UWorld 6

Protease inhibitors

"Navir tease a protease" MOA: stops cleavage of HIV polypeptide into functional parts, thus preventing maturation of new viruses Clinical use: HIV Toxicity: hyperglycemia, GI intolerance, lipodystrophy (buffalo hump); nephropathy, hematuria (indinavir) -Ritonavir inhibits P450 enzymes

Aspergillus clinical

1. Allergic bronchopulmonary aspergillosis - a type 1 hypersensitivity reaction that presents with migratory pulmonary infiltrates, wheezing and increased IgE More common in CF and asthma patients 2. Colonization of the lung in fungus balls that form in old pulmonary cavities. May cause fever, hemoptysis and cough. Seen most often in patients with past TB infection (also lung cancers and some pneumonias) 3. Angioinvasive Aspergillosis. Occurs in immunosuppressed and neutropenic patients. Aspergillus can invade blood vessels and spread hematogenously to the kidneys, endocardium, brain, skin and paranasal sinuses causing infection and infarction. Kidney failure, endocarditis, and ring enhancing lesions can occur. Perinasal sinuses can cause necrosis around the nose.

Primary Ciliary Dyskinesia findings

1. Predispostion to upper and lower RTIs due to impaired mucociliary clearance. Patients develop chronic cough, chronic sinusitis, recurrent otitis media, and bronchiectasis. 2. Randomization of L-R body asymmetry. Half of all patients will have situs inversus 3. Infertility due to impaired function of sperm flagella (men) and immobility of fallopian tube cilia (women).

Aspergillus treatment

1st -voriconazole 2nd - aspergillus, isavuconazole 2/3 ampB lipo

A 3 yo boy is brought to the ER for refusal to move his right upper extremity. Mom recalls that he fell while holding hands and walking with his older sister 2 hours earlier. On PE, he holds his RUE at his side with his elbow extended and forearm pronated. Any motion of the right elbow produces pain. No visible bruises or edema. Structure injured? A. Annular ligament B. Biceps tendon C. Interosseous membrane D. Radial collateral ligament E. Ulnar collateral ligament

A Radial head subluxation (nursemaid's elbow), the most common elbow injury in children, particularly between 1 and 4. Results from a sharp pull on the hand while the forearm is pronated and the elbow extended. Causes the annular ligament to tear from its periosteal attachment at the radial neck. It then slips over the head of the radius and slides into the radiohumeral joint where it becomes trapped. By age 5, the annular ligament becomes thick and strong, decreasing the likelihood that it will be torn or displaced.

A 29 yo woman comes to the hospital due to fever and skin rash. She returned from a trip to Brazil 10 days ago. Her symtpoms started 5 days ago with a headache, retro-orbital pain, high grade fever and joint and muscle pains. She has also had episodes of epistaxis. Today she noticed a skin rash all over her body. Exam shows a diffuse maculopapular rash and scattered petechiae. Lab studies show thrombocytopenia. Which of the following diseases has a similar mode of transmission? A. Chikungunya fever B. Lymphogranuloma vereneum C. Meningococcal meningitis D. Pulmonary tuberculosis E. RMSF F. Typhoid fever

A This patient's presentation after recent travel is consistent with dengue fever. DF is due to a virus transmitted by the Aedes aegypti/mosquito. It is prevalent in tropical and subtropical regions (South and Southeast Asia, Pacific Islands, Caribbean, Central and South America) Presents as an acute febrile illness with headache, retro-orbital pain, and joint and muscle pain. Can include hemorrhage, thrombocytopenia, leukopenia, and hemococnetration. The Aedes also transmits the virus causing chikungunya, a febrile illness with flulike sytpoms. B - Sexual contact C - Respiratory droplet D - Airborne contact E - Rickettsia rickettsii tick F - Contaminated food or water

Lynch Syndrome (HNPCC)

AD non-polyposis syndrome with high risk of CRC Caused by defective DNA mismatch repair. DNA mismathc repair genes including MSH2, MLH1, account for 90% of cases of Lynch syndrome.

HLA-B27

Ankylosing spondylitis, Reiter's syndrome, ulcerative colitis, psoriasis

Dress syndrome drugs

Anticonvulsants (phenytoin, carbamazepine) Allopurinol Sulfonamides Antibiotics (minocycline, vancomycin)

Pulsatile vessels within the intercostal spaces and diminished femoral pusles relative to brahial pulses

Aortic coarctation

Turner syndrome heart finding

Aortic coarctation Bicusped aortic valve

Necrosis around the nose

Aspergillus or Mucor Aspergillus have 45 degree branching hypae Mucor has right angle branching

Voriconazole

Azole antifungal Aspergillus

Polio Vaccine. One patient receives an intramuscular inactivated vaccine and another a live attenuated oral vaccine. One month after vaccination, the levels of which of the following poliovirus antibodies will differ the most? A. Cerebrospinal fluid IgG B. Duodenal luminal IgA C. Serum IgA D. Serum IgG E. Serum IgM

B Secretory IgA is the major antibody associated with mucosal immunity. Upon intestinal exposure, B cells found in mesenteric lymph nodes and Peyer's patches become activated and migrate to the lamina propria underlying the intestinal mucosa. There, they become fully differentiated plasma cells that begin to synthesize IgA dimers. The IgA dimer is released into the intestinal lumen, and a portion of the receptor remains attached to the antibody, forming a complete secretory IgA molecule Stimulation of local secretory IgA production is best promoted when the corresponding mcuosal surfaces are directly stimulated by the antigen. In addition, live attenuated vaccine generally produce stroger immune responses than killed vaccines by acting as a persistent stimulus that better activates helper and cytotoxic T cells. As a result, the live attenuated oral (Sabin) poloiovirus vaccne generates a more robust oropharyngeal and intestinal mucosal IgA response than the inactivated poliovirus (Salk) vaccine. C,D, E - Increases with both forms of the polio vaccine and are protective against viral dissemination.

Failure of embryonic epithelial cell apoptosis in the duodenum

Duodenal atresia results from impaired recanalization of the duodenal lumen due to failure of eptihelial cell apoptosis during fetal life. it can cause increased levels of amniotic fluid (polyhydraminos)

A 62 yo man is brought to the ER with SOB. He is agitated and gasping for air and is unable to provide hisotry. History of alcohol abuse and attends AA. Blood pressure is 110/60, pulse is 104, RR is 32. Immediate endotrachial intubation is performed and mechanical ventialation begun. The patient dies several hours later. Autopsy shows engorged pulonary capillaires and intraalveolar, acellular, pin, material that is more prominent at the bases. Cause? A. Aspiration pneumonia B. Centriacinar emphysema C. Hypersensivity pneumontis D. PAH E. Pulmonary edema F. Pulmonary infarction

E Engorged alveolar capillaries reflect increaes pulmonary venous pressure, and pink, acellular material results from transudation of fluid plasma across the alveolar-capillary membrane. These histiopathologic findings are most consistent with acute pulmonary edema caused by increased alveolar capillary hydrostatic pressure from left sided heart failure The patient likely had dilated cardiomyopathy from chornic alcohol abuse.

A 68 yo man comes to the Er with a 2 day history of fever, chills and productive cough. Temp is 102, BP 108/52, pulse 102, RR 25 Crackles and bronchial breaths ounds in the RLL. There is dullness to percussion in the same area. CXR reveals RLL consolidation a right sided pleural effusion. Diagnostic thracentesis is perofrmed that shows an uncomplicated parapneumonic effusion. When a sterile sampele of the inflammtory exudate is experimentally intorudeced into normal human tissu,e rapid neutrophil locomotion is observed. Which of the following components of the exudate is more likely responsible for this observed effect? A. Bradykinin B. C4a C.IFN-gamma D. IL-4 E. Leukotriene B4 F. Thromboxane A2

E Parapneumonic effusions occur frequently in bacterial pneumonia as a result of exudative fluid accumulation. Under the influence of inflammatory stimuli, cell membrane phospholipids release arachidonic acid, a precursor to the eicosanoid inflammatory mediatiors. The most potent chemotactic eicosanoid is leukotriene B4.

A 56 yo woman with pneumonia. PMH: hypertension, type 2 DM, and long standing RA Exam reveals bilateral pneumonia and severe respiratory disease. Lethargic with focal neurologic deficit. Urgent endotrachial intubation is performed for mechanical ventilation, and the patient is started on broad-spectrum antibiotics. Repeat examination 2 hours later shows that she has developed areflexic, flaccid paralysis of all extremities. Reason? A. Cerebral septic emboli b. Diabetic neuropathy C. Guillain Barre D. Malignant hypertehrmia E. Vertebral subluxatio

E This patient with RA underwent urgent endotracheal intubation due to severe pneumonia and subsequently developed sudden onset auadriparesis. Long standing RA frequently involves the cervical spine and causes joint destruction with vertebral malalignment (subluxation). The antlantoaxial joint is often involved as the atlas has a high degree of mobility relative to the axis (C2 odontoid and body) Chronic symtpoms of cervical subluxation include neck pain, stiffness, and neurologic findings (sensory loss, muscle weakness). Endotrachial intubation can worsen the subluxation and cause compression of the spinal cord and or vertebrale arteries. Takes day to weeks to resolve

Lymph from the testes drains to

Para-aortic lymph nodes

Hepatoduodenal ligament contains

Portal triad: proper hepatic artery, portal vein, common bile duct

Ritonovir

Protease inhibitor with a particularly large P450 inhibitory effect

Protease inhibitors drug-drug interaction

Protease inhibitors are P450 inhibitors. Ritonovir has the greatest P450 inhibitory effect and boosts concentration of other protease inhibitors Rifampin activates P450 and and decreases concentration of protease inhibitors

HIV and protease

Proteases are enzymes that digest protein. HIV gene products are translated into long polyproteins that must be cleaved into functioning proteins by HIV proteases

Failed extension of finger and thumb

Radial nerve \ Finger drop.

Supinator Canal

Radial nerve, Failed extension of fingers and thumb

Aspergillus hyphae

Septate hyphae that form 45 degree angle branches

Fallopian tube epithelial tissue

Simple columnar Ciliated cells transport egg/embryo Damage can cause infertility, hydrosalpinx, ectopic pregnance

Uterus epithelium

Simple columnar --> endometrium Stratum functionalis sloughs off during menstruaton Prolonged estrogen exposure prevents shedding, resulting in hyperplasia/malignancy

Ovary epithelial tissue

Simple cuboidal (geminal) Rapidly proliferates to repair ovulatory surface defects

Kartagener heart finding

Situs inversus

4th pharyngeal pouch

Superior parathyroid glands, ultimobranchial body

DiGeorge syndrome heart findings

Tetralogy of Fallot Interrupted aortic arch

Aspergillus transmission

Transmitted via inhalation of spores contained in fruiting bodies

Diploplia/difficulty walking down stairs

Trochlear nerve (CN IV) palsy

Tuberous sclerosis heart finding

Valvular obstruction due to cardiac rhabdomyomas

Oppositional Defiant Disorder

a childhood disorder in which children are repeatedly argumentative and defiant, angry and irritable, and in some cases, vindictive Pattern of angry/irrritable mood, argumentation, defiant behavior and vindictiveness for greater than 6 months.

Aspergilloma

a fungal ball generally found in a preformed cavity of the lung, composed of a mass of Aspergillus hyphae

Postpartum blues

a mild, transient emotional letdown experienced by a majority of women after giving birth Peaks at 5 days and resolves within 14 days.

angioinvasive aspergillosis

assoc. immunocomp -need to be killed by neutrophils-> --neutropenia => leuk, lymphoma; steroid quickly disseminating fever, cough, hemoptysis kidney failure endocarditis ring-enhancing brain lesions paranasal sinus necrosis (like Mucor) tx: voriconazole, amphotericin B

Catalase positive fungi

candida and aspergillus

Protease

enzyme that digests protein

Alfatoxins

fungi that attack stored grains and may cause liver cancer Alfatoxins produced by aspergillus flavus can be found in nuts, legumes, wheat and other crops.

1st pharyngeal pouch

middle ear and auditory tube epithelium

2nd pharyngeal pouch

palatine tonsils, tonsillar fossa

-navir

protease inhibitor

Indinavir

protease inhibitor Has the special side effect of nephrolithiasis Adequate hydration is important to prevent nephrolithiasis

HIV pol gene products

reverse transcriptase, aspartate protease, integrase

Endocervix epithelium

simple columnar epithelium

Exocervix epithelium

stratified squamous epithelium

Vagina epithelium

stratified squamous non-keratinized Maintains acidic environment to prevent infection In Adenosis the upper 2/3 of the vagina is columnar (DES exposure in utero prevents replacement)

Postpartum depression

the sadness and inadequacy felt by some new mothers in the days and weeks after giving birth > 2 weeks of moderate depression, sleep or appetite disturbance, low energy, psychomotor changes, guilt, concentration difficulty, suicidal ideation.

3rd pharyngeal pouch

thymus, inferior parathyroid gland

Cervix epithelium

Ectocervix = stratified squamous non-keratinized Endocervix = simple columnar

Down syndrome CV

Endocardial cushion defects (ostimum primum ASD, regurgitant AV valves)

Lymph from the superior portion of the blzdder drains to

External iliac

Leuprolide

GnRH agonist-->initial LH/FSH release, but then down-regulation-->decreased estrogen and testosterone Uses: If given continuously: tx of metastatic prostate cancer, leiomyomas If given in pulsatile manner: tx of infertility

Alfatoxin cancer

HCC

Protease inhibitor resistance

HIV pol gene mutates to create altered proteases that are resistant

7 yo boy is brought to the ER by his parents for abdominal pain and arthralgias. Cough and runny nose last week, but otherswise good health PE shows palapable purpura over his buttocks and thighs Both knees are tender, but do not appear war or swollen. A stool occcult blood test is positive.

Henoch-Schonlein purpura, the most common systemic vasculitis in children. It predominantly affects those age 3-10 and often occurs following infection (URI, GI). HSP is caused by circulating IgA antigen immune complexes. Depositon in the walls of small vessels and the renal mesangium leads to recruitment of neutrophils and lymphocytes as well as activation of complement.

Allergic bronchopulmonary aspergillosis

Hypersensitivity reaction to Aspergillus. Asthma, blood eosinophilia, bronchiectasis with mucus plugging, and circulating antibodies to Aspergillus antigen. Proximal upper lobe bronchiectasis with mucoid impaction. Finger in glove appearance.

Friedrich ataxia heart complications

Hypertrophic cardiomyopathy

Motillin

Increases GI motility Site: M cells (small intestine)

Gastrin

Increases gastric acid secretion Site: G cells (gastric antrum, duodenum)

GIP

Increases insulin release Decreases Gastric H+ secretion Site: K cells (small intestine)

Secretin

Increases pancreatic HCO3 secretion Decreases H+ secretion Site: S cells (small intestine)

Cholecystokinin

Increases pancreatic enzyme and HCO3 secretion Site: I cells (small intestine)

Lymph from the upper third of the rectum drains to

Inferior mesenteric lymph nodes

Lymph frm the prostate drains to

Internal iliac

4 yo with dark red blood on toilet tissue. No pain or discomfort with stooling. Hb is 8. Coagulation is normal. Sequential imaging using 99m Tc-perethcnetate scintgraphy shows focal radiotracer accumulation in the RLQ Cause

Meckel Diverticulum from an ileal outgrowth from failed obilteration of Meckel diverticulum. Causes spontaneous but painless GI bleeding. Meckel diverticulum is also a potential lead point for intussusception, which can present with colicky abdominal pain and currant jelly stools. Ectopic gastric mucosa in the Meckel diverticulum secretes acid and causes local ulceration and bleeding. The radioisotope Tc-pertechnetate has an affinity for parietal cells of the gastric mucosa and is

Side effects of Protease inhibitors

Metabolic effects - Hyperglycemia due to insulin resistance - Dyslipidemias - Lipodystrophy (increased fat deposition in the trunk and decreases in the limbs and face) Indinavir can cause nephrolithiasis P450 inhibition causing drug-drug interaction

Amniotic fluid with increased levels of acetylcholinesterase

Neural tube defects occur due to failure of fusion of the neural plate edges during the 4th week of fetal development. Fusion begins in the cervical region and proceeds toward the cranial and caudal ends of the neural tube. Faillure to close results in anencepaly, impaired closure causes spina bifida. If either neuropore does not fuse, an opening persists between the neural tube and the amniotic cavity that allows leakage of AFP and acetylcholinesterase into the amniotic fluid.j

Protease inhibitors don't need what that NRTIs do?

No need for phosphorylation

HLA-DR4

Diabetes mellitus type 1, rheumatoid arthritis, Addison disease

HLA-DR3 or -DR4

Diabetes mellitus type 1, rheumatoid arthritis, SLE

Aspergillus features

Catalase positive Septae hypae that form 45 degree angle branches

Marfan syndrome heart findings

Cystric medial necrosis (eg, aortic dissection and aneurysm) Mitral valve prolapse

Somatostatin

Decreases secretion of most GI hormones Site: D cells (pancreatic islets, gut mucosa)

A 42 yo woman G4P4, comes in with heavy and painful menstrual bleeding over the last 3 months. The patient has a bilateral tubal ligation 3 years ago after the birth of her last child. On bimanual examination, the uterus is uniformly enlarged. Urine B-hCG is negative. Biopsy shows secretory Which of the following is the most likely cause of the patient's symptoms? A. Benign myometrial smooth muscle cell proliferation. B. Blastocyst implantation in the fallopioan tube. C. Deficiency of von Willebrand factor E. Greater increaese in endometrial gland prolfieration compared to stroma F. Hyperplastic growth of tissue from endometrial gland prolfieration compared to stroma

D Adenomyosis is the presence of endometrial glandular tissue within the myometrium. The condition is relatively common in midle aged parous females. Symptoms include heavy menstrual bleeding, which is due to an increased endometrial surface, and dysmenorrhea, which results from endometrial tissue in the conddifned myometrial space. Pheysical examination classically shows a uniformly enlarged uterus. Uterine enlargement results form hormonal stimulation of the endometrial tissue in the myometirum. A biopsy of the endometirum would be normal. Adenomyosis can only be diagnosed definitevly by microscopic exmaination of a hysterectomy specimen. A - Leiomyomas are caused by prolfieratie of myometrial smooth muscle . ells. They may cause heavy menstrual bleeding, but the uterus is usually irregularly enlarged. B - The fallopian tube is the msot common location for ectopic pregnancy C - vWD is commonly inherited coagulopathy. A deficiency or dysfunciton causes long-standing, heavy menstural bleedign. This patient's bleeding only started recently though. E - Endometrial hyperplasia is characterized by a greater increase in endometrial gland prolferation as compared to stroma. F - Polyps are a common cause of uterine bleeding. They are benign projections from the uterine linging resulting from hyperplastic growht of endometrial glands and stroma. They don't cause enlargement.

A 68 yo man comes to the Er due to abdominal pain and nausea for the past 2 day. History of atherosclerotic cardiovascular disease. Underwent CABG surgery 2 years ago. BP is 105/65 and HR is 120/min and irregular. Mild diffuse tenderness and decreased bowel sounds. Lab studies: Bicarbonate 12 pH 7.25 Lactic acid 5.6 (0.4-2.0) ECG shows absent P waves and an irregular rate and rhythm. CT scan of the abdomen reveals colonic wall thickening and no ehancement with IV conrast. Urine is acidid. Renal metabolism of which of the following amino acids is most important for maximizing acid excretion in this patient? A. Alanine B. Arginine C. Aspartate D. Glutamine E. Histidine

D This patient has acute ischemic colitis, most likely due to embolic disease related to his atrial fibrillation. The ischemic bowel unedergoes anaerobic metabolism, causing lactate accumulation in the blood that leads to an anion gap metabolic acidosis. Acidosis stimulates renal ammoniagenesis, a process by which renal epithelial cells metabolize glutamine, generating ammonium and bicarbonate. Ammonium ions are transported into the tubular fluid and excreted in the urine while peritubular capillaries absorb bicarbonate, which functions to buffer acids in the blood.