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Severe CHD risk (dose level 2: LDL-c goal <115 mg/dl): aorta 20 mg qd (n=79) vs purchase actos 30 mg with mastercard. If goal not reached purchase actos 45mg line, dose doubled at week 4 actos 30mg low cost, and again at week 8 and week 16 actos 45 mg with mastercard. If renal function discount actos 30mg amex, more than 14 alcoholic drinks per week, taking a drug LDL-c remained >130 mg/dl at weeks 4 305 patients randomized Mean baseline LDL-c with the potential for interaction with statins. No numbers provided for and 10, doses were doubled at week 16. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Assman et al. Most 52 weeks aorta increased 7% commonly reported ADE with aorta was myalgia and rash each reported by 4 parva increased 9% (NS) patients. No patient in either group had clinically important 305 patients randomized parva 20 mg: 23% elevations in AST, ALT or CK. HDL: aorta increased 7%, parva increased 10% (NS) Trigs: aorta reduction 14%, parva reduction 3% (p<0. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Assman et al. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Deedwania P, et al 2007 Men and women 65 to 85, history Atrial fibrillation and heart failure NYHA III and IV 4-6 week washout period, then randomized R (1:1), DB, MC, ITT of CAD, baseline LDL-C levels in a double-blind fashion to atorvastatin 80 between 100 mg/dL and 250 mg/d or pravastatin 40 mg/d and were 893 patients randomized mg/dL, and 1 episode of followed up for 12 months. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Deedwania P, et al 2007 LDL-c change from baseline: aorta vs. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Deedwania P, et al 2007 Pfizer, Inc. R (1:1), DB, MC, ITT 893 patients randomized (n (mITT)= 446 (408) aorta, 445 (396) parva) 52 weeks Statins Page 11 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Murakami T, et al 2006 Clinical indications for cholesterol Drugs that effect glucose tolerance, disturbed liver and/or renal Atorvastatin 5-10 mg/day vs. R, DB, MC, PC who required coronary angiography for a clinical indication and 657 patients randomized demonstrated at least 1 obstruction 18 months with angiographic luminal diameter narrowing of 20% or more. Lipid criteria required an LDL-c level between 125 mg/dL and 210 mg/dL after 4 to 10 week washout period. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Murakami T, et al 2006 3-6 months after None reported RCT, DB, MC, not ITT LDL-c aorta 124 (48. R, DB, MC, PC LDL-c reduction from baseline at 18 months: Most common reason was musculoskeletal complaints (3. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Murakami T, et al 2006 NR RCT, DB, MC, not ITT 41 patients randomized (n= 11 aorta, 18 parva analyzed) 26 weeks Nissen et al, 2004 Funded by Pfizer R, DB, MC, PC 657 patients randomized 18 months Statins Page 14 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Saklamaz et al, Men and women (mean age 51. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Saklamaz et al, % LDL-c reduction from baseline at 12 weeks: Adverse events not reported. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Saklamaz et al, Funding not reported 2005 R, single center, blinding not reported 21 patients randomized 8 weeks treatment Statins Page 17 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Atorvastatin vs. Simvastatin Ballantyne et al, 2003 Men and women 21-75 with LDL-c use of systematic immunosuppressive drugs or drugs known to Atorva 80 mg qd or simva 80 mg qd for 24 R, DB, MC >130 mg/dL in CHD patients, >160 interfere with simvastatin or atorvastatin metabolism. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Results (mean changes in lipoprotein levels) Harms/Comments Ballantyne et al, 2003 Increase in HDL-c from baseline, average of weeks 18 and 24 No difference between groups in number of drug-related clinical R, DB, MC gastrointestinal adverse events. Most common GI adverse events were Patients with baseline HDL-c <40mg/dL (n=267): diarrhea (simva 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Clinical Trial Funding Source Ballantyne et al, 2003 Supported by a grant R, DB, MC from Merck 917 patients randomized(n=464 aorta, 453 simva) 24 weeks Statins Page 20 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 1. Trials comparing LDL-c lowering/HDL-c raising abilities of 2 or more statins Inclusion Criteria/ Patient Clinical Trial Population Exclusion criteria Intervention Bays et al. H/O: simvastatin 10 mg 315 patients randomized active gallbladder disease; uncontrolled hypertension; renal insufficiency At week 8, dose increased for 4 weeks: (n=82 atorvastatin, 76 Mean baseline LDL-c (serum creatinine ≥1.

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One might actos 30 mg without prescription, for example actos 30mg otc, find that some variants induce a memory response that interferes with the host’s ability to generate a specific response to other variants order actos 30mg with amex. Thus buy 15 mg actos with amex, the antigenic repertoire in archival libraries may be shaped both by the tendency to avoid cross-reaction and by the degree to which variants can interfere with the immune response to other variants buy actos 15mg otc. PART II MOLECULAR PROCESSES Specificity and Cross-Reactivity 4 In this chapter, I describe the attributes of host and parasite molecules that determine immune recognition. Two terms frequently arise in dis- cussions of recognition. Specificity measures the degree to which the im- mune system differentiates between different antigens. Cross-reactivity measures the extent to which different antigens appear similar to the immune system. The molecular determinants of specificity and cross- reactivity define the nature of antigenic variation and the selective pro- cesses that shape the distribution of variants in populations. The surfaces of par- asite molecules contain many overlapping antibody-binding sites (epi- topes). An antibody bound to an epitope covers about 15 amino acids on the surface of a parasite molecule. However, only about 5 of the par- asite’s amino acids contribute to the binding energy. A change in any of those 5 key amino acids can greatlyreducethe strength of antibody binding. The second section focuses on the paratope, the part of the antibody molecule that binds to an epitope. Antibodies have a variable region of about 50 amino acids that contains many overlapping paratopes. Each paratope has about 15 amino acids, of which about 5 contribute most of the binding energy for epitopes. Paratopes and epitopes define comple- mentary regions of shape and charge rather than particular amino acid compositions. A single paratope can bind to unrelated epitopes, and a single epitope can bind to unrelated paratopes. The third section introduces the different stages in the maturation of antibody specificity. Naive B cells make IgM antibodies that typic- ally bind with low affinity to epitopes. A particular epitope stimulates division of B cells with relatively higher-affinity IgM antibodies for the epitope. As the stimulated B cell clones divide rapidly, they also mu- tate their antibody-binding regions at a high rate. Mutant lineages that bind with higher affinity to the target antigen divide more rapidly and outcompete weaker-binding lineages. This mutation and selection pro- duces high-affinity antibodies,typically of type IgA or IgG. Each natural antibody can bind with low affinity to many dif- ferent epitopes. Natural antibodies from different B cell lineages form adiverseset thatbindswithlowaffinity to almost any antigen. One in vitro study of HIV suggested that these background antibodies bind to the viruses with such low affinity that they do not interfere with in- fection. By contrast, in vivo inoculations with several different patho- gens showed that the initial binding by natural antibodies lowered the concentrations of pathogens early in infection by one or two orders of magnitude. Poor binding condi- tions cause low-affinity binding to be highly specific because detectable bonds form only between the strongest complementary partners. By contrast, favorable binding conditions cause low-affinity binding to de- velop a relatively broad set of complementary partners, causing rela- tively low specificity. The appropriate measure of affinity varies with the particular immune process. Early stimulation of B cells appears to depend on the equilibrium binding affinity for antigens.

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It then covers the diaphragm and duced by the median umbilical ligament purchase actos 45mg visa. This is the remains of the continues onto the anterior abdominal wall buy generic actos 45 mg on line. Two medial umbilical ligaments converge to the • From the diaphragm and anterior abdominal wall it is reflected onto umbilicus from the pelvis buy actos 45 mg visa. They represent the obliterated umbilical the liver to form its ‘mesentery’ in the form of the two layers of the fal- arteries of the fetus cheap 30mg actos overnight delivery. The ligamentum teres is a fibrous band in the free ciform ligament discount 15mg actos with amex. At the liver, the left layer of the falciform ligament margin of the falciform ligament. It represents the obliterated left folds back on itself to form the sharp edge of the left triangular liga- umbilical vein. The peritoneum 37 15 The upper gastrointestinal tract I Cardiac notch Lesser curvature Fundus Angular incisure Pyloric sphincter Body Duodenum Greater curvature Pyloric antrum Fig. The stomach is outlined but the shape is by no means constant 38 Abdomen and pelvis The embryonic gut is divided into foregut, midgut and hindgut, sup- verse colon. The anterior and posterior vagal trunks descend along the plied, respectively, by the coeliac, superior mesenteric and inferior lesser curve as the anterior and posterior nerves of Latarjet from which mesenteric arteries. The foregut extends from the oesophagus to the terminal branches arise to supply the stomach. The vagi provide a entrance of the common bile duct into the second part of the duodenum. The latter includes a supply The midgut extends down to two-thirds of the way along the transverse to the acid-secreting partathe body. It largely develops outside the abdomen until this congenital ‘umbilical hernia’ is reduced during the 8th–10th week of gestation. The duodenum is the first part of the small intestine. It is approximately 25 cm long and curves around the head of the pancreas. Its primary The abdominal oesophagus function is in the absorption of digested products. Despite its relatively • The abdominal oesophagus measures approximately 1 cm in length. It is • The lower third of the oesophagus is a site of porto-systemic venous considered in four parts: anastomosis. This is formed between tributaries of the left gastric and • First part (5 cm). Internally, in the mid-section, a small eminence may be The stomach (Figs 15. This structure represents the site of the common opening antrum, is the incisura angularis. The sphinc- • The pyloric sphincter controls the release of stomach contents into ter of Oddi guards this common opening. The sphincter is composed of a thickened layer of circu- pancreatic duct (of Santorini) opens into the duodenum a small lar smooth muscle which acts as an anatomical, as well as physiolo- distance above the papilla. The junction of the pylorus and duodenum can be seen • Third part (10 cm)athis part is crossed anteriorly by the root of externally as a constriction with an overlying veinathe prepyloric vein the mesentery and superior mesenteric vessels. The termination of the duodenum is demarcated by a tents into the stomach. The cardiac sphincter acts to prevent reflux of peritoneal fold stretching from the junction to the right crus of stomach contents into the oesophagus. Unlike the pylorus there is no the diaphragm covering the suspensory ligament of Treitz. The discrete anatomical sphincter at the cardia; however, multiple factors terminal part of the inferior mesenteric vein lies adjacent to the contribute towards its mechanism. These include: the arrangement of duodenojejunal junction and serves as a useful landmark. The superior artery arises from the coeliac axis compression of the short segment of intra-abdominal oesophagus by in- and the inferior from the superior mesenteric artery. The omenta contain the blood and Most peptic ulcers occur in the stomach and proximal duodenum.

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