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2003 FRACP paper one

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Question 1 Top Download PDF

Question 1

A 65-year-old man with a two-year history of mild angina presents to the emergency department after 30 minuts of severe chest pain following unaccustomed heavy physical activity.  He has taken three glyceryl trinitrate tablets without relief.  The pain is relieved by oxygen.  Over the preceding six months, he has been stable on atenolol 50 mg/day, aspirin and isosorbide mononitrate 60 mg/day, he has only experienced angina twice, and has not used his glyceryl trinitrate over this period.

The most likely explanation for the failure of the glyceryl trinitrate to relieve his angina is:

  1. Poor absorption due to dry mouth
  2. Onset of unstable angina
  3. Reduced drug potency
  4. Nitrate tolerance
  5. Paroxysmal atrial fibrillation

 

Answer C

From mims
Anginine is a vasodilator which relieves angina pectoris. Pain in angina pectoris is believed to be the result of myocardial ischaemia secondary to coronary artery disease. In the relief of acute anginal pain the effect is apparent after two to three minutes and lasts for up to 20 or 30 minutes.

Pharmacology. Anginine redistributes blood blow along collateral channels and from epicardial to endocardial regions and thus may increase blood flow to ischaemic areas. Anginine also reduces oxygen demand by increasing venous capacitance causing pooling of blood in the peripheral veins and thereby reducing ventricular volume. Furthermore, the fall in arterial pressure will also reduce myocardial oxygen demand, although this may be offset by a reflex tachycardia. The beneficial effects of nitrates in pulmonary oedema depend on venous dilation and reduction of preload. Anginine causes coronary vasodilation in coronary arteries that are in spasm, and may relieve pain in variant angina by this mechanism.

Anginine is thought to exert its vasodilator effect through the activation of guanylate cyclase in vascular smooth muscle cells by nitric oxide. This results in an increased synthesis of cyclic guanosine monophosphate, which leads to smooth muscle relaxation.

Pharmacokinetics. Glyceryl trinitrate is readily absorbed through the buccal mucosa but is rapidly metabolised so it has a fleeting duration of action.
Peak plasma levels of glyceryl trinitrate given sublingually appear within four minutes.

Distribution. Glyceryl trinitrate has a volume of distribution of about 3 L/kg. It is taken up by vascular smooth muscle cells.

Metabolism. In smooth muscle cells the nitrate group is cleaved to inorganic nitrite and then to nitric oxide (thought to be responsible for glyceryl trinitrate's vasodilatatory effect). Glyceryl trinitrate also undergoes hydrolysis in plasma and is rapidly hydrolysed in the liver by glutathione organic nitrate reductase to dinitrates and mononitrates. At least half of the intact glyceryl trinitrate is cleared from the blood in one to three minutes.

Excretion. The main urinary metabolite of glyceryl trinitrate is the mononitrate.
Anginine should be stored in a cool place. It should not be carried close to the body and should be kept out of direct sunlight.

An unopened bottle has a shelf life of two years if stored below 25 deg. C. However, tablets unused three months after first opening a bottle should be discarded and a fresh supply obtained.

Topic

Pharmacology - Cardiovascular

 

Question 2 Top

Question 3 Top Download PDF


The predominant site of gastrointestinal absorption of dietary iron is the:
A. proximal small intestine.
B. gastric fundus.
C. terminal ileum.
D. pyloric antrum.
E. colon.

The Iron Cycle in Humans

    • Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin, the iron transport protein.
    • The iron-transferrin complex circulates in the plasma until the iron-carrying transferrin interacts with specific transferrin receptors on the surface of marrow erythroid cells. Diferric transferrin has the highest affinity for transferrin receptors; apotransferrin (transferrin not carrying iron) has very little affinity. While transferrin receptors are found on cells in many tissues within the body—and all cells at some time during development will display transferrin receptors—the cell having the greatest number of receptors (300,000 to 400,000/cell) is the developing erythroblast.
    • Once the iron-bearing transferrin interacts with its receptor, the iron-transferrin-receptor complex is internalized via clathrin-coated pits and transported to an acidic endosome, where the iron is released at the low pH. The iron is then made available for heme synthesis while the transferrin-receptor complex is recycled to the surface of the cell, where the bulk of the transferrin is released back into the circulation and the transferrin receptor reanchors into the cell membrane. At this point a certain amount of the transferrin receptor protein may be released into circulation.
    • Within the erythroid cell, iron that is in excess of the amount needed for hemoglobin synthesis binds to a storage protein, apoferritin, forming ferritin. This mechanism of iron exchange also takes place in other cells of the body expressing transferrin receptors, especially liver parenchymal cells where the iron can be incorporated into heme-containing enzymes or stored. The iron incorporated into hemoglobin subsequently enters the circulation as new red cells are released from the bone marrow. The iron is then part of the red cell mass and will not become available for reutilization until the red cell dies.
    • In a normal individual, the average red cell life span is 120 days. Thus, 0.8 to 1.0% of red cells turn over each day. At the end of its life span, the red cell is recognized as senescent by the cells of the reticuloendothelial (RE) system, and the cell undergoes phagocytosis. Once within the RE cell, the hemoglobin from the ingested red cell is broken down, the globin and other proteins are returned to the amino acid pool, and the iron is shuttled back to the surface of the RE cell, where it is presented to circulating transferrin.
    • Since each milliliter of red cells contains 1 mg of elemental iron, the amount of iron needed to replace those red cells lost through senescence amounts to 16 to 20 mg/d (assuming an adult with a red cell mass of 2 L). Any additional iron required for daily red cell production comes from the diet. Normally, an adult male will need to absorb at least 1 mg of elemental iron daily to meet needs, while females in the childbearing years will need to absorb an average of 1.4 mg/d.
    • However, to achieve a maximum proliferative erythroid marrow response to anemia, additional iron must be available. With markedly stimulated erythropoiesis, demands for iron are increased by as much as six- to eightfold. With hemolytic anemias, the rate of red cell destruction is increased, but the iron recovered from the red cells is efficiently reutilized for hemoglobin synthesis. In contrast, with blood loss anemia the rate of red cell production is limited by the amount of iron that can be mobilized from ferritin and hemosiderin stores. Typically, the rate of mobilization under these circumstances will not support red cell production more than 2.5 to 3 times normal. If the delivery of iron to the stimulated marrow is suboptimal, the marrow's proliferative response is blunted and normal hemoglobin synthesis is impaired. The result is a hypoproliferative marrow accompanied by microcytic, hypochromic anemia.
    • While blood loss or hemolysis places a demand for iron to be supplied to the erythroid marrow, other conditions such as inflammation interfere with iron release from stores and can result in a rapid decrease in the serum iron
    • The balance of iron metabolism in the organism is tightly controlled and designed to conserve iron for reutilization. There is no excretory pathway for iron, and the only mechanisms by which iron is lost from the body are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epidermal cells from the skin and gut. Normally, the only route by which iron comes into the body is via absorption from food (dietary iron intake) or from medicinal iron taken orally. Iron may also enter the body through red cell transfusions or injection of iron complexes. The margin between the amount of iron available for absorption and the requirement for iron in growing infants and the adult female is narrow. The narrowness of this margin accounts for the great prevalence of iron deficiency worldwide—currently estimated at one-half billion people.
    • External iron exchange—the amount of iron required from the diet to replace losses—averages about 10% of body iron content a year in men and 15% in women of childbearing age, equivalent to 1.0 and 1.4 mg of elemental iron daily, respectively. Dietary iron content is closely related to total caloric intake (approximately 6 mg of elemental iron per 1000 calories). Iron bioavailability is affected by the nature of the foodstuff, with heme iron (e.g., red meat) being most readily absorbed. In the United States, the average iron intake in an adult male is 15 mg/d with 6% absorption; for the average female, the daily intake is 11 mg/d with 12% absorption.
    • An individual with iron deficiency can increase iron absorption to about 20% of the iron present in a meat-containing diet but only 5 to 10% of the iron in a vegetarian diet. As a result, nearly one-third of the female population in the United States has virtually no iron stores. Vegetarians are at an additional disadvantage because certain foodstuffs that include phytates and phosphates reduce iron absorption by about 50%.
    • When ionizable iron salts are given together with food, the amount of iron absorbed is reduced. This is particularly true with iron in the ferric state. When the percentage of iron absorbed from individual food items is compared with the percentage for an equivalent amount of ferrous salt, iron in vegetables is only about one-twentieth as available, egg iron one-eighth, liver iron one-half, and heme iron one-half to two-thirds. Therefore, liver and heme iron are absorbed nearly as well as iron salt added to food, while the iron in vegetables and eggs is much less available.
    • Infants, children, and adolescents may be unable to maintain normal iron balance because of the demands of body growth and lower dietary intake of iron. In pregnancy during the last two trimesters, daily iron requirements increase to 5 to 6 mg. That is the reason why iron supplements are strongly recommended for pregnant women in developed countries.
    • Iron absorption takes place largely in the proximal small intestine and is a carefully regulated process. For absorption, iron must be taken up by the luminal cell. That process is facilitated by the acidic contents of the stomach, which maintains the iron in solution. At the brush border of the absorptive cell, the ferric iron is converted to the ferrous form by a ferrireductase. Transport across the membrane is accomplished by divalent metal transporter 1 (DMT 1, also known as Nramp 2 or DCT 1). DMT 1 is a general cation transporter. Once iron is inside the gut cell, the iron may be stored as ferritin or transported through the cell to be released at the basolateral surface to plasma transferrin. It is likely that another transporter acts here in concert with hephaestin, another ferroxidase. Hephaestin is similar to ceruloplasmin, the copper-carrying protein.
    • Iron absorption is influenced by a number of physiologic states. Erythroid hyperplasia, for example, stimulates iron absorption, even in the face of normal or increased iron stores. Patients with anemias associated with high levels of ineffective erythropoiesis absorb excess amounts of dietary iron. Over time, this may lead to iron overload and tissue damage. In iron deficiency, iron is much more efficiently absorbed from a given diet; the contrary is true in the presence of iron overload. This is possibly mediated through signals that become fixed before the jejunal crypt cell migrates up the villus to become an absorptive cell. The normal individual can reduce iron absorption in situations of excessive intake or medicinal iron intake; however, while the percentage of iron absorbed goes down, the absolute amount goes up. This accounts for the acute iron toxicity occasionally seen when children ingest large numbers of iron tablets. Under these circumstances, the amount of iron absorbed exceeds the transferrin binding capacity of the plasma, resulting in free iron that affects critical organs such as cardiac muscle cells.

    Topic

    Gastroenterology: Principles of nutrition.

     

    Question 4 Top

    Question 5 Top Download PDF

    Question 5

    The insulin analogue lispro (humalog) has a more immediate onset of action than regular human insulin.  This is because lispro:

    A. is a smaller sized molecule

    B. is more lipophilic

    C. does not form hexamers subcutaneously

    D. has greater affinity for the insulin receptor

    E. is less protein-bound

    Lispro

    • 1st commercially available short acting analog
    • Absorbed 3 times more rapidly from subcutaneous sites than  human insulin
    • Unlike regular insulin, lispro exists as a hexamer in commercially available formulations.  Unlike regular insulin, lispro dissociates into monomers almost instantaneously following injection.  This property results in the characteristic rapid absorption and shorter duration of action compared to regular insulin.
    • Answer C

    Topic

    Pharmacology: Endocrinology

    Question 6 Top Download PDF

    The presence of which one of the following histological findings in a biopsy of the distal oesophagus is most important for a diagnosis of Barrett’s oesophagus?
    A. Specialised intestinal metaplasia.
    B. Chronic inflammation.
    C. Dysplasia.
    D. Helicobacter infection in the mucosa.
    E. Eosinophils in the submucosa.

    • The metaplasia of esophageal squamous epithelium to columnar epithelium (Barrett's esophagus) is a complication of severe reflux esophagitis, and it is a risk factor for esophageal adenocarcinoma
    • Metaplastic columnar epithelium develops during healing of erosive esophagitis with continued acid reflux because columnar epithelium is more resistant to acid-pepsin damage than is squamous epithelium.
    • The metaplastic epithelium is a mosaic of different epithelial types including goblet cells and columnar cells that have features of both secretory and absorptive cells (incomplete or type III metaplasia).
    • Barrett's esophagus is arbitrarily divided into long-segment (>2–3 cm) or short-segment (<2–3 cm) groups; long-segment disease is present in 0.5% of the population and short-segment disease may occur in up to 15%.
    • Barrett's epithelium progresses through a dysplastic stage before developing into adenocarcinoma. The rate of cancer development is 0.5% per year; those with long-segment disease have a risk of developing esophageal cancer that is 30 to 125 times the risk of the general population.
    • Barrett's esophagus can also lead to chronic peptic ulcer of the esophagus with high (midesophageal) and long strictures.
    • Given the natural history, erosive esophagitis should be aggressively treated. The prevalence of intestinal metaplasia is estimated at 4 to 10% of patients with significant heartburn. Barrett's esophagus is more common in men, particularly white men, and prevalence increases with age. A one-time esophagoscopy is recommended in patients with persistent GERD symptoms at age 50 to identify patients with Barrett's esophagus. Established metaplasia does not regress with treatment; thus, acid suppression and fundoplication are indicated only when active esophagitis is also present.
    • The need and frequency of surveillance endoscopies in patients with established Barrett's esophagus are debated. The risk of developing esophageal adenocarcinoma is related to the length of involved esophageal mucosa. People with short segments of Barrett's esophagus (distal 2 to 3 cm) account for up to 25% of unselected patients undergoing endoscopy with or without GERD symptoms and appear to be at low risk. They are not routinely surveyed. However, those with long-segment Barrett's esophagus are advised to have endoscopic surveillance at 1-year intervals for 2 years and then every 2 to 3 years. The frequency is increased if dysplasia is detected independent of the length of the metaplasia. Optical methods of recognizing dysplasia during the endoscopy (laser-induced fluorescence spectroscopy, optical coherence tomography) are being developed. Once high-grade dysplasia is detected, treatment of choice is esophagectomy of the Barrett's segment. Photodynamic laser or thermocoagulative mucosal ablation and endoscopic mucosal resection are being evaluated as alternatives.

     

    DIAGNOSTIC CRITERIA — Endoscopic examination generally is required to diagnose Barrett's esophagus  Two criteria must be fulfilled:

    • The endoscopist must document that columnar epithelium lines the distal esophagus
    • Histologic examination of biopsy specimens from that columnar epithelium must reveal specialized intestinal metaplasia.

     

    PATHOLOGY — Traditionally, three types of columnar epithelia have been described in Barrett's esophagus :

      • Cardiac epithelium, which has a foveolar (pitted) surface and glands that are lined almost exclusively by mucus-secreting cells; these cells resemble those in the gastric cardia.
      • Gastric fundic-type epithelium which has a foveolar surface lined by mucus-secreting cells, and a deeper glandular layer that contains chief and parietal cells; these cells resemble those in the gastric fundus.
      • Specialized intestinal metaplasia (also called specialized columnar epithelium), which has intestinal-type crypts lined by mucus-secreting columnar cells and goblet cells

      Biopsy specimen of a patient with Barrett's esophagus shows intestinalized columnar epithelium with goblet cells.

      Topic

      Gastroenterology:oesophageal dysmotility, infections and reflux

       

      Question 7 Top

      Question 8 Top

      Question 9 Top

      Question 10 Top

      Question 11

      Question 12 Top

      Question 13 Top

      Question 14 Top

      Question 15 Top

      Question 16 Top Download PDF

      Which one of the following best describes endocrinological changes demonstrated in the serum of patients with major depression?

       

      Cortisol

      Corticotropin-releasing factor

      A.

      Suppressed

      Suppressed

      B.

      Suppressed

      Elevated

      C.

      Elevated

      Suppressed

      D.

      Elevated

      Elevated

      E.

      Elevated

      Normal

      What you need to know

      1. A basic understanding of the hypothalamic-pituitary-adrenal axis

      And

      1. Specific piece of knowledge of the findings in major depression

      This is an extract from:

      REVIEW: Glucocorticoid Receptors in Major Depression: Relevance to Pathophysiology and Treatment
      Carmine M. Pariante and Andrew H. Miller
      Biol Psychiatry 2001;49:391–404 © 2001 Society of Biological Psychiatry

      Introduction
      Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis in patients with major depression is one of the most consistent findings in biological psychiatry.  Specifically, patients with major depression have been shown to exhibit  increased concentrations of cortisol in plasma, urine, and cerebrospinal fluid (CSF); an exaggerated cortisol response to adrenocorticotropic hormone (ACTH); and an enlargement of both the pituitary and the adrenal glands (Gold et al 1988; Holsboer and Barden 1996; Nemeroff 1996; Owens and Nemeroff 1993). These HPA axis alterations are believed to be secondary to hypersecretion of corticotropin-releasing hormone (CRH), which has behavioral effects in animals that are similar to those seen in depressed patients, including alterations in activity, appetite, and sleep (Owens and Nemeroff 1993). Moreover, depressed patients exhibit increased concentrations of CRH in the CSF, increased CRH messenger RNA (mRNA) and protein in the paraventricular nucleus (PVN) of the hypothalamus (postmortem samples), and a blunted ACTH response to a CRH challenge (likely reflecting downregulation of pituitary CRH receptors) (Gold et al 1988; Nemeroff 1996).

      In summary CRH is increased in the presence of increased cortisol

      And

      1. ?Assumes some knowledge of the treatment of depresssion

      So in the answer
      B and C could be normal states
      Major depression would be more likely to reflect a stress state so you would assume that cortisol levels are high even if you didn’t know the above fact so A is out
      Which leaves D and E and knowing the fact above

      So the answer is D

      References:
      Harrisons

      Carmine M. Pariante and Andrew H. Miller REVIEW: Glucocorticoid Receptors in Major Depression: Relevance to Pathophysiology and Treatment
      Biol Psychiatry 2001;49:391–404 © 2001 Society of Biological Psychiatry

      Holsboer F, Bardent N. Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev. 1996 Apr;17(2):187-205. Review.

      Mann JJ  The medical management of depression. N Engl J Med. 2005 Oct 27;353(17):1819-34. Review.

      Topic

      Endocrinology Adrenal Disorders

       

      Question 17 Top Download PDF

      A 66-year-old man with chronic obstructive pulmonary disease (COPD) has a forced expiratory volume one second (FEV 1 ) of 0.5 L (27% of the predicted value). An overnight screening oximetry study with measurement of transcutaneous carbon dioxide (tcCO 2 ) is shown below for the period 23.00 hours to 04.00 hours.

       

      Which one of the following is the most likely mechanism of sleep-related oxygen desaturation in this man?

      A. Central sleep apnoea.

      B. Obstructive sleep apnoea.

      C. Bronchospasm.

      D. Hypoventilation.

      E. Ventilation-perfusion mismatching.


      The data provided in the question indicate:

      •  Severe COPD - FEV1 < 40%
      And

      •  Evidence of nocturnal hypoxaemia

      In COAD there are two main mechanisms of sleep related hypoxaemia

      •  Alveolar hypoventilation which is the most common - can occur in healthy people and is occurs especially in REM sleep
      and

      •  Ventilation -perfusion mismatching - not as much evidence

      Central Sleep apnoea and obstructive sleep apnoea are diseases process that may occur in conjunction with COPD but not because of

      Bronchospasm most common in asthma

      The answer is D

      Ref; editorial Is Chronic Obstructive Pulmondary Disease related to sleep apnea-hypopnea syndrome? Discusses results from The Sleep Heart Health Study
      American Journal of Respiratory and critical care med vol 167 2003 pg3-4

      Topic: Respiratory - sleep disorders

      Question 18 Top Download PDF

      Adensosine is commonly used in the diagnosis and management of supraventricular arrhythmias.  Concomitant administration of other drugs may potentiate or decrease the efficacy of adenosine.

      Reducing the dose of adenosine would be most appropriate with the concomitant administration of which of the following?

      1. Theophylline
      2. Warfarin
      3. Clopidogrel
      4. Dipyridamol
      5. Salbutamol

       

      Answer D: basically a drug fact

      Adenosine – antiarrhythmic agent

      Drug Interactions: Methylxanthines; dipyridamole; carbamazepine

      Theophylline – bronchospasm relaxant

      Wafarin -  anticoagulant

      Clopidogrel – anticoagulant
       
      Dipyridamole – antithrombotic (eg asasantin)

      Salbutamol – bronchospasm relaxant / bronchodilator

      Topic

      Pharmacology - Cardiovascular

       

      Question 19 Top Download PDF

      QUESTION 19
      In patients with untreated post-transfusion hepatitis C, the lifetime risk of progression to cirrhosis best approximates:
      A. 1%.
      B. 5%.
      C. 20%.
      D. 50%.
      E. 80%.

      • Infection with the hepatitis C virus (HCV) can result in both acute and chronic hepatitis. The acute process is most often asymptomatic; if symptoms are present, they usually abate within a few weeks. Acute infection rarely causes hepatic failure.
      • Acute HCV typically leads to chronic infection; 60 to 80 percent of cases develop chronic hepatitis (abnormal liver enzymes). Chronic HCV infection is usually slowly progressive; it may not result in clinically apparent liver disease in many patients if the infection is acquired later in life.
      • Approximately 20 to 30 percent of chronically infected individuals develop cirrhosis over a 20- to 30-year period of time. Chronic HCV is the most common cause of chronic liver disease and the most frequent indication for liver transplantation in the United States.

       

      • ACUTE HEPATITIS C — HCV is the cause of approximately 20 percent of cases of acute hepatitis in the United States . The presence of HCV RNA in serum or liver is the first biochemical evidence of HCV infection. HCV RNA is detectable in serum by PCR within days to eight weeks following exposure, depending in part upon the size of the inoculum. Serum aminotransferases become elevated approximately 6 to 12 weeks after exposure (range 1 to 26 weeks).
      • The majority of acutely infected patients are asymptomatic and have a clinically mild course; jaundice is present in fewer than 25 percent. As a result, periodic screening for infection may be warranted in patients who are at high risk for infection . Additional symptoms are similar to those in other forms of acute viral hepatitis, including malaise, nausea, and right upper quadrant pain. In patients who experience acute symptoms, the illness typically lasts for 2 to 12 weeks. Fulminant hepatic failure due to acute HCV infection is very rare, but may be more common in patients with underlying chronic hepatitis B virus infection .

       

      • CHRONIC HEPATITIS C — The risk of chronic infection after an acute episode of hepatitis C is high. In most studies, 80 to 100 percent of patients remain HCV-RNA positive, and 60 to 80 percent have persistently elevated liver enzymes . The rate of spontaneous clearance of virus after it has persisted for at least six months is very low.   The mechanism responsible for the high prevalence of chronic infection is unclear (viral and host factors
      • Symptoms — Most patients with chronic infection are asymptomatic or have only mild nonspecific symptoms . The most frequent complaint is fatigue; other less common manifestations include nausea, anorexia, myalgia, arthralgia, weakness, and weight loss.

       

      • Serum aminotransferases — There is wide variability in serum aminotransferase concentrations among individual patients with chronic HCV infection over time.
      • Natural history — The natural history of chronic hepatitis C has been difficult to clearly define because of the long course of the disease . Several studies have provided estimates of the proportion of patients with chronic infection who develop cirrhosis within 20 years [39-52]. As a general rule, estimates from retrospective studies (17 to 55 percent) have been higher than prospective studies (7 to 16 percent), possibly reflecting referral bias in the retrospective studies. A consensus statement issued by the National Institutes of Health suggests that the actual risk is closer to that derived from the prospective studies (www.consensus.nih.gov/cons/116/116cdc_intro.htm).

       

      • Hepatic decompensation — Cirrhosis is a prerequisite for most of the major complications of liver failure in patients with chronic HCV infection; however, not all patients with cirrhosis develop these complications
      • Hepatocellular carcinoma — Deaths associated with chronic hepatitis C in the United States are more likely to be due to end stage liver disease rather than hepatocellular carcinoma (HCC). However, HCV accounts for approximately one-third of HCC cases in the United States. Estimates of the risk of developing HCC once cirrhosis has developed have varied from 0 to 3 percent per year in various reports

       

      • In contrast to hepatitis B virus infection, HCC in patients with hepatitis C occurs almost exclusively in those with cirrhosis suggesting that it is cirrhosis that is the major risk factor.
      •   Alcohol intake — Alcohol promotes the progression of chronic HCV, even in patients with a relatively low alcohol intake. Alcohol increases HCV replication , and has also been linked to the acceleration of liver injury

       

        • Liver biopsy — The best clinical predictor of disease progression in chronic HCV infection is the amount of inflammation and fibrosis on liver biopsy.

        Topic

        Gastroenterology:viral hepatitis Question repeated 2004 paper one question 15

        Question 20 Top

        Question 21 Top

        Question 22 Top Download PDF

        In anorexia nervosa, the plasma concentration of which one of the following hormones is least likely to be reduced?

        A. Free triiodothyroinine (free T3)

        B. Oestradiol

        C. Follicle-stimulating homone (FSH)

        D. Cortisol

        E. Leptin

         

        Answer D

        What do you need to know

        1. basic definition of  anorexia nervosa and bullemia  - ?some management options

        Diagnostic criteria for anorexia nervosa and bulimia nervosa*
        Anorexia nervosa

        •  Body weight is maintained at least 15% below that expected or body mass index is 17.5 or lower†
        •  Weight loss is self induced by avoidance of “fattening foods” plus one or more of: self induced vomiting; self induced purging; excessive exercise; use of appetite suppressants or diuretics
        • Body image distortion in which dread of fatness persists as an intrusive, overvalued idea
        • Widespread endocrine disorder involving the hypothalamic-pituitary-gonadal and manifesting as amenorrhoea in women and loss of sexual interest and potency in men
        • If onset is prepubertal, puberty is delayed or arrested. With recovery, puberty is often normal, but the menarche is late

        Bulimia nervosa

        • Persistent preoccupation with eating; overeating episodes in which large amounts of food are eaten in short periods of time
        • The patient tries to counteract the “fattening” effects of food by one or more of: self induced vomiting or purgative abuse; alternating starvation and eating; use of appetite suppressants, thyroid preparations, or diuretics
        • The psychopathology consists of a morbid dread of fatness, and the patient sets herself or himself a precise weight threshold, well below the premorbid weight that constitutes the optimum or healthy weight in the opinion of the physician
        • Often a history of previous anorexia nervosa, with the interval ranging from a few months to several years

        *Based on ICD-10 (international classification of diseases, 10th revision); †Body mass index criterion does not apply for young people aged under 17

        So in the general definition we know that oestrodial and FSH are going to be reduced

        1. hormonal imbalances in eating disorders

        Current Concepts: Eating Disorders
        Becker A. E., Grinspoon S. K., Klibanski A., Herzog D. B.
         N Engl J Med 1999; 340:1092-1098, Apr 8, 1999. Review Articles

        Thyroid-function tests often reflect the euthyroid sick syndrome, characterized by decreased levels of triiodothyronine and thyroxine but a normal or moderately decreased level of thyroidstimulating hormone ; these tests are indicated only if true thyroid disease is likely.

        Hypercortisolemia and elevated urinary levels of free cortisol may be present both in patients of low weight who have anorexia nervosa and in patients of normal weight who have bulimia nervosa.

        In anorexia nervosa, amenorrhea is most often the result of a decrease in the pulsatility of gonadotropin-releasing hormone, resulting in hypogonadotropic hypogonadism and low or undetectable levels of serum estradiol. Puberty, including the onset of menarche, may be delayed in adolescents with anorexia nervosa, leading to the arrest of linear growth.

        In men, low weight is also associated with clinical hypogonadism and decreased levels of serum testosterone.

        A threshold level of weight or body fat is thought to be necessary for normal pulsatility of gonadotropin-releasing hormone, but the underlying mechanism of this association is unknown.
        Attention has focused on leptin, a product of the ob gene in adipocytes,   as a hormone that may regulate reproductive function and signal the hypothalamus when fat mass is decreased. Leptin levels are decreased in patients with anorexia nervosa, and this abnormality is closely correlated with fat mass.

        Although resumption of menses typically accompanies weight gain, in some cases amenorrhea persists even after the attainment of normal body weight and may be attributable to a low percentage of body fat, inadequate intake of dietary fats, excessive exercise, or depression or may be an adverse effect of a psychotropic medication.  Severe bone loss in anorexia nervosa probably has a variety of causes, including estrogen deficiency, vitamin and micronutrient deficiencies, hypercortisolemia, and a direct inhibitory effect of undernutrition on bone formation and osteoblast function.

        Furthermore, anorexia nervosa often occurs during adolescence, when accrual of bone mass is at its peak. Therefore, bone loss and inadequate bone formation in adolescents with anorexia nervosa may result in severe osteopenia. Periodic assessment of the lumbarspine bone density by dual-energy x-ray absorptiometry is reasonable to determine the risk of compression
        fractures and the degree of ongoing bone loss.

         

        So accordingly free T3  leptin have been found to be low and again you would expect the patients body to be exhibiting a stress like response so intuitively at least cortisol would be a good guess.

        References

        Current Concepts: Eating Disorders
        Becker A. E., Grinspoon S. K., Klibanski A., Herzog D. B.
         N Engl J Med 1999; 340:1092-1098, Apr 8, 1999. Review Articles

        Nicholls D, Viner R ABC of adolescence Eating disorders and weight problems British Medical Journal 2005 Apr 23;330(7497):950-3

        Topic

        Adolescence: Eating Disorders

        Question 23 Top

        Question 24 Top

        Question 25 Top Download PDF

        In a transfusion-dependent patient with idiopathic acquired sideroblastic anaemia, the most appropriate treatment for prevention of transfusional iron overload is:
        A. vitamin C.
        B. phlebotomy.
        C. desferrioxamine.
        D. ethylene-diamine tetra-acetic acid (EDTA).
        E. pyridoxine.

        Acquired idiopathic sideroblastic anemia (AISA) generally occurs in middle-aged and older individuals, although younger persons including children are not spared. The anemia develops insidiously and may be discovered during a routine examination or in association with an unrelated complaint. Older individuals more often experience symptoms of fatigue and angina, especially if there is coexisting coronary artery disease. Apart from pallor, hepatosplenomegaly is found in one-third to one-half of patients. With advanced iron overload, often after repeated transfusions, symptoms and signs of liver decompensation, as well as heart failure and arrhythmia, may occur.

        Diagnosis

        • In women, the hematologic phenotype in PSA or RARS is often indistinguishable from X-linked sideroblastic anemia; this latter disorder should therefore be excluded (
        • Complete blood count — The anemia is usually moderate and normocytic or macrocytic, with a variable population of hypochromic cells on the blood smear. Particularly characteristic are occasional siderocytes: hypochromic red cells with basophilic stippling that stains positive for iron
        • Leukocyte and platelet counts are often within the normal range in patients with AISA. The presence of moderate leukopenia and/or thrombocytopenia tends to be associated with other myelodysplastic features, such as the pseudo-Pelger anomaly. Leukocytosis and/or thrombocytosis are least common, and may reflect the presence of a myeloproliferative disorder.
        • Free erythrocyte protoporphyrin — The free erythrocyte protoporphyrin is characteristically increased, up to about 300 µg/dL (normal: 20 to 65). However, in some patients, values have ranged from 1055 to 10,514 µg/dL, and some have experienced photosensitivity
        • Iron studies — Serum iron and ferritin levels reflect the commonly associated iron overload, as in hereditary sideroblastic anemia
        • Bone marrow examination — Bone marrow aspiration shows the presence of erythroid hyperplasia, commonly with mild megaloblastic changes. The marrow macrophage iron content is increased and, in contrast to the hereditary form, ring sideroblasts are evident at all stages of maturation; their presence establishes the diagnosis.

        Management — Available treatment measures are supportive, as in hereditary sideroblastic anemia. However, a response to pyridoxine supplements is not expected. Curative treatment with hematopoietic cell transplantation, with the attendant risks, is considered an option for younger individuals, as in the other myelodysplastic syndromes.

        • Erythropoietin and G-CSF
        • Chemotherapeutic agents
        • Transfusion — If anemia is symptomatic or progresses to a symptomatic stage, regular red cell transfusions are necessary, especially in the presence of advanced age and/or other comorbid conditions, such as coronary artery disease.
        •  Removal of excess iron — Phlebotomy or deferoxamine are used to control the iron overload
        •  Risk of splenectomy — Similar to patients with hereditary sideroblastic anemia, splenectomy should be avoided at all costs

         

        Iron overload — The associated iron overload requires treatment for optimal prognosis, thereby minimizing or averting morbidity from parenchymal organ damage. Based on the severity of iron overload (eg, serum ferritin >500 µg/L), best documented by liver biopsy, an iron depletion program must be instituted. This is accomplished in one of two ways: therapeutic phlebotomy or iron chelation.

        Therapeutic phlebotomy — Graded phlebotomies can be performed in patients who have responded to pyridoxine supplements, and in all others with mild or moderate anemia (ie, hemoglobin >9 g/dL) when there are no contraindications to therapeutic phlebotomy, such as congestive heart failure . After initial de-ironing, maintenance phlebotomies are continued on a regular basis for life, in order to prevent reaccumulation of iron.

        Iron chelation therapy — In patients who have more severe anemia, and in those who require regular red cell transfusions, and thus cannot undergo phlebotomy, chelation of the excess iron with deferoxamine is performed. This agent, a siderophore, is poorly absorbed from the gastrointestinal tract and must be given parenterally. It avidly binds non-protein-bound, non-heme-bound iron that is in a transit phase within cells to form ferrioxamine, which freely exits cells and is readily excreted in urine and bile.
        A. vitamin C.
        Supplement as part of multivitamin
        B. phlebotomy.
        Correct – primary therapy
        C. desferrioxamine.
        Useful in conjunction with phlebotomy
        D. ethylene-diamine tetra-acetic acid (EDTA).
        EDTA is used for the treatment of sideroblastic anaemia proven to be caused by Lead poisoining
        E. pyridoxine.
        Pyridoxine (Vitamin B6 ) has been shown to be effective in hereditary sideroblastic anaemia

        Topic

        Haematology: anaemia

         

        Question 26 Top

        Question 27 Top

        Question 28 Top

        Question 29 Top

        Question 30 Top

        Question 31 Top Download PDF

        A 38-year-old woman is admitted to hospital with right lower lobe pneumonia and is treated with appropriate antibiotics. After six days, clinical and radiological signs of a right pleural effusion develop. A diagnostic pleural tap is performed.

        Which one of the following pleural fluid results is the best predictor of the need for pleural space drainage?

        A. pH <7.3.

        B. Pleural-serum lactate dehydrogenase (LDH) gradient >0.6 mmol/L.

        C. Pleural/serum protein ratio >0.5.

        D. Differential cell count demonstrating >90% neutrophils.

        E. Microscopy showing a positive Gram stain.

         

        Indications for thoracentesis - presence of a clinically significant pleural effusion (more than 10mm
        thick on ultrasonography or lateral decubitus radiography) with no known cause.

        B and C are both light's criteria either indicates that the fluid is an exudates

        D - a predominance of neutrophils in the pleural fluid (>50%) indicates that an acute process is affecting the pleura
        E - evidence of infection

        A - A pleural-fluid pH below 7.20 in a patient with a parapneumonic effusion indicates the need for drainage of the fluid

         

        In this clinical scenario the answer is E - Infection is the only definitive diagnostic criteria in the list and drainage will assist treatment

        Answer: E

         

        Pleural Effusion
        Light R. W. N Engl J Med 2002; 346:1971-1977, Jun 20, 2002. Clinical Practice

        Topic: Respiratory - Pleural Disease

        Question 32 Top Download PDF

        A 20-year-old athlete is resuscitated after an out-of –hospital cardiac arrest.  The most likely underlying aetiology is:
        A. Coronary plaque disruption
        B. Anomalous origin of a coronary artery
        C. Myocarditis
        D. Arrhythmogenic right ventricular dyplasia
        E. Hypertrophic cardiomyopathy

        Answer E

        Major causes of sudden cardiac death  - uptodate
        Ischemic heart disease

        • Coronary artery disease with myocardial infarction or angina
        • Coronary artery embolism
        • Nonatherogenic coronary artery disease (arteritis, dissection, congenital coronary artery anomalies)
        • Coronary artery spasm

        Nonischemic heart disease

        • Hypertrophic cardiomyopathy
        • Dilated cardiomyopathy
        • Valvular heart disease
        • Congenital heart disease
        • Arrhythmogenic right ventricular dysplasia
        • Myocarditis
        • Acute pericardial tamponade
        • Acute myocardial rupture
        • Aortic dissection

        No structural heart disease

        • Primary electrical disease (idiopathic ventricular fibrillation)
        • Brugada syndrome (right bundle branch block and ST segment elevation in leads V1 to V3)
        • Long QT syndrome
        • Preexcitation syndrome
        • Complete heart block
        • Familial sudden cardiac death
        • Chest wall trauma (commotio cordis)

        Noncardiac disease

        • Pulmonary embolism
        • Intracranial hemorrhage
        • Drowning
        • Pickwickian syndrome
        • Drug-induced
        • Central airway obstruction
        • Sudden infant death syndrome

        Medical Progress: Sudden Death in Young Athletes
        Maron B. J. N Engl J Med 2003; 349:1064-1075, Sep 11, 2003. Review Articles

        Topic

        Cardiology Cardiomyopathy

        Question 33 Top

        Question 34 Top

        Question 35 Top Download PDF

        Infusion of cryoprecipitate is principally indicated for the replacement of:
        A. factor IX.
        B. fibrinogen.
        C. immunoglobulin A (IgA).
        D. anti-thrombin.
        E. protein C.

        CRYOPRECIPITATE — When FFP is thawed at 4ºC, a precipitate remains, which can be separated by centrifugation; this material is termed cryoprecipitate (cryo). It is a concentrated preparation which contains virtually all of the factor VIII, fibrinogen, fibronectin, factor XIII, and von Willebrand factor (vWF) in fresh frozen plasma, reduced from an initial volume of 250 mL to a final volume of 10 to 15 mL. The remaining material can be refrozen and used as cryo-poor FFP
        Cryo contains about 200 mg of fibrinogen and 100 units of Factor VIII (80 to 110 IU) per bag and carries the same infectious risk as a unit of red cells, or of FFP. Cryo is used in the treatment of congenital and acquired deficiencies of fibrinogen and Factor XIII . Ten bags of cryo (obtained from 10 units of plasma) contain about 2 gm of fibrinogen and will raise the fibrinogen level about 70 mg/dL in a 70 kg recipient
        Because of past experience with viral transmission, cryo should no longer be used for the treatment of hemophilia A; pasteurized factor VIII concentrates derived from plasma or from recombinant DNA techniques are preferred sources of factor VIII for replacement therapy, as well as for vWF in many circumstances. . However, cryo does contain the large multimers of vWF and may be needed for the treatment of von Willebrand disease when there is no other recourse.

        Topic

        Haematology: Transfusion

        Question 36 Top

        Question 37 Top

        Question 39 Top Download PDF

        Question 39

        A healthy 85-year-old woman who is slightly below ideal body weight has a postprandial blood glucose level of 10.0 mmol/L [3.6-6.6]. Which one of the following is most likely to be responsible for the blood glucose result?

        A. Increased subcutaneous body fat

        B. Decreased circulating insulin levels

        C. Increased rate of glucose absorption

        D. Decreased insulin sensitivity

        E. Increased circulating growth hormone

         

        This lady has impaired glucose tolerance so the question is

        1. testing our knowledge of T2DM pathophysiology and
        2. some understanding of the changes in hormones with aging – 2nd question with this focus in 2003

        T2DM is characterized by three pathophysiological abnormalities

        1. Impaired insulin secretion
          • insulin compensatory increase in insulin output then decrease, mechanism unclear
        2. Peripheral insulin resistance
          • Obesity, particularly visceral or central, is very common in T2DM.  Adipocytes secrete a number of biologic products ( leptin, TNF-alpha, free fatty acids, resistin, and adiponectin) that modulate insulin secretion, insulin action and body weight and may contribute to the insulin resistance
          • Skeletal muscle
          • Combination of genetic susceptibility and obesity
          • Impairs glucose utilization by insulin-sensitive tissues and increased hepatic glucose output; both effects contribute to the hyperglycemia
        3. Excessive hepatic glucose production
          • Increased hepatic glucose output predominantly accounts for increased fasting plasma glucose , whereas decreased peripheral glucose usage results in postprandial hyperglycaemia

         

        • Answer A Increased subcutaneous body fat is Unlikely she is below ideal body fat
        • Answer B Decreased circulating insulin levels is unlikely as it represents the later stages of T2DM which is not evident from the question a healthy 85 year old woman
        • Answer C  Increased rate of glucose absorption is not likely as it would result in hypoglycemia if anything
        • Answer D Decreased insulin sensitivity is a good answer because it would explain the decreased peripheral glucose usage and therefore the postprandial hyperglycaemia
        • Answer E Increased circulating growth hormone is incorrect as growth hormone is decreased in aging see question 50 paper 1 2003
        Answer D

        Topic

        Endocrinology: The pathophysiological basis of insulin-dependent and non insulin-dependent diabetes and implications of this for treatment

         

        Question 40 Top

        Question 41 Top Download PDF

        A 63-year-old woman presents wit hweight gain, reduced energy and depression, five years after pituitary surgery and radiotherapy for a non-functionint pituitary adenoma.  Current medication are thyroxine 0.15mg/day, hydrocortisone 20 mg/day (equivalent to cortisone acetate 25mg /day) in divided doses, conjugated oestrogen 0.625mg/day, medroxyprogesterone 2.5 mg/day and fluoxetine 20mg day

        Examination is unremarkable except for truncal obesity.  Her body mass index (BMI) is 30kg/m2 [20-25] and her blood pressure is 145/85 mmHg.

        Which one of the following is the moste likely cause of her weight gain?

        A. Inadequate thyroxin replacement dose

        B. Excess hydrocortisone replacement dose

        C. Excess oestrogen replacement dose

        D. Growth hormone deficiency

        E. Fluoxetine therapy

        Answer D

        I thought this question required quite a lot of information to be confident in the answer actually, much more suited to a clinical application anyway:
        What do you need to know?

        1. A bit of an understanding of diagnosis and management of pituitary tumours (there are immediate, medium and long term issues)
        2. An appreciation of hypopituitarism as a consequence of surgical management, hormones involved and the impact of their defiency
        3. knowledge of the appropriate medications for defiency syndromes and doses
        4. Fluoxetine therapy

        Dosing – from therapeutic guidelins

        Thyroxine (0.15 mg / dau) – standard maintenance is 100-125 microg / day ( start with 50-100) ie dose is not inadequate is at the max maintenance

        Hydrocortisone (20 mg /day) (15 – 30 mg per day in divided doses)

        hydrocortisone,  is the glucocorticoid the adrenals make, use in a daily dose according to the patient's weight; suitable doses are approximately 20 mg/day for a patient who weighs 55 kg and 30 mg/day for a patient who weighs 80 kg

        so the dose is not excessive

        Gonadotropin
        Oestrogen 0.625 mg/day and medroxyprogesterone 2.5mg /day
        Medium dose

        • oestrogen 0.625mg/day
        • medroxyprogesterone 2.5 – 5

        no growth hormone replacement therapy

        Fluoxetine: starting dose 20mg  to max 80mg
        Adverse Reactions: CNS disturbances incl anxiety, insomnia, mania, seizures, tremor, dizziness; withdrawal reactions; hyponatraemia; GI upset; weight loss; allergy esp rash; asthenia; headache; others, see full PI. Children: headache; decr height gain, weight gain, alkaline phosphatase

          Side effect = weight gain but small dose cf lack of growth hormone replacement unlikely to be the most important cause

        Up to date

        Major symptoms and signs of hypothyroidism


        Mechanism

        Symptoms

        Signs

        Slowing of metabolic processes

        Fatigue and weakness
        Cold intolerance
        Dyspnea on exertion
        Weight gain
        Cognitive dysfunction
        Mental retardation (infant)
        Constipation
        Growth failure

        Slow movement and slow speech
        Delayed relaxation of tendon reflexes
        Bradycardia
        Carotenemia

        Accumulation of matrix substances

        Dry skin
        Hoarseness
        Edema

        Coarse skin
        Puffy facies and loss of eyebrows
        Periorbital edema
        Enlargement of the tongue

        Other

        Decreased hearing
        Myalgia and paresthesia
        Depression
        Menorrhagia
        Arthralgia
        Pubertal delay

        Diastolic hypertension
        Pleural and pericardial effusions
        Ascites
        Galactorrhea

         

        Hypopituitarism

        GENERAL PRINCIPLES — Damage to the anterior pituitary can occur suddenly or slowly, can be mild or severe, and can affect the secretion of one, several, or all of its hormones. As a result, the clinical presentation of anterior pituitary hormone deficiencies varies, depending upon the following factors:

        The rapidity with which a disease affects anterior pituitary cells. Some diseases, such as pituitary apoplexy, develop rapidly, causing sudden impairment of ACTH secretion and, consequently, sudden onset of symptoms of cortisol deficiency. Other insults, such as radiation therapy to the pituitary or hypothalamus, usually act slowly, causing symptoms many months or, more likely, years later.).
        The severity of the hormonal deficiency. Complete ACTH and cortisol deficiency, as an example, can cause symptoms under basal circumstances, while partial ACTH deficiency may cause symptoms only during times of physical stress.


        How many kinds of anterior pituitary cells are affected, leading to impairment in the secretion of one, a few, or all the pituitary hormones (called panhypopituitarism).

        As a general rule, the secretion of gonadotropins and growth hormone is more likely to be affected than ACTH and thyroid-stimulating hormone (TSH). Many exceptions occur, however, so that one may see a patient who has only isolated ACTH deficiency. Thus, one cannot make an assumption about the status of one pituitary hormone from the status of another; if the physician judges that it is clinically important to know the status of a particular pituitary hormone, the status of that hormone must be tested directly.


        ACTH deficiency

        The presentation of ACTH deficiency is almost exclusively that of the resulting cortisol deficiency. In its most severe form, cortisol deficiency leads to death due to vascular collapse, because cortisol is necessary for maintenance of peripheral vascular tone. A less severe form of the same phenomenon is postural hypotension and tachycardia. Mild, chronic deficiency may result in lassitude, fatigue, anorexia, weight loss, decreased libido, hypoglycemia, and eosinophilia. There are two important clinical distinctions between ACTH deficiency and primary adrenal insufficiency with a secondary increase in ACTH release:
        ACTH deficiency does not cause salt wasting, volume contraction, and hyperkalemia, because it does not result in clinically important deficiency of aldosterone.
        ACTH deficiency does not result in hyperpigmentation.
        Both forms of adrenal insufficiency can cause hyponatremia.   This abnormality is due to inappropriate secretion of antidiuretic hormone (vasopressin) that is caused by cortisol (not aldosterone) deficiency

        TSH deficiency

        The clinical presentation of TSH deficiency is exclusively that of thyroxine deficiency, which might include fatigue, lethargy, cold intolerance, decreased appetite, constipation, facial puffiness, dry skin, bradycardia, delayed relaxation phase of the deep tendon reflexes, and anemia. The degree of symptoms and abnormal physical findings usually parallels the degree of thyroxine deficiency, but, as the case with ACTH deficiency, some patients with marked TSH deficiency have few or no symptoms.

        .
        Gonadotropin deficiency

        Deficient secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) causes hypogonadism in both women and men.
        In women, hypogonadism means ovarian hypofunction, which results in the inability to ovulate, infertility, and decreased estradiolsecretion. The latter may be responsible for a variety of symptoms including oligo- or amenorrhea, vaginal dryness and atrophy, and fatigue. Estradiol deficiency due to hypopituitarism causes hot flashes, like estradiol deficiency due to ovarian disease. No physical findings of hypogonadism are detectable initially, but after several years, breast tissue decreases, fine facial wrinkles appear, and bone mineral density declines.

        Serum androgen concentrations in women with hypopituitarism (particularly those with both gonadotropin and ACTH deficiency) are lower than those in normal control women [2], and appear to be correlated with bone mineral density [3]. The clinical significance of this decrease has yet to be determined.


        In men, hypogonadism means testicular hypofunction, which results in infertility and decreased testosterone secretion. The latter causes decreased energy and libido, and hot flashes if sufficiently severe, within weeks to months, but does not cause decreased muscle mass (and perhaps strength) for several years. Testosterone deficiency also causes decreased bone mineral density


        Growth hormone deficiency

        Growth hormone deficiency in children typically presents as short stature. For many years, growth hormone deficiency beginning in adulthood was not thought to have any adverse consequences. However, evidence suggests that lack of growth hormone in adults might have a number of adverse effects. The evidence is of two kinds.

        1. The demonstration that patients who have growth hormone deficiency have a greater frequency of certain diseases than expected. Interpretation of this kind of evidence is confounded by the simultaneous deficiencies of other pituitary hormones and the variability of their replacement.
        2. The improvement these patients experience when they are treated with growth hormone. Interpretation of this kind of evidence is made difficult by the lack of placebo controls in most studies of growth hormone treatment.

        With the above qualifications, we should consider the possibility that growth hormone deficiency may result in the following:

        • Diminished muscle mass and increased fat mass. This effect is the best documented.
        • Increased serum low-density-lipoprotein (LDL) cholesterol.
        • Decreased bone mineral density.
        • Diminished sense of well being.
        • Increased risk of cardiovascular disease] and increased inflammatory cardiovascular risk markers (IL-6 and C-reactive protein).
        Diagnosis of GH deficiency
        • Gold standard for diagnosis is insulin tolerance test
        • stimulated Gh of less than 3 microg/L indicatie of severe GH deficiency
        • Low IGF-1 highly sugestive of GH deficiency in context of known pituitary disease but not sensitive

        Prolactin deficiency — The only known presentation of prolactin deficiency is the inability to lactate after delivery.

         

        Treatment of hypopituitarism


        SUMMARY — Treatment of patients with hypopituitarism is the sum of the treatments of each of the individual pituitary hormonal deficiencies detected when a patient with a pituitary or hypothalamic disease is tested. The treatments of corticotropin (ACTH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiencies are in many ways the same as the treatments of primary deficiencies of the respective target glands, but in other ways they differ.

        1. Lack of ACTH primarily induces cortisol deficiency. Treatment consists of the administration of hydrocortisone or other glucocorticoid in an amount and timing to mimic the normal pattern of cortisol secretion
        2. TSH deficiency, which results in thyroxine (T4) deficiency, is treated with L-thyroxine. The goal of therapy should be a normal serum T4 value. T4 should not be administered until adrenal function, including ACTH reserve, has been evaluated and either found to be normal or treated. Measurement of serum TSH cannot be used as a guide to the adequacy of L-thyroxine replacement therapy.
        3.  In men with gonadotropin deficiency, testosterone replacement is indicated when fertility is not desired. Men with secondary hypogonadism who wish to become fertile may be treated with gonadotropins, if they have pituitary disease or with either gonadotropins or gonadotropin-releasing hormone (GnRH) if they have hypothalamic GnRH deficiency.
        4. In women with gonadotropin deficiency, treatment depends upon the patient's goals. Estrogen and progestin replacement is indicated in women who are not pursuing fertility, while gonadotropin or pulsatile GnRH therapy may be used when ovulation induction and fertility are the goal.
        5. We currently do not recommend recombinant human growth hormone as routine treatment for all patients with adult-onset growth hormone deficiency. This issue is reviewed in detail elsewhere.
            • GROWTH HORMONE DEFICIENCY — The availability of several recombinant human growth hormone preparations (Humatrope®, Nutropin®, Serostim®, and Genotropin®) for treating adults with growth hormone deficiency allows physicians in the United States to prescribe this treatment. Patients with GH deficiency acquired as an adult must meet at least two criteria for therapy: a poor GH response to at least two standard stimuli; and hypopituitarism due to pituitary or hypothalamic damage. The criteria are different in children in whom GH is required for normal growth.

            Topic

            Endocrinology: Hypopituitarism

            Repeat Question 2002 paper one question 60

            Question 42 Top Download PDF

            A 25-year-old man sustains a soft tissue injury to the right shoulder in a football tackle.  Following the game he is noted to have weakness of right shoulder abduction (4/5) and internal rotations (3/5).  Reflexes are normal.  There is patchy sensory loss over the lateral forearm.

            The most likely injury is to the
            A.  axillary nerve
            B. suprascapular nerve
            C. C5 nerve root
            D. upper trunk of the brachial plexus
            E. musculocutaneous nerve.

            So this questions is a focus on C5 basically and all the things that could go wrong

            Reflexes:
            biceps jerk C5, C6 roots.  Musculocutaneous nerve (inside elbow)
            triceps jerk C6, C7, C8 roots. Radial nerve (outside elbow)
            supinators jerk c6, c7 roots. Radial nerve (wrist)
            Hoffman reflex C7, C8 (flick patient’s terminal phalanx look for thumb flexion)

            This man has have weakness of right shoulder abduction (4/5) and internal rotations (3/5).  Reflexes are normal.  There is patchy sensory loss over the lateral forearm.

            A.  axillary nerve – more than just axillary nerve

            B. suprascapular nerve – more than just suprascapular nerve

            C. C5 nerve root
            This is not consistent with a syndrome of root compression

            So basically this man has pranged surpascapular and axillary nerve so the answer is

            D. upper trunk of the brachial plexus consistent with presentation

            Upper plexus lesion (C5, C6)
            Traction on the arm at birth (Erb-Duchenne paralysis) or falling on the shoulder may damage the upper part (C5, C6) of the plexus
            Resulting in paralysis of deltoid, supraspinatus, infrasprinatus and elbow flexors biceps, brachialis
            Adductors of shoulder are mildly affected

            E. musculocutaneous nerve. – not consistent with presentation his reflexes are intact
            Later cord C5C6
            Sensory supply: lateral border of the arm
            Damaged by: Fracture of the humerus; Systemic causes
            Results in: Weakness of elbow flexion and forearm supination with characteristic sensory loss and absent biceps reflex

            Answer D

            Topic

            Neurology: Peripheral neuropathy

            Question 43 TopDownload PDF

            Which one of the following asbestos-related diseases requires the greatest exposure to asbestos fibres for its development?

            A. Bronchogenic carcinoma. - dose related exposure

            B. Pleural plaques. - low intermittent exposure in pleura

            C. Mesothelioma. - rare does not appear to be dose related

            D. Pulmonary fibrosis. - related to intensity and duration

            E. Diffuse pleural thickening. - less specific to asbestos sensitive pleura low intermittent


            So the answer is either A or D - given A also has a additive dose response curve in the context of cigarette smoking the most correct answer is D

            Answer: D

            From Harrisons
            Asbestosis is a diffuse interstitial fibrosing disease of the lung that is directly related to the intensity and duration of exposure. Except for its association with a history of exposure to asbestos (generally in a work setting), asbestosis resembles the other forms of diffuse interstitial fibrosis ( Chap. 243 ). Usually, moderate to severe exposure has taken place for at least 10 years before the disease becomes manifest.

            Physiologic studies reveal a restrictive pattern with a decrease in lung volumes. Flow rates are commonly reduced less than would be predicted on the basis of the volume reduction. An early sign of severe disease may be a reduction in diffusing capacity.

            Pulmonary fibrosis may occur following sufficient exposure to any of the asbestiform fiber types. The fibrotic lesions result from proinflammatory effects of reactive oxygen species released from phagocytes reacting with transition metals on the surface of the fibers. The clinical manifestations are typical of those physical findings in any patient with pulmonary fibrosis

            Lung cancer ( Chap. 75 ), either squamous cell carcinoma or adenocarcinoma, is the most frequent cancer associated with asbestos exposure. The excess frequency of lung cancer in asbestos workers is associated with a minimum lapse of 15 to 19 years between first exposure and development of the disease. Persons with more exposure are at greater risk of disease. In addition, there appears to be a significant multiplicative effect that leads to a far greater risk of lung cancer in persons who are cigarette smokers and have asbestos exposure than would be expected from the additive risk of each factor. To date, efforts to consider these high-risk individuals for special surveillance studies, including sputum cytologic examinations and repeated chest x-rays as frequently as every 4 to 6 months, have resulted in neither significant early detection nor prolonged survival once the lung cancer is found. The use of HRCT in such at-risk subjects is currently under investigation.

            Mesotheliomas ( Chap. 245 ), both pleural and peritoneal, are also associated with asbestos exposure. In contrast to lung cancers, these tumors do not appear to be associated with smoking. Relatively short-term asbestos exposures of 1 to 2 years or less occurring some 20 to 25 years in the past have been associated with the development of mesotheliomas (an observation that emphasizes the importance of obtaining a complete environmental exposure history). The risk for this type of tumor peaks 30 to 35 years after initial exposure. Since maximum exposure took place in the United States between 1930 and 1960, peak incidence of disease in men occurred in 1997, with a total of 2300 cases. Incidence is expected to decline over the next 30+ years to about 500 cases per year.

             

            From E medicine
            Pathogenesis
            The pleura are more sensitive than pulmonary parenchyma to the effects of the fibers. Thus, pleural plaques develop after low, intermittent exposure, whereas asbestosis is associated with cumulative, high-level, long-term, continuous exposure in association with a definite dose-effect relationship. Nonmanual workers in industries involving asbestos, inhabitants of areas immediately surrounding asbestos mills, and families of asbestos workers have an increased incidence of mesothelioma. However, even with significant industrial exposure, asbestosis is unusual.

            Pleural plaques are the most common manifestation of asbestos exposure, occurring after a latent period of approximately 20-40 years. A history of exposure can be elicited in more than 80% of patients. Histologically, pleural plaques consist of acellular collagen bundles that form a basket-weave pattern, which almost exclusively involves the parietal pleura. The plaques may contain chrysotile asbestos fibers.

            The precise pathogenesis of pleural plaques remains undetermined. That they were caused by the mechanical effect of asbestos fibers piercing the visceral pleura (the scratching theory) was assumed. Currently, however, the fibers are believed to be transported to the parietal pleura via lymphatic channels, where they incite an inflammatory response. Plaques slowly grow over time, even after cessation of exposure, but they are not considered premalignant.

            Calcification occurs later, often 30-40 years following exposure. Pleural plaques tend to occur in isolation without any other manifestations of asbestos-related disease; however, the converse is not true. Asbestosis is rarely seen in the absence of plaques.

            Diffuse pleural thickening is less specific for asbestos exposure than the presence of pleural plaques, since thickening also may be seen following TB pleuritis, hemothorax and empyema. Usually, the latent period is approximately 15 years. The pathogenesis is unclear, but it is believed to be due to inflammation and fibrosis of the visceral pleural lymphatics, and it has been considered to be an extension of parenchymal fibrosis. Histologically, the appearances are similar, although in diffuse pleural thickening, fusion of the visceral and parietal layers and asbestos bodies (which are absent in pleural plaques) is profuse. Development of diffuse pleural thickening has a similar time line as plaque formation.

            Benign asbestos-related pleural effusions are often the earliest manifestation of asbestos-related disease, typically occurring within 10 years of exposure. The effusions are exudative. Occasionally, they are hemorrhagic, but otherwise, their features are nonspecific. Effusions tend to be self-limiting, with a duration of a few months, but they can be chronic or recurrent. Diffuse pleural thickening not uncommonly develops following resolution of the effusion.

            Fibers not cleared by mucociliary action are believed to be transported into the interstitium, where they form aggregates, usually at the level of the respiratory bronchiole. Research results suggest that the fibers stimulate the release of a collagenase inhibitor-like protein that locally disturbs the balance of collagen turnover, resulting in fibrogenic changes within the interstitium.

            Asbestosis is usually seen when levels reach 10 million asbestos fibers per gram of pulmonary tissue. Asbestosis characteristically occurs following a latent period of 15-20 years, with a progression of disease even after exposure has ceased. Fibrosis first arises in and around the respiratory bronchioles, predominating in the subpleural portions of the lung in the lower lobes. This progresses to involve the alveolar walls, eventually causing honeycombing in a minority of patients.

            Folded lung (also termed round atelectasis, pulmonary pseudotumor, or Blesovsky syndrome) specifically refers to an area of atelectatic lung adjacent to pleural thickening, with characteristic in-drawing of bronchi and vessels. Blesovsky first reported folded lung in 1966. Although folded lung is strongly associated with asbestos exposure, it may also be seen as a consequence of any inflammatory or infective organizing pleural exudate.

            The presence of the effusion has been postulated to cause passive atelectasis, with infolding of the lung resulting in invagination of the adjacent pleura. This process causes tethering, which prevents reexpansion of the lung upon resolution of the effusion and which causes round atelectasis. A more accepted alternative explanation is that an insult to the pleura leads to localized inflammation and fibrosis, which results in volume loss and buckling of the underlying lung. Interestingly, the changes have been shown to resolve after decortication. The lingula is the most common site, followed by the middle and then the lower lobes, although lesions may be multiple and bilateral.

            Malignant pleural mesothelioma is a rare neoplasm, accounting for less than 5% of pleural malignancies. Malignant pleural mesothelioma is strongly associated with asbestos exposure, particularly crocidolite exposure, although the association does not appear to be dose-related because significant numbers of cases occur after trivial environmental or household exposure. No relevant history of any asbestos exposure is found in 20% of patients. The disease is frequently seen in the absence of any other manifestations of asbestos exposure and usually develops after a long latent period of 35-40 years.

            Mesothelioma is 80% pleural and 20% peritoneal in origin. Pleural effusions are not a precursor of mesothelioma, but they often antedate development of malignancy. A confident diagnosis is often difficult to make and usually requires ultrastructural analysis and histochemical and immunohistochemical tests. Histologically, 3 forms of malignant mesothelioma are recognized: epithelial, mixed, and sarcomatous or mesenchymal. These must be differentiated from mesothelial hyperplasia and metastatic adenocarcinoma. The most common histologic subtype is epithelial, accounting for 50% of cases.

            Bronchogenic carcinoma is estimated to develop in 20-25% of heavily exposed asbestos workers. Smoking has a cumulative effect, further increasing the risk of lung cancer to a factor of 90 versus a factor of 5 in exposed nonsmokers. Often, asbestos-related interstitial disease is associated; however, no correlation exists between the severity of asbestosis and the development of lung cancer. Furthermore, lung cancer has been reported in individuals without interstitial lung disease who are exposed to asbestos. A latency period of 25-35 years is usual. Histologically, the predominant subtype is bronchoalveolar cell carcinoma, but adenocarcinoma and squamous cell carcinoma also occur.

            Associations between asbestos exposure and other cancers have been reported anecdotally. Carcinomas of the larynx, esophagus, stomach, colon, and a variety of lymphoid malignancies have been described.

            Refs:

            Topic: Respiratory - occupational lung disease

            Question 44 Top Download PDF

            During pregnancy, many cardiovascular conditions are associated with an increased risk of maternal mortality
            Which one of the following cardiovascular conditions is associated with the highest rate of maternal mortality?

            Moderate to severe:

            A. Pulmonary hypertension

            B. Hypertrophic cardiomyopathy

            C. Coarctation

            D. Aortic regurgitation

            E. Peripartum cardiomyopathy

            Answer A

            from harrisons medical conditions in pregnancy chapter 6 Cardiac Disease

            Valvular Heart Disease

            Mitral Stenosis

            This is the valvular disease most likely to cause death during pregnancy. The pregnancy-induced increase in blood volume, cardiac output, and tachycardia can cause pulmonary edema in women with mitral stenosis. Pregnancy associated with long-standing mitral stenosis may result in pulmonary hypertension. Sudden death has been reported when hypovolemia has been allowed to occur in this condition. Careful control of heart rate, especially during labor and delivery, minimizes the impact of tachycardia and reduced ventricular filling times on cardiac function. Pregnant women with mitral stenosis are at increased risk for the development of atrial fibrillation and other tachyarrythmias. Medical management of severe mitral stenosis and atrial fibrillation with digoxin and beta blockers is recommended. Balloon valvulotomy can be carried out during pregnancy.

            Mitral Regurgitation and Aortic Regurgitation

            These are both generally well tolerated during pregnancy. The pregnancy-induced decrease in systemic vascular resistance reduces the risk of cardiac failure with these conditions. As a rule, mitral valve prolapse does not present problems for the pregnant patient, and aortic stenosis, unless very severe, is well tolerated. In the most severe cases of aortic stenosis, limitation of activity or balloon valvuloplasty may be indicated.

            For women with artificial valves contemplating pregnancy, it is important that warfarin be stopped and heparin initiated prior to conception. Warfarin therapy during the first trimester of pregnancy has been associated with fetal chondrodysplasia punctata. In the second and third trimester of pregnancy, warfarin may cause fetal optic atrophy and mental retardation. For women with prosthetic heart valves, prophylaxis against thrombosis with low-molecular-weight heparin (LMWH) is not recommended due to reports of valvular thrombosis despite adequate anticoagulation. Prophylaxis with unfractionated heparin is recommended for this group of women.

            Congenital Heart Disease

            The presence of a congenital cardiac lesion in the mother increases the risk of congenital cardiac disease in the newborn. Prenatal screening of the fetus for congenital cardiac disease with ultrasound is recommended. Atrial or ventricular septal defect is usually well tolerated during pregnancy in the absence of pulmonary hypertension, provided that the woman's prepregnancy cardiac status is favorable. Use of air filters on intravenous sets during labor and delivery in patients with intracardiac shunts is generally recommended.

            Other Cardiac Disorders

            Supraventricular tachycardia is a common cardiac complication of pregnancy. Treatment is the same as in the nonpregnant patient, and fetal tolerance of medications such as adenosine and calcium channel blockers is acceptable. When necessary, electrocardioversion may be performed and is generally well tolerated by mother and fetus.

            Peripartum cardiomyopathy is a rare disorder of pregnancy associated with myocarditis, and its etiology remains unknown. Treatment is directed toward symptomatic relief and improvement of cardiac function. Many patients recover completely; others are left with a progressive dilated cardiomyopathy. Recurrence in a subsequent pregnancy has been reported, and women should be counseled to avoid pregnancy after a diagnosis of peripartum cardiomyopathy.

            Specific High-Risk Cardiac Lesions

            Marfan Syndrome

            is an autosomal dominant disease, associated with a high risk of maternal morbidity. Approximately 15% of pregnant women with Marfan syndrome develop a major cardiovascular manifestation during pregnancy, with almost all women surviving. An aortic root diameter <40 mm is considered to be associated with a favorable outcome of pregnancy. Prophylactic therapy with beta blockers has been advocated, although large-scale clinical trials in pregnancy have not been performed.

            Pulmonary Hypertension

            Maternal mortality in the setting of severe pulmonary hypertension is high, and primary pulmonary hypertension is a contraindication to pregnancy. Termination of pregnancy may be advisable in these circumstances to preserve the life of the mother. In the Eisenmenger syndrome, i.e., the combination of pulmonary hypertension with right-to-left shunting due to congenital abnormalities maternal and fetal death occur frequently. Systemic hypotension may occur after blood loss, prolonged Valsalva maneuver, or regional anesthesia; sudden death secondary to hypotension is a dreaded complication. Management of these patients is challenging, and invasive hemodynamic monitoring during labor and delivery is generally recommended.

            In patients with pulmonary hypertension, vaginal delivery is less stressful hemodynamically than Cesarean section, which should be reserved for accepted obstetric indications.

            From
            New England Journal of Medicine Volume 349:Number 1 July 3, 2003: 52-59
            Valvular Heart Disease in Pregnancy  Sharon C. Reimold, M.D., and John D. Rutherford, M.B., Ch.B.

            primary pulmonary hypertension is associated with high maternal mortality (33 to 40 percent), as well as with an increased rate of adverse neonatal events.9 Secondary pulmonary hypertension due to valvular disease is associated with an increased rate of adverse maternal events, but the absolute risk of such events is unclear. A systolic pulmonary-artery pressure that is more than 75 percent as high as the systemic pressure places the woman at high risk.

            From Heart 2001;85:710-715 ( June ) http://heart.bmj.com.journals.library.austin.org.au/
            Heart  disease and pregnancy Samuel C Siu, Jack M Colman

             

            Marternal cardiac status and risk of cardiac complications during pregnancy
            Low risk

            • Small left to right shunts
            • Repaired lesions without residual cardiac dysfunction’
            • Isolated mitral valve prolapsewithout significant regurgitation
            • Bicuspid aortic valve without stenossi
            • Mild to moderate pulmonic stenosis
            • Valvar regurgitation with normal ventricular systolic function

            Intermediate risk

            • Unrepaired or palliated cyanotic congential heart disease
            • Large left to right shunt
            • Uncorrected coartcation of the aorta
            • Mitral or aortic stenosis
            • Mechanical prosthetic valves
            • Severe pulmonic stenosis
            • Moderate to severe systemic ventricular dysfunction
            • History of peripartum cardiomyopathy with no residual ventricular dysfunction

            High Risk

            • New York Heart Association (NYHA) class III of IV symptoms
            • Severe pulmonary hypertension
            • Marfan syndrome with aortic root or major valvar involvement
            • Severe aortic stenosis

            The New York Heart Association (NYHA) Functional Classification:


            I

            No symptoms and no limitation in ordinary physical activity.

            II

            Mild symptoms and slight limitation during ordinary activity.
            Comfortable at rest.

            III

            Marked limitation in activity due to symptoms, even during less-than-ordinary activity.
            Comfortable only at rest.

            IV

            Severe limitations. Experiences symptoms even while at rest.

            Topic

            Cardiology Cardiac changes and problems in pregnancy

            Question 45 Top Download PDF

            A 45-year-old man undergoes bronchoscopy for investigation of haemoptysis. An endobronchial tumour is identified and cytology confirms carcinoma. Staging computed tomography (CT) scans of the chest and upper abdomen are shown opposite.

            Based on these diagnostic studies, the stage of the tumour can be best described as:

            A. T1N0M0.
            B. T2N1M0.
            C. T1N1M1.
            D. T2N1M1.
            E. T4N1M1.

            Answer: E

            International staging system for lung cancer, 1997 revision

            Primary tumor (T)
            T1 - Tumor <3 cm diameter without invasion more proximal than lobar bronchus
            T2 - Tumor >3 cm diameter OR Tumor of any size with any of the following: 
            Invades visceral pleura
            Atelectasis of less than entire lung
            Proximal extent at least 2 cm from carina
            T3 - Tumor of any size with any of the following:
            Invasion of chest wall
            Involvement of diaphragm, mediastinal pleura, or pericardium
            Atelectasis involving entire lung
            Proximal extent within 2 cm of carina
            T4 - Tumor of any size with any of the following:
            Invasion of mediastinum
            Invasion of heart or great vessels
            Invasion of trachea or esophagus
            Invasion of vertebral body or carina
            Presence of malignant pleural or pericardial effusion
            Satellite tumor nodule(s) within same lobe as primary tumor
            Nodal involvement (N)
            N0 - No regional node involvement
            N1 - Metastasis to ipsilateral hilar and/or ipsilateral peribronchial nodes
            N2 - Metastasis to ipsilateral mediastinal and/or subcarinal nodes
            N3 - Metastasis to contralateral mediastinal or hilar nodes OR ipsilateral or contralateral scalene or supraclavicular nodes

            Metastasis (M)
            M0 - Distant metastasis absent
            M1 - Distant metastasis present (includes metastatic tumor nodules in a different lobe from the primary tumor)
            Stage groupings of TNM subsets

            Stage IA T1   N0 M0
            Stage IB   T2 N0 M0
            Stage IIA   T1 N1 M0
            Stage IIB

            T2

            T3

            N1

            N0

            M0

            M0

            Stage IIIA

            T3

            T1-3

            N1

            N2

            M0

            M0

            Stage IIIB

            Any T

            T4

            N3

            Any N

            M0

            M0


            Stage IV     

            Any T 

            Any N

            M1

             Adapted from Mountain, CF, Chest 1997; 111:1710.

            Topic

            Respiratory Thoracic malignancy

             

            Question 46 Top

            Question 47 Top

            Question 48 Top

            Question 49 Top Download PDF

            A 72-year-old woman presents with severe diarrhoea. She commenced amoxycillin for an upper respiratory tract infection five days ago.
            Which one of the following tests would best confirm a diagnosis of Clostridium difficile-induced pseudomembranous colitis?


            A. C. difficile culture.
            B. C. difficile cytotoxin assay.
            C. C. difficile polymerase chain reaction (PCR).
            D. C. difficile immunoglobulin A (IgA).
            E. Faecal microscopy.

            Reference: Infectious Diseases A clinical Approach Yung, McDonald, Spelman, Street and Johnson 2001

            Pg 102
            Investigations – diarrhoea

            Faecal microscopy is particularly useful in the initial assessment of acute diarrhoea.  The presence or absence of faecal leucocytes (pus cells), red blood cells and parasites can be ascertained by direct microscopy of a fresh specimen

            Enterocolitis (usually bacterial) is indicated by the presence of leucocytes ± red cells. Microscopic examination nof fresh stoll specimens may reveal the cysts or trophozoites of Giardia lamblia in only about 50% of cases with this small bowel pathogen.  Repeated microscopic examination of stools and examination of duodenal aspirate will increase the yields.

            Positive identification of the cysts of Entamoeba histolytica requires considerable laboratory expertise athat is not generally available.  Detection of parasites is enhanced by faecal concentration.  Where there is a high index of suspicion (eg returned travellers), this should be requested.

            Viral pathogens can be detected by electron microscopy and rotavirus, adenovirus, Norwalk calicivirus and astrovirus by immunoassay also.  Viral cultures not used as a diagnostic procedure for gastrointestinal viruses.

            Faecal culture is useful despite the inherent delay because the finding of Salmonella spp., Campylobacter jejuni, Shigella or Clostridium difficile in a patient who has continuing diarrhoea may be an indication for specific treatment and aid public health investigations.  Toxin assay is now the preferred method for the diagnosis of Clostridium difficile infection.  Although culture for most pathogenic bacteria is routine, selective media are required and close communication with the microbiology laboratory is good practice.  Special techniques are necessary to detect vibrios, pathogenic E.coli, Aeromaonas, Listeria and Yersinia.

            A negative faecal culture does not exclude bacterial diarrhoea.  Occasionally, pathogens may be cultured in one specimen but not in another from the same patient on the same day, and not all patients in a common-source outbreak with typical symptoms will yield he causative pathogen.

            Investigations are selected on the basis of he patient’s illness and epidemiological setting.  Even with extensive investigation 20-40% of all diarrhoeal illness remain undiagnosed.

            Blood tests are indicated in more severe cases and help in the assessment of complications such as fluid, electrolyte and blood loss.  Febrile patients with enterocolitis should have blood cultures taken as the finding of bacteraemia is an indication for antibiotic therapy.  Diagnostic serology is not usually performed but an detect Campylobacter, Yersinia and amoebic infections.

            Sigmoidoscopy and colonoscopy are only necessary when there is persistent bleeding or protracted diarrhoea.  Normal sigmoidoscopic appearances generally exclude ulcerative colitis, antibiotic-induced colitis, shigellosis, and severe amoebic dysentery.  Sigmoidoscopic and rectal biopsy appearances in ulcerative colitis may be identical to those seen in infective colitis.  The presence of a pseudomembrane, however, is diagnostic of pseudomembranous colitis due to Clostridium difficile.

            Answer: B. C. difficile cytotoxin assay.

            Topic

            Infectious Diseases Enteritis

             

            Question 50 Top Download PDF

            Which one of the following hormones shows the most consistent decline in blood levels (in both sexes) with ageing?

            1. Cortisol
            2. Adrenocroticotrophic hormone (ACTH)
            3. Thyrotropin
            4. Dehydroepiandrosterone (DHEA)
            5. Insulin

            Answer D

             

            Cortisol

            Cortisol is a corticosteroid hormone produced by the adrenal cortex that is involved in the response to stress; it increases blood pressure, blood sugar levels, may cause infertility in women, and suppresses the immune system. In pharmacology, cortisol is referred to as hydrocortisone, and is used to treat allergies and inflammation.

            Diurnal variation
            The amount of cortisol present in the serum undergoes diurnal variation, with the highest levels present in the early morning, and the lowest levels present around midnight, 3-5 hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. The pattern is not present at birth (estimates of when it starts vary from two weeks to 9 months.)
            Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of  temperature.
            There is also significant individual variation, although a given person tends to have consistent rhythms.
            Effects
            In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.)
            It acts as a physiological antagonist to insulin by promoting gluconeogenesis, breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased blood glucose concentrations, resulting in increased glycogen formation in the liver. Prolonged cortisol secretion causes hyperglycemia.
            It lowers the activity of the immune system in the blood. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor. It reflects leukocyte redistribution to lymph nodes,bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution.
            It lowers bone formation. Cortisol moves potassium into cells in exchange for an equal number of sodium ions. This can cause a major problem with the hyperkalemia of metabolic shock from surgery.
            It helps to create memories when exposure is short-term; this is the proposed mechanism for storage of flash bulb memories. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning.
            It increases blood pressure.
            It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress.
            It increases the effectiveness of catecholamines.
            In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. (It binds with less affinity to it than aldosterone does, but the concentration of blood cortisol is higher than that of blood aldosterone.)
            Most serum cortisol, all but about 4%, is bound to proteins including corticosteroid binding globuin (CBG), and serum albumin. Only free cortisol is available to most receptors.

            Disorders

            • Cushings – increased cortisol
            • Addisons – decreased cortisol

             

            Adrenocroticotrophic hormone (ACTH)

            Adrenocorticotropic hormone (ACTH or corticotropin) is a polypeptide hormone produced and secreted by the pituitary gland. It is an important player in the hypothalamic-pituitary-adrenal axis.
            ACTH synthesised from pro-opiomelanocortin (POMC) and secreted from corticotropes in the anterior lobe of the pituitary gland in response to the hormone corticotropin-releasing hormone (CRH) released by the hypothalamus.
            ACTH acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. ACTH stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also mineralcorticoids and sex steroids (androgens).
            ACTH is also related to the circadian rhythm in many organisms.
            The half-life of ACTH in human blood is about 10 minutes.

             

            Thyrotropin

            Thyroid-stimulating hormone (also known as TSH or thyrotropin) is a hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland which regulates the endocrine function of the thyroid gland.
            Controlling the rate of release
            TSH stimulates the thyroid gland to secrete the hormones thyroxine (T4) and triidothyronine (T3). TSH production is controlled by a Thyrotropin Releasing Hormone, (TRH), which is manufactured in the hypothalamus and transported to the Anterior Pituitary gland, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.
            The level of Thyroid hormones (T3 and T4) in the blood have an additional effect on the pituitary release of TSH, When the levels of T3 and T4 are low, the production of TSH is increased, and conversely, when levels of T3 and T4 are high, then TSH production is decreased. This effect creates a regulatory negative feedback loop
            Subunits of TSH
            TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit.
            The alpha subunit is identical to that of human chorionic gonadotropin (HCG), lutenising hormone (LH), follicle-stimulating hormone (FSH).
            The β (beta) subunit is unique to TSH, and therefore determines its function.
            The TSH receptor
            The TSH receptor is found mainly on thyroid follicular cells. Stimulation of the receptor increases T3 and T4 production and secretion.
            Stimulating antibodies to this receptor mimic TSH action and are found in Graves’ disease.
            The TSH receptor
            The TSH receptor is found mainly on thyroid follicular cells. Stimulation of the receptor increases T3 and T4 production and secretion.
            Stimulating antibodies to this receptor mimic TSH action and are found in Graves’ disease.
             Diagnostic use
            TSH levels are tested in the blood of patients suspected of suffering from excess (hyperthyroidism), or deficiency (hypothyroidism) of thyroid hormone. Generally, a normal range for TSH for adults is between 0.3 and 3.0 ulU/mL (equivalent to mIU/L), but the interpretation depends also on what the blood levels of thyroid hormones (T3 and T4) are. The National Health Service in the UK considers a "normal" range to be more like 0.1 to 5.0 uIU/mL.
            TSH levels for children normally start out much higher. In 2002, the National Academy of Clinical Biochemistry (NACB) in the US recommended age-related reference limits starting from about 1.3-19 uIU/mL for normal term infants at birth, dropping to 0.6-10 uIU/mL at 10 weeks old, 0.4-7.0 uIU/mL at 14 months and gradually dropping to during childhood and puberty to adult levels, 0.4-4.0 uIU/mL The NACB also stated that it expected the normal (95%) range for adults to be reduced to 0.4-2.5 uIU/mL, because research had shown that adults with an initially measured TSH level of over 2.0 uIU/mL had "an increased odds ratio of developing hypothyroidism over the [following] 20 years, especially if thyroid antibodies were elevated"

            Dehydroepiandrosterone (DHEA)

             

            This is the correct answer – Levels of the adrenal sex steroid dehydroepiandrosterone (DHEA) and its sulfate ester fall progressively after 30 years of age, and after 60 years of age are less than half the levels in youth
            Ref: Aging and Fountain of Youth Hormone Paul M Stewart M.D. NEJM 355; 16 pp 1724-1726 2006

            DHEA is produced from cholesterol through two cytochrome P450 enzymes. Cholesterol is converted to pregnenolone by the enzyme P450 scc (side chain cleavage) and then another enzyme CYP17A1 converts pregnenolone to 17α-Hydroxypregnenolone and then to DHEA. In humans DHEA is the dominant steroid hormone and precursor of all sex steroids.

            DHEA production is very high during fetal life by the fetal adrenal glands, declines after birth and remains low during childhood. Production begins around 6 years of age, increasing in quantity until peaking in early adulthood, around the age of 25, and declines afterwards to approximately 10% of peak levels by age 80. It is theorized by some that this decline may be due to reduced oxygen and glucose supply to the adrenal glands as a result of age-related atherosclerosis.

            In a simple view DHEA can be understood as a prohormone for the sex steroids. Its DHEAS variation may be looked at as buffer and reservoir. Its production in the brain suggests that it also has a role as a neurosteroid. As most DHEA is produced by the zona reticularis of the adrenal, it is argued that there is a role in the immune and stress response. DHEA may have more biologic roles.
            As almost all DHEA is derived from the adrenal glands, blood measurements of DHEAS/DHEA are useful to detect excess adrenal activity as seen in adrenal cancer or hyperplasia, including certain forms of congenital adrenal hyperplasia. Women with polycystic ovary syndrome tend to have normal or mildly elevated levels of DHEAS.

            Insulin

            Insulin (from Latin insula, "island", as it is produced in the Islets of Langerhans in the panceas) is a polypeptide hormone that regulates carbohydrate metabolism. Apart from being the primary agent in carbohydrate homeostasis, it has effects on fat metabolism and it changes the liver's activity in storing or releasing glucose and in processing blood lipids, and in other tissues such as fat and muscle. The amount of insulin in circulation has extremely widespread effects throughout the body.

            Topic

            Endocrinology: Hormones

            Question 51 Top

            Question 52 Top Download PDF

            A 47-year-old man with severe haemophilia A and a high titre factor VIII inhibitor is scheduled for hip replacement surgery. The peri-operative replacement coagulation product of choice is:

            A. recombinant activated factor VII.
            B. recombinant factor VIII.
            C. recombinant factor IX.
            D. fresh frozen plasma.
            E. cryoprecipitate.

            Haemophilia
            The hemophilias are a group of related bleeding disorders that most commonly are inherited. Inherited bleeding disorders include abnormalities of coagulation factors as well as platelet function; the most common of these disorders is von Willebrand disease. However, when the term "hemophilia" is used, it most often refers to one of the following two disorders:

            • Factor VIII deficiency (hemophilia A)
            • Factor IX deficiency (hemophilia B, Christmas disease)

             Management

            PREVENTIVE AND COMPREHENSIVE CARE —

            • Circumcision — Approximately 50 percent of undiagnosed hemophilics bleed in association with circumcision  For this reason, male infants born to known or suspected carrier mothers should not be circumcised until hemophilia has been excluded.
            • Routine immunizations — Routine immunizations, such as diphtheria-tetanus-pertussis or measles-mumps-rubella, may be given in the deep subcutaneous tissue or via the usual route. The smallest gauge needle should be used and pressure and ice applied to the site for three to five minutes post injection.
            • Hepatitis B vaccine should be given to all infants with hemophilia as soon after birth as possible, while hepatitis A vaccine is given after the age of one year
            • Dental care — Dental care is essential for individuals with congenital bleeding diatheses. C
            • Counseling and education

            REPLACEMENT THERAPY — Clotting factor concentrates are given to prevent bleeding and to limit existing hemorrhage. Dosing is reasonably standard, but the choice of product and the use of primary and secondary prophylaxis require expert intervention.   Treatment of patients with inhibitors requires considerable expertise.

             

            Patients with hemophilia, particularly those with severe disease, develop bleeding episodes that are treated with replacement of the missing factor (ie, factor VIII or factor IX concentrates). A complication of hemophilia is the development of an inhibitor which usually occurs shortly after replacement therapy has been initiated. The inhibitors are antibodies (primary IgG) directed against the specific deficient factor.

             

            INHIBITORS IN HEMOPHILIA A — The development of inhibitors is more common in patients with hemophilia A than in those with hemophilia B.

            Incidence — Factor VIII inhibitors have been reported in approximately 25 percent of patients with severe hemophilia A

            Predisposing factors

            • Severe disease -  the virtual complete lack of circulating factor VIII in patients with severe disease prevents the induction of tolerance and predisposes them to antibody formation after exposure to normal factor VIII. The concept that self factor VIII, even if altered, contributes to tolerance to factor VIII is supported by the lower frequency and often transient nature of inhibitors in patients with less severe hemophilia A
            • Product-related factors can lead to inhibitor formation with certain preparations. This possibility should be suspected when antibodies first form in multiply-transfused patients who have been switched to a new product.
            • Patient age at the time of initial replacement treatment, as well as the early use of prophylaxis, may influence inhibitor formation.

            Clinical manifestations — The clinical manifestations of factor VIII antibodies in patients with hemophilia A depend in part upon the severity of the disease. In general, the inhibitor does not lead to a marked increase in the frequency of bleeding events except when a moderate or mild deficient patient is converted to a more severe state. However, patients with inhibitors have more difficulty in controlling hemostasis and tend to have more musculoskeletal complications; in this setting, the bleeding frequency may increase due to the presence of acute and chronic synovitis.

            Inhibitors make the treatment of bleeding episodes more difficult. Thus, an inhibitor should be suspected when any bleeding episode is refractory to usual therapy, particularly in patients with severe hemophilia.

            Mechanism of action — The alloantibodies formed after exposure to factor VIII concentrates are directed against specific epitopes on the factor VIII molecule. Factor VIII consists of a heavy chain with A1 and A2 domains, a connecting region with a B1 domain that is not required for clotting, and a light chain with A3, C1, and C2 domains. Most antibodies are directed against the C2 [27,28], A2 [27,29,30], and other light chain epitopes that include the A3 domain [27,31]. In one series of 34 patients with hemophilia A, more than 80 percent had two or more inhibitor antibodies (A2, C2, and other light chain epitopes AR3-A3-C1) whether treated with plasma or recombinant factor VIII [27]. The antibodies were directed against C2 in 82 percent, A2 in 70 percent, and both in 25 percent. This pattern is different from that in patients without hemophilia who form autoantibodies against factor VIII: these patients are more likely to have a single antibody, directed particularly against C2 [27].

             Proteolysis — Some antibodies have direct catalytic (proteolytic) activity against factor VIII [39]. In one study, significant proteolytic activity against human factor VIII was detected in 13 of 24 patients with severe hemophilia A and factor VIII inhibitors [40]. The rate of hydrolysis of factor VIII by purified IgG from these patients correlated positively with its factor VIII neutralizing activity.

            Diagnosis — Factor VIII inhibitor activity generally is measured by the Bethesda assay, which both establishes the diagnosis of a factor VIII inhibitor and quantifies the antibody titer.

            Treatment — Comprehensive Hemophilia Treatment Centers provide expertise for these specialized patients and should be consulted for the development of any treatment plan in a hemophilic patient with an inhibitor .
            The two components to therapy are

            • treatment of active bleeding and
            • inhibitor ablation via immune tolerance induction.

              Active bleeding — The general approach to the treatment of bleeding episodes in patients with hemophilia A and inhibitors requires knowledge of the inhibitor type (high versus low responding): In patients with usual bleeding episodes involving the joints and muscle who are high responders, inhibitor bypassing products are generally employed regardless of the present inhibitor titer. Bypassing products include prothrombin complex concentrates (PCCs, or the original factor IX complex concentrates) and their activated counterparts (APCCs: FEIBA® and Autoplex®), and recombinant human factor VIIa (NovoSeven®). PCCs and APCCs may be associated with reactions due to activation of the complement and bradykinin systems when infused rapidly, as well as other complications such as frank thromboembolic events, myocardial infarction, and disseminated intravascular coagulation . NovoSeven does not produce an anamnestic antibody response and markedly reduces the risk of disseminated intravascular coagulation and thrombosis due to its mechanism of action, which provides more localized hemostatic control at the site of injury or bleeding. In patients with life or limb threatening episodes, the present inhibitor titer is used to determine the appropriate infusion therapy regardless of inhibitor type (high versus low responding). In such patients, an immediate human and porcine factor VIII inhibitor titer should be established to determine if human or porcine factor VIII will provide hemostasis. These patients are best managed by a comprehensive hemophilia center experienced in the management of such patients.

             High purity factor VIII concentrates — Although high purity factor VIII concentrates can be used in patients with low inhibitor levels (<10 Bethesda units), their main use is in the treatment of life-threatening hemorrhage or emergency surgery in patients with low inhibitor levels or moderate inhibitor levels that have been reduced by plasmapheresis or immunoadsorption  In these settings, physiologic factor VIII levels can be attained before the anamnestic response occurs.

              Porcine factor VIII concentrates — Porcine factor VIII is used primarily to treat patients who are high responders with high human factor VIII inhibitor titers and porcine factor VIII titers less than 10 Bethesda units who have life threatening episodes.

            The administration of porcine factor VIII can be associated with hypersensitivity reactions in 1 to 2 percent of patients, mostly in those treated with higher doses.

              Prothrombin complex concentrates and activated prothrombin complex concentrates — Manufacturers of the prothrombin complex concentrates (PCCs) increased the concentration of active proteases, resulting in production of activated prothrombin complex concentrates (APCCs); the latter preparations include FEIBA® and Autoplex®

            Since the activated proteases that account for the procoagulant activity of APCCs are short-lived, initial hemostasis may be followed by breakthrough bleeding between doses that may create difficulty for maintenance of hemostasis. In addition, both PCCs and APCCs are associated with a risk of thrombosis, including myocardial infarction, which is most likely to occur when large doses are given . Other risk factors include crush injuries, surgery, and liver function abnormalities, leading to a decreased ability to clear activated products.

            In summary, therapy with PCCs or APCCs is expensive, provides unpredictable hemostasis without the ability to monitor clinical efficacy with a laboratory test, and carries the risk of significant complications.

             Recombinant human factor VIIa — Recombinant human factor VIIa (Novo-Seven®, rFVIIA) produces an excellent or effective response in over 90 percent of patients. Because factor VIIa requires tissue factor to be active, it promotes coagulation only at the local level and should minimize the risk of systemic coagulation seen with PCCs and APCCs. The usual dose is 90 microg/kg at two to three hour intervals until hemostasis is achieved, with further dosing and lengthening of the interval based upon the patient's clinical circumstances.

            A starting dose of 90 microg/kg is used in patients undergoing surgery

            Immune tolerance induction — Long-term management of hemophilic patients with factor VIII inhibitors is aimed at eliminating the inhibitors . The primary method used is the attempt at immune tolerance induction (ITI) via the administration of repetitive doses of factor VIII with or without immunosuppressive therapy. Many responders have an initial rise in antibody titers caused by the anamnestic response, followed by a progressive reduction to a low or undetectable titer [3,65]. Immune tolerance usually must be maintained by continued exposure to factor VIII.

            INHIBITORS IN HEMOPHILIA B — The incidence of factor IX inhibitors in hemophilia B is much lower than that seen with factor VIII inhibitors in hemophilia A. The estimated incidence is 3 to 5 percent in patients with severe hemophilia B but is population-dependent.

            In addition to diminished responsiveness to factor IX concentrates, patients with factor IX inhibitors also are at risk for anaphylaxis following factor IX infusion

            Diagnosis — As in factor VIII deficiency, an inhibitor is suspected in patients with factor IX deficiency when they fail to respond to infusion therapy or when an anaphylactic reaction occurs. The diagnosis should be confirmed in the laboratory with a Bethesda assay for factor IX.

            Treatment — A family history of inhibitors in factor IX deficient patients should lead to the utmost caution when treating any newly diagnosed patient. It has been recommended that the first 20 infusions of factor IX be administered where facilities for resuscitation are immediately available in patients with severe disease and a known high-risk mutation or when the mutation is unknown .

              Active bleeding — The optimal therapy of active bleeding should be determined by the treatment center. In patients without anaphylaxis, PCCs or APCCs can be given, although they will lead to continued stimulation of antibody production . There is also a risk of thrombosis, including myocardial infarction .

            Immune tolerance induction — Immune tolerance induction (ITI), similar to that described above for patients with factor VIII, can be attempted.

            FRESH FROZEN PLASMA — Fresh frozen plasma (FFP) is prepared from single units of whole blood or from plasma collected by apheresis techniques. It is frozen at -18 to -30ºC within eight hours of collection and, when appropriately stored, is usable for one year from the date of collection. Standard FFP units derived from a single unit of whole blood have a volume of about 250 mL; "jumbo" units prepared by hemapheresis may be as large as 800 mL.

            FFP contains all of the coagulation factors and other proteins present in the original unit of blood, slightly diluted by the citrate-containing anticoagulant solution used to collect the blood. FFP is not a concentrate of any of the circulating plasma proteins, and, in general, should not be used to treat coagulation defects caused by known deficiencies of a single factor, or for replacing factors better provided in concentrated form (eg, factor VIII concentrates for hemophilia A). FFP should not be used as a source of albumin or other nutrients, or as a volume expander .

            Dose and indications — As a general rule, hemostasis can be achieved when the activity of coagulation factors is at least 25 to 30 percent of normal, in the absence of an inhibitor such as heparin, and when the level of fibrinogen is at least 75 to 100 mg/dL  

            Indications for the use of FFP must be carefully followed: FFP may be needed

            • For inherited factor XI deficiency
            • as a source of factor V in severe cases of disseminated intravascular coagulation (DIC) when platelet concentrates and cryoprecipitate do not correct the factor V, VIII, and fibrinogen consumption defects.
            • to correct a bleeding condition caused by a deficiency of multiple coagulation factors, such as is seen in warfarin overdose, vitamin K deficiency, liver failure, or dilutional coagulopathy following massive transfusion
            • FFP should not be used as primary therapy for a specific coagulation defect (eg, hemophilia A, hemophilia B, factor VII or XIII deficiency) when specific coagulation factor concentrates are available.

            Limitations — Given that the INR of FFP units can be as high as 1.3, transfusion of FFP will have little effect on minimally elevated INRs.

            Side effects —

            • Infections
            • TRALI 
            • Allergic reaction, rigors
            • Anaphylactic reactions following transfusion of plasma may occur in patients with IgA deficiency and antibodies to IgA

            CRYOPRECIPITATE — When FFP is thawed at 4ºC, a precipitate remains, which can be separated by centrifugation; this material is termed cryoprecipitate (cryo). It is a concentrated preparation which contains virtually all of the factor VIII, fibrinogen, fibronectin, factor XIII, and von Willebrand factor (vWF) in fresh frozen plasma, reduced from an initial volume of 250 mL to a final volume of 10 to 15 mL. The remaining material can be refrozen and used as cryo-poor FFP
            Cryo contains about 200 mg of fibrinogen and 100 units of Factor VIII (80 to 110 IU) per bag and carries the same infectious risk as a unit of red cells, or of FFP. Cryo is used in the treatment of congenital and acquired deficiencies of fibrinogen and Factor XIII . Ten bags of cryo (obtained from 10 units of plasma) contain about 2 gm of fibrinogen and will raise the fibrinogen level about 70 mg/dL in a 70 kg recipient
            Because of past experience with viral transmission, cryo should no longer be used for the treatment of hemophilia A; pasteurized factor VIII concentrates derived from plasma or from recombinant DNA techniques are preferred sources of factor VIII for replacement therapy, as well as for vWF in many circumstances. . However, cryo does contain the large multimers of vWF and may be needed for the treatment of von Willebrand disease when there is no other recourse.

             

            A. recombinant activated factor VII. ‘
            Correct
            B. recombinant factor VIII.
            Not appropriate – he has developed an inhibitor to his required factor VIII
            C. recombinant factor IX.
            Used in haemophilia B not A
            D. fresh frozen plasma.
            FFP is not a concentrate of any of the circulating plasma proteins, and, in general, should not be used to treat coagulation defects caused by known deficiencies of a single factor, or for replacing factors better provided in concentrated form (eg, factor VIII concentrates for hemophilia A).
            E. cryoprecipitate.
            Can be used in treatment of von Willebrand disease

            Topic

            Haematology: haemophilia

             

            Question 53 Top Download PDF

            Which one of the following interventions is most beneficial for improving prognosis in patients with cardiogenic shock complicating myocardial infarction with acute ST elevation

            A.  Infusion of intravenous adrenergic agent

            B. Early coronary revascularization

            C. Insertion of a Swan=Ganz catheter to monitor therapy

            D. Intra-aortic balloon counter pulsation

            E. Administration of intravenous heparin

            Answer B

            Fibrinolysis not appropriate therapy in cardiogenic shock so E wrong

            Guidelines for the management of acute coronary syndromes 2006
            Acute Coronary Syndrome Guidelines Working Group. Med J Aust 2006; 184 (8): S1-S32.

            Management of STEMI
            Reperfusion therapy
            Reperfusion may be obtained with fibrinolytic therapy or PCI. A combination of fibrinolysis and PCI may also be used (facilitated or rescue PCI). Coronary artery bypass graft (CABG) surgery may occasionally be more appropriate — particularly in patients who have suitable anatomy and are not candidates for fibrinolysis or PCI. CABG surgery may also be considered in patients with cardiogenic shock or in association with mechanical repair.

            19 Eagle KA, Guyton RA, Davidoff R, et al; American College of Cardiology/ American Heart Association Task Force on Practice Guidelines Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery; American Society for Thoracic Surgery; Society of Thoracic Surgeons. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 2004; 44: 1146-1154, e213-310.

            9.2.4. ST-Segment Elevation MI (STEMI)
            Class I
            1. Emergency or urgent CABG in patients with STEMI should be undertaken in the following circumstances:
            a. Failed angioplasty with persistent pain or hemodynamic instability in patients with coronary anatomy suitable for surgery. (Level of Evidence: B)
            b. Persistent or recurrent ischemia refractory to medical therapy in patients who have coronary anatomy
            suitable for surgery, who have a significant area of myocardium at risk, and who are not candidates for
            PCI (Level of Evidence: B)
            c. At the time of surgical repair of postinfarction ventricular septal rupture or mitral valve insufficiency.
            (Level of Evidence: B)
            d. Cardiogenic shock in patients less than 75 years old with ST-segment elevation or left bundle-branch
            block or posterior MI who develop shock within 36 hours of MI and are suitable for revascularization
            that can be performed within 18 hours of shock, unless further support is futile because of the patient’s
            wishes or contraindications/unsuitability for further invasive care. (Level of Evidence: A)
            e. Life-threatening ventricular arrhythmias i n the presence of greater than or equal to 50% left main
            stenosis and/or triple-vessel disease. (Level of Evidence: B)
            Class IIa
            1. CABG may be performed as primary reperfusion in patients who have suitable anatomy and who are not
            candidates for or who have had failed fibrinolysis/ PCI and who are not in the early hours (6 to 12 hours) of evolving STEMI (Level of Evidence: B)
            2. In patients who have had an ST-segment elevation MI or non–ST-segment elevation MI, CABG mortality
            is elevated for the first 3 to 7 days after infarction, and the benefit of revascularization must be balanced against this increased risk. Beyond 7 days after infarction, the criteria for revascularization described in previous sections are applicable. (Level of Evidence: B)
            Class III
            1. Emergency CABG should not be performed in patients with persistent angina and a small area of
            myocardium at risk who are hemodynamically stable. (Level of Evidence: C)
            2. Emergency CABG should not be performed in patients with successful epicardial reperfusion but
            unsuccessful microvascular reperfusion. (Level of Evidence: C)

            Topic

            Cardiology myocardial infarction

            Question 54 Top

            Question 55 Top

            Question 56 Top

            Question 57 Top

            Repeat question 2004 paper two question 79

            Question 58 Top

            Question 59 Top

            Question 60 Top Download PDF

            A 37-year-old man presents to the emergency department with symptoms of meningitis. Gram stain of the cerebrospinal fluid reveals the presence of gram-negative diplococci.
            His 12-week pregnant partner should receive which one of the following as prophylaxis?
            A. Ciprofloxacin.
            B. Ceftriaxone.
            C. Penicillin.
            D. Meningococcal vaccine.
            E. Erythromycin.

            Reference: Infectious Diseases A clinical Approach Yung, McDonald, Spelman, Street and Johnson 2001
            Therapeutic Guidelines Antiobiotics 2006
            wikapeadia
            http://en.wikipedia.org/wiki/Gram-negative
            http://en.wikipedia.org/wiki/Gram-positive

            Common clinically relevant bacteria

            Gram positive: Bacillus; Listeria; Staphylococcus; Streptococcus; Enterococcus; Clostridium

            Gram negative cocci: Neisseria gonorrhoea (STD); Neisseria meningitidis (meningitis); Moraxella catarrhalis (respiratory)

            Gram negative bacilli: Haemophilus influenzea; Klebsiella pneumonia; Legionella pneumonia; Pseudomonas aeruginesia (respiratory) | Escherichia coli; Proteus mirabilis; Enterobacter cloacae; Serratia marcescens (urinary tract) | Helicobacter pylori; Salmonella enteritias; Salmonella typhi (GI)

            80% bacterial meningitis caused by
            Streptococcus pneumonia – gram positive
            Neisseria meningitis – gram negative cocci
            Haemophilis influenzea- gram negative bacilli

            Treatment: (Therapeutic Guidelines)

            If the organism or susceptibility is not known, empirical therapy should cover the most common pathogens. In patients over 3 months of age, use:


            1

            ceftriaxone 4 g (child: 100 mg/kg up to 4 g) IV, daily
            or ceftriaxone 2 g (child: 50 mg/kg up to 2 g) IV, 12-hourly

             

            OR

             

            2

            cefotaxime 2 g (child: 50 mg/kg up to 2 g) IV, 6-hourly.

            Listeria monocytogenes is resistant to cephalosporins. If the patient is immunosuppressed or Listeria infection is suspected, add to the above regimen either:


            1

            benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) IV, 4-hourly

             

            OR

             

            2

            amoxy/ampicillin 2 g (child: 50 mg/kg up to 2 g) IV, 4-hourly.

            Add vancomycin if Gram-positive diplococci are seen or a pneumococcal antigen assay in CSF is positive, or if the patient has been heavily pretreated with a beta lactam (eg for recurrent ear infections). This is to ensure that Streptococcus pneumoniae isolates that display intermediate or higher resistance to penicillin and/or cephalosporins are adequately covered prior to the availability of culture and susceptibility results. Consider vancomycin also if Gram-positive cocci resembling staphylococci are seen, or if neutrophils are present but organisms are not seen, and if viral meningitis or meningococcal disease are unlikely. Use:

             

            vancomycin 12.5 mg/kg up to 500 mg (child <12 years: 15 mg/kg up to 500 mg) IV, 6-hourly (monitor blood levels and adjust dose accordingly, slow infusion required).

            Cease vancomycin if an organism likely to be susceptible to ceftriaxone/cefotaxime is isolated or if a penicillin-susceptible pneumococcus (MIC <0.125 mg/L) is isolated.
            For patients with immediate penicillin or cephalosporin hypersensitivity, use:


            1

            vancomycin 12.5 mg/kg up to 500 mg (child <12 years: 15 mg/kg up to 500 mg) IV, 6-hourly (monitor blood levels and adjust dose accordingly; slow infusion required).

             

            PLUS

             

             

            ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) IV, 12-hourly

             

            OR

             

            2

            moxifloxacin 400 mg (child: 10 mg/kg up to 400 mg) IV, daily.

            Choose one of the directed regimens once the organism has been identified and susceptibility results are available.
            If no pathogen is isolated continue the empirical regimen for a minimum of 10 days, depending on response.
            Consider ceasing antibiotics if the CSF examination is consistent with viral meningitis.
            For neonates and infants under 3 months, the likely organisms are Streptococcus agalactiae, enteric Gram-negative rods or, rarely, Listeria monocytogenes. Treat as for severe sepsis in children under 6 months of age in whom meningitis has not been excluded. Intravenous treatment should continue for a minimum of 2 weeks. Repeat lumbar puncture(s) are usually done to directly assess bacteriological response. Complications during therapy are not infrequent and expert advice should be sought.

            Directed Therapy

            For meningitis due to Neisseria meningitidis (meningococcal meningitis), use:

             

            benzylpenicillin 1.8 g (child: 45 mg/kg up to 1.8 g) IV, 4-hourly for 3 to 5 days.

            For patients hypersensitive to penicillin (excluding immediate hypersensitivity), use:


            1

            ceftriaxone 4 g (child: 100 mg/kg up to 4 g) IV, daily for 3 to 5 days
            or ceftriaxone 2 g (child: 50 mg/kg up to 2 g) IV, 12-hourly for 3 to 5 days

             

            OR

             

            2

            cefotaxime 2 g (child: 50 mg/kg up to 2 g) IV, 6-hourly for 3 to 5 days.

            For patients with immediate penicillin or cephalosporin hypersensitivity, use:

             

            ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) IV, 12 hourly for 3 to 5 days.

            Prophylaxis and/or immunisation is essential for close contacts. Prophylaxis is also necessary for patients who have received only benzylpenicillin, since this does not reliably clear nasal carriage.
            MICs to penicillin and ceftriaxone/cefotaxime should be determined for all Streptococcus pneumoniae isolates. For strains with a penicillin MIC ≥0.125 mg/L, use vancomycin plus either ceftriaxone or cefotaxime (see Empirical therapy for doses). Specialist advice must be sought particularly if the MIC of these cephalosporins is elevated. Rifampicin or moxifloxacin are possible alternatives to vancomycin.
            For penicillin-susceptible strains (MIC <0.125 mg/L), use:

             

            benzylpenicillin 1.8 g (child: 45 mg/kg up to 1.8 g) IV, 4-hourly for 10 to 14 days.

            Very ill patients may require treatment for up to 3 weeks.

            For meningitis due to Haemophilus influenzae type b, use:


            1

            ceftriaxone 4 g (child: 100 mg/kg up to 4 g) IV, daily for 7 days
            or ceftriaxone 2 g (child: 50 mg/kg up to 2 g) IV, 12-hourly for 7 days

             

            OR

             

            2

            cefotaxime 2 g (child: 50 mg/kg up to 2 g) IV, 6-hourly for 7 days.

            If the organism is proven to be susceptible, use:


            1

            benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) IV, 4-hourly for 7 days

             

            OR

             

            2

            amoxy/ampicillin 2 g (child: 50 mg/kg up to 2 g) IV, 4-hourly for 7 days.

            For patients with immediate penicillin or cephalosporin hypersensitivity, use:


            1

            chloramphenicol 1 g (child: 20 to 25 mg/kg up to 1g) IV, 6-hourly for 7 days

             

            OR

             

            1

            ciprofloxacin 400 mg (child: 10 mg/kg up to 400 mg) IV, 12-hourly for 7 days

            For meningitis due to Listeria monocytogenes, penicillin and amoxy/ampicillin appear equally efficacious. Use:


            1

            benzylpenicillin 2.4 g (child: 60 mg/kg up to 2.4 g) IV, 4-hourly

             

            OR

             

            2

            amoxy/ampicillin 2 g (child: 50 mg/kg up to 2 g) IV, 4-hourly.

            In patients hypersensitive to penicillin, trimethoprim+sulfamethoxazole may be used alone:

             

            trimethoprim+sulfamethoxazole 160+800 mg (child: 4+20 mg/kg up to 160+800 mg) IV, 6-hourly.

            There is limited evidence that combination therapy with beta lactam plus trimethoprim+sulfamethoxazole improves outcomes. The value of adding an aminoglycoside is not clear.
            The usual duration of therapy is 3 weeks, with extension to 6 weeks in immunocompromised patients. Oral therapy with trimethoprim+sulfamethoxazole may be used to complete the course after initial 3 weeks if there has been a good response to IV therapy.

            Streptococcus agalactiae is the commonest cause of meningitis in the newborn. Use:

             

            benzylpenicillin 60 mg/kg up to 2.4 g IV, 4-hourly for 14 to 21 days.

            Cryptococcal meningitis is caused either by Cryptococcus neoformans (particularly in immunocompromised patients) or Cryptococcus gattii (previously known as C. neoformans var. gattii). Monitoring of CSF pressure is a critical part of management to ensure that communicating hydrocephalus does not develop and cause permanent neurological sequelae. Consultation with those experienced in the management of this condition is strongly recommended.
            The standard treatment for cryptococcal meningitis is:

             

            amphotericin B desoxycholate 0.7 mg/kg IV, daily (dosage to be adjusted according to tolerance) for 6 to 10 weeks

             

            PLUS

             

             

            flucytosine 25 mg/kg IV or orally, 6-hourly for 6 to 10 weeks (monitor plasma levels),

            Patients infected with Cryptococcus gattii may be slower to respond and require a longer treatment course. Alternatively, if the CSF is culture negative after 2 weeks of therapy, cease the amphotericin B desoxycholate and flucytosine and commence:

             

            fluconazole 800 mg (child: 20 mg/kg up to 800 mg) orally or IV for the first dose, then 400 mg (child: 10 mg/kg up to 400 mg) orally, daily for at least 10 weeks of therapy.

            Itraconazole has been successfully used when fluconazole cannot be used.
            In HIV-infected patients, the regimen as outlined above has been shown to be successful, without the need for culture negativity at 2 weeks (
            In the immunocompromised, long-term suppressive therapy may be required. If there has been a successful response after 10 weeks of fluconazole at the above dose, reduce the dose to:

             

            fluconazole 200 mg (child: 5 mg/kg up to 200 mg) orally, daily indefinitely as secondary prophylaxis.

            Note 1: Lipid or liposomal formulations of amphotericin have been successfully used when toxicity from amphotericin B desoxycholate has become a problem; however, there is limited data in the literature to guide dose and duration of therapy.

            Note 2: Oral flucytosine is not registered for use in Australia; available via Special Access Scheme.

            Chemoprophylaxis for meningitis

            Introduction
            Chemoprophylaxis for meningitis or other infections caused by Neisseria meningitidis (meningococcus) and the now much less common Haemophilus influenzae type b (Hib) is offered to close (usually household) contacts of the index case. Among close contacts there will be a person or persons asymptomatically carrying the organism which caused the index infection. Chemoprophylaxis aims to eradicate asymptomatic carriage in the network of contacts so that susceptible members of the group do not acquire the organism and get an invasive infection. The Guidelines for early clinical and public health management of meningococcal disease in Australia provide definitions of a close contact, and appropriate prophylactic regimens. See also the Australian Immunisation Handbook. Prophylaxis outside the immediate family should be initiated and coordinated by public health authorities.
            Despite prophylaxis, disease can still occur. Parent education regarding frequent, careful observation and the need for examination by a medical practitioner at the first signs of any unexplained illness is essential.

            Neisseria meningitidis (meningococcus)

            Suitable regimens for Neisseria meningitidis (meningococcus) prophylaxis are:


            1
            ceftriaxone 250 mg (child: 125 mg) IM as a single dose (preferred option during pregnancy)

             

            OR

             

            1

            ciprofloxacin (adult and child ≥12 years) 500 mg orally, as a single dose (preferred option for women taking oral contraceptives)

             

            OR

             

            1

            rifampicin 600 mg (neonate <1 month: 5 mg/kg; child: 10 mg/kg up to 600 mg) orally, 12-hourly for 2 days (preferred option for children).

            Rifampicin is associated with multiple drug interactions and is contraindicated in pregnancy, alcoholism and severe liver disease.

            Haemophilus influenzae type b (Hib)

            A suitable regimen for Haemophilus influenzae type b (Hib) prophylaxis is:

             

            rifampicin 600 mg (neonate <1 month: 10 mg/kg; child: 20 mg/kg up to 600 mg) orally, daily for 4 days.

            Alternatively, although data are limited, if rifampicin is considered unsuitable, use:

             

            ceftriaxone 1 g (child: 25 mg/kg up to 1 g) IM, daily for 2 days.

            Where the index case is under 2 years of age, commence a full course of Hib vaccination as soon as possible after recovery, regardless of any previous Hib immunisation. Unvaccinated contacts under 5 years of age should be immunised as soon as possible.


            Note 1: Communicable Diseases Network Australia. Guidelines for the early clinical and public health management of meningococcal disease in Australia. Commonwealth Department of Health and Aged Care; 2001. http://www.health.gov.au/internet/wcms/publishing.nsf/Content/cda-pubs-other-mening.htm/

            Answer B. Ceftriaxone.

            Topic

            Infectious Disease: Meningitis
            Question repeated 2004 paper one question 45

            Question 61 Top Download PDF

            A 64-year-old woman undergoes a dual-energy X-ray absorptiometry scan.  The report is shown below.

            According to the World Health Organisation (WHO) definitions, the patient’s lumbar spine bone density is:
            A.  High normal
            B.  normal
            C. osteopenic
            D. osteoporotic
            E. severely osteoporotic

            BONE QUALITY — Bone strength is determined by bone mineral density (BMD) and other properties of bone that are often collectively called "bone quality" [6]. Non-BMD determinants of bone strength include bone turnover, architecture (size and shape, or bone geometry), microarchitecture (eg, trabecular thickness, trabecular connectivity, trabecular perforation, cortical thickness, and cortical porosity), damage accumulation, matrix properties, mineralization, and mineral properties (eg, crystal size and orientation).

            1994 World Health Organization Definitions of Osteoporosis Based on Bone Density Levels 


            Normal.
            Bone Density is within 1 SD (+1 or -1) of the young adult mean.

            Low Bone Mass.
            Bone density is 1 to 2.5 SD below the young adult mean (-1 to -2.5 SD). 

            Osteoporosis.
            Bone density is 2.5 SD or more below the young adult mean (> -2.5 SD).

            Severe (established) osteoporosis.
            Bone density is more than 2.5 SD below the young adult mean and there has been one or more osteoporotic fractures.

            BMD testing is a widely available clinical tool to diagnose osteoporosis, predict fracture risk, and monitor response to therapy. While BMD testing at any skeletal site with a variety of technologies can predict fracture risk , dual-energy X-ray absorptiometry (DXA) of the spine, hip and forearm is the only method for diagnosis of osteoporosis and monitoring changes in BMD over time

            DXA TECHNOLOGY — A typical DXA instrument consists of a padded table on which the patient lies and a movable C-arm with an X-ray tube below the patient and a detector above the patient . The X-ray tube generates photon beams of two different energy levels, thus the term "dual-energy." A collimator below the table limits the scatter of the photons and directs them toward the area of interest. The difference in attenuation (reduction in intensity) of the two photon beams as they pass through body tissue of variable composition distinguishes bone from soft tissue and allows quantification of BMD. Denser and thicker tissue contains more electrons and allows fewer photons to pass through to the detector. A computer with specially designed proprietary software designed by each manufacturer completes the DXA "system."
            Radiation exposure to the patient is very small, usually of a similar magnitude to daily background radiation. Radiation scatter beyond the edge of the DXA table is negligible. No shielding of the technologist or the room is necessary. As a safety precaution, the technologist should not sit within three feet of the table edge while the patient is being scanned.

            DXA measures bone mineral content (BMC, in grams) and bone area (BA, in square centimeters), then calculates "areal" BMD in g/cm2 by dividing BMC by BA. T-score, the value used for diagnosis of osteoporosis, is calculated by subtracting the mean BMD of a young-adult reference population from the patient's BMD and dividing by the standard deviation (SD) of young-adult population. Z-score, used to compare the patient's BMD to a population of peers, is calculated by subtracting the mean BMD of an age-, ethnicity-, and sex-matched reference population from the patient's BMD and dividing by the SD of the reference population. The mean BMD and SD of the reference populations used for these calculations is a critical variable in the determination of T-scores and Z-scores.

            International Society for Clinical Densitometry indications for bone density testing
             

            • Women aged 65 years and older.
            • Postmenopausal women under age 65 years with risk factors for osteoporosis.
            • Men aged 70 years and older.
            • Adults with fragility fracture.
            • Adults with a disease or condition associated with low bone mass or bone loss.
            • Adults taking medication associated with low bone mass or bone loss.
            • Anyone being considered for pharmacological osteoporosis therapy.
            • Anyone being treated for low bone mass to monitor treatment effect.
            • Anyone not receiving therapy in whom evidence of bone loss would lead to treatment.
            • Women discontinuing estrogen should be considered for bone density testing according to the indications listed above.

            Data from: Indications and reporting for dual-energy X-ray absorptiometry. J Clin Densitom 2004; 7:37.

            Contraindicated in pregnancy

            Question
            This ladies T score – the score used for the diagnosis of osteoporosis in her lumbar spine ranges from -2.70 to -3.42
            As we have not been told about any osteoporotic fractures the answer is D – osteoporosis – although I thought E initially

            Topic

            Endocrinology bone mineral density reports

             

            Question 62 Top

            Question 63 Top Download PDF

            Which one of the following medications is most appropriate for the treatment of nausea and vomiting in parkinson’s disease?

            1. prochloperazine
            2. promethazine
            3. droperidol
            4. metoclopramide
            5. domperidone

            Answer E: domperidone

            The pathognomonic histological feature of Parkinson's disease is a loss of neuromelanin-containing dopaminergic cells in the substantia nigra pars compacta. Microscopically, this cell loss is accompanied by the presence of intracytoplasmic inclusions known as Lewy bodies in the substantia nigra. Neurologically, this loss of cells in the substantia nigra results in a loss of dopaminergic input to the basal ganglia via the nigrostriatal pathway, and therefore an imbalance in the output pathways of the striatum, which form the extrapyramidal motor system. The imbalance in this motor system produces the motor symptoms that characteristic of this disorder.

            DIAGNOSIS OF PD — Correct diagnosis is fundamental to the appropriate therapy of Parkinson's disease (PD), although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The four cardinal signs of parkinsonism are rest tremor, rigidity, akinesia, and gait disturbance. Usual criteria for a clinical diagnosis of PD require the presence of at least two of these four features; diagnostic certainty increases in proportion to the predominance of rest tremor as a finding, especially if it is unilateral

            Treatment
            Levodopa — Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD. It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.
            Levodopa is combined with a peripheral decarboxylase inhibitor to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension. In the United States, the decarboxylase inhibitor is carbidopa. The combination drug carbidopa/levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg, with the numerator referring to carbidopa and the denominator referring to the levodopa dose. An immediate-release formulation of carbidopa/levodopa (Parcopa) is available that dissolves on the tongue and can be taken without water, but there are no published studies of this formulation, and its onset of action is no different from Sinemet.
            In Europe and Canada, benserazide is the peripheral decarboxylase inhibitor. The combination drug benserazide/levodopa (Madopar or Prolopa) is available in 25/100 and 50/200 mg tablets.
            Controlled-release formulations of carbidopa/levodopa and benserazide/levodopa are available as Sinemet CR and Madopar HBS, respectively.
            Ref
            An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines Olanow CW; Watts RL; Koller WC
            Neurology 2001 Jun;56(11 Suppl 5):S1-S88

            Prochlorperazine - stemetil

            Prochlorperazine is a phenothiazine with a piperazine moiety in the side chain. It possesses strong antiemetic and antipsychotic activity with less sedative action than chlorpromazine.
            Pharmacology. As with other phenothiazines, prochlorperazine has actions on several neurotransmitter systems as follows.
            Antidopamine action, which probably contributes to both the therapeutic effect and unwanted effects including extrapyramidal disorders and endocrine disturbances.
            alpha-Adrenoreceptor antagonism, which contributes to cardiovascular side effects, e.g. orthostatic hypotension and reflex tachycardia.
            Potentiation of noradrenaline by blocking its reuptake into nerve terminals.
            Weak anticholinergic action. Weak antihistamine action. Weak serotonin antagonism.
            Prochlorperazine also has an effect on temperature control and blocks conditioned avoidance responses.

            Promethezine

            Promethazine, a phenothiazine derivative, is a long acting antihistamine with mild atropine-like anticholinergic effects and some antiserotonin effects, and because of its marked effect on the central nervous system (CNS), acts as an antiemetic, hypnotic, tranquillizer, and a potentiator of anaesthetics, hypnotics, sedatives and analgesics.

            Droperidol

            Neuroleptic drug of the butyrophenone group, which also includes haloperidol.
            Pharmacology. Droperidol produces general quiescence and a reduced responsiveness to environmental stimuli in several animal species.
            There is little or no effect on respiration or myocardial contractile force, heart rate and cardiac output in dogs. The blood pressure is lowered, in part as a direct vasodilator effect and in part because of adrenergic blockade.
            Droperidol markedly reduces the ability of apomorphine to produce emesis in dogs. It is effective in protecting rats against experimentally induced traumatic shock and in protecting dogs against adrenaline induced ventricular arrhythmias.
            Human pharmacology. Droperidol produces marked tranquillization and sedation. It also produces an antiemetic effect as evidenced by the antagonism of the emetic effect of apomorphine in dogs. It potentiates other CNS depressants, e.g. pentobarbitone and narcotic analgesics such as fentanyl. It also produces mild alpha-adrenergic blockade, peripheral vascular dilatation, and reduction of the pressor effect of adrenaline.
            Droperidol can produce hypotension and decrease peripheral vascular resistance. It may decrease pulmonary arterial pressure, particularly if it is abnormally high. It may reduce the incidence of adrenaline induced arrhythmias but it does not prevent other cardiac arrhythmias. The onset of action is from three to ten minutes following intravenous or intramuscular administration. The full effect, however, may not be apparent for 30 minutes. The duration of the sedative and tranquillizing effects of droperidol generally is two to four hours. Alteration of consciousness may persist as long as 12 hours.

            Metoclopramide

            Maxolon stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary or pancreatic secretions. Its mode of action is unclear. It seems to sensitise tissues to the action of acetylcholine. The effect of Maxolon on motility is not dependent on intact vagal innervation, but it can be abolished by anticholinergic drugs.
            Maxolon increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower oesophageal sphincter. It has little, if any, effect on the motility of the colon or gall bladder.
            Maxolon has dopamine antagonist activity. Like the phenothiazines and related drugs, which are also dopamine antagonists, Maxolon produces sedation and may produce extrapyramidal reactions (see Precautions). Maxolon inhibits the central and peripheral effects of apomorphine, induces release of prolactin and causes a transient increase in circulating aldosterone levels.

            Domperidone

            Motilium is a dopamine antagonist with antiemetic properties similar to those of metoclopramide and certain neuroleptic drugs. Unlike these drugs, however, Motilium does not readily cross the blood-brain barrier. It seldom causes extrapyramidal side effects, but does cause a rise in prolactin levels. Its antiemetic effect may be due to a combination of peripheral (gastrokinetic) effects and antagonism of central dopamine receptors in the chemoreceptor trigger zone which lies in the area postrema and is regarded as being outside the blood-brain barrier.

            Topic

            Neurology: Parkinsons Disease
            Pharmacology: Neurology

            Question 64 Top Download PDF

              A 19-year-old woman presents with recent-onset right leg swelling and pleuritic chest pain and is found to have iliofemoral thrombosis on Doppler ultrasound examination. Results of a ventilation-perfusion lung scan indicate a high probability of pulmonary emboli. She had been taking the oral contraceptive pill for the last three years but has now ceased. She is a non-smoker. There is no significant medical history and no known family history of venous thromboembolism.
            The results of which one of the following investigations for an underlying hypercoagulable state are most likely to be affected by the presence of the extensive thrombosis?

            A. Anti-phospholipid antibody screen.
            B. Anti-thrombin level.
            C. Assessment of prothrombin and factor V genotypes.
            D. Activated partial thromboplastin time (APTT).
            E. Full blood count including blood film.

             The most common presentations of venous thrombosis are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism. The causes of venous thrombosis can be divided into two groups: hereditary and acquired.

            Causes of venous thrombosis

            Inherited thrombophilia

            • Factor V Leiden mutation
            • Prothrombin gene mutation
            • Protein S deficiency
            • Protein C deficiency
            • Antithrombin (AT) deficiency
            • Rare disorders
            • Dysfibrinogenemia

            INHERITED THROMBOPHILIA — Inherited thrombophilia is a genetic tendency to venous thromboembolism that usually presents in young patients (less than 50 years of age) and is often recurrent. The most frequent causes of the syndrome are the factor V Leiden mutation and a prothrombin gene mutation, which account for 50 to 60 percent of cases. Defects in protein S, protein C, and antithrombin (formerly known as antithrombin III) account for most of the remaining cases, while a rare cause is certain dysfibrinogenemias

            Fifty percent of thrombotic events in patients with inherited thrombophilia are associated with the additional presence of an acquired risk factor (eg, surgery, prolonged bed rest, pregnancy, oral contraceptives). Some patients have more than one form of inherited thrombophilia or more than one form of acquired thrombophilia and appear to be at even greater risk for thrombosis

            Acquired disorders

            • Malignancy
            • Presence of a central venous catheter
            • Surgery, especially orthopedic
            • Trauma
            • Pregnancy
            • Oral contraceptives
            • Hormone replacement therapy
            • Tamoxifen
            • Immobilization
            • Congestive failure
            • Antiphospholipid antibody syndrome
            • Myeloproliferative disorders
            • Polycythemia vera
            • Essential thrombocythemia
            • Paroxysmal nocturnal hemoglobinuria
            • Inflammatory bowel disease
            • Nephrotic syndrome
            • Hyperviscosity
            • Waldenstrom's macroglobulinemia
            • Multiple myeloma
            • Marked leukocytosis in acute leukemia
            • Sickle cell anaemia

             

            A. Anti-phospholipid antibody screen.
            Part of lupus anticoag screen – not affected by VTE  - altered by use of heparin
            B. Anti-thrombin level.
            If normal anti-thrombin antibody can be excluded, however if low this cannot be excluded as may be consumed by clot = answer
            C. Assessment of prothrombin and factor V genotypes.
            Molecular markers will not be affected by anticoagulation or presence of VTE
            D. Activated partial thromboplastin time (APTT).
            Altered by herparin use
            E. Full blood count including blood film.
            No change

            Wafarin will affect protein C and protein s levels

            Topic

            Haematology: Thrombosis Repeat question 2001 paper one question 19

             

            Question 65 Top

            Question 66 Top Download PDF

            QUESTION 66
            The investigation most useful in the management of cytomegalovirus (CMV) disease in the immunocompromised host is:
            A. CMV blood culture.
            B. direct CMV antigen detection in peripheral blood mononuclear cells (PBMCs).
            C. CMV immunoglobulin M (IgM).
            D. plasma CMV DNA concentration (viral load).
            E. early antigen detection in supernatant after culture of PBMCs for 48 hours.

            Reference: Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments Gandhi MK, Khanna R The Lancet Infectious Diseases - Vol. 4, Issue 12, December 2004, Pages 725-738

            Diagnosis of cytomegalovirus infection and disease

            History/examination
            Presence of cytomegalovirus in tissue might simply be a bystander effect and does not necessarily imply causality. Cytomegalovirus-associated disease should be diagnosed on clinical grounds in combination with detection of virus.

            Viral cultures
            Requires at least 21 days to be reported negative. Not routinely done, but can be useful in resistance testing.

            Detection of early antigen fluorescent foci
            24h turn-around. Infected fibroblasts stained with fluorescent antibody specific for the antigen MIE p72.Insufficiently sensitive to be routinely recommended after allogeneic stem-cell transplantation.

            Antigenaemia assay
            Quantitates leucocytes positive for pp65. Since uninfected cells can harbour cytomegalovirus protein, provides an indirect assessment of infection.Reliable, rapid, and sensitive. In common use.

            Qualitiative PCR
            Can be used on whole blood, leucocytes, and plasma. Rapid and sensitive, easily automated. Threshold needs careful calibrating to over detection of cytomegalovirus infection.

            Quantitative PCR
            Allows response to treatment to be monitored. Useful as a surrogate marker of clinical or viral resistance. Correlation between high degrees of viral DNA and presence of clinical symptoms in transplant recipients and patients with AIDS and the congenital infection of pregnancy has been shown.

            Hybrid capture assay
            RNA probes used to detect viral DNA in an ELISA-type format. Can be used on whole blood stored for up to 48 h. Limited experience but results to date promising.

            Nucleic assay sequence-based amplification
            Allows the specific nucleic assay sequence-based amplification of unspliced viral mRNAs in a background of DNA. Experience in transplant and AIDS patients encouraging.

            Panel 2. Monitoring of cytomegalovirus-specific immunity

            Serology
            Highly specific and sensitive in immunocompetent individuals. IgM titres rise 2–6 weeks after infection and can persist for 2 years and be detectable during episodes of reactivation. IgG seropositivity is usually lifelong although antibody concentrations can decline with age. Unreliable and not used in monitoring of cytomegalovirus reactivation in immunocompromised patients. IgG antibody avidity assays (low avidity suggests infection within 3 months) can be useful in identifying pregnant women at risk of transmitting intrauterine infection.

            Tetramer assays
            Remains a research method to detect peptide-specific CD8+ T-cells. Data in allogeneic stem-cell transplant setting suggest a protective threshold below which patients at high risk of reactivation can be identified

            Cytokine assays
            Research method to enable high throughput detection of virus-specific T-cells. Being assessed in transplant patients. As with tetramer assays, when combined with sensitive, rapid viral detection techniques, may be of use in monitoring post-transplant patients and to assist decision-making in pre-emptive or prophylaxis strategies.

            Answer: D. plasma CMV DNA concentration (viral load).

            Topic

            Infectious Diseases: Viral infection

            Question 67 Top

            Question 68 Top

            Question 69 Top

            Question 70 Top Download PDF

            Maximal oxygen consumption (V.O2 maximum) is the best measure of aerobic capacity or cardiovascular fitness and declines with age. In healthy ageing, the most important physiological change which contributes to this decline is a reduction in:
            A. maximum heart rate.
            B. stroke volume.
            C. arterial PO2.
            D. forced expiratory volume in 1 second (FEV1).
            E. total lung capacity.

            Answer:

            The influences on maximal oxygen consumption can be represented by Fick’s equation

            VO2: oxygen (O2) uptake; SV: stroke volume; HR: heart rate; PiO2: partial pressure inspired O2: FiO2 x Patmospheric; CaO2: arterial oxygen content; CvO2: mixed venous oxygen content.

            Stroke Volume and HR most physiological factors influenced by age – HR numerically influenced by increasing age (220-age)

            So answer is A

            Topic

            Respiratory: Understanding of basic respiratory and sleep physiology

            Cardiology;Normal cardiac anatomy and physiology.