Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption.

OBJECTIVE: Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS: Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS: SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ≈35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS: In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures.

Key role of estrogens and endothelial estrogen receptor α in blood flow-mediated remodeling of resistance arteries.

OBJECTIVE: Flow- (shear stress-)mediated outward remodeling of resistance arteries is involved in collateral growth during postischemic revascularization. As this remodeling is especially important during pregnancy, we hypothesized that estrogens may be involved. A surgical model eliciting a local increase in blood flow in 1 mesenteric resistance artery was used in 3-month-old ovariectomized female rats either treated with 17-ß-estradiol (E2) or left untreated. METHODS AND RESULTS: After 14 days, arterial diameter was greater in high-flow arteries than in normal-flow vessels. An ovariectomy suppressed high-flow remodeling, while E2 restored it. High-flow remodeling was absent in mice lacking the estrogen receptor α but not estrogen receptor ß. The kinetics of inflammatory marker expression, macrophage infiltration, oxidative stress, and metaloproteinases expression were not altered by the absence of E2 after 2 and 4 days, that is, during remodeling. Nevertheless, E2 was required for the increase in endothelial nitric oxide synthase expression and activation at day 4 when diameter expansion occurs. Finally, the impact of E2 on the endothelium appeared crucial for high-flow remodeling, as this E2 action was abrogated in mice lacking endothelial NOS, as well as in Tie2-Cre(+) ERα(f/f) mice. CONCLUSIONS: We demonstrate the essential role of E2 and endothelial estrogen receptor α in flow-mediated remodeling of resistance arteries in vivo.

Perception of Health-Care Professionals on Presumed Consent in Formulation of Proper Organ Transplantation Regulatory System.

Background: Owing to the advancement in organ transplantation, treating an individual with organ failure in today's world has become possible. However, organ transplantation is lagging in the absence of adequate organ donations. Shortage of organs for transplantation is a challenge to developing countries like Nepal and developed countries like the USA and UK. Despite various efforts to increase the rate of organ donation, the problem persists. The primary reason for the failure to accomplish adequacy in organ do-nation is the immediate dependency on an available donor. On top of that, reluctance to decide on organ donation after death, regarded as an onerous moment, at least by the general public, has another impact on the subject. Some countries have shifted while some are planning to change from an informed consent system to a presumed consent system, in which if an individual does not make any decision during life-time, it is presumed that his/her organ can be removed for organ transplantation after death. Objective: To perceive the perception of healthcare professionals of the tertiary care centre of eastern Nepal regarding the presumed consent system. Methods: Purposive sampling of 221 health care professionals (Faculties, Nursing In-charges, Lab-technicians, and Radiology technicians) participated in the study. Results: Most healthcare professionals (90.5%) support using a presumed consent system in Nepal and agree on considering the family's opinion in the decision-making for cadaveric organ donation. Conclusion: Most healthcare professionals have shown their perception in favors of presumed consent to support the increasing organ donation rate.

Development of a Valid and Reliable Questionnaire to Identify Professional Opinion Regarding Organ Transplantation System.

BACKGROUND: Currently, the Nepalese law permits organ donation by an individual who falls into the category of a "close relative" of the recipient. There is a need for expansion of the live organ donor pool beside close relatives. Different systems of organ transplantation are followed by several countries and the professional opinions that underpin these systems need to be studied. OBJECTIVE: To generate a questionnaire related to different organ transplant systems and validate it so that it can be used to collect mass professional opinions. METHODS: Item generation, item reduction, item scaling, and pretesting were used to develop a questionnaire. The final version of the questionnaire was reviewed by experts for its content validity and then was used twice for participants at a 20-day interval to calculate Cronbach's alpha for testing its internal consistency and Intra-class correlation for testing its test and retest reliability. RESULTS: The questionnaire was found to be valid and reliable with an overall Cronbach's alpha of 0.701. Intra-class correlation scores for each question in both test and retest were correlated. CONCLUSION: A valid and reliable questionnaire was developed that can be used to collect mass professional opinions to assist policy makers to establish a better organ transplant system.

Structural requirements of flavonoids to induce heme oxygenase-1 expression.

Population studies suggest cardiovascular health benefits of consuming fruits and vegetables rich in polyphenolic compounds such as flavonoids. We reported previously that the flavonoid quercetin protects arteries from oxidant-induced endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E gene knockout mice, with induction of heme oxygenase-1 (Hmox1) playing a critical role. The present study investigated the structural requirements of flavonoids to induce Hmox1 in human aortic endothelial cells (HAEC). We identified ortho-dihydroxyl groups and an α,ß-unsaturated system attached to a catechol as the key structural requirements for Hmox1 induction. Active but not inactive flavonoids had a low oxidation potential and prevented ascorbate autoxidation, suggesting that Hmox1 inducers readily undergo oxidation and that oxidized, rather than reduced, flavonoids may be the biological inducer of Hmox1. To test this hypothesis, we synthesized stable derivatives of caffeic acid (3-(3,4-dihyroxyphenyl)-2-propenoic acid) containing either ortho-dihydroxy or ortho-dioxo groups. Compared with the dihydroxy compound, the quinone analog induced Hmox1 more potently in HAEC and also provided enhanced protection to arteries of wild type animals against oxidant-induced endothelial dysfunction. In contrast, the quinone analog failed to provide protection against oxidant-induced endothelial dysfunction in arteries of Hmox1-/- mice, establishing a key role for Hmox1 in vascular protection. These results suggest that oxidized forms of dietary polyphenols are the likely inducers of Hmox1 and may explain in part the protective cardiovascular effects of diets rich in these compounds.

Seipin deficiency alters brown adipose tissue thermogenesis and insulin sensitivity in a non-cell autonomous mode.

Loss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2-/-) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic ß3 agonist treatment, Bscl2-/- mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2-/- mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2-/- BAT properties. Finally, Bscl2-/- BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals.

Dens Evaginatus: A Problem-Based Approach.

Dens evaginatus is an uncommon developmental anomaly of human dentition characterized by the presence of tubercle on the occlusal surface of mandibular premolars and lingual surface of anterior teeth. Due to occlusal trauma this tubercle tends to fracture thus exposing the pathway to the pulp chamber of teeth. This case report is about the presentation of dens evaginatus in mandibular premolars bilaterally; among them tooth 44 was associated with chronic apical periodontitis. Fractured tubercle of three premolars was sealed with composite resin. Root canal treatment was performed with tooth 44. Routine endodontic treatment did not result in remission of infection. Therefore, culture and sensitivity tests were performed to identify the cause and modify treatment plan accordingly. Triple antibiotic paste was used as an intracanal medicament to disinfect the root canal that resulted in remission of infection.

The cardiovascular effects of salidroside in the Goto-Kakizaki diabetic rat model.

Many factors, including hyperglycemia, hypertension, obesity, dyslipidemia, and a sedentary lifestyle, contribute to a high prevalence of cardiovascular disease. Specific vascular impairment treatments in the context of diabetes and vascular risk need to be improved. Salidroside is the primary active component of Rhodiola rosea and has documented antioxidative, cardioprotective, and vasculoprotective properties. The aim of this study was to test the hypothesis that salidroside has protective effects against hyperglycemia, hypertension, and vasodilation impairment in the Goto-Kakizaki (GK) rat model of diabetes. We evaluated cardiovascular parameters (e.g., daytime/nighttime systolic and diastolic blood pressure, heart rate, and activity), metabolic parameters (e.g., body weight, food and water consumption, serum fructosamine level, glucose tolerance), eNOS / phospho-eNOS expression level and in vitro vascular reactivity of aorta and second-order mesenteric arteries in Wistar-Kyoto (control) and GK (diabetic) rats treated with salidroside (40 mg/kg) or placebo (water) for 5 weeks. GK rats showed hypertension, marked glucose intolerance, and impaired endothelium-dependent and endothelium-independent vasodilation capacity. Salidroside showed beneficial effects on endothelial and non-endothelial vasodilation and likely acts on the endothelium and smooth muscle cells through the soluble guanylyl cyclase pathway. Despite its vascular effects, salidroside had no effect on blood pressure and heart rate in GK and control rats, it did not improve glucose metabolism or limit hypertension in the GK model of type 2 diabetes.

Osmotic delivery systems for the beta-adrenoceptor antagonists metoprolol and oxprenolol: design and evaluation of systems for once-daily administration.

The essential features and mode of action of oral osmotic drug delivery systems (Oros) for metoprolol fumarate and oxprenolol succinate are described. Critical aspects in the development of systems for once-daily administration of both drugs are discussed, and methods for evaluating in vitro release characteristics are presented. In vitro testing confirmed that drug delivery corresponded closely to the theoretical release behaviour predicted from the physicochemical and membrane permeability characteristics for both oxprenolol and metoprolol systems. In vitro release rates were also shown to be unaffected by pH, in vitro test procedures, dissolution media and long-term storage at different temperatures.