Bim Links ER Stress and Apoptosis in Cells Expressing Mutant SOD1 Associated with Amyotrophic Lateral Sclerosis

Endoplasmic reticulum (ER) stress is an important pathway to cell death in amyotrophic lateral sclerosis (ALS). We previously demonstrated that ER stress is linked to neurotoxicity associated with formation of inclusions of mutant Cu,Zn-superoxide dismutase 1 (SOD1). Cells bearing mutant inclusions undergo mitochondrial apoptotic signalling. Here, we demonstrate that the BH3-only protein, Bim, is a direct link between ER stress and mitochondrial apoptosis. In the murine neuroblastoma cell line, Neuro2a, bearing mutant SOD1 inclusions, indicators of both ER stress and apoptosis are expressed. Bim knockdown by siRNA significantly reduced nuclear apoptotic features in these inclusion-bearing cells (but did not affect the proportion of cells overall that bear inclusions). Further, both Bax recruitment to mitochondria and cytochrome c redistribution were also decreased under Bim-depletion conditions. However, upregulation of CHOP, a marker of ER stress, was not reduced by Bim knockdown. Significantly, knockdown of CHOP by siRNA reduced the extent of apoptosis in cells bearing mutant SOD1 inclusions. These sequential links between ER stress, CHOP upregulation, and Bim activation of mitochondrial apoptotic signalling indicate a clear pathway to cell death mediated by mutant SOD1

Attitudes to colorectal cancer screening among ethnic minority groups in the UK

Background: Colorectal screening by Flexible Sigmoidoscopy (FS) is under evaluation in the UK. Evidence from existing cancer screening programmes indicates lower participation among minority ethnic groups than the white-British population. To ensure equality of access, it is important to understand attitudes towards screening in all ethnic groups so that barriers to screening acceptance can be addressed.Methods: Open- and closed-ended questions on knowledge about colorectal cancer and attitudes to FS screening were added to Ethnibus (TM) - a monthly, nationwide survey of the main ethnic minority communities living in the UK (Indian, Pakistani, Bangladeshi, Caribbean, African, and Chinese). Interviews (n = 875) were conducted, face-to-face, by multilingual field-workers, including 125 interviews with white-British adults.Results: All respondents showed a notable lack of knowledge about causes of colorectal cancer, which was more pronounced in ethnic minority than white-British adults. Interest in FS screening was uniformly high (> 60%), with more than 90% of those interested saying it would provide 'peace of mind'. The most frequently cited barrier to screening 'in your community' was embarrassment, particularly among ethnic minority groups.Conclusion: Educational materials should recognise that non-white groups may be less knowledgeable about colorectal cancer. The findings of the current study suggest that embarrassment may be a greater deterrent to participation to FS screening among ethnic minority groups, but this result requires exploration in further research

An Inducer of VGF Protects Cells against ER Stress-Induced Cell Death and Prolongs Survival in the Mutant SOD1 Animal Models of Familial ALS

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS

Leaf-level photosynthetic capacity in lowland Amazonian and high elevation, Andean tropical moist forests of Peru

We examined whether variations in photosynthetic capacity are linked to variations in theenvironment and/or associated leaf traits for tropical moist forests (TMFs) in the Andes/west-ern Amazon regions of Peru. We compared photosynthetic capacity (maximal rate of carboxylation of Rubisco (Vcmax),and the maximum rate of electron transport (Jmax)), leaf mass, nitrogen (N) and phosphorus(P) per unit leaf area (Ma,Naand Pa, respectively), and chlorophyll from 210 species at 18field sites along a 3300-m elevation gradient. Western blots were used to quantify the abun-dance of the CO₂-fixing enzyme Rubisco. Area- and N-based rates of photosynthetic capacity at 25°C were higher in upland than low-land TMFs, underpinned by greater investment of N in photosynthesis in high-elevation trees. Soil [P] and leaf Pa were key explanatory factors for models of area-based Vcmax and Jmax but did not account for variations in photosynthetic N-use efficiency. At any given Na and Pa, the fraction of N allocated to photosynthesis was higher in upland than lowland species. For a smallsubset of lowland TMF trees examined, a substantial fraction of Rubisco was inactive. These results highlight the importance of soil- and leaf-P in defining the photosyntheticcapacity of TMFs, with variations in N allocation and Rubisco activation state further influenc-ing photosynthetic rates and N-use efficiency of these critically important forests

Relationship between visual field loss and contrast threshold elevation in glaucoma

BACKGROUND: There is a considerable body of literature which indicates that contrast thresholds for the detection of sinusoidal grating patterns are abnormally high in glaucoma, though just how these elevations are related to the location of visual field loss remains unknown. Our aim, therefore, has been to determine the relationship between contrast threshold elevation and visual field loss in corresponding regions of the peripheral visual field in glaucoma patients. METHODS: Contrast thresholds were measured in arcuate regions of the superior, inferior, nasal and temporal visual field in response to laser interference fringes presented in the Maxwellian view. The display consisted of vertical green stationary laser interference fringes of spatial frequency 1.0 c deg(-1 )which appeared in a rotatable viewing area in the form of a truncated quadrant extending from 10 to 20° from fixation which was marked with a central fixation light. Results were obtained from 36 normal control subjects in order to provide a normal reference for 21 glaucoma patients and 5 OHT (ocular hypertensive) patients for whom full clinical data, including Friedmann visual fields, had been obtained. RESULTS: Abnormally high contrast thresholds were identified in 20 out of 21 glaucoma patients and in 2 out of 5 OHT patients when compared with the 95% upper prediction limit for normal values from one eye of the 36 normal age-matched control subjects. Additionally, inter-ocular differences in contrast threshold were also abnormally high in 18 out of 20 glaucoma patients who had vision in both eyes compared with the 95% upper prediction limit. Correspondence between abnormally high contrast thresholds and visual field loss in the truncated quadrants was significant in 5 patients, borderline in 4 patients and absent in 9 patients. CONCLUSION: While the glaucoma patients tested in our study invariably had abnormally high contrast thresholds in one or more of the truncated quadrants in at least one eye, reasonable correspondence with the location of the visual field loss only occurred in half the patients studied. Hence, while contrast threshold elevations are indicative of glaucomatous damage to vision, they are providing a different assessment of visual function from conventional visual field tests

The value of age and medical history for predicting colorectal cancer and adenomas in people referred for colonoscopy

<p>Abstract</p> <p>Background</p> <p>Colonoscopy is an invasive and costly procedure with a risk of serious complications. It would therefore be useful to prioritise colonoscopies by identifying people at higher risk of either cancer or premalignant adenomas. The aim of this study is to assess a model that identifies people with colorectal cancer, advanced, large and small adenomas.</p> <p>Methods</p> <p>Patients seen by gastroenterologists and colorectal surgeons between April 2004 and December 2006 completed a validated, structured self-administered questionnaire prior to colonoscopy. Information was collected on symptoms, demographics and medical history. Multinomial logistic regression was used to simultaneously assess factors associated with findings on colonoscopy of cancer, advanced adenomas and adenomas sized 6 -9 mm, and ≤ 5 mm. The area under the curve of ROC curve was used to assess the incremental gain of adding demographic variables, medical history and symptoms (in that order) to a base model that included only age.</p> <p>Results</p> <p>Sociodemographic variables, medical history and symptoms (from 8,204 patients) jointly provide good discrimination between colorectal cancer and no abnormality (AUC 0.83), but discriminate less well between adenomas and no abnormality (AUC advanced adenoma 0.70; other adenomas 0.67). Age is the dominant risk factor for cancer and adenomas of all sizes. Having a colonoscopy within the last 10 years confers protection for cancers and advanced adenomas.</p> <p>Conclusions</p> <p>Our models provide guidance about which factors can assist in identifying people at higher risk of disease using easily elicited information. This would allow colonoscopy to be prioritised for those for whom it would be of most benefit.</p

The effect of alcohol advertising, marketing and portrayal on drinking behaviour in young people: systematic review of prospective cohort studies

<p>Abstract</p> <p>Background</p> <p>The effect of alcohol portrayals and advertising on the drinking behaviour of young people is a matter of much debate. We evaluated the relationship between exposure to alcohol advertising, marketing and portrayal on subsequent drinking behaviour in young people by systematic review of cohort (longitudinal) studies.</p> <p>Methods</p> <p>studies were identified in October 2006 by searches of electronic databases, with no date restriction, supplemented with hand searches of reference lists of retrieved articles. Cohort studies that evaluated exposure to advertising or marketing or alcohol portrayals and drinking at baseline and assessed drinking behaviour at follow-up in young people were selected and reviewed.</p> <p>Results</p> <p>seven cohort studies that followed up more than 13,000 young people aged 10 to 26 years old were reviewed. The studies evaluated a range of different alcohol advertisement and marketing exposures including print and broadcast media. Two studies measured the hours of TV and music video viewing. All measured drinking behaviour using a variety of outcome measures. Two studies evaluated drinkers and non-drinkers separately. Baseline non-drinkers were significantly more likely to have become a drinker at follow-up with greater exposure to alcohol advertisements. There was little difference in drinking frequency at follow-up in baseline drinkers. In studies that included drinkers and non-drinkers, increased exposure at baseline led to significant increased risk of drinking at follow-up. The strength of the relationship varied between studies but effect sizes were generally modest. All studies controlled for age and gender, however potential confounding factors adjusted for in analyses varied from study to study. Important risk factors such as peer drinking and parental attitudes and behaviour were not adequately accounted for in some studies.</p> <p>Conclusion</p> <p>data from prospective cohort studies suggest there is an association between exposure to alcohol advertising or promotional activity and subsequent alcohol consumption in young people. Inferences about the modest effect sizes found are limited by the potential influence of residual or unmeasured confounding.</p

Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells

Amyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms

Self-reported colorectal cancer screening of Medicare beneficiaries in family medicine vs. internal medicine practices in the United States: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The benefit of screening for decreasing the risk of death from colorectal cancer (CRC) has been shown, yet many patients in primary care are still not undergoing screening according to guidelines. There are known variations in delivery of preventive health care services among primary care physicians. This study compared self-reported CRC screening rates and patient awareness of the need for CRC screening of patients receiving care from family medicine (FPs) vs. internal medicine (internists) physicians.</p> <p>Methods</p> <p>Nationally representative sample of non-institutionalized beneficiaries who received medical care from FPs or internists in 2006 (using Medicare Current Beneficiary Survey). The main outcome was the percentage of patients screened in 2007. We also examined the percentage of patients offered screening.</p> <p>Results</p> <p>Patients of FPs, compared to those of internists, were less likely to have received an FOBT kit or undergone home FOBT, even after accounting for patients' characteristics. Compared to internists, FPs' patients were more likely to have heard of colonoscopy, but were less likely to receive a screening colonoscopy recommendation (18% vs. 27%), or undergo a colonoscopy (43% vs. 46%, adjusted odds ratios [AOR], 95% confidence interval [CI]-- 0.65, 0.51-0.81) or any CRC screening (52% vs. 60%, AOR, CI--0.80, 0.68-0.94). Among subgroups examined, higher income beneficiaries receiving care from internists had the highest screening rate (68%), while disabled beneficiaries receiving care from FPs had the lowest screening rate (34%).</p> <p>Conclusion</p> <p>Patients cared for by FPs had a lower rate of screening compared to those cared for by internists, despite equal or higher levels of awareness; a difference that remained statistically significant after accounting for socioeconomic status and access to healthcare. Both groups of patients remained below the national goal of 70 percent.</p