Maternal hyperleptinemia is associated with male offspring’s altered vascular function and structure in mice

Children of mothers with gestational diabetes have greater risk of developing hypertension but little is known about the mechanisms by which this occurs. The objective of this study was to test the hypothesis that high maternal concentrations of leptin during pregnancy, which are present in mothers with gestational diabetes and/or obesity, alter blood pressure, vascular structure and vascular function in offspring. Wildtype (WT) offspring of hyperleptinemic, normoglycemic, Lepr db/+ dams were compared to genotype matched offspring of WT-control dams. Vascular function was assessed in male offspring at 6, and at 31 weeks of age after half the offspring had been fed a high fat, high sucrose diet (HFD) for 6 weeks. Blood pressure was increased by HFD but not affected by maternal hyperleptinemia. On a standard diet, offspring of hyperleptinemic dams had outwardly remodeled mesenteric arteries and an enhanced vasodilatory response to insulin. In offspring of WT but not Leprdb/+ dams, HFD induced vessel hypertrophy and enhanced vasodilatory responses to acetylcholine, while HFD reduced insulin responsiveness in offspring of hyperleptinemic dams. Offspring of hyperleptinemic dams had stiffer arteries regardless of diet. Therefore, while maternal hyperleptinemia was largely beneficial to offspring vascular health under astandard diet, it had detrimental effects in offspring fed HFD. These results suggest that circulating maternal leptin concentrations may interact with other factors in the pre- and post-natal environments to contribute to altered vascular function in offspring of diabetic pregnancie

Cardiac ß-adrenoceptor expression is markedly depressed in Ossabaw swine model of cardiometabolic risk

U Deniz DincerDepartment of Pharmacology, Ufuk University School of Medicine, Ankara, TurkeyAbstract: Ossabaw swine have a “thrifty genotype” and consumption of excess calories induces many classical components of the metabolic syndrome, including obesity, insulin resistance, impaired glucose tolerance, dyslipidemia, hyperleptinemia, and hypertension. Earlier studies indicate that the metabolic syndrome is associated with diminished cardiac function; however, to what degree this impairment is associated with alterations in myocardial ß1- and ß2-adrenoceptor (AR) expression has not been fully elucidated. Accordingly, the present study was designed to investigate the effects of the metabolic syndrome on cardiac ß1- and ß2-AR expression. Studies were conducted on left ventricular tissue samples obtained from control lean and chronically (50 weeks) high-fat-fed obese animals. Chronic feeding significantly increased fasting plasma insulin, total cholesterol, triglycerides, blood glucose, systolic and diastolic blood pressure, and heart rate. Real-time polymerase chain reaction revealed no significant alterations in cardiac ß1- and ß2-AR mRNA expression. In contrast, Western blot analysis revealed a significant decrease in ventricular ß1- and ß2-AR protein expression. This is the first report in a novel large animal model that induction of metabolic syndrome is accompanied by a significant reduction in cardiac ß1- and ß2-AR protein expression that could contribute to impaired cardiac function.Keywords: hypertension, metabolic syndrome, ß-AR, impaired cardiac functio

Comparative Clinical Effectiveness of Management Strategies for Sciatica: Systematic Review and Network Meta-Analyses

Background There are numerous treatment approaches for sciatica. Previous systematic reviews have not compared all these strategies together. Purpose To compare the clinical effectiveness of different treatment strategies for sciatica simultaneously. Study design Systematic review and network meta-analysis. Methods: We searched 28 electronic databases and online trial registries, along with bibliographies of previous reviews, for comparative studies evaluating any intervention to treat sciatica in adults, with outcome data on global effect or pain intensity. Network meta-analysis methods were used to simultaneously compare all treatment strategies and allow indirect comparisons of treatments between studies. The study was funded by the UK National Institute for Health Research (NIHR) HTA programme; there are no potential conflict of interests. Results Of 122 relevant studies, 90 were randomised controlled trials (RCTs) or quasi-RCTs. Interventions were grouped into 21 treatment strategies. Internal and external validity of included studies was very low. For overall recovery as the outcome, compared with inactive control or conventional care, there was a statistically significant improvement following disc surgery, epidural injections, non-opioid analgesia, manipulation, and acupuncture. Traction, percutaneous discectomy and exercise therapy were significantly inferior to epidural injections or surgery. For pain reduction as the outcome, epidural injections and biological agents were significantly better than inactive control, but similar findings for disc surgery were not statistically significant. Biological agents were significantly better for pain reduction than bed rest, non-opioids, and opioids, or radiofrequency treatment. Opioids, education/advice alone, bed rest, and percutaneous discectomy and radiofrequency treatment were inferior to most other treatment strategies; although these findings represented large effects, they were statistically equivocal. Conclusions For the first time many different treatment strategies for sciatica have been compared in the same systematic review and meta-analysis. This approach has provided new data to assist shared decision-making. The findings support the effectiveness of non-opioid medication, epidural injections and disc surgery. They also suggest that spinal manipulation, acupuncture, and experimental treatments such as anti-inflammatory biological agents, may be considered. The findings do not support the effectiveness of opioid analgesia, bed rest, exercise therapy, education/advice (when used alone), percutaneous discectomy or traction. The issue of how best to estimate the effectiveness of treatment approaches according to their order within a sequential treatment pathway remains an important challenge

MRI Assessment of Cardiomyopathy Induced by β1-Adrenoreceptor Autoantibodies and Protection Through β3-Adrenoreceptor Overexpression

The cardiopathogenic role of autoantibodies (aabs) directed against β1-adrenoreceptors (β1-AR) is well established. In mouse models, they cause progressive dilated cardiomyopathy (DCM) whose characterization with echocardiography requires prolonged protocols with numerous animals, complicating the evaluation of new treatments. Here, we report on the characterization of β1-aabs-induced DCM in mice using 11.7T MRI. C57BL/6J mice (n = 10 per group) were immunized against the β1-AR and left ventricular (LV) systolic function was assessed at 10, 18 and 27 weeks. Increase in LV mass/tibial length ratio was detected as the first modification at 10 weeks together with dilation of cavities, thereby outperforming echocardiography. Significant impairment in diastolic index was also observed in immunized animals before the onset of systolic dysfunction. Morphometric and histological measurements confirmed these observations. The same protocol performed on β3-AR-overexpressing mice and wild-type littermates (n = 8-12 per group) showed that transgenic animals were protected with reduced LV/TL ratio compared to wild-type animals and maintenance of the diastolic index. This study demonstrates that MRI allows a precocious detection of the subtle myocardial dysfunction induced by β1-aabs and that β3-AR stimulation blunts the development of β1-aabs-induced DCM, thereby paving the way for the use of β3AR-stimulating drugs to treat this autoimmune cardiomyopathy