Vesicular Stomatitis Virus-Based Ebola Vaccine Is Well-Tolerated and Protects Immunocompromised Nonhuman Primates

Ebola virus (EBOV) is a significant human pathogen that presents a public health concern as an emerging/re-emerging virus and as a potential biological weapon. Substantial progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against EBOV. Among these prospects, a vaccine based on recombinant vesicular stomatitis virus (VSV) is particularly robust, as it can also confer protection when administered as a postexposure treatment. A concern that has been raised regarding the replication-competent VSV vectors that express EBOV glycoproteins is how these vectors would be tolerated by individuals with altered or compromised immune systems such as patients infected with HIV. This is especially important as all EBOV outbreaks to date have occurred in areas of Central and Western Africa with high HIV incidence rates in the population. In order to address this concern, we evaluated the safety of the recombinant VSV vector expressing the Zaire ebolavirus glycoprotein (VSVΔG/ZEBOVGP) in six rhesus macaques infected with simian-human immunodeficiency virus (SHIV). All six animals showed no evidence of illness associated with the VSVΔG/ZEBOVGP vaccine, suggesting that this vaccine may be safe in immunocompromised populations. While one goal of the study was to evaluate the safety of the candidate vaccine platform, it was also of interest to determine if altered immune status would affect vaccine efficacy. The vaccine protected 4 of 6 SHIV-infected macaques from death following ZEBOV challenge. Evaluation of CD4+ T cells in all animals showed that the animals that succumbed to lethal ZEBOV challenge had the lowest CD4+ counts, suggesting that CD4+ T cells may play a role in mediating protection against ZEBOV

Human Fatal Zaire Ebola Virus Infection Is Associated with an Aberrant Innate Immunity and with Massive Lymphocyte Apoptosis

Ebolavirus, especially the species Zaïre (ZEBOV), causes a fulminating hemorrhagic fever syndrome resulting in the death of most patients within a few days. In vitro studies and animal models have brought some insight as to the immune responses to ZEBOV infection. However, human immune responses have as yet been poorly investigated, mainly due to the fact that most outbreaks occur in remote areas of central Africa. Published studies, based on small numbers of biological samples have given conflicting results. We studied a unique collection of 50 blood samples obtained during five outbreaks that occurred between 1996 and 2003 in Gabon and Republic of Congo. We measured the plasma levels of 50 soluble factors known to be involved in immune responses to viral diseases. For the first time, using a cell staining technique, we analyzed circulating lymphocytes from ZEBOV-infected patients. We found that fatal outcome in humans is associated with aberrant innate immunity characterized by a “cytokine storm,” with hypersecretion of numerous proinflammatory mediators and by the noteworthy absence of antiviral interferon. The adaptive response is globally suppressed, showing a massive loss of CD4 and CD8 lymphocytes and the immune mediators they produce. These findings may have important pathological and therapeutic implications

Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease

Effect of intravenous metoclopramide on intraocular pressure: A prospective, randomized, double-blind, placebo-controlled study

<b>Background:</b> Prevention of rise in intraocular pressure (IOP) is essential in patients undergoing surgery for perforated eye injuries. Metoclopramide, a prokinetic agent, is commonly used to hasten gastric emptying in emergency surgeries. <b>Aim:</b> To study the change in IOP after intravenous metoclopramide and to study the influence of metoclopramide on change in IOP after succinylcholine and tracheal intubation. <b>Settings and Design:</b> A randomized, double-blind, placebo-controlled study of 60 patients undergoing non-ophthalmic elective surgery. <b>Materials and Methods:</b> Sixty American Society of Anesthesiologists (ASA) I adult patients were randomly assigned to receive normal saline (Group C) or metoclopramide 10 mg (Group M) 30 min before the induction of anesthesia. Thiopentone was used for induction and succinylcholine for tracheal intubation. Intraocular pressure was measured in both the eyes pre and post drug treatment and succinylcholine and tracheal intubation using Perkins applanation tonometer. <b>Statistical Analysis:</b> Student&#x2032;s t-test and repeated measures ANOVA were used. A <i> P</i> value &#60; 0.05 was considered as significant. <b>Results:</b> Intraocular pressure was consistently lower in Group M than in Group C after the test drug, though the difference was not statistically significant. Intraocular pressure decreased significantly after administration of thiopentone and increased significantly in Groups C and M after tracheal intubation (<i> P</i> &lt; 0.01). Intraocular pressure was comparable between the groups at all the times. <b>Conclusions:</b> Metoclopramide does not cause a clinically significant change in IOP nor does it influence the changes in IOP during anesthesia and tracheal intubation. Metoclopramide shows a trend towards decrease in IOP, though clinically insignificant. Therefore metoclopramide can be used to promote gastric emptying in patients with perforated eye injury

Nitridation of Sapphire as a Precursor to GaN Growth: Structure and Chemistry

Nitridation of sapphire substrates is used as a precursor to the growth of GaN films to provide a wetting layer which is closer in terms of structure and chemistry to the overlayer. Nitridation has been carried out by metal-organic chemical vapor deposition at 530, 800, and 1100 degrees C in an environment of NH3 and H-2. The structure and chemistry of the nitrided layer grown at these different temperatures have been studied by X-ray photoelectron spectroscopy, electron diffraction, high resolution electron microscopy, and electron energy loss spectroscopy. The low temperature nitridation process results in a nitrided layer in which oxygen has been partially replaced by nitrogen to form a cubic spinel-AL(x)O(y)N(z) structure. Nitridation at 800 degrees and 1100 degrees C results in complete substitution of oxygen atoms by nitrogen to form a cubic rock salt AIN structure. These structures are stable on thermal annealing at 1000 degrees C prior to epitaxial GaN growth

A single dose of preoperative gabapentin for pain reduction and requirement of morphine after total mastectomy and axillary dissection: Randomized placebo-controlled double-blind trial

Background : Gabapentin has been recently found to be useful for reducing acute postoperative pain when administered preoperatively. Although various dose regimens have been tried in different surgical settings, the minimum effective dose is not established. Aims : We aimed to evaluate the analgesic efficacy of single low dose gabapentin in patients undergoing total mastectomy and axillary dissection. Settings and Design : Prospective randomized placebo-controlled double-blind trial in a tertiary care teaching hospital. Materials and Methods : Fifty women scheduled for total mastectomy and axillary dissection were randomized to receive either gabapentin 600 mg or placebo orally 1 h preoperatively. The intraoperative and postoperative management was standardized. Postoperative pain was assessed at rest and on movement for 12 h using the numerical rating scale (NRS). Morphine was administered if NRS exceeded 30. Primary outcome measure was total morphine consumption. Statistical Analysis : The morphine consumption was compared using independent t test while pain and sedation scores were analyzed using Mann-Whitney U test. Results : Forty-six patients completed the trial. The postoperative morphine consumption was significantly less (5.8 ± 4.2 vs. 11.0 ± 3.4 mg; P ≤ 0.001) and the median [IQR] time to first analgesic was significantly longer (90 [37.5-120] vs. 0 [0-90] min; P < 0.001) in the gabapentin group than in the placebo group. The incidence of side effects was similar in the two groups. Conclusions : A single low dose of 600 mg gabapentin administered 1 h prior to surgery produced effective and significant postoperative analgesia after total mastectomy and axillary dissection without significant side effects

Changing Trends in Computational Drug Repositioning

Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated&mdash;&ldquo;The most fruitful basis for the discovery of a new drug is to start with an old drug&rdquo;. However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of &ldquo;serendipity&rdquo;, discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules&mdash;pharmacologically relevant sub-networks of biomolecules and/or pathways&mdash;from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning

Nitridation of Sapphire as a Precursor to GaN Growth: Structure and Chemistry

Nitridation of sapphire substrates is used as a precursor to the growth of GaN films to provide a wetting layer which is closer in terms of structure and chemistry to the overlayer. Nitridation has been carried out by metal-organic chemical vapor deposition at 530, 800, and 1100 degrees C in an environment of NH3 and H-2. The structure and chemistry of the nitrided layer grown at these different temperatures have been studied by X-ray photoelectron spectroscopy, electron diffraction, high resolution electron microscopy, and electron energy loss spectroscopy. The low temperature nitridation process results in a nitrided layer in which oxygen has been partially replaced by nitrogen to form a cubic spinel-AL(x)O(y)N(z) structure. Nitridation at 800 degrees and 1100 degrees C results in complete substitution of oxygen atoms by nitrogen to form a cubic rock salt AIN structure. These structures are stable on thermal annealing at 1000 degrees C prior to epitaxial GaN growth