Die Rolle des TEA/ATTS-Transkriptionsfaktors CaTEC1p bei der Hyphenbildung und Virulenz von Candida albicans

The ability of the human pathogenic fungus Candida (C.) albicans to change his cell morphology between a yeast and a Hypheform (dimorphism) is regarded as an important virulence property. In the course of such morphological development processes is the spatial and temporal expression of the phase-specific genes in fungi such as controlled in higher eukaryotes of transcription factors. In C. albicans, a new member of the family of the TEA / ATTS transcription factors have been identified [1, 2]. According to its functional homology to the Saccharomyces (S.) cerevisiae TEC1 this gene C. albicans TEC1 (CaTEC1) was called. CaTEC1 is predominantly in the hyphal phase of C. albicans expressed. Also has a homozygous catec1/catec1-Mutante in vitro defects in hyphae formation. These data already indicate that CaTEC1 fulfills an important regulatory role in the development of C. albicans hyphae. As part of the thesis presented here is also shown that C. albicans has deficiencies in the absence of CaTEC1 virulence. In catec1/catec1-Mutante be important virulence factors, such as the hyphen specific proteinase SAP4, SAP5 SAP6 and no longer expressed and Evasion from macrophages is suppressed in vitro. In a murine model of systemic candidiasis is catec1/catec1-Mutante the virulence of attenuated, although formed in vivo in the infected organs and on the vaginal epithelium, hyphen similar cell lines. Furthermore, it was shown that the morphogenetic defects and virulence deficiencies of C. albicans strains with mutations in the signaling cascades of hyphae formation which comprise Ras1p, a MAPK cascade and a cAMP-signaling pathway are compensated by the controlled overexpression of CaTEC1 . Moreover, the virulence of a C. albicans wild type strain is amplified by the CaTEC1 overexpression. From these results it could be concluded that the different signal transduction pathways converge on the transcription factor CaTec1p to ensure the activation of selected virulence gene, which are essential for the pathogenicity of C. albicans. The TEA / ATTS transcription factors have been attributed only regulatory functions in development processes. In this work, a member of this family was identified with the C. albicans transcription factor CaTec1p for the first time, the regulator a central role in virulence in microbial pathogenicity takes over

Evidence to support the use of vildagliptin monotherapy in the treatment of type 2 diabetes mellitus

The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, vildagliptin, as monotherapy have been widely confirmed in a large body of clinical studies of up to 2 years’ duration in various populations with type 2 diabetes mellitus. This paper reviews the data supporting the use of vildagliptin in monotherapy. Consideration based on baseline glycated hemoglobin levels and age is given to patient segments where metformin is not appropriate. In addition, although prediabetes is not an indication, this manuscript briefly reviews some of the existing data showing that the mechanisms at work in diabetic populations are active in patients currently classified as prediabetic, with impaired glucose tolerance or impaired fasting glucose. Finally, the rationale for vildagliptin dosing frequency in monotherapy is discussed. In summary, this review aims to define where in community practice the use of vildagliptin as monotherapy is most desirable, focusing on segments of the population with type 2 diabetes mellitus that might receive the greatest benefit from vildagliptin in the management of their disease

Efficacy of vildagliptin versus sulfonylureas as add-on therapy to metformin: comparison of results from randomised controlled and observational studies.

Randomised control trials (RCTs) do not always reflect real-life outcomes for glucose-lowering drugs. In this work we compared RCT and real-life data on the efficacy of the dipeptidyl peptidase-IV (DPP-4) inhibitor vildagliptin or sulfonylureas when added to metformin

Vildagliptin Reduces Glucagon during Hyperglycemia and Sustains Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes.

Context: The dipeptidyl peptidase-4 inhibitor, vildagliptin, inhibits glucagon secretion at hyperglycemia but appears to enhance glucagon counterregulation during hypoglycemia in type 2 diabetes.Objective:The objective of the investigation was to study whether vildagliptin also improves α-cell function in type 1 diabetes (T1D). Patients and Methods: The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 28 patients with C-peptide negative and antibody positive T1D [21 males, seven females, glycosylated hemoglobin 57.9 mmol/mol (7.5%)]. Patients received vildagliptin (50 mg twice a day) or placebo as an add-on to their insulin therapy for 4 wk each. On d 28 of the respective treatment period, patients were served a standard meal (500 kcal) to raise the circulating incretin hormone levels followed by a hyperinsulinemic hypoglycemic clamp at 2.5 mmol/liter. Main Outcome Measure: The increase in plasma glucagon levels during the 30-min hypoglycemic clamp (min 165-195 of the test) was measured.Results:During the meal, glucagon levels were lower with vildagliptin than with placebo (120 min area under the curve(glucagon) 2.4 ± 0.2 vs. 2.6 ± 0.2 nmol/liter × minutes, P = 0.022 for between group difference). In contrast, during hypoglycemia, the glucagon counterregulation was not reduced by vildagliptin (increase in glucagon 1.5 ± 1.0 pmol/liter with vildagliptin vs. 1.7 ± 0.8 pmol/liter with placebo, P = NS). In addition, the counterregulatory responses in epinephrine, norepinephrine, cortisol, and pancreatic polypeptide were not different between the treatments. During the 4-wk treatment period, vildagliptin reduced the mean glycosylated hemoglobin, whereas there was no change with placebo [between group difference was -3.4 ± 1.0 mmol/mol (-0.32 ± 0.09%; P = 0.002)] from baseline of 57.9 mmol/mol (7.5%). Conclusions: Vildagliptin, although inhibiting glucagon secretion during hyperglycemia, does not compromise the glucagon counterregulatory response during hypoglycemia in T1D

Vildagliptin therapy reduces postprandial intestinal triglyceride-rich lipoprotein particles in patients with type 2 diabetes

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Post-discharge prognosis of patients admitted to hospital for heart failure by world region, and national level of income and income disparity (REPORT-HF): a cohort study

Background: Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality. Methods: Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature. Findings: Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction [HFrEF] vs preserved ejection fraction [HFpEF]), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001). Interpretation: Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT. Funding: Novartis Pharma