Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

Cost-effectiveness of general practice care for low back pain: a systematic review

Care from a general practitioner (GP) is one of the most frequently utilised healthcare services for people with low back pain and only a small proportion of those with low back pain who seek care from a GP are referred to other services. The aim of this systematic review was to evaluate the evidence on cost-effectiveness of GP care in non-specific low back pain. We searched clinical and economic electronic databases, and the reference list of relevant systematic reviews and included studies to June 2010. Economic evaluations conducted alongside randomised controlled trials with at least one GP care arm were eligible for inclusion. Two reviewers independently screened search results and extracted data. Eleven studies were included; the majority of which conducted a cost-effectiveness or cost-utility analysis. Most studies investigated the cost-effectiveness of usual GP care. Adding advice, education and exercise, or exercise and behavioural counselling, to usual GP care was more cost-effective than usual GP care alone. Clinical rehabilitation and/or occupational intervention, and acupuncture were more cost-effective than usual GP care. One study investigated the cost-effectiveness of guideline-based GP care, and found that adding exercise and/or spinal manipulation was more cost-effective than guideline-based GP care alone. In conclusion, GP care alone did not appear to be the most cost-effective treatment option for low back pain. GPs can improve the cost-effectiveness of their treatment by referring their patients for additional services, such as advice and exercise, or by providing the services themselves

Serum homocysteine, vitamin B 12 and folic acid levels in different types of glaucoma

BACKGROUND: This study was performed to compare levels of serum homocysteine (Hcy), vitamin B12 and folic acid in patients with primary open-angle glaucoma (POAG), pseudoexfoliative glaucoma (PEXG), normotensive glaucoma (NTG) and healthy controls. METHODS: Twentyfive patients with POAG, 24 with PEXG, and 18 with NTG, along with 19 control healthy subjects were included this prospective study. Levels of serum Hcy were measured using immunoassay, and those of serum vitamin B12 and folic acid were measured using competitive chemiluminescent enzyme immunoassay. RESULTS: The mean Hcy concentration in the PEXG group was significantly higher (P < 0.001) as compared to the other groups. There were no significant differences with respect to the mean Hcy concentrations among other groups (P > 0.05). There were no statistical differences in serum vitamin B12 levels among POAG, PEXG, NTG and control subjects (P > 0.05). The mean serum folic acid level was significantly lower in the subjects with PEXG (P < 0.009). However, the mean folic acid concentrations among the other groups did not differ significantly (P > 0.05). CONCLUSION: Elevated levels of Hcy in PEXG may explain the role of endothelial dysfunction among patients with PEXG

TOI-2046b, TOI-1181b, and TOI-1516b, three new hot Jupiters from TESS: planets orbiting a young star, a subgiant, and a normal star

We present the confirmation and characterization of three hot Jupiters, TOI-1181b, TOI-1516b, and TOI-2046b, discovered by the TESS space mission. The reported hot Jupiters have orbital periods between 1.4 and 2.05 d. The masses of the three planets are 1.18 ± 0.14 MJ, 3.16 ± 0.12 MJ, and 2.30 ± 0.28 MJ, for TOI-1181b, TOI-1516b, and TOI-2046b, respectively. The stellar host of TOI-1181b is a F9IV star, whereas TOI-1516b and TOI-2046b orbit F main sequence host stars. The ages of the first two systems are in the range of 2–5 Gyrs. However, TOI-2046 is among the few youngest known planetary systems hosting a hot Jupiter, with an age estimate of 100–400 Myrs. The main instruments used for the radial velocity follow-up of these three planets are located at Ondřejov, Tautenburg, and McDonald Observatory, and all three are mounted on 2–3 m aperture telescopes, demonstrating that mid-aperture telescope networks can play a substantial role in the follow-up of gas giants discovered by TESS and in the future by PLATO

Psychosocial factors and their predictive value in chiropractic patients with low back pain: a prospective inception cohort study

BACKGROUND: Being able to estimate the likelihood of poor recovery from episodes of back pain is important for care. Studies of psychosocial factors in inception cohorts in general practice and occupational populations have begun to make inroads to these problems. However, no studies have yet investigated this in chiropractic patients. METHODS: A prospective inception cohort study of patients presenting to a UK chiropractic practice for new episodes of non-specific low back pain (LBP) was conducted. Baseline questionnaires asked about age, gender, occupation, work status, duration of current episode, chronicity, aggravating features and bothersomeness using Deyo's 'Core Set'. Psychological factors (fear-avoidance beliefs, inevitability, anxiety/distress and coping, and co-morbidity were also assessed at baseline. Satisfaction with care, number of attendances and pain impact were determined at 6 weeks. Predictors of poor outcome were sought by the calculation of relative risk ratios. RESULTS: Most patients presented within 4 weeks of onset. Of 158 eligible and willing patients, 130 completed both baseline and 6-week follow-up questionnaires. Greatest improvements at 6 weeks were in interference with normal work (ES 1.12) and LBP bothersomeness (ES 1.37). Although most patients began with moderate-high back pain bothersomeness scores, few had high psychometric ones. Co-morbidity was a risk for high-moderate interference with normal work at 6 weeks (RR 2.37; 95% C.I. 1.15–4.74). An episode duration of >4 weeks was associated with moderate to high bothersomeness at 6 weeks (RR 2.07; 95% C.I. 1.19 – 3.38) and negative outlook (inevitability) with moderate to high interference with normal work (RR 2.56; 95% C.I. 1.08 – 5.08). CONCLUSION: Patients attending a private UK chiropractic clinic for new episodes of non-specific LBP exhibited few psychosocial predictors of poor outcome, unlike other patient populations that have been studied. Despite considerable bothersomeness at baseline, scores were low at follow-up. In this independent health sector back pain population, general health and duration of episode before consulting appeared more important to outcome than psychosocial factors

Designing a workplace return-to-work program for occupational low back pain: an intervention mapping approach

<p>Abstract</p> <p>Background</p> <p>Despite over 2 decades of research, the ability to prevent work-related low back pain (LBP) and disability remains elusive. Recent research suggests that interventions that are focused at the workplace and incorporate the principals of <it>participatory ergonomics </it>and return-to-work (RTW) coordination can improve RTW and reduce disability following a work-related back injury. Workplace interventions or programs to improve RTW are difficult to design and implement given the various individuals and environments involved, each with their own unique circumstances. Intervention mapping provides a framework for designing and implementing complex interventions or programs. The objective of this study is to design a best evidence RTW program for occupational LBP tailored to the Ontario setting using an intervention mapping approach.</p> <p>Methods</p> <p>We used a qualitative synthesis based on the intervention mapping methodology. Best evidence from systematic reviews, practice guidelines and key articles on the prognosis and management of LBP and improving RTW was combined with theoretical models for managing LBP and changing behaviour. This was then systematically operationalized into a RTW program using consensus among experts and stakeholders. The RTW Program was further refined following feedback from nine focus groups with various stakeholders.</p> <p>Results</p> <p>A detailed five step RTW program was developed. The key features of the program include; having trained personnel coordinate the RTW process, identifying and ranking barriers and solutions to RTW from the perspective of all important stakeholders, mediating practical solutions at the workplace and, empowering the injured worker in RTW decision-making.</p> <p>Conclusion</p> <p>Intervention mapping provided a useful framework to develop a comprehensive RTW program tailored to the Ontario setting.</p

An interdisciplinary clinical practice model for the management of low-back pain in primary care: the CLIP project

<p>Abstract</p> <p>Background</p> <p>Low-back pain is responsible for significant disability and costs in industrialized countries. Only a minority of subjects suffering from low-back pain will develop persistent disability. However, this minority is responsible for the majority of costs and has the poorest health outcomes. The objective of the Clinic on Low-back pain in Interdisciplinary Practice (CLIP) project was to develop a primary care interdisciplinary practice model for the clinical management of low-back pain and the prevention of persistent disability.</p> <p>Methods</p> <p>Using previously published guidelines, systematic reviews and meta-analyses, a clinical management model for low-back pain was developed by the project team. A structured process facilitating discussions on this model among researchers, stakeholders and clinicians was created. The model was revised following these exchanges, without deviating from the evidence.</p> <p>Results</p> <p>A model consisting of nine elements on clinical management of low-back pain and prevention of persistent disability was developed. The model's two core elements for the prevention of persistent disability are the following: 1) the evaluation of the prognosis at the fourth week of disability, and of key modifiable barriers to return to usual activities if the prognosis is unfavourable; 2) the evaluation of the patient's perceived disability every four weeks, with the evaluation and management of barriers to return to usual activities if perceived disability has not sufficiently improved.</p> <p>Conclusion</p> <p>A primary care interdisciplinary model aimed at improving quality and continuity of care for patients with low-back pain was developed. The effectiveness, efficiency and applicability of the CLIP model in preventing persistent disability in patients suffering from low-back pain should be assessed.</p

Feasibility and antihypertensive effect of replacing regular salt with mineral salt -rich in magnesium and potassium- in subjects with mildly elevated blood pressure

<p>Abstract</p> <p>Background</p> <p>High salt intake is linked to hypertension whereas a restriction of dietary salt lowers blood pressure (BP). Substituting potassium and/or magnesium salts for sodium chloride (NaCl) may enhance the feasibility of salt restriction and lower blood pressure beyond the sodium reduction alone. The aim of this study was to determine the feasibility and effect on blood pressure of replacing NaCl (Regular salt) with a novel mineral salt [50% sodium chloride and rich in potassium chloride (25%), magnesium ammonium potassium chloride, hydrate (25%)] (Smart Salt).</p> <p>Methods</p> <p>A randomized, double-blind, placebo-controlled study was conducted with an intervention period of 8-weeks in subjects (n = 45) with systolic (S)BP 130-159 mmHg and/or diastolic (D)BP 85-99 mmHg. During the intervention period, subjects consumed processed foods salted with either NaCl or Smart Salt. The primary endpoint was the change in SBP. Secondary endpoints were changes in DBP, daily urine excretion of sodium (24-h dU-Na), potassium (dU-K) and magnesium (dU-Mg).</p> <p>Results</p> <p>24-h dU-Na decreased significantly in the Smart Salt group (-29.8 mmol; p = 0.012) and remained unchanged in the control group: resulting in a 3.3 g difference in NaCl intake between the groups. Replacement of NaCl with Smart Salt resulted in a significant reduction in SBP over 8 weeks (-7.5 mmHg; p = 0.016). SBP increased (+3.8 mmHg, p = 0.072) slightly in the Regular salt group. The difference in the change of SBP between study groups was significant (p < 0.002).</p> <p>Conclusions</p> <p>The substitution of Smart Salt for Regular salt in subjects with high normal or mildly elevated BP resulted in a significant reduction in their daily sodium intake as well as a reduction in SBP.</p> <p>Trial Registration</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN01739816">ISRCTN01739816</a></p

p21WAF1/CIP1expression in stage I cutaneous malignant melanoma: its relationship with p53, cell proliferation and survival

The expression of p21, p53 and proliferating cell nuclear antigen (PCNA) was analysed by immunohistochemistry in a consecutive series of 369 clinical stage I cutaneous malignant melanoma patients. Correlation of the detected expression levels with each other, with clinicopathological data and with melanoma survival were statistically evaluated. p21 expression was significantly associated with p53 and PCNA expression levels. In addition, high levels of p53 and PCNA were significantly interrelated. Tumour thickness, recurrent disease, high TNM category and older (≥ 55 years) age at diagnosis were inversely associated with p21 expression. Gender, bleeding, tumour thickness, Clark's level of invasion, TNM category and p53 index were all important predictors of both recurrence-free and overall survival of melanoma. In Cox's multivariate analysis including 164 patients with a complete set of data, only high tumour thickness and bleeding predicted poor recurrence-free survival (P= 0.0042 and 0.0087 respectively) or overall survival (P= 0.0147 and 0.0033 respectively). Even though elevated p21 expression may be associated with more favourable prognosis in clinical stage I cutaneous melanoma, our results suggest that cell cycle regulatory effects of p21 can be overcome by some other and stronger, partly yet unknown, mechanisms. 1999 Cancer Research Campaig

Coffee, Alcohol, Smoking, Physical Activity and QT Interval Duration: Results from the Third National Health and Nutrition Examination Survey

Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration.We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988-1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview.In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were -1.2 ms (95% CI -4.4 to 2.0) for coffee, and -2.0 ms (-11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (-0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (-0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (-2.9 to 5.2) and 1.7 ms (-2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was -0.8 ms (-3.0 to 1.4).Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity