Fertility preservation and management of pregnancy in melanoma patients requiring systemic therapy.

Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients-from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.

[Insulin therapy-new insulin analogues]. / Insulintherapie ­ neue Insulinanaloga.

A multitude of short-acting and long-acting insulin analogues are currently available for the treatment of diabetes mellitus, which mimic physiological insulin secretion better than normal insulins. By the use of ultrarapid insulin analogues postprandial glucose increases can be significantly reduced. Newer long-acting insulin analogues have a very stable action profile and reduce the rate of hypoglycemia, especially nocturnal hypoglycemia, even more than first generation long-acting insulin analogues. Future developments focus on a further acceleration of prandial insulin effects with a simultaneous shorter effect time and an even more prolonged action of long-acting insulin analogues.

[Patients with a wearable cardioverter-defibrillator (WCD) : Prescription, function and rehabilitation support]. / Patienten mit einer tragbaren Defibrillatorweste ("wearable cardioverter-defibrillator", WCD) : Verschreibung, Wirkweise und Nachsorge.

Assessment of a permanent risk of life-threatening ventricular arrhythmia in patients with severely reduced left ventricular ejection fraction (LVEF <35%), e. g. after myocarditis, dilated cardiomyopathy, acute myocardial infarction, in patients with postpartum cardiomyopathy or implantable cardioverter-defibrillator (ICD) and cardiac resynchronization treatment plus defibrillator (CRT-D) infection with temporary explantation of the system is a medical challenge. This is time-consuming and unsafe because life-threatening ventricular arrhythmias may occur during the time of risk assessment. During this phase of risk stratification, a wearable cardioverter-defibrillator (WCD) is indicated. The WCD, which is usually worn by the patient for several months, combines continuous retrievable electrocardiogram (ECG) recordings with a reliable defibrillation capability. The prescription of a WCD guarantees safe rehabilitation procedures for patients following acute inpatient treatment. Rehabilitation measures in patients with a WCD are indicated because of the underlying systolic cardiac insufficiency due to severe myocardial disease. In almost half of the patients, who are potentially threatened by ventricular tachyarrhythmias or sudden cardiac death (SCD), the LVEF and heart failure symptoms improve under controlled medication within a few months. Thus, the risk of SCD is lowered so that in many cases a first line ICD implantation is no longer necessary. The purpose of this article is to provide recommendations for rehabilitation procedures of patients with a WCD. A review of the currently available data on WCD publications was carried out with special emphasis on the current national and international guidelines.

[Electrical cardioversion for non-valvular atrial fibrillation--underestimated risk for thromboembolic complications?]. / Elektrische Kardioversion bei nichtvalvulärem Vorhofflimmern--eine unterschätzte Gefahr für Thromboembolien?

Electrical cardioversions are performed to restore sinus rhythm in patients with non-valvular atrial fibrillation to improve symptoms. It has been known for decades that cardioversion without adequate anticoagulation for 3-4 weeks prior to and for 4 weeks after cardioversion results in thromboembolic complication of about 5%. It is much less known that cardioversion is also associated with a higher risk of thromboembolism (stroke, peripheral embolism) in patients treated with usual anticoagulation. The control arms (warfarin) of the three studies with the new anticoagulants dabigatran, rivaroxaban, and apixaban for the prevention of thromboembolism in non-valvular atrial fibrillation report a monthly thromboembolic risk of 0,13-0,2%. The risk for thromboembolic complication in the month following cardioversion is about three to six times higher than without cardioversion in patients with non-valvular atrial fibrillation treated with usual anticoagulation. Since most cardioversions are performed by DC shock it is not known whether electrical and pharmacological cardioversions carry the same risk for thromboembolism. Although thromboembolic complications do not often occur following cardioversion the increased risk due to this procedure should be acknowledged. Strict anticoagulation (e. g. INR value > 2,5) in the first 10-14 days following cardioversion could possibly minimize the risk of thromboembolism.

[Fitness to drive in patients with implanted cardioverter-defibrillator]. / Fahr-Eignung bei Patienten mit implantiertem Cardioverter-Defibrillator.

A physician who takes care for patients with implanted cardioverter-defibrillator (ICD) must inform them about their fitness to drive since these patients carry a higher risk for the occurrence of syncope or sudden cardiac death at the wheel. The driver's license law in Germany does not mention patients with ICD. The fitness to drive of patients with ICD is covered by the Advisory Board for Traffic Medicine in Germany (Bundesanstalt für Straßenwesen). These guidelines, however, are outdated and cannot be used to inform patients. Actually, these guidelines are under revision. Currently, the position paper of the German Society of Cardiology on "Fitness to drive and cardiovascular diseases" together with a recently published Dutch paper on this topic forms the basis of these recommendations. One week after ICD implantation for primary or one month after implantation for secondary prevention the patient may resume to drive. After adequate shocks the fitness to drive can be expected 2-4 months (3 months) later. The assessment of the fitness to drive has to be performed individually, taking into account also possible other influencing factors. In individual cases it appears to be justified that patients with ICD work as professional drivers.

The proteomic signature of insulin-resistant human skeletal muscle reveals increased glycolytic and decreased mitochondrial enzymes.

AIMS/HYPOTHESIS: The molecular mechanisms underlying insulin resistance in skeletal muscle are incompletely understood. Here, we aimed to obtain a global picture of changes in protein abundance in skeletal muscle in obesity and type 2 diabetes, and those associated with whole-body measures of insulin action. METHODS: Skeletal muscle biopsies were obtained from ten healthy lean (LE), 11 obese non-diabetic (OB), and ten obese type 2 diabetic participants before and after hyperinsulinaemic-euglycaemic clamps. Quantitative proteome analysis was performed by two-dimensional differential-gel electrophoresis and tandem-mass-spectrometry-based protein identification. RESULTS: Forty-four protein spots displayed significant (p < 0.05) changes in abundance by at least a factor of 1.5 between groups. Several proteins were identified in multiple spots, suggesting post-translational modifications. Multiple spots containing glycolytic and fast-muscle proteins showed increased abundance, whereas spots with mitochondrial and slow-muscle proteins were downregulated in the OB and obese type 2 diabetic groups compared with the LE group. No differences in basal levels of myosin heavy chains were observed. The abundance of multiple spots representing glycolytic and fast-muscle proteins correlated negatively with insulin action on glucose disposal, glucose oxidation and lipid oxidation, while several spots with proteins involved in oxidative metabolism and mitochondrial function correlated positively with these whole-body measures of insulin action. CONCLUSIONS/INTERPRETATION: Our data suggest that increased glycolytic and decreased mitochondrial protein abundance together with a shift in muscle properties towards a fast-twitch pattern in the absence of marked changes in fibre-type distribution contribute to insulin resistance in obesity with and without type 2 diabetes. The roles of several differentially expressed or post-translationally modified proteins remain to be elucidated.

Long-term graft function of cryostored alginate encapsulated rat islets.

Microencapsulation of pancreatic islets before transplantation is a promising approach to enable graft function in an immunocompetent recipient without immunosuppression. However, the insufficient availability of allogenic islet tissue is a major problem. One concept to overcome these shortcomings is the cryopreservation of encapsulated allogenic islets. Recently, we reported a gentle cryopreservation protocol for rat islets encapsulated in an alginate-based microcapsule system. Here, we report for the first time long-term transplantation data of these cryopreserved microencapsulated islets. We detected a stable graft function for more than 12 month (experiments still continuing) after transplantation of 2500 cryopreserved microencapsulated CD rat islets in streptozotocin-diabetic Wistar rats. Moreover, the glucose clearance rate during an IPGTT was well preserved up to 56 weeks after transplantation. In addition, hyperglycemic blood glucose levels after removal of rat islet grafts 12 and 56 weeks after transplantation confirmed the efficacy of the encapsulated islets. Finally, the retrieved encapsulated rat islets responded well with a 7-fold increase of insulin secretion to a glucose stimulus (12 and 56 weeks). In conclusion, our study demonstrates for the first time that cryopreservation of encapsulated rat islets is possible without substantial losses on graft function for a very long time.

[New differential therapy of type 2 diabetes]. / Neue Möglichkeiten der Differenzialtherapie des Typ-2-Diabetes.

A variety of different drugs with distinct approaches are available for the treatment of type 2 diabetes. Different treatment options, as well as new developments, are needed, since an acceptable quality of glucose control often requires drug combinations. Furthermore, type 2 diabetes is known as a heterogeneous disease that is characterized by different phases and individual characteristics, such as risk profiles and contraindications. In particular the impact of antihyperglycemic therapies on cardiovascular risk, body weight and the risk for hypoglycemia is important, but also the consideration of other co-morbidities, occupational and social aspects plays a role. So far, each therapeutic step is based on lifestyle-interventions and, if possible, metformin. Dipeptidylpeptidase 4 (DPP 4) inhibitors und glucagon-like peptid 1 (GLP 1) mimetics represent a new important tool in the differential therapy of type 2 diabetes. The advantage of incretin-based concepts is an improvement of glucose quality without induction of hypoglycemia and additional weight gain. It is, however, still not known, whether these advantages will still be seen in end point studies, e. g. concerning the cardiovascular risk.

In vitro phage display in a rat beta cell line: a simple approach for the generation of a single-chain antibody targeting a novel beta cell-specific epitope.

AIMS/HYPOTHESIS: The aim of the present study was to evaluate in vitro phage display in a beta cell line as a novel strategy for the isolation of beta cell-specific agents/biomarkers. METHODS: A single-chain antibody (SCA) library was pre-incubated with AR42J cells in order to eliminate SCAs with exocrine binding properties. It was then panned against INS-1 cells to select beta cell-targeted antibodies. RESULTS: By these means, we isolated a novel antibody, SCA B5, that binds rapidly (6.0 min) and with a 450-fold higher specificity to beta cells relative to exocrine cells. We estimated for SCA B5 a binding affinity in the low micromol/l range and 858 binding sites per beta cell. Confocal microscopy showed binding to the beta cell surface and confirmed subsequent internalisation. Moreover, staining of rat and human pancreatic tissue sections with SCA B5 suggests that the target epitope is presented in pancreatic beta cells of different origins. Infrared imaging revealed that labelling of beta cells with tracer SCA B5 is strictly dependent on beta cell mass. With competition assays we excluded insulin, glutamate decarboxylase, C-peptide and islet amyloid polypeptide as SCA B5 targets. In accordance with these predictions, SCA B5 homed in vivo highly selectively to normal beta cells and dysfunctional beta cells of diabetic rats. Moreover, accumulation of radioactively labelled SCA B5 in the pancreas was reduced by 80% after pre-injection with unlabelled SCA B5, thereby confirming the specific uptake in the pancreas. CONCLUSIONS/INTERPRETATION: We report a simple strategy for the generation of an SCA targeting a novel beta cell-specific epitope.

[Hepatomegaly und elevated transaminases in a 24-year-old with type I diabetes mellitus]. / Ausgeprägte Hepatomegalie und Transaminasenerhöhung bei 24-Jährigem mit Typ-1-Diabetes.

Poorly controlled type I diabetes mellitus can lead to excessive hepatic glycogen storage, which is accompanied by elevated transaminases and hepatomegaly. Few cases have been reported and described as glycogenic hepatopathy. There is characteristically no progression to fibrosis and cirrhosis and the symptoms are reversible with improved glycemic control.

Effects of a short-term improvement in glycaemic control on skin microvascular dysfunction in Type 1 and Type 2 diabetic patients.

AIMS: To investigate whether Type 1 and Type 2 diabetic patients differ in the effects of short-term improvement in glycaemic control on skin microvascular dysfunction. METHODS: Fourteen Type 1 and 14 Type 2 diabetic patients admitted to hospital to improve glycaemic control were investigated. Two age- and sex-matched groups of non-diabetic subjects served as controls. Capillary blood cell velocity (CBV) was assessed at the dorsal middle phalangeal area of the ring finger at rest and after 3-min arterial occlusion using laser Doppler anemometry. RESULTS: Comparing the measurements before and after improvement in glycaemic control, there were no significant changes in peak CBV, time to peak CBV and vasomotion amplitudes in Type 1 and Type 2 diabetic patients. On admission to hospital, time to peak CBV was prolonged in Type 1 (20.9 +/- 2.9 vs. 12.3 +/- 1.6 s, P = 0.003) and Type 2 diabetic patients (20.6 +/- 2.6 vs. 11.9 +/- 1.3 s, P = 0.021) compared with control subjects. After improvement in glycaemic control, there was no significant difference in time to peak CBV between Type 1 diabetic patients and their control subjects (17.8 +/- 4.2 vs. 12.3 +/- 1.6 s, P = 0.535). In Type 2 diabetic patients, the time to peak CBV increased non-significantly. CONCLUSIONS: Short-term improvement in glycaemic control did not appear to reverse microcirculatory dysfunction in Type 1 and Type 2 diabetes. However, there was an improvement of the delayed reactive hyperaemia in Type 1 diabetic patients.

Regulation of glucose-6-phosphatase gene expression by insulin and metformin.

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.

Influence of the duration of type 2 diabetes on early functional and morphological markers of atherosclerosis compared to the impact of coexisting classic cardiovascular risk factors.

AIM: The increased incidence of atherosclerotic macrovascular disease in type 2 diabetic patients is associated both with diabetes specific factors and coexisting classic cardiovascular risk factors as components of the metabolic syndrome. The aim of this study was to investigate the association between the duration of diabetes and early functional and morphological markers of atherosclerosis compared to the impact of coexisting cardiovascular risk factors such as hypertension, dyslipoproteinemia and cigarette smoking. METHODS: 63 type 2 diabetic patients and 25 non-diabetic control subjects were investigated. Lumen diameter of the brachial artery was measured by high-resolution ultrasound at rest and after 5-min suprasystolic arterial compression. Endothelium-independent dilatation of the brachial artery was measured 4 min after sublingual administration of 400 mug of glycerol trinitrate (GTN). Percentage change of arterial lumen diameter during reactive hyperemia (FMD%) and after GTN administration (GTN%) relative to the baseline measurements were calculated. The intima-media thickness (IMT) of the common carotid artery was measured bilaterally and averages were calculated. RESULTS: FMD% (3.8+/-0.8% vs. 6.9+/-0.9%; p<0.01) and GTN% (5.6+/-0.7% vs. 14.9+/-1.7%; p<0.01) were reduced in the diabetic patients compared to their control subjects. IMT was increased in diabetic patients compared to their controls (0.82+/-0.02 mm vs. 0.62+/-0.02 mm; p<0.01). The age-adjusted diabetes duration was inversely related to FMD% (r=-0.27; p=0.016). On multiple regression analysis including packyears, hypertension, hypercholesterolemia, and hypertriglyceridemia, only diabetes duration remained a significant independent determinant of FMD. GTN% and IMT were not associated with diabetes duration, packyears, hypertension, hypercholesterolemia, and hypertriglyceridemia when all variables were taken into account. CONCLUSION: The present data lend support to the suggestion that diabetic specific factors compared to coexisting cardiovascular risk factors such as hypertension, hyperlipoproteinemia, and smoking are of major importance for the pathogenesis of endothelial dysfunction in type 2 diabetes, because only the diabetes duration was shown to be related to endothelium-dependent vasodilation when all variables were taken into account.

[The metabolic syndrome]. / Das metabolische Syndrom.

The "metabolic syndrome" consists of some common risk factors for cardiovascular diseases: central obesity, diabetes mellitus, hyperlipidaemia and hypertension. The metabolic syndrome (MTS) leads to increased morbidity and mortality and to higher direct and indirect healthcare costs. The MTS can be diagnosed using the NCEP/ATP III criteria. The prevalence of the MTS in Germany is estimated at 23.8% and is expected to rise further, due to increasing obesity among children and adolescents. Studies have shown that the MTS leads to increased cardiovascular and total mortality and thus to a decreased life expectancy. Studies estimating the total costs of MTS are missing, but after addition of the costs for all the risk factors it is assumed that MTS costs amount to 5% of total healthcare costs. This is the result of the more frequent demand of health services and longer hospitalisation of patients with MTS. Even moderate weight loss can decrease the rates of morbidity and healthcare costs.

[New concepts in the treatment of type 2 diabetes]. / Neue Konzepte in der Behandlung des Typ-2-Diabetes.

The development of a variety of new substances will considerably expand the therapeutic choices in the treatment of type 2 diabetes. In 2006, the endocannabinoid receptor blocker Rimonabant has been approved for the treatment of type 2 diabetes in Germany. This compound has led to significant reductions of body weight along with improvements of HbA1c levels and lipid profiles, but the lack of health insurance coverage limits its large scale use in germany. In April 2007, the first members of the GLP 1 analogues/incretin mimetics (exenatide, Byetta) and DPP 4 inhbitors (sitagliptin, Januvia) have become available for the treatment of type 2 diabetes in Germany. Both drugs have significantly lowered HbA1c levels in clinical studies. In addition, the incretin mimetics have caused a progressive reduction of body weight, while the DPP 4 inhibitors have been rather weight neutral. Sitagliptin can be administered orally, whereas exenatide has to be injected subcutaneously. Neither the DPP 4 inhibitors, nor the incretin mimetics have led to the development of hypoglycaemia, unless combined with sulfonylureas. Overall, the introduction of these new drug classes will certainly broaden our therapeutic choices in the management of type 2 diabetes. The long-term effects of these drugs on the development of diabetic complications in long-term trials remains to be awaited.

Synthesis and evaluation of a glibenclamide glucose-conjugate: a potential new lead compound for substituted glibenclamide derivatives as islet imaging agents.

The search for novel SUR1-ligands originates from the idea to influence the in vivo behaviour by adding new structural moieties to the glibenclamide structure while preserving its binding affinity. Important application of novel conjugates might be their use as radioactively labelled tracer probes in the non-invasive investigation of the islet mass. It is known that the imaging quality of a tracer could be improved by increasing its hydrophilicity, which leads to a reduced plasma protein binding and diminished the unspecific uptake by various organs. In this study the glucose molecule was chosen as a substitute of glibenclamide to enhance hydrophilicity. As expected glucose conjugation leads to a 12-fold increase of the hydrophilicity. In vitro evaluation showed that the conjugate binds with high affinity to SUR1. Interestingly, in vivo the hypoglycaemic action of the conjugate was of significant shorter duration compared to glibenclamide. In accordance, the conjugate was cleared much faster from the blood stream, due to a significant lower plasma protein binding. In conclusion, glycosylation proved to be a powerful tool for the development of a high affinity glibenclamide ligand with completely different pharmacodynamics. Therefore, the glucose-conjugate could be a potential lead compound for the design of substituted glibenclamide derivatives as islet imaging ligands.