[Diagnosis and therapy of hyperthyreosis]

Hyperthyreosis, diabetes and calcium disorders are frequent endocrine diseases that are often encountered by the primary care physician. The diagnosis of hyperthyreosis can be established by many different laboratory and analytical tests. However, the clinical context can often guide a specific diagnostic approach. Graves disease and toxic adenomas are the most frequent causes of hyperthyreosis. Diagnosis of Graves disease is most frequent between age 35 and 60 and about 10-20% of patients show already initially signs of endocrine orbithopathy. Measurement of thyroid stimulating immunoglobulins (TSI) is especially valuable in unclear cases. Toxic adenomas are always diagnosed by thyroid uptake studies. Rare causes of hyperthyreosis include thyreoiditis, which is characterized by transient hyperthyreosis (<2 months), and thyrotoxicosis factitia. Here, we discuss diagnosis and therapy of different causes of hyperthyreosis based on three clinical examples.

Diabetes-related knowledge among medical and nursing house staff

To assess the diabetes-related knowledge of medical and nursing house staff with particular focus on inpatient diabetes management and insulin therapy.

Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia

Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS).

Chapter III: Management of cardiovascular risk factors and medical therapy

Critical limb ischaemia (CLI) is a particularly severe manifestation of lower limb atherosclerosis posing a major threat to both limb and life of affected patients. Besides arterial revascularisation, risk-factor modification and administration of antiplatelet therapy is a major goal in the treatment of CLI patients. Key elements of cardiovascular risk management are smoking cessation and treatment of hyperlipidaemia with dietary modification or statins. Moreover, arterial hypertension and diabetes mellitus should be adequately treated. In CLI patients not suitable for arterial revascularisation or subsequent to unsuccessful revascularisation, parenteral prostanoids may be considered. CLI patients undergoing surgical revascularisation should be treated with beta blockers. At present, neither gene nor stem-cell therapy can be recommended outside clinical trials. Of note, walking exercise is contraindicated in CLI patients due to the risk of worsening pre-existing or causing new ischaemic wounds. CLI patients are oftentimes medically frail and exhibit significant comorbidities. Co-existing coronary heart and carotid as well as renal artery disease should be managed according to current guidelines. Considering the above-mentioned treatment goals, interdisciplinary treatment approaches for CLI patients are warranted. Aim of the present manuscript is to discuss currently existing evidence for both the management of cardiovascular risk factors and treatment of co-existing disease and to deduct specific treatment recommendations.

An Actor-Critic based controller for glucose regulation in type 1 diabetes

A novel adaptive approach for glucose control in individuals with type 1 diabetes under sensor-augmented pump therapy is proposed. The controller, is based on Actor-Critic (AC) learning and is inspired by the principles of reinforcement learning and optimal control theory. The main characteristics of the proposed controller are (i) simultaneous adjustment of both the insulin basal rate and the bolus dose, (ii) initialization based on clinical procedures, and (iii) real-time personalization. The effectiveness of the proposed algorithm in terms of glycemic control has been investigated in silico in adults, adolescents and children under open-loop and closed-loop approaches, using announced meals with uncertainties in the order of ±25% in the estimation of carbohydrates. The results show that glucose regulation is efficient in all three groups of patients, even with uncertainties in the level of carbohydrates in the meal. The percentages in the A+B zones of the Control Variability Grid Analysis (CVGA) were 100% for adults, and 93% for both adolescents and children. The AC based controller seems to be a promising approach for the automatic adjustment of insulin infusion in order to improve glycemic control. After optimization of the algorithm, the controller will be tested in a clinical trial.

Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes

BACKGROUND: This study was undertaken to determine whether use of the direct renin inhibitor aliskiren would reduce cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. METHODS: In a double-blind fashion, we randomly assigned 8561 patients to aliskiren (300 mg daily) or placebo as an adjunct to an angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker. The primary end point was a composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level. RESULTS: The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P=0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P<0.001 for both comparisons). CONCLUSIONS: The addition of aliskiren to standard therapy with renin-angiotensin system blockade in patients with type 2 diabetes who are at high risk for cardiovascular and renal events is not supported by these data and may even be harmful. (Funded by Novartis; ALTITUDE ClinicalTrials.gov number, NCT00549757.).

Extrinsic causes of erosion. Diet. Chemical factors

pH value, calcium, and phosphate and to a lesser extent fluoride content of a drink or foodstuff are important factors explaining erosive attack. They determine the degree of saturation with respect to tooth minerals, which is the driving force for dissolution. Solutions oversaturated with respect to dental hard tissue will not dissolve it. Addition of calcium (and phosphate) salts to erosive drinks showed protection of surface softening. Today, several Ca-enriched soft drinks are on the market or products with naturally high content in Ca and P are available (such as yoghurt), which do not soften the dental hard tissue. The greater the buffering capacity of the drink or food, the longer it will take for the saliva to neutralize the acid. The buffer capacity of a solution has a distinct effect on the erosive attack when the solution remains adjacent to the tooth surface and is not replaced by saliva. A higher buffer capacity of a drink or foodstuff will enhance the processes of dissolution because more ions from the tooth mineral are needed to render the acid inactive for further demineralization. Further, the amount of drink in the mouth in relation to the amount of saliva present will modify the process of dissolution. There is no clear-cut critical pH for erosion as there is for caries. Even at a low pH, it is possible that other factors are strong enough to prevent erosion.

A coronary heart disease risk model for predicting the effect of potent antiretroviral therapy in HIV-1 infected men

BACKGROUND: Many HIV-infected patients on highly active antiretroviral therapy (HAART) experience metabolic complications including dyslipidaemia and insulin resistance, which may increase their coronary heart disease (CHD) risk. We developed a prognostic model for CHD tailored to the changes in risk factors observed in patients starting HAART. METHODS: Data from five cohort studies (British Regional Heart Study, Caerphilly and Speedwell Studies, Framingham Offspring Study, Whitehall II) on 13,100 men aged 40-70 and 114,443 years of follow up were used. CHD was defined as myocardial infarction or death from CHD. Model fit was assessed using the Akaike Information Criterion; generalizability across cohorts was examined using internal-external cross-validation. RESULTS: A parametric model based on the Gompertz distribution generalized best. Variables included in the model were systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, diabetes mellitus, body mass index and smoking status. Compared with patients not on HAART, the estimated CHD hazard ratio (HR) for patients on HAART was 1.46 (95% CI 1.15-1.86) for moderate and 2.48 (95% CI 1.76-3.51) for severe metabolic complications. CONCLUSIONS: The change in the risk of CHD in HIV-infected men starting HAART can be estimated based on typical changes in risk factors, assuming that HRs estimated using data from non-infected men are applicable to HIV-infected men. Based on this model the risk of CHD is likely to increase, but increases may often be modest, and could be offset by lifestyle changes.

Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study

BACKGROUND: Human immunodeficiency virus (HIV)-infected persons may be at increased risk for developing type 2 diabetes mellitus because of viral coinfection and adverse effects of treatment. METHODS: We studied associations of new-onset diabetes mellitus with hepatitis B virus and hepatitis C virus coinfections and antiretroviral therapy in participants in the Swiss HIV Cohort Study, using Poisson regression. RESULTS: A total of 123 of 6513 persons experienced diabetes mellitus during 27,798 person-years of follow-up (PYFU), resulting in an incidence of 4.4 cases per 1000 PYFU (95% confidence interval [CI], 3.7-5.3 cases per 1000 PYFU). An increased incidence rate ratio (IRR) was found for male subjects (IRR, 2.5; 95% CI, 1.5-4.2), older age (IRR for subjects >60 years old, 4.3; 95% CI, 2.3-8.2), black (IRR, 2.1; 95% CI, 1.1-4.0) and Asian (IRR, 4.9; 95% CI, 2.2-10.9) ethnicity, Centers for Disease Control and Prevention disease stage C (IRR, 1.6; 95% CI, 1.04-2.4), and obesity (IRR, 4.7; 95% CI, 3.1-7.0), but results for hepatitis C virus infection or active hepatitis B virus infection were inconclusive. Strong associations were found for current treatment with nucleoside reverse-transcriptase inhibitors (IRR, 2.22; 95% CI, 1.11-4.45), nucleoside reverse-transcriptase inhibitors plus protease inhibitors (IRR, 2.48; 95% CI, 1.42-4.31), and nucleoside reverse-transcriptase inhibitors plus protease inhibitors and nonnucleoside reverse-transcriptase inhibitors (IRR, 3.25; 95% CI, 1.59-6.67) but were not found for treatment with nucleoside reverse-transcriptase inhibitors plus nonnucleoside reverse-transcriptase inhibitors (IRR, 1.47; 95% CI, 0.77-2.82). CONCLUSIONS: In addition to traditional risk factors, current treatment with protease inhibitor- and nucleoside reverse-transcriptase inhibitor-containing regimens was associated with the risk of developing type 2 diabetes mellitus. Our study did not find a significant association between viral hepatitis infection and risk of incident diabetes.

Continuous subcutaneous insulin infusion therapy: effects on quality of life

To compare the diabetes-specific quality of life in subjects with type 1 diabetes treating their diabetes with multiple daily injections (MDI) to that of subjects on continuous subcutaneous insulin infusion (CSII).

[Treatment of hypertension in type 2 diabetes mellitus--2002 update]

Arterial hypertension and diabetes are potent independent risk factors for cardiovascular, cerebral, renal and peripheral (atherosclerotic) vascular disease. The prevalence of hypertension in diabetic individuals is approximately twice that in the non-diabetic population. Diabetic individuals with hypertension have a greater risk of macrovascular and microvascular disease than normotensive diabetic individuals. Hypertension is a major contributor to morbidity and mortality in diabetes, and should be recognized and treated early. Type 2 diabetes and hypertension share certain risk factors such as overweight, visceral obesity, and possibly insulin resistance. Life-style modifications (weight reduction, exercise, limitation of daily alcohol intake, stop smoking) are the foundation of hypertension and diabetes management as the definitive treatment or adjunctive to pharmacological therapy. Additional pharmacological therapy should be initiated when life-style modifications are unsuccessful or hypertension is too severe at the time of diagnosis. All classes of antihypertensive drugs are effective in controlling blood pressure in diabetic patients. For single-agent therapy, ACE-inhibitors, angiotensin receptor blocker, beta-blockers, and diuretics can be recommended. Because of concerns about the lower effectiveness of calcium channel blockers in decreasing coronary events and heart failure and in reducing progression of renal disease in diabetes, it is recommended to use these agents as second-line drugs for patients who cannot tolerate the other preferred classes or who require additional agents to achieve the target blood pressure. The choice depends on the patients specific treatment indications since each of these drugs have potential advantages and disadvantages. In patients with microalbuminuria or clinical nephropathy, both ACE-inhibitors and angiotensin receptor blockers are considered first line therapy for the prevention of and progression of nephropathy. Since treatment is usually life-long, cost effectiveness should be included in treatment evaluation.

[Intensive insulin therapy--is it worth the effort?]

Diabetes mellitus is associated with a number of well-known, specific macro- and microvascular as well as neuropathic complications. The typical and specific association of microvascular and neuropathic complications with diabetes suggests a causal relationship with hyperglycemia or associated metabolic abnormalities. The results of the Diabetes Control and Complications Trial (DCCT) as well as other recent studies have demonstrated that in patients with insulin-dependent diabetes mellitus (IDDM) the incidence of retinopathy, nephropathy and neuropathy can be reduced by intensive treatment. Strategies of intensified insulin therapy and the clinical importance of improved diabetic control are outlined in view of these studies.

Persistent microalbuminuria in adolescents with type I (insulin-dependent) diabetes mellitus is associated to early rather than late puberty. Results of a prospective longitudinal study

Microalbuminuria is generally accepted to be highly predictive of overt diabetic nephropathy which is the leading cause of end-stage renal failure and, consequently, of death in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM). Its early identification and therapy are exceedingly important. We studied prospectively the occurrence of microalbuminuria (MA) in relation to puberty and its pubertal stages in 164 children and adolescent patients (83 girls and 81 boys) with IDDM. Analysing 100 healthy subjects, normal values for albumin excretion (range: 0-10.1 micrograms/min/1.73 m2) according to sex and the different pubertal stages were defined. No significant difference between the groups were noted and, therefore, 20 micrograms/min per 1.73 m2 (3 SD above the mean) was generally defined as cutoff for MA. Of the patients with IDDM studied, 20% (20 females and 12 males) developed persistent MA (22.1-448.2 micrograms/min/1.73 m2) during the study period of 8 years. The first manifestation of persistent MA was in 69% (13 females and 9 males) during stages of early and midpuberty; and in 28% (6 females and 3 males) at a late pubertal stage or at the end of puberty. The only child who developed MA before the onset of puberty (range: 23.5-157.4 micrograms/min/1.73 m2) was found to have dystopic kidney. Therefore, all patients with IDDM should be screened for MA regardless of diabetes duration, sex and level of diabetes control beginning at the very first stage of puberty and neither earlier nor after puberty as suggested by the American Diabetes Association.

[Will type I diabetes mellitus be treated with immunosuppressive drugs in the future?]

Even if the pathogenesis of type-I (insulin-dependent) diabetes mellitus is still not clarified in every detail, there is general agreement that this form of diabetes is induced by autoimmune mechanisms leading to beta-cell destruction. Therefore, it should theoretically be feasible to suppress the mechanism leading to type-I diabetes with appropriate and early immunotherapy. The current clinical data clearly document that the rate and duration of remissions in patients with newly diagnosed type-I diabetes can be increased significantly using appropriate immunosuppressive regimens. However, before these therapies can become standard therapy of type-I diabetes, the following important clinical requirements have to be fulfilled: the toxicity (especially to kidneys and beta-cells) has to be reduced, the patients should be diagnosed and treated in 'pre-diabetic' states, more selective immunosuppressive regimens have to be available in order to reduce the occurrence of treatment-associated lymphomas and neoplasias. Since accurate detection of 'pre-diabetic' patients is difficult and presents an immense logistic problem, it may take a long time before large-scale immunosuppressive therapies of type-I diabetes are feasible.

[Pancreas transplantation as treatment of diabetes mellitus]

Pancreatic transplantation is able to normalize blood glucose metabolism and achieve normoglycemia in a majority of patients with insulin-dependent diabetes mellitus. Hoping that normoglycemia will favorably influence development of late complications of diabetes, an increasing number of pancreas transplantations has been performed over the last years. However, the need for immunosuppressive therapy with its problems and possible complications confines pancreatic transplantation mainly to three groups of patients: patients who undergo kidney transplantation for diabetic nephropathy, patients who have already undergone kidney transplantation for diabetic nephropathy and, rarely, patients with extreme difficulties with metabolic control. The results of pancreatic transplantation have continuously improved over the last decade, and a limited number of controlled studies is providing some evidence of a favorable effect on late complications.