Discovery and spectroscopy of the young jovian planet 51 Eri b with the Gemini Planet Imager.

Directly detecting thermal emission from young extrasolar planets allows measurement of their atmospheric compositions and luminosities, which are influenced by their formation mechanisms. Using the Gemini Planet Imager, we discovered a planet orbiting the ~20-million-year-old star 51 Eridani at a projected separation of 13 astronomical units. Near-infrared observations show a spectrum with strong methane and water-vapor absorption. Modeling of the spectra and photometry yields a luminosity (normalized by the luminosity of the Sun) of 1.6 to 4.0 × 10(-6) and an effective temperature of 600 to 750 kelvin. For this age and luminosity, "hot-start" formation models indicate a mass twice that of Jupiter. This planet also has a sufficiently low luminosity to be consistent with the "cold-start" core-accretion process that may have formed Jupiter.

Effects of long-acting somatostatin analogues on redox systems in rat lens in experimental diabetes.

The effects of long-acting somatostatin analogues, angiopeptin (AGP) and Sandostatin (SMS), on the early decline in the lens content of glutathione (GSH), ATP and NADPH and increase in sorbitol were studied in STZ diabetic rats, and comparison was made with the effect of insulin. Three factors prompted this study: (i) the known increase in IGF-1 in ocular tissue in diabetes and antagonistic effect of somatostatins, (ii) the known effect of IGF-1 in increasing lens aldose reductase and (iii) the lack of effect of somatostatins on diabetic hyperglycaemia, the latter enabling a differentiation to be made between effects of hyperglycaemia per se and site(s) of IGF-1/somatostatins. All four metabolites studied showed a significant restoration towards the normal control level after 7 days of treatment with AGP and SMS, and AGP was more effective on levels of GSH and ATP. A significant correlation was found between GSH and ATP across all groups at 7 days treatment. The redox state changes in diabetes include both NADP+/NADPH and NAD+/NADH in the conversion of glucose to sorbitol and via sorbitol dehydrogenase to fructose with a linked decrease in ATP formation via NAD+/NADH regulation of the glycolytic pathway. The interlinked network of change includes the requirement for ATP in the synthesis of GSH. The present study points to possible loci of action of somatostatins in improving metabolic parameters in the diabetic rat lens via effects on aldose reductase and/or glucose transport at GLUT 3.

G-CSF regulates hematopoietic stem cell activity, in part, through activation of Toll-like receptor signaling.

Recent studies demonstrate that inflammatory signals regulate hematopoietic stem cells (HSCs). Granulocyte colony-stimulating factor (G-CSF) is often induced with infection and has a key role in the stress granulopoiesis response. However, its effects on HSCs are less clear. Herein, we show that treatment with G-CSF induces expansion and increased quiescence of phenotypic HSCs, but causes a marked, cell-autonomous HSC repopulating defect associated with induction of Toll-like receptor (TLR) expression and signaling. The G-CSF-mediated expansion of HSCs is reduced in mice lacking TLR2, TLR4 or the TLR signaling adaptor MyD88. Induction of HSC quiescence is abrogated in mice lacking MyD88 or in mice treated with antibiotics to suppress intestinal flora. Finally, loss of TLR4 or germ-free conditions mitigates the G-CSF-mediated HSC repopulating defect. These data suggest that low-level TLR agonist production by commensal flora contributes to the regulation of HSC function and that G-CSF negatively regulates HSCs, in part, by enhancing TLR signaling.

Heavy alcohol use as a risk factor for severe outcomes among adults hospitalized with laboratory-confirmed influenza, 2005-2012.

We examined heavy alcohol use as a risk factor for severe influenza (intensive care admission or death) among hospitalized adults. In <65- and ≥65-year-olds, heavy alcohol use increased disease severity [relative risk (RR) 1.34; 95 % confidence interval (CI): 1.04-1.74, and RR 2.47; 95 % CI: 1.69-3.60, respectively]. Influenza vaccination and early, empiric antiviral treatment should be emphasized in this population.

Effects of long-term experimental diabetes on adrenal gland growth and phosphoribosyl pyrophosphate formation in growth hormone-deficient dwarf rats.

The availability of growth hormone (GH)-deficient dwarf rats with otherwise normal pituitary function provides a powerful tool to examine the relative role of hyperglycaemia and the reordering of hormonal factors in the hypertrophy-hyperfunction of the adrenal gland that is seen in experimental diabetes. Here, we examine the effects of long-term (6 months) experimental diabetes on the growth of the adrenal glands; their content of phosphoribosyl pyrophosphate (PRPP); and the activity of the PRPP synthetase, G6P dehydrogenase and 6PG dehydrogenase enzymes in GH-deficient dwarf rats compared to heterozygous controls. These parameters were selected in view of the known role of PRPP in both de novo and salvage pathways of purine and pyrimidine synthesis and in the formation of NAD, and in view of the role of the oxidative enzymes of the pentose phosphate pathway in both R5P formation and the generation of the NADPH that is required in reductive synthetic reactions. This study shows that GH deficiency prevents the increase in adrenal gland weight, PRPP synthetase, PRPP content and G6P dehydrogenase and 6PG dehydrogenase. This contrasts sharply with the heterozygous group that showed the expected increase in these parameters. The blood glucose levels of the groups of long-term diabetic rats, both GH-deficient and heterozygous, remained at an elevated level throughout the experiment. These results are fully in accord with earlier evidence from studies with somatostatin analogues which showed that the GH-insulin-like growth factor I (IGF-I)-axis plays a key role in the adrenal diabetic hypertrophy-hyperfunction syndrome.

Effects of long-acting somatostatin analogues on adrenal growth and phosphoribosyl pyrophosphate formation in experimental diabetes.

Adrenal growth and increased adrenal function occur in experimental diabetes. Previously, we have shown that phosphoribosyl pyrophosphate (PRPP) and PRPP synthetase increased rapidly between 3 and 7 days after induction of diabetes with streptozotocin (STZ), with less marked changes in enzymes of the pentose phosphate pathway. The present study examines the earlier phase of 1-3 days following induction of diabetes, seeking to elucidate whether control of PRPP production is a result of diabetic hyperglycaemia, or to a more general re-ordering of hormonal factors. To investigate this question, the role of insulin and two different long-acting somatostatin analogues, Angiopeptin and Sandostatin, were used in a well-established animal model. PRPP was chosen specifically as a target for these studies in view of its central role in nucleotide formation and nicotinamide mononucleotide synthesis via Nampt which is the rate-limiting step in the synthesis of NAD and which has been shown to have multiple roles in cell signalling in addition to its known function in glycolysis and energy production. Treatment with the somatostatin analogues ab initio effectively abolished the adrenal growth, the increase in PRPP formation and the rise of PRPP synthetase activity in the first 7 days of diabetes, without having any significant effect on blood glucose values. This suggests that elevated glucose per se is not responsible for the diabetic adrenal hypertrophy and implies that growth factors/hormones, regulated by somatostatin analogues, play a significant role in adrenal growth processes.

Long-term follow-up and survival of antiretroviral-naive patients with cryptococcal meningitis in the pre-antiretroviral therapy era, Gauteng Province, South Africa.

Cryptococcal meningitis (CM) is a major cause of death among HIV-infected persons in sub-Saharan Africa. We conducted a study to describe the long-term outcomes during the pre-antiretroviral post-ART therapy period. Enrolled cases were those detected through population-based surveillance in Gauteng Province, South Africa, and diagnosed during March-November 2002 and July-September 2003 from eight large hospitals representing academic, provincial and rural settings. Of 1089 case-patients diagnosed with CM, 721 (70%) survived to discharge. Among the 256 with follow-up information, 154 (60%) were established to have died, 44% of whom died as outpatients. Overall, the 14- and 90-day survival post-diagnosis was 68% and 41%, respectively. On Cox proportional hazards multivariable analysis, severe disease was associated with shorter survival time; having received any antifungal treatment for the cryptococcal episode was associated with increased survival time at follow-up. Although most patients in this cohort survived the initial hospitalization, only 41% were still alive three months after diagnosis, with nearly half of deaths occurring outside a hospital. These data are an important baseline from which to measure effectiveness of public health management of CM in South Africa.

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization.

Under normal conditions, the great majority of hematopoietic stem/progenitors cells (HSPCs) reside in the bone marrow. The number of HSPCs in the circulation can be markedly increased in response to a number of stimuli, including hematopoietic growth factors, myeloablative agents and environmental stresses such as infection. The ability to 'mobilize' HSPCs from the bone marrow to the blood has been exploited clinically to obtain HSPCs for stem cell transplantation and, more recently, to stimulate therapeutic angiogenesis at sites of tissue ischemia. Moreover, there is recent interest in the use of mobilizing agents to sensitize leukemia and other hematopoietic malignancies to cytotoxic agents. Key to optimizing clinical mobilizing regimens is an understanding of the fundamental mechanisms of HSPC mobilization. In this review, we discuss recent advances in our understanding of the mechanisms by which granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing agent, induces HSPC mobilization.

Age-related changes in the response of rat adipocytes to insulin: evidence for a critical role for inositol phosphoglycans and cAMP.

Adipose tissue plays a pivotal role in ageing and longevity; many studies, both human and animal, have focussed on the effects of food limitation. Here we present a new model based on striking differences between two 'normal' inbred strains of albino Wistar rats the Charles River (CR) and Harlan Olac (HO) that have marked differences in age-related accumulation of fat and insulin-stimulated rates of glucose incorporation into lipid in the epididymal fat pads (EFP). The incorporation [U-(14)C]glucose into lipid by adipocytes showed that the CR group had a twofold higher basal rate of lipogenesis and a greater response to insulin in vitro, exceptionally, adipocytes from CR group maintained the high response to insulin to late adulthood while retaining the lower EFP weight/100 g body weight. Inositol phosphoglycan A-type (IPG-A), a putative insulin second messenger, was 3.5-fold higher and cAMP significantly lower per EFP in the CR versus HO groups. Plasma insulin levels were similar and plasma leptin higher in CR versus HO groups. The anomaly of a higher rate of lipogenesis and response to insulin and lower EFP weight in the CR group is interpreted as the resultant effect of a faster turnover of lipid and stimulating effect of leptin in raising fatty acid oxidation by muscle, potentially key to the lower accumulation of visceral fat. The metabolic profile of the CR strain provides a template that could be central to therapies that may lead to the lowering of both adipose and non-adipocyte lipid accumulation in humans in ageing.

Engineered neuronal circuits shaped and interfaced with carbon nanotube microelectrode arrays.

Standard micro-fabrication techniques which were originally developed to fabricate semi-conducting electronic devices were inadvertently found to be adequate for bio-chip fabrication suited for applications such as stimulation and recording from neurons in-vitro as well as in-vivo. However, cell adhesion to conventional micro-chips is poor and chemical treatments are needed to facilitate the interaction between the device surface and the cells. Here we present novel carbon nanotube-based electrode arrays composed of cell-alluring carbon nanotube (CNT) islands. These play a double role of anchoring neurons directly and only onto the electrode sites (with no need for chemical treatments) and facilitating high fidelity electrical interfacing-recording and stimulation. This method presents an important step towards building nano-based neurochips of precisely engineered networks. These neurochips can provide unique platform for studying the activity patterns of ordered networks as well as for testing the effects of network damage and methods of network repair.

Reciprocal control of pyruvate dehydrogenase kinase and phosphatase by inositol phosphoglycans. Dynamic state set by "push-pull" system.

Reversible phosphorylation of proteins regulates numerous aspects of cell function, and abnormal phosphorylation is causal in many diseases. Pyruvate dehydrogenase complex (PDC) is central to the regulation of glucose homeostasis. PDC exists in a dynamic equilibrium between de-phospho-(active) and phosphorylated (inactive) forms controlled by pyruvate dehydrogenase phosphatases (PDP1,2) and pyruvate dehydrogenase kinases (PDK1-4). In contrast to the reciprocal regulation of the phospho-/de-phospho cycle of PDC and at the level of expression of the isoforms of PDK and PDP regulated by hormones and diet, there is scant evidence for regulatory factors acting in vivo as reciprocal "on-off" switches. Here we show that the putative insulin mediator inositol phosphoglycan P-type (IPG-P) has a sigmoidal inhibitory action on PDK in addition to its known linear stimulation of PDP. Thus, at critical levels of IPG-P, this sigmoidal/linear model markedly enhances the switchover from the inactive to the active form of PDC, a "push-pull" system that, combined with the developmental and hormonal control of IPG-P, indicates their powerful regulatory function. The release of IPGs from cell membranes by insulin is significant in relation to diabetes. The chelation of IPGs with Mn2+ and Zn2+ suggests a role as "catalytic chelators" coordinating the traffic of metal ions in cells. Synthetic inositol hexosamine analogues are shown here to have a similar linear/sigmoidal reciprocal action on PDC exerting push-pull effects, suggesting their potential for treatment of metabolic disorders, including diabetes.

Insight into the role of inositol phosphoglycans in insulin response and the regulation of glucose and lipid metabolism illustrated by the response of adipocytes from two strains of rats.

Differences in biochemical and hormone profiles between two strains of rats provide insights into the relationships between insulin response, inositol phosphoglycans and lipid metabolism in adipose tissue. The results suggest the apparent anomaly of a higher rate of lipogenesis and response to insulin with a lower fat pad weight in the Charles River vs. Harlan Olac group relates to: (i) enzyme pre-programming with IPG-A, (ii) faster turnover of lipid, (iii) effects of leptin and cAMP.

[Therapeutic penetrating keratoplasty for microbial keratitis].

BACKGROUND: Microbial keratitis is a potentially sight threatening disease. Most cases respond well to antimicrobial therapy. However, in cases that progress despite intensive medical therapy, an urgent therapeutic penetrating keratoplasty (TPKP) is required. AIM: To evaluate the indications and results of TPKP in Israel. METHODS: A retrospective study reviewed the TPKP performed at the Goldschleger Eye Institute, Sheba Medical Center, between 1990-2003. The study included 18 cases of at least one-year follow-up. RESULTS: The indications for TPKP included severe infectious keratitis unresponsive to medical treatment in 33% of the patients and severe corneal destruction in 66% of them. The infectious keratitis was diagnosed as bacterial keratitis in 44% of the patients, unidentified pathogen in 39%, mycotic in 11% and acanthamoeba in 6% of the patients. Risk factors in the patients with microbial keratitis requiring TPKP included: previous ocular disease in 39%, previous ocular surgery in 66%, systemic disorders in 28% and ocular risk factors in 28% patients. TPKP was successful in bacterial and acanthamoeba keratitis as far as the transparency of the graft and elimination of the infection and improvement of visual acuity. However, TPKP failed in mycotic and unidentified keratitis. The risk factors for failure included: previous ocular disease or surgeries, systemic disorders or large corneal grafts. CONCLUSIONS: Therapeutic penetrating keratoplasty is an important and effective therapeutic tool for intractable bacterial and acanthamoeba keratitis. Prognostic factors for graft success include lack of ocular disease or previous surgeries, lack of systemic disorders or small corneal graft size.

Optisol vs Dexsol as storage media for preservation of human corneal epithelium.

PURPOSE: To compare the efficacy of two storage media, Optisol GS and Dexsol, in preservation of donor corneal epithelium. METHODS: A total of 12 pairs of corneas not suitable for transplantation, all with intact epithelium, were used in this study, with one cornea of the pair stored in Optisol GS and its other counterpart in Dexsol. At each of three durations of storage--1, 2, and 4 days--four of these paired corneas were prepared for light microscopy and scanning and transmission electron microscopy. Another four pairs of control cornea were prepared in the same way and placed in universal fixative. MAIN OUTCOME MEASURES: Evaluation of the corneas was made by two observers masked as to the identity of the storage medium and length of storage. Loss of epithelial cells was evaluated by light microscopy. The attachment of the epithelium to the basement membrane,cellular integrity, intercellular junctions, and intracellular organelles were evaluated and compared by electron microscopy. RESULTS: The magnitude of epithelial loss correlated with the length of storage time. Control corneas maintained normal epithelium with preservation of all epithelial cell layers. Corneas stored for 1 day had minimal damage of the epithelium. Corneas stored for 2 days had a slight increase in epithelial damage, and corneas stored for up to 4 days showed a marked increase in epithelial damage. There were no significant differences between the two storage media. The basal cell layer was maintained in both the media at all time points, usually in good condition with mild-to-moderate damage in some cases. CONCLUSIONS: Loss of donor epithelium is related mainly to the length of storage and is similar in both Optisol GS and Dexsol. The storage time should be less than 4 days,especially when performing penetrating keratoplasty on patients with ocular surface disorders.

An investigation of the suitability of bra fit in women referred for reduction mammaplasty.

Reduction mammaplasty is rationed in NHS plastic surgery provision, despite abundant evidence that most women who undergo this operation obtain significant improvement in their physical health and quality of life. We suspected that women seeking reduction mammaplasty often wear ill-fitting bras, which may exacerbate some of their symptoms. Therefore, we studied 103 women who attended a nurse-run pre-assessment clinic, asking them what size bra they currently wore and then measuring them to see whether their bra size was correct. We also questioned bra manufacturers, designers and shop bra fitters about bra manufacture, sizing and fitting techniques, and we reviewed these findings. Of the 102 women suitable for inclusion in the study, all wore the wrong size bra. Their mean 'claimed' back measurement was 36 inches (range: 30-42 in.) and their mean cup size was F (range: C-J). We found that all but one underestimated their back measurement (by a mean of 4 in.; range: -2-10 in.) and overestimated their cup size (by a mean of three sizes; range: one size smaller to seven sizes larger) when compared with manufacturers' fitting guidelines. Multiple regression analysis used to assess the relationships of various factors to incorrect bra sizing showed a strong link (Pearson correlation=0.54; P<0.001) between obesity and inaccurate back measurement. The reasons why women with breast hypertrophy wear incorrectly fitting bras are discussed. We conclude that obesity, breast hypertrophy, fashion and bra-fitting practices combine to make those women who most need supportive bras the least likely to get accurately fitted bras, so exacerbating the symptoms for which they seek surgery.

Therapeutic value of eptifibatide at community hospitals transferring patients to tertiary referral centers early after admission for acute coronary syndromes. PURSUIT Investigators.

OBJECTIVES: We aimed to evaluate the benefits of the glycoprotein (GP) IIb/IIIa antagonist, eptifibatide, after patients with acute coronary syndromes (ACS) were admitted to hospitals that approach revascularization for ACS through early transfer to tertiary referral centers. BACKGROUND: Across a variety of hospital settings, GP IIb/IIIa inhibition, after patients were admitted to the hospital for non-ST segment elevation ACS, is associated with a reduction in death or myocardial infarction (MI) before and during a percutaneous coronary intervention. METHODS: The outcomes of 429 patients from 153 sites in the Platelet glycoprotein IIb/IIIa in unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, who were transferred during study drug infusion ("transfer patients"), were compared with those of 1,987 patients who either remained in the hospital at those sites or were transferred after study drug termination ("nontransfer patients"). RESULTS: The baseline characteristics of transfer and nontransfer patients were similar. Patients receiving eptifibatide were transferred less frequently than those receiving placebo (16% vs. 20%, p = 0.014). Transfer patients underwent more procedures and experienced a greater 30-day incidence of death or MI, as compared with nontransfer patients (21% vs. 12%, p = 0.001). Eptifibatide was associated with a reduction in death or MI through 30 days, independent of transfer status (2.5% absolute reduction), as well as for those transferred (5.5% absolute reduction). CONCLUSIONS: For patients with ACS admitted to community hospitals, eptifibatide is associated with a reduced need for transfer and improved clinical outcomes.

Comparison of medicine alone, coronary angioplasty, and left internal mammary artery-coronary artery bypass for one-vessel proximal left anterior descending coronary artery disease.

Despite the deleterious and sometimes catastrophic consequences of proximal left anterior descending (LAD) artery occlusion, there is a paucity of data to guide the treatment of patients with such disease. Our aim was to describe outcomes with medical therapy, angioplasty, or left internal mammary artery (LIMA) bypass grafting in patients with 1-vessel, proximal LAD disease. We retrospectively analyzed prospectively collected data from 1,188 patients first presenting only with proximal LAD disease at 1 center over 9 years. We assessed the rates of death, acute myocardial infarction, and repeat intervention by initial treatment over a median 5.7 years of follow-up. Patients undergoing angioplasty or LIMA bypass were more often men and had progressive or unstable angina; those receiving medical therapy had a lower median ejection fraction. Both revascularization procedures offered slightly better adjusted survival versus medicine (hazard ratio for angioplasty, 0.82; 95% confidence interval, 0.60 to 1.11; hazard ratio for bypass, 0.74; 95% confidence interval, 0.44 to 1.23). Bypass, but not angioplasty, was associated with significantly fewer composite end point events (death, infarction, or reintervention, p <0.0001), and angioplasty was associated with a higher composite event rate than bypass or medical therapy (p <0.0001 and p = 0.0003, respectively). The initial advantages of bypass and medicine over angioplasty diminished over time; angioplasty became more advantageous than medicine after 1 year (p = 0.05) and not significantly different from bypass. Treatment of 1-vessel, proximal LAD disease with medicine, angioplasty, or UMA bypass resulted in comparable adjusted survival. However, LIMA bypass alone reduced the long-term incidence of infarctions and repeat procedures.