Fat distribution and storage: how much, where, and how?

Obesity does not necessarily imply disease and similarly obese individuals may manifest obesity-related morbidity or seemingly be in reasonably good health. Recent studies have shown that patterns of lipid partitioning are a major determinant of the metabolic profile and not just obesity per se. The underlying mechanisms and clinical relevance of lipid deposition in the visceral compartment and in insulin-sensitive tissues are described. Increased intramyocellular lipid deposition impairs the insulin signal transduction pathway and is associated with insulin resistance. Increased hepatic lipid deposition is similarly associated with the majority of the components of the insulin resistance syndrome. The roles of increased circulating fatty acids in conditions of insulin resistance and the typical pro-inflammatory milieu of specific obesity patterns are provided. Insights into the patterns of lipid storage within the cell are provided along with their relation to changes in insulin sensitivity and weight loss.     

Exercise and heart disease in women: why, how, and how much?

Despite a traditional view that cardiovascular disease primarily affects men, a growing body of information now recognizes that it is a disease that equally affects women and is the leading cause of morbidity and mortality in women in the United States. Both physical activity and physical fitness have been shown to have an inverse association with coronary heart disease and cardiovascular risk factors. Furthermore, physical inactivity is now recognized by the American Heart Association as an independent risk factor for coronary heart disease. However, national surveillance programs have reported that 1/4 of adults are currently sedentary, and 1/3 of women do not engage in any leisure-time physical activity. Regular exercise may significantly impact coronary heart disease in women, as some coronary risk factors have a stronger predictive value for coronary heart disease in women as compared with men. Recent studies have shown that women who exercise regularly are less likely to develop diabetes mellitus; exercise may reduce blood pressure and produce improvements in lipid profiles. Conflicting data exist regarding the dose and intensity of exercise necessary to achieve significant health benefits; however, many reports demonstrate a reduced risk of mortality from cardiovascular diseases and from all causes with only moderate intensity physical activity. The Centers for Disease Control, American Heart Association, and American College of Sports Medicine recommend a regular pattern of physical activity of moderate intensity, which can be accumulated throughout the day and should be performed at least 3 to 5 days per week. In addition, the benefit of weight-bearing exercise should be underscored in women, because it plays an important role in the prevention and treatment of osteoporosis. Continued efforts are necessary to encourage the many American women who are currently inactive to make even modest increases in levels of physical activity to achieve substantial cardiovascular, as well as other, health benefits.     

Sport therapy for hypertension: why, how, and how much?

Exercise may prevent or reduce the effects of metabolic and cardiovascular diseases, including arterial hypertension. Both acute and chronic exercise, alone or combined with lifestyle modifications, decrease blood pressure and avoid or reduce the need for pharmacologic therapy in patients with hypertension. The hypotensive effect of exercise is observed in a large percentage of subjects, with differences due to age, sex, race, health conditions, parental history, and genetic factors. Exercise regulates autonomic nervous system activity, increases shear stress, improves nitric oxide production in endothelial cells and its bioavailability for vascular smooth muscle, up-regulates antioxidant enzymes. Endurance training is primarily effective, and resistance training can be combined with it. Low-to-moderate intensity training in sedentary patients with hypertension is necessary, and tailored programs make exercise safe and effective also in special populations. Supervised or home-based exercise programs allow a nonpharmacological reduction of hypertension and reduce risk factors, with possible beneficial effects on cardiovascular morbidity.     

Treating undifferentiated arthritis. What, when, how and how long?

With the establishment of early arthritis clinics, patients can now be increasingly attended early in the course of their disease. This means that a significant proportion of these patients cannot be classified into a specific diagnosis using the traditional American College of Rheumatology (ACR) classification criteria. In these patients with undifferentiated arthritis (UA), even more important than assigning a diagnosis is the need to distinguish between patients who will develop a persistent and/or erosive disease and will be candidates for prompt treatment with disease-modifying antirheumatic drugs (DMARD), and patients in whom the disease is self limiting. Serologic markers in combination with clinical features at presentation, integrated into predictive models, are the tools currently available to the clinician for identifying these patients. Several studies have demonstrated the advantages of early treatment in UA.     

Metabolic sensing and the brain: who, what, where, and how?

Unique subpopulations of specialized metabolic sensing neurons reside in a distributed network throughout the brain and respond to alterations in ambient levels of various metabolic substrates by altering their activity. Variations in local brain substrate levels reflect their transport across the blood- and cerebrospinal-brain barriers as well as local production by astrocytes. There are a number of mechanisms by which such metabolic sensing neurons alter their activity in response to changes in substrate levels, but it is clear that these neurons cannot be considered in isolation. They are heavily dependent on astrocyte and probably tanycyte metabolism and function but also respond to hormones (e.g. leptin and insulin) and cytokines that cross the blood-brain barrier from the periphery as well as hard-wired neural inputs from metabolic sensors in peripheral sites such as the hepatic portal vein, gastrointestinal tract, and carotid body. Thus, these specialized neurons are capable of monitoring and integrating multiple signals from the periphery as a means of regulating peripheral energy homeostasis.     

Insulin secretagogues: Who,what, when,and how?

Sulfonylurea compounds were the first available oral antidiabetic agents and they remain an important tool in our quest for optimal glycemic control. The more recent introduction of meglitinides offers an approach to short-term insulin release with minimal hypoglycemic risk during fasting periods. Published trials suggest that individuals with a hemoglobin A_1c above 8.5% are unlikely to reach currently recommended targets (6.5% to 7%) without the use of one of these insulin secretagogues. Starting and probable maximally effective doses for glimepiride are 1 to 2 mg initially and 4 mg thereafter. For glyburide and glipizide, these are 2.5 to 5 mg initially, and 10 mg effective at a maximum. The large majority of the effect can be seen within a week, making them very attractive when rapid lowering of glucose is needed. An understanding of the principles will facilitate more effective use of initial and combination therapy.     

Diagnosing occupational asthma: how, how much, how far?

Diagnosing occupational asthma is still a challenge because it is based on a stepwise approach in which the depth of investigative means may vary depending on resources. The authors herewith review the existing investigative means from the approach of outlining controversies and queries. There is no validated clinical questionnaire for diagnosing occupational asthma. Immunological investigation is limited by the lack of standardised extracts for skin-prick testing and specific immunoglobulin E assessments. Criteria for interpretation of changes in peak expiratory flow rates and bronchial responsiveness to pharmacological agents are still open to discussion. It is worth improving the methodology of specific inhalation challenges, either in the laboratory or in the workplace, to facilitate more extensive use of these tests. Validation of new means that assess airway inflammation, such as exhaled nitric oxide and induced sputum, needs to be performed. There is a need to increase the use of these diagnostic tests because the diagnosis is still too often based on "clinical impression".     

Genomic medicine and thrombotic risk: who, when, how and why?

Major advances in Human Genome research could significantly change the clinical medical practice, providing new possibilities for both diagnosing and treating common pathologies. Many genetic tests are now commercially available for predicting future risk of common disorders. However, genetic testing has potential benefits but also limitations for the patients, and it should not be used to 'screen' the general population. Diagnostic assays for a predisposition of both venous and arterial thrombosis are among the most requested genetic tests in molecular diagnostics laboratories. However, there is considerable uncertainty as to how this information should be utilized in patient management. Both the medical community and the patients need to obtain accurate information concerning the appropriate use of genetic testing. The purpose of this article is to discuss the usefulness and the practical applications of thrombotic genetic testing in order to define which patients should be tested for both venous and arterial thrombotic risk as well as to have an acceptable cost/benefit ratio and to prevent patients' anxiety.     

Liver biopsy: When, how, by whom, and where?

Liver biopsy remains an important diagnostic tool in the management of liver disease. Complications, though infrequent, are potentially disastrous. Risks and discomfort can be minimized with good technique, although prospective data to prove the superiority of one method over another are often lacking. Image direction is preferred in all cases, as is a transjugular approach when bleeding risks are judged to be high. Bleeding is essentially a random event. Outpatient liver biopsy is appropriate in almost every instance if immediate hospitalization facilities are available. It should be more widely practiced. Liver biopsies should only be done if, after thoughtful assessment, benefits are thought to exceed risks.     

Anxiety and depression in cardiology patients: how to diagnose, how to treat?

IMPORTANCE: Anxiety and depression are frequent problems in patients with heart diseases. Prevalences vary between 15 and 50%, depending on diagnostic criteria as well as on sociodemographic and medical patient characteristics. During the last 10-15 years, a large number of studies have shown that anxiety and depression strongly affect overall well-being, cardiac and non-specific symptom reporting and overall quality of life. This leads to increased health care utilization, early retirement and imposes a financial burden on individuals and social security systems. In addition, anxious and especially depressed patients with heart disease tend to exhibit unhealthy illness behavior, low compliance and suboptimal risk factor control. Together with the known physiological effects of negative affect on cardiac autonomic balance, inflammation and platelet function, these behavioral mechanisms may lead to the frequently observed increase of cardiac event and mortality rates in depressed patients wit coronary artery disease. DIAGNOSIS: Despite their clinical relevance and unsatisfactory spontaneous remission rate, anxiety and depression still go unrecognized and undertreated in most cardiac patients. Case-identification can be improved by a graded approach. In the first step, symptoms of anxiety and depression should explicitly be asked for as part of a routine cardiological work-up. As an adjunct, validated self-rating questionnaires can be used for screening purposes. Patients screened positive should receive a thorough diagnostic interview and a criteria-based diagnosis. TREATMENT: Once a diagnosis has been obtained, several treatment options are available: In less severe cases (minor depression or adjustment disorders), supportive care by primary care physicians or cardiologists may be sufficient. Patients with major depression or panic disorder should receive structured psychotherapy and/or antidepressant medication. Exercise training can also improve symptoms of anxiety and depression. Although both psychotherapy and antidepressants, especially if integrated in a concept of comprehensive cardiac care, can be expected to result in marked subjective benefit for the majority of patients, the impact of these treatments on cardiac event and mortality rates still needs to be determined.     

Combination therapy for mucormycosis: why, what, and how?

The high mortality rate of mucormycosis with currently available monotherapy, particularly in hematology patients, has stimulated interest in studying novel combinations of antifungal agents to determine whether superior outcomes might be achieved. Combination lipid polyene-echinocandin therapy is the most promising of such regimens based on safety profile, the availability of parenteral formulations of echinocandins, their synergy in murine models of mucormycosis, and observational clinical data that are concordant. Other options include combination lipid polyene plus deferasirox or posaconazole therapy. Definitive, randomized, placebo-controlled phase III clinical trials are needed to determine whether combination therapy with any of these options is superior to monotherapy. Until such studies are conducted, clinicians will continue to be placed in the unacceptable position of not knowing if and when to administer combination therapy. Such a state of confusion may lead to undertreatment if combination therapy is indeed superior but is not used and, conversely, may lead to unacceptable toxicity and cost to patients if combination therapy is not superior but is used. It is critical that sponsors step forward with funding to conduct these clinical trials to determine whether outcomes from these devastating infections can be improved.     

When, for whom and how to use sibutramine?

Sibutramine is the first of a new generation of weight management drugs, and offers long-term control of weight when used as an adjunct to diet and exercise. This paper considers the criteria set down by the European Union's regulatory agency for its use and how this relates to the information now available on its efficacy, side-effect profile and benefits in different patient groups. The data presented relate to 18-65y olds; its use in other age groups has not been established. The EU licence permits continuous treatment for periods of up to 1 y; the STORM study has now led the US Food and Drug Administration to extend clearance to 2 y. The addition of sibutramine to a regimen of diet, exercise and lifestyle modification results in 3-5 times more patients responding to a weight-reduction programme, ie achieving more than 5% weight maintenance. Sibutramine is indicated for use in obese patients (BMI > 30 kg/m2) and also overweight patients with a BMI > 27 kg/m2 who have additional obesity-related risk factors such as type 2 diabetes or dyslipidaemia.     

Why and how to implement sodium, potassium, calcium, and magnesium changes in food items and diets?

The present average sodium intakes, approximately 3000-4500 mg/day in various industrialised populations, are very high, that is, 2-3-fold in comparison with the current Dietary Reference Intake (DRI) of 1500 mg. The sodium intakes markedly exceed even the level of 2500 mg, which has been recently given as the maximum level of daily intake that is likely to pose no risk of adverse effects on blood pressure or otherwise. By contrast, the present average potassium, calcium, and magnesium intakes are remarkably lower than the recommended intake levels (DRI). In USA, for example, the average intake of these mineral nutrients is only 35-50% of the recommended intakes. There is convincing evidence, which indicates that this imbalance, that is, the high intake of sodium on one hand and the low intakes of potassium, calcium, and magnesium on the other hand, produce and maintain elevated blood pressure in a big proportion of the population. Decreased intakes of sodium alone, and increased intakes of potassium, calcium, and magnesium each alone decrease elevated blood pressure. A combination of all these factors, that is, decrease of sodium, and increase of potassium, calcium, and magnesium intakes, which are characteristic of the so-called Dietary Approaches to Stop Hypertension diets, has an excellent blood pressure lowering effect. For the prevention and basic treatment of elevated blood pressure, various methods to decrease the intake of sodium and to increase the intakes of potassium, calcium, and magnesium should be comprehensively applied in the communities. The so-called 'functional food/nutraceutical/food-ceutical' approach, which corrects the mineral nutrient composition of extensively used processed foods, is likely to be particularly effective in producing immediate beneficial effects. The European Union and various governments should promote the availability and use of such healthier food compositions by tax reductions and other policies, which make the healthier choices cheaper than the conventional ones. They should also introduce and promote the use of tempting nutrition and health claims on the packages of healthier food choices, which have an increased content of potassium, calcium, and/or magnesium and a lowered content of sodium. Such pricing and claim methods would help the consumers to choose healthier food alternatives, and make composition improvements tempting also for the food industry.     

Hypertriglyceridemia-why, when and how should it be treated?

Summary The relationship between serum triglyceride levels and cardiovascular disease has remained enigmatic despite four decades of research. The majority of the available evidence tends to support the role of hypertriglyceridemia as an independent risk factor for cardiovascular disease. However, there are no guidelines recommending a target triglyceride level for prevention of cardiovascular disease. The focus of lipid lowering therapy still remains the reduction of global cardiovascular risk by optimizing LDL cholesterol levels. Therapeutic options for triglyceride-lowering include lifestyle modification and pharmacological agents, such as fibrates, omega 3 fatty acids and niacin. Post-hoc analyses of the Helsinki Heart Study, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial and Bezafibrate Infarction Prevention Study suggest a beneficial effect of the treatment of hypertriglyceridemia with fibrates, mainly in obese subjects with insulin resistance. However, in order to establish the actual clinical relevance of lowering triglyceride levels, prospective trials need to be conducted with the specific purpose of studying the effects of triglyceride reduction on clinical end points, i. e. coronary events and stroke.      

Endoscopic ultrasonography-guided biliary drainage: Who,when, which,and how?

Both endoscopic ultrasonography(EUS)-guided choledochoduodenostomy( EUS- CDS) and EUS-guided hepaticogastrostomy(EUS-HGS) are relatively well established as alternatives to percutaneous transhepatic biliary drainage(PTBD). Both EUSCDS and EUS-HGS have high technical and clinical success rates(more than 90%) in high-volume centers. Complications for both procedures remain high at 10%-30%. Procedures performed by endoscopists who have done fewer than 20 cases sometimes result in severe or fatal complications. When learning EUSguided biliary drainage(EUS-BD), we recommend a mentor's supervision during at least the first 20 cases. For inoperable malignant lower biliary obstruction, a skillful endoscopist should perform EUS-BD before EUS-guided rendezvous technique(EUS-RV) and PTBD. We should be select EUS-BD for patients having altered anatomy from malignant tumors before balloon-enteroscope-assisted endoscopic retrograde cholangiopancreatography, EUS-RV, and PTBD. If both EUS-CDS and EUS-HGS are available, we should select EUS-CDS, according to published data. EUSBD will potentially become a first-line biliary drainage procedure in the near future.