The Need for New Anti-Hepatitis C Virus Therapeutic Strategies : Targeting the cellular micro-ribonucleic acids?

Infection with the hepatitis C virus (HCV) is a worldwide problem. Patients with chronic HCV infection who are non-responders to standard therapy represent a growing population within the HCV epidemic.Novel, more efficient and tolerable therapies are urgently needed. This review discusses the recent results showing that targeting miR-122, a micro-ribonucleic acid (MicroRNA) that enhances HCV replication, is a new anti-HCV therapy with a high barrier to resistance

Measles on the Rise: The importance of vaccination

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Noise Pollution in Maize Milling Smes

Maize milling SMEs emit high levels of noise which can have adverse effects on humanbeings and therefore require controlling. This paper reports on a study that involvedassessment and measurement of noise level in maize milling SMEs in DSM and Morogorourban, gathering opinions of workers and the neighbouring population on noise problems,and suggesting solutions for noise control. Noise measurements in 41 SMEs were recordedfrom 89-103 dBA in DSM and 92-103 dBA in Morogoro near the milling machines. Thesevalues were higher than the safe level of 85 dBA for 8 hours working shift. Measurementalso indicated high noise in the immediate neighbourhood of the milling plants. Machineoperators and neighbours indicated health problems which could be a result of machinenoise. Causes of high noise were identified to include loose or untightened machine parts,improper installation of machine system, use of worn out machine bearings, and the use ofimproperly designed and unbalanced milling hammers. Possible administrative andtechnical solutions for these problems were suggested. It is concluded from this study thatmost of maize milling SMEs produce high noise which is indeed pollutant to workers andthe neighbouring population. Therefore, it is important to implement the suggestedadministrative and technical solutions to minimise this problem

Analysis of Blood Cultures in Major Burns in Tertiary Care Burn Unit in Oman

Objectives: In this study we review blood stream infections of major burns in a tertiary care burn unit to determine the most prevalent organisms in order to have a better empirical therapy protocol. Methods: This is a retrospective study where blood stream infection of major burns (>20% Total Body Surface Area) were analysed. Results:155 patients fulfilled the criteria. Median age was 33 years.  Median TBSA was 38%. 57.42% were males and 42.58% were females. Mortality was 25.16%. 50.9% of patients had positive blood culture. Expired patients had higher TBSA, Abbreviated Burns Severity Index score and earlier first positive blood culture. The most prevalent organisms grown from all blood cultures were Acinetobacter, staphylococci, Klebsiella, Enterococcus and pseudomonas. Candida is also commonly grown in blood cultures. All Acinetobacter species are always multidrug resistant. 8 of 14 patients had multidrug resistant Klebsiella.  There were only 4 patients who had Methicilin resistant Staphylococcus Aureus (MRSA) grown. The number of blood cultures samples taken ranged from 1 to 28 (median 6). First positive blood culture showed that Staphylococcus epidermidis   and Acinetobacter are the most common organisms. Conclusion: In conclusion multidrug resistant Acinetobcater has become the most predominant microorganism grown in blood cultures of major burns in our unit. Empirical therapy should include antibiotics that are effective against it to reduce the mortality. Keywords: Infection; Blood; Burn; Resistance; Antibiotics; Culture

Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses

Correlates of immune-mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of 40 volunteers followed for up to 1 yr after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity, including complement, the inflammasome, and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (modular immune in vitro construct [MIMIC] system), by the coordinated up-regulation of transcripts for specific transcription factors, including STAT1, IRF7, and ETS2, which are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of master transcription factors that lead to the development of a broad, polyfunctional, and persistent immune response that integrates all effector cells of the immune system

The Genome of a Pathogenic Rhodococcus: Cooptive Virulence Underpinned by Key Gene Acquisitions

We report the genome of the facultative intracellular parasite Rhodococcus equi, the only animal pathogen within the biotechnologically important actinobacterial genus Rhodococcus. The 5.0-Mb R. equi 103S genome is significantly smaller than those of environmental rhodococci. This is due to genome expansion in nonpathogenic species, via a linear gain of paralogous genes and an accelerated genetic flux, rather than reductive evolution in R. equi. The 103S genome lacks the extensive catabolic and secondary metabolic complement of environmental rhodococci, and it displays unique adaptations for host colonization and competition in the short-chain fatty acid–rich intestine and manure of herbivores—two main R. equi reservoirs. Except for a few horizontally acquired (HGT) pathogenicity loci, including a cytoadhesive pilus determinant (rpl) and the virulence plasmid vap pathogenicity island (PAI) required for intramacrophage survival, most of the potential virulence-associated genes identified in R. equi are conserved in environmental rhodococci or have homologs in nonpathogenic Actinobacteria. This suggests a mechanism of virulence evolution based on the cooption of existing core actinobacterial traits, triggered by key host niche–adaptive HGT events. We tested this hypothesis by investigating R. equi virulence plasmid-chromosome crosstalk, by global transcription profiling and expression network analysis. Two chromosomal genes conserved in environmental rhodococci, encoding putative chorismate mutase and anthranilate synthase enzymes involved in aromatic amino acid biosynthesis, were strongly coregulated with vap PAI virulence genes and required for optimal proliferation in macrophages. The regulatory integration of chromosomal metabolic genes under the control of the HGT–acquired plasmid PAI is thus an important element in the cooptive virulence of R. equi

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Genetic insights into resting heart rate and its role in cardiovascular disease

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development