Sialylation of campylobacter jejuni lipo-oligosaccharides: impact on phagocytosis and cytokine production in mice

<p>Background: Guillain-Barré syndrome (GBS) is a post-infectious polyradiculoneuropathy, frequently associated with antecedent Campylobacter jejuni (C. jejuni) infection. The presence of sialic acid on C. jejuni lipo-oligosaccharide (LOS) is considered a risk factor for development of GBS as it crucially determines the structural homology between LOS and gangliosides, explaining the induction of cross-reactive neurotoxic antibodies. Sialylated C. jejuni are recognised by TLR4 and sialoadhesin; however, the functional implications of these interactions in vivo are unknown.</p> <p>Methodology/Principal Findings: In this study we investigated the effects of bacterial sialylation on phagocytosis and cytokine secretion by mouse myeloid cells in vitro and in vivo. Using fluorescently labelled GM1a/GD1a ganglioside-mimicking C. jejuni strains and corresponding (Cst-II-mutant) control strains lacking sialic acid, we show that sialylated C. jejuni was more efficiently phagocytosed in vitro by BM-MΦ, but not by BM-DC. In addition, LOS sialylation increased the production of IL-10, IL-6 and IFN-β by both BM-MΦ and BM-DC. Subsequent in vivo experiments revealed that sialylation augmented the deposition of fluorescent bacteria in splenic DC, but not macrophages. In addition, sialylation significantly amplified the production of type I interferons, which was independent of pDC.</p> <p>Conclusions/Significance: These results identify novel immune stimulatory effects of C. jejuni sialylation, which may be important in inducing cross-reactive humoral responses that cause GBS</p&gt

A Vaccine against Nicotine for Smoking Cessation: A Randomized Controlled Trial

BACKGROUND: Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period. METHODOLOGY/PRINCIPAL FINDINGS: 229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qbeta (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012). CONCLUSIONS: Whereas Nicotine-Qbeta did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction. TRIAL REGISTRATION: Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616

Impact of physical activity level and dietary fat content on passive overconsumption of energy in non-obese adults

Background: Passive overconsumption is the increase in energy intake driven by the high-fat energy-dense food environment. This can be explained in part because dietary fat has a weaker effect on satiation (i.e. process that terminates feeding). Habitually active individuals show improved satiety (i.e. process involved in post-meal suppression of hunger) but any improvement in satiation is unknown. Here we examined whether habitual physical activity mitigates passive overconsumption through enhanced satiation in response to a high-fat meal. Methods: Twenty-one non-obese individuals with high levels of physical activity (HiPA) and 19 individuals with low levels of physical activity (LoPA) matched for body mass index (mean = 22.8 kg/m2) were recruited. Passive overconsumption was assessed by comparing ad libitum energy intake from covertly manipulated high-fat (HFAT; 50% fat) or high-carbohydrate (HCHO; 70% carbohydrate) meals in a randomized crossover design. Habitual physical activity was assessed using SenseWear accelerometers (SWA). Body composition, resting metabolic rate, eating behaviour traits, fasting appetite-related peptides and hedonic food reward were also measured. Results: In the whole sample, passive overconsumption was observed with greater energy intake at HFAT compared to HCHO (p  0.05). SWA confirmed that HiPA were more active than LoPA (p  0.05 for all). Conclusions: Non-obese individuals with high or low physical activity levels but matched for BMI showed similar susceptibility to passive overconsumption when consuming an ad libitum high-fat compared to a high-carbohydrate meal. This occurred despite increased total daily energy expenditure and improved body composition in HiPA. Greater differences in body composition and/or physical activity levels may be required to impact on satiation

Research approvals iceberg: how a 'low-key' study in England needed 89 professionals to approve it and how we can do better.

BACKGROUND: The red tape and delays around research ethics and governance approvals frequently frustrate researchers yet, as the lesser of two evils, are largely accepted as unavoidable. Here we quantify aspects of the research ethics and governance approvals for one interview- and questionnaire-based study conducted in England which used the National Health Service (NHS) procedures and the electronic Integrated Research Application System (IRAS). We demonstrate the enormous impact of existing approvals processes on costs of studies, including opportunity costs to focus on the substantive research, and suggest directions for radical system change. MAIN TEXT: We have recorded 491 exchanges with 89 individuals involved in research ethics and governance approvals, generating 193 pages of email text excluding attachments. These are conservative estimates (e.g. only records of the research associate were used). The exchanges were conducted outside IRAS, expected to be the platform where all necessary documents are provided and questions addressed. Importantly, the figures exclude the actual work of preparing the ethics documentation (such as the ethics application, information sheets and consent forms). We propose six areas of work to enable system change: 1. Support the development of a broad range of customised research ethics and governance templates to complement generic, typically clinical trials orientated, ones; 2. Develop more sophisticated and flexible frameworks for study classification; 3. Link with associated processes for assessment, feedback, monitoring and reporting, such as ones involving funders and patient and public involvement groups; 4. Invest in a new generation IT infrastructure; 5. Enhance system capacity through increasing online reviewer participation and training; and 6. Encourage researchers to quantify the approvals processes for their studies. CONCLUSION: Ethics and governance approvals are burdensome for historical reasons and not because of the nature of the task. There are many opportunities to improve their efficiency and analytic depth in an age of innovation, increased connectivity and distributed working. If we continue to work under current systems, we are perpetuating, paradoxically, an unethical system of research approvals by virtue of its wastefulness and impoverished ethical debate

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

Proximal femoral canal shape is more accurately assessed on AP hip radiographs than AP pelvis radiographs in primary hip osteoarthritis.

The objectives of the present study were to determine whether differences in the radiographic appearance of the of the proximal femoral canal exist on corresponding AP pelvis and AP hip radiographs, and whether radiographic assessment of canal shape is accurate with reference to computed tomography (CT). In a retrospective study, corresponding radiographs and CT scans of 100 consecutive patients with primary hip OA were evaluated. Active shape modelling (ASM) was performed to assess the variation in proximal femoral canal shape and to identify differences between AP hip and AP pelvis views. Differences in the medial cortical flare between radiographs and CT were quantified using least squares curve fitting. ASM identified significant differences in the assessment of canal shape on corresponding AP hip and AP pelvis views. Curve fitting demonstrated a good agreement between AP hip radiographs and CT. Agreement between AP pelvis radiographs and CT was less good. In contrast to AP pelvis radiographs, AP hip radiographs allow a more accurate and reliable assessment of proximal femoral canal shape in the frontal plane in primary hip OA. Our findings may improve stem fit in total hip arthroplasty without the routine use of CT