The murine cataractogenic mutation, Cat Fraser, segregates independently of the gamma crystallin genes

The murine mutation, Cat Fraser (Cat(Fr)), causes dominantly inherited ocular cataracts. Lenses of adult mice bearing this mutation contain reduced amounts of all seven γ-crystallin proteins and their corresponding transcripts. Levels of other lens proteins and transcripts appear normal and no extra-ocular effects of the mutation have been observed. The selective effect of this mutation on the γ-crystallins is consistent with the possibility that the site at which it occurs is involved in the coordinated regulation of the family of genes which encodes them. We have shown that several restriction fragment length polymorphisms in the γ-crystallin genes segregate independently of the Cat(Fr) mutation. Therefore, despite its selective effect on the expression of the γ-crystallin genes, the mutation is not linked to them. This observation rules out the possibility that the mutation is in a cis-acting regulatory site.published_or_final_versio

Augmentation index assessed by applanation tonometry is elevated in Marfan Syndrome

<p>Abstract</p> <p>Background</p> <p>To examine whether augmentation index (AIx) is increased in Marfan syndrome (MFS) and associated with increased aortic root size, and whether a peripheral-to-central generalised transfer function (GTF) can be applied usefully in MFS.</p> <p>Methods</p> <p>10 MFS patients and 10 healthy controls (matched for sex, age and height) were studied before and after 400 μg sub-lingual GTN. Arterial waveforms were recorded using applanation tonometry. AIx and pulse pressure (PP) were determined for the radial and carotid arteries. Pulse wave velocity (PWV) was measured between carotid and femoral arteries. GTFs were generated to examine the relationship between radial and carotid waveforms.</p> <p>Results</p> <p>AIx was greater in MFS compared to controls at radial (mean -31.4 (SD 14.3)% v -50.2(15.6)%, p = 0.003) and carotid (-7.6(11.2)% v -23.7(12.7)%, p = 0.004) sites. Baseline PP at all measurement sites, and PWV, did not differ between subject groups. Multivariate analysis demonstrated that PWV and carotid AIx were positively correlated with aortic root size (p < 0.001 and p = 0.012 respectively), independent of the presence of MFS. PP was not associated with aortic root size. GTN caused similar decreases in AIx in both controls and patients. Significant differences were found in GTFs between MFS and control subjects, which changed following GTN administration. However, when an independent GTF was used to derive carotid waves from radial waves, no differences were found in the degree of error between MFS and controls.</p> <p>Conclusion</p> <p>AIx is sensitive to the vascular abnormalities present in MFS, and may have a role as an adjunct to measurement of central PP and PWV. Differences between MFS and controls in the nature of the peripheral-to-central GTF are present, although have little effect on the pulse contour.</p

Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective

Integrative Analysis of Low- and High-Resolution eQTL

The study of expression quantitative trait loci (eQTL) is a powerful way of detecting transcriptional regulators at a genomic scale and for elucidating how natural genetic variation impacts gene expression. Power and genetic resolution are heavily affected by the study population: whereas recombinant inbred (RI) strains yield greater statistical power with low genetic resolution, using diverse inbred or outbred strains improves genetic resolution at the cost of lower power. In order to overcome the limitations of both individual approaches, we combine data from RI strains with genetically more diverse strains and analyze hippocampus eQTL data obtained from mouse RI strains (BXD) and from a panel of diverse inbred strains (Mouse Diversity Panel, MDP). We perform a systematic analysis of the consistency of eQTL independently obtained from these two populations and demonstrate that a significant fraction of eQTL can be replicated. Based on existing knowledge from pathway databases we assess different approaches for using the high-resolution MDP data for fine mapping BXD eQTL. Finally, we apply this framework to an eQTL hotspot on chromosome 1 (Qrr1), which has been implicated in a range of neurological traits. Here we present the first systematic examination of the consistency between eQTL obtained independently from the BXD and MDP populations. Our analysis of fine-mapping approaches is based on ‘real life’ data as opposed to simulated data and it allows us to propose a strategy for using MDP data to fine map BXD eQTL. Application of this framework to Qrr1 reveals that this eQTL hotspot is not caused by just one (or few) ‘master regulators’, but actually by a set of polymorphic genes specific to the central nervous system

Population level determinants of acute mountain sickness among young men: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Many visitors, including military troops, who enter highland regions from low altitude areas may suffer from acute mountain sickness (AMS), which negatively impacts workable man-hours and increases healthcare costs. The aim of this study was to evaluate the population level risk factors and build a multivariate model, which might be applicable to reduce the effects of AMS on Chinese young men traveling to this region.</p> <p>Methods</p> <p>Chinese highland military medical records were used to obtain data of young men (n = 3727) who entered the Tibet plateau between the years of 2006-2009. The relationship between AMS and travel profile, demographic characteristics, and health behaviors were evaluated by logistic regression. Univariate logistic models estimated the crude odds ratio. The variables that showed significance in the univariate model were included in a multivariate model to derive adjusted odds ratios and build the final model. Data corresponding to odd and even years (2 subsets) were analyzed separately and used in a simple cross-validation.</p> <p>Results</p> <p>Univariate analysis indicated that travel profile, prophylactic use, ethnicity, and province of birth were all associated with AMS in both subsets. In multivariate analysis, young men who traveled from lower altitude (600-800 m <it>vs</it>. 1300-1500 m, adjusted odds ratio (AOR) = 1.32-1.44) to higher altitudes (4100-4300 m <it>vs</it>. 2900-3100 m, AOR = 3.94-4.12; 3600-3700 m <it>vs</it>. 2900-3100 m, AOR = 2.71-2.74) by air or rapid land transport for emergency mission deployment (emergency land deployment <it>vs</it>. normal land deployment, AOR = 2.08-2.11; normal air deployment <it>vs</it>. normal land deployment, AOR = 2.00-2.20; emergency air deployment <it>vs</it>. normal land deployment, AOR = 2.40-3.34) during the cold season (cold <it>vs</it>. warm, AOR = 1.25-1.28) are at great risk for developing AMS. Non-Tibetan male soldiers (Tibetan <it>vs</it>. Han, AOR = 0.03-0.08), born and raised in lower provinces (eastern <it>vs</it>. northwestern, AOR = 1.32-1.39), and deployed without prophylaxis (prophylactic drug <it>vs</it>. none, AOR = 0.75-0.76), also represented a population at significantly increased risk for AMS. The predicted model was built; the area under receiver operating characteristic curve was 0.703.</p> <p>Conclusion</p> <p>Before a group of young men first enter a high altitude area, it is important that a health service plan should be made referring to the group's travel profile and with respect to young men's ethnicity and province of birth. Low-cost Chinese traditional prophylactic drugs might have some effect on decreasing the risk of AMS, although this needs further verification.</p

A Higher Correlation of HCV Core Antigen with CD4+ T Cell Counts Compared with HCV RNA in HCV/HIV-1 Coinfected Patients

Development of HCV infection is typically followed by chronic hepatitis C (CHC) in most patients, while spontaneous HCV viral clearance (SVC) occurs in only a minority of subjects. Compared with the widespread application of HCV RNA testing by quantitative RT-PCR technique, HCV core antigen detection may be an alternative indicator in the diagnosis of hepatitis C virus infections and in monitoring the status of infectious individuals. However, the correlation and differences between these two indicators in HCV infection need more investigation, especially in patients coinfected by HIV-1. In this study, a total of 354 anti-HCV and/or anti-HIV serum positive residents from a village of central China were enrolled. Besides HCV-related hepatopathic variables including clinical status, ALT, AST, anti-HCV Abs, as well as the altered CD4+/CD8+ T cell counts, HCV core antigen and HCV viral load were also measured. The concentration of serum HCV core antigen was highly correlated with level of HCV RNA in CHC patients with or without HIV-1 coinfection. Of note, HCV core antigen concentration was negatively correlated with CD4+ T cell count, while no correlation was found between HCV RNA level and CD4+ T cell count. Our findings suggested that quantitative detection of plasma HCV core antigen may be an alternative indicator of HCV RNA qPCR assay when evaluating the association between HCV replication and host immune status in HCV/HIV-1 coinfected patients

Whole genome sequence and manual annotation of Clostridium autoethanogenum, an industrially relevant bacterium

Clostridium autoethanogenum is an acetogenic bacterium capable of producing high value commodity chemicals and biofuels from the C1 gases present in synthesis gas. This common industrial waste gas can act as the sole energy and carbon source for the bacterium that converts the low value gaseous components into cellular building blocks and industrially relevant products via the action of the reductive acetyl-CoA (Wood-Ljungdahl) pathway. Current research efforts are focused on the enhancement and extension of product formation in this organism via synthetic biology approaches. However, crucial to metabolic modelling and directed pathway engineering is a reliable and comprehensively annotated genome sequence

Mixed-strain housing for female C57BL/6, DBA/2, and BALB/c mice: validating a split-plot design that promotes refinement and reduction

Abstract Background Inefficient experimental designs are common in animal-based biomedical research, wasting resources and potentially leading to unreplicable results. Here we illustrate the intrinsic statistical power of split-plot designs, wherein three or more sub-units (e.g. individual subjects) differing in a variable of interest (e.g. genotype) share an experimental unit (e.g. a cage or litter) to which a treatment is applied (e.g. a drug, diet, or cage manipulation). We also empirically validate one example of such a design, mixing different mouse strains -- C57BL/6, DBA/2, and BALB/c -- within cages varying in degree of enrichment. As well as boosting statistical power, no other manipulations are needed for individual identification if co-housed strains are differentially pigmented, so also sparing mice from stressful marking procedures. Methods The validation involved housing 240 females from weaning to 5 months of age in single- or mixed- strain trios, in cages allocated to enriched or standard treatments. Mice were screened for a range of 26 commonly-measured behavioural, physiological and haematological variables. Results Living in mixed-strain trios did not compromise mouse welfare (assessed via corticosterone metabolite output, stereotypic behaviour, signs of aggression, and other variables). It also did not alter the direction or magnitude of any strain- or enrichment-typical difference across the 26 measured variables, or increase variance in the data: indeed variance was significantly decreased by mixed- strain housing. Furthermore, using Monte Carlo simulations to quantify the statistical power benefits of this approach over a conventional design demonstrated that for our effect sizes, the split- plot design would require significantly fewer mice (under half in most cases) to achieve a power of 80 %. Conclusions Mixed-strain housing allows several strains to be tested at once, and potentially refines traditional marking practices for research mice. Furthermore, it dramatically illustrates the enhanced statistical power of split-plot designs, allowing many fewer animals to be used. More powerful designs can also increase the chances of replicable findings, and increase the ability of small-scale studies to yield significant results. Using mixed-strain housing for female C57BL/6, DBA/2 and BALB/c mice is therefore an effective, efficient way to promote both refinement and the reduction of animal-use in research

Dementia and Physical Activity (DAPA) - an exercise intervention to improve cognition in people with mild to moderate dementia: Study protocol for a randomized controlled trial

Background: Dementia is more common in older than in younger people, and as a result of the ageing of the population in developed countries, it is becoming more prevalent. Drug treatments for dementia are limited, and the main support offered to people with dementia and their families is generally services to mitigate against loss of function. Physical exercise is a candidate non-pharmacological treatment for dementia. Methods/Design: DAPA is a randomised controlled trial funded by the National Institute for Health Research Health Technology Assessment programme to estimate the effect of a 4-month, moderate- to hard-intensity exercise training programme and subsequent advice to remain active, on cognition (primary outcome) at 12 months in people with mild to moderate dementia. Community-dwelling participants (with their carers where possible), who are able to walk 3 metres without human assistance, able to undertake an exercise programme and do not have any unstable or terminal illness are recruited. Participants are then randomised by an independent statistician using a computerised random number generator to usual care or exercise at a 2:1 ratio in favour of exercise. The exercise intervention comprises 29, 1-hour-long exercise classes, run twice weekly at suitable venues such as leisure centres, which include aerobic exercise (on static bikes) and resistance exercise (using weights). Goals for independent exercise are set while the classes are still running, and supported thereafter with phone calls. The primary outcome is measured using ADAS-cog. Secondary outcome measures include behavioural symptoms, functional ability, quality of life and carer burden. Primary and secondary outcomes will be measured at baseline and at 6 and 12 months after randomisation, by researchers masked to participant randomisation in the participants' own homes. An economic evaluation will be carried out in parallel to the RCT, as will a qualitative study capturing the experiences of participants, carers and staff delivering the intervention. Discussion: The DAPA study will be the first large, randomised trial of the cognitive effects of exercise on people with dementia. The intervention is designed to be capable of being delivered within the constraints of NHS service provision, and the economic evaluation will allow assessment of its cost-effectiveness. Trial registration: DAPA was registered with the ISRCTN database on 29 July 2011, registration number ISRCTN32612072. © 2016 Atherton et al