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In polycystic ovary syndrome (PCOS) hyperandrogenism and metabolic dysfunction increase cardiovascular risk. Vitamin D3 deficiency is a common comorbidity in PCOS. Our aim was to examine the alterations of insulin-induced vasodilation and receptor expression in rat aorta in a PCOS model. Methods: Female Wistar rats were treated as follows: 1. vitamin D supplemented group (D+T−); 2. vitamin D deficient (D−T−), 3. vitamin D supplemented with transdermal testosterone application (D+T+) and 4. vitamin D deficient with transdermal testosterone (D−T+). Wire myograph was used for testing insulin relaxation of aorta rings in physiological salt solution and under NOS inhibition. Insulin (IR) and vitamin D receptor (VDR) density was examined by immunohistochemistry. Results: Insulin-induced vasodilatation of the aorta rings were significantly lower in both vitamin deficient compared to the vitamin supplemented groups (p < 0.05). NOS inhibition significantly reduce the relaxation. Aorta endothelial IR expression was significantly higher in the vitamin D deficient group, meanwhile in the testosterone-treated groups (D+T+; D−T+) the expression was significantly lower (Area%: D+: 0.830 ± 0.10; D+T+: 0.298 ± 0.06; D−: 1.364 ± 0.12; D−T+: 0.354 ± 0.15, p < 0.05 in D− & D+T+ & D−T+ vs D+. p < 0.01 D+T+ & D−T+ vs D−). VDR density was significantly higher in the vitamin D deficient groups in comparison to the supplemented groups (Area% VDR: D+: 41.56 ± 5.58 vs D−: 60.63 ± 5.23) Testosterone treatment have not any effect on VDR expression. Conclusion: Vitamin-D deficiency causes impaired insulin induced vasodilation. Increased IR density could not compensate altered insulin-induced relaxation.

Context: An in situ gelling liquid suppository is liquid at room temperature but forms a gel at body temperature. In our work, Metolose® SM-4000 (methylcellulose) is studied that basically shows thermal gelation at 68°C (2%, w/w). Objective: The objective was to study the potency of different factors (concentration, pH, additives) to change the value of thermal gelation temperature ( T t) for Metolose® to form an in situ gelling liquid suppository. Materials and methods: We studied the effect of Metolose® concentration, pH, and salts (sodium chloride, potassium chloride, sodium hydrogen carbonate, and sodium monohydrogen phosphate) on T t by viscosimetry. To choose the appropriate compound, in vitro drug release was examined. Rectal safety test was performed on rats in vivo after 12-hour application. Results: Increasing the Metolose® concentrations (0.5-4%, w/w), T t can be decreased, but it also altered the consistency of gel. pH does not affect the T t. The water-soluble salts allowed reducing the gelation temperature to 37°C. Sodium monohydrogen phosphate in 4.5% concentration was found to be the most appropriate. The impact of examined factors on in vitro drug release of piroxicam from the in situ-formed gel was characterized according to Fickian diffusion. Metolose® and the chosen salt did not cause any morphological damage on the rectal tissues. Discussion: According to our study, Metolose® has the physical and chemical potential to be used as base for liquid suppositories. [ABSTRACT FROM AUTHOR]

Capsaicin-sensitive extrinsic afferent nerves have been demonstrated to release biologically active substances in the gastrointestinal (GI) tract. This fact may be useful for identifying sensory transmitter substances in isolated organ experiments. In the GI tract of animals neuropeptides like tachykinins and calcitonin gene-related peptide (CGRP) mediate specific excitatory and inhibitory effects of capsaicin; some evidence indicates a participation of purinergic mechanisms as well. The human gut (especially the circular musculature) is powerfully relaxed by capsaicin, and this effect seems to have a completely different transmitter background (nitric oxide (NO) and maybe VIP, neither of them of intrinsic neuronal origin). We propose that NO may be a sensory neurotransmitter. The "local efferent" (mediator-releasing) effect of extrinsic afferent neurons can also be demonstrated in vivo, both in animals and man. Yet, nearly normal motility of the small and large intestines (i.e., the most "autonomous" part of the GI tract) is maintained in animals with functionally inhibited capsaicin-sensitive nerves. The importance of this system in regulating GI movements may be exaggerated under pathopysiological conditions, first of all inflammation. The afferent function of capsaicin-sensitive nerves plays a role in sympathetic reflexes, such as the inhibition of GI motility after laparotomy or by peritoneal irritation. [ABSTRACT FROM AUTHOR]

The activation of the poly(ADP-ribose) polymerase (PARP) plays an important role in the pathophysiology of various diseases associated with oxidative stress. We found increased amounts of poly(ADP) ribosylated proteins in diabetic kidneys of Lepr(db/db) (BKsJ) mice, suggesting increased PARP activity. Therefore, we examined the effects of two structurally unrelated PARP inhibitors (INO-1001 and PJ-34) on the development of diabetic nephropathy of Lepr(db/db) (BKsJ) mice, an experimental model of type 2 diabetes. INO-1001 and PJ-34 were administered in the drinking water to Lepr(db/db) mice. Both INO-1001 and PJ-34 treatment ameliorated diabetes-induced albumin excretion and mesangial expansion, which are hallmarks of diabetic nephropathy. PARP inhibitors decreased diabetes-induced podocyte depletion in vivo and blocked hyperglycemia-induced podocyte apoptosis in vitro. High glucose treatment of podocytes in vitro led to an early increase of poly(ADP) ribosylated modified protein levels. Reactive oxygen species (ROS) generation appears to be a downstream target of hyperglycemia-induced PARP activation, as PARP inhibitors blocked the hyperglycemia-induced ROS generation in podocytes. INO-1001 and PJ-34 also normalized the hyperglycemia-induced mitochondrial depolarization. PARP blockade by INO-1001 and PJ-34 prevented hyperglycemia-induced nuclear factor-kappaB (NFkappaB) activation of podocytes, and it was made evident by the inhibitor of kappaBalpha phosphorylation and NFkappaB p50 nuclear translocation. Our results indicate that hyperglycemia-induced PARP activation plays an important role in the pathogenesis of glomerulopathy associated with type 2 diabetes and could serve as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract Background Excessive use of antibiotics is worldwide the most important reason for development of antimicrobial resistance. As antibiotic resistance may spread across borders, high prevalence countries may serve as a source of bacterial resistance for countries with a low prevalence. Therefore, bacterial resistance is an important issue with a potential serious impact on all countries. Initiatives have been taken to improve the quality of antibiotic prescribing in primary care, but only few studies have been designed to determine the effectiveness of multifaceted strategies across countries with different practice setting. The aim of this study was to evaluate the impact of a multifaceted intervention targeting general practitioners (GPs) and patients in six countries with different health organization and different prevalence of antibiotic resistance. Methods GPs from two Nordic countries, two Baltic Countries and two Hispano-American countries registered patients with respiratory tract infections (RTIs) in 2008 and 2009. After first registration they received individual prescriber feedback and they were offered an intervention programme that included training courses, clinical guidelines, posters for waiting rooms, patient brochures and access to point of care tests (Strep A and C-Reactive Protein). Antibiotic prescribing rates were compared before and after the intervention. Results A total of 440 GPs registered 47011 consultations; 24436 before the intervention (2008) and 22575 after the intervention (2009). After the intervention, the GPs significantly reduced the percentage of consultations resulting in an antibiotic prescription. In patients with lower RTI the GPs in Lithuania reduced the prescribing rate by 42%, in Russia by 25%, in Spain by 25%, and in Argentina by 9%. In patients with upper RTIs, the corresponding reductions in the antibiotic prescribing rates were in Lithania 20%, in Russia 15%, in Spain 9%, and in Argentina 5%. Conclusion A multifaceted intervention programme targeting GPs and patients and focusing on improving diagnostic procedures in patients with RTIs may lead to a marked reduction in antibiotic prescribing. The pragmatic before-after design used may suffer from some limitations and the reduction in antibiotic prescribing could be influenced by factors not related to the intervention.