Dynein structure and power stroke

Dynein ATPases are microtubule motors that are critical to diverse processes such as vesicle transport and the beating of sperm tails; however, their mechanism of force generation is unknown. Each dynein comprises a head, from which a stalk and a stem emerge. Here we use electron microscopy and image processing to reveal new structural details of dynein c, an isoform from Chlamydomonas reinhardtii flagella, at the start and end of its power stroke. Both stem and stalk are flexible, and the stem connects to the head by means of a linker approximately 10 nm long that we propose lies across the head. With both ADP and vanadate bound, the stem and stalk emerge from the head 10 nm apart. However, without nucleotide they emerge much closer together owing to a change in linker orientation, and the coiled-coil stalk becomes stiffer. The net result is a shortening of the molecule coupled to an approximately 15-nm displacement of the tip of the stalk. These changes indicate a mechanism for the dynein power stroke

Functional health status in subjects after a motor vehicle accident, with emphasis on whiplash associated disorders: design of a descriptive, prospective inception cohort study

Contains fulltext : 70254.pdf (publisher's version ) (Open Access)BACKGROUND: The clinical consequences of whiplash injuries resulting from a motor vehicle accident (MVA) are poorly understood. Thereby, there is general lack of research on the development of disability in patients with acute and chronic Whiplash Associated Disorders. METHODS/DESIGN: The objective is to describe the design of an inception cohort study with a 1-year follow-up to determine risk factors for the development of symptoms after a low-impact motor vehicle accident, the prognosis of chronic disability, and costs. Victims of a low-impact motor vehicle accident will be eligible for participation. Participants with a Neck Disability Index (NDI) score of 7 or more will be classified as experiencing post-traumatic neck pain and will enter the experimental group. Participants without complaints (a NDI score less than 7) will enter the reference group. The cohort will be followed up by means of postal questionnaires and physical examinations at baseline, 3 months, 6 months, and 12 months. Recovery from whiplash-associated disorders will be measured in terms of perceived functional health, and employment status (return to work). Life tables will be generated to determine the 1-year prognosis of whiplash-associated disorders, and risk factors and prognostic factors will be assessed using multiple logistic regression analysis. DISCUSSION: Little is known about the development of symptoms and chronic disability after a whiplash injury. In the clinical setting, it is important to identify those people who are at risk of developing chronic symptoms.This inception prospective cohort study will provide insight in the influence of risk factors, of the development of functional health problems, and costs in people with whiplash-associated disorders

Illustrating risk difference and number needed to treat from a randomized controlled trial of spinal manipulation for cervicogenic headache

<p>Abstract</p> <p>Background</p> <p>The number needed to treat (NNT) for one participant to benefit is considered a useful, clinically meaningful way of reporting binary outcomes from randomized trials. Analysis of continuous data from our randomized controlled trial has previously demonstrated a significant and clinically important difference favoring spinal manipulation over a light massage control.</p> <p>Methods</p> <p>Eighty participants were randomized to receive spinal manipulation or a light massage control (n = 40/group). Improvements in cervicogenic headache pain (primary outcome), disability, and number in prior four weeks were dichotomized into binary outcomes at two thresholds: 30% representing minimal clinically important change and 50% representing clinical success. Groups were compared at 12 and 24-week follow-up using binomial regression (generalized linear models) to compute the adjusted risk difference (RD) between groups and number needed to treat (NNT) after adjusting for baseline differences between groups. Results were compared to logistic regression results.</p> <p>Results</p> <p>For headache pain, clinically important improvement (30% or 50%) was more likely for spinal manipulation: adjusted RD = 17% to 27% and NNT = 3.8 to 5.8 (p = .005 to .028). Some statistically significant results favoring manipulation were found for headache disability and number.</p> <p>Conclusion</p> <p>Spinal manipulation demonstrated a benefit in terms of a clinically important improvement of cervicogenic headache pain. The use of adjusted NNT is recommended; however, adjusted RD may be easier to interpret than NNT. The study demonstrated how results may depend on the threshold for dichotomizing variables into binary outcomes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NLM identifier NCT00246350.</p

Ultrasound imaging versus morphopathology in cardiovascular diseases. Coronary collateral circulation and atherosclerotic plaque

This review article is aimed at comparing the results of histopathological and clinical imaging studies to assess coronary collateral circulation in humans. The role of collaterals, as emerging from morphological studies in both normal and atherosclerotic coronary vessels, is described; in addition, present role and future perpectives of echocardiographic techniques in assessing collateral circulation are briefly summarized

Colorectal cancer prevention for low-income, sociodemographically-diverse adults in public housing: baseline findings of a randomized controlled trial

Background: This paper presents the study design, intervention components, and baseline data from Open Doors to Health, a study designed to address social contextual factors in colorectal cancer (CRC) prevention for low-income, racial/ethnic minority populations. Methods: A cluster randomized design with 12 housing sites as the primary sampling units was used: 6 sites were assigned to a Peer-led plus Screening Access (PL) condition, and 6 were assigned to Screening Access only (SCR) condition. Study-related outcomes were CRC screening, physical activity (measured as mean steps/day), and multivitamin use. Results: At baseline (unweighted sample size = 1554), two-thirds self-reported that they were current with screening recommendations for CRC (corrected for medical records validation, prevalence was 52%), with half having received a colonoscopy (54%); 96% had health insurance. Mean steps per day was 5648 (se mean = 224), and on average 28% of the sample reported regular multivitamin use. Residents reported high levels of social support [mean = 4.40 (se = .03)] and moderately extensive social networks [mean = 2.66 (se = .02)]. Conclusion: Few studies have conducted community-based studies in public housing communities; these data suggest areas for improvement and future opportunities for intervention development and dissemination. Findings from the randomized trial will determine the effectiveness of the intervention on our health-related outcomes as well as inform future avenues of research

A Computational Approach to Finding Novel Targets for Existing Drugs

Repositioning existing drugs for new therapeutic uses is an efficient approach to drug discovery. We have developed a computational drug repositioning pipeline to perform large-scale molecular docking of small molecule drugs against protein drug targets, in order to map the drug-target interaction space and find novel interactions. Our method emphasizes removing false positive interaction predictions using criteria from known interaction docking, consensus scoring, and specificity. In all, our database contains 252 human protein drug targets that we classify as reliable-for-docking as well as 4621 approved and experimental small molecule drugs from DrugBank. These were cross-docked, then filtered through stringent scoring criteria to select top drug-target interactions. In particular, we used MAPK14 and the kinase inhibitor BIM-8 as examples where our stringent thresholds enriched the predicted drug-target interactions with known interactions up to 20 times compared to standard score thresholds. We validated nilotinib as a potent MAPK14 inhibitor in vitro (IC50 40 nM), suggesting a potential use for this drug in treating inflammatory diseases. The published literature indicated experimental evidence for 31 of the top predicted interactions, highlighting the promising nature of our approach. Novel interactions discovered may lead to the drug being repositioned as a therapeutic treatment for its off-target's associated disease, added insight into the drug's mechanism of action, and added insight into the drug's side effects

Effectiveness of manual therapies: the UK evidence report

<p>Abstract</p> <p>Background</p> <p>The purpose of this report is to provide a succinct but comprehensive summary of the scientific evidence regarding the effectiveness of manual treatment for the management of a variety of musculoskeletal and non-musculoskeletal conditions.</p> <p>Methods</p> <p>The conclusions are based on the results of systematic reviews of randomized clinical trials (RCTs), widely accepted and primarily UK and United States evidence-based clinical guidelines, plus the results of all RCTs not yet included in the first three categories. The strength/quality of the evidence regarding effectiveness was based on an adapted version of the grading system developed by the US Preventive Services Task Force and a study risk of bias assessment tool for the recent RCTs.</p> <p>Results</p> <p>By September 2009, 26 categories of conditions were located containing RCT evidence for the use of manual therapy: 13 musculoskeletal conditions, four types of chronic headache and nine non-musculoskeletal conditions. We identified 49 recent relevant systematic reviews and 16 evidence-based clinical guidelines plus an additional 46 RCTs not yet included in systematic reviews and guidelines.</p> <p>Additionally, brief references are made to other effective non-pharmacological, non-invasive physical treatments.</p> <p>Conclusions</p> <p>Spinal manipulation/mobilization is effective in adults for: acute, subacute, and chronic low back pain; migraine and cervicogenic headache; cervicogenic dizziness; manipulation/mobilization is effective for several extremity joint conditions; and thoracic manipulation/mobilization is effective for acute/subacute neck pain. The evidence is inconclusive for cervical manipulation/mobilization alone for neck pain of any duration, and for manipulation/mobilization for mid back pain, sciatica, tension-type headache, coccydynia, temporomandibular joint disorders, fibromyalgia, premenstrual syndrome, and pneumonia in older adults. Spinal manipulation is not effective for asthma and dysmenorrhea when compared to sham manipulation, or for Stage 1 hypertension when added to an antihypertensive diet. In children, the evidence is inconclusive regarding the effectiveness for otitis media and enuresis, and it is not effective for infantile colic and asthma when compared to sham manipulation.</p> <p>Massage is effective in adults for chronic low back pain and chronic neck pain. The evidence is inconclusive for knee osteoarthritis, fibromyalgia, myofascial pain syndrome, migraine headache, and premenstrual syndrome. In children, the evidence is inconclusive for asthma and infantile colic.</p