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Co-Director, University of Missouri-Columbia School of Medicine

Variceal bleeding is more likely once the pressure gradient between the portal and systemic venous systems rises above 12 mmHg (measured as the wedged hepatic venous pressure). Fifty per cent die from hypovolaemia or associated complications after a first oesophageal or gastric variceal haemorrhage, manifest as melaena or haematemesis. The use of central venous access and monitoring is recommended; correction of coagulopathy with platelets and clotting factors appears logical. The relation 548 Liver and biliary tract between bacterial infection and haemorrhage is intriguing; bacterial infection is often found at presentation and 60% have evidence of infection within 7 days of haemorrhage. It is unclear whether infection increases the risk of haemorrhage or is a consequence. Bacterial infection should be treated, or anticipated, using broad-spectrum antibiotics with Gram-negative cover in line with local prescribing policy. Many patients cease bleeding spontaneously, but over half re-bleed within 10 days. If bleeding varices are suspected, give terlipressin, as it reduces splanchnic blood flow, increases systemic blood pressure and reduces haemorrhage, which aids diagnostic endoscopy. Oesophageal band ligation is the treatment of choice for bleeding varices identified at endoscopy. Varices are obliterated by application of small elastic bands under direct vision by an experienced operative. This has supplanted injection sclerotherapy, which involved injecting sclerosant into and around varices but which carried a higher rate of complications (oesophagitis, oesophageal stricture/perforation and distant sclerosant embolisation). Direct injection of superglue into the varix, the treatment of choice for bleeding gastric varices, requires considerable expertise. Bleeding is controlled in 90% of patients after oesophageal band ligation in conjunction with terlipressin. Obliteration of oesophageal varices requires repeated band ligation over a prolonged period. Somatostatin and the synthetic analogue octreotide reduce portal pressure by decreasing splanchnic blood flow. Octreotide has the advantage of a longer duration of action and is given as bolus injection. It can be used as an alternative to terlipressin, with similar efficacy and indications, but does not carry a risk of cerebral or cardiac ischaemia. Direct pressure on varices can be applied with an inflatable triple-lumen tube that abuts the gastro-oesophageal junction providing temporary control of bleeding in 90%. Re-bleeding is common when the tube is withdrawn and use is often complicated by aspiration, oesophageal ulceration or perforation. Advantages of this approach are safer transfer of patients to units with expertise or as a temporary measure before definitive therapy. Prevention of variceal haemorrhage Endoscopic oesophageal band ligation repeated at regular intervals until varices are obliterated is the treatment of choice for secondary prevention of variceal haemorrhage and substantially reduces the incidence of re-bleeding. Endoscopic band ligation is also the preferred approach for primary prevention of variceal haemorrhage for those at high risk, defined by endoscopic criteria. Pharmacological reduction of portal pressure Vasopressin, in addition to its action on renal collecting ducts (through V2 receptors), constricts smooth muscle (V1 receptors) in the cardiovascular system and particularly in splanchnic blood vessels, reducing splanchnic blood flow. Systemic, cerebral and coronary artery vasoconstriction are predictable complications necessitating treatment withdrawal in 20% of older patients. In patients with cardiovascular disease and uncontrolled haemorrhage that precludes definitive endoscopic therapy, simultaneous administration of glyceryl trinitrate (transdermally, sublingually or intravenously) allows continued use of vasopressin, reducing cardiac risk, and also reduces portal venous resistance and pressure directly. Vasopressin is cleared rapidly from the circulation so is given by continuous intravenous infusion; with concerns about distant ischaemia, the short tЅ of vasopressin is advantageous. The synthetic analogue, terlipressin (triglycyllysinevasopressin) has supplanted vasopressin. This prodrug is converted in vivo to vasoactive lysine vasopressin, which has biological activity for 3­4 h, and is effective as bolus Pharmacological therapy Non-selective b-blockers. They reduce cardiac output via b1-receptor antagonism and induce splanchnic vasoconstriction via b2-receptor antagonism, allowing unopposed a-adrenergic vasoconstriction. Propranolol is extracted extensively in a single pass through the liver so systemic availability is less predictable in cirrhosis with portal hypertension due to variations in hepatic blood flow and portosystemic shunts. Ideally, the dose of propranolol (given twice daily) should be adjusted by measuring the wedged hepatic venous pressure since haemorrhage is rare if this is below 12 mmHg. As an 549 Section 7 Gastrointestinal system Those without natriuresis should have diuretic therapy withdrawn.

Included within this definition is the expression of the gene, the relationship of the sequence and structure of the gene product to other gene products in the same or other organisms, and the molecular interactions of the gene product the high throughput determination of structural motifs and complete protein structures and the relationship between these and function the use of sequence similarity and comparative gene order (synteny) to determine gene function and phylogeny the study of the proteome, i. The term includes protein­protein and protein­small molecule interactions as well as expression profiling the study of the transcriptome, i. This site also is the entry point to PubMed which enables researchers to access abstracts and journal articles on-line. It contains many useful pages and the ones on model organisms are well worth visiting. Rather, there are major differences between the genomes of bacteria, viruses and organelles on the one hand and the nuclear genomes of eukaryotes on the other. This wide variability means that the mapping and sequencing strategies involved depend on the individual genome being studied. The largest viral genomes are 1­2 Ч 105 bp and are just a little smaller than the smallest cellular genomes, those of some mycoplasmas (5 Ч 105 bp). Simple unicellular eukaryotes have a genome size (1­2 Ч 107 bp) that is not much larger than that of the largest bacterial genomes. Primitive multicellular organisms such as nematodes have a genome size about four times larger. Not surprisingly, an examination of the genome sizes of a wide range of organisms has shown that the minimum C-value found in a particular phylum is related to the structural and organizational complexity of the members of that phylum. Thus the minimum genome size is greater in organisms that evolutionarily are more complex. Is there really a 100-fold variation in the number of genes needed to specify different flowering plants? Are some plants really more organizationally complex than humans, as these data imply? Although there is evidence that birds with smaller genomes are better flyers (Hughes & Hughes 1995) and that plants are more responsive to elevated carbon dioxide concentrations (Jasienski & Bazzaz 1995) as their genomes increase in size, this is not sufficient to explain the size differential. The resolution of this apparent C-value paradox was provided by the analysis of sequence complexity by means of reassociation kinetics. Secondly, the temperature of incubation must be high enough to weaken intrastrand secondary structure. In practice, the optimum temperature for reassociation is 25°C below the melting temperature (Tm), that is, the temperature required to dissociate 50% of the duplex. The reassociation of a pair of complementary sequences results from their collision and therefore the rate depends on their concentration. Because the rate of reassociation depends on the concentration of complementary sequences, the C0t1/2 for organism B will be 200 times greater than for organism A. Experimentally it has been shown that the rate of reassociation is indeed dependent on genome size. If the slow fraction is made up of unique sequences, each of which occurs only once in the calf genome, then the sequences of the rapid fraction must be repeated 100 000 times, on average. The complexities of each of these components are 340 bp, 6 Ч 105 bp and 3 Ч 108 bp, respectively. Percentage reassociated (1 ­ C/C0) 100 75 50 20 0 10­4 10­3 10­2 10­1 1 C0t 101 102 103 104 Fast component Per cent of genome C0t1/2 Complexity (bp) Repetition frequency Intermediate component 30 1. The data could be explained only by assuming the existence of interruptions in the middle of the protein-coding sequences. Furthermore, these insertions appeared to be present in both expressing and non-expressing cells. The gene insertions that are not translated into protein were termed introns and the sequences that are translated were called exons. Since the original discovery of introns, a large number of split genes has been identified in a wide variety of organisms. In Saccharomyces cerevisiae, sequencing of the complete genome suggests that there are 235 introns compared with over 6000 open-reading frames and that introns account for less than 1% of the genome (Goffeau et al. Those genes which do have introns usually have only one small one and the longest intron is only 1 kb in size. However, proceeding up the evolutionary tree, the number of split genes, and the number and size of introns per gene, increases. More important, genes that are related by evolution have exons of similar size, i. However, the introns may vary in length, giving rise to variation in the length of ·· Organization and structure of genomes 15 Table 2.

The negative predictive value of skin testing with native semisynthetic penicillins is unknown, and there is no consensus regarding the appropriate concentration that should be used. Administration of ampicillin and amoxicillin is associated with the development of a delayed maculopapular rash in 5% to 10% of patients. Most patients will tolerate future administration of penicillin other than ampicillin and amoxicillin. If ampicillin or amoxicillin is administered again, the patient may develop a similar eruption or no reaction at all. It is postulated that many amoxicillin/ampicillin-associated delayed maculopapular rashes require the presence of a concurrent viral illness. In the case of patients with Epstein-Barr virus infections, almost 100% will develop a nonpruritic rash. If the penicillin skin test result is negative, the patient should be approached as outlined in the prior discussion about penicillin. If the penicillin skin test result is positive, the patient should be given an alternative antibiotic or undergo induction of drug tolerance to penicillin. Cephalosporins (Figure 2) Summary Statement 92: the overall reaction rate to cephalosporins is approximately 10-fold lower than it is for penicillin. Skin testing should be performed as described in the penicillin section with a prick/puncture test followed by an intracutaneous test (if the prick-test reaction is negative in 10 to 15 minutes). If the previous clinical reaction was documented as anaphylactic and life-threatening, testing should start at a further 10-fold dilution or lower. A positive cephalosporin skin test result (using a nonirritating concentration) implies the presence of drug specific IgE antibodies, and the patient should receive an alternate drug or undergo induction of drug tolerance. A negative cephalosporin skin test (using a nonirritating concentration) does not rule out the presence of drug specific IgE antibodies. IgE antibodies to cephalosporin degraded products not used in the testing may be present but not detectable. Therefore, because the negative predictive value of cephalosporin skin testing is unknown, a cautious graded challenge should be performed (eg, 1/100 of the therapeutic dose, increasing 10-fold every 30 to 60 minutes up to the full therapeutic dose). The number of steps in the graded challenge and the pace of the challenge are determined by the reaction history. Graded challenges require may be performed in an outpatient setting, without intravenous access, but with preparedness to treat severe allergic reactions, such as anaphylaxis. If the previous history is consistent with a severe IgE-mediated reaction, induction of drug tolerance with the cephalosporin may be undertaken instead. Cephalosporin Administration to Patients With a History of Penicillin Allergy (Figure 2) Summary Statement 97: Since 1980, studies show that approximately 2% of penicillin skin test­positive patients react to treatment with cephalosporins, but some of these reactions may be anaphylactic reactions. Benzyl penicillin and these cephalosporins share a similar side chain, a finding that could account for increased crossreactivity. Also, during this time, some early first-generation cephalosporins were contaminated with trace amounts of penicillin. If patients with a history of allergy to penicillin are not skin tested but given cephalosporins directly, the chance of a reaction is probably less than 1%. This figure is based on the fact that only approximately 10% of penicillin history­positive patients have positive skin test results,17,18 and of those, only 2% will react to a cephalosporin. Physicians in these "real-world" studies were probably less likely to treat with cephalosporins if patients had more severe or recent reaction histories, and, in some cases, pharmacists intervened to prevent patients with severe reaction histories from receiving cephalosporins. Groups of -Lactam Antibiotics That Share Identical R1-Group Side Chainsa Amoxicillin Cefadroxil Cefprozil Cefatrizine Ampicillin Cefaclor Cephalexin Cephradine Cephaloglycin Loracarbef Ceftriaxone Cefotaxime Cefpodoxime Cefditoren Ceftizoxime Cefmenoxime Cefoxitin Cephaloridine Cephalothin Cefamandole Cefonicid Ceftazidime Aztreonam a Each column represents a group with identical R1 side chains. It is also possible that some patients with a history of penicillin allergy react to cephalosporins because of their underlying propensity to develop reactions to unrelated drugs rather than allergic cross-reactivity between the -lactams. In patients with documented allergic-like reactions to penicillins, the relative risk for allergic-like reactions was elevated for both cephalosporins and sulfonamides. The following are options that may be considered: (1) substitute a non­ -lactam antibiotic; (2) perform penicillin skin testing; (3) perform cephalosporin skin test and if the result is negative perform a graded challenge; or (4) treat with the cephalosporin. The fourth option should be considered only in the absence of a severe and/or recent penicillin allergy reaction history.

Anti-inflammatory agents can commence either with sodium cromoglicate or low-dose inhaled glucocorticoid (Step 2). The inhaled glucocorticoids in current use Drug treatment this varies with the severity and type of asthma. The scheme starts with a 9 British Thoracic Society 2008 Guidelines on the management of asthma. This property is important, as it minimises the systemic effects of inhaled glucocorticoid, 80­90% of which is actually swallowed. Precisely for this reason, prednisolone or hydrocortisone would have less advantage (over oral administration) if inhaled, because they are absorbed from the gut and enter the circulation with relatively little pre-systemic metabolism. Inhaled glucocorticoids also exhibit higher lipid solubility and potency than those usually administered orally. Chapter 28 Antimicrobials should be prescribed only if there is high suspicion of a bacterial respiratory tract infection. Note that macrolide antibiotics, such as erythromycin and clarithromycin, interfere with theophylline metabolism. The airways may become refractory to b2-adrenoceptor agonists after 36­48 h, partly for pharmacological reasons (possibly receptor desensitisation) and partly due to the prolonged respiratory acidosis. The mucous plugs, which are the hallmark of the condition, may also prevent inhaled drugs from reaching the distal airways. The following lists, with some explanation, the recommendations of the British Thoracic Society9 for managing acute severe asthma: Inhaled glucocorticoids are generally safe at low doses. Topical effects (oral candida and hoarseness) are eliminated by using a spacer device and rinsing the mouth. High doses (> 2000 micrograms/day) are reported to carry a slightly increased risk of cataract and glaucoma; this may reflect local aerosol deposition rather than a true systemic effect. Bone turnover is also increased in adults, suggesting a long-term risk of accelerated osteoporosis, and bone growth may be reduced in children (although evidence indicates that normal adult height can be attained10). Therefore, it is important that patients are maintained on the minimum dose of inhaled glucocorticoid necessary for symptom control. Oral prednisolone is very effective for severe exacerbations and short courses. Provided symptoms and peak flows respond promptly, more prolonged courses or prolonged reduction of dose are unnecessary. When oral glucocorticoids are used long term (Step 5), doses should be adjusted much more slowly. Adverse corticosteroid effects may also be minimised by administering a single morning dose to coincide with the normal peak cortisol concentration (and thus the least suppression of feedback to the hypothalamic­adrenal axis). This is possible because of the long duration of their biological effect (18­36 h) compared with plasma tЅ (3 h for prednisolone). Morning dosing with inhaled glucocorticoid may also have a prednisolone-sparing effect. Some patients may get further prednisolone-sparing by addition of nebulised high-dose budesonide, 1­2 mg twice daily or fluticasone 500 micrograms twice daily. Carbon dioxide narcosis is rare in asthma and 60% can be used if the diagnosis is not in doubt. If the patient is improving, continue: Chest infections in asthma Antimicrobials are over-prescribed for exacerbations of asthma. Respiratory tract infections do cause increased airflow obstruction and bronchial hyperresponsiveness, but viral not bacterial pathogens are the commonest culprits. The British Thoracic Society guideline no longer recommends intravenous aminophylline without consultation with a senior physician. Doubtless, this reflects an equal lack of evidence base for benefit and the very clear potential for harm if given to patients already taking oral theophyllines. Though the relationship between the use of b2receptor agonists and death is presumed to be causal, the actual mechanism of death is uncertain; overdose causing cardiac arrhythmia is not the sole factor. The subsequent development of selective b2-receptor agonists was a contribution to safety, but a review in New Zealand during the 1980s found that the use of fenoterol (b2 selective) by metered-dose inhalation was associated with increased risk of death in severe asthma,13 and later analysis concluded that it was the most likely cause. If the patient is still not improving: · Consider intravenous infusion of aminophylline · (0. Transfer (accompanied by doctor with facilities for intubation) is required if: · any of the above deteriorates, despite maximal treatment · the patient becomes exhausted, drowsy, or confused · coma or respiratory arrest occurs.

Hydrochlorothiazide has far less ability to inhibit carbonic anhydrase compared to chlorothiazide. It is also more potent, so that the required dose is considerably lower than that of chlorothiazide. Mechanism of action: the thiazide derivatives act mainly in the distal tubule to decrease the reabsorption of Na+в"apparently by inhibition of a Na+/Cl- cotransporter on the luminal membrane of the distal convoluted tubule (see Figure 22. As a result, these drugs increase the concentration of Na+ and Cl- in the tubular fluid. Increased excretion of Na+ and Cl-: Chlorothiazide causes diuresis with increased Na+ and Cl- excretion, which can result in the excretion of a very hyperosmolar urine. This latter effect is unique; the other diuretic classes are unlikely to produce a hyperosmolar urine. The diuretic action is not affected by the acid-base status of the body, nor does chlorothiazide change the P. The relative changes in the ionic composition of the urine during therapy with thiazide diuretics are given in Figure 22. Loss of K+: Because thiazides increase the Na+ in the filtrate arriving at the distal tubule, more K+ is also exchanged for Na+, resulting in a continual loss of K+ from the body with prolonged use of these drugs. Therefore, it is imperative to measure serum K+ often (more frequently at the beginning of therapy) to assure that hypokalemia does not develop. Loss of Mg2+: Magnesium deficiency requiring supplementation can occur with chronic use of thiazide diuretics, particularly in the elderly. Decreased urinary calcium excretion: Thiazide diuretics decrease the Ca2+ content of urine by promoting the reabsorption of Ca2+. This contrasts with the loop diuretics, which increase the Ca2+ concentration of the urine. Reduced peripheral vascular resistance: An initial reduction in blood pressure results from a decrease in blood volume and, therefore, a decrease in cardiac output. However, there are continued hypotensive effects, resulting from reduced peripheral vascular resistance caused by relaxation of arteriolar smooth muscle. Hypertension: Clinically, the thiazides have long been the mainstay of antihypertensive medication, because they are inexpensive, convenient to administer, and well tolerated. They are effective in reducing systolic and diastolic blood pressure for extended periods in the majority of patients with mild to moderate essential hypertension (see p. After 3 to 7 days of treatment, the blood pressure stabilizes at a lower level and can be maintained indefinitely by a dailydosage level of the drug, which causes lower peripheral resistance without having a major diuretic effect. Many patients can be continued for years on the thiazides alone, although a small percentage of patients require additional medication, such as ОІ-adrenergic blockers. Heart failure: Thiazides can be the diuretic of choice in reducing extracellular volume in mild to moderate heart failure. Hypercalciuria: the thiazides can be useful in treating idiopathic hypercalciuria, because they inhibit urinary Ca2+ excretion. This is particularly beneficial for patients with calcium oxalate stones in the urinary tract. Diabetes insipidus: Thiazides have the unique ability to produce a hyperosmolar urine. Thiazides can substitute for antidiuretic hormone in the treatment of nephrogenic diabetes insipidus. The urine volume of such individuals may drop from 11 L/day to about 3 L/day when treated with the drug. Most thiazides take 1 to 3 weeks to produce a stable reduction in blood pressure, and they exhibit a prolonged biologic half-life (40 hours). All thiazides are secreted by the organic acid secretory system of the kidney (see Figure 22. Adverse effects: Most of the adverse effects involve problems in fluid and electrolyte balance. Potassium depletion: Hypokalemia is the most frequent problem encountered with the thiazide diuretics, and it can predispose patients who are taking digitalis to ventricular arrhythmias (Figure 22. Often, K+ can be supplemented by diet alone, such as by increasing the intake of citrus fruits, bananas, and prunes.