Clinical Sciences-2

Dobutamine is an example of: Alpha-1 agonist Alpha-2 agonist Beta-1 antagonist Beta-2 antagonist Beta-1 agonist

Beta-1 agonist Adrenoceptor agonists Alpha-1 agonists phenylephrine Alpha-2 agonists clonidine Beta-1 agonists dobutamine Beta-2 agonists salbutamol Beta-3 agonists being developed, may have a role in preventing obesity (stimulation causes lipolysis)

The chance of a 45-year-old mother giving birth to a child with Down's syndrome is approximately: 1 in 5 1 in 10 1 in 50 1 in 100 1 in 500

1 in 50 Down's syndrome: epidemiology and genetics Risk of Down's syndrome with increasing maternal age Age (years) Risk 20 1 in 1,500 30 1 in 800 35 1 in 270 40 1 in 100 45 1 in 50 or greater One way of remembering this is by starting at 1/1,000 at 30 years and then dividing the denominator by 3 (i.e. 3 times more common) for every extra 5 years of age Cytogenetics Mode % of cases Risk of recurrence Non-disjunction 94% 1 in 100 if under mother < 35 years Robertsonian translocation (usually onto 14) 5% 10-15% if mother is translocation carrier 2.5% if father is translocation carrier Mosaicism 1% The chance of a further child with Down's syndrome is approximately 1 in 100 if the mother is less than 35 years old. If the trisomy 21 is a result of a translocation the risk is much higher

A small study is designed to look at the link between drinking alcohol and liver cirrhosis. One hundred patients with liver cirrhosis were questioned and it was found that 80 of them drank excessive alcohol. As a control, one hundred patients without liver cirrhosis were questioned and only 20 of these patients drank excessively. What is the odds ratio of developing liver cirrhosis for people who drink excessively compared to those who do not? 2 4 0.25 16 3

16 The odds of a patient with liver cirrhosis having a history of excessive drinking is 80/20 = 4. The odds of a patient without liver cirrhosis having a history of excessive drinking is 20/80 = 0.25. Therefore the odds ratio = 4 / 0.25 = 16 Odds and odds ratio Odds are a ratio of the number of people who incur a particular outcome to the number of people who do not incur the outcome. The odds ratio may be defined as the ratio of the odds of a particular outcome with experimental treatment and that of control. Odds vs. probability In contrast, probability is the fraction of times you'd expect to see an event in many trials. When expressed as a single number probability is always between 0 and 1. So, if we take the example of rolling a dice: the probability of rolling a six is 1/6 or 0.166666 the odds of rolling a six is 1/5 or 0.2 Odds ratios are the usual reported measure in case-control studies. It approximates to relative risk if the outcome of interest is rare. For example, if we look at a trial comparing the use of paracetamol for dysmenorrhoea compared to placebo we may get the following results Total number of patients Achieved = 50% pain relief Paracetamol 60 40 Placebo 90 30 The odds of achieving significant pain relief with paracetamol = 40 / 20 = 2 The odds of achieving significant pain relief with placebo = 30 / 60 = 0.5 Therefore the odds ratio = 2 / 0.5 = 4

A 31-year-old woman is diagnosed with familial hypercholesterolaemia. Genetic testing shows that she is heterozygous for the condition. You discuss the possibility of screening her relatives. What is the chance her brother will also be affected? 50% 66% 25% 100% 0%

50% As familial hypercholesterolaemia is an autosomal dominant condition 50% of the first-degree relatives of heterozygotes will be affected. Please see the PLoS link for more details. Familial hypercholesterolaemia Familial hypercholesterolaemia (FH) is an autosomal dominant condition that is thought to affect around 1 in 500 people. It results in high levels of LDL-cholesterol which, if untreated, may cause early cardiovascular disease (CVD). FH is caused by mutations in the gene which encodes the LDL-receptor protein. Clinical diagnosis is now based on the Simon Broome criteria: in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or children TC > 6.7 mmol/l and LDL-C > 4.0 mmol/l, plus: for definite FH: tendon xanthoma in patients or 1st or 2nd degree relatives or DNA-based evidence of FH for possible FH: family history of myocardial infarction below age 50 years in 2nd degree relative, below age 60 in 1st degree relative, or a family history of raised cholesterol levels Management the use of CVD risk estimation using standard tables is not appropriate in FH as they do not accurately reflect the risk of CVD referral to a specialist lipid clinic is usually required the maximum dose of potent statins are usually required first-degree relatives have a 50% chance of having the disorder and should therefore be offered screening. This includes children who should be screened by the age of 10 years if there is one affected parent statins should be discontinued in women 3 months before conception due to the risk of congenital defects

A new anti-epileptic drug is trialled for children with absence seizures. There are 250 children in the control group and 150 children assigned to take the new drug. After 4 months 100 children in the control group had had a seizure compared to 15 children in the group taking the new medication. What is the relative risk reduction? 4 30% 3.33 75% 40%

75% Relative risk reduction = (EER - CER) / CER Experimental event rate, EER = 15 / 150 = 0.1 Control event rate, CER = 100 / 250 = 0.4 Relative risk reduction = (EER - CER) / CER = (0.1 - 0.4) / 0.4 = -0.75 or a 75% reduction Relative risk Relative risk (RR) is the ratio of risk in the experimental group (experimental event rate, EER) to risk in the control group (control event rate, CER). The term relative risk ratio is sometimes used instead of relative risk. To recap EER = rate at which events occur in the experimental group CER = rate at which events occur in the control group For example, if we look at a trial comparing the use of paracetamol for dysmenorrhoea compared to placebo we may get the following results Total number of patients Experienced significant pain relief Paracetamol 100 60 Placebo 80 20 Experimental event rate, EER = 60 / 100 = 0.6 Control event rate, CER = 20 / 80 = 0.25 Therefore the relative risk ratio = EER / CER = 0.6 / 0.25 = 2.4 If the risk ratio is > 1 then the rate of an event (in this case experiencing significant pain relief) is increased compared to controls. It is therefore appropriate to calculate the relative risk increase if necessary (see below). If the risk ratio is < 1 then the rate of an event is decreased compared to controls. The relative risk reduction should therefore be calculated (see below). Relative risk reduction (RRR) or relative risk increase (RRI) is calculated by dividing the absolute risk change by the control event rate Using the above data, RRI = (EER - CER) / CER = (0.6 - 0.25) / 0.25 = 1.4 = 140%

Which one of the following statements regarding the normal menstrual cycle is incorrect? A number of follicles develop in the follicular phase under the influence of FSH The luteal phase is also known as the secretory phase The follicular phase follows menstruation and occurs around day 5 - 13 A surge of FSH causes ovulation Progesterone levels are low in the follicular phase

A surge of FSH causes ovulation LH surge causes ovulation Menstrual cycle The menstrual cycle may be divided into the following phases: Days Menstruation 1-4 Follicular phase (proliferative phase) 5-13 Ovulation 14 Luteal phase (secretory phase) 15-28 Further details are given in the table below Follicular phase (proliferative phase) Luteal phase (secretory phase) Ovarian histology A number of follicles develop. One follicle will become dominant around the mid-follicular phase Corpus luteum Endometrial histology Proliferation of endometrium Endometrium changes to secretory lining under influence of progesterone Hormones A rise in FSH results in the development of follicles which in turn secrete oestradiol When the egg has matured, it secretes enough oestradiol to trigger the acute release of LH. This in turn leads to ovulation Progesterone secreted by corpus luteum rises through the luteal phase. If fertilisation does not occur the corpus luteum will degenerate and progesterone levels fall Oestradiol levels also rise again during the luteal phase Cervical mucus Following menstruation the mucus is thick and forms a plug across the external os Just prior to ovulation the mucus becomes clear, acellular, low viscosity. It also becomes 'stretchy' - a quality termed spinnbarkeit Under the influence of progesterone it becomes thick, scant, and tacky Basal body temperature Falls prior to ovulation due to the influence of oestradiol Rises following ovulation in response to higher progesterone levels

You are a ST1 doctor in medicine. Whilst on-call you review a 60-year-old woman who is known to have COPD. She has been admitted with an infective exacerbation and has not responded to nebulisers and intravenous aminophylline. Her most recent blood gases show a worsening respiratory acidosis. You feel that non-invasive ventilation (NIV) is needed and bleep the on-call physio. After discussing the blood gas results over the phone she says that NIV is not indicated in her opinion and refuses to set it up. What is the most appropriate action? Phone her back in 30 minutes and exaggerate the clinical picture to persuade her to come in Accept her professional opinion and reassess the situation in 30 minutes Set-up the NIV equipment yourself to avoid any further delay As there is a disagreement on management speak to the consultant on-call Transfer the patient to another hospital

As there is a disagreement on management speak to the consultant on-call By far the best option here is to speak to the consultant on-call. The physio may be experienced in providing NIV but it is ultimately a medical decision about whether to start a treatment. Accepting her opinion is a poor option as she has not reviewed the patient herself and is only giving an opinion on the basis of blood gases. Setting up NIV equipment requires training. If done incorrectly it could potentially harm a patient. Transferring an acutely unwell patient simply because the physio won't come in is not appropriate. Lying about clinical information is a very poor option.

Which one of the following causes of primary immunodeficiency is due to a defect in both B-cell and T-cell function? Di George syndrome Chronic granulomatous disease Bruton's congenital agammaglobulinaemia Leukocyte adhesion deficiency Ataxic telangiectasia

Ataxic telangiectasia Combined B- and T-cell disorders: SCID WAS ataxic (SCID, Wiskott-Aldrich syndrome, ataxic telangiectasia) Primary immunodeficiency Primary immunodeficiency disorders may be classified according to which component of the immune system they affect. Neutrophil disorders Disorder Underlying defect Notes Chronic granulomatous disease Lack of NADPH oxidase reduces ability of phagocytes to produce reactive oxygen species Causes recurrent pneumonias and abscesses, particularly due to catalase-positive bacteria (e.g. Staphylococcus aureus and fungi (e.g. Aspergillus) Negative nitroblue-tetrazolium test Abnormal dihydrorhodamine flow cytometry test Chediak-Higashi syndrome Microtubule polymerization defect which leads to a decrease in phagocytosis Affected children have 'partial albinism' and peripheral neuropathy. Recurrent bacterial infections are seen Giant granules in neutrophils and platelets Leukocyte adhesion deficiency Defect of LFA-1 integrin (CD18) protein on neutrophils Recurrent bacterial infections. Delay in umbilical cord sloughing may be seen Absence of neutrophils/pus at sites of infection B-cell disorders Disorder Underlying defect Notes Common variable immunodeficiency Many varying causes Hypogammaglobulinemia is seen. May predispose to autoimmune disorders and lymphona Bruton's (x-linked) congenital agammaglobulinaemia Defect in Bruton's tyrosine kinase (BTK) gene that leads to a severe block in B cell development X-linked recessive. Recurrent bacterial infections are seen Absence of B-cells with reduce immunoglogulins of all classes Selective immunoglobulin A deficiency Maturation defect in B cells Most common primary antibody deficiency. Recurrent sinus and respiratory infections Associated with coeliac disease and may cause false negative coeliac antibody screen T-cell disorders Disorder Underlying defect Notes DiGeorge syndrome 22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate Combined B- and T-cell disorders Disorder Underlying defect Notes Severe combined immunodeficiency Many varying causes. Most common (X-linked) due to defect in the common gamma chain, a protein used in the receptors for IL-2 and other interleukins. Other causes include adenosine deaminase deficiency Recurrent infections due to viruses, bacteria and fungi. Reduced T-cell receptor excision circles Stem cell transplantation may be successful Ataxia telangiectasia Defect in DNA repair enzymes Autosomal recessive. Features include cerebellar ataxia, telangiectasia (spider angiomas), recurrent chest infections and 10% risk of developing malignancy, lymphoma or leukaemia Wiskott-Aldrich syndrome Defect in WAS gene X-linked recessive. Features include recurrent bacterial infections, eczema, thrombocytopaenia. Low IgM levels Increased risk of autoimmune disorders and malignancy

Cystic fibrosis is due to a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Which chromosome is this gene located on? Chromosome 3 Chromosome 7 Chromosome 11 Chromosome 14 Chromosome 15

Chromosome 7 Cystic fibrosis Cystic fibrosis (CF) is an autosomal recessive disorder causing increased viscosity of secretions (e.g. lungs and pancreas). It is due to a defect in the cystic fibrosis transmembrane conductance regulator gene (CFTR), which codes a cAMP-regulated chloride channel In the UK 80% of CF cases are due to delta F508 on the long arm of chromosome 7. Cystic fibrosis affects 1 per 2500 births, and the carrier rate is c. 1 in 25 Organisms which may colonise CF patients Staphylococcus aureus Pseudomonas aeruginosa Burkholderia cepacia* Aspergillus *previously known as Pseudomonas cepacia

Interferon-alpha may be used in the management of each one of the following, except: Metastatic renal cell cancer Hepatitis B Kaposi's sarcoma Hepatitis C Chronic granulomatous disease

Chronic granulomatous disease Interferon Interferons (IFN) are cytokines released by the body in response to viral infections and neoplasia. They are classified according to cellular origin and the type of receptor they bind to. IFN-alpha and IFN-beta bind to type 1 receptors whilst IFN-gamma binds only to type 2 receptors. IFN-alpha produced by leucocytes antiviral action useful in hepatitis B & C, Kaposi's sarcoma, metastatic renal cell cancer, hairy cell leukaemia adverse effects include flu-like symptoms and depression IFN-beta produced by fibroblasts antiviral action reduces the frequency of exacerbations in patients with relapsing-remitting MS IFN-gamma produced by T lymphocytes & NK cells weaker antiviral action, more of a role in immunomodulation particularly macrophage activation may be useful in chronic granulomatous disease and osteopetrosis

Which type of secondary messenger system does adrenaline stimulate? Calcium Protein kinase Phosphoinositide Cyclic AMP Cyclic GMP

Cyclic AMP Second messengers Overview many different types allow amplification of external stimulus cAMP system Phosphoinositol system cGMP system Tyrosine kinase system Ligand: Neurotransmitters (Receptor) Epinephrine (α2, β1, β2) Acetylcholine (M2) Epinephrine (α1) Acetylcholine (M1, M3) - - Ligand: Hormones ACTH, ADH, calcitonin, FSH, glucagon, hCG,LH, MSH, PTH, TSH, GHRH* angiotensin II, GnRH, GHRH*, Oxytocin, TRH ANP, Nitric oxide insulin, growth hormone, IGF, PDGF Primary effector Adenylyl cyclase Phospholipase C Guanylate cyclase Receptor tyrosine kinase Secondary messenger cAMP (cyclic adenosine monophosphate) IP3 (inositol 1,4,5 trisphosphate) and DAG (Diacylglycerol) cGMP Protein phosphatase

Northern blotting is used to: Detect and quantify proteins Amplify DNA Detect RNA Detect DNA Amplify RNA

Detect RNA Molecular biology techniques SNOW (South - NOrth - West) DROP (DNA - RNA - Protein) Molecular biology techniques The following table shows a very basic summary of molecular biology techniques Technique Description Southern blotting Detects DNA Northern blotting Detects RNA Western blotting Detects proteins Uses gel electrophoresis to separate native proteins by 3-D structure Examples include the confirmatory HIV test Molecular biology techniques SNOW (South - NOrth - West) DROP (DNA - RNA - Protein) Enzyme-linked immunosorbent assay (ELISA) a type of biochemical assay used to detect antigens and antibodies a colour changing enzyme is attached to the antibody if looking for an antigen and to an antigen if looking for an antibody the sample therefore changes colour if the antigen or antibody is detected an example includes the initial HIV test

Which one of the following statements regarding growth hormone is incorrect? Doesn't act directly on chondrocytes or osteoblasts Is an anabolic hormone Is responsible for changes in protein, lipid, and carbohydrate metabolism Is secreted by the somatotroph cells Acts on a transmembrane receptor

Doesn't act directly on chondrocytes or osteoblasts Growth hormone acts both directly on tissues (e.g. stimulates division and multiplication of cartilage chondrocytes) and also indirectly following the secretion of insulin-like growth factor 1 Growth hormone Growth hormone (GH) is an anabolic hormone secreted by the somatotroph cells of the anterior lobe of the pituitary gland. It has actions on multiple organ systems and is important in postnatal growth and development. Growth hormone is also responsible for changes in protein, lipid, and carbohydrate metabolism Mechanism of action acts on a transmembrane receptor for growth binding of GH to the receptor leads to receptor dimerization acts directly on tissues and also indirectly via insulin-like growth factor 1 (IGF-1), primarily secreted by the liver Conditions associated with GH disorders excess GH: acromegaly GH deficiency: resulting in short stature

A 34-year-old man is reviewed in clinic. He has recently had his annual echocardiogram showing no change in the dilation of his aortic sinuses or mitral valve prolapse. You note he is tall with pectus excavatum and arachnodactyly. His condition is primarily due to a defect in which one of the following proteins? Polycystin-1 Fibrillin Type IV collagen Type I collagen Elastin

Fibrillin Although fibrillin is the primary protein affected (due to a defect in the fibrillin-1 gene) it should be noted that fibrillin is used as a substrate of elastin Marfan's syndrome Marfan's syndrome is an autosomal dominant connective tissue disorder. It is caused by a defect in the fibrillin-1 gene on chromosome 15 and affects around 1 in 3,000 people. Features tall stature with arm span to height ratio > 1.05 high-arched palate arachnodactyly pectus excavatum pes planus scoliosis of > 20 degrees heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic aneurysm, aortic dissection, aortic regurgitation, mitral valve prolapse (75%), lungs: repeated pneumothoraces eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera, myopia dural ectasia (ballooning of the dural sac at the lumbosacral level) The life expectancy of patients used to be around 40-50 years. With the advent of regular echocardiography monitoring and beta-blocker/ACE-inhibitor therapy this has improved significantly over recent years. Aortic dissection and other cardiovascular problems remain the leading cause of death however.

A 14-year-old girl is admitted to hospital following a ruptured ectopic pregnancy. She comes from a family of Jehovah's Witnesses. Her haemoglobin on admission is 6.9 g/dl. She consents to a blood transfusion but her mother refuses. What is the most appropriate course of action? Advise the parents she will have to get a High Court injunction in order to stop the transfusion Give the blood transfusion Transfer the patient to a hospital run by Jehovah's Witnesses Respect parental wishes and withhold the blood transfusion Ask the hospital lawyer to come in and decide upon the correct course of action

Give the blood transfusion The GMC gives the following guidance: 'You should encourage young people to involve their parents in making important decisions, but you should usually abide by any decision they have the capacity to make themselves' With respect to Jehovah's witnesses: 'You should not make assumptions about the decisions that a Jehovah's Witness patient might make about treatment with blood or blood products. You should ask for and respect their views and answer their questions honestly and to the best of your ability. You may also wish to contact the hospital liaison committees established by the Watch Tower Society (the governing body of Jehovah's Witnesses) to support Jehovah's Witnesses faced with treatment decisions involving blood. These committees can advise on current Society policy regarding the acceptability or otherwise of particular blood products. They also keep details of hospitals and doctors who are experienced in 'bloodless' medical procedures.' A blood transfusion is clearly in the patient's best interests and in the scenario described above may potentially be life-saving. Whilst a child cannot refuse treatment they are able to provide consent. Giving the blood transfusion is therefore both clinically and ethically the right course of action. Not giving the blood transfusion not only fails to respect the patient's wishes but also causes potential harm.

SdThe atrial natriuretic peptide receptor is an example of a: Ligand-gated ion channel Intracellular receptor Guanylate cyclase receptor G protein-coupled receptor Tyrosine kinase receptor

Guanylate cyclase receptor

The nitric oxide receptor is an example of a: Ligand-gated ion channel MAPK/ERK receptor Guanylate cyclase receptor G protein-coupled receptor Tyrosine kinase receptor

Guanylate cyclase receptor The nitric oxide receptor is a soluble, intracellular guanylate cyclase Nitric oxide Previously known as endothelium derived relaxation factor, nitric oxide (NO) has emerged as a molecule which is integral to many physiological and pathological processes. It is formed from L-arginine and oxygen by nitric oxide synthetase (NOS). An inducible form of NOS has been shown to be present in macrophages. Nitric oxide has a very short half-life (seconds), being inactivated by oxygen free radicals Effects acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing Ca2+ levels vasodilation, mainly venodilation inhibits platelet aggregation Clinical relevance underproduction of NO is implicated in hypertrophic pyloric stenosis lack of NO is thought to promote atherosclerosis in sepsis increased levels of NO contribute to septic shock organic nitrates (metabolism produces NO) is widely used to treat cardiovascular disease (e.g. angina, heart failure) sildenafil is thought to potentiate the action of NO on penile smooth muscle and is used in the treatment of erectile dysfunctions

Which one of the following genetic conditions is the most prevalent in a Caucasian population? Wilson's disease Sickle cell anaemia Cystic fibrosis Alpha-1 antitrypsin Haemochromatosis

Haemochromatosis Haemochromatosis is more common than cystic fibrosis Haemochromatosis is an autosomal recessive disorder with a carrier rate of 1 in 10 and is present in about 1 in 200-400 people. Cystic fibrosis (CF) has a carrier rate of 1 in 25 and is present in about 1 in 2,500 births. CF is often quoted as being the most common lethal inherited condition in Caucasians Haemochromatosis: features Haemochromatosis is an autosomal recessive disorder of iron absorption and metabolism resulting in iron accumulation. It is caused by inheritance of mutations in the HFE gene on both copies of chromosome 6*. It is often asymptomatic in early disease and initial symptoms often non-specific e.g. lethargy and arthralgia Epidemiology 1 in 10 people of European descent carry a mutation genes affecting iron metabolism, mainly HFE prevalence in people of European descent = 1 in 200 Presenting features early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands) 'bronze' skin pigmentation diabetes mellitus liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition) cardiac failure (2nd to dilated cardiomyopathy) hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism) arthritis (especially of the hands) Questions have previously been asked regarding which features are reversible with treatment: Reversible complications Cardiomyopathy Skin pigmentation Irreversible complications Liver cirrhosis** Diabetes mellitus Hypogonadotrophic hypogonadism Arthropathy *there are rare cases of families with classic features of genetic haemochromatosis but no mutation in the HFE gene **whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not

Which one of the following would shift the oxygen dissociation curve to the right? Alkalosis HbF Low 2,3-DPG levels High pCO2 levels Methaemoglobin

High pCO2 levels Oxygen dissociation curve shifts Left - Lower oxygen delivery - Lower acidity, temp, 2-3 DPG - also HbF, carboxy/methaemoglobin shifts Right - Raised oxygen delivery - Raised acidity, temp, 2-3 DPG Oxygen dissociation curve The oxygen dissociation curve describes the relationship between the percentage of saturated haemoglobin and partial pressure of oxygen in the blood. It is not affected by haemoglobin concentration Basics shifts to left = for given oxygen tension there is increased saturation of Hb with oxygen i.e. decreased oxygen delivery to tissues shifts to right = for given oxygen tension there is reduced saturation of Hb with oxygen i.e. enhanced oxygen delivery to tissues Shifts to Left = Lower oxygen delivery Shifts to Right = Raised oxygen delivery HbF, methaemoglobin, carboxyhaemoglobin Low [H+] (alkali) Low pCO2 Low 2,3-DPG Low temperature Raised [H+] (acidic) Raised pCO2 Raised 2,3-DPG* Raised temperature The L rule Shifts to L → Lower oxygen delivery, caused by Low [H+] (alkali) Low pCO2 Low 2,3-DPG Low temperature Another mnemonic is 'CADET, face Right!' for CO2, Acid, 2,3-DPG, Exercise and Temperature

A 69-year-old female with a history of multiple myeloma is admitted with confusion. The following results are obtained: Na+ 147 mmol/l K+ 4.7 mmol/l Urea 14.2 mmol/l Creatinine 102 µmol/l Adjusted calcium 3.9 mmol/l What is the most appropriate initial management? IV 0.45% saline IV zoledronic acid Oral prednisolone IV pamidronate IV 0.9% saline

IV 0.9% saline The raised sodium is a function of dehydration and will correct once the patient is adequately rehydrated Hypercalcaemia: management The initial management of hypercalcaemia is rehydration with normal saline, typically 3-4 litres/day. Following rehydration bisphosphonates may be used. They typically take 2-3 days to work with maximal effect being seen at 7 days Other options include: calcitonin - quicker effect than bisphosphonates steroids in sarcoidosis There is a limited role for the use of furosemide in hypercalcaemia. It may be useful in patients who cannot tolerate aggressive fluid rehydration

What level of evidence does a study offer which is obtained from a meta-analysis of randomised controlled trials? Ia Ib IIa IIb IV

Ia Study design: evidence and recommendations Levels of evidence Ia - evidence from meta-analysis of randomised controlled trials Ib - evidence from at least one randomised controlled trial IIa - evidence from at least one well designed controlled trial which is not randomised IIb - evidence from at least one well designed experimental trial III - evidence from case, correlation and comparative studies IV - evidence from a panel of experts Grading of recommendation Grade A - based on evidence from at least one randomised controlled trial (i.e. Ia or Ib) Grade B - based on evidence from non-randomised controlled trials (i.e. IIa, IIb or III) Grade C - based on evidence from a panel of experts (i.e. IV)

You are a ST1 doctor in General Medicine. During an on-call you are in A&E seeing a patient who has a pneumothorax. On arriving you find the A&E ST2 doctor attempting to perform an aspiration. He appears to about to insert the needle at the wrong landmark. What is the most appropriate action? Tell your colleagues about what happened in the mess to ensure they are aware of the doctors limitations Say nothing, stay with the patient and take over when he asks for help Go and get the A&E consultant Say nothing at the time but fill in a clinical incident form Immediately voice your concerns and ask him to stop

Immediately voice your concerns and ask him to stop If you have concerns regarding the management of a patient it is important to act on them. It may be that you are wrong - the ST2 doctor may actually be performing the aspiration using a recognised, safe technique. This should not however stop you voicing your concerns - failing to do so may put the patient at risk. If you feel unable to do you should discuss your concerns with someone who is in a position to act. Saying nothing puts the patient at potential harm. Filling in a clinical incident form after the event will not alter this. Spreading rumours in the mess about a doctors ability is unprofessional and unlikely to lead to a resolution of the problem.

Which one of the following immunological changes is seen in progressive HIV infection? Increase in IL-2 production Increase in B2-microglobulin levels Increased type IV hypersensitivity responses Increased natural killer (NK) cell function A rise in the CD4/CD8 ratio

Increase in B2-microglobulin levels HIV: immunology The following immunological changes are seen in progressive HIV: reduction in CD4 count increase B2-microglobulin decreased IL-2 production polyclonal B-cell activation decrease NK cell function reduced delayed hypersensitivity responses

A patient who takes bendroflumethiazide is noted to have a potassium of 3.1 mmol/l. What is the main mechanism causing hypokalaemia in patients taking bendroflumethiazide? Decreased flow rate in the nephron resulting in a decreased potassium gradient Increased sodium reaching the collecting ducts Inhibition of renin-angiotensin-aldosterone system secondary to hypovolaemia Decreased sodium reaching the distal convoluted tubule Opening of potassium channel in proximal convoluted tubule

Increased sodium reaching the collecting ducts Bendroflumethiazide - mechanism of hypokalaemia: increased sodium reaching the collecting ducts activation of the renin-angiotensin-aldosterone Increased delivery of sodium to the collecting ducts causes the sodium-potassium exchanger to release more potassium into the urine. Another cause is activation of the renin-angiotensin-aldosterone system secondary to hypovolaemia Thiazide diuretics Thiazide diuretics work by inhibiting sodium absorption at the beginning of the distal convoluted tubule (DCT). Potassium is lost as a result of more sodium reaching the collecting ducts. Thiazide diuretics have a role in the treatment of mild heart failure although loop diuretics are better for reducing overload. The main use of bendroflumethiazide was in the management of hypertension but recent NICE guidelines now recommend other thiazide-like diuretics such as indapamide and chlortalidone. Common adverse effects dehydration postural hypotension hyponatraemia, hypokalaemia, hypercalcaemia gout impaired glucose tolerance impotence Rare adverse effects thrombocytopaenia agranulocytosis photosensitivity rash pancreatitis

What is the most common adverse effect experienced by women taking the progestogen only pill? Irregular vaginal bleeding Acne Mood swings Reduced libido Weight gain

Irregular vaginal bleeding Progestogen only pill: advantages/disadvantages Advantages highly effective (failure rate = 1 per 100 woman years) doesn't interfere with sex contraceptive effects reversible upon stopping can be used whilst breast-feeding can be used in situations where the combined oral contraceptive pill is contraindicated e.g. in smokers > 35 years of age and women with a history of venous thromboembolic disease Disadvantages irregular periods: some users may not have periods whilst others may have irregular or light periods. This is the most common adverse effect doesn't protect against sexually transmitted infections increased incidence of functional ovarian cysts common side-effects include breast tenderness, weight gain, acne and headaches. These symptoms generally subside after the first few months

A 33-year-old woman presents with back pain which radiates down her right leg. This came on suddenly when she was bending down to pick up her child. On examination straight leg raising is limited to 30 degrees on the right hand side due to shooting pains down her leg. Sensation is reduced on the dorsum of the right foot, particularly around the big toe and big toe dorsiflexion is also weak. The ankle and knee reflexes appear intact. A diagnosis of disc prolapse is suspected. Which nerve root is most likely to be affected? L2 L3 L4 L5 S1

L5 L5 lesion features = loss of foot/big toe dorsiflexion + sensory loss dorsum of the foot Lower back pain: prolapsed disc A prolapsed lumbar disc usually produces clear dermatomal leg pain associated with neurological deficits. Features leg pain usually worse than back pain often worse when sitting The table below demonstrates the expected features according to the level of compression: Site of compression Features L3 nerve root compression Sensory loss over anterior thigh Weak quadriceps Reduced knee reflex Positive femoral stretch test L4 nerve root compression Sensory loss anterior aspect of knee Weak quadriceps Reduced knee reflex Positive femoral stretch test L5 nerve root compression Sensory loss dorsum of foot Weakness in foot and big toe dorsiflexion Reflexes intact Positive sciatic nerve stretch test S1 nerve root compression Sensory loss posterolateral aspect of leg and lateral aspect of foot Weakness in plantar flexion of foot Reduced ankle reflex Positive sciatic nerve stretch test Management similar to that of other musculoskeletal lower back pain: analgesia, physiotherapy, exercises if symptoms persist then referral for consideration of MRI is appropriate

A 57-year-old patient with acute pulmonary oedema is admitted to the ITU department. She has no past medical history of note. A Swan-Ganz catheter is inserted to enable measurement of the pulmonary capillary wedge pressure. Which chamber of the heart does this pressure generally equate to? The difference between the left atrium and right ventricle Left ventricle Left atrium Right ventricle Right atrium

Left atrium Pulmonary capillary wedge pressure Pulmonary capillary wedge pressure (PCWP) is measured using a balloon tipped Swan-Ganz catheter which is inserted into the pulmonary artery. The pressure measured is similar to that of the left atrium (normally 6-12 mmHg). One of the main uses of measuring the PCWP is determining whether pulmonary oedema is caused by either heart failure or acute respiratory distress syndrome. In many modern ITU departments PCWP measurement has been replaced by non-invasive techniques.

Which one of the following best describes the Hering-Bruer reflex? Lung distension causing slowing of the respiratory rate Raised hydrogen ion concentration in the ECF stimulating respiration Low pO2 stimulating the carotid and aortic bodies Lung distension causing increase of the respiratory rate Decreased hydrogen ion concentration in the ECF stimulating respiration

Lung distension causing slowing of the respiratory rate Respiratory physiology: control Control of respiration central regulatory centres central and peripheral chemoreceptors pulmonary receptors Central regulatory centres medullary respiratory centre apneustic centre (lower pons) pneumotaxic centre (upper pons) Central and peripheral chemoreceptors central: raised [H+] in ECF stimulates respiration peripheral: carotid + aortic bodies, respond to raised pCO2 & [H+], lesser extent low pO2 Pulmonary receptors stretch receptors, lung distension causes slowing of respiratory rate (Hering-Bruer reflex) irritant receptor, leading to bronchoconstriction juxtacapillary receptors, stimulated by stretching of the microvasculature

Which one of the following cells secretes the majority of tumour necrosis factor in humans? Neutrophils Macrophages Natural killer cells Killer-T cells Helper-T cells

Macrophages Tumour necrosis factor Tumour necrosis factor (TNF) is a pro-inflammatory cytokine with multiple roles in the immune system TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting mainly in a paracrine fashion: activates macrophages and neutrophils acts as costimulator for T cell activation key mediator of bodies response to Gram negative septicaemia similar properties to IL-1 anti-tumour effect (e.g. phospholipase activation) TNF-alpha binds to both the p55 and p75 receptor. These receptors can induce apoptosis. It also cause activation of NFkB Endothelial effects include increase expression of selectins and increased production of platelet activating factor, IL-1 and prostaglandins TNF promotes the proliferation of fibroblasts and their production of protease and collagenase. It is thought fragments of receptors act as binding points in serum Systemic effects include pyrexia, increased acute phase proteins and disordered metabolism leading to cachexia TNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe rheumatoid TNF blockers infliximab: monoclonal antibody, IV administration etanercept: fusion protein that mimics the inhibitory effects of naturally occurring soluble TNF receptors, subcutaneous administration adalimumab: monoclonal antibody, subcutaneous administration adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination Infliximab is also used in active Crohn's disease unresponsive to steroids

Vital capacity may be defined as: Volume inspired or expired with each breath at rest Volume of air remaining after maximal expiration Maximum volume of air that can be inspired at the end of a normal tidal inspiration Maximum volume of air that can be expired at the end of a normal tidal expiration Maximum volume of air that can be expired after a maximal inspiration

Maximum volume of air that can be expired after a maximal inspiration Respiratory physiology: lung volumes Tidal volume (TV) volume inspired or expired with each breath at rest 500ml in males, 350ml in females Inspiratory reserve volume (IRV) = 2-3 L maximum volume of air that can be inspired at the end of a normal tidal inspiration inspiratory capacity = TV + IRV Expiratory reserve volume (ERV) = 750ml maximum volume of air that can be expired at the end of a normal tidal expiration Residual volume (RV) = 1.2L volume of air remaining after maximal expiration increases with age RV = FRC - ERV Vital capacity (VC) = 5L maximum volume of air that can be expired after a maximal inspiration 4,500ml in males, 3,500 mls in females decreases with age VC = inspiratory capacity + ERV Total lung capacity (TLC) is the sum of the vital capacity + residual volume Physiological dead space (VD) VD = tidal volume * (PaCO2 - PeCO2) / PaCO2 where PeCO2 = expired air CO2

Which one of the following cell organelles contains double-stranded circular DNA? Nucleus Ribosome Nucleolus Golgi apparatus Mitochondria

Mitochondria Cell organelles The table below summarises the main functions of the major cell organelles: Organelle/macromolecule Main function Endoplasmic reticulum Rough endoplasmic reticulum translation and folding of new proteins manufacture of lysosomal enzymes site of N-linked glycosylation examples of cells with extensive RER include pancreatic cells, goblet cells, plasma cells Smooth endoplasmic reticulum steroid, lipid synthesis examples of cells with extensive SER include those of the adrenal cortex, hepatocytes, testes, ovaries Golgi apparatus Modifies, sorts, and packages these molecules that are destined for cell secretion Site of O-linked glycosylation Mitochondrion Aerobic respiration. Contains mitochondrial genome as circular DNA Nucleus DNA maintenance and RNA transcription Lysosome Breakdown of large molecules such as proteins and polysaccharides Nucleolus Ribosome production Ribosome Translation of RNA into proteins Peroxisome Catabolism of very long chain fatty acids and amino acids Results in the formation of hydrogen peroxide Proteasome Along with the lysosome pathway involved in degradation of protein molecules that have been tagged with ubiquitin

A 67-year-old man presents feeling 'generally unwell' and complaining of pain in his back and legs. His wife also reports that he has been slightly confused for the past two weeks. Basic blood tests are ordered: Hb 12.1 g/dl Platelets 411 * 109/l WBC 7.6 * 109/l Na+ 143 mmol/l K+ 5.3 mmol/l Urea 15.7 mmol/l Creatinine 208 µmol/l Bilirubin 20 µmol/l ALP 110 u/l ALT 55 u/l γGT 67 u/l Albumin 31 g/l Total protein 84 g/l Calcium 3.10 mmol/l Phosphate 0.79 mmol/l What is the most likely underlying diagnosis? Multiple myeloma Renal cancer with bony metastases Sarcoidosis Primary hyperparathyroidism Prostate cancer with bony metastases

Multiple myeloma Hypercalcaemia, renal failure, high total protein = myeloma One of the stand out results is the high calcium level. This immediately narrows the differential diagnosis considerably. Remember the two most common causes of hypercalcaemia are malignancy and primary hyperparathyroidism. Neither of these alone would however explain the renal failure and high total protein, both common features of untreated myeloma. Myeloma: features Multiple myeloma is a neoplasm of the bone marrow plasma cells. The peak incidence is patients aged 60-70 years. Clinical features bone disease: bone pain, osteoporosis + pathological fractures (typically vertebral), osteolytic lesions lethargy infection hypercalcaemia (see below) renal failure other features: amyloidosis e.g. Macroglossia, carpal tunnel syndrome; neuropathy; hyperviscosity Diagnosis is based on: monoclonal proteins (usually IgG or IgA) in the serum and urine (Bence Jones proteins) increased plasma cells in the bone marrow bone lesions on the skeletal survey Hypercalcaemia in myeloma primary factor: due primarily to increased osteoclastic bone resorption caused by local cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells much less common contributing factors: impaired renal function, increased renal tubular calcium reabsorption and elevated PTH-rP levels

Each one of the following is a feature of pseudohypoparathyroidism, except: Short fourth and fifth metacarpals Round face Normal calcium and phosphate levels Cognitive impairment Short stature

Normal calcium and phosphate levels Pseudohypoparathyroidism Pseudohypoparathyroidism is caused by target cell insensitivity to parathyroid hormone (PTH) due to a mutation in a G-protein. In type I pseudohypoparathyroidism there is a complete receptor defect whereas in type II the cell receptor is intact. Pseudohypoparathyroidism is typically inherited in an autosomal dominant fashion* Bloods PTH: high calcium: low phosphate: high Features short fourth and fifth metacarpals short stature cognitive impairment obesity round face Investigation infusion of PTH followed by measurement of urinary phosphate and cAMP measurement - this can help differentiate between type I (neither phosphate or cAMP levels rise) and II (cAMP rises but phosphate levels do not change) *it was previously thought to be an X-linked dominant condition

A 47-year-old man is seen in the respiratory clinic. He has been referred due to progressive shortness of breath. A CT scan showed emphysematous changes in the lungs. As he has never smoked alpha 1-antitrypsin levels were ordered and reported to be 10% of normal. What is the most likely genotype of this patient? PiZZ PiSS PiMS PiMM PiMZ

PiZZ Alpha-1 antitrypsin deficiency Alpha-1 antitrypsin (A1AT) deficiency is a common inherited condition caused by a lack of a protease inhibitor (Pi) normally produced by the liver. The role of A1AT is to protect cells from enzymes such as neutrophil elastase. Genetics located on chromosome 14 inherited in an autosomal recessive / co-dominant fashion* alleles classified by their electrophoretic mobility - M for normal, S for slow, and Z for very slow normal = PiMM homozygous PiSS (50% normal A1AT levels) homozygous PiZZ (10% normal A1AT levels) Features patients who manifest disease usually have PiZZ genotype lungs: panacinar emphysema, most marked in lower lobes liver: cirrhosis and hepatocellular carcinoma in adults, cholestasis in children Investigations A1AT concentrations Management no smoking supportive: bronchodilators, physiotherapy intravenous alpha1-antitrypsin protein concentrates surgery: volume reduction surgery, lung transplantation *trusted sources are split on which is a more accurate description

Which one of the following causes of hyponatraemia is least associated with a urinary sodium > 20 mmol/L? Diuretics Addison's Psychogenic polydipsia Syndrome of inappropriate ADH Hypothyroidism

Psychogenic polydipsia Hyponatraemia Hyponatraemia may be caused by water excess or sodium depletion. Causes of pseudohyponatraemia include hyperlipidaemia (increase in serum volume) or a taking blood from a drip arm. Urinary sodium and osmolarity levels aid making a diagnosis Urinary sodium > 20 mmol/l Sodium depletion, renal loss (patient often hypovolaemic) diuretics Addison's diuretic stage of renal failure Patient often euvolaemic SIADH (urine osmolality > 500 mmol/kg) hypothyroidism Urinary sodium < 20 mmol/l Sodium depletion, extra-renal loss diarrhoea, vomiting, sweating burns, adenoma of rectum Water excess (patient often hypervolaemic and oedematous) secondary hyperaldosteronism: heart failure, cirrhosis reduced GFR: renal failure IV dextrose, psychogenic polydipsia

A 19-year-old man with a history of learning disabilities and ectopia lentis is diagnosed as having homocystinuria. Supplementation of which one of the following may help improve his condition? Folic acid Niacin Pyridoxine Vitamin B7 Thiamine

Pyridoxine Homocystinuria - give vitamin B6 (pyridoxine) Homocystinuria Homocystinuria is a rare autosomal recessive disease caused by deficiency of cystathionine beta synthase. This results in an accumulation of homocysteine which is then oxidized to homocystine. Features often patients have fine, fair hair musculoskeletal: may be similar to Marfan's - arachnodactyly etc neurological patients may have learning difficulties, seizures ocular: downwards (inferonasal) dislocation of lens increased risk of arterial and venous thromboembolism also malar flush, livedo reticularis Diagnosis is made by the cyanide-nitroprusside test, which is also positive in cystinuria Treatment is vitamin B6 (pyridoxine) supplements

Each one of the following is seen in Klinefelter's syndrome, except: Small, firm testes Lack of secondary sexual characteristics Infertility Increased incidence of breast cancer Reduced gonadotrophin levels

Reduced gonadotrophin levels Klinefelter's syndrome Klinefelter's syndrome is associated with karyotype 47, XXY Features often taller than average lack of secondary sexual characteristics small, firm testes infertile gynaecomastia - increased incidence of breast cancer elevated gonadotrophin levels Diagnosis is by chromosomal analysis

A 64-year-old man is having a dual chamber pacemaker inserted. The ventricular lead is to be inserted via the coronary sinus. Where does the coronary sinus drain into? Right atrium Left ventricle Right ventricle Inferior vena cava Left atrium

Right atrium Coronary circulation Arterial supply of the heart left aortic sinus → left coronary artery (LCA) right aortic sinus → right coronary artery (RCA) LCA → LAD + circumflex RCA → posterior descending RCA supplies SA node in 60%, AV node in 90% Venous drainage of the heart coronary sinus drains into the right atrium

Where is secretin secreted from? I cells in upper small intestine G cells in stomach K cells in upper small intestine D cells in the pancreas S cells in upper small intestine

S cells in upper small intestine Gastrointestinal hormones Below is a brief summary of the major hormones involved in food digestion: Source Stimulus Actions Gastrin G cells in antrum of the stomach Distension of stomach, vagus nerves (mediated by gastrin-releasing peptide), luminal peptides/amino acids Inhibited by: low antral pH, somatostatin Increase HCL, pepsinogen and IF secretion, increases gastric motility, stimulates parietal cell maturation CCK I cells in upper small intestine Partially digested proteins and triglycerides Increases secretion of enzyme-rich fluid from pancreas, contraction of gallbladder and relaxation of sphincter of Oddi, decreases gastric emptying, trophic effect on pancreatic acinar cells, induces satiety Secretin S cells in upper small intestine Acidic chyme, fatty acids Increases secretion of bicarbonate-rich fluid from pancreas and hepatic duct cells, decreases gastric acid secretion, trophic effect on pancreatic acinar cells VIP Small intestine, pancreas Neural Stimulates secretion by pancreas and intestines, inhibits acid secretion Somatostatin D cells in the pancreas & stomach Fat, bile salts and glucose in the intestinal lumen Decreases acid and pepsin secretion, decreases gastrin secretion, decreases pancreatic enzyme secretion, decreases insulin and glucagon secretion inhibits trophic effects of gastrin, stimulates gastric mucous production

Which one of the following is least associated with hypercalcaemia? Thyrotoxicosis Secondary hyperparathyroidism Tertiary hyperparathyroidism Thiazide diuretics Primary hyperparathyroidism

Secondary hyperparathyroidism Hypercalcaemia: causes The most common causes of hypercalcaemia are malignancy (bone metastases, myeloma, PTHrP from squamous cell lung cancer) and primary hyperparathyroidism Other causes include sarcoidosis* vitamin D intoxication acromegaly thyrotoxicosis Milk-alkali syndrome drugs: thiazides, calcium containing antacids dehydration Addison's disease Paget's disease of the bone** *other causes of granulomas may lead to hypercalcaemia e.g. Tuberculosis and histoplasmosis **usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation

A 29-year-old man presents with a productive cough, fever and pleuritic chest pain. A chest x-ray shows lobar consolidation and a sputum culture grows Haemophilus influenzae. This is his fourth chest infection in the past seven months. Streptococcus pneumoniae has been grown from the sputum of the previous three episodes. Six-weeks following the latest infection a full blood count, urea and electrolytes, CRP and chest x-ray are all reported as normal. What is the most appropriate next investigation? Serum immunoglobulins Spirometry HIV test Colonoscopy Urinalysis

Serum immunoglobulins This patient has had repeated infections with encapsulated bacteria which should raise the suspicion of immunoglobulin deficiency. HIV would be suggested by infections associated with impaired cellular immunity. Immunoglobulins The table below summarises the characteristics of the 5 types of immunoglobulin found in the body: IgG 75% Monomer Enhance phagocytosis of bacteria and viruses, pass to fetal circulation IgA 15% Monomer/ dimer Found in secretions, provide localized protection on mucous membranes IgM 10% Pentamer first to be secreted, anti-A, B blood antibodies IgD 1% Monomer Involved in activation of B cells IgE 0.1% Monomer Involved in allergic reactions

Fragile X is associated with each one of the following, except: Small, firm testes Mental retardation Hypotonia Short stature Large low set ears

Small, firm testes Fragile X Fragile X is a trinucleotide repeat disorder Features in males learning difficulties large low set ears, long thin face, high arched palate macroorchidism hypotonia autism is more common mitral valve prolapse Features in females (who have one fragile chromosome and one normal X chromosome) range from normal to mild Diagnosis can be made antenatally by chorionic villus sampling or amniocentesis analysis of the number of CGG repeats using restriction endonuclease digestion and Southern blot analysis

When establishing a screening programme, which one of the following is not a key criteria as defined by Wilson and Junger? There should be a recognised latent or early symptomatic stage The condition should be an important public health problem The test or examination should be acceptable to the population There should be agreed policy on whom to treat as patients The condition should be potentially curable

The condition should be potentially curable Screening: Wilson and Junger criteria 1. The condition should be an important public health problem 2. There should be an acceptable treatment for patients with recognised disease 3. Facilities for diagnosis and treatment should be available 4. There should be a recognised latent or early symptomatic stage 5. The natural history of the condition, including its development from latent to declared disease should be adequately understood 6. There should be a suitable test or examination 7. The test or examination should be acceptable to the population 8. There should be agreed policy on whom to treat 9. The cost of case-finding (including diagnosis and subsequent treatment of patients) should be economically balanced in relation to the possible expenditure as a whole 10. Case-finding should be a continuous process and not a 'once and for all' project

Membrane receptors

There are four main types of membrane receptor: ligand-gated ion channels, tyrosine kinase receptors, guanylate cyclase receptors and G protein-coupled receptors Ligand-gated ion channel receptors generally mediate fast responses e.g. nicotinic acetylcholine, GABA-A & GABA-C, glutamate receptors Tyrosine kinase receptors intrinsic tyrosine kinase: insulin, insulin-like growth factor (IGF), epidermal growth factor (EGF) receptor-associated tyrosine kinase: growth hormone, prolactin, interferon, interleukin Guanylate cyclase receptors contain intrinsic enzyme activity e.g. atrial natriuretic factor, brain natriuretic peptide G protein-coupled receptors generally mediate slow transmission and affect metabolic processes activated by a wide variety of extracellular signals e.g. Peptide hormones, biogenic amines, lipophilic hormones, light 7-helix membrane-spanning domains consist of 3 main subunits: alpha, beta and gamma the alpha subunit is linked to GDP.Ligand binding causes conformational changes to receptor, GDP is phosphorylated to GTP,and the alpha subunit is activated G proteins are named according to the alpha subunit (Gs, Gi, Gq) Gs Gi Gq Mechanism Stimulates adenylate cyclase → increases cAMP → activates protein kinase A Inhibits adenylate cyclase → decreases cAMP → inhibits protein kinase A Activates phospholipase C → splits PIP2 to IP3 & DAG → activates protein kinase C Examples • Beta-1 receptors (epinephrine, norepinephrine, dobutamine) • Beta-2 receptors (epinephrine, salbuterol) • H2 receptors (histamine) • D1 receptors (dopamine) • V2 receptors (vasopressin) • Receptors for ACTH, LH, FSH, glucagon, PTH, calcitonin, prostaglandins • M2 receptors (acetylcholine) • Alpha-2 receptors (epinephrine, norephinephrine) • D2 receptors (dopamine) • GABA-B receptor • Alpha-1 receptors (epinephrine, norepinephrine) • H1 receptors (histamine) • V1 receptors (vasopressin) • M1, M3 receptors

You are advising a patient who has recently been diagnosed with chronic kidney disease stage 4 with regards to her diet. Which one of the following foods should she eat in moderation due to the high potassium content? Tomatoes Plums Cranberry juice Grapes Green beans

Tomatoes Hyperkalaemia Plasma potassium levels are regulated by a number of factors including aldosterone, acid-base balance and insulin levels. Metabolic acidosis is associated with hyperkalaemia as hydrogen and potassium ions compete with each other for exchange with sodium ions across cell membranes and in the distal tubule. ECG changes seen in hyperkalaemia include tall-tented T waves, small P waves, widened QRS leading to a sinusoidal pattern and asystole Causes of hyperkalaemia: acute renal failure drugs*: potassium sparing diuretics, ACE inhibitors, angiotensin 2 receptor blockers, spironolactone, ciclosporin, heparin** metabolic acidosis Addison's rhabdomyolysis massive blood transfusion Foods that are high in potassium: salt substitutes (i.e. Contain potassium rather than sodium) bananas, oranges, kiwi fruit, avocado, spinach, tomatoes *beta-blockers interfere with potassium transport into cells and can potentially cause hyperkalaemia in renal failure patients - remember beta-agonists, e.g. Salbutamol, are sometimes used as emergency treatment **both unfractionated and low-molecular weight heparin can cause hyperkalaemia. This is thought to be caused by inhibition of aldosterone secretion

Which of the following is least recognised as a cause of macroglossia? Amyloidosis Turner's syndrome Duchenne muscular dystrophy Acromegaly Hurler syndrome

Turner's syndrome Macroglossia Causes hypothyroidism acromegaly amyloidosis Duchenne muscular dystrophy mucopolysaccharidosis (e.g. Hurler syndrome) Patients with Down's syndrome are now thought to have apparent macroglossia due to a combination of mid-face hypoplasia and hypotonia

A 54-year-old woman is admitted to the Emergency Department following what sounds like an episode of vasovagal syncope. Blood gases on admission show a metabolic acidosis. Blood tests are reported as follows: Na+ 143 mmol/l K+ 3.0 mmol/l Chloride 116 mmol/l Bicarbonate 18 mmol/l Urea 4.0 mmol/l Creatinine 88 µmol/l Which one of the following is most likely to explain the metabolic acidosis? Lithium overdose Aspirin overdose Recent myocardial infarction Alcoholic ketoacidosis Ureterosigmoidostomy

Ureterosigmoidostomy The anion gap is normal, (143 + 3.0) - (116 + 18) = 12 mmol/l, which is consistent with a ureterosigmoidostomy. Aspirin overdose, myocardial infarction and alcoholic ketoacidosis would cause a raised anion gap Metabolic acidosis Metabolic acidosis is commonly classified according to the anion gap. This can be calculated by: (Na+ + K+) - (Cl- + HCO-3). If a question supplies the chloride level then this is often a clue that the anion gap should be calculated. The normal range = 10-18 mmol/L Normal anion gap ( = hyperchloraemic metabolic acidosis) gastrointestinal bicarbonate loss: diarrhoea, ureterosigmoidostomy, fistula renal tubular acidosis drugs: e.g. acetazolamide ammonium chloride injection Addison's disease Raised anion gap lactate: shock, hypoxia ketones: diabetic ketoacidosis, alcohol urate: renal failure acid poisoning: salicylates, methanol Metabolic acidosis secondary to high lactate levels may be subdivided into two types: lactic acidosis type A: shock, hypoxia, burns lactic acidosis type B: metformin