Myocardial hypertrophy and enhanced left ventricular contractility in Zucker diabetic fatty rats.

Heart failure is known to be a complication of insulin-dependent (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) even in the absence of coronary heart disease or hypertension. The mechanisms leading to diabetic cardiomyopathy are unknown. The aim of the study was to characterize structural and functional alterations in hyperinsulinemic Zucker diabetic fatty (ZDF) rats treated with or without insulin. Diabetic animals showed a twofold increase in cardiomyocyte volume with increased left ventricular ANP but not BNP mRNA levels in spite of a reduced plasma renin activity (PRA) 2 months after onset of diabetes compared to nondiabetic littermates. These changes were associated with an increase in left ventricular performance as assessed by echocardiography. Insulin treatment led to a significant increase in body weight (BW), total heart weight, myocardial protein content, and left ventricular mass (LVM). Perivascular fibrosis and laminin thickness were significantly augmented in diabetic rat myocardium irrespective of insulin treatment, whereas interstitial collagen I and fibronectin were similarly found in diabetic and control myocardium. Initial stages of diabetic cardiomyopathy in hyperinsulinemic rats are characterized by cardiomyocyte hypertrophy and enhanced cardiac contractility. It is suggested that hyperinsulinemia may be involved in cardiac hypertrophy.     

Production of IL-12, IL-23 and IL-27p28 by bone marrow-derived conventional dendritic cells rather than macrophages after LPS/TLR4-dependent induction by Salmonella Enteritidis

Induction of the interleukin-12 (IL-12) cytokine family comprising IL-12, IL-23, IL-27, and IL-12p40 by intracellular pathogens is required for orchestration of cell-mediated immune responses. Macrophages (MΦ) have been shown to be a source of IL-12 following TLR4-dependent activation by Salmonella (S.). In this study another antigen-presenting cell type, the conventional dendritic cell (cDC), was analyzed and its cytokine responses compared with those of MΦ. We generated bone marrow-derived conventional dendritic cells (BMDC) and macrophages (BMMΦ) by incubating murine bone marrow cells with supernatants containing granulocyte/macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF), respectively. Stimulation of BMDC and BMMΦ with S. enterica serovar Enteritidis (SE) or LPS resulted in the release of IL-12 and IL-23 by BMDC but not by BMMΦ. Furthermore, BMDC secreted approx. 20-fold more IL-12p40 and IL-27p28 than BMMΦ. However, BMDC and BMMΦ produced similar levels of IL-10. Using BMDC originating from wild-type (wt), TLR2^def and TLR4^def mice, we show that in BMDC the induction of IL-12, IL-23, and IL-27p28 by SE is dependent on TLR4, whereas low-level production of p40 is also mediated by pattern recognition receptors (PRR) other than TLR4. Interestingly, LPS- and SE-provoked responses of BMDC were remarkably similar indicating that LPS is the primary danger molecule of SE. Taken together, our results point to cDC rather than MΦ as the major producers of the IL-12 family members during in vitro infection with SE. The mechanisms of recognition of SE, however, appear to be the same for cDC and MΦ     

Mechanical Activation of Pharmaceutical Systems

Mechanical activation has become a phenomenon of general significance in pharmaceutics. This report describes the extent of activation induced by relevant processes. With the use of the Eyring equation the transformation of structurally stored energy into chemical energy and the implied free enthalpy as well as the excess free enthalpy (activity) were evaluated from the rate of an indicator reaction. A comparison was made between different kinds of milling and tabletting with respect to pharmaceutical conditions. An optimization of these processes was derived.     

[3H] UK-14,304, a new agonist ligand of α2-adrenoceptors: a comparative study with human and rat tissue

Summary [³H] UK-14,304 was used to investigate ₂-adrenoceptors in rat brain and human platelets. Receptor pharmacology revealed that the ligand binds with high affinity to ₂-adrenoceptors. Psychoactive substances like neuroleptics, antidepressants, and-carbolines displace [³H] UK-14,304 from its binding sites in the lower micromolar range. A Hill number around 2 for most neuroleptics suggests a positive cooperativity with the ₂-adrenoceptors.Comparative studies with [³H] UK-14,304 and [³H] clonidine utilizing platelet membranes from human volunteers demonstrated that the former ligand is more suitable to investigate possible changes of ₂-adrenoceptors; [³H] UK-14,304 labels more receptors with a lower standard deviation, whereby the volume of the blood sample amounted to 35 ml instead of 50 ml required for [³H] clonidine as ligand. No sex differences of binding constants were detected, however an inverse correlation of maximum number of binding sites and affinity was found for female subjects with both ligands.No age-dependent changes of B_max and K_D-values were observed in the range of 24 to 59 years.     

Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects

Summary The effects of barbiturates on the GABA-receptor complex and the A₁ adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [³⁵S]t-butylbicyclophosphorothionate ([³⁵S]TBPT) and enhanced the binding of [³H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [³⁵S]TBPT binding, they showed varying degrees of maximal enhancement of [3H]diazepam binding; (±)methohexital was identified as the most efficacious compound for this enhancement. At the A₁ adenosine receptor all barbiturates inhibited the binding of [³H]N⁶-phenylisopropyladenosine ([³H]PIA) in a competitive manner. The comparison of the effects on [³H]diazepam and [³H]PIA binding showed that excitatory barbiturates interact preferentially with the A₁ adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/anaesthetic properties of barbiturates.Abbreviations GABA -aminobutyric acid - TBPT t-butylbicyclophosphorothionate 1073 - DMBB 5-(1,3-dimethyl)butyl-5-ethylbarbituric acid - MCB N-methyl-5-(1-cyclohexen-1-yl)-5-ethylbarbituric acid - MPPB N-methyl-5-phenyl-5-propylbarbituric acid - PIA N⁶-phenylisopropyladenosine Send offprint requests to M. J. Lohse at the above address     

Importance of Structural Free Space to the Solvent Power of Water

The contribution of structural free space to the solvent power of water was examined by a systematic modification of the geometric factor. Gaps and holes, available to foreign molecule occupation, are thought to be filled at low concentrations (max. 1 %) of aliphatic alcohols. The effect upon solvency reached approximately 10%, which suggests that spatial parameters affect solvent power. The results demonstrate the importance of solvent purity in the dissolution process.     

Specifics of chronic fatigue syndrome coping strategies identified in a French flash survey during the COVID-19 containment

The COVID-19 pandemic has focused health systems on supporting patients affected by this virus. Meanwhile in the community, many other contained patients could only use self-care strategies, especially in countries that have set up a long and strict containment such as France. The study aimed to compare coping strategies deployed by patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS; a poorly recognised syndrome) to those with better known and referenced chronic conditions. An online flash survey was conducted during the containment period in partnership with French Patients Organizations including ME/CFS national association. Therefore, ‘Brief COPE’ version of Lazarus and Folkman's Ways of Coping Check List has been adapted to the specificity of the containment. The survey was e-distributed in France from 15 April to 11 May 2020. Differences of coping strategies were analyzed using Wilcoxon–Mann–Withney test. Amongst 637 responses, 192 were complete, presenting a wide variety of diseases, including 93 ME/CFS. The latter have significantly different coping strategies than recognised diagnosed diseases patients: similar uses of emotion focused coping but less uses of seek social support and problem-focused copings. In conclusion, coping strategies are different for those who deal with the daily experience of ME/CFS, highly disabling chronic condition with diagnostic ambiguity, low degree of medical and social recognition and without treatment. Better understanding of those strategies is needed to provide the means for health promotion researchers, managers and clinicians, to accompany those patients.     

Vitamin D food fortification in European countries: the underused potential to prevent cancer deaths

European Journal of Epidemiology - Background: Meta-analyses of randomized controlled trials have shown that vitamin D supplementation reduces cancer mortality by 13%. Vitamin D fortification of...