The long term outcomes of community acquired hepatitis C infection in a cohort with sera stored from 1971-1975

Aim: To examine the long term outcomes of hepatitis C virus (HCV) infection in a cohort of patients admitted with acute viral hepatitis between 1971 and 1975. The availability of stored sera enabled testing to identify anti-HCV positive subjects. Methods: A retrospective cohort study design was chosen. The exposure of interest was the presence of anti-HCV in stored sera. Systematic approaches were used to locate the cohort and outcomes assessed with the SF-36 questionnaire, a study specific questionnaire and by clinical, serological, virological and biochemical assessment. Results: Sixteen percent (n=238) of the cohort tested anti-HCV positive and formed the exposed group. The unexposed group (n=476) was randomly selected from those who were anti-HCV negative. Complete follow up was achieved on 98 anti- HCV positive individuals and 202 negatives. At 25 years follow-up, 54% of the anti-HCV positive group had evidence of chionic HCV infection (both anti-HCV and HCV RNA positive). Of those chronically infected 69% had elevated serum ALT levels, but only 8% had progressed to overt chronically and no cases of HCC were identified. Anti-HCV positive subjects were 4 times more likely to have died from suicide or drug overdose than from HCV related disease. Quality of life measures were significantly reduced in the exposed group and significantly worse for anti-HCV positive individuals aware of their serostatus, compared to those unaware. Discussion: The reduced quality of life in those aware of their HCV diagnosis may be partially an effect of 'labelling'. Anti-HCV positive study subjects were at increased risk of liver related pathology after 25 years follow up, but few had progressed to overt cirrhotic liver disease- Excess mortality in the anti-HCV positive group was not due to liver disease. This suggests that the natural history of community acquired HCV may be more benign than previously thought

Protein fiber linear dichroism for structure determination and kinetics in a low-volume, low-wavelength couette flow cell

High-resolution structure determination of soluble globular proteins relies heavily on x-ray crystallography techniques. Such an approach is often ineffective for investigations into the structure of fibrous proteins as these proteins generally do not crystallize. Thus investigations into fibrous protein structure have relied on less direct methods such as x-ray fiber diffraction and circular dichroism. Ultraviolet linear dichroism has the potential to provide additional information on the structure of such biomolecular systems. However, existing systems are not optimized for the requirements of fibrous proteins. We have designed and built a low-volume (200 μL), low-wavelength (down to 180 nm), low-pathlength (100 μm), high-alignment flow-alignment system (couette) to perform ultraviolet linear dichroism studies on the fibers formed by a range of biomolecules. The apparatus has been tested using a number of proteins for which longer wavelength linear dichroism spectra had already been measured. The new couette cell has also been used to obtain data on two medically important protein fibers, the all-β-sheet amyloid fibers of the Alzheimer's derived protein Aβ and the long-chain assemblies of α1-antitrypsin polymers

The Association of Defensin HNP-2 with Negatively Charged Membranes: A Combined Fluorescence and Linear Dichroism Study

The association of defensin HNP-2 with negatively charged membranes has been studied using a new approach that combines fluorescence and linear dichroism (LD) spectroscopies with simulated LD spectra in order to characterise the binding kinetics and bound configurations of the peptide. Binding to membranes composed of mixtures of diacylglycerophosphocholines (PC) with either diacylglycerophosphoglycerol (PG) or diacylglycerophosphoserine (PS) was conducted at lipid:peptide ratios that yielded binding, but not membrane fusion. HNP-2 association with membranes under these conditions was a 2 stage-process, with both stages exhibiting first order kinetics. The fast initial step, with a half-life of 3 min. Conversion between the states was estimated to have an enthalpy of activation of approximately 10 kJ mol− 1 and an entropy of activation of − 0.2 kJ K mol− 1. LD spectra corresponding to each of the membrane bound states were generated by non-linear regression using a standard kinetic model. These spectra are interpreted in comparison with spectra calculated using the program Dichrocalc and reveal that the peptide associates with membranes in a small number of stable configurations. All of these configurations have a significant proportion of β-sheet structure residing in the plane of the membrane. Two configurations support structures previously proposed for defensins in membranes

Micro-volume couette flow sample orientation for absorbance and fluorescence linear dichroism

Linear dichroism (LD) can be used to study the alignment of absorbing chromophores within long molecules. In particular, Couette flow LD has been used to good effect in probing ligand binding to DNA and to fibrous proteins. This technique has been previously limited by large sample requirements. Here we report the design and application of a new micro-volume Couette flow cell that significantly enhances the potential applications of flow LD spectroscopy by reducing the sample requirements for flow linear dichroism to 25 μL (with concentrations such that the absorbance maximum of the sample in a 1-cm pathlength cuvette is not, vert, similar1). The micro-volume Couette cell has also enabled the measurement of fluorescence-detected Couette flow linear dichroism. This new technique enables the orientation of fluorescent ligands to be probed even when their electronic transitions overlap with those of the macromolecule and conversely. The potential of flow-oriented fluorescence dichroism and application of the micro-volume Couette LD cell are illustrated by the collection of data for DNA with minor groove and intercalating ligands: DAPI, Hoechst, and ethidium bromide. As with conventional fluorescence, improved sensitivity compared with absorbance LD is to be expected after instrumentation optimization

Effectiveness of interventions aimed at reducing HIV acquisition and transmission among gay and bisexual men who have sex with men (GBMSM) in high income settings: A systematic review.

INTRODUCTION: HIV transmission continues among gay and bisexual men who have sex with men (GBMSM), with those who are younger, or recent migrants, or of minority ethnicity or who are gender diverse remaining at increased risk. We aimed to identify and describe recent studies evaluating the effectiveness of HIV prevention interventions for GBMSM in high income countries. METHODS: We searched ten electronic databases for randomized controlled trials (RCTs), conducted in high income settings, and published since 2013 to update a previous systematic review (Stromdahl et al, 2015). We predefined four outcome measures of interest: 1) HIV incidence 2) STI incidence 3) condomless anal intercourse (CLAI) (or measure of CLAI) and 4) number of sexual partners. We used the National Institute for Health and Care Excellence (UK) Quality Appraisal of Intervention Studies tool to assess the quality of papers included in the review. As the trials contained a range of effect measures (e.g. odds ratio, risk difference) comparing the arms in the RCTs, we converted them into standardized effect sizes (SES) with 95% confidence intervals (CI). RESULTS: We identified 39 original papers reporting 37 studies. Five intervention types were identified: one-to-one counselling (15 papers), group interventions (7 papers), online interventions (9 papers), Contingency Management for substance use (2 papers) and Pre-exposure Prophylaxis (PrEP) (6 papers). The quality of the studies was mixed with over a third of studies rated as high quality and 11% rated as poor quality. There was some evidence that one-to-one counselling, group interventions (4-10 participants per group) and online (individual) interventions could be effective for reducing HIV transmission risk behaviours such as condomless anal intercourse. PrEP was the only intervention that was consistently effective at reducing HIV incidence. CONCLUSIONS: Our systematic review of the recent evidence that we were able to analyse indicates that PrEP is the most effective intervention for reducing HIV acquisition among GBMSM. Targeted and culturally tailored behavioural interventions for sub-populations of GBMSM vulnerable to HIV infection and other STIs should also be considered, particularly for GBMSM who cannot access or decline to use PrEP

Antimicrobial activity of an iron triple helicate

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. Here we investigated the potential of the synthetic metallomolecules [Fe2L3]4+ and [Cu2(L’)2]2+ as antibacterial agents. Both molecules have been shown to bind DNA; [Fe2L3]4+ binds in the major groove and causes DNA coiling, whilst [Cu2(L’)2]2+ can act as an artificial nuclease. The work described here shows that only [Fe2L3]4+ is bactericidal for Bacillus subtilis and Escherichia coli. We demonstrate that [Fe2L3]4+ binds bacterial DNA in vivo and, strikingly, that it kills B. subtilis cells very rapidly

Cluster of falciparum malaria cases in UK airport.

A cluster of 6 cases of Plasmodium falciparum malaria occurred in a UK airport among 30 travelers returning to the United States from East Africa. Molecular genotyping analysis indicated that all had been exposed to different parasites. The travelers' use of chemoprophylaxis was poor; their perception of risk was limited

Supramolecular Nucleoside-Based Gel:Molecular Dynamics Simulation and Characterization of Its Nanoarchitecture and Self-Assembly Mechanism

Among the diversity of existing supramolecular hydrogels, nucleic acid-based hydrogels are of particular interest for potential drug delivery and tissue engineering applications because of their inherent biocompatibility. Hydrogel performance is directly related to the nanostructure and the self-assembly mechanism of the material, an aspect that is not well-understood for nucleic acid-based hydrogels in general and has not yet been explored for cytosine-based hydrogels in particular. Herein, we use a broad range of experimental characterization techniques along with molecular dynamics (MD) simulation to demonstrate the complementarity and applicability of both approaches for nucleic acid-based gelators in general and propose the self-assembly mechanism for a novel supramolecular gelator, N4-octanoyl-2′-deoxycytidine. The experimental data and the MD simulation are in complete agreement with each other and demonstrate the formation of a hydrophobic core within the fibrillar structures of these mainly water-containing materials. The characterization of the distinct duality of environments in this cytidine-based gel will form the basis for further encapsulation of both small hydrophobic drugs and biopharmaceuticals (proteins and nucleic acids) for drug delivery and tissue engineering applications