H. Eugene Hoyme, M.D.

• Sanford School of Medicine
• University of South Dakota
• Sioux Falls, SD

A long-term study on the effects of testosterone treatment showed that bone mineral density continues to increase in the lumbar spine after 18 to 30 months of treatment arteria plantaris medialis cheap zebeta 5 mg otc. To date blood pressure different in each arm generic zebeta 10 mg buy line, no adequately powered trial has yet explored the impact of therapy on hip and vertebral fracture arrhythmia icd 9 code buy zebeta 10 mg on-line. Recurrent falls in the elderly are associated with considerable mortality and economic burden arteria carotida externa zebeta 10 mg buy amex. Risk of falling has been shown to be clearly associated with loss of lean muscle especially in the lower limbs of ageing men blood pressure lowering 5 mg zebeta buy visa. The message is that benefits occur relatively early but treatment must be considered for the long term. Cognitive function There is evidence that hypogonadism is associated with decreased cognitive function and that testosterone administration enhances performance on spatial cognition and mathematical reasoning. However, in the 10- year longitudinal assessment of multiple cognitive domains, higher free testosterone predicted better scores on visual and verbal memory, visual-spatial functioning, visual motor scanning, and a reduced rate of longitudinal decline in visual memory. The lifetime prevalence of depression, at 24%, is known to be three times higher in type 2 diabetics than the general population and the most commonly cited reason is the burden of co-morbidities in diabetes. Diabetes was found to be a greater risk factor for depression in male than in female type 2 diabetics and sexual problems were the complication most associated with depression. There was a 6% incidence of raised haematocrit (>50%) without significant consequences and no deaths in the active treatment group versus five in the placebo cohort. Calof69 also found that patients on testosterone were 12 times more likely to get a prostate biopsy but no more likely to have a positive finding. Because of logistic and ethical reasons, the ideal long-term study is unlikely to be done and until then physicians will have to practice on using the best available evidence. Dehydroepiandrogen this weak androgen precursor is available as a food supplement in the United States, with little convincing evidence for cardiovascular benefit. A recent 12-month double-blind placebo-controlled study 902 100 90 80 70 60 50 40 30 20 10 2. Of the 417 studies thus identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men > or = 45 years old with low or low-normal testosterone level, randomized controlled trial, and medically stable men. In the 19 studies that met eligibility criteria, 651 men were treated with testosterone and 433 with placebo. The frequency of cardiovascular events, or death was not significantly different between the two groups. These patients also appear to develop insulin resistance, hyperinsulinemia, and hyperglycaemia. The risks of diabetes mellitus increase by 44% and mortality of cardiovascular diseases by 16% during a follow-up of up to 10 years. Sexual function in the ageing male For the older couple, retirement often allows for more shared time and increased intimacy. Sexual function may be a higher priority for the couple than the doctor perceives. Men who are widowed or divorced still expect to be sexually active in new relationships, and this should be positively encouraged, as evidence suggests that men living alone have markedly reduced life expectancy. Notes: A meta-analysis of randomized clinical trials to determine the risks of adverse events associated with testosterone replacement in older men. Of the 417 studies thus identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men 45 years old with low or low-normal testosterone level, randomized controlled trial, and medically stable men. Testosterone replacement in older men was associated with a significantly higher risk of detection of prostate events and of haematocrit >50% than was placebo. Increased demand for testosterone supplementation will be a natural consequence of this correction of previous underdiagnosis and undertreatment. This process introduces some complex management and financial (for the patient and the physician) issues as both medications may be required long term for an effective outcome. Conclusions the benefits of conventional cardiovascular risk reduction by exercise and weight loss are fundamental to healthy ageing. These may potentially denied to patients by fears over prostate and cardiovascular risk that are not currently supported by evidence. Ideally, we need large long-term studies to resolve these issues with certainty but such studies will be challenging for logistic and financial reasons. Relationship between low levels of anabolic hormones and 6 year mortality in older men in the Chianti area. Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. Low testosterone levels predict incident stroke and transient ichaemic attack in older men. Association of low testosterone levels with all-cause mortality by different cut-offs from recent studies. Low testosterone level is associated with significant increase in mortality in patients with type 2 diabetes. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes, Correlations with bioavailable testosterone and visceral adiposity. Low levels of sex hormone-binding globulin and testosterone predict the development of non-insulin-dependent diabetes mellitus in men. Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebocontrolled study. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. British Society for Sexual Medicine Guidelines on the management of erectile dysfunction. Endogenous sex hormones and the development of type 2 diabetes in older men and women; the Rancho Bernardo study. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam Study. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Clinical and biochemical assessment of hypogonadism in men with type 2 diabetes: correlations with bioavailable testosterone and visceral adiposity. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolemia in hypogonadal men with Type 2 diabetes. Effect of testosterone on insulin sensitivity in men with idiopathic hypogonadotropic hypogonadism. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Testosterone gel improves sexual function, mood, muscle strength and body composition in hypogonadal men. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor inolder men. Lifestyle modification can reverse hypogonadism in men impaired glucose tolerance. Relations of endogenous anabolic hormones and physical activity to bone mineral density and lean body mass in elderly men. Age, hormones and cognitive function among middle-aged and elderly men: cross sectional evidence from the Massachusetts Male Ageing study. Long term testosterone gel treatment maintains beneficial effects on sexual function, lean and fat mass, and bone mineral density in hypogonadal men. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. The decline in androgen levels in elderly men and its clinical and therapeutic implications. Effects of testosterone supplementation on depressive symptoms and sexual dysfunction in hypogonadal men with the metabolic syndrome. Effects of testosterone on cognition and mood in male patients with Alzheimer disease and healthy male men. Effect of long lasting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomised controlled trial. Adverse events associated with testosterone replacement in middle aged and older men; A meta-analysis of randomised placebo controlled trials. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. Increased risk of nonfatal myocardial infarction following testosterone therapy prescription in men. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. Long-term treatment of transsexuals with cross-sex hormones: extensive clinical experience. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. Onset of effects of testosterone replacement and time span until maximal effect is achieved. Testosterone undecanoate restores erectile function in a subset of patients with venous leakage: a series of case reports. Endogenous sex hormones and prostate cancer: A collaborative analysis of 18 prospective studies. Benign prostatic hypertrophy and lower urinary tract symptoms, epidemiology and risk factors. Effect of testosterone replacement therapy on prostate tissue in men with late onset hypogonadism; a randomised controlled trial. Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review. Higher sex hormonebinding globulin and lower bioavailable testosterone are linked to positive prostate cancer biopsy. Effect of dihydrotestosterone treatment on exercise induced ischemia in men with stable ischemic heart disease. This physically and often psychologically devastating disorder causes penile deformities including curvature, hinging, narrowing, and shortening as well as painful erections. Penile pain is a common feature that resolves in most patients 6­18 months after onset. Pain and deformity progression occur during the acute phase, whereas pain resolution with either deformity regression or stabilization identifies its stable phase. One may ask the patient to estimate the degree and direction of erect penile curvature, although only 20% of patients accurately report the degree of curvature with 56% overestimating and 26% underestimating curvature with an average difference of 20 degrees. Therefore, preoperative objective measures of erect deformity are necessary in order to accurately counsel patients, recommend appropriate treatment, and objectively evaluate outcomes. Shortening may be the most psychologically devastating symptom, occurring in 70% of patients and ranging from 1­10 cm. Diminished rigidity, which is commonly seen, may be psychogenic in nature and/or due to underlying medical conditions. Penile pain is a relative contraindication except when it may be due to a strong erection imparting torque-like pressure on the penis. A stretched penile length must be obtained because of the concern for further shortening. With the patient in the supine position, the glans is grasped, and pulled to full stretch perpendicular to the plane of the body. Preoperative penile sensitivity can be assessed with light touch and biothesiometry, though no standard evaluation of this parameter has been established. Deformity assessment of an erect penis is the most important part of the clinical diagnosis. Pharmacologically induced erection via injection of vasoactive agent is the most reliable method when compared to vacuum-induced or photograph. Curvature is then measured in the erect state while a simple string can be used to measure girth at the base, subcoronal, and any area of indentation or hourglass narrowing. Men who have a ventral curvature of greater than 60 degrees tend to have the greatest potential loss of penile length. Several other side effects have been reported including narrowing (0­17%), pain associated with sutures, and tactile and sexual sensitivity changes (0­21%). The authors support the use of combination therapy using oral and injectable agents (for their biological effects) together with external traction therapy (for its mechanical effects) to create a synergy to reduce deformity and improve sexual function. Partial plaque excision has also been suggested, where the area of maximum deformity is excised particularly if it is associated with severe indentation. Successful straightening has been reported in 63­100% with patient satisfaction ranging from 41­96%, partner satisfaction 77%, and successful coitus in 79­100%. Extensive plaque calcification can also be an indication, as can significant 911 Table 7. The tunical incision is made with the cylinders deflated, using the cautery to release the tunic with an effort to preserve the cavernosal tissue over the implant.

Adjuvant topical therapy Adjuvant therapies instilled percutaneously or through a ureteral stent have been assessed after conservative management prehypertension 131 discount zebeta 10 mg buy on-line. The most reliable access to the upper urinary tract remains via a nephrostomy tube large enough pulse pressure lying down order discount zebeta. This procedure allows for reliable and iterative exposure of the urothelium to the topical agent blood pressure chart by who zebeta 10 mg buy amex. The topical agent can be delivered by retrograde reflux from the bladder with an indwelling double-J stent in the Trendelenbourg position arrhythmia gatorade order cheap zebeta on line. One major drawback with ureteric stents³ 4F is the possible ureteric obstruction and subsequent pyelovenous influx during instillation hypertension handout safe zebeta 5 mg. Furthermore, a ureteric catheter can theoretically lead to an increased risk of injury of the pyelocaliceal mucosae. In addition, it is often difficult to complete filling of the pyelocaliceal system and often the superior calyx remains unfilled. No individual study has shown a statistical improvement in survival and recurrence rates. Results of adjuvant chemotherapy come from small studies and conclusions are difficult to make. There is probably a gain in recurrence-free survival but no gain of cancer-specific survival in particular for advanced stage (<pT3) or metastatic patients. In addition, not all the patients receive this treatment because of co-morbidities and impaired renal function after radical surgery. Adjuvant chemotherapy can somehow achieve a recurrence-free rate of up to 50% but has clearly no impact on survival. Radical treatment allows minimizing the risk of local recurrence and the risk is mainly a regional or distant recurrence, with risk factors described earlier. However, regular cystoscopy is mandatory because bladder recurrence is always possible. In case of a conservative management, follow-up is extremely important and stringent. Cystoscopy, ipsilateral ureteroscopy and in situ cytology are required at three, six months, than every six months for two years and than yearly for three years. However, it may be performed for symptomatic patients in a palliative situation to ease pain and local symptoms. Upper urinary tract urothelial cell carcinoma: location as a predictive factor for concomitant bladder carcinoma. Multifocal carcinoma in situ of the upper tract is associated with high risk of bladder cancer recurrence. Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location. Oncologic outcomes following three different approaches to the distal ureter and bladder cuff in nephroureterectomy for primary upper urinary tract urothelial carcinoma. Independent predictors of contralateral metachronous upper urinary tract transitional cell carcinoma after nephroureterectomy: multi-institutional dataset from three European centers. Gender differences in radical nephroureterectomy for upper tract urothelial carcinoma. A proportion of hereditary upper urinary tract urothelial carcinomas are misclassified as sporadic according to a multi-institutional database analysis: proposal of patientspecific risk identification tool. Genetic variability in 8q24 confers susceptibility to urothelial carcinoma of the upper urinary tract and is linked with patterns of disease aggressiveness at diagnosis. Renal collecting (Bellini) duct carcinoma displays similar characteristics to upper tract urothelial cell carcinoma. This trend demonstrates perfectly that new insights, new concepts, new clinical and basic research, and new therapeutic findings are becoming readily available. Template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract: impact on patient survival. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (lynch syndrome) tumor spectrum. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Cancer-specific survival after radical nephroureterectomy for upper urinary tract urothelial carcinoma: proposal and multi-institutional validation of a post-operative nomogram. Impact of diagnostic ureteroscopy on intravesical recurrence and survival in patients with urothelial carcinoma of the upper urinary tract. Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma. Narrow-band imaging digital flexible ureteroscopy in detection of upper urinary tract transitional-cell carcinoma: initial experience. A population-based assessment of perioperative mortality after nephroureterectomy for upper-tract urothelial carcinoma. Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature. Significant predictive factors for prognosis of primary upper urinary tract cancer after radical nephroureterectomy in Taiwanese patients. Prognostic value of extranodal extension and other lymph node parameters in patients with upper tract urothelial carcinoma. Evidence-based sexrelated outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: results of large multicenter study. Advanced patient age is associated with inferior cancer-specific survival after radical nephroureterectomy. Chronological age is not an independent predictor of clinical outcomes after radical nephroureterectomy. Racial differences in the outcome of patients with urothelial carcinoma of the upper urinary tract: an international study. Location of the primary tumor is not an independent predictor of cancer specific mortality in patients with upper urinary tract urothelial carcinoma. Impact of tumour location versus multifocality in patients with upper tract urothelial carcinoma treated with nephroureterectomy and bladder cuff excision: a homogeneous series without perioperative chemotherapy. Ureteral and multifocal tumours have worse prognosis than renal pelvic tumours in urothelial carcinoma of the upper urinary tract treated by nephroureterectomy. The impact of tumor multifocality on outcomes in patients treated with radical nephroureterectomy. Impact of smoking status at diagnosis on disease recurrence and death in upper tract urothelial carcinoma. Impact of smoking on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Prognostic factors for upper urinary tract urothelial carcinomas: stage, grade, and smoking status. Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma. Impact of histological variants on clinical outcomes of patients with upper urinary tract urothelial carcinoma. Handling and pathology reporting of specimens with carcinoma of the urinary bladder, ureter, and renal pelvis. Does preoperative symptom classification impact prognosis in patients with clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. Diagnostic accuracy of transitional cell carcinoma on multidetector computerized tomography urography in patients with gross hematuria. Multi-institutional validation of the ability of preoperative hydronephrosis to predict advanced pathologic tumor stage in upper-tract urothelial carcinoma. Urinary cytology has a poor performance for predicting invasive or high-grade upper-tract urothelial carcinoma. Low biopsy volume in ureteroscopy does not affect tumor biopsy grading in upper tract urothelial carcinoma. High-grade ureteroscopic biopsy is associated with advanced pathology of upper-tract urothelial 40. Does the surgical technique for management of the distal ureter influence the outcome after nephroureterectomy Urothelial carcinoma of the upper urinary tract: surgical approach and prognostic factors. Impact of distal ureter management on oncologic outcomes following radical nephroureterectomy for upper tract urothelial carcinoma. Lymphadenectomy at the time of nephroureterectomy for upper tract urothelial cancer. A critical appraisal of the value of lymph node dissection at nephroureterectomy for upper tract urothelial carcinoma. Comparison of oncologic outcomes for open and laparoscopic nephroureterectomy: a multiinstitutional analysis of 1249 cases. Comparison between laparoscopic and open radical nephroureterectomy in a contemporary group of patients: are recurrence and disease-specific survival associated with surgical technique Oncological outcomes after laparoscopic and open radical nephroureterectomy: results from an international cohort. Laparoscopic versus open nephroureterectomy: perioperative and oncologic outcomes from a randomised prospective study. Oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: Comparison over the three decades. Endoscopic management of upper urinary tract transitional cell carcinoma: long-term experience. Segmental ureterectomy can safely be performed in patients with transitional cell carcinoma of the ureter. Nephroureterectomy and segmental ureterectomy in the treatment of invasive upper tract urothelial carcinoma: a population-based study of 2299 patients. Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study. Upper urinary tract transitional cell carcinoma: recurrence rate after percutaneous endoscopic resection. Risk stratification of patients with nodal involvement in upper tract urothelial carcinoma: value of lymph-node density. Influence of positive surgical margin status after radical nephroureterectomy on upper urinary tract urothelial carcinoma survival. Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients. Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma. Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ confined urothelial carcinoma following radical nephroureterectomy. Concomitant carcinoma in situ and tumour size are prognostic factors for bladder recurrence after nephroureterectomy for upper tract transitional cell carcinoma. Prognostic effect of urinary bladder carcinoma in situ on clinical outcome of subsequent upper tract urothelial carcinoma. The role of American Society of Anesthesiologists scores in predicting urothelial carcinoma of the upper urinary tract outcome after radical nephroureterectomy: results from a national multi-institutional collaborative study. Obesity adversely impacts disease specific outcomes in patients with upper tract urothelial carcinoma. Molecular and histological markers in urothelial carcinomas of the upper urinary tract. Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma. Predicting clinical outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. Cancer-specific survival after radical nephroureterectomy for upper urinary tract urothelial carcinoma: proposal and multi-institutional validation of a postoperative nomogram. Should bladder cuff excision remain the standard of care at nephroureterectomy in patients with urothelial carcinoma of the renal pelvis Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration. Adjuvant radiotherapy with and without concurrent chemotherapy for locally advanced transitional cell carcinoma of the renal pelvis and ureter. Antegrade perfusion with bacillus Calmette-Guerin in patients with non-muscle-invasive urothelial carcinoma of the upper urinary tract: who may benefit Intravesical instillation of bacille Calmette-Guerin for carcinoma in situ of the urothelium involving the upper urinary tract using vesicoureteral reflux created by a double-pigtail catheter. Changes in renal function following nephroureterectomy may affect the use of perioperative chemotherapy. Surgery is the mainstay of treatment for organ-confined and locally advanced disease. A plethora of novel targeted therapies are now available for the treatment of metastatic disease, some with promising results. More than 90% of kidney tumours are renal cell carcinoma, which has several distinct subtypes-clear cell, papillary, chromophobe, and collecting duct. The remaining 10% are comprised of upper tract urothelial carcinoma, lymphoma, sarcoma, and benign solid tumours such as oncocytoma and angiomyolipoma.

Such findings promise eventually to enhance identification zolpidem arrhythmia buy zebeta visa, prevention hypertension diagnosis 10 mg zebeta purchase fast delivery, and treatment of atherosclerotic disease arrhythmia cause purchase zebeta 5 mg without prescription. Observational studies have shown that societies with high consumption of saturated fat and prevalent hypercholesterolemia have greater mortality from coronary disease than countries with traditionally low saturated fat intake and low serum cholesterol levels blood pressure medication valturna purchase zebeta. Similarly hypertension classification jnc 7 discount zebeta 10 mg on-line, data from the Framingham Heart Study and other cohorts have shown that the risk of ischemic heart disease increases with higher total serum cholesterol levels. The coronary risk is approximately twice as high for a person with a total cholesterol level of 240 mgjdL compared with a person whose cholesterol level is 200 mgjdL. Heterozygotes with this condition have one normal and one defective gene coding for the receptor. Lipid-Altering Therapy Strategies that improve abnormal lipid levels can limit the consequences of atherosclerosis. Many large studies of patients with coronary disease show that dietary or pharmacologic reduction of serum cholesterol can prevent cardiovascular events. Lifestyle modifications that may be beneficial include avoidance of tobacco, maintenance of healthy diet and weight, and augmented physical activity. Yet, even intensive lifestyle modification may not be sufficient to prevent cardiovascular events in individuals with long established atherosclerotic risk factors. Hence, many individuals require pharmacologic agents to optimize cardiovascular outcomes. These agents inhibit the rate-limiting enzyme responsible for cholesterol biosynthesis. However, in 2013, the American College of Cardiology and American Heart Association issued updated guidelines that advocate a different approach. Based on evidence from multiple randomized controlled clinical trials, the new recommendations focus therapy on groups of patients most likely to benefit from lipid-lowering therapy (Thble 5-2) and recommends dosages of statins that were employed in such trials, rather than titrating dosages based on serum lipoprotein levels. In particular, such studies have affirmed that more intense doses of statins improve outcomes in acute and chronic coronary heart disease more than lower-dose regimens. Other potentially beneficial actions (so-called "pleiotropic effects") include reduced inflammation, a driver of atherosclerosis and its complications. Similarly, clinical trials of drug therapies that reduce elevated triglyceride levels. Such drugs are now used primarily to reduce severely elevated levels of serum triglycerides to prevent the associated complication of pancreatitis. Tobacco Smoking Numerous studies have shown that tobacco smoking predisposes to atherosclerosis and ischemic heart disease. Even low level smoking leads to adverse outcomes, but the heaviest smokers have the greatest risk of cardiovascular events. Extrapolation from animal experiments suggests that smoking not only accelerates atherogenesis but also increases the propensity for thrombosis-both components of the "vulnerable patient. People who stop smoking greatly reduce their likelihood of coronary heart disease, compared with those who continue to smoke. In one study, after 3 years of cessation, the risk of coronary artery disease for former smokers became similar to subjects who never smoked. Hypertension Elevated blood pressure (either systolic or diastolic) augments the risk of developing atherosclerosis, coronary heart disease, and stroke (see Chapter 13). The association of elevated blood pressure with cardiovascular disease does not appear to have a specific threshold. Systolic pressure predicts adverse outcomes more reliably than does diastolic pressure, particularly in older persons. Animal studies have shown that elevated blood pressure injures vascular endothelium and may increase the permeability of the vessel wall to lipoproteins. Thus, hypertension may also promote atherogenesis by contributing to a prooxidant and inflammatory state. Antihypertensive Therapy Like dyslipidemias, treatment of hypertension should start with lifestyle modifications but often requires pharmacologic intervention. Many medications effectively lower blood pressure, as described in Chapters 13 and 17. Diabetes Mellitus and the uMetabolic Syndrome" Diabetes mellitus affects an estimated 170 million people worldwide, a prevalence projected to grow 40% worldwide by 2030. With a three- to fivefold increased risk of acute coronary events, 80% of diabetic patients succumb to atherosclerosis-related conditions, including coronary heart disease, stroke, and peripheral artery disease. The predisposition of diabetic patients to atherosclerosis may relate in part to accompanying dyslipidemia, to nonenzymatic glycation of lipoproteins (which enhances uptake of cholesterol by scavenger macrophages, as described earlier), or to the associated prothrombotic tendency and antifibrinolytic state. Tight control of serum glucose levels in diabetic patients reduces the risk of microvascular complications, such as retinopathy and nephropathy. Yet demonstration of a reduction of macrovascular outcomes, such as myocardial infarction and stroke, by glycemic control remains much more elusive. Indeed, studies have suggested that intense glucose lowering may even augment the incidence of adverse cardiovascular events. In contrast to the uncertain benefits of intense glycemic control for macrovascular events, treatment of hypertension and dyslipidemia in diabetic patients convincingly reduces the risk of cardiac and cerebrovascular complications. This constellation associates with a high risk for atherosclerosis in both diabetic and nondiabetic patients, and using currently accepted criteria, 25% of Americans have this condition. The presence of insulin resistance in this syndrome appears to promote atherogenesis long before affected persons develop overt diabetes. Observational studies of both men and women indicate that even modest activities, such as brisk walking, for as little as 30 minutes per day can protect against cardiovascular mortality. Estrogen Status Cardiovascular disease dominates other causes of mortality in women, including breast and other cancers. This observation suggests that estrogen (the levels of which decline after menopause) may have atheroprotective properties. Experimentally, estrogen also exhibits potentially beneficial antioxidant and antiplatelet actions and improves endothelium-dependent vasodilation. Early observational studies suggested that hormone therapy reduced the risk of coronary artery disease in postmenopausal women, prompting many physicians to prescribe such medications for cardiovascular prevention purposes. However, the Heart and Estrogen/Progestin Atherosclerosis 131 Replacement Study demonstrated an association between such hormone use and an early increased risk of vascular events in women with preexisting coronary disease. Because currently available clinical trial data do not show that gonadal hormone therapy lowers cardiovascular events and that it may actually be harmful, such therapy should not be commenced for the sole goal of reducing cardiovascular risk. Biomarkers of Cardiovascular Risk Despite identification of the well-established risk factors just described, one out of five cardiovascular events occurs in patients lacking these attributes. In conjunction with growing knowledge about the pathogenesis of atherosclerosis, several novel markers of risk have emerged. These biomarkers serve three primary roles: (1) as a means to help stratify the risk of atherosclerotic disease and thus guide the choice of therapies, (2) as clinical measures to assess treatment effects, and (3) as potential targets of new therapeutic regimens. Apo(a) structurally resembles plasminogen, a plasma protein important in the endogenous lysis of fibrin clots (see Chapter 7). Thus, the detrimental effect attributed to Lp(a) may relate to competition with normal plasminogen activity. Lp(a) is able to enter the arterial intima, and in vitro studies have shown that it encourages inflammation and thrombosis. Lp(a) levels in the population are skewed and not normally distributed, showing a trailing prevalence of the higher levels. Not all population studies support a link between Lp(a) and cardiovascular events, though people with the highest Lp(a) levels do appear to have increased risk. Of current lipid-lowering agents, niacin has the greatest effect on Lp(a), lowering its concentration by as much as 20%. However, thus far, there is no evidence that reduction of Lp(a) by drug therapy improves cardiovascular outcomes. Recall that the process of lipoprotein entry and modification in the vessel wall triggers the release of cytokines, followed by leukocyte infiltration, more cytokine release, and smooth muscle migration intoand proliferation within-the intima. Given the critical role of inflammation in atherogenesis, ongoing clinical trials are testing available and novel anti-inflammatory medications for the prevention of recurrent cardiovascular events among patients with coronary disease. Outlook Despite accumulating knowledge of the pathogenesis of atherosclerosis and its clinical sequelae, this disease remains a major cause of death throughout the world. Although improvements in cardiovascular care have reduced age-adjusted mortality from this condition, it will continue to grow as a menace as the population ages and as developing countries embrace the adverse dietary and activity habits of a Western lifestyle. Ongoing research of the biology of atherosclerosis, as well as advances in therapeutic procedures and medications, will undoubtedly continue to further our abilities to combat this condition. Yet we have not fully capitalized on what we already know-that much cardiovascular risk is modifiable. Effective control of the risk factors described earlier remains a critical component to tame this global scourge. It is here that the relationship between the patient and health care provider, and the role of medical professionals as community leaders advocating healthy lifestyles, remain of cardinal importance. Acknowledgments Contributors to the previous editions of this chapter were Jordan B. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. In celebration of the 100th anniversary of the lipid hypothesis of atherosclerosis. Lipoprotein(a as a potential causal genetic risk factor of cardiovascular disease: A rationale for increased efforts to understand its pathophysiology and develop targeted therapies. Ully Chapter Outline Detenninants of Myacardial Oxygen Supply and Demand Myocardial Oxygen Supply Myocardial Oxygen Demand Pathophysiology of Ischemia Fixed Vessel Narrowing Endothelial CeU Dysfunction Other Causes of Myocardial Ischemia Consequences of Ischemia Ischemic Syndromes Clinical Features of Chronic Stable Angfm1 History Physical Examination Diagnostic Studies Natural History Treatment Medical Treatment of an Acute Episode of Angina Medical Treatment to Prevent Recurrent Ischemic Episodes Medical Treatment to Prevent Acute Cardiac Events Revascularization Medical versus Revascularization Therapy n 1772, the British physician William Heberden reported a disorder in which patients developed an uncomfortable sensation in the chest when walking. Labeling it angina pectoris, Heberden noted that this discomfort would disappear soon after the patient stood stili but would recur with similar activities. Although he did not know the cause, it is likely that he was the first to describe the symptoms of ischemic heart disease, a condition of imbalance between myocardial oxygen supply and demand most often caused by atherosclerosis d the coronary arteries. Ischemic heart disease now afflicts millions d Americans and is the leading cause of death in industrialized nations. The clinical presentation of ischemic heart disease can be highly variable and forms a spectrum of syndromes (Table 6·1). For example, ischemia may be accompanied by the same exertional symptoms described by Heberden. In other cases, it may occur without any clinical manifestations at all, a condition tenned silent ischemia. This article describes the causes and consequences of chronic ischemic heart disease syndromes and provides a framework fur the diagnosis and treatment of affected patients. Angina pectoris remains the most common manifestation of ischemic heart disease and literally means "strangling in the chest. Even during vigorous exercise, when the metabolic needs of the heart increase, so does the delivery of oxygen to the myocardial cells so that the balance is maintained. P, ventricular pressure; Contractility ·- r, ventricular radius; h, ventricular wall thickness. I -, 136 Chapter 6 Myocardial Oxygen Supply the supply of oxygen to the myocardium depends on the oxygen content of the blood and the rate of coronary blood flow. The oxygen content is determined by the hemoglobin concentration and the degree of systemic oxygenation. In contrast, coronary blood flow is much more dynamic, and regulation of that flow is responsible for matching the oxygen supply with metabolic requirements. That is, Q aR p However, unlike other arterial systems in which the greatest blood flow occurs during systole, the predominance of coronary perfusion takes place during diastole. The reason for this is that systolic flow is impaired by the compression of the small coronary branches as they course through the contracting myocardium. Coronary flow is unimpaired in diastole because the relaxed myocardium does not compress the coronary vasculature. Thus, in the case of the coronaries, perfusion pressure can be approximated by the aortic diastolic pressure. Conditions that decrease aortic diastolic pressure (such as hypotension or aortic valve regurgitation) decrease coronary artery perfusion pressure and may lessen myocardial oxygen supply. Coronary vascular resistance is the other major determinant of coronary blood flow. In the normal artery, this resistance is dynamically modulated by (1) forces that externally compress the coronary arteries and (2) factors that alter intrinsic coronary tone. External Compression External compression is exerted on the coronary vessels during the cardiac cycle by contraction of the surrounding myocardium. The degree of compression is directly related to intramyocardial pressure and is therefore greatest during systole, as described in the previous section. Moreover, when the myocardium contracts, the subendocardium, adjacent to the high intraventricular pressure, is subjected to greater force than are the outer muscle layers. This is one reason that the subendocardium is the region most vulnerable to ischemic damage. Intrinsic Control of Coronary Arterial Tone Unlike most tissues, the heart cannot increase oxygen extraction on demand because in its basal state, it removes nearly as much oxygen as possible from its blood supply. Thus, any additional oxygen requirement must be met by an increase in blood flow, and autoregulation of coronary vascular resistance is the most important mediator of this process. Factors that participate in the regulation of coronary vascular resistance include the accumulation of local metabolites, endothelium-derived substances, and neural innervation. Metabolic Factors the accumulation of local metabolites significantly affects coronary vascular tone and acts to modulate myocardial oxygen supply to meet changing metabolic demands. Adenosine is a potent Ischemic Heart Disease 137 vasodilator and is thought to be the prime metabolic mediator of vascular tone. By binding to receptors on vascular smooth muscle, adenosine decreases calcium entry into cells, which leads to relaxation, vasodilatation, and increased coronary blood flow. Other metabolites that act locally as vasodilators include lactate, acetate, hydrogen ions, and carbon dioxide. EndotheL;aL Factors Endothelial cells of the arterial wall produce numerous vasoactive substances that contribute to the regulation of vascular tone. Its direct effect on vascular smooth muscle cells is to cause vasoconstriction, but when an intact endothelial lining overlies the smooth muscle cells, vasodilatation occurs instead. Endothelin 1 is a potent vasoconstrictor produced by endothelial cells that partially counteracts the actions of the endothelial vasodilators.

They improve endothelial function as evidenced by enhanced synthesis of nitric oxide blood pressure glucose levels purchase zebeta 5 mg with amex. They further promote plaque stability by inhibiting monocyte penetration into the arterial wall and reducing macrophage secretion of metalloproteinases hypertension causes purchase zebeta 10 mg fast delivery, enzymes that degrade and weaken the fibrous caps of plaques blood pressure response to exercise purchase zebeta from india. The most significant potential adverse effects are hepatotoxicity and myopathy skeletal muscle toxicity) arrhythmia echocardiogram discount zebeta 5 mg with mastercard. Symptoms disappear almost immediately after the drug is discontinued heart attack demi lovato mp3 order zebeta australia, but transaminase levels may remain elevated for weeks. The risk of statinassociated hepatic toxicity is higher in patients who drink excessive amounts of alcohol. Myopathy, typically involving the proximal leg or arm muscles symmetrically, can range from vague aches to intense myalgias and muscle weakness and rarely may lead to rhabdomyolysis (destruction of muscle) with myoglobinuria and renal failure. While benign muscle aches are reported in 2% to 10% of patients on statins, significant myositis (defined as an elevated serum level of muscle-derived creatine kinase greater than 10 times the upper limit of normal) develops in less than 0. However, the incidence of muscle injury is increased by concomitant therapy with certain other drugs, including other lipid-lowering agents. Notably, pravastatin, rosuvastatin, and fluvastatin are not substantially dependent on the cytochrome P450 3A4 isoform for their metabolism and may be less likely to cause myopathy in combination with these other drugs. As described in Chapter 5, statins form the foundation of lipid-lowering drug therapy. Bile Add-Binding Agents this group includes the resins cholestyramine and colestipol and the hydrophilic polymer colesevelam. As a consequence, more hepatic cholesterol is converted into newly produced bile acids. However, unlike statins, 452 Chapter 17 new hepatic cholesterol production is also stimulated by the reduced intrahepatic cholesterol content. In one of the first drug trials of patients with hypercholesterolemia, cholestyramine significantly reduced the risk of fatal and nonfatal myocardial infarctions. Thus, the bile acid-binding agents are only occasionally used, mainly as second-line lipid-regulating drugs, in patients who cannot tolerate statins. Because they can elevate the serum triglyceride level, they should be avoided in patients with hypertriglyceridemia. The bile acid-binding agents interfere with the absorption of fat-soluble vitamins and certain drugs. Thus, other medications should be consumed 1 hour before or 3 to 4 hours after these agents. Because bile acid-binding agents are not absorbed into the circulation, they do not cause systemic side effects. Cholesterol Absorption Inhibitors Ezetimibe, the first member of this class, is a selective inhibitor of cholesterol uptake at the brush border of epithelial cells in the small intestine. It acts by competitively inhibiting a transporter known as the Niemann-Pick Cl-like 1 protein. Normally, a portion of dietary and biliary cholesterol taken up in this manner is esterified and incorporated into chylomicrons, which then enter into the circulation and are transported to the liver (see Box 5-1). A recent prospective clinical trial of patients soon after experiencing an acute coronary syndrome showed that the combination of ezetimibe plus a statin was modestly superior to statin therapy alone at preventing subsequent cardiovascular events. When combined with a statin, the incidence of transaminase elevation is only slightly greater than that of statin therapy alone. The addition of ezetimibe to a statin regimen does not appear to significantly increase the risk of statin-associated myopathy. Niadn Niacin is one of the oldest lipid-regulating drugs and has favorable effects on all the circulating lipid fractions. As a result, fewer fatty acids are transported to the liver and hepatic triglyceride synthesis declines. In the 1970s, prior to the introduction of statins, a study of men with prior myocardial infarction showed that niacin reduced the risk of future cardiac events, and lowered the mortality rate, in long-term follow-up. These episodes are prostaglandin mediated and can be minimized by taking aspirin prior to the daily niacin dose. Gastrointestinal side effects include nausea and exacerbation of peptic ulcer disease. Niacin should be used cautiously in diabetic patients because it can contribute to insulin resistance and hyperglycemia. It also raises serum uric acid levels and can precipitate gout in susceptible patients. Rare cases of myopathy have been reported with niacin; the incidence is increased when niacin is prescribed concurrently with a statin. Fibrates the fibric acid derivatives ("fibrates") gemfibrozil and fenofibrate are used primarily to treat marked hypertriglyceridemia. A large study of men with hypercholesterolemia, but no known coronary disease, showed that gemfibrozil reduced the number of subsequent myocardial infarctions, without lowering the total death rate. In a 5-year study of patients with type 2 diabetes, fenofibrate reduced the incidence of nonfatal myocardial infarction but not total cardiovascular mortality. Thus, they should be avoided or prescribed at lower dosages for patients with impaired liver or kidney function. Therefore, if these drugs are prescribed concurrently, it is recommended that the serum creatine kinase (a marker of muscle inflammation or necrosis) be monitored routinely. Fibrates augment the effect of warfarin by displacing it from albumin-binding sites, possibly necessitating a decrease in the anticoagulant dosage. Acknowledgments Contributors to previous editions of this chapter were Christopher A. Endothelin receptor antagonists for the treatment of pu1monary artery hypertension. Comparison of the efficacy and safety of the new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. To some extent, these mechanisms are similar to those that occur in nonheritable disorders. Thus, the pathophysiologic principles that distinguish genetic disease focus not so much on the affected organ system as on the mechanisms of genetic and genomic changes, inheritance, and molecular pathways from genotype to phenotype. This article begins with a discussion of the tenninology used to describe inherited conditions, the prevalence of genetic disease, and some major principles and considerations in medical genetics. Important terms and key words used throughout the chapter are defined in Table 2-1. Although osteogenesis imperfecta is often considered a single entity, different pathogenic variants and different genes subject to alteration lead to a wide spectrum. This serves as a paradigm for newborn screening programs and for treatment of genetic disease. Several genetic conditions have been found to depend not only on the gene being inherited but also on the phenotype or the sex of the parent As an example of a condition that exhibits non-autosomal inheritance, fragile X-assodated. Another group of disorders that depend on the phenotype and sex of the parent consists of those that affect the mitochondrial genome. These illustrate the principles of mitochondrial inheritance and its pathophysiology. Finally, this chapter considers how genome sequences and sequencing are improving our understanding of pathophysiology for many diseases. With the completion of the annotation of the human genome and technological advances that allow individual genomes to be sequenced rapidly and inexpensively, prospects are at hand to identify genetic components of any human phenotype and to provide medical care that is truly personalized. Deflnltlan Acrocentrfc Allelic heterogeneity Amorphlc Aneuploidy Antlmorphlc Refers tothe tennlnal locatlon ofthe centromereon chromosomes 13, 14, 15, 21, and 22. The situation In which multlple alleles at a single locus can produce one or more disease phenotypes. Refers to pathogenic variants that cause a complete loss offunction for the respective gene and therefore yteld the same phenotype as a complete gene deletlon. Ascertainment bias the situation In which lndlvlduals or famllles In a genetic study are not representative of the general populatlon because of the way In which they are Identified. Such segments are frequeMly unmetl1ylated and located close to ublqultously expressed genes. The end of prophase during female meiosis I in which fetal oocytes are arrested prior to ovulation. Dominant negative A type of pathophysiologic mechanism that occurs when a mutant allele interferes with the nonnal function of the nonmutant gene product Dosage compensation En~product Mechanism by which a difference In gene dosage between two cells Is equalized. A pathologlc mechanism In which absence or reduction In the product of a partlcular enzymatic reectlon leads to disease. One of several possible explanatlons for an unexpectedly high frequency of a deleterious gene In a populatlon. The egg or sperm cell that represents a potential reproductive contribution to the next generation. Gametes have undergone meiosis and so contain half the normal number of chromosomes found In ~otlc cells. The principle that the amount mproduct expressed for a particular gene is proportionate to the number of gene copies present per cell. Possible explanations Include ascertainment bias or a multlstep mutational mechanism such as expansion of triplet repeats. Aterm referring to the presence of only one allele at a locus, either because the other allele Is deleted or because It Is normally not present; eg, X-linked genes in males. During recent evolution, carriers (ie, heterozygotes) are postulated to haw had a higher fitness than homozygous wild-type individuals. Refers to a variant that reduces but does not eliminate the activity of a particular gene product. Most commonly, the process whereby expression of a gene depends on whether It was Inherited from the mother or the father. Acondition in which certain combinations of closely linked alleles, or haplotypes, are present in a population at frequendes not predicted by their Individual allele frequendes. Asituation In which pathogenic variants of different genes produce slmllar or Identical phenotypes. A reduction In zygotic cells from two to one In the number of copies for a particular chromosomal segment or chromosome. Asituation in which a genetic alteration is present in some but not all ofthe cells of a single individual. In germ line or gonadal mosaicism, the alteration is present in germ cells but not somatic cells. In somatic mosaicism, the genetic alteration is present In some but not all ofthe somatic cells (and Is generally not present In the germ cells). Refers to a variant that Imparts a novel function to Its gene product and consequently results In a phenotype distinct from an alteration In gene dosage. In a population, reduced penetrance refers to the rate at which Individuals of a variant genotype cannot be recognized according to specific phenotyplc criteria. The sltuadon that occurs when pathogenic vartants of a single gene produce multlple different phenotypes. A mutational event that occurs after fertilization and that commonly give rise to mosaldsm. Agenetic change that does not result In a phenotype Itself but has a high probablllty of de11eloplng a second alteration-a fully pathogenic Viilriantlfull mutatio~that does cause a phenotype. Monosomy Mosaicism Neomorphlc Nondisjunction Penetrance Phenotyplc heterogeneity Postzygotic Premutatlon Primordial germ cell the group of cells set aside early In development that go on to give rise to gametes. Recessive A pettem of Inheritance or mechanism of gene action In which a particular mutant allele harborlng a pathogenic variant causes a phenotype only In the absence of a normal allele. Thus, for autosomal conditions, the variant or disease phenotype Is manifest when two copies of the allele harboring a pathogenic Viilriiilnt are present. For X-linked conditions, the Viilriant or disease phenotype Is manifest In cells, tissues, or lndlvlduals In which the normal allele Is either Inactivated (a heterozygous female) or not present (a heml~us male). Atype of translocation In which two acrocentrlc chromosomes are fused together with a sing le functional centromere. Acarrier of a robertsonlan translocation with 45 chromosomes has a normal amount of chromosomal material and Is said to be euplold. Single nucleotide polymorphism-one of the most common typeS of genetic Viilriation. Adeletion, insertion, or more complex rearrangement, usually caused by recombination between repetitive elements. Most structural variants involve deletions or insertions thatare relatively small (<1 okb) and do not cause any dinical phenotype. Larger structural variants (>100 kb) are Increasingly likely to have dlnlcal effects. An abnormal situation in which there are three, instead of two, copies of a chromosomal segment or chromosome per cell. A variant can be classlfled further using modifiers such as ·pathogenlc;llkely pathogenic;" "uncertain slgnlflcance,··111ce1y benign,· and "benign;" Use of this nomenclature has replaced the previously used terms "polymorphism" and "mutation: Trisomy Variant diseases are caused by (1) stru. In most genetic diseases, every cell in an affected individual carries the mutated gene or genes as a consequence ofits inheritance via a mutant egg or sperm cell (gamete). However, mutation of the gametic cell may have arisen during its development, in which case somatic cells of the parent do not carry the variant. Depending on the time ofemhryogenesis and cell type in which a new variant arises, an individual ma:y carry the alteration in some but not all of their germ cells (germline moaai. It is helpful to begin with a brief review of terms that are commonly used in discussing genetic disease with patients and their families. A genetic variant arises via a biochemical event such as a nucleotide change, deletion, or insertion that has produced a new allele.

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