Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus

<b>BACKGROUND:</b> The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p> <b>RESULTS:</b> Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p> <b>CONCLUSIONS:</b> Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established

Adapted motivational interviewing to improve the uptake of treatment for glaucoma in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: Glaucoma is a chronic eye disease associated with irreversible visual loss. In Africa, glaucoma patients often present late, with very advanced disease. One-off procedures, such as laser or surgery, are recommended in Africa because of lack of or poor adherence to medical treatment. However, acceptance of surgery is usually extremely low. To prevent blindness, adherence to treatment needs to improve, using acceptable, replicable and cost-effective interventions. After reviewing the literature and interviewing patients in Bauchi (Nigeria) motivational interviewing (MI) was selected as the intervention for this trial, with adaptation for glaucoma (MIG). MI is designed to strengthen personal motivation for, and commitment to a specific goal by eliciting and exploring a person's reasons for change within an atmosphere of acceptance and compassion. The aim of this study is to assess whether MIG increases the uptake of laser or surgery amongst glaucoma patients where this is the recommended treatment. The hypothesis is that MIG increases the uptake of treatment. This will be the first trial of MI in Africa. METHODS: This is a hospital based, single centre, randomized controlled trial of MIG plus an information sheet on glaucoma and its treatment (the latter being "standard care") compared with standard care alone for glaucoma patients where the treatment recommended is surgery or laser.Those eligible for the trial are adults aged 17 years and above who live within 200 km of Bauchi with advanced glaucoma where the examining ophthalmologist recommends surgery or laser. After obtaining written informed consent, participants will be randomly allocated to MIG plus standard care, or standard care alone. Motivational interviewing will be delivered in Hausa or English by one of two MIG trained personnel. One hundred and fifty participants will be recruited to each arm. The primary outcome is the proportion of participants undergoing laser or surgery within two months of the date given to re attend for the procedure. MIG quality will be assessed using the validated MI treatment integrity scale. DISCUSSION: Motivational interviewing may be an important tool to increase the acceptance of treatment for glaucoma. The approach is potentially scalable and may be useful for other chronic conditions in Africa. TRIAL REGISTRATION: ISRCTN79330571 (Controlled-Trials.com)

Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts

The functional gastrointestinal disorders (FGIDs), are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. Methods: A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. Results: Five criteria are proposed: 1) presence of the abnormality in a subset of patients; 2) temporal association between proposed mechanism and symptom(s); 3) correlation between the level of impairment of the mechanism and symptom(s); 4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and 5) treatment response by a therapy specifically correcting the underlying disorder, or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these 5 criteria, a plausibility score is proposed. Conclusion: Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these 5 plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies

Advances in prevention and therapy of neonatal dairy calf diarrhoea : a systematical review with emphasis on colostrum management and fluid therapy

Neonatal calf diarrhoea remains the most common cause of morbidity and mortality in preweaned dairy calves worldwide. This complex disease can be triggered by both infectious and non-infectious causes. The four most important enteropathogens leading to neonatal dairy calf diarrhoea are Escherichia coli, rota-and coronavirus, and Cryptosporidium parvum. Besides treating diarrhoeic neonatal dairy calves, the veterinarian is the most obvious person to advise the dairy farmer on prevention and treatment of this disease. This review deals with prevention and treatment of neonatal dairy calf diarrhoea focusing on the importance of a good colostrum management and a correct fluid therapy

An integrated whole genome analysis of Mycobacterium tuberculosis reveals insights into relationship between its genome, transcriptome and methylome.

Human tuberculosis disease (TB), caused by Mycobacterium tuberculosis (Mtb), is a complex disease, with a spectrum of outcomes. Genomic, transcriptomic and methylation studies have revealed differences between Mtb lineages, likely to impact on transmission, virulence and drug resistance. However, so far no studies have integrated sequence-based genomic, transcriptomic and methylation characterisation across a common set of samples, which is critical to understand how DNA sequence and methylation affect RNA expression and, ultimately, Mtb pathogenesis. Here we perform such an integrated analysis across 22 M. tuberculosis clinical isolates, representing ancient (lineage 1) and modern (lineages 2 and 4) strains. The results confirm the presence of lineage-specific differential gene expression, linked to specific SNP-based expression quantitative trait loci: with 10 eQTLs involving SNPs in promoter regions or transcriptional start sites; and 12 involving potential functional impairment of transcriptional regulators. Methylation status was also found to have a role in transcription, with evidence of differential expression in 50 genes across lineage 4 samples. Lack of methylation was associated with three novel variants in mamA, likely to cause loss of function of this enzyme. Overall, our work shows the relationship of DNA sequence and methylation to RNA expression, and differences between ancient and modern lineages. Further studies are needed to verify the functional consequences of the identified mechanisms of gene expression regulation

Modelling the public health impact of male circumcision for HIV prevention in high prevalence areas in Africa

Background: Recent clinical trials in Africa, in combination with several observational epidemiological studies, have provided evidence that male circumcision can reduce HIV female-to-male transmission risk by 60% or more. However, the public health impact of large-scale male circumcision programs for HIV prevention is unclear. Methods: Two mathematical models were examined to explore this issue: a random mixing model and a compartmental model that distinguishes risk groups associated with sex work. In the compartmental model, two scenarios were developed, one calculating HIV transmission and prevalence in a context similar to the country of Botswana, and one similar to Nyanza Province, in western Kenya. Results: In both models, male circumcision programs resulted in large and sustained declines in HIV prevalence over time among both men and women. Men benefited somewhat more than women, but prevalence among women was also reduced substantially. With 80% male circumcision uptake, the reductions in prevalence ranged from 45% to 67% in the two "countries", and with 50% uptake, from 25% to 41%. It would take over a decade for the intervention to reach its full effect. Conclusion: Large-scale uptake of male circumcision services in African countries with high HIV prevalence, and where male circumcision is not now routinely practised, could lead to substantial reductions in HIV transmission and prevalence over time among both men and women

The effect of cataract on early stage glaucoma detection using spatial and temporal contrast sensitivity tests

Background: To investigate the effect of cataract on the ability of spatial and temporal contrast sensitivity tests used to detect early glaucoma. Methods: Twenty-seven glaucoma subjects with early cataract (mean age 60 ±10.2 years) which constituted the test group were recruited together with twenty-seven controls (cataract only) matched for age and cataract type from a primary eye care setting. Contrast sensitivity to flickering gratings at 20 Hz and stationary gratings with and without glare, were measured for 0.5, 1.5 and 3 cycles per degree (cpd) in central vision. Perimetry and structural measurements with the Heidelberg Retinal Tomograph (HRT) were also performed. Results: After considering the effect of cataract, contrast sensitivity to stationary gratings was reduced in the test group compared with controls with a statistically significant mean difference of 0.2 log units independent of spatial frequency. The flicker test showed a significant difference between test and control group at 1.5 and 3 cpd (p = 0.019 and p = 0.011 respectively). The percentage of glaucoma patients who could not see the temporal modulation was much higher compared with their cataract only counterparts. A significant correlation was found between the reduction of contrast sensitivity caused by glare and the Glaucoma Probability Score (GPS) as measured with the HRT (p<0.005). Conclusions: These findings indicate that both spatial and temporal contrast sensitivity tests are suitable for distinguishing between vision loss as a consequence of glaucoma and vision loss caused by cataract only. The correlation between glare factor and GPS suggests that there may be an increase in intraocular stray light in glaucoma

A comparison of the sensitivity of EQ-5D, SF-6D and TTO utility values to changes in vision and perceived visual function in patients with primary open-angle glaucoma

Background: Economic viability of treatments for primary open-angle glaucoma (POAG) should be assessed objectively to prioritise health care interventions. This study aims to identify the methods for eliciting utility values (UVs) most sensitive to differences in visual field and visual functioning in patients with POAG. As a secondary objective, the dimensions of generic health-related and vision-related quality of life most affected by progressive vision loss will be identified. Methods: A total of 132 POAG patients were recruited. Three sets of utility values (EuroQoL EQ-5D, Short Form SF-6D, Time Trade Off) and a measure of perceived visual functioning from the National Eye Institute Visual Function Questionnaire (VFQ-25) were elicited during face-to-face interviews. The sensitivity of UVs to differences in the binocular visual field, visual acuity and visual functioning measures was analysed using non-parametric statistical methods. Results: Median utilities were similar across Integrated Visual Field score quartiles for EQ-5D (P = 0.08) whereas SF-6D and Time-Trade-Off UVs significantly decreased (p = 0.01 and p = 0.001, respectively). The VFQ-25 score varied across Integrated Visual Field and binocular visual acuity groups and was associated with all three UVs (P ≤ 0.001); most of its vision-specific sub-scales were associated with the vision markers. The most affected dimension was driving. A relationship with vision markers was found for the physical component of SF-36 and not for any dimension of EQ-5D. Conclusions: The Time-Trade-Off was more sensitive than EQ-5D and SF-6D to changes in vision and visual functioning associated with glaucoma progression but could not measure quality of life changes in the mildest disease stages

Changes in the Circadian Rhythm in Patients with Primary Glaucoma

Purpose The current study was undertaken to investigate whether glaucoma affects the sleep quality and whether there is any difference between patients with primary glaucoma (primary open angle glaucoma, POAG and primary angle-closure glaucoma, PACG) and healthy subjects, using a validated self-rated questionnaire, the Pittsburgh Sleep Quality Index (PSQI). Methods The sleep quality of patients with POAG and PACG was tested against normal controls. Subjects were divided into three sub-groups according to age. Differences in the frequency of sleep disturbances (PSQI score >7) were assessed. The differences of sleep quality within the three groups and within the POAG group depending on the patients’ intraocular pressure (IOP) and impairment of visual field (VF) were also studied. Results 92 POAG patients, 48 PACG patients and 199 controls were included. Sleep quality declined with age in control and POAG group (tendency chi-square, P0.05). No significant differences were found in POAG group between patients with a highest IOP in daytime and at nighttime (χ2-test, P>0.05). Conclusions The prevalence of sleep disorders was higher in patients with POAG and PACG than in controls. PACG patients seemed to have a more serious problem of sleep disorders than POAG patients between 61 to 80 years old. No correlation was found between the prevalence of sleep disorders and impairment of VF or the time when POAG patients showed a highest IOP