The G protein-coupled orphan receptor 146 (GPR146) was found to be highly expressed in murine and human adipose tissue. We revealed an adipose GPR146 increase during a 3-month weight reduction in our human MAINTAIN study. Therefore, we analyzed GPR146 correlations in MAINTAIN and metabolically characterized Gpr146-deficient mice (GPR146-/-).

Objective: The aim of this study was to assess the association of chronic kidney disease (CKD) with all-cause and cardiovascular (CV) mortality in patients surviving their first ischemic stroke and enrolled in the Croatian part of the ESH Stroke Survey. Design and method: The cohort consisted of 292 consecutive patients (171 m, mean age 64 y) admitted to UHC Zagreb and diagnosed with ischemic stroke between 2011–2014. The mean follow-up period was 6.3 years. Data were collected from medical records. CKD was defined as eGFR < 60 ml/min/1,73m2 (CKD-Epi). Mortality data were obtained from the Croatian National Public Health database. Results: Hypertension, smoking, diabetes, dyslipidemia and atrial fibrillation were diagnosed in 75%, 27.3%, 24.5%, 17.4%, 11.7%, respectively. CKD was detected in 51.7% (men vs women 41% vs 67%; p = 0.000001). CKD stages 1, 2, 3a, 3b, 4 and 5 were diagnosed in 6.8%, 41%, 31.8%, 14.7%, 3.4% and 1.7%, respectively. During the follow-up period, 91 patients (31.1%) died. The major cause of death was stroke (60.4%), followed by other causes (15.3%), cancer (14.2%) and CV diseases (9.8%). All-cause mortality was significantly higher in the CKD than in the non-CKD group (37.1% vs 21.2%: p = 0.0000) as were stroke mortality (24.6% vs. 15.1%; p = 0.0049) and composite CV mortality (stroke, coronary heart disease, heart failure) (42.7% vs 16.2%; p = 0.0015). In a linear multivariate regression model, age was the most important determinant of death (B −0.011 SE 0.202; Beta −0.27; p < 0.000000) followed by CKD (B −0.101 SE 0.058 Beta −0.109; p = 0.085). In a model including age, gender, systolic BP at the time of stroke and CKD (R2 = 0.323), the impact of CKD on mortality risk was 9%. Conclusions: CKD is highly prevalent in patients with ischemic stroke. It is associated with higher all-cause and CV mortality. CKD should be considered a risk and a prognostic factor in patients with ischemic stroke.

Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 A in the insulin-binding region and 4.2 A in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.

Background: Diabetic retinopathy is a main cause of blindness in industrialized countries and is accompanied by glial activation, vasoregression and neurodegeneration. Advanced glycation endproducts (AGEs) are important metabolits in diabetic patients and causing vascular and neuronal damages in the retina. MG, a reactive α-dicarbonacid and precursor of AGEs, modifies proteins and regulates gene expression in diabetes. However, the role of MG in diabetic retinopathy is unknown.

To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.

Die diabetische Retinopathie zeichnet sich durch Defekte in der neurovaskulären Einheit der Retina aus. Die zugrunde liegenden Schädigungsmechanismen schließen reaktive Intermediate und Wachstumsfaktor-abhängige Signalwege ein, sind aber bezüglich der Interaktionen von Metabolismus und Zellwachstum weitgehend unbekannt. Insbesondere der Beitrag von Hyperglykämie und Insulinresistenz ist nicht bekannt. Welchen Einfluss eine Hyperglykämie und/oder Hyperinsulinämie auf die Genexpression der Retina haben, soll hier durch geeignete Ratten-Modelle untersucht werden. Idealerweise lassen sich durch die Bestimmung der Genexpressionsmuster der Retina Rückschlüsse auf generelle systemische metabolische Störungen ziehen.

Obese Zucker-diabetic-fatty (ZDF) Ratten entwickeln einen Type-2 Diabetes Phänotyp mit initialer Hyperinsulinämie und langanhaltender Hyperglykämie. Typische mikrovaskuläre Spätschäden sind in diesem Modell experimentell gut belegbar. Fragestellung unserer Studie war, mit welchen molekukaren Veränderungen die experimentell noch weniger charaktieriserte Retinopathie in diesem Modell einhergeht.

INTRODUCTION Lipoprotein associated phospholipase A2 (Lp PLA2) represent new cardiovascular risk factor and potential treatment target. We aimed to analyze the epidemiological situation of this factor in Czech population. METHODS AND RESULTS The study population consisted from 1 962 subjects, a random samples of general population (postMONICA study), and from patients with manifest coronary or cerebrovascular disease (Czech samples of EUROASPIRE III survey). Lp PLA2 activity was estimated using commercial kits by diaDexus Inc. in frozen samples. Increased activity (by definition, i.e. > 195 nmol/ min/ ml) was observed in 21.1 % of sample, no apparent difference between subject with and without manifest vascular disease was found. Males showed higher Lp PLA2 activity, than females (179.6 vs 146, resp., p < 0.0001), while no substantial increase with age was observed. Taking Lp PLA2 activity > 195 as dependent variable, following independent variables entered the multiple logistic regression: male gender [with odds ratio 4.26 (3.26- 5.58)], low HDL cholesterol (i.e. < 1.0 mmol/ l in males or < 1.2 mmol/ l in females) [3.49 (2.62- 4.64)], LDLcholesterol > 2.5 mmol/ l [6.95 (4.79- 10.07)] and lipid lowering treatment [0.59 (0.44- 0.79)]. In subject without manifest vascular disease, 6.3 % of them showed co incidence of markedly increased Lp PLA2 activity with high conventional risk (SCORE > 10 %). Expanding this group by intermediate risk subjects (ie. with Lp PLA2 activity 152- 194 and/ or SCORE 5- 9.9 %) leads to increase of this prevalence to 28.9 % of primary prevention subjects. CONCLUSION Increased Lp PLA2 activity is in Czech population highly prevalent and with exception of lipid parameters, generally independent from conventional cardiovascular risk. However, up to 29 % of subject in primary prevention amalgamate increased Lp PLA2 activity with high conventional cardiovascular risk.

Die Aktivierung der Proteinkinase C spielt in der Hyperglykämie-vermittelten Gefäßschädigung bei diabetischer Retinopathie nach vorliegenden Daten eine Rolle. PKC-Aktivierung durch Hyperglykämie, reaktive Sauerstoffradikale und Diacylglycerol führen intraendothelial zur VEGF Hochregulation mit den möglichen Folgen der gestörten Blut-Retina-Schranke und der pathologischen Angiogenese.

Objective: The aim of our study was to assess longitudinal trends in major CV risk factors in a representative population sample of the Czech Republic.Methods: Three cross-sectional surveys of CV risk factors were conducted within the WHO MONICA project in six Czech districts in 1985 (n = 2570), 1988 (n = 2768), and 1992 (n = 2343). In 1997/98, 2000/01, and 2007/08, another three screenings for CV risk factors (a 1% random sample, aged 25-64, mean age 45 years) were conducted in the six original districts (n = 1990; 2055; and 2246, respectively).Results: Over a period of 22/23 years, there was a significant decrease in the prevalence of smoking in males (from 45.0 to 30.5%; p < 0.001) and no change in smoking habits in females. BMI increased in males and did not change in females. Both systolic and diastolic blood pressure decreased significantly in both genders, while the prevalence of hypertension declined only in females. Awareness of hypertension also rose as did the proportion of individuals treated by antihypertensive drugs in both genders. Hypertension control improved in either gender. A remarkable drop in total cholesterol was seen in both sexes (males: from 6.21 +/- 1.29 to 5.29 +/- 1.10 mmol/L; p < 0.001; females: from 6.18 +/- 1.26 to 5.30 +/- 1.06 mmol/L; p < 0.001).Conclusions: The striking improvement in CV risk factors documented between 1985 and 2007/8 most likely contributed to the decrease in CV mortality in the Czech Republic. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Reduced bioavailability of nitric oxide (NO) is a hallmark of diabetes mellitus-induced vascular complications. In the present study we investigated whether a pharmacological increase of endothelial NO synthase (eNOS) production can restore the impaired hindlimb flow in a rat model of severe diabetes.A model of diabetes mellitus was induced in male Sprague-Dawley rats by a single injection of streptozotozin. Rats were treated chronically with the eNOS transcription enhancer AVE3085 (10 mg [kg body weight](-1) day(-1); p.o.) or vehicle for 48 days and compared with controls. Endothelial function and arterial BP were investigated in vivo using an autoperfused hindlimb model and TIP-catheter measurement, respectively. Protein production of eNOS, total and phosphorylated vasodilator-stimulated phosphoprotein (VASP) were assessed in their quadriceps muscle tissue, whereas cyclic GMP (cGMP) concentrations were assessed in blood plasma. RNA levels of intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1) were measured by real-time PCR.Untreated diabetic rats showed significantly reduced quadriceps muscle contents of eNOS (-64%) and phosphorylated VASP (-26%) protein associated with impaired vascular function (maximum vasodilatation: -30%, p < 0.05) and enhanced production of ICAM-1 (+121%) and VCAM-1 (+156%). Chronic treatment with AVE3085 did not alter arterial BP or severe hyperglycaemia, but did lead to significantly increased production of eNOS (+95%), cGMP (+128%) and VASP phosphorylation (+65%) as well as to improved vascular function (+36%) associated with reduced production of ICAM-1 (-36%) and VCAM-1 (-58%).In a rat model of severe diabetes, pharmacological enhancement of impaired eNOS production and NO-cGMP signalling by AVE3085 restores altered hindlimb blood flow and prevents vascular inflammation.