Water-pipe Smoking as a Risk Factor for Transmitting .

Unlabelled: A 20-year-old Swiss male presented at the emergency department with acute onset of febrile temperatures and hemoptysis and a 3-month history of productive cough. An X-ray and CT scan of the chest, sputum samples for acid-fast bacilli, polymerase chain reaction(PCR), and cultures for Mycobacteria revealed pulmonary infection with . None of the classical risk factors for tuberculosis were present, but the patient reported regularly smoking a water pipe.

Safety, Feasibility, and Efficiency of a New Cooling Device Using Intravenous Cold Infusions for Fever Control.

Background: Fever control plays a key role in therapy of patients with acute brain injury. The infusion of cold saline could serve as an alternative or additional method for targeted temperature management. However, it is difficult to estimate the amount of fluid required to achieve normothermia merely on the basis of body weight.

Cerebral venous thrombosis requiring invasive treatment for elevated intracranial pressure in women with combined hormonal contraceptive intake: risk factors, anatomical distribution, and clinical presentation.

OBJECTIVE Women taking combined hormonal contraceptives (CHCs) are generally considered to be at low risk for cerebral venous thrombosis (CVT). When it does occur, however, intensive care and neurosurgical management may, in rare cases, be needed for the control of elevated intracranial pressure (ICP). The use of nonsurgical strategies such as barbiturate coma and induced hypothermia has never been reported in this context.

Decision tree analysis in subarachnoid hemorrhage: prediction of outcome parameters during the course of aneurysmal subarachnoid hemorrhage using decision tree analysis.

OBJECTIVEThe aim of this study was to create prediction models for outcome parameters by decision tree analysis based on clinical and laboratory data in patients with aneurysmal subarachnoid hemorrhage (aSAH).METHODSThe database consisted of clinical and laboratory parameters of 548 patients with aSAH who were admitted to the Neurocritical Care Unit, University Hospital Zurich. To examine the model performance, the cohort was randomly divided into a derivation cohort (60% [n = 329]; training data set) and a validation cohort (40% [n = 219]; test data set).

Temperature variability in the day-night cycle is associated with further intracranial pressure during therapeutic hypothermia.

Background: To assess whether circadian patterns of temperature correlate with further values of intracranial pressure (ICP) in severe brain injury treated with hypothermia.

Methods: We retrospectively analyzed temperature values in subarachnoid hemorrhage patients treated with hypothermia by endovascular cooling. The circadian patterns of temperature were correlated with the mean ICP across the following day (ICP).

Lumbar total disc replacement: correlation of clinical outcome and radiological parameters.

Background: The objective of this study was to correlate various radiological parameters with clinical outcome in patients who had undergone lumbar total disc replacement (TDR). Lumbar TDR is one possible treatment option in patients with low back pain (LBP), offering an alternative to lumbar fusion. Favourable clinical outcome hinges on a number of radiological parameters, such as mobility, sintering, and-most importantly-accurate positioning of the implant.

Recruitment of brown adipose tissue as a therapy for obesity-associated diseases.

Brown adipose tissue (BAT) has been recognized for more than 20 years to play a key role in cold-induced non-shivering thermogenesis (CIT, NST), and body weight homeostasis in animals. BAT is a flexible tissue that can be recruited by stimuli (including small molecules in animals), and atrophies in the absence of a stimulus. In fact, the contribution of BAT (and UCP1) to resting metabolic rate and healthy body weight homeostasis in animals (rodents) is now well established.

Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.

The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood.

Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.

Background: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans.

Sirtuins--novel therapeutic targets to treat age-associated diseases.

Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation-deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas. Here, we discuss current knowledge and data that strengthens sirtuins as a druggable set of enzymes for the treatment of age-associated diseases, including activation of SIRT1 in type 2 diabetes.

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival.

Targeting PGC-1 alpha to control energy homeostasis.

The prevalence of Type 2 diabetes is increasing at an alarming rate in most parts of the world. Effective therapeutic drugs are urgently needed, not only to control the disease but also to prevent or delay its progression. Therapies that target the underlying pathogenesis could, in theory, hold such potential.

Resveratrol improves health and survival of mice on a high-calorie diet.

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival.

The obesity epidemic: current and future pharmacological treatments.

The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity drugs are approved for long-term use and only a few compounds are in clinical development.

Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors.

beta-Adrenergic control of stearoyl-CoA desaturase 1 repression in relation to sympathoadrenal regulation of thermogenesis.

Mice lacking beta-adrenoceptors, which mediate the thermogenic effects of norepinephrine and epinephrine, show diminished thermogenesis and high susceptibility to obesity, whereas mice lacking stearoyl-CoA desaturase 1 (SCD1), which catalyzes the synthesis of monounsaturated fatty acids, show enhanced thermogenesis and high resistance to obesity. In testing whether beta-adrenergic control of thermogenesis might be mediated via repression of the SCD1 gene, we found that in mice lacking beta-adrenoceptors, the gene expression of SCD1 is elevated in liver, skeletal muscle and white adipose tissue. In none of these tissues/organs, however, could a link be found between increased sympathetic nervous system activity and diminished SCD1 gene expression when thermogenesis is increased in response to diet or cold, nor is the SCD1 transcript repressed by the administration of epinephrine.

Adipose targets for obesity drug development.

The prevalence of obesity is increasing rapidly in most parts of the world and effective therapeutic drugs are urgently needed. The discovery of leptin in 1994 initiated a new understanding of adipose tissue function, and adipose tissue is now known to not only store and release fatty acids, but also to produce a wealth of factors that have an impact on the regulation of body weight and blood glucose homeostasis. Also, adipocytes express proteins that engage signalling pathways playing important roles in fuel substrate and energy metabolism.

Divergence of melanocortin pathways in the control of food intake and energy expenditure.

Activation of melanocortin-4-receptors (MC4Rs) reduces body fat stores by decreasing food intake and increasing energy expenditure. MC4Rs are expressed in multiple CNS sites, any number of which could mediate these effects. To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase.

GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization.

A critical defect in type 2 diabetes is impaired insulin-stimulated glucose transport and metabolism in muscle and adipocytes. To understand the metabolic adaptations this elicits, we generated mice with targeted disruption of the GLUT4 glucose transporter in both adipocytes and muscle (AMG4KO). In contrast to total body GLUT4-null mice, AMG4KO mice exhibit normal growth, development, adipose mass, and longevity.

Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.

The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1 alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism.

Leptin directly stimulates thermogenesis in skeletal muscle.

Using a method involving repeated oxygen uptake (MO(2)) determinations in skeletal muscle ex vivo, the addition of leptin was found to increase MO(2) in soleus muscles from lean mice. These effects were found to be inhibited by phosphatidylinositol 3-kinase inhibitors, absent in muscles from obese Lepr(db) mice which have the dysfunctional long form of leptin receptor, and blunted in muscles from diet-induced obese mice in the fed state but not during fasting. These findings indicate that leptin has direct thermogenic effects in skeletal muscle, and that these effects require both the long form of leptin receptors and phosphatidylinositol 3-kinase signalling.

Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes.

beta cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2's role in regulating insulin secretion.

Effects of estrous cycle and steroid replacement on the expression of leptin and uncoupling proteins in adipose tissue in the rat.

Among other actions, leptin has been suggested to increase energy expenditure and to modulate the menstrual cycle. In fact, the main effect of leptin seems to be modulating the sympathetic nervous system and gonadotropin-releasing hormone pulsatility. We investigated whether changes in the plasma steroid concentrations during the estrous cycle and after ovariectomy and steroid replacement can modulate plasma leptin levels, adipose tissue leptin mRNA expression, and some of the candidates for mediating energy expenditure (uncoupling proteins (UCP) 1, 2, and 3 mRNA) in white and brown adipose tissue.

Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance.

Previous reports indicate that the expression and/or activity of the protein-tyrosine phosphatase (PTP) LAR are increased in insulin-responsive tissues of obese, insulin-resistant humans and rodents, but it is not known whether these alterations contribute to the pathogenesis of insulin resistance. To address this question, we generated transgenic mice that overexpress human LAR, specifically in muscle, to levels comparable to those reported in insulin-resistant humans. In LAR-transgenic mice, fasting plasma insulin was increased 2.