS ON: - Rate of cell production: mitotic rate. -Growth fraction: number of cells remaining in the preoperative pool. -Rate of cell loss by cell shedding. -Degree of differentiation -->Directly proportional to the malignant tumor growth rate. --> Poorly differentiated → aggressive growth pattern. - Other influences -->Adequacy of blood supply --> Pressure constraints SPREADING EITHER BY DIRECT INVASION OR METASTASIS: Local invasion (direct spread) 1. Benign: expand and push aside normal tissue without invading, infiltrating or metastasizing. Not all benign tumors are encapsulated. 2. Malignant: expand, invade, infiltrate and destroy the surrounding tissue. They have no well‐defined capsules.

A/09. Cerebral infarction

The brain is a HIGHLY oxygen-dependent tissue that requires a continual blood supply of glucose and oxygen from the blood. Although, it's not a big organ, it receives 15% of the CO, and it's blood flow is stable over a wide range of pressures due to autoregulation of the arterioles. The brain may be deprived of oxygen by two general mechanisms: -Functional hypoxia: caused by low-partial pressure of O2 (high altitude), impaired o2-carrying capacity (severe anemia), toxins that interfere with o2 use (cyanide poisining). -Ischemia/transient --> eventually permanent damage due to tissue hypoperfusion, which can be cause dby hypotension, cascuar obstruction or both GLOBAL CEREBRAL ISCHEMIA: Widespread ischemic-hypoxic injury can occur in the setting of severe systemic hypotension, usually when systolic pressures fall below 50mmHgm, as in cardiac failure or shock. -Neurons are more susceptible to hypoxic injury than glial cells, and the most susceptible are pyramidal cells of the hippocampus, and Purkinje cells of the cerebellum. (In some individuals, even mild global ischemia insults may cause damage to these vulnerable areas. During severe global cerebral ischemia, widespread neuronal death occurs irrespective of regional vulnerability. The term "brain dead" is used to describe someone who doesn't have voluntarily or reflex brain and brain stem function intact anymore - this includes the respiratory drive! FOCAL CEREBRAL ISCHEMIA: Cerebral arterial occlusion leads first to focal ischemia, and then to infarction in the distribution of the compromised vessel. Embolic infarction: Are more common than infarctions due to thrombus. -The source is usually a cardiac mural thrombus, where myocardial dysfunction, atrial fibrillation, valvular disease are predisposing factors! -It is the middle cerebral artery and the direct extension of the internal carotid artery that is the most common places affected by an embolism. -Emboli of venous origin may cross over to the arterial circulation if the patient has an intact foramen ovale, and this can lodge into the brain! THIS IS CALLED A PARADOXICAL EMBOLISM! Thrombic occlusions: causing cerebral infarction is usually superimposed on atherosclerotic plaques. Thrombotic occlusions causing small infarcts at only a few mm, are called "lacunar infarcts", usually happens due to long-standing hypertension where the small penetrating arteries are occluded due to chronic damage. NONHEMORRHAGIC INFARCTS RESULTS FROM ACUTE VASCULAR OCCLUSIONS AND MAY INVOLVE INTO HEMORRHAGIC INFARCTS. MORPHOLOGY: MACROSCOPIC: brain becomes swollen, with wide gyri and narrowed sulci. The cut surface also shows poor demarcation between white and grey matter. EARLY CHANGES OF IRREVERSIBLE ISCHEMIC INJURY: 12-24 hrs after insult, include acute neuronal cell change (red neurons). They show microvacoulization followed by cytoplasmic eosiniphilia, and nuclear pyknosis. SUBACUTE CHANGES: 24hrs -2 weeks, include necrosis of tissue, influx of macrophages vascular prolif REPAIR: seen after 2 weeks where the necrotic tissue is removed

B/09. BRCA1, BRCA2 and ATM genes and their roles in tumor development

The proteins encoded by the breast-cancer-susceptibility genes, BRCA1 and BRCA2, have recently been implicated in DNA-repair processes, thereby improving our understanding of how the loss of these genes contributes to cancer initiation and progression. It appears that the role of BRCA1 in DNA repair, which could involve the integration of several pathways, is broader than that of BRCA2. BRCA1 functions in the signalling of DNA damage and its repair by homologous recombination, nucleotide-excision repair and possibly non-homologous end-joining. BRCA2 has a more specific role in DNA repair, regulating the activity of RAD51, which is required for homologous recombination We have 3 different DNA repair mechanisms in oncology: 1)Mistmatch repair: Mismatch repair (MMR) genes encode proteins responsible for repairing errors that occur during the normal replication of DNA. As new DNA strands are synthesized, errors such as insertion of an incorrect (mismatched) base or small loops of DNA may occur. Done by MSH 1 and 6 genes as well as MLH1. Cancers: Colorectal-, ovarium-, endometrium-, stomach cancer 2)Nucleotide excision repair: In nucleotide excision repair (NER), damaged bases are cut out within a string of nucleotides, and replaced with DNA as directed by the undamaged template strand. This repair system is used to remove pyrimidine dimers formed by UV radiation as well as nucleotides modified by bulky chemical adducts. Done by XPA XPC XPG genes Cancers: Basocellular-, planocellular carcinoma, melanoma 3) Homolog recombination repair: Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks (DSB) Done by BRCA1 and BRCA2 genes, with the aid of ATM! Cancers (BRCA1): Breast-, ovarium-, prostata carcinoma Cancers (BRCA2): Breast-, ovarium-, pancreas, stomach carcinoma, melanoma Cancers (ATM): Ataxia teleangiectasia, breast carcinoma, different sporadic neoplasms MECHANISM: ATM recognition mutation → phosphorylates BRCA1 → complexes with BRCA2 and RAD51 →RAD51 wraps around the ssDNA where the break is and binds the comeplementary NT on the sister chromatid, which corrects the mutation → mutations in any of these genes impairs the system → cancer develops!!! (Individuals with inherited mutations of genes involved in DNA repair systems are at greatly increased risk for the development of cancer! -Patients with hereditary nonpolyposis colon carcinoma (HNPCC) syndrome dramatically illustrates the role of defect mismatch repair genes in the development of cancer. These patients' genome show microsatellite instability (MSI) characterized by changes in length of short tandem repeating sequences throughout the genome. -Patients with Xerodoma pigmentosum have defects in the nucleotide excision repair pathway! They are at increased risk for the development of skin cancers in sites exposed to sunlight because of an inability to repair pyrimidine dimers induced by UV light) DISEASES WITH DEFECTS IN DNA REPAIR BY HOMOLOGOUS RECOMBINATION: -Syndromes involving defects in the homologous recombination DNA repair system constitute a group of AR disorders - Bloom syndrome, ataxia-telangiectasia and Fanconi anemia - that are characterized by hypersensitivity to DNA-damaging agents such as ionizing radiation. BRCA1 and BRCA2, which are mutated in familial breast cancers, also are involved in homol. DNA repair -ATAXIA TELANGIECTASIA: is a disorder that features neural symptoms. It is the ATM gene that is mutated, which encodes an important protein kinase needed to sense DNA damage caused by ionizing radiation and then directing p53 to initiate the DNA damage response!

B/11. Cytogenetic aberrations and the role of telomer in carcinogenesis

There can be numerical abberations (=polyploidy, aneuploidy) or structural abberations (translocation, deletion, amplification, inversion, isochromosomes, ring chromosome formation etc) Most common structural abnormalities TRANSLOCATIONS: i. Balanced translocations - An even exchange of material with no extra/missing genetic information. It is functionally ideal. 1.) Lymphoid cells are often the targets of gene rearrangement, since they have the ability of VDJ rearrangement (DNA breaks during antibody production for example). 2) It is also seen in solid tumors (Ewing's sarcoma). a. Some translocations result in overexpression of proto‐oncogenes: the genes are moved to a place where there is a very active promoter. i. Seen in Burkitt's lymphoma (90%) - Translocation leads to overexpression of the MYC gene combined with the gene for immunoglobulin heavy chain formation. b. Translocation may also create fusion genes - encoding hybrid proteins. i. Philadelphia chromosome is an important example (seen in 90% of chronic myelogenous leukemia). BCR‐ABL rearrangement. ii. Ewing's sarcoma (small, round, blue cell tumor usually found in bone and soft tissue) is a result of fusion between chromosome 11 (FLI1 gene) and chromosome 22 (EWS gene). DELETIONS: The deletion of specific genes in a chromosome may result in loss of function. This is especially important with deletions of tumor suppressor genes. This type of karyotypic abnormality is more common in non‐hematopoietic solid tumors. a. Generally requires loss in both alleles to be carcinogenic. i. The most frequent mechanism is an inactivating point mutation in one allele, followed by deletion of the other allele. b. Deletions involving 13q14 is associated with RB gene, and deletion of 17p is associated with p53 gene. GENE AMPLIFICATION: Gene overexpression is dangerous, because proto‐oncogenes can be amplified (which leads to amplification of their protein product). In some cases these genes may produce chromosomal changes that can lead to cancer. --> In gene amplification - two patterns may be seen: a. Double minute chromosomes: small fragments of extrachromosomal DNA (eccDNA) due to amplification during tumor development. i. They are composed of chromatin and replicate within the nucleus during cell division. They frequently contain oncogenes and genes involved with drug resistance. ii. They do not contain telomeres or centromeres, and they are usually circular. b. Homogenously staining regions: amplified genes are inserted in new chromosomal locations, which can be distant from their normal location. i. If a proto‐oncogenic segment is amplified the segment can become much longer. HER2 (ERBB2) is often overexpressed in 20% of breast cancer cases! Aneuploidy - It is a type of chromosomal abnormality where the cell contains an abnormal number of chromosomes. 1. Usually seen in all cancers. It is the result of a weakened mitotic checkpoint. a. Usually the cell would be arrested in order to get all the components ready for division, but in this case this doesn't occur. This may lead to an earlier cell division. (E.g. the chromosomes are aligned at the center when division occurs). 2. There are different types of mechanisms related to this: a. Completely inactive mitotic checkpoints: nondisjunction; could result in disjointed set (no similar elements) of genetic material. b. Merotelic attachement: when both mitotic spindles attach to the same kinetochore. c. Multipolar spindles: more than two spindles form. One daughter cell for each spindle will form → unpredictable number of chromosomes in each cell. d. Monopolar spindle: a single daughter cell with a double copy of chromosomes is formed. May produce a tetrapolar intermediate as the end product (the cell produce four copies with an uneven number of chromosomes). TELOMERES IN CARCINOGENESIS: -Tumor cells, unlike normal cells, are capable of limitless replication. -Normal cells have a limited capacity of division at the most at 70 divisions! Thereafter, the cell lose the ability to divide and enter replicative senescence. This phenomenon has been described to be closely related to the shortening of the telomeres at the end of chromsomes! -Telomeres are replenished by telomerase reverse transcriptase (TERT). iii. Telomeres shrink with each replication due to DNA replication mechnisms, oxidative stress and low TERT expression in human cells. -Markedly eroded telomeres are recognized by the DNA repair machinery as ds-DNA breaks, leading to cell cycle arrest and senescence, mediated by TP53 and RB! In cells where TP53 and RB are disabled due to mutations, the non-homologous end-joining pathways is activated in a last effort to save the cell, joining the shortened ends of two chromosomes!!!! -Such an inappropriately activated repair system results in dicentric chromosomes that are pulled apart in anaphase, resulting in new ds-DNA breaks!! -This eventually leads to a huge mitotic apoptosis pool! -For tumor cells to aquire the ability to grow indefinitely, both cellular senescence AND mitotic catastrophe MUST BE AVOIDED!!! -If during crisis, the cell manages to reactivate it's telomerase (remember that stem cells have the highest activity of telomerase, while somatic cells have none, or very low concentration of telomerase), the catastrophe will cease and the cell is able to avoid death! -However, during this period of genomic instability, numerous mutations would accumulate helping the cell march towards MALIGNANCY!

A/12. Atherosclerosis

Atherosclerosis means hardening of the arteries and generally means arterial wall thickening and loss of elasticity. It is highly related to increased morbidity and mortality in the western world today, and it's pathogenesis underlies many other vascular diseases. There are 3 types of sclerosis of the vessels: -Arteriosclerosis: which affects small arteries and arterioles, and may cause downstream ischemic injury. It's related to hypertension. -Möckenberg medial sclerosis: calcification of the walls of muscular arteries. Related to age, but does not protrude into vessel lumen so does not have very high mortality rate -Atherosclerosis: Is characterized by the presence of intimal atherosclerotic plaques protruding into the vascular lumen. The plaques consist of soft, lumpy lipid cores (cholesterol and cholesteryl esters) which we call necrotic cores, with a fibrous cap on top. This fibrous cap is made up of smooth muscle cells, collagen, macrophages, foamy cells, lymphocytes etc. Atherosclerotic plaques obstruct blood flow as well as weakning the underlying tunica media which can lead to aneurisms, and rupture of the vessel. It is the shoulder of the plaque that is the most fragile and usually the place of rupture MAJOR CAUSITIONAL FACTORS OF ATHEROSCLEROSIS: These factors cannot be changed. -age --> A.S plaque formation is progressive and between 40-60 years of age, the risk of MI increases by 5-fold -gender --> women are protected by estrogen, which means that post menopausal women are at the same risk as men MI + A.S -genetics --> familial predisposition MAJOR MODIFIABLE FACTORS: These factors can be modified to try to prevent the onset and further progression of the disease. -Hyperlipideamia (related to the LDL/HDL ratio). It is the HDL that removes the cholesterol from the cells and brings it to the liver, which is good to keep the cholesterol concentration in the cells low. However, LDL takes the LDL from the liver and deposits it inside the cells. Smoking and lack of exercise increases LDL levels -Hypertension: Increased risk of A.S with 60% on it's own due to the increased mechanical stress put on the endothel of the vessels -Smoking --> 1 pack a year increases A.S by x 200-fold! -Diabetes mellitus: DM induces hypercholesteremia ADDITIONAL RISK FACTORS: -inflammation -obesity -lack of exercise -stress -type A person Fragminhou study There is not a linear relationship between the risk factors and atherosclerosis, but an exponential one where having 2 risk factors increases the risk of athersclerosis double as much (?) PATHOGENESIS -> 2 MAIN THEORIES: ENDOTHELIAL THEORY/ RESPONSE TO INJURY: This theory states that A.S is a chronic inflammation response to endothelial cell injury. Injury to the vessel results in thickening of the tunica intima, however the endothelium is still intact, but dysfunctional. These dysfunctional cells will have increased permeability, increased leukocyte aggregation and gene expression, which are all important contributing factors to atherosclerosis. The two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholestermia. The hemodynamic disturbances are related to places where the flow turns turbulent, which is why A.S plaques tend to occur at opening of vessels, brancing points etc. This explains why the abdominal aorta is such a common place for A.S plaques. Chronic hyperlipidemia causes two important factors to A.S. Lipoproteins will accumulate in the tunica intima and this leads to two pathogenic derivatives: oxidized LDL and cholesterol crystals. This will lead to the macrophages trying to engulfe the ox-LDL through their scavenger receptors and their i.c LDL concentration will increase and they will turn foamy. As soon as there is injury to the vessel endothelium, inflammatory cells will adhere via molecules called vascular cell adhesion molecules 1 (VCAM-1) to bind monocytes and T lymphocytes. Macrophages will start producing ROS that will further oxidize the LDL. The aggregation of inflammatory cells will cause proliferation of smooth muscle cells and ECM, which will generate a plaque from an initial "fatty streak". MONOCLONAL ATHEROSCLEROTIC THEORY: The monoclonal theory states that the cells of any particular plaque are likely to arrive as a clone from a singular progenitor smooth muscle cell. The hypothesis was created based on an observation that a heterozygotic female for the X-linked G-6-P DH who had atherosclerotic plaques, frequently exhibited only ONE OF THE ISOTYPES, A OR B. In a normal, healthy person there would be a mix of the isotypes, but in atherosclerotic plaque, there is only 1 isotype of the enzyme present. Either only A or only B. MORPHOLOGY: Fatty streaks: Appear as yellow, flat macules that elongate 1cm or more. They are composed of lipid-filled foamy macrophages and do not disturb blood flow. They may appear on the aorta of infants and are present in all children above 10 years old. Fatty streaks may involve into plaques, but not all are destined to. ATHEROSCLEROTIC PLAQUES: White to yellow raised patches in the vessel lumen/wall that can range from 0,3cm - 1,5cm in diameter (can be bigger). Are typically found in vessels where the flow turn turbulent. The plaque is composed of: 1) A fibrous cap consisting of smooth muscle cells, macrophages and T cells and collagen 2) necrotic center with cholesterol esters, cell debris, foam cells, calcium PREVENTION OF A.S: Primary: How to raise a child properly: good diet, activity, prevention of smoking (passive smoking from parents) Secondary: When the patient already have symptoms and the aim is to reduce the further progression of A.S Examples: control blood pressure, diet, cholesterol levels, using aspirin to prevent thrombus formation

B/23. Pathological, genetic, immunological and molecular diagnostics of tumors

LABORATORY DIAGNOSIS OF CANCER: -Several sampling approaches exist for the diagnosis of tumors including excision, biopsy, fine-needle aspiration, and cytologic smears. -Immunohistochemistry and flow cytometry studies help in the diagnosis and classification of tumors, because distinct protein expression patterns define different entities - Proteins released into the serum by tumors, such as PSA, can be used to screen populations for cancer and to monitor for recurrence after treatment -Molecular analyses are used to determine diagnosis and prognosis, to detect minimal residual disease, and to diagnose patients with a hereditary predisposition to cancer. Such molecular analysis include FISH (fluorescence in situ hybridization), and array hybridization. -Molecular profiling of tumors by RNA expression profiling, DNA sequencinG, and DNA copy number arrays are useful in molecular stratification of otherwise identical tumors or those of distinct histogenesis that share a mutation for the purpose of targeted treatment and prognostication. -Assays of circulating tumor cells and of DNA shed into blood, stool, sputum, and urine are under development!

B/19. Caracteristics and morphology of preneoplastic disorders

Preneoplastic disorders can be put into two different categories: heriditary and aqcuired. Acquired conditions that predispose to cancer include disorders associated with chronic inflammation, immunodeficiency states, and precursor lesions. Many chronic inflammatory conditions create a fertile "soil" for development of malignant tumors. Tumors arising in the context of chronic inflammation are mostly carcinomas, while immunodeficient states mainly predispose to virus-induced cancers, including specific types of lymphoma and carcinoma. Precursor lesions are localized disturbances of epithelial differentiation that are associated with an elevated risk for dev carcinoma. They may either arise secondary to chronic inflammation or hormonal distrubances, or may occur spontaneously. It is important to recognize precursor lesions because their removal or reversal lowers cancer risk. EXAMPLES OF PRECURSOR LESIONS: -Squamous metaplasia and dysplasia of bronchial mucosa seen in habitial smokers - a risk for lung cancer development -Endometrial hyperplasia and dysplasia seen in women with too much estrogenic stimulation - a risk factor for endometrial carcinoma -Leukoplakia of the oral cavity, vulva and penis which may progress to basal cell carcinoma -Villous adenoma of the colon associated with a high risk for progression to colorectal carcenoma. One can also mention that each benign tumor is associated with a particular level of risk for further malignant development, ranging from high to virtually nonexistant. -Another example is for example liver cirrhosis! HERIDITARY PRECANCEROUS LESIONS: Cancer behaves like an inherited trait in some families, usually due to germ line mutations, that affect the function of a gene that supresses cancer. A good example is APC, adenomatous polypolyposis colon. In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APC gene and sporadic loss of teh sole normal allele causes the development of hundreds of colonic polyps at a young age. These will inevitably develop into colonic cancer! somatic loss of both alleles are seen in 70% of sporadic colon cancers! In contrast, maligant development of leiomyomas of the uterus are extremely rare! - Another example is the risk for breast cancer in females who inherit mutated copies of BRCA1 and BRCA2 tumor supressor genes. If the female inherits one mutation, the chance of getting breast cancer inceases by a 3x fold for women born after 1940.

B/24. Tumor therapy (surgical, radiation, chemo, target molecular and immunotherapy)

SURGERY AND RADIOTHERAPY ARE LOCAL ACTING THERAPIES, CHEMO, TARGETED THERAPY, HORMONE THERAPY AND IMMUNOTHERAPY ARE SYSTEMIC! SURGERY: -Curative vs Palliative surgical intervention -Resection of regional lymph nodes -Role of the pathologist CHEMOTHERAPY: Chemotherapeutic drugs that are alkylating agents are used to treat certain types of tumors. These agents cause DNA damage, which tumor cells are more sensitive to than normal cells are, to kill the tumor cells. However, they are carcinogenic by themselves, and can cause acute myeloid leukaemia. -Cytostatic and cytotoxic drugs -DNA damage, inhibition of the cell cycle/cell division -Independently, or combined with other modalities RADIOTHERAPY: -DNA damage caused by ionizing radiation -After surgery or independently -Combined with chemotherapy „One size fits all" replaced by a Personalised approach to cancer therapy!!! The right drug to the right patient at a right dose at the right time!Cancer Therapy: A success story of personalised medicine--> CML SKRIV MER! IMMUNOTHERAPY: The future looks very bright for cancer immunotherapy and efforts have been made to develop personlised tumor vaccines using neoantigens identified in the tumors of individual patients. mmune checkpoints , which are inhibitory pathways that normally are crucial for maintaining self-tolerance and controlling the size and duration of immune responses so as to minimize colleteral tissue damage. One of the best-characterized immune checkpoints involves a protein called PD-L1 (programmed cell death ligand 1) which is often expressed on the surface of tumor cells. When it binds to it's receptor on CTLs, the cytotoxic T cell becomes unresponsive and lose their ability to kill tumors! The discovery of checkpoints to shut off anti-tumor immunity has led to the development of ab's that block these checkpoints abd release the brakes on the immune response. Current checkpoint blockade therapies have resulted in response rates of solid tumors (melanoma, lung cancer, bladder), and even higher rates in som e hematologic malignancies such as Hodgkin lymphoma!

A/14. Cystic fibrosis

-Cystic fibrosis is an AR disease caused by mutations in the CFTR gene encoding for cystic fibrosis transmembrane regulator PATHOGEN: -The principal defect is of chloride ion transport, resulting in high salt concentrations in sweat and viscous luminal secretions in respiratory and GI tract -CFTR mutations can be severe (like with deltaF508), resulting in multisystem disease or mild, with limited disease extent and severity CLINICAL FEATURES: -Cardiopulmonary complications constitute the most common cause of death: pulmonary infections, especially with resistant pseudomonas or Burkholderia species. Bronchiectasis and right-sided heart failure are soon to follow -Pancreatic insufficiency is extremely common: infertility caused by congenital bilateral absence of vas deferens is a characteristic finding in adult patients with CF -Liver disease, including cirrhosis, is increasing in frequency as life expectancy increases TREATMENT: -Molecular therapies that enhance transport or stability of mutant CFTR protein are useful in patients who harbor certain CFTR alleles.

A/11. Types of fatty degeneration and its organ manifestation

-Degeneration is a form of deterioration. It can be explained as the change of a tissue to a lower or less functionally active form. -Degeneration is sublethal injuries to the cells. It doesn't kill the tissue, but the tissue will have some damages or flaws that can make it less functional. Many of them are related to aging and genetics and can get worse by a poor lifestyle and eating habits. -There are many types of degeneration, and all of them are characterized by accumulation of something inside the cell. For example: Parenchymal degeneration has water accumulation and fatty degeneration has fat accumulation. PATHOGENESIS: Fatty degeneration is the abnormal accumulation of triglycerides within parenchymal cells. It's often seen in cells participating in fat metabolism, like in liver, heart, muscle and kidney. It's also called steatosis. CAUSES: -Toxins -Protein malnutrition -Diabetes mellitus -Obesity -Anoxia (near absence of o2) -Alcohol abuse The most common causes in developed nations are alcohol abuse and nonalcoholic fatty liver disease due to diabetes and obesity. When you drink alcohol, NADH will accumulate and NAD+ will be depleted, and this will result in an increased lipid synthesis. Daily intake of 80g (six beers) alcohol generate a significant risk for severe hepatic injury. However, short term ingestion of e.g. six beers generally produces a mild reversible hepatic steatosis. The liver steatosis can result from these factors: -Exposure to alcohol, dysfunction of mitochondrial and cellular membranes, hypoxia and oxidative stress. -Impaired assembly and secretion of lipoproteins lead to steatosis. -Increased peripheral catabolism of fat MORPHOLOGY: Macro: Macroscopically, the fatty liver of chronic alcoholism is large, can weight up to 4-6 kg and looks yellow and greasy. This increase in weight of the liver is called hepatomegaly. Some fibrous tissue may also develop around the terminal hepatic veins and extend into the adjacent sinusoids with heavy alcohol abuse. This liver fibrosis is called hepatic cirrhosis. Also, in the beginning, the fat will accumulate in only some parts of the liver (centrolobular or peripherolobular) but becomes panlobular with prolonged alcohol consumption. Micro: Microscopically, microvesicular lipid droplets may be seen in hepatocytes in moderate alcohol intake. If there's chronic alcohol abuse, clear macrovesicular globules are present, and they will compress the nucleus of the hepatocytes and eventually displace it to the periphery of the cell. TREATMENT: Total alcohol withdrawal and a special diet is considered sufficient treatment for fatty degeneration, as its reversible. ORGAN MANIFISTATION: -Steatosis may happen in the heart, often due to poor oxygenation. The fat is distributed away from the vessels and produces a "tiger-striped heart". -Accumulation of fat in phagocytic cells is also possible. The fat is usually made up from cholesterol esters= foamy macrophages! -In atherosceloris, smooth muscle cells and macrophages within tunica intima of aorta and big arteries are filled with lipid vacuoles. Most of the lipid vacuoles are made up of cholesterol and cholesteryl esters.

A/13. Amyloidosis

Amyloidosis is a disorder characterized by the extracellular deposits of proteins that are prone to aggregate and form insoluble fibrils. These aggregations consists of improperly folded proteins which are now insoluble causing aggregates. It is called amyloidosis as it's deposits show staining characteristics that resemble those of starch (amylose). Amyloidosis is not a single disease, but a group of diseases that have deposition of similar-appearing proteins in common. CLASSIFICATION: Either by location: -Local. - Nodular, tumor‐like deposits of amyloid on a single organ. -Systemic. - affects more than one body organ or system. or if it's primary(=Primary amyloidosis arises from a disease with disordered immune cell function, such as multiple myeloma, or other immunocyte dyscrasias. → AL) or secondary (=(reactive). Secondary amyloidosis occurs as a complication of some other chronic inflammatory or tissue‐destroying disorder. → AA)! 3 MOST COMMON TYPES: -AL (amyloid light chain) amyloid or just called primary amyloidosis; plasma cell proliferation associated with amyloidosis. This is of the AL type and is usually systemic in distribution! This is the most common form of amyloidosis and is distributed in the systemic circulation. It is caused by a clonal proliferation of plasma cells that synthetize abnormal immunoglobulins. There will be free kappha or lambda light chains which will deposit in the tissues as amyloid, also called a RUSSEL BODY. Myeloma of plasma cells is typical with AL amyloidosis and the prognosis is very bad (2-3 years of living median). -AA (amyloid-associated) amyloid or just called reactive systemic amyloidosis (secondary to inflammation) is composed of a protein derived from proteolysis from a larger precursor called SAA (serum-associated amyloid) produced in the liver. AA amyloid previously belonged to the secondary amyloidosis category, as it is secondary to an associated inflammatory condition. Previously, tuberculosis, bronchitis etc was the most important underlying conditions, but now, these conditions frequently resolve around antibiotic treatment. Today, the most prominent underlying conditions to AA amyloidosis is chron's disease, ulcerative colitis, rheumatoid arthritis. (AA amyloidosis is very common in drug-abusers as they have constant skin infections in their needle holes. This is called "skin-popping"). -Beta-amyloid protein is a peptide derived by proteolysis from APP (amyloid precursor protein) --> ALZHEIMER'S -Transthyretin (TTR) i. This is a serum and cerebrospinal fluid carrier of thyroid hormone T4 (thyroxine) and retinol‐binding protein bound to retinol. ii. This amyloid is found in familial amyloid polyneuropathy and familial amyloid cardiomyopathy as well as senile systemic amyloidosis. 1. Genetic disorder of a carrier protein MORPHOLOGY: Related to enlargement of organs as well as the surface of the organs being waxy. The most important organ taht is affected by amyloid aggregates is the kidney. The amyloid aggregates in the glomeruli, obliterating the capillary lumens with amyloid aggregates causing renal failure!!! This is very dangerous --> fatal. The spleen can be affected in the same way, but in this organ we can see tapioca like granules on gross inspection called sago spleen. The heart can also become enlarged and firm. The aggregations deposits in the subendocardial areas causing restrictive cardiomyopathy. Microscopically, we use congo red staining to stain the amyloid aggregates, or a polarizing microscope. CLINICAL FORMS OF AMYLOIDOSIS: a) Immune dyscresias (primary) ‐ Dyscresia means abnormal mixture. This comes from AL amyloid. Associated with multiple myeloma, light chain precipitation in different organs. These proteins are also secreted into the urine (Bence‐Jones protein). b) Reactive systemic amyloidosis (secondary) - Come from AA amyloid. In this case, the patient has long‐standing inflammation. I.e. auto‐immune diseases. c) Familial amyloidosis - hereditary (Mediterranean fever) - caused by mutation of pyrin (gene defect). Pyrin is a protein which NORMALLY actually stops and decreases the activity and proliferation of polymorphonuclei. So in inflammation, response is proliferation of neutrophils and pyrin comes and reduces the activity. In these patients, however, there is mutation or absence of pyrin and inflammation (IL-1) is kept high. d) Local amyloidosis - Nodular, tumor‐like deposits of amyloid on a single organ. Come from AL light chain. The organ develops a neoplasm; in the neoplasm, amyloid is acting away. This is distinct from the systemic form. e) Endocrine amyloidosis - On certain endocrine tumors. This occurs in those neoplasms which produce endocrine hormones and the hormones are therefore progenitors of the amyloid. APUD are neuroendocrine cells producing serotonin, bradykinin and other hormones. f) Amyloidosis aging - This is transtyrtein related (TTR) deposition. In this amyloidosis, the heart can be affected or the brain can be affected (Senile systemic amyloidosis) g) Nephrotic syndrome h) Restrictive cardiomyopathy / arrhythmia CLINICAL SYMPTOMS: No specific symptoms, however there are some important diagnostic tools we need to know: -Renal involvement gives rise to proteinuria that may be severe enough to cause the nephrotic syndrome, eventually leading to renal failure. -Cardiac amyloidosis may present as congestive heart failure as the aggregates block the conduction of the heart causing arrhythmias, which may prove fatal. -GI amyloidosis may show diarrhea, malabsorption etc. The most common ways of diagnosis of amyloidosis is by biposing the kidney, rectal or gingival tissues in patients suspected to have systemic amyloidosis. In suspected cases of AL amyloidosis, serum and urine protein electrophoresis should be performed. OTHER PROTEIN ACCUMULATION TYPES OF DISEASES: -Excess secretion of protein: Too many proteins in the blood, will make it impossible for the glomerulus apparatus to filter properly and thus the body will loose essential proteins in the urine --> PROTEINUREA (FOAMY URINE DUE TO EXCESS CONC OF PROTEINS). Disease called glomerulonephritis. -Excess production of protein: In nepolastic cells, for example in multiple myeloma, there is excess production of immunoglobulins. The plasma cell starts to accumulate Ig's inside the cell. This is called a Russel body. When the accumulation is within the nuclei of the plasma cell it is called a Ducher body. -Cell injury The hepatocyte may accumulate protein as a result of toxicity due to excess alcohol consumption. This is called a Mallory body. -Folding problems: It is under this category that amyloidosis falls as there is a problem with the folding of proteins by chaperones leading to accumulation of misfolded protein, which are now insoluble and called AMYLOIDS. Another important example of this is alpha-1 antitrypsin isnufficiency. This protein is produced in the liver, and is important in protecting the body against inflammation. It is especially important in the lung where it protects/blocks against enzymes that degrades connective tissue. When there is a insufficiency of this protein, meaning that the degrading enzymes aren't block, the lung CT is broken down leading to EMPHYSEMA!!! The heart must now pump harder to compensate and this leads to hypertrophy of the right ventricle and eventually right sided heart failure!

A/31. Types of emboli

An embolus is a detached intravascular solid, liquid or gaseous mass that is carried by the blood from its point of origin to a distant site, where it often causes tissue dysfunction or infarction. The vast majority of emboli derive from a dislodged thrombus - hence termed thromboembolism. TYPES OF EMBOLI: PULMONARY THROMBOEMBOLISM: Originate from deep venous thromboses and are responsible for the most common from of thromboembolic disease. Depending on it's size, the PE can occlude the main pulmonary artery, lodge at the bifurcation of the R and L pulmonary arteries (saddle embolus). or pass into smaller arterioles. Usually the emboli bypasses the right side of the heart and thus occludes the pulmonary, smaller sized arteries. -Most of the time, a pulmonary embolism is small and clinically silent. The embolus become incorporated into the vessel wall if small enough. -Bigger emboli can cause sudden death -A medium sized embolus of the lung can cause pulmonary hemmorhage, however it doesn't cause anexia of the lung (extreme hypoxia) as the lung has dual blood supply. If the pulmonary artery is occluded, then the lung still receives blood through an intact bronchial circulation, HOWEVER, if the bronchial arteries experience diminshed perfusion like in left sided heart failure, then this can lead to a pulmonary infarct. -Multiple pulmonary embolisms can cause corpulmonale (R.V.H) SYSTEMIC THROMBOEMBOLISM: 80% of systemic thromboembolism arise from intracardiac mural thrombi. 2/3 of which are associated with left ventricular infarcts and dilated left atria. The remainder originate from aortic aneurysms, thrombi overlying atherosclerotic plaques and valve vegetations that have dislodged. -Common arteriolar embolization sites include the lower extremeties and CNS, also kidney's, intestines and spleen which are way less common. -The consequences of the embolism varies, but arterial emboli often lodge in end arteries and cause infarction. FAT EMBOLISM: UNUSUAL Soft tissue crush injury or rupture of bone marrow may cause this, like for example a long bone fracture by releasing microscopic fat globules into the circulation. -The symptoms doesn't show until 1-3 days after the injury in the form of sudden tachypnea (abnormally rapid breathing), tachycardia, irritability and restlessness, which can progress to rapidly to delirium and coma. -Fat emboli occlude both pulmonary and cerebral microvasculature, both DIRECTLY and by triggering platelet aggregation. This deleterious effect is made more severe by fatty acid release from lipid globules, which causes local toxic endothelial injury --> platelet activation and granulocyte recruitment AMNIOTIC FLUID EMBOLISM UNUSUAL This is an example of liquid embolism which is an uncommon, but very grave complication of labor. The mortality rate of this approcahes 80%. -The underlying cause is the entry of amniotic fluid and it's contents into the maternal circulaton via tears in the placental membranes and/or uterine vein rupture. AIR EMBOLISM: This is an example of gaseous embolus. Gas bubbles within the circulation can obstruct vascular flow and cause distal ischemic injury. -This can be caused during a surgery, even one performed laproscopically, which can cause hypoxia and even death -A particular form of gas embolism called decompression sickness is caused by sudden changes in atm pressure. This is mostly associated with scuba divers. When they breathe in at high pressures (like under a deep dive), there is an increased amount of gas being dissolved in the blood and tissues. The gas that most often become dissolved is Nitrogen that bubbles out into the blood as a gas embolus as the diver descends too quickly, causing tissue ischemia. --> Placing affected people in a high pressure chamber forces the gas back into solution as a treatment for acute decompression sickness.

A/52. Single-gene disorders with atypical patterns of inheritance

3 groups of diseases that do not follow Mendalian rules of inheritance! DISEASES WITH TRIPLET REPEAT MUTATIONS: FRAGILE X SYNDROME: -CGG repeats --> leads to mental retardation and is a loss-of-function mutation HUNTINGTON'S DISEASE: -Repeats leads to a gain-of-function type of mutation in a protein (huntingtin) DISEASES DUE TO MITOGCHONDRIAL GENE MUTATIONS: Due to maternal inheritance -Example: LEBER HERIDATARY OPTIC NEUROPATHY which is a degenerative disease causing blindness! DISEASES DUE TO CHANGES OF IMPRINTED REGIONS OF GENOME: PRADER-WILLI SYNDROME: Paternal deletion of chromosome 15, maternal UPD ANGELMAN SYNDROME: maternal deletion of chromosome 15, paternal UPD (Uniparental disomy. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.)

A/53. Pathogeneis of congenital anomalies

A congenital disorder is a medical condition that is present at or before birth. DEFECTS PRESENT AT BIRTH: -MALFORMATIONS: Primary errors of morphogenesis which leads to an abnormal development process -DISRUPTION: Secondary degree destruction of an organ that was previously normal in development --> is extrinsic -DEFORMATION: extrinsic factors which alter the growing of fetus -AGENESIS: Complete absence of an organ -ATRESIA: Absence of an opening, for example biliary atresia -SEQUATION: One alteration, followed by another CAUSES OF CONGENITAL DISORDERS: 1) GENETIC CAUSES: chromosomal alterations and mutations 2) ENVIRONMENTAL CAUSES: infections, drugs, chemicals, radiation, maternal diet (??), alcohol 3) MULTIFACTORIAL INHERITANCE: Examples include cleft lip/palate and neural tube defects! EXAMPLES OF CONGENITAL ABNORMALITIES: PERINATAL INFECTIONS: -Transvisceral (ascending) ascending infections, which include most bacterial and some viral infections -Transplacental infections may pass from mother to fetu --> Examples: Toxoplasm, transcervical infections (passes through amniotic fluid), rubella virus, cytomegalovirus, herpes virus! EARLY IN GESTATION: growth restriction, mental retardation, cardiac abnormalities LATER IN GESTATION: inflammation tissue injury for exmaple pneumonia and myocarditis!

A/39. Type I. and Type II. Hypersensitivity reactions and their pathological presentations

A hypersensitivity reaction is an injurious immune reaction. CAUSES OF HYPERSENSITIVITY REACTIONS: Reaction against self-antigens: Normalle, the body tolerates it's own cells, but in some cases, the self-tolerance fails and the body starts attacking it's own cells. Reaction against microbes: The immune system should react against microbes to get rid of them, however in some cases the immune reaction is too aggressive or the microbe is very persistent and hard to get rid of. Antibodies against microbes are usually not present in the blood for a long time, but if the microbe is persistent can the presence of high levels of antibodies actually cause harm. The antibodies can bind to the microbe antigens and form immune complexes, which can deposit in tissues and cause harm. Persistent microbes also cause prolonged inflammation, which is what causes tissue injury in tuberculosis for example. Environmental factors: When our body has an immune reaction towards non-harmful allergens in the environment like grass, dust and gluten. HYPERSENSITIVITY RXN TYPE 1: PATHOGENESIS: This type of hypersensitivity reaction is also called immediate hypersensitivity because it occurs very quickly (within minutes). It is the type of reaction that occurs in hay fever, seasonal rhinitis, asthma or even anaphylaxis. It begins when an allergen is taken up by an antigen-presenting cell, which will present it to a Th2 cell. The Th2 cell will respond by producing three interleukins, each with different functions: IL-4 stimulates B-cells to start isotype switching to produce IgE antibodies. IL-5 activates and recruits eosinophils to the site of the inflammation IL-13 activates epithelial cells and stimulates mucus secretion B-cells then produce IgE antibodies against the allergen. The Fc-part (not the antigen-binding part) of these antibodies will bind to a type of Fc-receptor on the surface of mast cells called FcεRI. Now that the mast cells are covered in IgE antibodies (that point outward) do we say that the mast cells are sensitized. When the patient with sensitized mast cells meets the allergen later will the allergen not be taken up by antigen-presenting cells but instead bind to the IgE antibodies on the surface of mast cells. This activates the mast cells, causing them to release three groups of molecules: Vasoactive amines like histamine. Adenosine, proteases and chemotactic factors for neutrophils and eosinophils is also released. These molecules are stored in granules inside the mast cell and the granules are released. Histamine causes vasodilation, smooth muscle contraction and increased permeability. Adenosine causes bronchoconstriction and inhibits platelet aggregation. The proteases may damage tissues. Arachidonic acid derivatives, like prostaglandins and leukotrienes. These molecules aren't stored in granules but are instead produced when the activation happens. Prostaglandins cause intense bronchospasm and increases mucus production. Leukotrienes are both chemotactic for neutrophils and are very strong vasodilators and bronchoconstrictors. Cytokines like TNFα, IL-4, IL-5 and IL-13, which amplify the immune reaction by the mechanisms described above. TNFα activates other leukocytes. IMMEDIATE AND LATE RESPONSE OF HYPERSENSITIVTY RXN: The immediate response is characterized by vasodilation, oedema and smooth muscle spasm, which appears 5-30 minutes after exposure to the antigen and ends after 60 minutes. The late-phase response starts 2-24 hours after exposure and is characterized by inflammation and tissue destruction. Eosinophils, neutrophils, basophils, monocytes and Th2-cells are important in this reaction. Mucosal epithelial damage occurs. CLINICAL MANIFISTATIONS: Clinical manifestations of type 1 hypersensitivity range from just annoying to life-threatening. Local hypersensitivity reactions like hay fever or grass or gluten allergy, cause symptoms like urticaria, diarrhoea or running nose. Systemic reactions however can cause anaphylactic shock, which can occur in bee, peanut or penicillin allergies for example. The tendency to have type 1 hypersensitivity reactions has a genetic component, and patients with this tendency are said to have atopy. Patients who have atopy usually develop one or more of the following: eczema, hay fever or allergic asthma. If someone has one of these conditions is the probability of also having the others high as well. It can be local or systemic depending on the route of exposure. If it is local the antigen is confined to a particular site. For example: GI --> diarrhea. Inhalation --> bronchoconstriction. Usually skin and food allergies, hay fever, some asthma forms. Systemic examples: protein antigens (e.g. bee venom) or drugs (e.g. penicillin). Causes itching, hives, systemic vasodilation --> anaphylactic shock --> death. HYPERSENSITIVITY REACTION 2: PATHOGENESIS: This type of hypersensitivity, also called antibody-mediated hypersensitivity is characterized by the body producing antibodies against antigens it should normally leave alone, like host antigens or harmless exogenous antigens. Opsonization is an important term here. Normally, when a bacterium or virus enters the body will the immune system produce antibodies against them. These antibodies will bind to and cover the pathogen. Opsonization is the term for covering something in antibodies. Complement factors like C3 can then bind to the opsonized pathogen. What happens next is that phagocytes like macrophages and neutrophils can phagocytose the pathogens by recognizing the opsonization. Phagocytes carry receptors that recognize both the complement factors and antibodies and use these receptors to bind and ingest the pathogen. Opsonized pathogens that aren't phagocytosed will be eliminated in the spleen. What we call "mediated cell phagocytosis" Inflammation occurs because the complement system is activated (via the classical pathway) by opsonized pathogens or cells. The complement system has many functions, and one of them is to cause inflammation. Leukocytes (that aren't phagocytes) can also recognize the opsonized cells and cause inflammation. "Antibody-mediated inflammation." Antibodies can disrupt cell function in other ways as well, without causing phagocytosis and inflammation. As is the case in myasthenia gravis will antibodies bind to nicotinic acetylcholine receptors in neuromuscular junctions (without activating the receptor). When the acetylcholine receptors are occupied by antibodies can they not bind acetylcholine, effectively paralyzing the muscle. In Graves disease will antibodies bind to the TSH receptors found on thyroid epithelial cells, and activate the receptors (unlike in m. gravis). This tricks the thyroid to believe that the levels of TSH in the blood is very high, which stimulates the thyroid to produce more thyroid hormones, causing hyperthyroidism. EXAMPLES: -Graves disease -Myasthenia Gravis -Autoimmune haemolytic anemia -Acute rheumatic fever -Goodpasture syndrome

B/29. Angina pectoris, chronic ischemic heart disease

ANGINA PECTORIS: Angina pectoris is an intermittent chest pain caused by transient, reversible myocardial ischemia. The pain is a consequence of ischemia-induced release of adenosine, bradykinin, and other molecules that stimulate autonomic nerves. 3 important forms exist: Stable angina is the most common form. A critical stenosis is present, but the perfusion of the myocardium is still sufficient in rest. However, as soon as the myocardial blood requirement increases, such as during walking up stairs or exercise, will the perfusion be insufficient for the myocardium. This causes the angina pectoris pain. Symptoms are relieved upon rest or after application of nitro-glycerine, a vasodilator. Prinzmetal's angina/varient angina isn't associated with coronary artery disease at all, although it can also be present. In Prinzmetal's angina is there a strong vasospasm of an epicardial artery, which decreases the perfusion. This type of angina is unrelated to physical activity, heart rate or blood pressure. This type of angina typically responds promptly to vasodilators such as nitroglycerin and calcium channel blockers! Unstable angina/crescendo angina is the condition where angina pectoris can occur even in rest. Morphologically it happens because of a thrombosis stuck to a plaque, which is kinda loose so it sometimes blocks the artery and sometimes not. Unstable angina is usually a warning sign that an acute myocardial infarct may occur in the near future. CHRONIC ISCHEMIC HEART DISEASE (CIHD): Chronic IHD (or ischaemic cardiomyopathy) is a progressive heart failure that occurs due to ischaemic myocardial damage. The myocardial damage is often due to a previous myocardial infarct, but in some cases can severe coronary artery disease cause myocardial ischaemia and dysfunction without infarction or symptoms. The healthy myocardium that isn't damaged by ischaemia will always try to compensate for the damaged myocardium. Left ventricular hypertrophy and dilation are usual findings, along with fibrosis of the damaged myocardium. Microscopically we find myocardial hypertrophy, fibrosis and diffuse subendocardial vacuolization.

B/39. Arteriolosclerosis

Arteriosclerosis literally means "hardening of the arteries", and reflects arterial wall thickening and loss of elasticity! FOUR DISTINCT TYPES ARE RECOGNIZED: ARTERIOSCLEROSIS: affects small arteries and arterioles and may cause downstream ischemic injury. There are two varients to it: -HYALINE ARTERIOSCLEROSIS: that is associated with benign hypertension, and is marked by homogeneous, pink hyaline thickening of the arteriolar walls, with loss of underlyingstructural detail and luminal narrowing! It stems from increased ECM production by smooth muscle cells in response to chronic hemodynamic stress. It is especially important in the kidney's as it leads to nephrosclerosis! It is said to be more generalized -HYPERPLASTIC ARTERIOSCLEROSIS: is more typical and severe in people with hypertension. Here, the vessel exhibit "onion skin" with concentric, laminar thickening of the wall plus luminal narrowing. Necrotizing arteriosclerolitis may occur, especially in the kidney. MöNCKEBERG MEDIAL SCLEROSIS: is characterized by the presence of calcific deposits in muscular arteries, usually in the internal elastic lamina, and is typical for people over the age of 50. It is not very clinically important as the lesions do not protrude into the lumen of the vessel. FIBROMUSCULAR INTIMAL HYPERPLASIA: is a non-atherosclerotic process that occurs in muscular arteries larger than arterioles. It is a process driven by inflammation, predominantly SMC-and-ECM rich process, or by mechanical injury. It is the major long-term limitation of solid organ transplants ATHEROSCLEROSIS: is from greek and means gruel hardening. it is the most frequent and clinically important pattern of these types.

B/26. Right-sided heart failure

CAUSES: Right sides heart failure is usually the consequence of left-sided heart failure, since ANY pressure increases in the pulmonary circulation inevitably produces an increased burden on the right side of the heart. -Isolated right sides heart failure is often referred to COR PULMONALE as it typically occurs due to lung disorders, however the symptoms do not have to do with bad respiration!!! -It's main cause is increased pulmonary hypertension! MORPHOLOGY: -congestive hepatomegaly --> nutmeg liver. When left-sided heart failure also is present, severe central hypoxia produces CENTRILOLOBULAR NECROSIS, with long standing right-sided heart failure, these areas become fibrotic and are called CARDIAC CIRRHOSIS! -Portal hypertension -Splenomegaly -Pleural, pericardial and peritoneal effusion! -Subcutaneous edema of feet and lower legs are said to be a hallmark for right-sided heart failure. CLINICAL FEATURES OF RS HEART FAILURE: SYMPTOMS: Not respiratory related! But related to systemic and portal venous congestion, ascites, hepatic and splenic enlargement etc. as CHF progresses, patients may become frankly cyanotic and acidotic, as a consequence of decreased tissue perfusion resulting from diminshed CO and increased congestion!

A/58. Techniques for identifying infectious agents

CLINICAL SIGNS: Most infectious diseases present with some clinical signs. They depend however on the immune states of the host and the virulence of the microbe. We need history, physical examination, radiographic findings and laboratory data. MICROBIAL EXAMINATION: -Direct examination techniques shows us the gross pathology and included microscopy and immunofluressence/immunassays, these detect specific microbial antigens. MICROSCOPY: 1. Some can be seen in HE stains, some need special stains. 2. E.g. gram stains for bacteria 3. Acid fast stain for mycobacteria, nocaridae 4. Silver stains for fungi, legionella, Pneumocystis 5. PAS stain for fungi, amebae 6. Mucicarmine for cryptococci 7. Geimsa for Leishmaniae, Plasmodium -Culturing: can be used in most cases, but is not as sensitive as molecular techniques. We both have nonselective media which will allow any organism to grow, and selective media that only allows certain cultures to grow -Serological antibody identification which can be used to identify if there is an acute infection or has been an infection previously. --> Ab titers -Nucleic acid tests / molecular diagnostics i. DNA probes can be used to identify the agent on species level ii. PCR: nucleic acid amplification

B/18. Epidemiology of neoplasms

Cancer is the second cause of death in the united states! CAUSES: EXTERNAL FACTORS: -Tobacco (NUMBER 1) -alcohol -chemicals -radiation -microbial pathogens INTERNAL FACTORS: -Hormones -Immune conditions -Inherited mutations RISK FACTORS: -Age is an important risk factor for cancer. Cancer incidence increases with age, usually by the age of 55. Especially, colorectal, lung and prostate cancers increase wiht age, whereas malignant melanoma peak and then decreases with a certain age. -Racial differences also affect cancer development. Melanoma is more common in countries where their skin is more fair as they do not have such high concentrations of melanin and it's thus a decreased amount of it's protective function. African-americans have a higher risk at developing prostate cancer, while japense people have a higher risk at developing stomach cancer. CANCERS IN CHILDREN: Malignant neoplasm is the leading cause of death (non-injurious ) in kids from 1-14 years. -Top 3 cancers: -->Leukemia (AML) -->CNS -->Neuroblastoma TOP 3 CANCERS IN MEN: -Prostate -lung -colorectal TOP 3 IN WOMEN: -breast -lung -colorectal PREVENTION: 1) Lifestyle: stop smoking cigarettes, reduce weight (more adipocytes= more aromatase activity to produce more estrogens which increases the risk of breast cancer), reduce diatery saturated animal fat (colorectal cancer), reduce alcohol consumption, use sunscreen protection! 2)Immunization: -HBV vaccination: decreases the risk to develop hepatocellular cancer due to HPV-induce postnecrotic cirrhosis -HPV vaccination: decreases risk of developing squamous cell carcinoma at the cervix or penis 3)Screening: -Cervical papanicolaou (PAP SMEAR), decreases the risk of cervical cancer due to HPV 16, 18. -Colonoscopy -Mammogram -Prostate-specific antigens: too sensitive to be diagnostic, as benign hyperplasia of the prostate can cause a false positive answer 4) Treatment of conditions that can be pre-disposed to cancer development: -Treatment of Helicobacter pylori infections decreases the risk of developing malignang melanoma, but it does not decrease the risk of developing adenocarcenoma in the stomach -Treatment of GERD, decreases the risk of developing distal adenocarcenoma due to Barrett's esoph.

B/07. EGFR, ABL and BCL2 genes and their roles in tumor development

Cancers may secrete their own growth factors or induce stromal cells to produce GF's in the tumor microenvironment. Most soluble GF's are produced by one cell, where the receptor is not expressed on that cell, but another one leading to PARACRINE SIGNALLING! Tumor cells break this, by both expressing GF's and having it's receptor, so that they can continue to grow and proliferate uncontrollably = SELF-SUFFICIENCY! EGF AND EGF-R (CALLED ERBB1): -ERBB1 is a gene for another growth factor receptor. The growth factor in this case is epidermal growth factor (EGF). ERBB1 is overexpressed in: 80% of lung squamous cell carcinomas >50% of glioblastomas 80-100% of head and neck carcinomas -ERBB2, also called HER2, is another tyrosine kinase receptor, however we still don't know its physiological ligand. HER2 is overexpressed in: 15-25% of breast carcinomas Adenocarcinomas of ovary, lung, stomach and salivary glands Biological treatment for HER2 positive breast carcinoma is a monoclonal antibody called herceptine. These antibodies cause the breast carcinoma cells to internalize the HER2 receptor, limiting its harmful potential and effectively treating the cancer. ABL: -ABL is a proto-oncoprotein with tyrosine kinase activity, which is dampened by integral negative reg pathways. -It regulates processes of cell differentiation, cell division, and cell adhesion. Translocation between chromosome 9 and 22, creates a hybrid called PHILIDELPHIA CHROMOSOME that will put the ABL of the 9q on the BCR gene of 22p, thus creating tyrosine kinase activity and downstream signal transduction --> lead to CML in 90% of cases!! The crucial role of BCR-ABL in cancer has been confirmed by the dramatic clinical response of patients with CML to BCR-ABL inhibitors BCL: -It is the Bcl-2 which controls the permeability of the mitochondrial membrane. It does so by holding Bak and Bax in check by interacting with growth factors etc. When cells are deprived of growth factors and survival signals, accumulate misfolded proteins or are exposed to damaged DNA, BH3 sensors are activated causing Bak-Bax to dimerize. This dimerization move into the mitochondrial membrane, forming pores in which cytochrome C can leak out. After the protein cyt-c enters the cytosol, it activates caspase-9, leading to more activation of other caspases. -Some cancers avoid cell death by overexpressing anti-apoptotic members of the BCL2-family, such as BCL2, BCL-XL and MCL 1, which protect against the action of BAK and BAX (the pro-apoptotic members of the family -In a large majority of follicular B cell lymphomas, bcl2 levels are high due to a translocation (14;18) that fuses the BCL2 gene with regulatory elements of the ig heavy chain gene. -THERAPUTIC AGENTS AGAINST THIS ARE BEING DEVELOPED, by giving inhibitors of the BCL2 family members to try and induce the death of cancer cells through stimulation of the intrinsic pathway of apoptosis.

B/15. Chemical and radiation carcinogenesis

Carcinogenic agents inflict genetic damage, which lies at the heart of carcinogenesis CHEMICAL CARCINOGENS: More than 200 years ago, a london surgeon correctly attributed scrotal cancer in chimney sweeps to chronic exposure to soot. On the basis of the same observation, the Danish Chimney sweep guild ruled that every member of its guild must take a bath every day. -Chemical carcinogens have highly reactive electrophile groups that directly damage DNA, leading to mutations and eventually cancer!!!!!!!! -Directly-acting agents do not require metabolic conversion to become carcinogenic, while indirectly-acting agents are not active until converted to an ultimate carcinogen by endogenous metabolic pathways. Hence, polymorphisms of endogen. enzymes such as cytochrome p450 may influence carcinogenesis by altering the conversion of indrect-acting agents to active carcinogens -After exposure of a cell to a mutagen or an initiator, tumorigenesis can be enhanced by exposure to promoters, which stimulate proliferation of the mutated cells. -Examples of human carcinogenes are direct-acting agents (e.g alkylating agents used for chemotherapy as they are quite weak), indirect-acting agents (e.g benzo(a)pyrene, azo dyes, aflatoxin) and tumor promoters EXAMPLES OF INDIRECT ACTING CHEMICAL AGENTS: Tobacco from cigarette smoking: polycyclic hydrocarbons: benzopyrene is transformed to epoxide with increased temperature (combustion) → carcinomas of oropharynx, esophagus, lung, kidney, and bladder. --> These are also found in burning fossil fuels. --> Similar can be produced from smoking fish / meat → nitrites → stomach carcinoma . -2‐Naplithylamine from cigarette smoke → aromatic amines, amides → urothelial carcinomas of the bladder. -Aspergillus in stored grains → aflatoxins → hepatocellular carcinoma (mutation in p53). - Alcohol → squamous cell carcinomas of oropharynx / upper esophagus, pancreatic carcinoma, hepatocellular carcinoma. -Asbestos → lung carcinoma. - Insecticides, fungicides. - Nickel, chromium. - Vinyl chloride. - Nitrites → food preservatives. They cause nitrosylation of amines contained in the food. RADIATION CARCINOGENESIS -Ionizing radiation caused by X-rays and gamma rays: causes chromosome breakage, chromosome rearr., and, less freq, point mutations, any of which may affect cancer genes and thereby drive carcinogenesis. Cancers induced by this are: AML, CML and papillary carcinomas of the thyroid. -Non-ionizing radation: UV rays in sunlight induce the formation of pyrimidine dimers within DNA, leading to mutations that can give rise to squamous cell carcinomas and melanomas of the skin!

A/36. Chronic inflammation, fibrosis, scarring

Chronic inflammation is a prolonged host response to persistant stimuli that may follow unresolved acute inflammation or it may be chronic from the onset. It is caused by microbes that resist elimination, immune responses against self and environmentalantigens, and some toxic substances (for example silica). It is characterised by coexisting inflammation, tissue injury, attempted repair by scarring and immune response. The cellular infiltrate consists of macrophages, lymphocytes, plasma cells, and other leukocytes. It is mediated by cytokines produced by macrophages and lymphocytes (notably T lymphocytes), bidirectional interactions between these cells tend to amplify and prolong the inflammatory reaction. Granulomatous inflammation is a morpholigical specific pattern of chronic inflammation induced by T cell and macrophage activation in response to an agent that is resistant to eradication. FIBROSIS: Composed of largely, inactive, spingle-shaped fibroblasts, dense collagen, fragments of elastic tissue and other ECM materials. Pathologists often use special stains to identify different protein constituents of scar and fibrotic tissues. The trichrome stain detects collagen fibers, and the elastin stain. Reticulin is also typical to view in fibrotic tissues and contain large amounts of type 3 collagen which can be stained black using an iron staining or Van gieson staining. SCAR FORMATION: The main steps in repair by scarring are clot formation, inflammation, angiogenesis and formation of granulation tissue, migration and prolif of fibroblasts, collagen synthesis and CT remodeling. Macrophages are critical for orchestrating the reapir process by eliminating offending agents and producing cytokines and growth factors that stimulate the prolif of the cell types involved in repair. TGF-beta is a potent fibrogenic agent; ECM deposition depends on the balance among fibrogenic agents, matrix metalloproteinaseses (MMPs), that digest the ECM and the tissue inhibitors of MMPs called TIMPs.

A/04. Coagulative necrosis and its organ manifestation

Coagulative necrosis is a form of underlying tissue necrosis, where the architecture of the tissue is preserved for several days after cell death, meaning that the affected tissue take on a firm texture. This is because the necrosis inactivates not only proteins, but also enzymes, thereby blocking the proteolysis of the dead cells. Leukocytes are recruited to the site of necrosis, and the dead cells are ultimately digested by action of lysosomal enzymes of the leukocytes!!!! Coagulative necrosis (a "pale infarct") is often due to interruption of blood supply, causing tissue ischemia and intracellular accumulation of lactic acid. Lactic acid buildup induces protein denaturation, followed by enzymatic break down and nuclear chromatin clumping to inhibit protein synthesis. This presents microscopically as pale, pink tissue with its architecture generally preserved for 1-2 days. Grossly, tissue that has undergone coagulative necrosis is firm. Pale infarcts occur in organs supplied by end arteries with limited collateral circulation (e.g. spleen, heart, kidney). The school calls pale infarcts "anaemic". Coagulative necrosis is characteristic of infarcts (areas of necrosis caused by ischemia) in all solid organs EXCEPT THE BRAIN. In a renal infarction for example, the fibroblasts around the necrotic area will create a fibrotic tissue that will pull the sides of the area making an indentation. There is usually no symptoms of a renal infarction, as the rest of the kidney compensates for the necrotic area. (Hemorrhagic necrosis (a "red infarct") occurs when hemorrhage is superimposed upon coagulative necrosis in organs with dual blood supply (liver, lungs, in loose organs (testes), or in organs following reperfusion (myocardial infarct following t-PA infusion).)

B/37. Cor pulmonale

Cor pulmonale results from pulmonary hypertension due to primary lung parenchymal or vascular disorders. Hypertrophy of both the right ventricle and right atrium is characteristic; dilation may also be seen when failure supervenes! Cor pulmonale can be both acute in onset, or slow and insidious.In acute, the ventricle only shows dilation, and if an embolism causes sudden death, the heart might even be of normal sze. In chornic, the right ventricular and often atrial chamber dilates. It may even exceed the wall of the LV if the hypertrophy is severe enough. The pulmonary arteries often contain atheromatous plaques and other lesions, which reflects long-standing pressure elevations. ACUTE COR PULMONALE: Is due to a pulmonary embolism that will obstruct more than 50% of the pulmonary blood supply, which leads to dilation of the right ventricle SUBACUTE CORPULMONALE: Often due to lung metastasis, we will have dilation and hypertrophy of right ventricle! CHRONIC CORPULMONALE: Is secondary to prolonged pressure overload caused by emphysema, interstiital pulmonary fibrosis, primary pulmonary HTs. The consequences will be that we will have both ventricular and also atrial hypertrophy and dilation (right) which may develop into ventricular failure due to arrhytmias etc. Also, due to the increased pulmonary pressures, pulmonary arteries may contain atherosclerotic plaques and other lesions!

A/51. Cytogenetic disorders caused by chromosomal aberrations

Cytogenetics = the study of chromosomes (karyotyping) There can be numerical abberations (=polyploidy, aneuploidy) or structural abberations (translocation, deletion, amplification, inversion, isochromosomes, ring chromosome formation etc) NUMERICAL ABBERATIONS SOMATIC CELLS: 1) TRISOMY = DOWN'S SYNDROME -Chromosome count = 47 -Caused by mitotic non-disjunction -The frequency of the disease increases with age -CLINICAL FEATURES: --epicanthic folds --severe mental retardation --short neck --congenital heart defect --suscebtability to leukemia 2) TRISOMY 13 = PATAU SYNDROME: -Symptoms: small head, cleft lip, polydactylyl 3) TRISOMY 18 = EDWARD'S SYNDROME: -Caused by nondisjunction during oogenesis -symptoms include clenched fist showing overlapping fingers, rocker bottom feet, congenital heart defects, micrognathia, mental retardation; usually patients die within a few years of life NUMERICAL ABBERATIONS INVOLVING SEX CHROMOSOMES: TURNER SYNDROME: -45, X0 -ONLY VIABLE MONOSOMY -Hypogonadism -short stature -webbing of neck -High BP KLINEFELTER SYNDROME: -47, XXY -Hypogonadism -gynecomastia -testicular atrophy -infertility!!! STRUCTURAL ABBERATIONS: A) CRI DU CHAT SYNDROME: -5P deletion (short arm of cs 5) -Baby will have moonface and cry like a cat B) DIGEORGE SYNDROME: -22q 11.2 deletion!! -Cardiac defects

A/30. DIC

DIC (disseminated intravascular coagulation) is a widespread thrombosis within the microcirculation that may be of sudden or insidious onset. It has two phases: -Thrombotic phase: Microthrombi develop in the capillaries of all organs due to endothelial damage and stasis of blood flow. This depletes the blood of clotting factors as well as platelets and coagulation factors -Consumptional coagulopathy: Because the above mentioned phase, there will be no more clotting factors causing bleeding. You will have a patient that will both exhibit excessive clotting and bleeding at the same time! The thrombi are microscopic, but so many that they together can cause a circulatory insufficiency in brain, lungs, heart and kidneys. Capillary blood becomes filled with microthrombi so it resembles sludge, which obviously doesn't circulate well. OBSTETRIC CAUSES (=related to child birth) OF DIC (MOST COMMON EARLIER DURING CHILD BIRTH) Amniotic fluid embolism Ecclampsia Placental abruption CAUSES: -infections - gram positive bacteria --> sepsis --> toxin release, coagulative system increases -neoplastic diseases: acute promyelocytic leukemia -trauma COMMON LOCATION: -kidney --> sweeling of endothelial cells, glomerulolitis, infarcts in cortex and cortico necrosis -adrenals --> water house fredriksen syndrome (defined as adrenal gland failure due to bleeding into the adrenal glands, commonly caused by severe bacterial infection. Typically, it is caused by Neisseria meningitidis.) -brain --> hemmorhage Acute DIC --Z bleeding Chronic DIC --.> thrombosis SIGNS OF DIC: -thrombocytopenia -prolonged PT and PPT DIC is not a primary condition but instead always appears secondary to other conditions, such as shock. The DIC can be triggered by extrinsic pathway or intrinsic pathway.(THE PATHOGENESIS IS THE INTRINSIC AND EXTRINSIC PATHWAYS)

A/56. Transmission and Dissemination of microbes

DISSEMINATION/SPREAD OF MICROBES: Some microorganisms, proliferate locally, at the site of initial infection, whereas others penetrate the epithelial barrier and spreasd to distant sites by way of the lymphatics, the blood and the nerves. In contrast to those who disseminate, pathogens can cause superficial infections and stay confined to the lumen or hollow viscera, or interact exclusively with epithelial cells like the human papilomaviruses for example. Microbes can spread within the body in several ways: Lysis and invasion: Some e.c bacteria, fungi and helmiths secrete lytic enzymes that destroy tissues and allow direct invasion. An example is staphylococcus auerus which relases hyaluronidase which degrades the ECM between the host cells. Through blood and lymph: Microorganisms may either spread throgh the e.c fluid or within host cells. Many microorganisms are transported in the plasma. Leukocytes can for example carry herpesvirus and HIV. Through cell-to-cell transmission: Most viruses spreasd locally from cell-to-cell by replication and release of their infectious virions. The consequence of bloodborne spead of pathogens vary widely depending on the virulence of the organism, the magnitude of the infection, the pattern of seeding, and host factors such as immune status. The major manifistations of infectious disease may appear at sites distant from the point of microbe entry. Ex: measles virus that enter trhought the airways, but cause rashes on the skin. TRANSMISSION OF MICROBES: Transmission depends on the hardiness of the microbe. Some microbes can survive for extended periods in dust, food or water. Transmission of infections can occur via: Contact (direct and nondirect): The skin acts as a protective barrier with it's tough keritinized barrier, low pH, Fa's and normal microbiotica Respiratory droplets: IgA antibodies are present in mucosal barriers to protect our body of pathogens. The resp tract also contains alveolar macrophgaes and mucociliary clearance by bronchial epithelium Fecal-oral route: The GI has an acidic gastric pH, viscious mucous, pancreatic enzymes and bile, defensins, IgA and normal flora Sexual transmission: The urogenital tract has repeated flushing and acididc environment created by commensal vaginal flora. Vertical transmission from mother to fetus or newborn: Via placenta or breast milk Insects/arthropod vectors

B/32. Degenerative valvular heart disease (calcific aorta stenosis, mitral prolapse)

Degenerative valve disease is a term used to describe changes that affect the integrity of valvular ECM. Degenerative changes include the following: DEGENERATIVE CHANGES: -Calcifications: which can be cuspal (typically in the aortic valve) or annular (in the mitral valve). Mitral annular calcifications usually are asymptomatic unless it affects the adjacent conduction system. -Alterations in the ECM: Some changes can be due to an increase in the proteoglycan concentration, or alternatively diminished fibrillar collagen and elastin, in which the valve becomes fibrotic and scarred! -Changes in the production of matrix metalloproteinases or their inhibitors. -Degenerative changes in the cardiac valves is an ineviatble aspect of aging related to the perspective of mechanical stresses to which the valves are subjected to over the years! CALCIFIC AORTA STENOSIS: CAUSES: -Is the most common cause of aortic stenosis (calcification is). -In most cases it's asymptomatic and is only discovered at an autopsy, or at a routine check-up chest radiograph! -If it is severe, then surgery is a necessity! -One can also view valvular calcification as a counterpart to age-related arteriosclerosis, thus, hyperlipidemia, hypertension, chronic inflammation are said to contribute to valvular diseases, as well as arteriosclerosis MORPHOLOGY: -The hallmark of calcific aortic stenosis is HEAPED-UP CALCIFIED MASSES ON THE OUTFLOW SIDE OF THE CUSPS, THUS HINDERING THEM FROM OPENING PROPERLY! CLINICAL FEATURES: -In severe cases, the valve orifices can be comprimised as much as 70-80%. -CO is therefore maintained only by virtue of concentric LV hypertrophy, but the hypertrophied myocardium is prone to ischemia and angina may develop. -Systolic and diastolic dysfunction may lead to CHF (congestive heart failure). -This carries a poor prognosis and 50-80% of the patients die within 2-3 years MITRAL VALVE PROLAPSE/ MYXOMATOUS MITRAL VALVE: -Refers to the scenario where one or both mitral leaflets are floppy and prolapse, baloon back into the left ventricle during systole. PATHOGENESIS: There are two types: --> PRIMARY, which is the most common form, where women are affected as much as 7-fold more than men. We do not know the cause of this, but believe it has to do with an intrinsic defect of CT synthesis, which is why mitral valve prolapse is a common feature in MARFAN SYNDROME, where fibrillin-1 is mutated. --> SECONDARY, affects men and women equally and can occur in any setting where mitral regurgitation is caused by another underlying tissue. Secondary myxomatous change presumably results from injury to the valve myofibroblasts, imposed by chronically abberent hemodynamic forces. MORPHOLOGY: -It is characterized by the ballooning/hooding of the mitral leaflets. -The affected leaflets are enlarged, redundant, thick and rubbery, in which the cordae tendinae also tend to be elongated, thinned and eventually ruptured! -In those with primary mitral prolapse, concomitant tricupsid valve involvement is frequent. -Histologically, the valve's fibrosa layer is thinned, and there is an expansion of the middle spongiosa layer due to the increased deposition of myxomatous (mucoid) material. CLINICAL FEATURES: -Most patients are asymptomatic, and the disease is discovered incidentially! -In few of the cases, the patients complain of dyspnea, atypical chest pain. -The physician may hear a midsystolic click, due to the abrupt tension caused by the chordae tendinae when the valve tried to close. -Patients with primary mitral prolapse are at increased risk for the development of inefective endocarditis, as well as SCD due to ventricular arrhythmias. Stroke may also occur.

A/61. Pathology of alcohol-related disorders

EFFECTS OF ALCOHOL: When used in moderation, the effects of alcohol are non-injereous. With excessive use however, alcohol causes physicaø and psychological damage. 5-10% of adults in the western world have chronic alcoholism. 50% of related alcohol deaths are due to drunk driving and alcohol-related homicides. 25% of deaths are due to cirrhosis of the liver. MECHANISMS OF MOOD ALTERATION AND PROCESSING: Consumpted alcohol is absorbed in the stomach and small intestine and teh distributed to all tissues and fludis of the body through the blood. Less than 10% of the alcohol is excreted unchanged in the kidney's, sweat and breath. The individual rate of metabolism affects the blood alcohol levels. Thus people with chronic alcoholism can tolerate higher levels due to a 5-10x increase in cyt p-450 enzyme in the liver!!! MOST OF THE ALCOHOL IN THE BLOOD IS METABOLIZED TO ACETALDEHYDE IN THE LIVER BY 3 MECHANISMS: 1) ALCOHOL DEHYDROGENASE, which is found in the cytosol. Causes a decrease in available NAD+ and an increase in NADH. NAD+ is needed for fatty acid ox in the liver, this it's def causes an increase of fat accumulation in the liver! 2) CYT P-450 ISOENZYMES: also called the microsomal ethanol-oxidizing system. The most common enzyme is CYP2E1! The mtabolism by this enzyme results in ROS production and lipid peroxidation if cell membranes. It is located in the SER. --> Because this system is upregulated in chronic alcoholics, it means they have increased susceptibility to other compounds also metabolized by this system (cocaine, acetaminophen, anesthetics, carcinogens and industrial solvents). If alcohol is in thei system, administering drugs will potentiate their effects since alcohol competes for this system with them 3) CATALASE: Acetaldehyde has many toxic effects. It might cause some of the acute effects seen with alcohol consumption. Metabolism of acetyldehyde is different in various populations An example includes that 50% of asians have a defective from of acetaldehyde dehydrogenase. Meaning that after ingestion of alcohol, the present with flushing, tachycardia and hyperventiliation due to acetaldehyde acc. STAGES OF DRUNKENESS: -Drunk: 80mg/dL of alcohol in the blood -drowsiness: 200mg/dL -stupor: 300mg/dL -any higher and there is a possibility of coma and respiratory arrest. ACUTE ALCOHOLISM: -CNS effects: Alcohol is a depressant, which affects first the subcortical areas that modulate cerebral cortical activity. Then there is stimulation and disordered cortical, motor and intellectual behaviour. At higher blood levels, cortical neurons and lower medullary centers are depressed, including those for respiration. -Liver effects: Even with small amounts of alcohol intake, there is FATTY CHANGE/ STEATOSIS -Stomach effects: Gastric damage occurs by means of acute gastritis and ulceration. CHRONIC ALCOHOLISM: WILL AFFECT ALL ORGANS AND TISSUES. These people suffer from significant morbidity and have a shorter life span, mostly due to damage of the liver, GI tract, CNS, cardiovascular system and pancreas. -Liver: Main site of chronic injury. Fatty change. Alcohollic hepatitis and cirrhosis. This leads to portal hypertension and increased risk of hepatocellular carcinoma -GI tract: massive bleeding from gastritis, gastric ulcer, esophageal varices, which can be fatal -Thiamine deficiency: leads to lesions. Peripheral neuropathies and Wernicke-Korsakoff syndrome. Can also lead to cerebral atrophy, cerebellar degeneration and optic neuropathy. -Cardiovascular system: Myocardial injury leads to dilated congestive cardiomyopathy (also called alcoholic cardiomyopathy). Chronic alcohlism leads to increased hypertension, decreased levels of HDL and increased risk of coronary heart disease. NB!: Moderate levels of alcohol consuption leads to increased levels of HDL and inhibition of platelet aggregation, which can protect against coronary heart disease. -Pancreas: Acute and chronic pancreatitis risk increases -During pregnancy: Fetal alcohol syndrom risk increases. INcludes microcephaly, growth retardation and facial abnormalities in the newborn, and reduced mental function in oler children. Consumption during the first trimester is most harmful!!!! -Cancer risk increase --> oral cavity, esophagus, liver and breast -Malnutrition and deficiencies --> especially vit B!

A/60. Pathology of smoking-related disorders

ENVIRONMENT: various outdoor, indoor and occupational settings in which humans live and work. It includes the air breathed, food and water consumed and toxic agents people are exposed to. -PERSONAL ENVIRONMENT: refers to tobacco use, alcohol ingestion, therapeutic and "recreational drugs" diet etc. These tend to have a larger effect in human health. -ENVIRONMENTAL DISEASE: disorders caused by exposure to chemical or physical agents in the ambient, workplace and personal environments. These are common. Especially when there is chronic exposure to relatively low levels of contaminants. TOBACCO: Is the most common exogeneous cause of human cancers (90% of lung cancer). Usually due to cigarette smoking, but can also be the snuff, chewing tobacco or holding cigars in the mouth (oral cancer). There is a personal risk, but also a secondary one of passive inhalation of the environment. Smoking usually leads to cardiovascular disease, cancer formation and chronic respiratory problems. Smoking is the most preventable cause of human health! CHEMICALS FOUND IN TOBACCO: -Tar --> carcinogenesis -Polycyclic aromatic hydrocarbons --> carcinogenesis -Nicotine - ganglionic stimulation and depression, tumor protein. It is also a highly addictive substance, which causes acute effects like increase HR, BP, cardiac contractability and output. -Phenol --> tumor promotion; mucosal irritation -Benzopyrene --> carcinogenesis -CO --> impaired o2 trans and utilization -Formaldehyde --> toxic to cilia and causes mucosal irritation -Oxides of nitrogen --> same as formaldehyde -Nitrosamine --> carcinogenesis DISEASES CAUSED BY SMOKING: -Mostly involves the lung (emphysema, chroic bronchitis and lung cancer). The mechanisms is that the smoke is a direct irritant if tracheobronchal mucosa causing inflammation and increased mucus production (bronchitis). Next is the recruitment of leukocytes to the lung which increases the elastase production, which injuries the lung tissue and now we have emphysema. Lung cancer is mostly due to polycyclic hydrocarbons and nitrosamines. The development of lung cancer is directly related to the intensity of the exposure. However, smoking multiplies the risk of other carcinogenes, like abestos, uranium miners and alcohol consumption. -Atherosclerosis and MI are strongly linked to smoking cigarettes- The mechanism: increased platelet aggr, decreased myocardial o2 supply (due to hypoxia from the CO in smoke) with increased o2 demand and devcreased treshold of V fibrillation. The risk becomes multiplied when combined with hypertension and hypercholesterolemia. -Oral cavity, esophagus, pancreas and bladder cancers have increased risk in ppl who smoke tobacco. -Combination of tobacco and alcohol gas many effects non oral, laryngeal, and esophageal cancers. -Maternal smoking will increase the risk of spontaneous abortions and preterm birth. There is intrauterine growth retardation. Mothers who stop smoking before pregnany have normal weight babies. -Environmental/secondary tobacco smoke exposure has detrimental effects like lung cancer, coronary atherosclerosis, fatal MI, resp illnesses and astmha!

A/49. Familial hypercholesterinemia

Familial hypercholestermia is a "receptor disease" caused by loss-of-function mutations in the gene encoding the LDL-receptor which is involved in the transport and metabolism of cholesterol. It is an AD disorder. As a consequence of receptor abnormalities there is a loss of feedback control that normally holds cholesterol synthesis in check. The resultant eleavted cholesterol levels induce premature atherosclerosis and greatly increases the risk of MI. The plasma LDL levels are inversely related to the activity of LDL receptor PATHOGENESIS: High levels of serum cholesterol: i. Impaired intracellular transport and catabolism of LDL → accumulation of LDL in the plasma. ii. Also impairs transport of IDL into the liver → more plasma IDL is converted to LDL. b. Hypercholesterolemia → increase of cholesterol moment into monocyte‐ macrophages and vascular walls (scavenger receptor) → skin & tendon sheath xanthomas and premature atherosclerosis. In heterozygotes, elevated serum cholesterol greatly increases the risk of atherosclerosis and resultant coronary artery disease; homozygpous have an even greater increase in serum cholesterol and a higher frequency of ischemic heart disease. Cholesterol, as mentioned, also deposits along tendon sheaths to produce xanthomas.

A/07. Fat, caseous and fibrinoid necrosis and its organ manifestation

Fat necrosis: Refers to focal areas of fat destruction, typically resulting from the release of activated pancreatic lipases into the substance of the pancreas and peritoneal cavity. This is occurs in acute pancreatitis. In this disorder, pancreatic enzymes that have leaked out of acinar cells, liquefy the membranes on fat cells in the peritoneum. The lipases then split the triglyceride esters contained in the fat cells and fatty acids are released. These FA's combine with calcium to produce grossly visible chalky white areas (fat saponification). Caseous necrosis: Typical for tuberculous infection and other other focal infections. Caseous means "cheese-like", which refers to the yellow-white necrosis viewable in gross examination. It differs from coagulative necrosis, as the architecture of the tissue is completely obliterated and cellular outlines cannot be discerned. Caseous necrosis is often surrounded by a collection of macrophages and other inflammatory cells. The appearance is characteristic of nodular inflammatory lesion called a granuloma. Fibrinoid necrosis: This is a special form of necrosis in which the immune complexes formed between antibodies and antigens are deposited in the walls of blood vessels. These complexes form a bright pink, amorphous appearance in HE preparations called a fibrinoid. Fibrinoid necrosis is characterized by deposition of fibrin-like protein into the walls of small muscular blood vessels due to damaged basement membranes, which results in bright pink staining of vessel walls. This necrosis is typical for blood vessels and immunologically mediated diseases like polyarteritis nodosa.

A/55. Fetal Hydrops

Fetal hydrops = accumulation of edema fluid during intrauterine growth. It can be both localized (which is compatible with life) or generalized which is lethal!!!! CAUSES: -Cardiovascular causes like tachyarrhythmias, malformations etc -Chromosomal, Turner syndrome, trisomy 21 and 18 -Thoracic, diaphragmatic hernia -Fetal anemia: immune hydrops due to rh or ABO incompatability -Twin gestation: twin-to-twin transduction -Infections: syphilis, cytomegalovirus infections -Tumors -Genitourinary tract disorders IMMUNE HYDROPS -Is due to antibody induced hemolysis due to blood group incompatability, where either Rh or ABO antigens initiate the reaction. Happens with the fetus inherits RBC antigens from the father, that are incompatible with the mother. This leads to anemia, jaundice and reduced protein! We can prevent Rh incompatability with anti-D anitbodies but there is no way to prevent ABO incompatability! Occurs in infants of blood group A or B born to mothers who are blood group O. i. These women possess IgG antibodies against A or B antigens (usually they are IgM and thus do not cross placenta). ii. Thus the firstborn can be affected. e. There is no way to prevent this hemolytic disease.! NON-IMMUNE HYDROPS, this is now the most common cause as rh antibody prophylaxis is developed: 1) Cardiovascular defects: leads to cardiac failure and thus fetal hydrops 2) Chromosomal alteraions: Turner syndrome and trisomies 3) Fetal anemia (non-immune initiated) due to parvovirus B19, which arrest RBC maturations. So one can find circulating immature erythroid precursors in erythroblastosis! Will result in the fetus either being stillborn, die within a few days of life or recover completely! CLINICAL FEATURES: EARY RECOGNITION IS VITAL!!!!!!! -Amntiotic fluid testing can show increased bilirubin which inducation hemolysis. This can go into the basal ganglia and brain stem, particularly in premature infants and we call it KERNICTERUS). This can happen because the BBB is less developed in neonatal life than in adulthodd, so bilirubin can cross the BBB! -Rh incompatability is easy to predict due to Rh antibodies found in mother. We do a COOMBS ANTIGLOBULIN TEST -ABO incomp is harder to spot, but seen with blood incomp of parents: phototherapy after birth or axchnage transfusion

A/37. Granulomatous inflammation

Granulomatous inflammation is a morpholigical specific pattern of chronic inflammation induced by T cell and macrophage activation in response to an agent that is resistant to eradication. It may lead to central necrosis. The macrophages activated may develop abundant cytoplasm and begin to resemble epithelial cells, and are called EPITHELIOID CELLS. Some macrophages may fuse, forming multinucleated giant cells. Granulation tissue is characterized by proliferation of fibroblasts and new-thin walled, delicate capillaries in a loose ECM, often with admixed inflammatory cells, mainly macrophages. This tissue progressively invades the site of injury: the amount of granulation tissue that is formed depends on the size of the tissue deficit created by the wound and the intensity of inflammation. There are two types of granulomas, which differ in their pathogenesis: -Immune granulomas: which are caused by a variety of agents that are capable of inducing a persistent T-cell mediated immune response that traps the pathogen. In these responses, the macrophages activate the T cells to start producing cytokines, such as IL-2, which causes further prolif of T cells, and IFN-gamma which again activates macrophages. -Foreign body granulomas: are seen as a response to inert foreign bodies, in the ABSENCE OF T-CEL MEDIATED IMMUNE RESPONSES. Typically, these granulomas are formed around materials such as talc (in IV drug abusers), sutures and other fibers large enough to preclude phagocytosis by a macrophage, but are not immunogenic!! The foreign material can usually be identified within the center of the granuloma. We can use a polarized light to view the foreign item as it may appear refractile. EXAMPLES OF DIASES OF GRANULOMATOUS INFLAMMATION: -Tuberculosis -->In certain infectious diseases ( infection by mycobacterium tuberculosis), there is a central zone of necrosis = caseous necrosis. Grossly, this has a granular, cheesy appearance, and microscopically it appears as amorphous, structureless, esoinophillic, granular debris, with loss of cellular details. -Syphilis -Leprosy -Chron's disease --> Granulomas in this disease tend to be noncaseating. -Cat-scratch disease Healing of granulomas is accompanied by fibrosis that may be extensive!

B/30. Hypertensive heart disease

HYPERTENSIVE HEART DISEASE: Is a consequence of the increased demands placed on the heart by hypertension, causing pressure overload and ventricular hypertrophy! Myocyte hypertrophy is an adaptive response to pressure overload; there are limits to myocardial adaptive capacity, however, a persistent hypertension can lead to many consequences, including heart failure and sudden death! SYSTEMIC (LEFT-SIDED) HYPERTENSIVE HEART DISEASE: PRESSURE OVERLOAD! Criteria for this: 1) LV hypertrophy in the absence of other cardiovascular pathology 2) A history of pathological evidence of hypertension, a theory show that even a mild hypertension over a long period of time induced LV hypertrophy!!!!!!! (25% of the U.S population has at least this mild hypertrophy)! The chronic pressure overload of systemic hypertension causes LV CONCENTRIC hypertrophy, often associated with left atrial dilation due to impaired diastolic filling of the ventricle! Microscopically, LV hypertrophy causes interstitial fibrosis that increases the wall thickness and stiffness. There is also a prominent nuclear enlargement and hyperchromasia (BOXCAR NUCLEI = boxy shaped nuclei) Compensated LV hypertrophy is typically asymptomatic is suspected only if patient has elevated BP, pressure on phys. exam, or if ECG suggests it! The patient may also show a fibrillation, secondary to left atrial enlargement! PULMONARY HYPERTENSIVE HEART DISEASE - COR PULMONALE: VOLUME OVERLOAD Cor pulmonale results frompulmonary hypertension due to primary lung parenchymal or vascular disorders. Hypertrophy of both the right ventricle and right atrium is characteristic; dilation may also be seen when failure supervenes! Cor pulmonale can be both acute in onset, or slow and insidious. The pulmonary arteries often contain atheromatous plaques and other lesions, which reflects long-standing pressure elevations. The thickness of the RV might even, in severe cases, exceed that of the LV!

A/32. Types of hemorrhages and their clinical presentation

Hemmorhage is the defined as the extravasation (leakage of fluid) of blood from vessels and is most often the result of damage to blood vessels or defective clot formation. -Hemmorrhagia per rhexim --> ruptured vessels. Example is apoplexia: hypertension in brain which causes rupture of Charcot-Bouchart aneurysm around basal ganglia or aortic dissection -Hemmorhagia per arrosinem --> erosion of vessels from outside. Ex: stomach ulcer -Hemmorhagia per diapedesim --> slow leakage from capillaries. Ex: petechia, purpura. The risk of hemmorhage is increased in a wide varity of clinical disorders collectively known as hemmorhagic diatheses.These have diverse causes, including inherited or aquired defects in vessel walls, platelets or coagulation factors, all which must function properly to ensure homeostasis. TYPES OF HEMMORHAGES: HEMATOMA: May be external or accumulate within a tissue as a hematoma which ranges in significance from trivial (a bruise) to fatal (a massive retroperitoneal hematoma resulting from a rupture of dissecting aortic aneurysm). Large bleedings into body cavities are named according to their location: -hemothorax -hemopericardium -hemarthrosis PETECHIA: are 1-2mm hemmorhages into skin, mucous membranes or serosal surfaces. The causes include low platelet count (thrombocytopenia), defective platelet function, and loss of vascular wall support as in vit C def. PURPURA: These are slightly larger, 3-5mm and they result from the same causes as petechiae, as well as trauma, inflammation of the vessels and increased vascular fragility. ECCHYMOSES: They are larger, 1-2cm subcutaneous hematomas (commonly known as bruises). The extravasated RBC's are phagocytosed and degraded by macrophages explaining the color changing of a bruise from it's red-blue color (enzymatic conversion of hemoglobin), to blue-green (when hbg is converted to bilirubin), and eventually it's golden-brown color due to the pigment hemosiderin. CLINICAL SIGNS: The clinical significance of the hemmorhage depends on the volume of blood that is lost and the rate of bleeding. Great losses can cause hypovolemic shock. The location of the hemmorhage is also important, bleeding that would be trivial in subcutanous tissues could be fatal in the brain for ex. Frequent or chronic external blood loss (like peptic ulcer or menstrual bleeding) may culminate iron deficiency anemia.

A/15. Hyaline accumulation and its organ manifestation

Hyaline is not a single chemical, but just a name of substances that stain is glassy and stain pink using HE staining. It is usually acellular and proteinaceous material. It stains bright magenta using PAS staining. ORGAN MANIFISTATION OF HYALINE ACCUMULATION: KIDNEY: 1) Hyaline arteriosclerosis: Associated with HT, in which the hemodynamic stress causes an increased production of ECM by smooth muscle cells. We can therefore see a homogenous, pink, hyaline thickening of the arteriolar walls causing a loss of structrue and a luminal narrowing. --DM --Hypertension --some drugs 2) Hyaline glomeruli: This occurs when there is a leakage of the filtration barrier and therefore, the damage caused by glomerular nephritis (inflammation of the glomeruli). --> There is leakage of plasma protein and excess production of extracellular matrix, and there is a precipitation of hyalinic material and this is sometimes this is called end‐stage kidney. LIVER: Mallory hyaline: This is a globular red hyaline material within hepatocytes. Cytoskeleton percipitates in hepatocytes. It is also known as alcoholic hyaline as it is known to be found in patients with chronic alcoholism LUNG: Hyaline membrane disease. Hyaline membrane disease is related to alveolar destruction of the lung and leakage of plasma from the alveoli. There is endothelial damage of the alveoli and plasma leaks and precipitates around the alveolar endothelium and this makes a membranous amorphous tissue. It is related to: a. Adult respiratory distress syndrome. --> due to toxins b. Infant respiratory distress syndrome --> under hypoxic conditions In both cases, endothelial damage occurs and this leaks plasma proteins into the alveoli and makes hyaline membrane disease.

A/26. Congestion and its organ manifestation

Hyperemia and congestion both refer to an increase in blood volume within a tissue, but have different underlying mechanisms. We say that hyperemia is an active process resulting in arteriolar dilation and increased blood inflow, as occurs typically at sites of inflammation or in exercising muscle. This can happen in e.g. acute conjunctivitis, acute gastritis, acute bronchitis and erythaema (redness of skin). CONGESTION: Congestion is said to be a passive process of hyperemia, where the blood volume in a tissue increases due to the decreased venous drainage. Aka, it refers to imparied venous outflow, and can occur either systematically, as in cardiac failure, or locally as a consequence of an isolated venous obstruction. Congested tissues have an abnormal blue-red color (cyanosis) that stems from the acc. of deoxygenated hbg in the affected area. In long-standing congestion, inadequate tissue perfusion and persistant hypoxia may lead to parenchymal cell death and secondary tissue fibrosis, and the elevated intracellular pressures may cause edema or somtimes rupture capillaries which causes hemorrhages. MORPHOLGY WITH CLINICAL EXAMPLES/ORGAN MANIFISTATIONS: MACROSCOPIC: Cut surfaces of hyperemic or congested tissues feel wet and typically ooze blood. Acute pulmonary congestion: (due to left-sided heart failure) Is marked by blood-engorged alveolar capillaries and variable degrees of alveolar septal edema and intraalveolar hemorrhage. Chronic pulmonary congestion: The septa becomes thickened and fibrotic, and the alveolar spaces contain numerous macrophages laden with .hemosiderin ("heart failure cells") derived from phagocytosed RBC. Acute hepatic congestion: The central vein and sinusoids are distended with blood, and there may even be necrosis of centrally located hepatocytes. The periportal hepatocytes experience less severe hypoxia as they get better oxygenated due to their proximity to the hepatic arterioles. They may only develop fatty, reversible change. Chronic hepatic congestion: Here, the central regions of the hepatic lobules that we can view on gross examination, are red-brown and slightly depressed due to cell loss (=nutmeg liver). Microscopic findings include: centrilolobular hepatocyte necrosis, hemorrhage and henosiderin-laden macrophages.

A/23. Pathomechanism of hyperplasia, examples

Hyperplasia refers to increased cell numbers in response to hormones and other growth factors that occurs in tissue that is able to divide or contain an abundant tissue stem cells. Hyperplasia occurs in cells capable of replication, and it may occur simultaneously with hypertrophy, and often in response to the same stimuli. PHYSIOLOGICAL HYPERPLASIA: Hormonal: This refers to the increase in functional capacity of an organ when needed, for ex of the glandular epithelium of the breast when a female is pregnant. Compensationary: After a liver donation, the donator's liver will regenerate itself to it's normal size. PATHOLOGICAL HYPERPLASIA: A common cause of pathological hyperplasia is the overproduction /stimulus of hormones. Examples include: Endometrial hyperplasia: Excessive proliferation of the cells of the endometrium due to high levels of estrogen and insufficient levels of progesterone-like hormones which normally act to negatively inhibit proliferatory effects. Prostate hyperplasia: This frequently develops in men above the age of 50 and is more physiological than pathological. When men age, there is an increase in estrogen, which causes adenomuscular hyperplasia of the prostate. This causes problems for the men to urinate as there is constriction of the urethra and a transurethral resection is used to treat it and release the urine. MECHANISM: Testosterone gets converted into dihydrotestosterone (DHT) in the stromal cells of the prostate. The DHT will then bind to the androgen receptors of the stromal and epithelial cell nuclei, making the cells produce more growth factor and receptors. If there is an increased demand for, for example oxygen, then bone marrow hyperplasia may occur, or if there is an increased demand for lymph due to incr in antigens --> follicular hyperplasia.

A/22. Myocardial hypertrophy and its clinical forms

Hypertrophy is an increased cell and organ size; often in response to increased workload induced by growth factors produced in response to mechanical stress or other stimuli. Occurs in tissues NOT capable of cell division! Hypertrophy can be both physiological and pathological. PATHOGENESIS: An example of pathological hypertrophy is the cardiac enlargement that occurs with hypertension or aortic valve disease. The differences between normal, adapted, and irreversibly injured cells are illustrated by the responses of the heart to different types of stress. Myocardium subjected to a persistently increased workload, as in hypertension or with a narrowed (stenotic) valve, adapts by undergoing hypertrophy to generate the required higher contractile force. The mechanisms driving cardiac hypertrophy involve at least two types of signals: -mechanical triggers, such as stress, and soluble mediators that stim cell growth, such as growth factors and adrenergic hormones. These stimuli turn on signal transduction pathways that lead to induction of growth genes . The results are higher production of myofibrils and more proteins, which increases the force generated with each contraction, enabling the cell to meet increased work demands. --There may also be a switch in contractile proteins from adult to fetal or neonatal forms, which produces slower, more energetically economic contractions. An adaptation to stress suchas hypertrophy can progress to functionally significant cell injury if the stress is not relieved. Whatever the cause of hypertrophy, a limit is reached beyond which the enlargement of muscle mass can no longer compensate for the indreased burden. When this happens, several degen changes occur like: -fragmentation and loss of myofibrillar contractile elements. THE NET CHANGES OF MYOCARDIAL HYPERTROPHY IS VENTRICULAR DILATION AND ULTIMATELY CARDIAC FAILURE!

A/21. Pathomechanism of atrophy and hypertrophy, examples

Hypertrophy is an increased cell and organ size; often in response to increased workload induced by growth factors produced in response to mechanical stress or other stimuli. Occurs in tissues NOT capable of cell division! Hypertrophy can be both physiological and pathological. Physiological examples include hypertrophy of the breast tissue during puberty, or hypertrophy of the uterus during pregnancy. Pathological examples include hypertrophy of the heart or skeletal muscle as adult muscle cells have limited capacity to divide. PATHOMECHANISM OF HYPERTROPHY: The mechanism driving hypertrophy involve at least two types of signals: mechanical signals such as stretch. As well as soluble signals such as growth factors and adrenergic hormones. These stimuli turn og signal transduction pathways that lead to the induction of a number of genes, which in turn stimulates the synthesis of many proteins. The result will be that the cell will synthetize a lot more proteins and myofilaments PER CELL, which in muscle cells will enable the cell to endure a stronger work force. There is a limit to how much a cell/organ can go through hypertrophy and it will eventually stop. What is important to note is that during muscle hypertrophy, the alpha-myosin heavy chain is replaced by the fetal beta form of the myosin heavy chain, which produces slower, more energetically economical contractions!!!! An adaptation to stress such as hypertrophy (as this is a reversible adaptation) can progress to functionally significant cell injury if the stress is not relived. LEFT VENTRICULAR HYPERTROPHY: Causes: Hypertrophy of the left ventricle (shouldn't exceed 1,5cm) is an adaption of increased afterload (the force the muscle has to work/pump against) which can happen because of: -systemic hypertension -aortic valve stenosis -aortic coarcitation (rare, narrowing of the aortic arch) Consequences: -Diastolic failure: when the heart cannot relax properly leading to incomplete filling and incomplete pumping of CO. This may lead to stasis (stagnation of flow) which may lead to atrial dilation -Atrial dilation: due to stasis of blood -Chronic ischemic heart disease: Due to the the hypertrophy, the blood supply is not enough to cover the total volume of the myocardium. This may lead to ischemia. -Renal failure: athersclerosis -Apoplexia: When the blood pressure in the brain is so high that it leads to hemorrhage. The above mentioned is called concentric hypertrophy in which the wall thickness of the left ventricle increases and the ventricle volume decreases. However, we also have one type of hypertrophy called eccentric hypertrophy in which the wall thickness increases in proportion to the chamber radius. This occurs as a response to the Frank-Starling mechanism, which states that if you want the heart to generate more force, then you have to stretch it. RIGHT VENTRICULAR HYPERTROPHY: (shouldn't exceed 3mm) Causes: Related to increased resistance in the lungs, thus these diseases may be the cause: -Emphysema: which is a progressive degeneration of the lung paranchyme, thus needing more pressure to pass through the blood -Bronchitis -Bronchiecstasis: increased number of inflammatory cells in the bronchi, causing increased mucus production which increases the resistance of the bronchi, thus needing more pressure to push blood through. -Tuberculosis: causes granuloma in lungs which increases R -Thromboembolism: in femoral vein, increased R -Scoliosis: where the lungs get compressed and thus R incr Consequences: Nutmeg liver: also called congested liver, is a result of right sided heart failure. The blood will dam back in IVF and back to the hepatic veins and it's branches, thus increasing the pressure in these veins, causing engorgement and nutmeg like appearance. PATHOMECHANISM OF ATROPHY: Atrophy refers to decreased cell and organ size, as a result of decreased nutrient supply or disuse, associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles and autophagy. Cellular autophagy results from a decreased synthesis of proteins and an increased degradation of proteins via the ubiquitin-proteasome pathway. It is important to note that although autophagic cells have diminshed functions, they are not dead. Causes: -Decreased workload, due to immobilization of a limb due to a fracture -loss of innervation (pathological only) -Diminished blood supply -inadequate nutrition -loss of endocrine stimulation (this can be physiological, for example the loss of hormone stimulation during menopause) -aging (also physiological, when the brain goes throgh atrophy = senile) Consequences: -Example of atrophy of the brain is when elderly people becomes senile. -Osteoporosis

B/17. Tumor immunity and immune surveillance

IMMUNE SURVEILLANCE: Immune surveillance is a concept formalized by Thomas and Burnet, based on a theory made by Paul Ehrlich that stated; tumor cells can be recognized as foreign and be eliminated by the immune system. It's definition is this: "based on the premise that a normal function of the immune system is to constantly "scan" the body for emerging malignant cells and destroy them." This idea has been supported by many observations. One should consider a few overreaching principles: -Cancer cells express a variety of ag's that stimulate the host immune system, which appear to have an improtant role in preventing the emergence of cancers. -Despite the antigenicity of cancer cells, the immune response to established tumors is ineffective, and in some instances may actually promote cancer growth, due to acquired changes that allow cancer cells to evade anti-tumor responses and foster pro-tumor responses. -Defining mechanisms of immune evasion and "immuno-manipulation" by cancer cells has led to effective nrw immunotherapies that work by reactivating latent host immune responses. TUMOR IMMUNITY: The term cancer immunoediting/tumor immunity has been used to describe the ability of the immune system to promote the darwinian selection of the tumor subclones that are most able to avoid host immunity or even manipulate the immune system for their own malignant purposes. Since it is the CTL t cells that are most improtant in the defense against tumors, it isn't a surprise that tumor cells show a variety of alerations that inhibit CTL responses. These include acquired mutations in beta2-microglobulin (is a part of MHC I receptor) that prevent the assembly of functional MHC class I molecules, and increased expression of a variety of proteins that inhibit CTL function. These proteins work by activating what is referred to as immune checkpoints , which are inhibitory pathways that normally are crucial for maintaining self-tolerance and controlling the size and duration of immune responses so as to minimize colleteral tissue damage. One of the best-characterized immune checkpoints involves a protein called PD-L1 (programmed cell death ligand 1) which is often expressed on the surface of tumor cells. When it binds to it's receptor on CTLs, the cytotoxic T cell becomes unresponsive and lose their ability to kill tumors! The discovery of checkpoints to shut off anti-tumor immunity has led to the development of ab's that block these checkpoints abd release the brakes on the immune response. Current checkpoint blockade therapies have resulted in response rates of solid tumors (melanoma, lung cancer, bladder), and even higher rates in som e hematologic malignancies such as Hodgkin lymphoma!

B/01. General caracteristics of neoplasms (benign, malignant tumors)

IMPORTANT TO KNOW THAT CANCER IS NOT ONE DISEASE BUT RATHER MANY DISORDERS THAT SHARE A PROFOUND GROWTH DYSFUNCTION!!! We do not say cancer regarding brain cancer, but brain tumor, and not blood cancer but leukemia. So the term cancer usually includes epithelial neoplasms! NEOPLASMS= "New growth". An autonomous growing mass. It is an uncontrolled growth. In most cells, growth is under regulation, but this is uncontrolled. A neoplasm harbors genetic abnormalities and there are several steps to have a neoplastic tissue. A single genetic abnormality is not enough. --> Neoplasms are unregulated, irreversible and monoclonal (from 1 single mother cell) BENIGN TUMORS: These are an acute neoplasm. There are several features for a benign tumor: -No invasion. It is only expansive. It remains in the area and pushes aside the normal tissue, stays local. -No metastasis. - No re‐growth after surgery. No relapse. - Well differentiated with no anaplasia. MALIGNANT TUMORS: These invade the surrounding tissue. They spread, disseminating through vascular channels and make metastasis. There is re‐occurrence after surgery of the tumor. However, in all cases, there are exceptions: A brain tumor, for example, never metastasizes. So that is a feature missing from a malignant brain neoplasm. SEMI-MALIGNANT TUMORS: There are features partially having benign and partially having malignant characteristics. A tumor may have local invasion but no metastasis, or they may have no invasion but may have recurrence after surgery. There are two neoplasms which fall into this category: -Basal cell carcinoma of the skin. (Krompecher tumor) This means it will remain at the stratum basale. Usually due to overexposure to sun light. This tumor rarely metastasizes. -Pleomorphic adenoma of the parotid (salivary gland). This is a benign neoplasm that grows without invasion and it is capsulated. The problem is that it grows on the face and you may have nerves and vessels and the tumor has processes. There are projections that come out of the tumor and when the surgeons remove the tumor, they remove the majority, but cannot remove the small processes because they surround the vessels and nerves. Therefore, there is recurrence from the rest of the tumor. Therefore, from a clinical aspect, it is semi‐malignant because it is difficult to remove. BORDERLINE TUMORS: It is cytologically malignant. It looks bad, but it does not invade into the tissue. The epithelial layer is separated by a basement membrane. This is a characteristic for ovarian cystadenoma. This means early stage. NEOPLASTIC TUMORS CONSITS OF: PARENCHYMA: Parenchyma itself is a neoplastic tissue. STROMA: Subcortical tissue which is part of the normal tissue. CHARACTERISTICS OF NEOPLASTIC TUMORS CELLS: - Abnormal regulation of growth. A cell has a receptor and a receptor for growth. In order to have a stimulus, you need a ligand. In a neoplastic cell, the cell has a capacity to produce ligand and express receptor. This is called autocrine function to grow. - Resistance to apoptosis. It is very important because cells use apoptosis to balance a cell population to control growth. If this is blocked, this makes a pathological hyperplasia. -Limitless capacity of cell replication. There are certain signals which stop the growth of cells and regulate the cell cycle. Cells should go to G0 but the cell is blocked from going to senescence. - Loss of cell differentiation. New cells differentiate into specific cells. For example, basal cells in epithelium differentiate stromal epithelial cells in regeneration of tissue. In neoplasms, one characteristic is to block differentiation and an early progenitor remains that is undifferentiated. - Induction of angiogenesis. Tumors don't have nutrition and so they secrete factors (VGEF) to induce it. - Invasion into tissue. There is the capacity to invade other tissue. - Metastasis. Neoplastic cells have a capacity to get into the vascular structure and travel with the vascular structure and form metastasis in the distance. - Remodeling metabolic pathway. - Insensitivity of growth inhibition signal. When cells proliferate, there are receptors and certain ligands block growth. These neoplastic cells lose the sensitivity and there is uncontrolled growth. -Evasion of immune reaction. So when we have a neoplastic cell which is different from the normal cells found in the body, the immune system should eliminate it. But neoplastic cells have a mechanism to evade immune regulation. TO SUMMARIZE THE FEATURES OF DIFFERENT NEOPLASMS: Benign: slow growing, well circumscribed, distinct, mobile. Malignant: rapidly growing, poorly circumscribed, infiltrative, fixed to surrounding tissue. Semi‐malignant: looks malignant, but no metastases. E.g. basal cell carcinoma of the skin, fibromatosus (retroperitoneum, abdominal wall) Borderline: cannot predict their behavior from morphological presentation. E.g. ovarian‐ cystic borderline tumors, hemiangoendotheliomas, carcinoids (neuroendocrine tumors, e.g. appendix, lung). ANAPLASIA =This means lack of differentiation. Parenchymal cells lose their morphological characteristics of mature cells and their orientation to one another. This is a mark of malignancy! Characteristics: *Pleomorphism: Variation in cell size and shape. Benign cells look the same, malignant ones don't. Hallmark of malignancy. *Block of maturation: accumulation of undifferentiated precursor cells, typical for childhood neoplasms *Abnormal cytoplasm/nuclear ratio: Generally in a differentiated cell, there is a large cytoplasm. In neoplastic cells, we have a large (hypercrhomatic) nucleus and small cytoplasm. ----> Normal n:c ratio is 1:4 → neoplasia could be 1:1. *Mitosis: The amount of mitosis is increased and usually atypical in anaplastic cells. Cells can be tripolar/quadropolar and have clumped, coarse chromatin! *Loss of polarity: Loss of cell polarity/direction (e.g. epithelium) no recognizable pattern of orientation. *Functional activity: In a differentiated cell, it serves a function. There is a loss of capacity to produce normal cells.

A/06. Hemorrhagic infarction and its organ manifestation

INFARCTION= NECROSIS INDUCED/SUPERIMPOSED ON ISCHEMIA! Hemorrhagic necrosis (a "red infarct") occurs when hemorrhage is superimposed upon coagulative necrosis in organs with dual blood supply (liver, lungs, brain and liver, basically in loose organs (testes), or in organs following reperfusion (myocardial infarct following t-PA infusion). Examples include hemorrhagic acute myocardial infarction, pulmonary infarction and intestinal infarction. Pulmonary infarction usually occurs in patients with deep vein thrombosis.

A/62. Pathology of medication-related disorders and pharmaceutical side effects

INJURY BY THERAPEUTIC DRUGS: ADVERSE DRUG REACTION: =effects of drugs that are administered in cinventional therapeutic settings. These reactons are extremely common and they do prove fatal! The most common type is menopausal hormone therapy. In which, only giving estrogen to non-hysterectomized women increases the risk of cervical and breast cancer på severel tenfolds! MHT effects depend on the type of hormone therapy regiment used (combinations of estrogen with other hormones, or estrogen alone), the age and risk factor status of the woman at the start of the treatment, the hormone dose, formulation and route of administration. -Same with oral contraceptives! Ex's: -Blood --> dysccrasias (hemolytic anemia, granulocytopenia) -cutaneous --> urticaria -Kidney --> glomerulonephritis -Liver --> hepatic fatty change -Cardiac --> arrhythmia, cardiomyopathy ASPIRIN OVERDOSE: usually, overdose is taken by accidental ingestion in young children or suicide attempts in adults. Causes: Acute erosive gastritis, as there might be bleeding since aspirin IRREVERSIBLY inhibits COX and blocks the ability to make thromboxane A2 (an activator of platelet aggregation). ACETAMINOPHEN OVERDOSE --> centrolobular hepatic necrosis/liver failure THALIDOMID --> Phocomelia in infants BIOLOGICAL TEST: -Ames test: used to assess the mutagenic potential of chemical components -Single cell gel electrophoresis assay (COMET) CHECKING FOR DRUG DEVELOPMENT: -Preclinical drug development: --> Tissue model --> animals -Clinical drug development: --> healthy volunteers (?) -->patients

B/16. Tumor antigens

In addition to pathogenic driver mutations, cancers, due to their inherent genetic instability, accumulate passenger mutations also. All of these varied mutationsmay generate new protein sequences (NEOANTIGENS) that the immune system has not seen and therefoe is not tolerant of and can react to! In some instances, unmutated proteins expressed by tumor cells also can stimulate the host immune system. =Antigens that elicit an immune response in the host. These antigens are often found with tumors. b) Classification of tumor antigens: i. Old way: 2 categories 1. Tumor‐specific antigens: present only on tumor cells and not on any normal cells 2. Tumor‐associated antigens: present on tumor cells and also some normal cells ii. These two categories are not enough, because many antigens thought to be tumor‐specific were also found on normal cells. Modern classification: molecular structure and source. EXAMPLES OF TUMOR ANTIGENS: TYROSINASE, is an example of such a tumor antigen. Normally, it is an enzyme involved in melanin biosynthesis that is expressed only in melanocytes and melanomas. The explanation as to why our body responds to this as foreign, instead of a normal self-antigen is because tyrosinase is normally produced in such small amounts and in so few nromal cells that it is not recognized by the immune system and fails to induce tolerance. CANCER-TESTIS ANTIGENS: are another group of tumor antigens encoded genes that are silent in all adult issues except germ cell sin the testis. Although the protein is present in the testis, it is not expressed on the surface of cells in a way that can be recognized by CD8+ T cells, because sperm do not express MHC class I molecules. Thus, for all practical purposes, these ag's are tumor specific and are therefore capacble of stimulating anti-tumor immune responses! In addition to these, another important class of tumor antigens consists of viral proteins that are expressed in cancer cells transformed by oncogenic viruses. The most potenet of these ag's are proteins produced by cells that are latently infected with DNA viruses, like HPV and EBV! Or embryonic tumor ag's that are normally expressed only during embryogenesis! Examples of this include: CEA (carcino‐embryonic antigen), α fetoprotein, which, if reexpressed in the liver or colon might cause tumor development. Can also have Cell type‐specific differentiation antigens, for exmaple that lymphomas are of B cell origin if they express CD20. Most tumors have increased amount / abnormal forms of surface glycoproteins and glycolipids. These can be diagnostic markers or therapy targets, Ex: MUC-1 in breast cancers! The normal mechanism of tumor destruction by CTLs is: it is initiated by by the death of individual cancer cells which occurs at some frequency in all cancers due to dysregulated growth, metabolic stresses and hypoxia dye to insufficient blood supply. When tumor cells die they release "danger signals" called DAMPs (damage associated molecular patterns) that stimulates the innate immune cells, including resident phagocytes and ag presenting cells. Some of the dead tumor cells are also phagocytosed by dendritic cells, which migrate to lymph nodes to present tumor neoantigens in the context of MHC class I molecules, a process termed cross-presentation. These displayed tumor antigens are recognized by ag-specific CD8+ T cells, which become activated, proliferate, differentiate into CTLs, and then home to the site of the tumor where they recognize and kill tumor cells presenting neoantigens in the context of their own MHC class I molecues. Th1 helper cells may also contribute by releasing IFN-gamma to activate macrophages which contribute in the tumor destruction process.

B/34. Noninfective endocarditis (thrombotic endocarditis, Libman-Sacks endocarditis)

NONBACTERIAL THROMBOTIC ENDOCARDITIS (NBTE): -Is characterized by the deposition of sterile thrombi on cardiac valves , typically of patients in hypercoagulative state. -Although this can occur in healthy individuals, it typically occurs in a wide variety of diseases associated with physical weakness, thus it is also called MARANTIC ENDOCARDITIS. -The vegetations are typically small (1-5mm in dia), and valvular damage is not a prereq. -Usually occurs on prev healthy valves. -Hypercoagulative states caused by; chronic DIC, hyperestrogenic states and mucinous adenocarcinomas can cause NBTE -Endocardial trauma such as an indwelling catheter is a well-recognzed predisposing condition. -Eventhough, the condition is usually trivial, it can become much more serious if the vegetations gives rise to emboli that can cause infarcts in the brain, heart and other organs. -It is also important to include that the vegetations can be areas of bacterial growth, thus leading to infective endocarditis. LIBMAN-SACKS ENDOCARDITIS: -Characterized by the presence of sterile vegetations on valves of patients with SLE. -Occurs in about 10% of the patients - It is believed that the vegetations develop as a result of the immune complex deposition, leading to inflammation, fibrinoid necrosis and eventually lesions resembling those of rheumatic heart disease -These lesions can occur ANYWHERE on the valve surface, the chords, or even the atrial and ventricular endocardium!

B/25. Left-sided heart failure

LEFT-SIDED HEART FAILURE CAUSES: -Ischemic heart disease -systemic hypertension -mitral or aortic valve disease -primary diseases of the myocardium like amyloidosis. MORPHOLOGY: -The left ventricule is hypertrophied, and might be dilated, with accompanying atrial dilation and mitral insuffciency = risk of A fib -The lungs will be heavy and boggy as the rising pressures in the pulmonary veins lead to congestion and edema, as well as pleural effusion due to the increased hydrostatic pressure. Edema fluid will accumulate in the alveolar spaces!!! ---> In chronic heart failure, breakdown of RBC's and hemoglobin leads to the apperance of hemosiderin-laden alveolar macrophages called HEART FAILURE CELLS that reflects prev. episodes of pulmonary edema! CLINICAL FEATURES OF LS HEART FAILURE SYMPTOMS: -The earliest and most significant symptom is dyspnoe on exertion, as well as coughing due to the accumulated edema in the alveolar spaces. This will eventually develop into orthopnea, where shortness of breath is experienced even when lying down, which is why patient's with this symptom usually sleep in a half-upright position. -Cardiomegaly, tachycardia, a third heart sound and crackling of the lungs -Diminshed CO leads to decreased renal perfusion that in turn triggers RAS to increase intravasc V + P -In severe CHF, diminished perfusion of the brain may lead to HYPOXIC ENCEPHALOPATHY in which the patient is irritable, has diminshed cognition and feels restless. TREATMENT: The treatment of CHF is often focues on correcting the underlying cause. The clinical approach includes: -Salt restriction -Diuretics -Positive inotropes (increase contractability) -reduce afterload with adrenergic blockers or inhibitors of RAS. These inhibitors also help by limiting hypertrophy!!!

B/28. Myocardial infarction, sudden cardiac death

MYOCARDIAL INFARCTION IS ON TOPIC A/08!!!! SUDDEN CARDIAC DEATH: Sudden cardiac death is defined as unexpected death due to a lethal arrhytmia such as asystole or sustained ventricular fibrillation, USUALLY WITHOUT MYOCYTE NECROSIS! It is the end result of both MI, CIHD, CHF etc and the mortality rate is high! CAUSES: Coronary artery disease is the leading cause, but unfortunately SCD may be the first manifestation of ischemic heart disease!!! Autopsy shows severe atherosclerotic disease, but without evidence of acute plaque disruption so in a lot of the casses, there is no association of MI! IN YOUNGER VICTIMS, NONATHEROSCLEROTIC CAUSES ARE COMMON LIKE: -Hereditary (channelopathies) or aquired abnormalities of teh cardiac conduction system -congential coronary arterial abnormalities -Mitral valve prolaps -Myocarditis or sarcoidosis -Dilated or hypertrophy cardiomyopathy -Pulmonary hypertension -Myocardial hypertrophy --> N.B: Increased cardiac mass is an INDEPENDENT RISK FACTOR OR SCD, thus in some individuals who die suddenly, including atheletes, the only finding is an increased cardiac mass!!!! TREATMENT: The prognosis of the patient's with risk of SCD, is markedly improved by implantation of a pacemaker or automatic cardioverter defibrillator, which senses and counteracts an episode of ventricular fibrillation.

A/24. Pathomechanism of metaplasia and dysplasia, examples

Metaplasia is the replacement of one healthy cell type to another (but still healthy) cell type which is not usually characteristic for the actual site. This usually occurs in response to some environmental change, and the new cell type is more suited to handle that change. EXAMPLES OF METAPLASIA: Bronchial metaplasia: This usually occurs in smokers in which the constant irritation of the smoke down the bronchial system, triggers metaplasia of the bronchial epithelium (from ciliated pseudostratified columnar epithelium) to be replaced by stratified squamous non-keritinized epithelium. The body does this since the squamous non-k epithelium can survive the noxious chemicals in cigarette smoke that the more fragile pseudostrat columnar epith can't tolerate. Although the new epithelium has survival advantages, some important, protective mechanisms are lost such as mucous secretion and ciliary clearance of particular matter. Barrett's metaplasia: This is a special type of metaplasia in the esophagus where the normal stratified squamous non-keratinizing epithelium in the lower part of the oesophagus is replaced by simple columnar epithelium with goblet cells, so-called "intestinal" epithelium. This change/metaplasia occurs due to a chronic exposure of gastric content to the esophagus, which is often seen in gastroesophageal reflux disease. The intestinal epithelium is better equipped to handle the chronic exposure to gastric acid. Metaplasia of the gallbladder during chronic cystitis. Squamous metaplasia of the cervical glands. DYSPLASIA: Refers to abnormal, but not neoplastic proliferation. The cells do not change TYPE, but become abnormal in other ways. It is because the presence of them often increase the risk for cancer; they are pre-cancerous lesions. Squamous metaplasia in the bronchi due to smoking is an important risk factor for developing lung cancer. Colorectal polyps with dysplasia (adenomatous polyps) have increased risk for developing into cancer, while polyps without dysplasia don't. The more dysplasia is found in the cervix, the higher the risk for developing cervical cancer. Histologically, variations in size shape and orientation, hyperchromatia and nuclear enlargement. Metaplasia can turn into dysplasia which can become cancerous! In this matter, dysplasia can be seen as a transitional stage, connecting metaplasia and neoplasm.

A/01. Causes, morphology and mechanism of cell necrosis

NECROSIS: Form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell. CELL DEATH: Cells actively interact with their environment, constantly adjusting their structure and function to accomodate changing demands and e.c stress. If the cells adaptive capability is exceeded or if the external stress is inherently harmful or excessive, cell injury develops. Within certain limits, injury is reversible . However, if the stress is severe it results in irreversible injury and death of the affected cells. Cell death can go about in two different ways: apoptosis, programmed cell death which can also occur in healthy tissue, or necrosis which is not regulated and a pathological response to cell injury. CAUSES OF NECROSIS: Hypoxia and ischemia: Hypoxia (O2 deficiency) and ischemia (reduced blood supply) are among the most common causes of cell injury. The most common cause of these conditions is arterial obstruction, however hypoxia can also occur due to inadequate oxygenation of the blood. Toxins: Excessive exposure to air pollutants, insecticides, cigarette smoke, ethanol and drugs can cause cell damage Infectious agents: Viruses, bacteria, fungi and protozoans are disease-causing pathogens which can induce injury to cells. Immunologic reactions: The immune system can inititate reactions within the body that can be harmful and cause cell death. Example include autoimmune reactions against each own's tissues and allergic reactions. In all of these situations, immune responses elicit inflammatory reactions which are often the cause of damage to cells and tissues Genetic abnormalities: Genetic defects may cause cell injury as a consequence of deficiency of functional proteins. Nutritional imbalances: Protein-calorie insufficiency remain a major cause of cell injury. Another example is when cells have too much fat in them, they may undergo cell death Physical agents: Trauma, extremes in temperature, radiation and electric shock are examples Aging: Cellular senescence results in diminished ability of cells to respond to stress and, eventually, the death of the cells and of the organism. MORPHOLOGY: Firstly, we must differentiate between the morphological changes in a reversible injured cell and an irreversible injured cell, as this is very important. Reversible cell injury changes: Cellular swelling occurs as a result of increasing permeability of the membrane. There may also be seen fatty vacoules filled with TAGs and pinched-off segments of the ER. Irreversible cell injury changes (necrosis): Cytoplasmic changes: Necrotic cells will show increased eosinophilia (become more red stained with eosin), as the pH goes down due to the increased anaerobic phosphorylation creating an increased amount of lactic acid. Myelin figures can be see in the cytoplasm as well as enlarged, vacouled organelles. Myelin figures are formed by the degradation of the phospholipids in the plasma membrane, which are degraded to TAGs and then calcified into myelin figures. Nuclear changes: There will be fragmentation of the nuclear membane, condensation of chromatin and lastly, pyknosis will occur = nuclear shrinkage and increased basophilia PATHOMEHCANISM: 1)Hypoxia and ischemia: Deficiency of O2 leads to failure of many energy-dep metabolic pathways and ultimately death. Most cellular ATP is produced from ADP by oxidative phosphorylation in the mitochondria. When the cell is deprived of O2, HIF-1 (hypoxia-inducable factor) is produced to help the cell to survive the low O2 conditions. Persistent hypoxia/ischemia eventually leads to depletion of ATP from the cell and without this critical energy, the activity of the Na+/K+-pump (3 Na+ out, 2 K+ in) will be reduced, resulting in i.c accumulation of of Na+ and K+ efflux. The net gain of solute (due to the 3Na+ which is supposed to be pumped out), is accompanied by isoosmotic gain of water, causing cell swelling and dilation of ER. The increase anaerobic phosphorylation decreases the pH of the cell as lactic acid concentration increases. The depletion of ATP causes structural disruption of protein synthesis as the ribosomes of the RER detaches. There will also be irreversible damage to mitochondrial and lysosomal membranes, however this is a late event in the cell injury cascade Ca2+ inlux: ?? Reperfusion injury: neste topic Toxins: Different types of toxins induce cell injury by two general mechanism. Direct-acting toxins, act directly by combining with a critical molecular compound or cellular organelle. An example is mercury, which binds to sulfhydryl groups of various cell membrane proteinsm causing increased membrane permeability.These toxins often cause damage to molecules needed for essential functions such as protein synthesis and ion transport. Latent-acting toxins are not toxic themselves, however, their metabolites are. An example is CCl4 (carbontetracholride) which for a long time was used in the dry cleaning industry. CCl4 produces free radicals when it is broken down by Cyt-P 450 in the liver which results in cell death ER stress: During normal protein synthesis, chaperones in the ER control the proper folding of newly synthetized proteins, while misfolded proteins are ubiquitinated and targeted for proteolysis. If unfolded/misfolded proteins accumulate in the ER, a response called the unfolded protein response is induced. When a large amount of misfolded proteins accumulate, and the adaptive response can't cope with it, apoptosis is initiated through the mitochondrial intrinsic pathway. Another pathway may induce necrosis.

B/02. Classification of neoplasms on histology basis

Neoplasm means new growth. All neoplastic cells depend on the host for their nutrition and blood supply. All tumours have two main components: -Parenchyma, made up of transformed/neoplastic cells -Stroma, made up of CT, blood vessels and host-derived inflamm cells. It is the supporting, host-derived, non-neoplastic part of the tumour. The stroma is crucial to the growth of the neoplasm, since it carries the blood supply and provides support for the grwoth of parenchymal cells. BENIGN TUMORS: A tumour is said to be benign when its microscopic and gross characteristics are considered to be relatively innocent, implying it will remain localized and is amenable to local surgical removal. -Adenoma= applied to epithelial neoplasms that produce gland-like structures, or they can be epithelial neoplasms that are derived from glands but LACK a glandular growth pattern -Papilloma= benign epith neoplasms that grow on any surfice -Polyp= mass that projects above a mucosal surface, as in the gut, to form macroscopically visible structures. MALIGNANT TUMORS: -Malignant tumors arising in "solid" mesenchymal tissues or its derivatives are called SARCOMAS, whereas those arising from the mesenchymal cells of the blood are called leukemias and lymphomas. --> Sarcomas are designated based on their cell-type composition, which presumably reflects their cell of origin. Ex: lipomas, chondromas etc -While the epithelia of the body are dervied from all three germ layers, malignant neoplasms of epithelial cells are called carcinomas regardless of the tissue of origin. --> Carcinomas are divided further: adenocarcinoma = carcinomas that grow in a glandular pattern, squamous cell carcinoma = carcinomas that produce sq cells. NB!: Benign tumors do not metastase, but malignant ones do, EXCEPT FOR BASAL CELL CARCINOMA WHICH INVADE, BUT DOES NOT METASTASE! - We also have mixed tumours, that are still of monoclonal origin, however, they have the capacity to differentiate down more than one cell lineage. HISTOLOGIC EXAMINATION IS DONE TO ESTABLISH: -Type of tumour: based on origin of cells -Degree of differentiation: Is the tumor tissue similar to the normal surrounding tissue? Is the tissue pleiomorphic (degree/variability of size and shape), or anaplastic (not differentiated). What is the proportions of the mitotic spindles? -Evidence of local invasion: vascular, lymphatic and perineural spread -Presence of metastasis: -Presence/abstence of other prognostic factors: estrogen receptors in breast carcinoma cells makes for a better prognosis

A/19. Metastatic calcification and its organ manifestation

PATHOGENESIS: Metastatic calcification is related to hypercalcemia (>2,5mM e.c) and can occur in normal tissues. The major causes of hypercalcemia are: -Increased seceretion of PTH which acts to lower the phosphate concentration of the blood by inhibiting the reabsorption of it in the kidney. This is done since the phosphate binds calcium and PTH acts to indirectly increase the free calcium levels of the blood. Increased PTH secretion is usually due to primary parathyroid tumors or production of PTH-related protein by other malignant tumours -Destruction of bone will increase the ca2+ concentration in the blood. Can be due to leukemia, multiple myeloma, bone diseases like Pagat disease etc -Vit-D related disorders like Vit D intoxification -Renal failure in which phosphate retention leads to secondary hyperparathyroidism. (Men dette er jo hypocalcemia??) MORPHOLOGY: grossly, the same as dystrophic calcification. They can deposit anywhere in the body, but usually deposits the interstitial tissues of the vasculature, kidney, lungs and gastric mucosa. The calcium deposits here as the acidic pH promotes salt formation. The diseases are the same as the above mentioned causes of hypercalcemia.

A/18. Dystrophic calcification and its organ manifestation

Pathologic calcification is a common process in a wide variety of disease states and is the result of abnormal deposition of calcium salts, together with small amounts of iron, magnesium and other minerals. There are two ways of pathological calcium to deposit: dystrophic calcification and metastatic calcification PATHOGENESIS: Dystrophic calcification is initiated by the e.c deposition of crystalline calcium phosphate in membrane-bound vesicles. They may be derived from injured cells or from the intracellular deposition of calcium in the mitochondria of dying cells. The crystals then form larger deposits. MORPHOLOGY: No matter if the calcification is dystrophic of metastatic, the deposit will be a gritty, white granule/clumps. Microscopically, dystrophic calcification can appear as i.c and/or e.c basophilic deposits. MECHANISM: In this form of calcification, the calcium metabolism is normal (this is not the case in metastatic calcification), but it deposits in injured or dead tissue, such as areas of necrosis of any type. It is found everywhere in the arterial lesions of advanced atherosclerosis. Although dystrophic calcification may be an incidental finding indicating insignificant past cell injury, or it may be a cause of organ dysnfunction. CLINICAL SIGNS/CONSEQUENCES: Calcification can develop in aging cells or damaged heart valves, resulting in severely comprimised valve function. Dystrophic calcification in the heart valves is an important cause of aortic stenosis in elderly people. Difficult outflow will eventually lead to left ventricular hypertrophy. Artficial valves: An artificial heart valve is a device implanted into the heart of a patient to replace a dysfunctional native heart valve. Calcification is a consequence of these artifical valves. Atherosclerosis: Inflammation: Some inflammatory diseases generates calcification in necrotic tissues. One good example of this is tubercolosis infection of the lung that causes caseous necrosis. Neoplasm. To maintain their structure, neoplastic cells need a blood supply. This tumor growth is uncontrolled and they grow more cells than the vascular supply provides. In the middle, necrosis occurs. This central necrosis calcifies and is used for diagnostic processes. Two ways to diagnose cancer: a. Calcification of central necrosis. If calcification occurs, there is an electron‐dense picture on the x‐ray film. b. Psammon bodies. These are spherical precipitations found in certain neoplasms. Their presence provides a definite diagnosis of cancer. Psammoma bodies are concentric calcified structures commonly found in meningioma, thyroid carcinoma and ovarian carcinoma

A/38. Tissue repair, wound healing

REPAIR BY REGENERATION: Different tissues consist of contineously dividing cells, normally quiscent cells that are capable of prolif. and non-dividing cells like neurons, skeletal and cardiac muscle. The regenerative capacity of a tissue depends on the proliferative potential of its constituent cells. Cell proliferation is controlled by the cell cycle, and is stimulated by growth factors and interactions of cells with the ECM. Regeneration of the liver is a classic example of repair by regeneration. It is triggered by cytokines and growth factrs åroduced in response to loss of liver mass and inflam. WOUND HEALING: The main phases of cutaneous wound healing are inflam, formation of granular tissue and ECM remodeling. Cut. wounds can heal by primary union or secondary ynion. Secondary healing involves more extensive scarring and wound contraction. Wound healing can be altered by many conditions, particularly infection and DM. The type, volume and location of injury are important factors that influence healing process. Excessive production of ECM can cause keloids in the skin. Persistent stimulation of collagen synthesis in chronic inflammatory disease leads to tissue fibrosis, often with extensive loss of tissue and functional impairment JEG SKREV EGT MER HER, MEN DET BLE BORTE. FOR SUR TIL Å FIKSE OPP NÅ, SÅ GJØR DET EN ANNEN GANG!!! ARGH!

A/10. Reversible cell injury, types of degeneration and its organ manifestation

REVERSIBLE CELL INJURY: Reversible injury is the stage of cell injury at which the deranged function and morphology of the injured cels can return to normal if the damaging stimulus is removed. Cells and intracellular organelles typically become swollen because they take in water as a result of the failure of E-dependent ion pumps in the PM. There is also fatty change which is manifested by the appearance of triglyceride (same as TAGs) containing lipid vacoules in the cytoplasm. This is typically encountered in organs that are involved in lipid metabolism, such as the liver. In some situations, potentially injurious insults induce specific alterations in cellular organelles like the ER. During reversible cell injury, the ER hypertrophies as an adaptive response. A reversible cell injury becomes IRREVERSIBLE when: 1) The cell is unable to restore mitochondrial function (ox phosph) 2) loss of structure and functions of the PM and i.c membranes 3) loss of DNA and chromatin structural integrity The main point of irreversibility is the INFLUX OF CALCIUM!!! MAJOR FORMS OF DEGENERATION: We call it degeneration as it implies loss of cell function. 1) Parenchymous degeneration / cloudy degeneration: Intake of water due to the increased concentration of Na+ inside the cell as the Na+/K+ - pump is impaired. Pale and granular in appearance. Found in brain and kidney. REVERSIBLE! An example is cytotoxic edema in the brain (swelling in the brain, both i.c and e.c). 2) Steatosis/ fatty degeneration: Build-up and retention of abnormal lipids within the cell. It reflects the impairment of synthesis and elimination of triglyceride fats. Examples include fatty liver, due to the increased NADH/NAD ratio (as FA ox (which is degradation of fat and should happen so that it doesn't accumulate) requires NAD+ to oxidize the FA's), impairing FA oxidation, leading to accumulation of the fatty acids in the liver tissue. Fatty liver is reversible!!! When hepatocytes undergo necrosis this is called a Councilman cell! NUTMEG LIVER IS ANOTHER EXAMPLE OF REVERSIBLE CELL INJURY. Due to corpulmonale. Congestion of liver.

A/63. Pathomechanism of obesity and its consequences; examples

RISK FACTORS: -Sex -Genetics (Prader-Willi, Klinefelter) -Leptin gene or leptin receptor gene -Environmental (food intake, physical activity) -Metabolic inbalance --> hypothyrodism, cushing's disease AFFERENT SYSTEM INVOLVED: 1)LEPTIN Is secreted by adipocytes (the more adipocytes, the more leptin is secreted), when leptin conc is high, the hypothalamus will inhibit the feeling of hunger 2)ADIPONECTIN "fat-burning molecule", is against obesity It is anti-diabetic, anti-innflam, anti-prolif and cardioprotective -It's action occurs in the liver, where it increases FFA's ox, and increases insulin sensitivity by decresing glucose 3) GHRELIN: It is produced in the stomach and arcuate nucleus and increases food intake and apetite 4)PEPTIDE 44: opposes the actions of ghrelin MECHANISMS OF OBESITY AND CANCER: -Increases insulin, increases IGF-1, decreases adiponectin, causing a proinflamm state MEN: esophagus, thyroid, colon, kidney WOMEN: esoph, endometrium, gall bladder and kidney CLINICAL FEATURES: -Non-alcoholic fatty disease (as NADH is so high) -Cholelithiasis -Hypoventilation syndrome -Degenerative joint disease -Associated with insulin resistance and type 2 DM -Proinflammatory

A/33. Intracranial hemorrhages

Stroke is the clinical term for acute-onset neurological deficits resulting from hemorrhagic or obstrucitve vascular lesions. Hemorrhages within the brain are caused by hypertension and other diseases leading to vascular wall injury, structural lesions such as arteriovenous and cavernous malformations, and tumors. Subdural and epidural hemorrhages are related to trauma, while subarachnoid hemorrhages are associated with ruptured aneurisms or vascular malformations. Rupture of an intracerebral vessel is the cause of intracerebral haemorrhage, also called cerebral apoplexy. The most common cause is hypertension, which weakens the arteries and predisposes them to rupture. Arterial weakness due to amyloid deposition is more frequent in elderly, especially those who suffer from Alzheimer. Ruptured congenital arteriovenous malformations are more frequent in children. Subarachnoid haemorrhage most commonly occurs due to rupture of so-called berry aneurysms. These aneurysms are saccular and round and are often located in the circle of Willis. The risk for developing these aneurysms is increased in hypertension, smoking, autosomal dominant polycystic kidney disease and collagen disorders like Ehlers-Danlos and Marfan syndrome. The most characteristic symptom is what's often described as "the worst headache I've ever had". Epidural haematoma is a bleeding between the dura mater and the skull. It's often the consequence of blunt force trauma that fractures the skull which rupture the middle meningeal artery, causing it to bleed. Patients usually lose consciousness immediately after the trauma, however it is later regained as a period called the lucid interval starts. During this interval, which lasts minutes to hours, no neurological symptoms are experienced, but after this interval the intracranial pressure elevates and causes neurological symptoms, potentially even tonsillar herniation and death. Subdural haematoma is a bleeding between the dura and arachnoid maters. Rapid movement of the brain during trauma can rupture the bridging veins, causing a bleeding into the subdural space. People with brain atrophy, like people with neurodegenerative diseases, diabetes or chronic alcoholics, have increased susceptibility for subdural haematoma. When the brain atrophies the bridging veins are stretched, which makes it easier for them to rupture. Subdural haematomas don't always cause severe symptoms, especially if they're small. Especially alcoholics and elderly are prone to multiple minor head traumas, each of which will produce a subdural haematoma that will become organized. The presence of multiple organized subdural haematomas is called chronic subdural haematoma. Previous untreated subdural haematomas are also more prone to rebleeding, which also contributes to this.

A/17. Pathological changes of skin melanocytes

The main pigment of the skin is called melanin and is an endogenous, brown-black pigment that is synthesized by melanocytes located in the epidermis and acts as a screen against harmful UV radiation. Melanin is produced from tyrosine by the enzyme tyrosinase. The melanocytes are of neuroectodermal origin and have long processes. The melanin is transferred from the melanocytes to the epithelial cells by endocytosis. Although melanocytes are the only source of melanin, the adjacent basal keratinocytes in the skin can accumulate the pigment (ex: freckles), as can dermal macrophages. DISEASES RELATED TO PATHOLOGICAL MELANIN STORAGE: EPHELIS: not pathological Means freckles which are most commonly found in the face and arms. It is not pathological and relates to the intensity of the sun, thus it's frequency increases during the summer when there is more sun. The explanation is that the increased sun increases the transferrance of melanin from the melanocytes to the epithelial cells MELASMA: not pathological A matt‐like brown homogenous discoloration seen mostly in patients who are pregnant. In the late trimester of pregnancy this occurs in different areas of the body. Hormones influence this and this is again an increase in the transfer of melanocytes to the epithelial cells. After delivery of the baby, this goes away. VITILAGO: pathological This refers to the absence of melanocytes, which is most easily seen in black people as the absence of melanin becomes more obvious. Vitiligo could be local or systemic. If it is local, it could be due to an autoimmune disease acting against the melanocytes. If it is generalized, it is called albinism. Albinism is a mutation of tyrosinase, that prevents the conversion of tyrosine to melanin. MELANOCYTIC NEVI= fødselsmerke!!!: PATHOL Nevi are accumulations of melanocytes in the epidermis and dermis. All melanocytes are generated in the epidermis and during puberty, they migrate into the junctional region and into the deep area. Until adolescence, new melanocytic nevi are coming up. There are three types: i. Epidermal nevus ii. Junctional nevus iii. Intradermal nevus MALIGNANT MELANOMA: Most patients die very soon after developing this, causing massive metastasis. HOW TO DETECT MELANOCYTES: There are two ways we use: 1) Hydrogen peroxide reaction: stains the melanocytes white, which makes sense as hydrogen peroxide is normally used in bleach. 2) Immunohistochemical reaction: We can use two different antibody type stainings: S100 protein and melan-A. A specific staining, HMB45 is used to stain for malignant melanoma.

A/35. Morphologic patterns of acute inflammation according to the exudate, organ example

The morphological hallmarks of acute inflammatory reactions are dilation of small blood vessels and accumulation of leukocytes and fluid in the extravascular tissues. The symptoms for acute inflammation is: -edema -calor -rubor -tumor -dolor SEROUS INFLAMMATION: Serous inflammation is marked by the exudation of cell-poor fluid into spaces created by injury to suracfe epithelia or into body cavities lined by the peritoneum, pleura or pericardium. The fluid does not contain large numbers of leukocytes, but rather plasma due to the increased vasc. perm. and this kind of fluid accumulation in cavities is called EFFUSION. Examples include: skin blisters resulting from a burn or viral infection where fluid accumulates beneath the damaged epidermis of the skin. Others: endocarditis, meningitis, synovitis, bronchitis, rhinitis, pharyngitis FIBRINOUS INFLAMMATION: A fibrinous exeduate develops when the vascular leaks are so large that heigher molecular-weight molecules can pass out of the blood, like for example fibrinogen which will cause fibrin formation and deposition in extracellular spaces. (could also happen when there is a local procoagulant stimulus). This type of exaduate is characteristic for inflam lining the body cavities like meningitis, pericardium and pleura. The fibrin will appear like an eosinophilic meshwork upon histological examination. If the fibrin is not removed, it will lead to scarring. E.g. Fibrinous pericarditis, Fibrinous pleuritic, Fibrinous peritonitis, lobar pneumonia, pseudomembranous colitis, pseudomembrane of diphtheria, typhoid fever PURULENT INFLAMMATION AND ABCESS FORMATION: Purulent inflam is characterized by the formation of pus, an exaduate consisting of neutrophils, the liquefied debris of necrotic cells and edema fluid. The most frequent cause of this type of inflammation is infection with bacteria that cause liquefactive necrosis such as staphylococcus (called pyrogenic as they produce pus formation). E.g. purulent pleuritis, purulent meningitis, metastatic brown abscess, purulent bronchopneumonia and acute appendicitis. Abscesses are LOCALIZED COLLECTIONS OF PUS. They are produced by the seeding of of pyogenic bacteria into the tissue. Abscesses will have a central region that appears as a mass of necrotic leukocytes. The surrounding zone will have dilated vessels and fibroblastic proliferation, which indicates chronic inflammation and repair. When the abscess is persistent or at critical locations (such as the brain), it may have to drained surgically. Types: Empyema: in a body cavity b. Phlegmone: inflammation has no sharp border c. Skin stages: folliculitis → boil → carbuncle E.g. empyema vesicae felleae, purulent interstitial nephritis ULCER: An ulcer is a local defect or excavation of the surface of an organ or tissue that is produced by the shedding of inflamed necrtoic tissue. Ulceration can only occur when the tissue necrosis and resultant inflammation exist on or near a surface. It most commonly occurs: -in the mucosa of the mouth, stomach, intestines, urinary tract -skin and subcut. tissue of elderly people with back circulation Acute and chronic inflammation usually coexist in ulceration. And with chroniciity, the margins of the ulcer develop fibroblast proliferation, scarring and the acc. of lymphocytes, macrophages and plasma cells.

A/02. Reperfusion injury

Under certain circumstances, the restoration of blood flow to ischemic but viable tissues results, paradoxically in increased cell injury. This is the opposite of the expected outcome. This is a very clinically important phenomenon that may contribute significally to tissue damage, especially after myocardial and cerebral ischemia. ROS (reactive oxygen species) are produced in normal amounts during the redox reactions that occur during mitochondrial respiration and energy generation. These species include: O- (superoxide) which is converted to H2O2 (hydrogenperoxide) by superoxide dismutase (SUD). Even though both of them are ROS', H2O2 is much more stable than the free radical form of oxygen. ROS' are also produced in phagocytic leukocytes, mainly by neutrophils and macrophages, as a weapon for destroying ingested microbes. In leukocytes, H2O2 is converted to a highly reactive compound called hyperclorite by the enzyme myeloperoxidase. During O2 reduction, the mitochondria is one of the first organelles to be affected and therefore, once the O2 supply is back, the mitochondria hasn't gained it's strength yet. Thus, due to the now present O2, ROS are produced in a higher rate, tha the mitochondria is able to neutralize with superoxide dismutase enzyme (also catalase). Resulting in an excess of ROS which further drives the process of cell death.

B/43. Cardiac and Vascular tumors

VASCULAR TUMORS: Benign tumors: produce vascular channels filled with blood or lymph that are lined by normal-appearing endothelium Malignant tumors: are more cellular, show cytologic atypia, are prolif, do not form well-organized vessels and have anaplasia BENIGN TUMORS AND TUMOR-LIKE CONDITIONS: Vascular ectasias: generic term for any local dilation of a structure while, telangiecstasia is used to describe a perminent dilation of a preexisting small vessel that form a discrete red lesion. These are not true neoplasms, and can be congenital or aquired! Examples include: Nevus flammeus (birthmark), port-wine stain (a subtype of nevus flammeus), spider telangiectasias. -Hemangioma: Are very common tumors composed of blood-filled vessels, in which most of them are present from birth and initially increase in size, but eventually regress spontaneously. These lesions are usually confined to the head and neck, but they may be more extensive (called ANGIOMATOSIS) and arise internally; nearly 1/3 of these internal hemangiomas are found in the liver. May spon Characterized by increased nr of vessels filled with blood. Is localized, not systemic. Spontaneously regresses. The most common form is capillary hemangioma , but cavernous and pyogenic (nodule on skin or oral mucosa) also exist -Lymphangioma: The lymphatic counterpart of hemangioma, cap and cavernous types -Glomangioma: Are benign, equisitely painful tumors arising from specialized SMCs of glomus bodies, arteriovenous structures involved in thermmoregulation. Excision is curative! -BACILLARY ANGIOMATOSIS: Is a known infection in immunocompremised patients, aka people with AIDS. Caused by bartonella genus and cause vascular lesions that are red papules or nodules. It is the bacteria bartonella quintana (transmitted by human body lice) that caused the world known "TRENCH FEVER" during 1st world war! The gram-negative bacilli induce host tissues to produce hypoxia-inducible factor-1alpha (HIF-1alpha), which drives VEGF production and vascular proliferation. THE INFECTIONS ARE CURED BY ANTIBIOTIC TREATMENT! INTERMEDIATE/BORDER-LINE TUMORS: -KAPOCSI SARCOMA: -Is a vascular neoplasm caused by Kaposi sarcome herpesvirus/human herpesvirus 8. There is 4 tyoes: -classic -endemic african -transplant-associate -HIV-related IN 95% of the cases, HHV8 is involved, aka an STI: The morphology: -Patches on lower legs that spread proximally and become plaques, these plaques become nodular and neoplastic --> restricted to skin and is treated with surgery and radiation!!!!! -EPITHELIOID HEMANGIOENDOTHELIOMA: Are tumors of adults arising in med-to large veins. The clinical course is highly variable, however as many as 15% of patients die from this! Excision can be curative in majority of the cases! MALIGNANG TUMORS: -ANGIOSARCOMAS: Are malignant endothelial neoplasms ranging from highly differentiated tumors resembling hemangiomas to wildly anaplastic lesions. Clinically, these tumors are aggressive tumors that invade locally and metastaze. 5-year survival rates are as low as 30%!!!!! CARDIAC TUMORS: Primary neoplasms of the heart are fortunately beningn and UNCOMMON! -MYXOMAS: the most common primary tumor of the adult heart. 90% are atrial (left). Cause "ball-valve" obstruction, embolization, fever and malaise. Is due to the tumor cells secreting IL-6 which is a pro inflammatory acute phase cytokine! -RHABDOMYOMAS: Most frequent primary tumor in the heart of children, and cause valvular or outflow obstruction. They might actually spontaneously digress.

B/35. Valvular disease and their consequences

Valvular disease may result in stenosis, insufficiency (regurgitation or imcompetence) or both, however, it only involves ONE VALVE, in contrast to I.E. VALVULAR DISEASES: STENOSIS: Stenosis is the failure of a valve to open completely, obstructing forward flow. Valvular stenosis is almost always due to a primary cuspal abnormality stemming from a chornic process (for example calcification or valve scarring). INSUFFICIENCY: Results from failure of a valve to close completely, thereby allowing regurgitation (back flow) of blood. Valvular insufficiency can either be caused by an intrinsic disease of the valve cusps (e.g endocarditis), or disruption of the supporting structures (for example the aorta, mitral annulus, tendinous cord, papillary muscles, or ventricular wall) without primary cuspal injury. It can appear abruptly, as with chordal rupture or develop with time as a consequence of leaflet scarring and retraction. Stenosis and insufficiency may occur alone, or together in the same valve. CONSEQUENCES OF VALVULAR DISEASES: The turbulent flow caused by diseased valves typically produces abnormal heart sounds called murmurs, and can even sometimes be palpated as thrills. The outcome, degree of impairment, tempo of development etc depends upon each valvular disease. Example of rapid developing valvular disease is aortic valve cusp infection, while rheumatic mitral stenosis may develop over years, and its clinical effects are well tolerated until late in the course. The valvular abnormalities can be congenital or acquired. By far the most common congenital valvular disease is BICUSPID AORTIC VALVE, where the valve only have two leaflets instead of three. The disease is related to mutations in the Notch signalling pathway. The two cusps are of unequal size, with the larger cusp exhibiting a midline raphe that demonstrates incomplete cuspal separation. The bicuspid aortic valve is normally neither stenotic nor insufficient through early life, however, due to the increased strain the two leaflets must go through, they are prone to early and progressive degenrative calcification that gives rise to stenosis. OTHER VALVULAR DISEASES: -Inflammatory valve diseases cause postinflammatory neovascularization and scarring. Rheumatic heart disease results from anti-streptococcal ab's that cross-react with cardiac tissues; it most commonly affects the mitral valve and is responisble for almost all cases of acquired mitral stenosis. -Infective endocarditis can rapidly destroy normal valves, or can be indolent and minimally destructive of previously abnormal valves. Systemic embolization can produce septic infarcts -Nonbacterial thrombotic endocarditis occurs on prev normal valves as a result of hypercoagulative states; embolization is an important consequence.

B/10. DNA repair genes and role in carcinogenesis

We have 3 different DNA repair mechanisms in oncology: 1)Mistmatch repair: Mismatch repair (MMR) genes encode proteins responsible for repairing errors that occur during the normal replication of DNA. As new DNA strands are synthesized, errors such as insertion of an incorrect (mismatched) base or small loops of DNA may occur. Done by MSH 2 and 6 = MUTS alpha complex), and MSH 2 and 3 = MUTS beta, genes as well as MLH1. Cancers: Colorectal-, ovarium-, endometrium-, stomach cancer 2)Nucleotide excision repair: In nucleotide excision repair (NER), damaged bases are cut out within a string of nucleotides, and replaced with DNA as directed by the undamaged template strand. This repair system is used to remove pyrimidine dimers formed by UV radiation as well as nucleotides modified by bulky chemical adducts. Done by XPA XPC XPG genes Cancers: Basal cell carcinoma, squamous cell carcinoma, melanoma 3) Homolog recombination repair: Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks (DSB) Done by BRCA1 and BRCA2 genes, with the aid of ATM! Cancers (BRCA1): Breast-, ovarium-, prostata carcinoma Cancers (BRCA2): Breast-, ovarium-, pancreas, stomach carcinoma, melanoma Cancers (ATM): Ataxia teleangiectasia, breast carcinoma, different sporadic neoplasms Individuals with inherited mutations of genes involved in DNA repair systems are at greatly increased risk for the development of cancer! -Patients with hereditary nonpolyposis colon carcinoma (HNPCC) syndrome dramatically illustrates the role of defect mismatch repair genes in the development of cancer. These patients' genome show microsatellite instability (MSI) characterized by changes in length of short tandem repeating sequences throughout the genome. -Patients with Xerodoma pigmentosum have defects in the nucleotide excision repair pathway! They are at increased risk for the development of skin cancers in sites exposed to sunlight because of an inability to repair pyrimidine dimers induced by UV light -Syndromes involving defects in the homologous recombination DNA repair system constitute a group of disorders - Bloom syndrome, ataxia-telangiectasia and Fanconi anemia - that are characterized by hypersensitivity to DNA-damaging agents such as ionizing radiation. BRCA1 and BRCA2, which are mutated in familial breast cancers, also are involved in homol. DNA repair

A/42. Pathomechanism of autoimmume diseases

We know very little about the development of autoimmune diseases. The best guess of it's pathomechanism is that breakdown of self-tolerance and devlopment of autoimmunity result from the combined effects of susceptability genes (ex: HLA genes in RA and SLE, or C2 deficicency), which influence lymphocyte tolerance, and environmental factors (smoking increases risk of RA) such as infections or tissue injury, that alter the display of and responses to self antigens. (like in rheumatic heart disease)! Tolerance (unresponsiveness) to self antigens is a fundamental property of the immune system, and breakdown of tolerance is the basis of autoimmune diseases. -CENTRAL TOLERANCE: immature T and B lymphocytes that recognize self antigens (have too high affinity) in the central lymphoid organs are killed by apoptosis; In the bone marrow: High‐affinity self‐reactive B cells die by apoptosis. Some undergo a second round of gene rearrangement first, to express new receptors that are no longer self‐reactive (receptor editing). Thymic APCs with self MHC present self‐antigens to developing T cells. Any immature T cell that encounters a self‐antigen undergoes apoptosis (negative selection). T cells that complete maturation do not contain any self‐reactive cells. -PERIPERHAL TOLERANCE: mature lymphocytes that recognize self antigens in peripheral tissues become functionally inactive (anergic) are suppressed by regulatory T lymphocytes (imaintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, and CD25), or there is an inhibitory receptors and not a costimulatory receptor on T cells, then the T cell becomes anergic → cannot respond to antigen) or die by apoptosis. T lymphocyte goes through double negative (central tolerance) , and then double positive (periph). Then they go through psotive selection where they have to recognize MHC molecules. If they cannot do this they will be neglected. The factors that lead to a failure or self-tolerance and the development of autoimmunity include: 1) inheritance of susceptibility genes that disrupt different tolerance pathways 2) infections and tissue injury that expose self antigens and activate APCs and lymphocytes in the tissues ORGAN SPECIFIC EXAMPLES: -Hashimoto thyroiditis -Myasthenia Gravis -Graves disease -MS -Chron's disease -Autoimmune hemolytic anemia SYSTEMIC EXAMPLES: -SLE -PAN -Sjøgren syndrome -RA -Scleroderma

B/06. Inhibitory mechanisms of tumor suppressor genes and role in carcinogenesis

Whereas oncogenes encode proteins that promote cell growth, the product of tumor supressor genes apply brakes to cell proliferation. In principle, they exhibit anti-growth signals that can prevent cell proliferation by several complementary mechanisms. The signal may cause the dividing cell to enter G0 (quiescence) for example. RB - RETINOBLASTOMA GENE, GOVERNOR OF THE CELL CYCLE: -Was the first tumor suppressor gene to be discovered and is said to be the prototype of this family of genes. It was Knudson that discovered it in 1975 in a uncommon childhood tumor disease called retinoblastoma. -In 60% of the cases, retinoblastoma are sporadic, while in the rest it occurs due to familial causes! Two mutations are required to produce retinoblastoma. These mutations involve the Rb gene that has been mapped to chromosome 13q14. Both of the alleles of the RB locus must be inactivated for the development of the blastoma. In familial cases, children inherit one defective copy of the RB gene, while the other copy is normal. This means however, that only one somatic mutation is needed for the retinoblastoma to develop! The trait is said to have an AD inheritance pattern. In sporadic cases, Both normal RB alleles are lost by somatic mutation in one of the retinoblasts. ALTHOUGH THE LOSS OF NORMAL RB GENES INITIALLY WAS DISCOVERED IN RETINOBLASTOMAS, IT IS NOW EVIDENT THAT BIALLELIC LOSS OF THIS GENE IS FAIRLY COMMON IS SEVERAL CANCERS, INCLUDING BREAST, LUNG (SMALL CELL) AND BLADDER CANCERS, + risk of developing other types of cancers increase! MECHANISM: -Rb exerts anti-prliferatice effects by controlling the G1-to-S transition of the cell cycle. In its active form, RB is hypophosphorylated and binds to E2F transcription factors. This interaction prevents cyclin E to bind which is important for DNA replication, thus THE CELLS ARE ARRESTED IN G1! -GF signalling leads to inactivaton of RB, due to the increased cyclin D expression that will bind to CDK4/6 and phosphorylate RB leading to its inactivation. Loss of cell cycle control is fundamental to malignant transformation. Almost ALL cancers have a disabled G1 checkpoint due to mut in either RB directly or other proteins that affect RB function, exampels of these include cyclin D, CDK4, CDK inhibtors. -MANY ONCOGENIC DNA VIRUSES, LIKE HPV, ENCODE PROTEINS THAT BIND RB AND RENDER IT DYSFUNCTIONAL! TP53 - THE GUARDIAN OF THE GENOME: -The p53-encoding tumor supressor gene, TP53, is the most commonly mutated gene in human cancer and monitors stress of the cell. It can be activated by: anoxia, inappropriate oncogene signalling or DNA damage. -Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNA repair, cellular senscence and apoptosis. -It is activated through the process of phosphorylation, usually due to DNA damage. The activated p53 then drives transcription of p21, which will prevent phosph of RB (keeping it activated), thereby causing a G1-to-S cell cycle block. This pause allows the cell to repair DNA damage -If DNA damage cannot be repaired, p52 induces cellular senescence or apoptosis -Of human tumors, 70% demonstarte biallelic mut in tP53. Patients with the rare LI-FRAUMENI SYNDROME inherit one defective copy of TP53, so that only one somatic mutation is enough to lose normal p53 function. These patients are prone to develop a wide variety of tumors NORMALLY: -p53 normally has a short half‐life due to continuous degradation by MDM2 (mouse double minute homologue 2). MDM2 will bind ubiquitin to p53 in the cytosol which marks it for degradation by proteasomes. This is reversible. -As with RB, p53 can be incapacitated when bound by proteins encoded by oncogenic DNA viruses such as HPV! APC GENES - ADENOMATOUS POLYPOSIS COLI DISEASE: Although much is known about the circuitry that applies brakes to the cell cycle, the molecules that transmit antiproliferative signals to cells are less well recognized but also important. -TGF-beta inhibits prolferation of many cell types by activation of growth-inhibting genes such as CDK inhibitors and supression of growht promoting genes such as MYC and encoding cyclins. -It's function is compromised in many tumors by mutations of its receptors (examples include colon, stomach and endometrium) or by mutational inactivation of SMAD genes that transduce TGF-beta signaling (pancreas). -E-cadherin maintains contact inhibition, which is lost in malignant cells, allowing tumor cells to grow on top of each other. -The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein beta-catenin, which anchors E-cadherin responsible for contact inhibition of cells. With the loss of APC, beta-catenin is NOT DESTROYED, but is rather translocated into the nucleus where it acts as a growth-promoting TF that make cells behave as if they are under constant stimulation by the WNT pathway -In familial adenomatous polyposis syndrome, inheritance of a germ line mutation in the APC gene and sporadic loss of teh sole normal allele causes the development of hundreds of colonic polyps at a young age. These will inevitably develop into colonic cancer! somatic loss of both alleles are seen in 70% of sporadic colon cancers!