Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis.

BACKGROUND AND PURPOSE: Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19. METHODS: We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I2 statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194. RESULTS: Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I2  = 0%, P = 0.82). CONCLUSIONS: Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke.

Bariatric surgery - a dermatologic perspective.

Bariatric surgery has become a standard option in morbid obesity for patients not responding to conventional treatment. A major and stable weight loss can be achieved. Since obesity and weight loss may affect skin diseases, we performed this review to analyse the impact of bariatric surgery on a number of skin diseases. We categorized the skin diseases into three main groups: (i) diseases with a possible benefit from bariatric surgery, (ii) diseases that may develop after bariatric surgery and (iii) diseases that may persist. We hope that dermatologists will achieve an updated knowledge of benefits and possible hazards of this type of surgically induced weight loss.

Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio.

OBJECTIVE: We hypothesized that genes within recently identified loci associated with waist-hip ratio (WHR) exhibit fat depot-specific mRNA expression, which correlates with obesity-related traits. METHODS: Adipose tissue (AT) mRNA expression of 6 genes (TBX15/WARS2, STAB1, PIGC, ZNRF3 and GRB14) within these loci showing coincident cis-expression quantitative trait loci was measured in 222 paired samples of human visceral (vis) and subcutaneous (sc) AT. The relationship of mRNA expression levels with obesity-related quantitative traits was assessed by Pearson's correlation analyses. Multivariate linear relationships were assessed by generalized linear regression models. RESULTS: Whereas only PIGC, ZNFR3 and STAB1 mRNA expression in sc AT correlated nominally with WHR (P<0.05, adjusted for age and sex), mRNA expression of all studied genes in at least one of the fat depots correlated significantly with vis and/or sc fat area (P ranging from 0.05 to 4.0 × 10(6), adjusted for age and sex). Consistently, the transcript levels of WARS, PIGC and GRB14 were nominally associated with body mass index (BMI) (P ranging from 0.02 to 9.2 × 10(5), adjusted for age and sex). Moreover, independent of sex, obesity and diabetes status, differential expression between vis and sc AT was observed for all tested genes (P<0.01). Finally, the rs10195252 T-allele was nominally associated with increased GRB14 sc mRNA expression (P=0.025 after adjusting for age, sex and BMI). CONCLUSIONS: Our data including the inter-depot variability of mRNA expression suggests that genes within the WHR-associated loci might be involved in the regulation of fat distribution.

Lipidomic profiling before and after Roux-en-Y gastric bypass in obese patients with diabetes.

Bariatric surgery is a well-established approach to improve metabolic disease in morbidly obese patients with high cardiovascular risk. The post-operative normalization of lipid metabolism has a central role in the prevention of future cardiovascular events. The aim of the present study therefore was to characterize changes of plasma lipidomic patterns, consisting of 229 lipid species of 13 lipid classes, 3 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients with and without diabetes. RYGB resulted in a 15-32% decrease of body mass index, which was associated with a significant reduction of total cholesterol (TC, -28.3%; P=0.02), LDL-cholesterol (LDL-C, -26.8%; P=0.03) and triglycerides (TGs, -63.0%; P=0.05) measured by routine clinical chemistry. HDL-cholesterol remained unchanged. The effect of RYGB on the plasma lipidomic profile was characterized by significant decreases of 87 lipid species from triacylglycerides (TAGs), cholesterol esters (CholEs), lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), phosphatidylethanolamine ethers (PEOs), phosphatidylinositols (PIs) and ceramides (Cers). The total of plasma lipid components exhibited a substantial decline of 32.6% and 66 lipid species showed a decrease by over 50%. A direct correlation with HbA1C values could be demonstrated for 24 individual lipid species (10 TAG, three CholE, two LPC, one lysophosphatidylcholine ethers (LPCO) (LPC ether), one PC, two phosphatidylcholine ethers (PCO) and five Cer). Notably, two lipid species (TAG 58:5 and PEO 40:5) were inversely correlated with HbA1C. LPCO, as single whole lipid class, was directly related to HbA1C. These data indicate that RYGB-induced modulation of lipidomic profiles provides important information about post-operative metabolic adaptations and might substantially contribute to improvements of glycemic control. These striking changes in the human plasma lipidome may explain acute, weight independent and long-term effects of RYGB on the cardiovascular system, mental status and immune regulation.

Metagenomic sequencing of the human gut microbiome before and after bariatric surgery in obese patients with type 2 diabetes: correlation with inflammatory and metabolic parameters.

Roux-en-Y gastric bypass (RYGB) has become a prominent therapeutic option for long-term treatment of morbid obesity and type 2 diabetes mellitus (T2D). Cross talk and pathogenetic consequences of RYGB-induced profound effects on metabolism and gut microbiome are poorly understood. The aim of the present study therefore was to characterize intra-individual changes of gut microbial composition before and 3 months after RYGB by metagenomic sequencing in morbidly obese patients (body mass index (BMI)>40 kg m(-)(2)) with T2D. Subsequently, metagenomic data were correlated with clinical indices. Based on gene relative abundance profile, 1061 species, 729 genera, 44 phyla and 5127 KO (KEGG Orthology) were identified. Despite high diversity, bacteria could mostly be assigned to seven bacterial divisions. The overall metagenomic RYGB-induced shift was characterized by a reduction of Firmicutes and Bacteroidetes and an increase of Proteobacteria. Twenty-two microbial species and 11 genera were significantly altered by RYGB. Using principal component analysis, highly correlated species were assembled into two common components. Component 1 consisted of species that were mainly associated with BMI and C-reactive protein. This component was characterized by increased numbers of Proteobacterium Enterobacter cancerogenus and decreased Firmicutes Faecalibacterium prausnitzii and Coprococcus comes. Functional analysis of carbohydrate metabolism by KO revealed significant effects in 13 KOs assigned to phosphotransferase system. Spearmen's Rank correlation indicated an association of 10 species with plasma total- or low-density lipoprotein cholesterol, and 5 species with triglycerides. F. prausnitzii was directly correlated to fasting blood glucose. This is the first clinical demonstration of a profound and specific intra-individual modification of gut microbial composition by full metagenomic sequencing. A clear correlation exists of microbiome composition and gene function with an improvement in metabolic and inflammatory parameters. This will allow to develop new diagnostic and therapeutic strategies based on metagenomic sequencing of the human gut microbiome.

[Prevalence of undetected diabetes mellitus in invasive and interventional cardiology. Silent diabetes in the catheterization laboratory]. / Prävalenz unentdeckter Glukosestoffwechselstörungen in der invasiven und interventionellen Kardiologie. "Silent diabetes" im Herzkatheterlabor.

In most randomized controlled trials on revascularization therapy for patients with ischemic coronary artery disease (CAD), the diabetes prevalence ranges between 15% and 35%. However, the true prevalence of diabetes is probably considerably underestimated in these trials. The European heart survey diabetes and the heart published in 2004 supplied strong evidence that there are many additional cases of undetected prediabetics and diabetics in any cardiology patient cohort. The long-term outcome of newly detected diabetics was found to be comparable to patients with already known diabetes mellitus. With this in mind, the Dresden silent diabetes study investigated the prevalence of undetected diabetes mellitus by oral glucose tolerance testing (OGTT) and comparative HbA1c sampling in 1,015 patients admitted for coronary angiography. Patients with known diabetes were excluded from the study.According to the OGTT only 513 patients (51%) were classified with normal glucose tolerance (NGT), 10 (1%) with isolated impaired fasting glucose (IFG), 349 (34%) with impaired glucose tolerance (IGT) and 143 (14%) were diagnosed with newly detected diabetes mellitus (DM). According to the HbA1c measurements 588 patients (58%) were classified as normal, 385 (38%) as borderline and only 42 (4%) were diagnosed with diabetes (DM). There was a significant correlation between the extent of CAD and glycemic status as defined by the OGTT. The number of patients with IGT and diabetes increased with the extent of CAD (IGT group p<0.001, diabetes group p=0.01). However, no such correlation was observed when glycemic status was defined by HbA1c testing.Based on these results an OGTT should be routinely performed in patients with known or suspected coronary artery disease undergoing coronary angiography for diagnosis of diabetes, as HbA1c measurements alone appear to miss a substantial proportion of patients. These findings are of high clinical relevance with regard to optimal coronary revascularization procedure chosen in catheterization laboratories, preferably drug-eluting stents in cases of diabetes mellitus or newly detected diabetes mellitus and preferably coronary bypass surgery in diabetics with multi-vessel disease and high SYNTAX scores.

Oral glucose tolerance test and HbA1c for diagnosis of diabetes in patients undergoing coronary angiography: [corrected] the Silent Diabetes Study.

AIMS/HYPOTHESIS: The primary aim of this study was to compare the results of HbA(1c) measurements with those of an OGTT for early diagnosis of 'silent diabetes' in patients with coronary artery disease (CAD) undergoing angiography without prediagnosed diabetes. A secondary aim was to investigate the correlation between the extent of CAD and the glycaemic status of the patient. METHODS: Data from 1,015 patients admitted for acute (n = 149) or elective (n = 866) coronary angiography were analysed. Patients with known diabetes were excluded from the study. Using the OGTT results, patients were classified as having normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or diabetes. According to the results of the HbA(1c) measurements, patients were classified into three groups: normal (HbA(1c) <5.7% [<39 mmol/mol]), borderline (HbA(1c) 5.7-6.4% [39-47 mmol/mol]) and diabetes (HbA(1c) ≥6.5% [≥48 mmol/mol]). RESULTS: Based on the OGTT, 513 patients (51%) were classified with NGT, 10 (1%) with IFG, 349 (34%) with IGT and 149 (14%) were diagnosed with diabetes. According to HbA(1c) measurements, 588 patients (58%) were classified as normal, 385 (38%) as borderline and 42 (4%) were diagnosed with diabetes. The proportion of patients with IGT and diabetes increased with the extent of CAD (IGT ρ = 0.14, p < 0.001, diabetes ρ = 0.09, p = 0.01). No differences in HbA(1c) were seen among the groups with different extents of CAD (p = 0.652). CONCLUSIONS/INTERPRETATION: An OGTT should be performed routinely for diagnosis of diabetes in patients with CAD undergoing coronary angiography, since HbA(1c) measurement alone appears to miss a substantial proportion of patients with silent diabetes. A limitation of the study is that the OGTT was not performed before the angiography.

Reduced frequency of peripheral plasmacytoid dendritic cells in type 1 diabetes.

Dendritic cells (DCs) as antigen presenting cells play an important role in the initiation of an autoimmune disease like type 1 diabetes. Although there is evidence from the NOD mouse model that the function and frequency of DCs is altered in type 1 diabetes, there is little data on dendritic cells in human type 1 diabetes. We investigated peripheral blood myeloid (mDC1 and mDC2) and plasmacytoid dendritic cells (pDCs) in 15 type 1 diabetes patients with recent onset (within the last 3 months) of type 1 diabetes as well as in 15 patients with long standing (more than 5 years) type 1 diabetes by flow cytometry. Both groups were compared to age matched controls. We observed a significantly reduced percentage of pDCs of peripheral blood mononuclear cells (PBMCs) in both recent onset (0.13 vs. 0.25%, p=0.01) and long standing type 1 diabetes patients (0.13 vs. 0.24%, p=0.01). The absolute counts of pDCs per ml of blood were also significantly lower in both recent onset (mean 9560 vs. 13524, p=0.048) and long-standing diabetes (mean 7869 vs. 12202; p=0.05). The percentage of mDC1 was significantly diminished in recent onset (0.21% vs. 0.30%, p=0.034), but not in long standing type 1 diabetes. Our study demonstrates a persisting reduction of peripheral plasmacytoid DCs in type 1 diabetes patients. Since pDCs are involved in the control of immune responses and inducing regulatory cells, a reduced number of pDCs may predispose to an autoimmune reaction in the pancreatic islets.

Short-term changes in hsCRP and NT-proBNP levels in hypertensive emergencies.

Hypertension is associated with high cardiovascular risk. Both hsCRP and NT-proBNP also have been associated with elevated cardiovascular risk, at least in the long term. Much less is known about the short-term changes in these markers, for example, in hypertensive emergencies. In 59 consecutive patients with hypertensive emergencies, hsCRP and NT-proBNP were measured at baseline and at days 3-4 and 7-10 after admission. All patients with hsCRP levels above 10 mg/l during the study were excluded due to possible infections. We found elevated levels of hsCRP at baseline with a significant decline on days 3-4 (day 0: median 2.53 mg/l, days 3-4: median 1.65 mg/l [p<0.01 vs. baseline], days 7-10 median: 2.00 mg/l). Women had higher hsCRP levels than men, and patients with hypertensive cardiomyopathy by echocardiographic criteria had significantly higher hsCRP levels compared with patients without hypertensive cardiomyopathy throughout the study. NT-proBNP levels were clearly elevated at admission (median 158 ng/l) and declined highly significantly thereafter (day 3-4: 61 ng/l, p<0.0001 vs. baseline; day 7-10: 76 ng/l, p<0.0001 vs. baseline). Patients with hypertensive cardiomyopathy had higher NT-proBNP levels compared with those patients without. In hypertensive emergencies, NT-proBNP levels correspond to levels described in acute coronary syndrome and decline significantly under antihypertensive therapy. In addition, we found an acute decline in hsCRP in the short term after hypertensive emergencies. These data may have importance in the clinical setting of hypertensive emergencies and in the interpretation of epidemiological data.

Reduced frequency of peripheral dendritic cells in type 2 diabetes.

OBJECTIVE: It is a common clinical experience that type 2 diabetic patients are susceptible to opportunistic infections. The underlying reasons for this immune deficiency are not yet understood. Dendritic cells (DC) play a key role in initiating innate and adapted immune responses. DESIGN: In order to investigate changes in the DC compartment in the peripheral blood in type 2 diabetes, we analyzed blood from patients under poor and good metabolic control and compared them to healthy controls. PATIENTS: 5 mls of blood were collected from 15 healthy controls, 15 diabetic patients with an HbA1c <7.0 and 15 patients with an HbA1c >9.5%. Age range was 44-80 years. Patients were age-matched with the control group. MEASUREMENT: Blood DC were enumerated by flow cytometry after staining with antibodies against the blood dendritic cells antigens 1-3 (BDCA 1-3). This allows quantification of the DC subtypes: myeloid dendritic cells type 1 (mDC1, mDC2) and plasmacytoid dendritic cells (pDC). RESULTS: The relative and absolute frequency for both mDC1 and pDC was clearly diminished in patients with poor metabolic control as compared to healthy controls. In patients with good metabolic control the reduction of DC was less pronounced but still significant, particularly for mDC1. CONCLUSION: Hyperglycemic metabolism does affect the pool of peripheral DCs and leads to a reduction of both, mDC1 and pDC. Even patients considered to be under good metabolic control appear to have a reduced peripheral pool of DC.

Implementing sustainable sanitation concepts in Luxembourg: methodological approach and outcomes.

The present paper reports the approaches adopted to involve and inform stakeholders at various levels and to identify barriers and needed actions towards the implementation of sustainable sanitation concepts in Luxembourg. The study was split into two phases, starting with a workshop and interviews of important actors/professionals of the water sector such as public administrations, engineering companies and sanitary firms. The second phase consisted of a survey among end-users, developed in order to analyse enabling and disabling factors with respect to sustainable water use in households, and for which over 200 questionnaires were evaluated. Valuable conclusions for the project orientation were derived from these studies in terms of further needs for awareness raising, information and formation. The water professionals pointed to specific questions with respect to the feasibility of sustainable sanitation, such as hygienic concerns or maintenance issues for decentralised technology. A moderate financial commitment towards environmentally friendly techniques as well as a considerable lack of knowledge concerning innovative sanitation concepts was detected for end-users. Based on these findings, tailor-made communication strategies for key stakeholder groups were elaborated and pilot projects were initiated.

High frequency of unrecognized hypoglycaemias in patients with Type 2 diabetes is discovered by continuous glucose monitoring.

AIMS: To evaluate the use of a CGMS in the detection of hypoglycaemia in people with type 2 diabetes as an outpatient procedure. METHODS: 31 type 2 diabetic patients underwent glucose monitoring by means of CGMS (Medtronic MiniMed) for up to three days. Patients took part in at least four SMBG (self monitoring blood glucose) tests per day. After three days of monitoring, the CGMS data was downloaded and analysed by a physician to identify the frequency of hypoglycaemias (< or =50 mg/dl) and borderline values (51-70 mg/dl), their duration and distribution. Findings were discussed with the patient and if necessary treatment was adjusted. Eight weeks later, monitoring was repeated to asses the effects of the adjusted treatment. RESULTS: Average duration of sensor wear was 4.19 days. Correlation between the sensor and the SMBG readings was high. A high number of hypoglycaemias and borderline values were detected by the CGMS, most of them unrecognized by the patient. The frequency of hypoglycaemias and borderline values just as the duration could be significantly reduced from first to second monitoring. CONCLUSION: Using the CGMS in type 2 diabetic patients achieved the detection of numerous hypoglycaemias and borderline values both nocturnal and/or unnoticed. The CGMS provides accurate data, which cannot be achieved by conventional SMBG tests. That opens the possibility for treatment adjustment and improvement in metabolic control. For patients it provides a better understanding of the effects of insulin or oral agents, nutrition and exercises to their glucose level.

Increased prolactin in acute coronary syndromes as putative Co-activator of ADP-stimulated P-selectin expression.

Prolactin and leptin are newly recognized platelet co-stimulators due to enhancement of ADP-induced platelet aggregation. The aim of our study was to assess whether both hormones prolactin and leptin play a role as co-activators of platelet activation in patients with acute coronary syndromes. Twenty-one patients with acute coronary syndromes, 10 with stable angina pectoris and 10 controls were studied. Patients with acute coronary syndromes showed significantly higher prolactin and leptin values and a significant increased P-selectin expression on platelets compared to patients with stable angina pectoris or controls. However, patients with acute myocardial infarction as a subgroup of acute coronary syndromes showed the highest prolactin levels as well as ADP stimulated P-selectin expression. In the myocardial infarction subgroup prolactin values showed a significant correlation to ADP stimulated P-selectin expression on platelets (r (2)=0.41; p=0.025), whereas leptin was not correlated. Our data indicate an association between increased prolactin values and enhanced P-selectin expression on platelets in patients with acute coronary syndromes. Therefore, the stress hormone prolactin could be a co-stimulator of platelet activation in these patients. In contrast, the putative platelet activator leptin does not seem to play a major role in acute coronary syndromes.

Effects of growth hormone treatment on B-type natriuretic peptide as a marker of heart failure in adults with growth hormone deficiency.

OBJECTIVE: Patients with growth hormone deficiency (GHD) have abnormalities of cardiac structure and function. Growth hormone replacement (GHR) therapy can induce an increase in cardiac mass and improvement in left ventricular ejection fraction. B-type natriuretic peptide (BNP) levels have been successfully used to identify patients with heart failure and they correlate with both disease severity and prognosis. DESIGN: To investigate the effect of growth hormone replacement on BNP and inflammatory cardiovascular risk factors in adults with GHD we determined NT-proBNP and high sensitive C-reactive protein (CrP) before, 6 and 12 months after GHR. PATIENTS: Thirty adults (14 males, 16 females) with GHD mean age: 41.7+/-14.5 years (range: 17.2 to 75.4 years) were recruited from the German KIMS cohort (Pfizer's International Metabolic Database). RESULTS: During 12 months of GHR, a significant increase of IGF-1 (85.4+/-72.1 VS. 172.0+/-98 mug/dl; p=0.0001; IGF-1 SDS mean+/-SD: -3.85+/-3.09 VS. -0.92+/-1.82) was detectable. Mean baseline NT-proBNP was 112+/-130 pg/ml (range: 7 to 562). Twelve patients had normal BNP, whereas 18 revealed NT-proBNP values corresponding to those of patients with heart failure NYHA classification I (n=10), NYHA II (n=6) and NYHA III (n=2), respectively. Baseline BNP levels correlated significantly (p=0.044) with increased baseline CrP values. After 12 months of GHR, a significant decrease (p=0.001) in NT-proBNP levels mean: 68+/-81 pg/ml (range: 5 to 395) was detectable, associated with an improvement in NYHA performance status in 10 of the 18 with increased baseline NT-proBNP. CONCLUSIONS: Based on our study, approximately two-thirds of patients with GHD have increased NT-proBNP levels which may be useful as screening/diagnostic laboratory parameter for heart failure in such patients. GHR therapy decreases BNP levels in most patients with GHD.

Transient chemokine receptor blockade does not prevent, but may accelerate type 1 diabetes in prediabetic NOD mice.

The influx of autoreactive lymphocytes into the site of an autoimmune inflammation is mediated by certain chemokines. Autoimmune insulitis in type 1 diabetes is viewed as the result of destructive Th-1-cells and their corresponding antigen-presenting cells infiltrating the pancreatic islets. Blocking the chemokine receptors that mediate a Th-1-reaction has been shown to reduce autoimmunity in other experimental autoimmune disorders. We used the NOD mouse model to investigate the potency of anti-CCR2 and anti-CCR5 antibodies to inhibit the influx of Th-1-cells into the pancreatic islets, thus preventing diabetes onset. Eleven-week-old female NOD mice were treated with 500 microg of a monoclonal anti-CCR5 or anti-CCR2 or an isotype control antibody every third day over two weeks. We did not observe any preventive effect in either treatment group, but accelerated diabetes onset in the anti-CCR5 treated group. The number of autoantigen-specific Th-1-cells detected in the two treated groups was not reduced, but increased in the anti-CCR5 group. Redundancy within the chemokine system may account for this lack of prevention, or the intervention may have come too late in the disease process. Furthermore, blocking Th-1 chemokine receptors in the late autoimmune process may also inhibit regulatory T-cells, thus accelerating rather than preventing the disease.

Adrenomedullin is a novel marker of tumor progression in neuroendocrine carcinomas.

Adrenomedullin is a multi-functional polypeptide hormone. Its involvement in angiogenesis and vasodilator action support the hypothesis that adrenomedullin may be a secretory product of neuroendocrine tumors and contribute to tumor progression. Plasma levels of adrenomedullin were measured by radioimmunoassay in 46 patients with neuroendocrine carcinomas of the gastroenteropancreatic and bronchial system. Tissue expression of adrenomedullin was studied using monoclonal antibodies on pretreated paraffin embedded tissues in a group of 31 patients. Adrenomedullin plasma levels were significantly elevated in patients compared to healthy age-matched controls (p < 0.001). The highest plasma levels were found in patients with neuroendocrine carcinomas of bronchial, midgut and unknown origin. Patients with progressive disease had higher plasma levels than patients with stable disease (p < 0.001). Of the examined tumor samples, 55 % showed cytoplasmic staining for adrenomedullin > 5 % of the total tumor area. Plasma levels and tissue expression of adrenomedullin did not correlate with functional activity of the tumors or presence of the carcinoid syndrome, but did with tumor progression (p < 0.001 and p < 0.014). In conclusion, plasma and tissue expression of the angiogenic peptide adrenomedullin are predictive of tumor progression in patients with neuroendocrine carcinomas. Adrenomedullin might represent a useful prognostic marker in patients with neuroendocrine carcinomas.

[Management of diabetes mellitus in patients with angiopathies]. / Führung des Diabetes mellitus bei Angiopathien.

Nowadays, about 6-8% of the German population suffers from diabetes mellitus mostly type 2 but in patients with angiopathies about 30% have known diabetes and a further 30% have newly diagnosed diabetes or impaired glucose tolerance. Therefore diagnosis and therapy of glucose impairment play a central role for management of these patients. The antidiabetic therapy for secondary prevention of cardiovascular disease has to be embedded in a multifactorial concept with management of hypertension, hyperlipidemia and hypercoagulability. The management of diabetes following guidelines is a stepwise therapy with lifestyle interventions (diet, exercise) and oral drugs or insulin. Metformin has shown favorable outcome in overweight patients if aware of side effects; insulin is a safe drug in multimorbid patients and with planned interventions or operations. We are awaiting the results of multiple endpoint studies with newer antidiabetic drugs which may change our current concept of management of diabetes mellitus in these patients in the near future.

Differences in platelet activation by prolactin and leptin.

Hormones such as prolactin and leptin have recently been recognized as potent platelet aggregation co-activators, and have therefore been postulated as an additional risk factor for both arterial and venous thrombosis. Clinical situations exist that are known to be associated with higher leptin and/or prolactin levels (obesity, pregnancy, prolactinomas and anti-psychotic therapy respectively) and increased venous thrombosis or atherosclerosis risk. Therefore, we compared the impact of both hormones on platelet activation in vitro and in vivo. First, we investigated platelet aggregation and P-selectin expression after stimulation with 1,000 mU/l prolactin or 100 ng/ml leptin in five healthy volunteers in vitro. Prolactin revealed significant higher levels of P-selectin expression and platelet aggregation than leptin in all subjects. We also compared the correlation of prolactin and leptin values with the P-selection expression on platelets. Previously, we detected a significant correlation between prolactin values and ADP-stimulated P-selectin expression on platelets in pregnant women, patients with pituitary tumours, and patients on anti-psychotic therapy. In contrast, leptin did not correlate with P-selectin expression in all subject groups investigated. However, leptin correlated with body mass index in the subjects investigated. Our data indicate that prolactin has a stronger effect on platelet activation as leptin in vitro and in vivo. Moreover, our data suggest that the stronger effect of prolactin on ADP-stimulated platelet aggregation, compared to leptin, depends on higher stimulation of CD62p expression by prolactin.

TSH-receptor autoantibodies - differentiation of hyperthyroidism between Graves' disease and toxic multinodular goitre.

Previous studies indicate pre-existing subclinical Graves' disease in many patients with the scintigraphic diagnosis of toxic multinodular goitre type A, equivalent to the in Germany so-called disseminated thyroid autonomy. Furthermore, after radioiodine treatment an increase or the induction of TSH-receptor antibodies (TRAb) in patients with Graves' disease or toxic multinodular goitre has been repeatedly reported. The distinction between both hyperthyroid conditions, Graves' disease and toxic multinodular goitre type A, depends on the diagnostic power of the TSH-receptor antibody determination. Bioassays using CHO cell lines expressing the hTSH-receptor or a new TBII assay based on competitive binding to recombinant human TSH-receptor showed a higher sensitivity for the detection of TSH-receptor antibodies in patients with Graves' disease than previous assays using solubilized porcine epithelial cell membranes. In up to 50 % of patients with toxic multinodular goitre A without antithyroid drug pretreatment TSH-receptor antibodies were detectable with a high correlation between thyroid-stimulating antibodies in the bioassay and the h-TBII assay. Moreover, in a recent study the development of TSH-receptor antibodies after radioiodine treatment was detectable in 36 % of patients with toxic multinodular goitre type A, whereas TSH-receptor antibodies were not detectable in patients with toxic multinodular goitre type B or in patients with toxic adenoma. In conclusion, thyroid-stimulating antibodies in a bioassay or TSH-receptor antibodies detected with the h-TBII assay have the highest diagnostic power to differentiate Graves' disease from toxic multinodular goitre. Because of its less cumbersome assay technique the h-TBII should be performed in all patients with hyperthyroidism to differentiate Graves' disease from non-autoimmune hyperthyroidism such as toxic multinodular goitre to select the appropriate therapy for these patients.