Assessment of insulin sensitivity during exercise training program in obese women. Comparison of simple indices with hyperinsulinemic euglycemic clamp technique

Insulin resistance is a key element of metabolic syndrome, which includes disturbances of glucose tolerance, obesity, hypertension, coronary heart disease dyslipidemia and many other defects. An important problem in scientific research is precise measurement of insulin sensitivity. The method considered "the gold standard" is glucose clamp, however, it is difficult to apply this method in large studies. Therefore, simple indices of insulin resistance are proposed. It remains unclear whether those indices are able to reflect changes occurring during insulin-sensitizing intervention. The aim of the present study was to assess the use of indirect indices for the changes in insulin sensitivity during exercise training and to compare those indices with results derived from clamp. Fourteen obese normoglycemic women participated in 12-week exercise training program, which included exercise performed on a bicycle ergometer, 5 days a week for 30 minutes. Insulin sensitivity (M/FFM value) before and after training was measured with hyperinsulinemic euglycemic clamp technique. Simple indices of insulin resistance were also assessed: fasting plasma insulin (INS), logarithm INS (log [INS]), homeostasis model assessment (HOMA), logarithm HOMA (log [HOMA]) and quantitative insulin sensitivity check index (QUICKI). Before training, all those indices were markedly related to M/FFM. After training, an increase in M/FFM was observed. None of the examined indices markedly changed after training. There was no correlations between changes of evaluated indices and in M/FFM during training, and no relationships of those parameters after training. Our study indicates that simple indices are not able to reflect changes occurring during insulin-sensitizing intervention.     

Dietary Natural Compounds and Vitamins as Potential Cofactors in Uterine Fibroids Growth and Development

An analysis of the literature generated within the past 20 year-span concerning risks of uterine fibroids (UFs) occurrence and dietary factors was carried out. A link between Vitamin D deficiency and UFs formation is strongly indicated, making it a potent compound in leiomyoma therapy. Analogs of the 25-hydroxyvitamin D3, not susceptible to degradation by tissue 24-hydroxylase, appear to be especially promising and tend to show better therapeutic results. Although research on the role of Vitamin A in the formation of fibroids is contradictory, Vitamin A-enriched diet, as well as synthetic retinoid analogues, may be preventative or limit the growth of fibroids. Unambiguous conclusions cannot be drawn regarding Vitamin E and C supplementation, except for alpha-tocopherol. Alpha-tocopherol as a phytoestrogen taking part in the modulation of estrogen receptors (ERs) involved in UF etiology, should be particularly avoided in therapy. A diet enriched in fruits and vegetables, as sources of carotenoids, polyphenols, quercetin, and indole-3-carbinol, constitutes an easily modifiable lifestyle element with beneficial results in patients with UFs. Other natural substances, such as curcumin, can reduce the oxidative stress and protect against inflammation in leiomyoma. Although the exact effect of probiotics on uterine fibroids has not yet been thoroughly evaluated at this point, the protective role of dairy products, i.e., yogurt consumption, has been indicated. Trace elements such as selenium can also contribute to antioxidative and anti-inflammatory properties of a recommended diet. In contrast, heavy metals, endocrine disrupting chemicals, cigarette smoking, and a diet low in antioxidants and fiber were, alongside genetic predispositions, associated with UFs formation.     

Synthesis and 5-HT1A/5-HT2A receptor activity of N-(4-arylpiperazin-1-yl)alkyl derivatives of 2-azaspiro([4.4]nonane and [4.5]decane-1,3-dione

Two series of N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane (5-10) and [4.5]decane-1,3-dione (11-16) derivatives were synthesized and their serotonin 5-HT1A and 5-HT2A receptor affinities were determined. Compounds with the methylene spacer (5-7 and 11-13) exhibited low 5-HT1A/5-HT2A receptor affinity, in contrast to their ethylene analogues regarded as potent 5-HT1A ligands, especially those containing a cyclohexane moiety (14-16; Ki = 5.1, 2.7 and 4.3 nM, respectively) in the 3-position of the pyrrolidine-2,5-dione ring. Moreover, derivatives with 3-chloro substituent (10 and 14) showed distinct affinity for 5-HT2A receptors. The functional activity of compounds 10, 14, 15 and 16 was tested in vivo in the commonly used animal models. In those experiments, the tested compounds showed features of agonists of pre- and postsynaptic (14), agonists of presynaptic and antagonists of postsynaptic (10, 15), or agonists of postsynaptic (16) 5-HT1A receptors. Additionally, 10 and 16 exhibited properties of potential 5-HT2A receptor antagonists. The above results suggested a crucial role of the spacer between the amide fragment and 4-arylpiperazine moiety, as well as of the size of the cycloalkyl ring at the 3-position of pyrrolidine-2,5-dione ring in functional 5-HT1A/5-HT2A properties.     

Brainstem system of hippocampal theta induction: The role of the ventral tegmental area

This article summarizes the results of studies concerning the influence of the ventral tegmental area (VTA) on the hippocampal theta rhythm. Temporary VTA inactivation resulted in transient loss of the hippocampal theta. Permanent destruction of the VTA caused a long‐lasting depression of the power of the theta and it also had some influence on the frequency of the rhythm. Activation of glutamate (GLU) receptors or decrease of GABAergic tonus in the VTA led to enhancement of dopamine release and increased hippocampal theta power. High time and frequency cross‐correlation was detected for the theta band between the VTA and hippocampus during paradoxical sleep and active waking. Thus, the VTA may belong to the broad network involved in theta rhythm regulation. This article also presents a model of brainstem–VTA–hippocampal interactions in the induction of the hippocampal theta rhythm. The projections from the VTA which enhance theta rhythm are incorporated into the main theta generation pathway, in which the septum acts as the central node. The neuronal activity that may be responsible for the ability of the VTA to regulate theta probably derives from the structures associated with rapid eye movement (sleep) (REM) sleep or with sensorimotor activity (i.e., mainly from the pedunculopontine and laterodorsal tegmental nuclei and also from the raphe). Synapse 69:553–575, 2015 . © 2015 Wiley Periodicals, Inc.     

Effect of intensive versus standard blood pressure control on major adverse cardiac events and serious adverse events: A bivariate analysis of randomized controlled trials

Background: Intensive blood pressure (BP) lowering may offer protective effects against major adverse cardiac event (MACE) but is also associated with a greater risk of a serious adverse event (SAE). The risk-benefit profile of intensive versus standard BP control has not been comprehensively assessed. Methods: Four studies were identified from a systematic literature search for randomized controlled trials comparing intensive versus standard BP lowering that reported both MACE and SAE endpoints. A previously described statistical approach was applied to characterize the efficacy-safety tradeoff of BP control. The bivariate outcome was computed to quantitatively assess the net clinical benefit (NCB) of intensive BP lowering as compared to standard treatment, with positive values indicating increased risks and negative values indicating decreased risks. Results: Data from the SPRINT trial demonstrated that intensive strategy was superior in MACE but inferior in SAE, thereby eroding the NCB (bivariate outcome: 0.33% [?0.50% to 1.21%]). Intensive strategy from the SPS3 trial fulfilled non-inferiority in both MACE and SAE but did not reach a favorable NCB (?1.31% [?2.25% to 0.01%]). The ACCORD trial suggested that intensive strategy was non-inferior in MACE but inferior in SAE (?0.19% [?0.79% to 1.37%]). Results from the VALISH trial were inconclusive for SAE but suggested non-inferiority in MACE (?1.19% [?3.24% to 0.68%]). Conclusions: Compared to the standard blood pressure target, pooled data from randomized controlled trials suggest that intensive strategy did not achieve a net clinical benefit when weighing the benefit of MACE reduction against the risk of SAE under the bivariate framework.Abbreviations: Blood pressure (BP), diastolic blood pressure (DBP), major adverse cardiac event (MACE), net clinical benefit (NCB), serious adverse event (SAE), systolic blood pressure (SBP).     

Intracerebroventricular infusion of neuropeptide Y up-regulates synthesis and accumulation of luteinizing hormone but not follicle stimulating hormone in the pituitary cells of prepubertal female lambs

Neuropeptide Y (NPY) is a putative neuroregulator of the reproductive axis in the central nervous system. In this study we evaluated the effects of central infusion of exogenous NPY on the secretory activity of pituitary gonadotrophic cells in prepubertal lambs. Immature female Merino sheep (n=12) were infused of Ringer solution (control) or 50 microg of NPY to the third ventricle for 5 min and then slaughtered 3 h later. Immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) cells were localised by immunohistochemistry using antibody raised against LHbeta and FSHbeta. Messenger RNA analyses were performed by in situ hybridisation using sense and antisense riboprobes produced from beta subunits of LH and FSH cDNA clones. The results were generated by computer image analysis to determine the area fraction occupied by immunoreactive and/or hybridising cells and optical density for immunostaining and hybridisation signal. LH in the blood plasma was determined by radioimmunoassay. It was found, that in the lambs infused with NPY the area fraction and optical density for immunoreactive LH cells and mRNA LHbeta-expressing cells increased significantly (P<0.001), compared to the vehicle-infused animals. The concentration of LH in the blood plasma did not differ between control and treated groups. The NPY infusions had no effect on the immunoreactivity of FSH cells or on expression of mRNA for FSHbeta. In conclusion we suggest that NPY may be an important component of mechanisms stimulating the synthesis and storage but not the release of LH in the pituitary gonadotrophs from prepubertal female sheep. In addition, this effect is specific for LH, no such effect was apparent on FSH.     

Near-ultraviolet light perceived by the retina generates the signal suppressing melatonin synthesis in the chick pineal gland-an involvement of NMDA glutamate receptors

Exposure of dark-adapted chicks to near ultraviolet (UV-A) light significantly decreased melatonin (MEL) content and the activity of serotonin N-acetyltransferase (AA-NAT; the penultimate and key regulatory enzyme in MEL production) in the pineal glands. Significant reduction in MEL level and AA-NAT activity was also found in pineals of animals whose heads were covered with black opaque tape, an observation suggesting that in the chicken UV-A light perceived by the eyes alone is capable of affecting MEL synthesis in the pineal gland. Covering the chick's eyes, in addition to the head, totally blocked the studied UV-A action. Although SCH 23390 (a selective D1-dopamine receptor antagonist), injected directly into both eyes at a dose of 10 nmol/eye, prevented the decline in pineal AA-NAT activity produced by retinal illumination with white light, the drug did not modify the UV-A light-evoked decrease in the enzyme activity. MK-801 (a selective antagonist of NMDA glutamate receptors; 1 nmol/eye) abolished the suppressive action of UV-A light on pineal AA-NAT activity, but it was inactive in the case of white light. Intraocularly injected sulpiride and CNQX (selective antagonists of D2-dopamine and AMPA/kainite glutamate receptors, respectively) had no effect on the actions of both UV-A and white light (acting on the eyes only) on pineal AA-NAT activity. It is concluded that in the chick retinally perceived UV-A light generates a signal which suppresses MEL production in the pineal gland. At the level of the retina, such signal does not involve dopamine, but is dependent on the stimulation of NMDA glutamate receptors.     

Epitope of the vaccine-type Bordetella pertussis strain 186 lipooligosaccharide and antiendotoxin activity of antibodies directed against the terminal pentasaccharide-tetanus toxoid conjugate

Lipooligosaccharides (LOS) isolated from Bordetella pertussis strains 186 and 606 were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-resolution magic angle spinning nuclear magnetic resonance (NMR). These analyses distinguished between the LOS of strains 186 and 606, suggesting that the structure of LOS in B. pertussis is heterogeneous. The pentasaccharide was selectively cleaved from LOS of B. pertussis strain 186, purified, and covalently linked to a monomer fraction of tetanus toxoid. Injection of rabbits with the neoglycoconjugate emulsified in complete Freund's adjuvant yielded immunoglobulin G antibodies that were reactive with the LOS. These antibodies reacted strongly with B. pertussis LOS possessing the complete dodecasaccharide, as determined by an enzyme-linked immunosorbent assay, immunoblotting, and flow cytometry with intact, live bacterial cells. The binding epitope within the pentasaccharide was investigated by saturation transfer difference (STD) NMR spectroscopy. Protons H-1 and H-4 of the terminal alpha-D-GlcpNAc and proton H-6 and protons of an N-methyl group at H-4 of 3-substituted beta-L-FucpNAc4NMe exhibited the largest saturation transfers. STD NMR experiments confirmed that the immunodominant epitope recognized by the antineoglycoconjugate antibodies is located predominantly in the distal trisaccharide of B. pertussis 186 LOS. The antipentasaccharide antibodies induced by the conjugate inhibited the secretion of tumor necrosis factor alpha, interleukin-6, and NO by LOS-stimulated J774A.1 cells.     

A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23

Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D?' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.