Differential expression of skeletal muscle genes following administration of clenbuterol to exercised horses.

BackgroundClenbuterol, a beta2-adrenergic receptor agonist, is used therapeutically to treat respiratory conditions in the horse. However, by virtue of its mechanism of action it has been suggested that clenbuterol may also have repartitioning affects in horses and as such the potential to affect performance. Clenbuterol decreases the percent fat and increases fat-free mass following high dose administration in combination with intense exercise in horses. In the current study, microarray analysis and real-time PCR were used to study the temporal effects of low and high dose chronic clenbuterol administration on differential gene expression of several skeletal muscle myosin heavy chains, genes involved in lipid metabolism and the β2-adrenergic receptor. The effect of clenbuterol administration on differential gene expression has not been previously reported in the horse, therefore the primary objective of the current study was to describe clenbuterol-induced temporal changes in gene expression following chronic oral administration of clenbuterol at both high and low doses.ResultsSteady state clenbuterol concentrations were achieved at approximately 50 h post administration of the first dose for the low dose regimen and at approximately 18-19 days (10 days post administration of 3.2 μg/kg) for the escalating dosing regimen. Following chronic administration of the low dose (0.8 μg/kg BID) of clenbuterol, a total of 114 genes were differentially expressed, however, none of these changes were found to be significant following FDR adjustment of the p-values. A total of 7,093 genes were differentially expressed with 3,623 genes up regulated and 3,470 genes down regulated following chronic high dose administration. Of the genes selected for further study by real-time PCR, down-regulation of genes encoding myosin heavy chains 2 and 7, steroyl CoA desaturase and the β2-adrenergic receptor were noted. For most genes, expression levels returned towards baseline levels following cessation of drug administration.ConclusionThis study showed no evidence of modified gene expression following chronic low dose administration of clenbuterol to horses. However, following chronic administration of high doses of clenbuterol alterations were noted in transcripts encoding various myosin heavy chains, lipid metabolizing enzymes and the β2-adrenergic receptor

Postmortem Cerebrospinal Fluid Pleocytosis: A Marker of Inflammation or Postmortem Artifact?

The aim of this paper is to reassess the significance of postmortem cerebrospinal fluid pleocytosis. Published articles of CSF changes after death were reviewed, and reanalysis, in the light of modern views on the significance of bacterial postmortem isolates, was undertaken. There is theoretical and experimental evidence that the blood brain barrier to the movement of protein and cells is preserved in the first few hours after death. The number of mononuclear cells in the cerebrospinal fluid does rise in the first 24 hours after death, and this is most probably due to detachment of leptomeningeal lining cells. But the marked increase in lymphocyte counts seen in some cases of sudden infant death syndrome (SIDS) and in other deaths in the paediatric age range could well be a marker of inflammation

The effect of Staphylococcus aureus carriage in late pregnancy on antibody levels to staphylococcal toxins in cord blood and breast milk.

We investigated the effect of carriage of Staphylococcus aureus in the later stages of pregnancy on levels of antibody specific to the S. aureus toxins, staphylococcal enterotoxin B (SEB), staphylococcal enterotoxin C (SEC) and toxic shock syndrome toxin-1 (TSST-1), in cord blood and breast milk and also explored the relationship between levels of antibody in antenatal serum and cord blood. Nasopharyngeal swabs and stool samples were collected on two occasions, from 96 women, during the last 6 weeks of pregnancy. Samples were cultured and S. aureus isolates were identified. Antenatal and cord blood samples from the same women and their infants were analysed for IgG antibody to SEB, SEC and TSST-1 by enzyme-linked immunosorbent assay. Breast milk samples were analysed for IgA antibody to the same toxins. We found that S. aureus carriage in pregnancy is common and exposure to a toxin-producing isolate boosts immunity. Over 89% of women and infants have some protective antibody to the toxins, and antitoxin IgG levels are higher in cord blood samples compared with antenatal samples. Levels of cord blood IgG and breast milk IgA specific for the staphylococcal toxins vary. Some infants lack protection and could be at risk of toxin-induced disease

First Spitzer Space Telescope Observations of Magnetic Cataclysmic Variables: Evidence for Excess Emission at 3--8 microns

We present the first observations of magnetic cataclysmic variables with the Spitzer Space Telescope. We used the Infrared Array Camera to obtain photometry of the polars EF Eri, GG Leo, V347 Pav, and RX J0154.0-5947 at 3.6, 4.5, 5.8, and 8.0 $\mu$m. In all of our targets, we detect excess mid-infrared emission over that expected from the component stars alone. We explore the origin of this IR excess by examining bremsstrahlung, cyclotron emission, circumbinary dust, and L/T brown dwarf secondary stars. Bremsstrahlung and cyclotron emission appear unlikely to be significant contributors to the observed fluxes. At present, the most likely candidate for the excess emission is dust that is probably located in a circumbinary disk with an inner temperature near 800 K. However, a simple dust disk plus any reasonable low mass or brown dwarf-like secondary star is unable to fully explain the observed flux densities in the 3--8 $\mu$m region.Comment: Accepted to ApJ Letter

Efficacy of miniaturized imacor trans-esophageal echocardiografm (TEE) prove in mechanical circulatory support.

Application of the miniaturized ImaCor Trans-Esophageal Echocardiogram (TEE) probe in Heart Transplant/Mechanical Cardiac Support Patients In the surgical cardiac care unit (SCCU), therapeutic interventions often need to be done at the bedside, necessitating the need for a rapidly employable diagnostic tool for the cardiac intensivist. We report the clinical utility of the miniature ImaCor TEE-probe in guiding management of post heart transplant (H-Txp) and mechanical cardiac support patients (MCS) and describe the economic benefit of such a device. This is an IRB approved retrospective review of MCS/H-Txp patients who had ImaCor TEE monitoring in the SCCU of our institution in 2011. The effect on management was stratified into 3 categories; Major (tamponade/device selection/RV failure), Moderate (weaning support device guidance/ inotrope management/fluid management/hemodynamic instability) and Minor (line placement/useful data). The ImaCor TEE-Probe was utilized in a total of 34 patients, of which 21 were either supported by MCS or were post H-Txp. Of these, 13 were on ECMO, 9 were post-VAD, 3 supported by the Impella device and 4 were post-H-Txp. 6 patients were placed on more than 1 method of MCS and 1 patient was supported by ECMO after a H-Txp. The device had a Major effect on management in 4 patients (19%), Moderate effect in 13 (62%) and a Minor effect in 4 (19%). The cost difference between this new device and the traditional TEE is also significant (900 USD vs 4000 USD). Our institution saved in excess of 150,000 USD with the use of this device instead of traditional TEE. This figure did not include the ability of this probe to be used repeatedly within a 72-hour time frame, and the potential cost of going to the operating theatre for further management. This device has proven to be an invaluable new adjunct in the SCCU by allowing previously unobtainable continuous real time monitoring of the MCS/H-Txp patient. Use of the ImaCor TEE-probe provides the cardiac intensivist with timely important clinical data that improves patient care and is economically advantageous

Treatment-resistant depression and peripheral C-reactive protein.

BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.This work was funded by a Wellcome Trust strategy award to the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) Consortium which is also funded by Janssen, GlaxoSmithKline, Lundbeck and Pfizer. Recruitment of patients was supported by the National Institute of Health Research (NIHR) Clinical Research Network: Kent, Surrey and Sussex & Eastern. SRC consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). ETB is employed half-time by the University of Cambridge and half-time by GlaxoSmithKline; he holds stock in GSK. In the last three years PJC has served on an advisory board for Lundbeck. NAH consults for GSK. PdB, DJ and WCD are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson

Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study

For second-line antiretroviral therapy, WHO recommends a boosted protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs). However, concerns about toxicity and cross-resistance motivated a search for regimens that do not contain NRTIs. We aimed to assess whether boosted lopinavir plus raltegravir would be non-inferior to boosted lopinavir plus NRTIs for virological suppression in resource-limited settings