Automatically extracting functionally equivalent proteins from SwissProt

In summary, FOSTA provides an automated analysis of annotations in UniProtKB/Swiss-Prot to enable groups of proteins already annotated as functionally equivalent, to be extracted. Our results demonstrate that the vast majority of UniProtKB/Swiss-Prot functional annotations are of high quality, and that FOSTA can interpret annotations successfully. Where FOSTA is not successful, we are able to highlight inconsistencies in UniProtKB/Swiss-Prot annotation. Most of these would have presented equal difficulties for manual interpretation of annotations. We discuss limitations and possible future extensions to FOSTA, and recommend changes to the UniProtKB/Swiss-Prot format, which would facilitate text-mining of UniProtKB/Swiss-Prot

Regional differences in the pattern of airway remodeling following chronic allergen exposure in mice

BACKGROUND: Airway remodeling present in the large airways in asthma or asthma models has been associated with airway dysfunction in humans and mice. It is not clear if airways distal to the large conducting airways have similar degrees of airway remodeling following chronic allergen exposure in mice. Our objective was to test the hypothesis that airway remodeling is heterogeneous by optimizing a morphometric technique for distal airways and applying this to mice following chronic exposure to allergen or saline. METHODS: In this study, BALB/c mice were chronically exposed to intranasal allergen or saline. Lung sections were stained for smooth muscle, collagen, and fibronectin content. Airway morphometric analysis of small (0–50000 μm(2)), medium (50000 μm(2)–175000 μm(2)) and large (>175000 μm(2)) airways was based on quantifying the area of positive stain in several defined sub-epithelial regions of interest. Optimization of this technique was based on calculating sample sizes required to detect differences between allergen and saline exposed animals. RESULTS: Following chronic allergen exposure BALB/c mice demonstrate sustained airway hyperresponsiveness. BALB/c mice demonstrate an allergen-induced increase in smooth muscle content throughout all generations of airways, whereas changes in subepithelial collagen and fibronectin content are absent from distal airways. CONCLUSION: We demonstrate for the first time, a systematic objective analysis of allergen induced airway remodeling throughout the tracheobronchial tree in mice. Following chronic allergen exposure, at the time of sustained airway dysfunction, BALB/c mice demonstrate regional differences in the pattern of remodeling. Therefore results obtained from limited regions of lung should not be considered representative of the entire airway tree

PPARβ activation inhibits melanoma cell proliferation involving repression of the Wilms’ tumour suppressor WT1

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that strongly influence molecular signalling in normal and cancer cells. Although increasing evidence suggests a role of PPARs in skin carcinogenesis, only expression of PPARγ has been investigated in human melanoma tissues. Activation of PPARα has been shown to inhibit the metastatic potential, whereas stimulation of PPARγ decreased melanoma cell proliferation. We show here that the third member of the PPAR family, PPARβ/δ is expressed in human melanoma samples. Specific pharmacological activation of PPARβ using GW0742 or GW501516 in low concentrations inhibits proliferation of human and murine melanoma cells. Inhibition of proliferation is accompanied by decreased expression of the Wilms’ tumour suppressor 1 (WT1), which is implicated in melanoma proliferation. We demonstrate that PPARβ directly represses WT1 as (1) PPARβ activation represses WT1 promoter activity; (2) in chromatin immunoprecipitation and electrophoretic mobility shift assays, we identified a binding element for PPARβ in the WT1 promoter; (3) deletion of this binding element abolishes repression by PPARβ and (4) the WT1 downstream molecules nestin and zyxin are down-regulated upon PPARβ activation. Our findings elucidate a novel mechanism of signalling by ligands of PPARβ, which leads to suppression of melanoma cell growth through direct repression of WT1

Regulatory control and the costs and benefits of biochemical noise

Experiments in recent years have vividly demonstrated that gene expression can be highly stochastic. How protein concentration fluctuations affect the growth rate of a population of cells, is, however, a wide open question. We present a mathematical model that makes it possible to quantify the effect of protein concentration fluctuations on the growth rate of a population of genetically identical cells. The model predicts that the population's growth rate depends on how the growth rate of a single cell varies with protein concentration, the variance of the protein concentration fluctuations, and the correlation time of these fluctuations. The model also predicts that when the average concentration of a protein is close to the value that maximizes the growth rate, fluctuations in its concentration always reduce the growth rate. However, when the average protein concentration deviates sufficiently from the optimal level, fluctuations can enhance the growth rate of the population, even when the growth rate of a cell depends linearly on the protein concentration. The model also shows that the ensemble or population average of a quantity, such as the average protein expression level or its variance, is in general not equal to its time average as obtained from tracing a single cell and its descendants. We apply our model to perform a cost-benefit analysis of gene regulatory control. Our analysis predicts that the optimal expression level of a gene regulatory protein is determined by the trade-off between the cost of synthesizing the regulatory protein and the benefit of minimizing the fluctuations in the expression of its target gene. We discuss possible experiments that could test our predictions.Comment: Revised manuscript;35 pages, 4 figures, REVTeX4; to appear in PLoS Computational Biolog

Information exchange networks for chronic illness care in primary care practices: an observational study

Contains fulltext : 88018.pdf (publisher's version ) (Open Access)BACKGROUND: Information exchange networks for chronic illness care may influence the uptake of innovations in patient care. Valid and feasible methods are needed to document and analyse information exchange networks in healthcare settings. This observational study aimed to examine the usefulness of methods to study information exchange networks in primary care practices, related to chronic heart failure, diabetes and chronic obstructive pulmonary disease. METHODS: The study was linked to a quality improvement project in the Netherlands. All health professionals in the practices were asked to complete a short questionnaire that documented their information exchange relations. Feasibility was determined in terms of response rates and reliability in terms of reciprocity of reports of receiving and providing information. For each practice, a number of network characteristics were derived for each of the chronic conditions. RESULTS: Ten of the 21 practices in the quality improvement project agreed to participate in this network study. The response rates were high in all but one of the participating practices. For the analysis, we used data from 67 health professionals from eight practices. The agreement between receiving and providing information was, on average, 65.6%. The values for density, centralization, hierarchy, and overlap of the information exchange networks showed substantial variation between the practices as well as between the chronic conditions. The most central individual in the information exchange network could be a nurse or a physician. CONCLUSIONS: Further research is needed to refine the measure of information networks and to test the impact of network characteristics on the uptake of innovations

Observational studies of depression in primary care: what do we know?

<p>Abstract</p> <p>Background</p> <p>We undertook a systematic review of observational studies of depression in primary care to determine 1) the nature and scope of the published studies 2) the methodological quality of the studies; 3) the identified recovery and risk factors for persistent depression and 3) the treatment and health service use patterns among patients.</p> <p>Methods</p> <p>Searches were conducted in MEDLINE, CINAHL and PsycINFO using combinations of topic and keywords, and Medical Subject Headings in MEDLINE, Headings in CINAHL and descriptors in PsycINFO. Searches were limited to adult populations and articles published in English during 1985–2006.</p> <p>Results</p> <p>40 articles from 17 observational cohort studies were identified, most were undertaken in the US or Europe. Studies varied widely in aims and methods making it difficult to meaningfully compare the results. Methodological limitations were common including: selection bias of patients and physicians; small sample sizes (range 35–108 patients at baseline and 20–59 patients at follow-up); and short follow-up times limiting the extent to which these studies can be used to inform our understanding of recovery and relapse among primary care patients with depression. Risk factors for the persistence of depression identified in this review were: severity and chronicity of the depressive episode, the presence of suicidal thoughts, antidepressant use, poorer self-reported quality of life, lower self-reported social support, experiencing key life events, lower education level and unemployment.</p> <p>Conclusion</p> <p>Despite the growing interest in depression being managed as a chronic illness, this review identified only 17 observational studies of depression in primary care, most of which have included small sample sizes and been relatively short-term. Future research should be large enough to investigate risk factors for chronicity and relapse, and should be conducted over a longer time frame.</p

Shortened time interval between colorectal cancer diagnosis and risk testing for hereditary colorectal cancer is not related to higher psychological distress

Current diagnostic practices have shortened the interval between colorectal cancer (CRC) diagnosis and genetic analysis for Lynch syndrome by MSI-testing. We studied the relation of time between MSI-testing since CRC diagnosis (MSI–CRC interval) and psychological distress. We performed a cross-sectional study in 89 patients who had previously been treated for CRC. Data were collected during MSI-testing after genetic counseling. Psychological distress was measured with the IES, the SCL-90 and the POMS; social issues with the ISS, ISB and the ODHCF. The median time of MSI–CRC interval was 24 months (range 0–332), with 23% of the patients diagnosed less than 12 months and 42% more than 36 months prior to MSI-testing. In 34% of the patients cancer specific distress was high (IES scores >26). Mean psychopathology (SCL-90) scores were low, mean mood states (POMS) scores were moderate. Interval MSI–CRC was not related to psychological distress. High cancer specific distress was reported by 24% of patients diagnosed with CRC less than 12 months ago versus 39 and 35% by those diagnosed between 12 and 36 months and more than 36 months ago respectively. Distress was positively related to female gender (P = 0.04), religiousness (P = 0.01), low social support (P = 0.02) and difficulties with family communication (P < 0.001). Shortened time interval between CRC diagnosis and MSI-testing is not associated with higher psychological distress. Females, religious persons, those having low social support and those reporting difficulties communicating hereditary colorectal cancer with relatives are at higher risk for psychological distress

Non-participation in population-based disease prevention programs in general practice

<p>Abstract</p> <p>Background</p> <p>The number of people with a chronic disease will strongly increase in the next decades. Therefore, prevention of disease becomes increasingly important. The aim of this systematic review was to identify factors that negatively influence participation in population-based disease prevention programs in General Practice and to establish whether the program type is related to non-participation levels.</p> <p>Methods</p> <p>We conducted a systematic review in Pubmed, EMBASE, CINAHL and PsycINFO, covering 2000 through July 6th 2012, to identify publications including information about characteristics of non-participants or reasons for non-participation in population-based disease prevention programs in General Practice.</p> <p>Results</p> <p>A total of 24 original studies met our criteria, seven of which focused on vaccination, eleven on screening aimed at early detection of disease, and six on screening aimed at identifying high risk of a disease, targeting a variety of diseases and conditions. Lack of personal relevance of the program, younger age, higher social deprivation and former non-participation were related to actual non-participation. No differences were found in non-participation levels or factors related to non-participation between the three program types. The large variation in non-participation levels within the program types may be partly due to differences in recruitment strategies, with more active, personalized strategies resulting in higher participation levels compared to an invitation letter.</p> <p>Conclusions</p> <p>There is still much to be gained by tailoring strategies to improve participation in those who are less likely to do so, namely younger individuals, those living in a deprived area and former non-participants. Participation may increase by applying more active recruitment strategies.</p

Effects of shared medical appointments on quality of life and cost-effectiveness for patients with a chronic neuromuscular disease. Study protocol of a randomized controlled trial

Contains fulltext : 96862.pdf (publisher's version ) (Open Access)BACKGROUND: Shared medical appointments are a series of one-to-one doctor-patient contacts, in presence of a group of 6-10 fellow patients. This group visits substitute the annual control visits of patients with the neurologist. The same items attended to in a one-to-one appointment are addressed. The possible advantages of a shared medical appointment could be an added value to the present management of neuromuscular patients. The currently problem-focused one-to-one out-patient visits often leave little time for the patient's psychosocial needs, patient education, and patient empowerment. METHODS/DESIGN: A randomized, prospective controlled study (RCT) with a follow up of 6 months will be conducted to evaluate the clinical and cost-effectiveness of shared medical appointments compared to usual care for 300 neuromuscular patients and their partners at the Radboud University Nijmegen Medical Center. Every included patient will be randomly allocated to one of the two study arms. This study has been reviewed and approved by the medical ethics committee of the region Arnhem-Nijmegen, The Netherlands. The primary outcome measure is quality of life as measured by the EQ-5D, SF-36 and the Individualized neuromuscular Quality of Life Questionnaire. The primary analysis will be an intention-to-treat analysis on the area under the curve of the quality of life scores. A linear mixed model will be used with random factor group and fixed factors treatment, baseline score and type of neuromuscular disease. For the economic evaluation an incremental cost-effectiveness analysis will be conducted from a societal perspective, relating differences in costs to difference in health outcome. Results are expected in 2012. DISCUSSION: This study will be the first randomized controlled trial which evaluates the effect of shared medical appointments versus usual care for neuromuscular patients. This will enable to determine if there is additional value of shared medical appointments to the current therapeutical spectrum. When this study shows that group visits produce the alleged benefits, this may help to increase the acceptance of this innovative and creative way of using one of the most precious resources in health care more efficiently: time. TRIAL REGISTRATION: DutchTrial Register http://www.trialregister.nlNTR1412

Renal ischemia–reperfusion injury causes intercalated cell-specific disruption of occludin in the collecting duct

Renal ischemic events open tight junctions and disrupt epithelial polarity. The purpose of this study was to examine the effects of ischemia–reperfusion (IR) injury on expression and distribution of the tight junction proteins, occludin and ZO-1, in the rat kidney. IR injury was induced by clamping both renal pedicles for 30 min and animals were killed at 6 h after the reperfusion. IR injury decreased blood bicarbonate level, but did not persistently alter pH, Na+, K+, or Cl−. In control kidneys, occludin immunoreactivity was intense in the tight junctions in the thick ascending limb, distal convoluted tubule, and collecting duct, moderate in the thin limbs of the loop of Henle, and was not detected in the proximal tubule, glomerulus, and blood vessels. ZO-1 was expressed in the same sites in which occludin was expressed, and additionally was also expressed in the proximal tubule, glomerulus, and vascular endothelial cells. IR kidneys exhibited damaged renal tubular epithelial cells in both proximal tubule and collecting duct segments in the outer medulla. In the collecting duct, the response of intercalated cells and principal cells differed. Following IR injury, intercalated cells, but not principal cells, lost their normal epithelial polarity and were frequently extruded into the tubule lumen. Occludin, instead of being localized to tight junctions, was localized diffusely in the cytoplasm in intercalated cells of IR kidneys. Principal cells, in contrast, were not detectably affected and neither occludin nor ZO-1 expression were altered in response to IR injury. The normal localization of ZO-1 expression to tight junction sites in both the proximal tubule and collecting duct was altered in response to IR, and, instead, ZO-1 expression was present diffusely in the cytoplasm. IR injury did not alter detectably either occludin or ZO-1 localization to the tight junction of the thick ascending limb cells. The abundance of total occludin protein by immunoblot analysis was not changed with IR injury. These results demonstrate that renal IR injury causes tight junction disruptions in both the proximal tubule and the collecting duct, and that altered distribution of the tight junction protein, occludin, may play a critical role in the collecting duct dysfunction which IR induces