Microparticles (MPs) are small (
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Τρίτη 5 Σεπτεμβρίου 2017
Absolute quantification of microparticles by flow cytometry in ascites of patients with decompensated cirrhosis: a cohort study
Altered Semmes–Weinstein monofilament test results are associated with oxidative stress markers in type 2 diabetic subjects
Different lines of evidence suggest that oxidative stress (OS) is implicated in the pathogenesis of diabetic neuropathy. The Semmes–Weinstein monofilament (SWM) test is an efficient tool for evaluating diabeti...
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Vocal Fold Immobility due to Birth Trauma: A Systematic Review and Pooled Analysis
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Association between Asthma and Chronic Rhinosinusitis Severity in the Context of Asthma Control
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Silicone Oil–Induced Nasal Polyposis: A Case Report
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Lingual Tonsillectomy for Pediatric Persistent Obstructive Sleep Apnea: A Systematic Review and Meta-analysis
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Management of Bleeding in Exclusive Endoscopic Ear Surgery: Pilot Clinical Experience
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Randomized Prospective Evaluation of Intraoperative Intravenous Acetaminophen in Pediatric Adenotonsillectomy
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Surgical Treatment for Early Stage Glottic Carcinoma with Involvement of the Anterior Commissure
Otolaryngology-Head and Neck Surgery, Ahead of Print.
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Effectiveness and cost-effectiveness of a cardiovascular risk prediction algorithm for people with severe mental illness (PRIMROSE)
Objectives
To determine the cost-effectiveness of two bespoke severe mental illness (SMI)-specific risk algorithms compared with standard risk algorithms for primary cardiovascular disease (CVD) prevention in those with SMI.
SettingPrimary care setting in the UK. The analysis was from the National Health Service perspective.
Participants1000 individuals with SMI from The Health Improvement Network Database, aged 30–74 years and without existing CVD, populated the model.
InterventionsFour cardiovascular risk algorithms were assessed: (1) general population lipid, (2) general population body mass index (BMI), (3) SMI-specific lipid and (4) SMI-specific BMI, compared against no algorithm. At baseline, each cardiovascular risk algorithm was applied and those considered high risk (> 10%) were assumed to be prescribed statin therapy while others received usual care.
Primary and secondary outcome measuresQuality-adjusted life years (QALYs) and costs were accrued for each algorithm including no algorithm, and cost-effectiveness was calculated using the net monetary benefit (NMB) approach. Deterministic and probabilistic sensitivity analyses were performed to test assumptions made and uncertainty around parameter estimates.
ResultsThe SMI-specific BMI algorithm had the highest NMB resulting in 15 additional QALYs and a cost saving of approximately £53 000 per 1000 patients with SMI over 10 years, followed by the general population lipid algorithm (13 additional QALYs and a cost saving of £46 000).
ConclusionsThe general population lipid and SMI-specific BMI algorithms performed equally well. The ease and acceptability of use of an SMI-specific BMI algorithm (blood tests not required) makes it an attractive algorithm to implement in clinical settings.
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Daycare attendance and respiratory tract infections: a prospective birth cohort study
Objective
We explored the burden of respiratory tract infections (RTIs) in young children with regard to day-care initiation.
DesignLongitudinal prospective birth cohort study.
Setting and methodsWe recruited 1827 children for follow-up until the age of 24 months collecting diary data on RTIs and daycare. Children with continuous daycare type and complete data were divided into groups of centre-based daycare (n=299), family day care (FDC) (n=245) and home care (n=350). Using repeated measures variance analyses, we analysed days per month with symptoms of respiratory tract infection, antibiotic treatments and parental absence from work for a period of 6 months prior to and 9 months after the start of daycare.
ResultsWe documented a significant effect of time and type of daycare, as well as a significant interaction between them for all outcome measures. There was a rise in mean days with symptoms from 3.79 (95% CI 3.04 to 4.53) during the month preceding centre-based daycare to 10.57 (95% CI 9.35 to 11.79) at 2 months after the start of centre-based daycare, with a subsequent decrease within the following 9 months. Similar patterns with a rise and decline were observed in the use of antibiotics and parental absences. The start of FDC had weaker effects. Our findings were not changed when taking into account confounding factors.
ConclusionsOur study shows the rapid increase in respiratory infections after start of daycare and a relatively fast decline in the course of time with continued daycare. It is important to support families around the beginning of daycare.
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Qualitative study to develop processes and tools for the assessment and tracking of African institutions capacity for operational health research
Objectives
Research is key to achieving global development goals. Our objectives were to develop and test an evidence-informed process for assessing health research management and support systems (RMSS) in four African universities and for tracking interventions to address capacity gaps.
SettingFour African universities.
Participants83 university staff and students from 11 cadres.
Intervention/methodsA literature-informed 'benchmark' was developed and used to itemise all components of a university's health RMSS. Data on all components were collected during site visits to four African universities using interview guides, document reviews and facilities observation guides. Gaps in RMSS capacity were identified against the benchmark and institutional action plans developed to remedy gaps. Progress against indicators was tracked over 15 months and common challenges and successes identified.
ResultsCommon gaps in operational health research capacity included no accessible research strategy, a lack of research e-tracking capability and inadequate quality checks for proposal submissions and contracts. Feedback indicated that the capacity assessment was comprehensive and generated practical actions, several of which were no-cost. Regular follow-up helped to maintain focus on activities to strengthen health research capacity in the face of challenges.
ConclusionsIdentification of each institutions' strengths and weaknesses against an evidence-informed benchmark enabled them to identify gaps in in their operational health research systems, to develop prioritised action plans, to justify resource requests to fulfil the plans and to track progress in strengthening RMSS. Use of a standard benchmark, approach and tools enabled comparisons across institutions which has accelerated production of evidence about the science of research capacity strengthening. The tools could be used by institutions seeking to understand their strengths and to address gaps in research capacity. Research capacity gaps that were common to several institutions could be a 'smart' investment for governments and health research funders.
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Qualitative meta-synthesis of barriers and facilitators that influence the implementation of community pharmacy services: perspectives of patients, nurses and general medical practitioners
Objectives
The integration of community pharmacy services (CPSs) into primary care practice can be enhanced by assessing (and further addressing) the elements that enable (ie, facilitators) or hinder (ie, barriers) the implementation of such CPSs. These elements have been widely researched from the perspective of pharmacists but not from the perspectives of other stakeholders who can interact with and influence the implementation of CPSs. The aim of this study was to synthesise the literature on patients', general practitioners' (GPs) and nurses' perspectives of CPSs to identify barriers and facilitators to their implementation in Australia.
MethodsA meta-synthesis of qualitative studies was performed. A systematic search in PubMed, Scopus and Informit was conducted to identify studies that explored patients', GPs' or nurses' views about CPSs in Australia. Thematic synthesis was performed to identify elements influencing CPS implementation, which were further classified using an ecological approach.
ResultsTwenty-nine articles were included in the review, addressing 63 elements influencing CPS implementation. Elements were identified as a barrier, facilitator or both and were related to four ecological levels: individual patient (n=14), interpersonal (n=24), organisational (n=16) and community and healthcare system (n=9). It was found that patients, nurses and GPs identified elements reported in previous pharmacist-informed studies, such as pharmacist's training/education or financial remuneration, but also new elements, such as patients' capability to follow service's procedures, the relationships between GP and pharmacy professional bodies or the availability of multidisciplinary training/education.
ConclusionsPatients, GPs and nurses can describe a large number of elements influencing CPS implementation. These elements can be combined with previous findings in pharmacists-informed studies to produce a comprehensive framework to assess barriers and facilitators to CPS implementation. This framework can be used by pharmacy service planners and policy makers to improve the analysis of the contexts in which CPSs are implemented.
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Feasibility randomised multicentre, double-blind, double-dummy controlled trial of anakinra, an interleukin-1 receptor antagonist versus intramuscular methylprednisolone for acute gout attacks in patients with chronic kidney disease (ASGARD): protocol study
Introduction
Acute gout occurs in people with chronic kidney disease, who are commonly older people with comorbidities such as hypertension, heart disease and diabetes. Potentially harmful treatments are administered to these vulnerable patients due to a lack of clear evidence. Newly available treatment that targets a key inflammatory pathway in acute gout attacks provides an opportunity to undertake the first-ever trial specifically looking treating people with kidney disease. This paper describes the protocol for a feasibility randomised controlled trial (RCT) comparing anakinra, a novel interleukin-1 antagonist versus steroids in people with chronic kidney disease (ASGARD).
Methods and analysisASGARD is a two-parallel group double-blind, double-dummy multicentre RCT comparing anakinra 100 mg, an interleukin-1 antagonist, subcutaneous for 5 days against intramuscular methylprednisolone 120 mg. The primary objective is to assess the feasibility of the trial design and procedures for a definitive RCT. The specific aims are: (1) test recruitment and retention rates and willingness to be randomised; (2) test eligibility criteria; (3) collect and analyse outcome data to inform sample and power calculations for a trial of efficacy; (4) collect economic data to inform a future economic evaluation estimating costs of treatment and (5) assess capacity of the project to scale up to a national multicentre trial. We will also gather qualitative insights from participants. It aims to recruit 32 patients with a 1:1 randomisation. Information from this feasibility study will help design a definitive trial and provide general information in designing acute gout studies.
Ethics and disseminationThe London-Central Ethics Committee approved the protocol. The results will be disseminated in peer-reviewed journals and at scientific conferences.
Trial registration numberEudraCT No. 2015-001787-19, NCT/Clinicalstrials.gov No. NCT02578394, pre-results, WHO Universal Trials Reference No. U1111-1175-1977. NIHR Grant PB-PG-0614–34090.
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What treatments work for anxiety in children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)? Systematic review
Objectives
Anxiety is more prevalent in children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) than in the general population. A systematic review was carried out to identify which treatment methods are most effective for children with CFS and anxiety.
DesignSystematic review using search terms entered into the Cochrane library and Ovid to search the databases Medline, Embase and psychINFO.
ParticipantsStudies were selected if participants were <18 years old, diagnosed with CFS/ME (using US Centers for Disease Control and Prevention, the National Institute for Health and Care Excellence or Oxford criteria) and had a valid assessment of anxiety.
InterventionsWe included observational studies and randomised controlled trials.
ComparisonAny or none.
OutcomesChange in anxiety diagnostic status and/or change in anxiety severity on a validated measure of anxiety from pretreatment to post-treatment.
ResultsThe review identified nine papers from eight studies that met the inclusion criteria. None of the studies specifically targeted anxiety but six studies tested an intervention and measured anxiety as a secondary outcome. Of these studies, four used a cognitive behavioural therapy (CBT)-type approach to treat CFS/ME, one used a behavioural approach and one compared a drug treatment, gammaglobulin with a placebo. Three of the CBT-type studies described an improvement in anxiety as did the trial of gammaglobulin. As none of the studies stratified outcomes according to anxiety diagnostic status or severity, we were unable to determine whether anxiety changed prognosis or whether treatments were equally effective in those with comorbid anxiety compared with those without.
ConclusionWe do not know what treatment should be offered for children with both anxiety and CFS/ME. Further research is therefore required to answer this question.
Trial registration numberThis review was registered on Prospective Register of Systematic Review Protocols (PROSPERO) and the protocol is available from http://ift.tt/2wEI6dF.
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Changes in mortality inequalities across occupations in Japan: a national register based study of absolute and relative measures, 1980-2010
Objective
Changes in mortality inequalities across socioeconomic groups have been a substantial public health concern worldwide. We investigated changes in absolute/relative mortality inequalities across occupations, and the contribution of different diseases to inequalities in tandem with the restructuring of the Japanese economy.
MethodsUsing complete Japanese national death registries from 5 year intervals (1980–2010), all cause and cause specific age standardised mortality rates (ASMR per 100 000 people standardised using the Japanese standard population in 1985, aged 30–59 years) across 12 occupations were computed. Absolute and relative inequalities were measured in ASMR differences (RDs) and ASMR ratios (RRs) among occupations in comparison with manufacturing workers (reference). We also estimated the changing contribution of different diseases by calculating the differences in ASMR change between 1995 and 2010 for occupations and reference.
ResultsAll cause ASMRs tended to decrease in both sexes over the three decades except for male managers (increased by 71% points, 1995–2010). RDs across occupations were reduced for both sexes (civil servants 233.5 to –1.9 for men; sales workers 63.3 to 4.5 for women) but RRs increased for some occupations (professional workers 1.38 to 1.70; service workers 2.35 to 3.73) for men and decreased for women from 1980 to 2010. Male relative inequalities widened among farmer, fishery and service workers, because the percentage declines were smaller in these occupations. Cerebrovascular disease and cancer were the main causes of the decrease in mortality inequalities among sexes but the incidence of suicide increased among men, thereby increasing sex related inequalities.
ConclusionsAbsolute inequality trends in mortality across occupations decreased in both sexes, while relative inequality trends were heterogeneous in Japan. The main drivers of narrowing and widening mortality inequalities were cerebrovascular disease and suicide, respectively. Future public health efforts will benefit from eliminating residual inequalities in mortality by considering the contribution of the causes of death and socioeconomic status stratification.
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Cohort profile: maternal lifestyle and diet in relation to pregnancy, postpartum and infant health outcomes in Vietnam: A multicentre prospective cohort study
Purpose
To determine modifiable maternal risk factors for adverse pregnancy, postpartum maternal and child health outcomes in Vietnam.
ParticipantsThis prospective cohort study included pregnant women seeking prenatal care at six hospitals in three large cities in Vietnam. After enrolment, eligible participants who gave their consent to participate in the study were interviewed at 24–28 weeks' gestation. Glucose testing was conducted and blood pressure was measured during this period. Each participant will be assessed prospectively during their postnatal visits at delivery, 1, 3, 6, 12, 18 and 24 months, and will be followed up for 5 years.
Findings to dateOf 2248 eligible pregnant women, 2030 were recruited (participation rate 90.3%) between August 2015 and July 2016. All participants completed the baseline assessment. Their mean (SD) age was 27.6 (5.3) years. The mean pre-pregnancy body mass index (BMI) was 20.2 (SD 2.6) kg/m2, with nearly two-thirds of participants having a normal pre-pregnancy BMI (18.5 to <23.0 kg/m2) and one-quarter being underweight (pre-pregnancy BMI <18.5 kg/m2). Overweight or obese mothers (pre-pregnancy BMI ≥23.0 kg/m2) accounted for 12.8%. No pregnant women reported smoking during their pregnancy while 13.4% of them had continued drinking. 22.8% of participants had hyperglycaemia. Their mean systolic blood pressure was 105.6 (SD 8.2) mm Hg, and diastolic blood pressure was 67.4 (SD 7.5) mm Hg.
Future plansThe relationships of maternal lifestyle and nutritional status with the health outcomes of pregnancy, postpartum maternity and infants will be analysed. Meanwhile, participants will be closely tracked to minimise loss to follow-up.
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APpropriAteness of percutaneous Coronary interventions in patients with ischaemic HEart disease in Italy: the APACHE pilot study
Objectives
To first explore in Italy appropriateness of indication, adherence to guideline recommendations and mode of selection for coronary revascularisation.
DesignRetrospective, pilot study.
Setting22 percutaneous coronary intervention (PCI)-performing hospitals (20 patients per site), 13 (59%) with on-site cardiac surgery.
Participants440 patients who received PCI for stable coronary artery disease (CAD) or non-ST elevation acute coronary syndrome were independently selected in a 4:1 ratio with half diabetics.
Primary and secondary outcome measuresProportion of patients who received appropriate PCI using validated appropriate use scores (ie, AUS≥7). Also, in patients with stable CAD, we examined adherence to the following European Society of Cardiology recommendations: (A) per cent of patients with complex coronary anatomy treated after heart team discussion; (B) per cent of fractional flow reserve-guided PCI for borderline stenoses in patients without documented ischaemia; (C) per cent of patients receiving guideline-directed medical therapy at the time of PCI as well as use of provocative test of ischaemia according to pretest probability (PTP) of CAD.
ResultsOf the 401 mappable PCIs (91%), 38.7% (95% CI 33.9 to 43.6) were classified as appropriate, 47.6% (95% CI 42.7 to 52.6) as uncertain and 13.7% (95% CI 10.5% to 17.5%) as inappropriate. Median PTP in patients with stable CAD without known coronary anatomy was 69% (78% intermediate PTP, 22% high PTP). Ischaemia testing use was similar (p=0.71) in patients with intermediate (n=140, 63%) and with high PTP (n=40, 66%). In patients with stable CAD (n=352) guideline adherence to the three recommendations explored was: (A) 11%; (B) 25%; (C) 23%. AUS was higher in patients evaluated by the heart team as compared with patients who were not (7 (6.8) vs 5 (4.7); p=0.001).
ConclusionsUse of heart team approaches and adherence to guideline recommendations on coronary revascularisation in a real-world setting is limited. This pilot study documents the feasibility of measuring appropriateness and guideline adherence in clinical practice and identifies substantial opportunities for quality improvement.
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Effects of external inspection on sepsis detection and treatment: a study protocol for a quasiexperimental study with a stepped-wedge design
Introduction
Inspections are widely used in health care as a means to improve the health services delivered to patients. Despite their widespread use, there is little evidence of their effect. The mechanisms for how inspections can promote change are poorly understood. In this study, we use a national inspection campaign of sepsis detection and initial treatment in hospitals as case to: (1) Explore how inspections affect the involved organizations. (2) Evaluate what effect external inspections have on the process of delivering care to patients, measured by change in indicators reflecting how sepsis detection and treatment is carried out. (3) Evaluate whether external inspections affect patient outcomes, measured as change in the 30-day mortality rate and length of hospital stay.
Methods and analysisThe intervention that we study is inspections of sepsis detection and treatment in hospitals. The intervention will be rolled out sequentially during 12 months to 24 hospitals. Our effect measures are change on indicators related to the detection and treatment of sepsis, the 30-day mortality rate and length of hospital stay. We collect data from patient records at baseline, before the inspections, and at 8 and 14 months after the inspections. We use logistic regression models and linear regression models to compare the various effect measurements between the intervention and control periods. All the models will include time as a covariate to adjust for potential secular changes in the effect measurements during the study period. We collect qualitative data before and after the inspections, and we will conduct a thematic content analysis to explore how inspections affect the involved organisations.
Ethics and disseminationThe study has obtained ethical approval by the Regional Ethics Committee of Norway Nord and the Norwegian Data Protection Authority. It is registered at http://ift.tt/PmpYKN (Identifier: NCT02747121). Results will be reported in international peer-reviewed journals.
Trial RegistrationNCT02747121; Pre-results.
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Effects of complex interventions in 'skin cancer prevention and treatment: protocol for a mixed-method systematic review with qualitative comparative analysis
Introduction
Occurring from ultraviolet radiation combined with impairing ozone levels, uncritical sun exposure and use of tanning beds an increasing number of people are affected by different types of skin cancer. But preventive interventions like skin cancer screening are still missing the evidence for effectiveness and therefore are criticised. Fundamental for an appropriate course of action is to approach the defined parameters as measures for effectiveness critically. A prerequisite should be the critical application of used parameter that are defined as measures for effectiveness. This research seeks to establish, through the available literature, the effects and conditions that prove the effectiveness of prevention strategies in skin cancer.
Method and analysisA mixed-method approach is employed to combine quantitative to qualitative methods and answer what effects can display effectiveness considering time horizon, perspective and organisational level and what are essential and sufficient conditions to prove effectiveness and cost-effectiveness in skin cancer prevention strategies. A systematic review will be performed to spot studies from any design and assess the data quantitatively and qualitatively. Included studies from each key question will be summarised by characteristics like population, intervention, comparison, outcomes, study design, endpoints, effect estimator and so on. Beside statistical relevancies for a systematic review the qualitative method of qualitative comparative analysis (QCA) will be performed. The estimated outcomes from this review and QCA are the accomplishment and absence of effects that are appropriate for application in effectiveness assessments and further cost-effectiveness assessment.
Ethics and disseminationFormal ethical approval is not required as primary data will not be collected.
Trial registration numberInternational Prospective Register for Systematic Reviews number CRD42017053859.
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Psychological distress following a motor vehicle crash: evidence from a statewide retrospective study examining settlement times and costs of compensation claims
Objective
To determine whether psychological distress associated with musculoskeletal injuries sustained in a motor vehicle crash (MVC), regardless of time of onset, impacts compensation outcomes such as claim settlement times and costs. Second, to identify factors routinely collected by insurance companies that contribute to psychological distress during the compensation process.
DesignStatewide retrospective study.
Data sourceAnalysis of the New South Wales statewide (Australia) injury register for MVC survivors who lodged a compensation claim from 2011 to 2013.
Participants6341 adults who sustained a musculoskeletal injury and who settled a claim for injury after an MVC. Participants included those diagnosed with psychological distress (n=607) versus those not (n=5734).
Main outcome measuresTime to settlement and total costs of claims, as well as socio-demographic and injury characteristics that may contribute to elevated psychological distress, such as socio-economic disadvantage, and injury severity.
ResultsPsychological distress in those with a musculoskeletal injury was associated with significantly longer settlement times (an additional 17 weeks) and considerably higher costs (an additional $A41 575.00 or 4.3 times more expensive). Multivariate logistic regression analysis identified risk factors for psychological distress including being female, social disadvantage, unemployment prior to the claim, not being at fault in the MVC, requiring ambulance transportation and rehabilitation as part of recovery.
ConclusionsResults provide compelling evidence that psychological distress has an adverse impact on people with musculoskeletal injury as they progress through compensation. Findings suggest that additional resources should be directed toward claimants who are at risk (eg, the socially disadvantaged or those unemployed prior to the claim), the major aim being to reduce risk of psychological distress, such as post-traumatic stress disorder, and associated risk of increased settlement times and claim costs. Prospective studies are now required that investigate treatment strategies for those at risk of psychological distress associated with an MVC.
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Real-life use of onabotulinumtoxinA for symptom relief in patients with chronic migraine: REPOSE study methodology and baseline data
Abstract
Background
Migraine is a debilitating neurological disorder that affects 14.1% of the US and 14.7% of the European populations. Chronic migraine (CM) is broadly defined as headache occurring on ≥15 days per month for ≥3 months, and has an estimated worldwide prevalence of 1.4% to 2.2%. OnabotulinumtoxinA is currently approved for the treatment of CM in most European countries, and is the only preventative treatment approved for adults with CM, based on results from the PREEMPT clinical trial programme. The ongoing prospective, observational REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilisation, and Patient-reported OutcomeS observed in practice (REPOSE) Study aims to describe real-world healthcare resource utilisation and patient-reported outcomes over a 2-year period in Germany, Italy, Norway, Russia, Spain, Sweden, and the United Kingdom, among patients with CM prescribed onabotulinumtoxinA.
Methods
Herein, methodology and baseline characteristics of patients who participated for ≥6 months in REPOSE are reported. No outcomes data are presented, although the methods for collecting these data are detailed. In REPOSE, onabotulinumtoxinA is administered at baseline and each follow-up visit (approximately every 3 months) during the 24-month treatment period, according to the treating physician's best clinical judgment and standard of care, guided by the terms of the marketing authorisation described in the Summary of Product Characteristics. Outcome assessments include Migraine-Specific Quality of Life Questionnaire (MSQ), EuroQol Group Questionnaire (EQ-5D), headache-day frequency, treatment satisfaction, headache-related healthcare resource utilisation (ie, healthcare professional visits, hospital admissions, medication use), onabotulinumtoxinA utilisation (ie, dose, sites), and safety/tolerability.
Results
As of the interim assessment date for this analysis, the study has enrolled 644 patients from 78 sites throughout Europe, and baseline data are available for 336 patients from 61 sites who participated in the study for ≥6 months. Baseline measures indicate substantial disease burden and healthcare resource utilisation.
Conclusions
Final results from the REPOSE Study will provide the largest real-world, long-term analysis of the clinical use of onabotulinumtoxinA for the treatment of CM and will add important information to existing real-world findings. Future analyses will assess the long-term safety and efficacy of onabotulinumtoxinA in this population.
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Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section
Abstract
Clinical examples of amyloid deposition in parathyroid glands are exceedingly rare and usually present as an incidental finding in a patient with amyloid goiter. Here, we present the first histologically documented case of parathyroid amyloid deposition that presented as a mass. The patient did not have hyperparathyroidism. The parathyroid gland was submitted for intra-operative frozen section and concern for medullary thyroid carcinoma was raised. An important histologic clue arguing against medullary thyroid carcinoma was the evenly dispersed nature of the amyloid. Histologic perinuclear clearing and parathyroid hormone immunohistochemistry confirmed parathyroid origin on permanent sections. The patient was also found to have associated amyloid goiter. Mass spectrometry of the amyloid showed it to be composed of kappa light chains. On further work-up, the patient was diagnosed with multiple myeloma. Awareness of parathyroid amyloid deposition is important as it is a histologic mimic of medullary thyroid carcinoma, especially on frozen section. Amyloid typing with evaluation for multiple myeloma in any patient with kappa or lambda light chain restriction is also important.
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Application of the thermostable β-galactosidase, BgaB, from Geobacillus stearothermophilus as a versatile reporter under anaerobic and aerobic conditions
Use of thermophilic organisms has a range of advantages, but the significant lack of engineering tools limits their applications. Here we show that β-galactosidase from Geobacillus stearothermophilus (BgaB) can b...
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Orofacial pain: pharmacological treatments
This review of pharmacological management of orofacial pain included 41 studies. Evidence suggests that for TMD joint pain NSAIDs, corticosteroids and hyaluronate injections are beneficial and that clonazepam and capsaicin are effective for burning mouth syndrome.
The post Orofacial pain: pharmacological treatments appeared first on National Elf Service.
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Temporal Bone Fracture Requiring Facial Nerve Decompression or Repair
Facial nerve paralysis is one of the complications with temporal bone fractures. While the majority of these are treated medically with observation and steroids, we review the indications and surgical approaches to the facial nerve along its course within the temporal bone. It is important to get an exam as early as possible to determine immediate vs delayed, and complete vs incomplete paralysis. Patients with immediate onset, complete facial nerve paralysis should receive electrodiagnostic testing 3 –7 days after onset, to allow for Wallerian degeneration. (Source: Operative Techniques in Otolaryngology - Head and Neck Surgery)
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Management of Retrobulbar Hematoma
This article presents a stepwise discussion of the surgical management of retrobulbar hematoma. (Source: Operative Techniques in Otolaryngology - Head and Neck Surgery)
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Introduction
Dear Readers, (Source: Operative Techniques in Otolaryngology - Head and Neck Surgery)
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Coalescent Mastoiditis
Coalescent mastoiditis occurs as bone is remodeled and resorbed from pressure necrosis, inflammation, and increased osteoclastic activity in the setting of an acute otologic infection. This finding necessitates treatment with antibiotics and surgery, which typically involves pressure equalizing tube placement and mastoidectomy. Herein, we review diagnostic and treatment considerations as well as surgical technique in the management of acute coalescent mastoiditis. (Source: Operative Techniques in Otolaryngology - Head and Neck Surgery)
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Editorial Board (p/u from previous issue)
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Cover 2 - Masthead (p/u from previous issue)
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Information for authors (p/u from previous issue)
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Future and recent issues (p/u from previous issue and update)
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Book Review: Vertigo and Disequilibrium: A Practical Guide to Diagnosis and Management
Annals of Otology, Rhinology &Laryngology, Ahead of Print.
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Clinical Features of a Family with Multiple Endocrine Neoplasia Type 2A Caused by the D631Y RET Mutation
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Editorial Board
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Columnar metaplasia in the remnant esophagus is a long-term indicator for pneumonia after radical esophagectomy
Abstract
Background
This study investigated the long-term risk factors for pneumonia after esophageal reconstruction using a gastric tube via the posterior mediastinal route following esophagectomy for esophageal cancer. The influence of columnar metaplasia in the remnant esophagus was specifically assessed.
Methods
Among 225 patients who underwent esophagectomy between January 2004 and December 2010, the subjects were 54 patients who could be followed up for more than 5 years. Routine oncologic follow-up consisted of CT scanning of the abdomen and chest every 4–6 months and annual endoscopy. Data on the occurrence of pneumonia were collected by retrospective review of chest CT scans. Risk factors for pneumonia investigated by univariate and multivariate analyses included the age, gender, diameter of the stapler, length of the intrathoracic remnant esophagus, anastomotic stricture, and presence of columnar metaplasia in the remnant esophagus.
Results
The median age was 62.4 years (interquartile range: 55.8–68.0 years). Forty-three patients were men. Pneumonia was detected in 39 patients (72.2%). The incidence of columnar metaplasia in the remnant esophagus increases with time. Anastomotic stricture was significantly related to the absence of columnar metaplasia on endoscopy in the first year after esophagectomy (p = 0.013). Univariate analysis showed that the frequency of pneumonia was significantly related to the intrathoracic remnant esophagus length ≥4.4 cm (p = 0.014), age over 65 years (p = 0.014), and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy (p = 0.005). Among them, age over 65 years and the presence of columnar metaplasia in the remnant esophagus in the fifth year after esophagectomy were found to be independent indicators of the postoperative pneumonia by multivariate analysis.
Conclusion
Pneumonia occurred in 72.2% (39/54) of patients after esophagectomy for esophageal cancer. The presence of columnar metaplasia after esophagectomy is an indicator for pneumonia over the long term.
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Descriptive Rules for Achalasia of the Esophagus, June 2012: 4th Edition
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Leaf proteomics of drought-sensitive and -tolerant genotypes of fennel
Publication date: Available online 5 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Ehsaneh Khodadadi, Barat Ali Fakheri, Saeed Aharizad, Abbasali Emamjomeh, Majid Norouzi, Setsuko Komatsu
Fennel is attracted attention as a useful resource as researching medicinal plant for drought tolerance. To elucidate the response mechanism in drought-sensitive and -tolerant genotypes of fennel leaf, a gel-free/label-free proteomic technique was used. Fifty-day-old plants were subjected to drought stress for 60days. The relative water and proline contents were decreased and increased in sensitive genotypes, respectively; however, they were not a big change in tolerant genotypes. Photosynthesis was decreased in the sensitive genotypes under drought; however, it was increased in the tolerant genotype. In both drought-sensitive and -tolerant genotypes, proteins related to protein metabolism and cell organization were predominately affected under drought stress. The abundance of phosphoribulokinase and phosphoglycerate kinase enzymes were decreased and increased in drought-sensitive and -tolerant genotypes, respectively; however, the abundance of RuBisCO and glyceraldehyde-3-phosphate dehydrogenase enzymes were increased and decreased in drought-sensitive and -tolerant genotypes, respectively. Under drought stress, the abundance of glycolysis-related proteins was decreased in sensitive genotypes; however, they were increased in tolerance genotypes. Commonly changed proteins with polyethylene glycol fractionation such as cobalamin-independent methionine synthase were decreased and increased in drought-sensitive and -tolerant genotypes, respectively. These results suggest that cobalamin-independent methionine synthetase is involved in the tolerance of drought-tolerant fennel leaf under drought stress.
Graphical abstract
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Beacon Hill Roll Call
SENATORS' VOTES WITH THEIR PARTY LEADERSHIP - This week, Beacon Hill Roll Call reports the percentage of times local senators voted with their party's leadership in 2017 through Sept.
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Ureter metastatic castration-resistant prostate cancer: a case report
In most cases, prostate cancer metastasizes to the lymph nodes, bone, and liver. In very rare cases, it metastasizes to the ureter. Due to the difficulty in making a preoperative diagnosis, ureteral metastasis...
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Focal Adhesion Kinase Activation Is Necessary for Stretch-Induced Alignment and Enhanced Differentiation of Myogenic Precursor Cells
Tissue Engineering Part A , Vol. 0, No. 0.
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Nanotopographic Influence on the In Vitro Behavior of Induced Pluripotent Stem Cells
Tissue Engineering Part A , Vol. 0, No. 0.
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Repair of Tympanic Membrane Perforations with Customized Bioprinted Ear Grafts Using Chinchilla Models
Tissue Engineering Part A , Vol. 0, No. 0.
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Use of RGD-Functionalized Sandwich Cultures to Promote Redifferentiation of Human Pancreatic Beta Cells After In Vitro Expansion
Tissue Engineering Part A , Vol. 0, No. 0.
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Wnt/Yes-Associated Protein Interactions During Neural Tissue Patterning of Human Induced Pluripotent Stem Cells
Tissue Engineering Part A , Vol. 0, No. 0.
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Tail-Anchored Protein Insertion by a Single Get1/2 Heterodimer
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Benjamin E. Zalisko, Charlene Chan, Vladimir Denic, Ronald S. Rock, Robert J. Keenan
The Get1/2 transmembrane complex drives the insertion of tail-anchored (TA) proteins from the cytosolic chaperone Get3 into the endoplasmic reticulum membrane. Mechanistic insight into how Get1/2 coordinates this process is confounded by a lack of understanding of the basic architecture of the complex. Here, we define the oligomeric state of full-length Get1/2 in reconstituted lipid bilayers by combining single-molecule and bulk fluorescence measurements with quantitative in vitro insertion analysis. We show that a single Get1/2 heterodimer is sufficient for insertion and demonstrate that the conserved cytosolic regions of Get1 and Get2 bind asymmetrically to opposing subunits of the Get3 homodimer. Altogether, our results define a simplified model for how Get1/2 and Get3 coordinate TA protein insertion.
Graphical abstract
Teaser
Tail-anchored membrane proteins are inserted into the endoplasmic reticulum via the post-translational GET pathway. Zalisko et al. combine single-molecule and bulk fluorescence measurements with quantitative in vitro insertion assays to define the architecture of the heterodimeric Get1/2 insertase and its engagement with the soluble chaperone Get3.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gKEZeM
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Dynamics of Presynaptic Diacylglycerol in a Sensory Neuron Encode Differences between Past and Current Stimulus Intensity
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Hayao Ohno, Naoko Sakai, Takeshi Adachi, Yuichi Iino
Memorizing the intensity of sensory stimuli enables animals to successfully deal with changing environmental conditions and contributes to cognitive functions such as auditory and visual working memory. However, how nervous systems process past and current stimulus intensity is largely unknown at the molecular level. Here, we employ in vivo diacylglycerol (DAG) imaging in the ASER taste neuron of Caenorhabditis elegans and demonstrate that associative learning between ambient salt concentrations and food can be explained by changes in presynaptic DAG. The abundance of DAG is regulated in response to external salt concentration changes via sensory transduction in ASER and can encode differences between past and current salt concentrations. The DAG dynamics are modulated downstream of the synaptic insulin/phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates the behavioral plasticity induced by starvation. These results provide insights into how a single neuron stores past input intensity and generates appropriate behavioral responses.
Graphical abstract
Teaser
Animals adapt to environmental changes by memorizing the intensity of sensory stimuli. By employing diacylglycerol imaging and behavioral analyses, Ohno et al. show the in vivo dynamics of neuronal diacylglycerol and present insights into how a single neuron processes past and current stimulus intensity.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f1AVmM
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Local Nucleation of Microtubule Bundles through Tubulin Concentration into a Condensed Tau Phase
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Amayra Hernández-Vega, Marcus Braun, Lara Scharrel, Marcus Jahnel, Susanne Wegmann, Bradley T. Hyman, Simon Alberti, Stefan Diez, Anthony A. Hyman
Non-centrosomal microtubule bundles play important roles in cellular organization and function. Although many diverse proteins are known that can bundle microtubules, biochemical mechanisms by which cells could locally control the nucleation and formation of microtubule bundles are understudied. Here, we demonstrate that the concentration of tubulin into a condensed, liquid-like compartment composed of the unstructured neuronal protein tau is sufficient to nucleate microtubule bundles. We show that, under conditions of macro-molecular crowding, tau forms liquid-like drops. Tubulin partitions into these drops, efficiently increasing tubulin concentration and driving the nucleation of microtubules. These growing microtubules form bundles, which deform the drops while remaining enclosed by diffusible tau molecules exhibiting a liquid-like behavior. Our data suggest that condensed compartments of microtubule bundling proteins could promote the local formation of microtubule bundles in neurons by acting as non-centrosomal microtubule nucleation centers and that liquid-like tau encapsulation could provide both stability and plasticity to long axonal microtubule bundles.
Graphical abstract
Teaser
Hernández-Vega et al. show that tau forms liquid-like drops in vitro. Tubulin gets enriched in these drops, enabling microtubule bundles polymerization within drops. Microtubule bundles deform tau drops, reshaping them into rod-like structures. Microtubules in these structures remain as stable bundles. The findings have potential implications for tau function in axonal projections.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2f1ATva
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Cbln1 and Cbln4 Are Structurally Similar but Differ in GluD2 Binding Interactions
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Chen Zhong, Jinlong Shen, Huibing Zhang, Guangyi Li, Senlin Shen, Fang Wang, Kuan Hu, Longxing Cao, Yongning He, Jianping Ding
SummaryUnlike cerebellin 1 (Cbln1), which bridges neurexin (Nrxn) receptors and δ-type glutamate receptors in a trans-synaptic triad, Cbln4 was reported to have no or weak binding for the receptors despite sharing ∼70% sequence identity with Cbln1. Here, we report crystal structures of the homotrimers of the C1q domain of Cbln1 and Cbln4 at 2.2 and 2.3 Å resolution, respectively. Comparison of the structures suggests that the difference between Cbln1 and Cbln4 in GluD2 binding might be because of their sequence and structural divergence in loop CD. Surprisingly, we show that Cbln4 binds to Nrxn1β and forms a stable complex with the laminin, nectin, sex-hormone binding globulin (LNS) domain of Nrxn1β. Furthermore, the negative-stain electron microscopy reconstruction of hexameric full-length Cbln1 at 13 Å resolution and that of the Cbln4/Nrxn1β complex at 19 Å resolution suggest that Nrxn1β binds to the N-terminal region of Cbln4, probably through strand β10 of the S4 insert.
Graphical abstract
Teaser
Cbln1 and Cbln4 share high sequence identity but have divergent functions. Zhong et al. find that Cbln4 forms a complex with Nrxn1β. Using crystal structures of the C1q domain of Cbln1 and Cbln4 and negative-stain EM reconstructions of Cbln1 and Cbln4/Nrxn1β, the authors examine similarities and divergence between Cbln1 and Cbln4.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gK39WF
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Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Jonathan M. Goodwin, William E. Dowdle, Rowena DeJesus, Zuncai Wang, Philip Bergman, Marek Kobylarz, Alicia Lindeman, Ramnik J. Xavier, Gregory McAllister, Beat Nyfeler, Gregory Hoffman, Leon O. Murphy
Iron is vital for many homeostatic processes, and its liberation from ferritin nanocages occurs in the lysosome. Studies indicate that ferritin and its binding partner nuclear receptor coactivator-4 (NCOA4) are targeted to lysosomes by a form of selective autophagy. By using genome-scale functional screening, we identify an alternative lysosomal transport pathway for ferritin that requires FIP200, ATG9A, VPS34, and TAX1BP1 but lacks involvement of the ATG8 lipidation machinery that constitutes classical macroautophagy. TAX1BP1 binds directly to NCOA4 and is required for lysosomal trafficking of ferritin under basal and iron-depleted conditions. Under basal conditions ULK1/2-FIP200 controls ferritin turnover, but its deletion leads to TAX1BP1-dependent activation of TBK1 that regulates redistribution of ATG9A to the Golgi enabling continued trafficking of ferritin. Cells expressing an amyotrophic lateral sclerosis (ALS)-associated TBK1 allele are incapable of degrading ferritin suggesting a molecular mechanism that explains the presence of iron deposits in patient brain biopsies.
Graphical abstract
Teaser
Goodwin et al. employ functional CRISPR screening approaches to show lysosomal ferritin turnover is autophagy-independent, revealing a role for TBK1 in iron homeostasis.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJWEmE
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Strong Clonal Relatedness between Serum and Gut IgA despite Different Plasma Cell Origins
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Rasmus Iversen, Omri Snir, Maria Stensland, José E. Kroll, Øyvind Steinsbø, Ilma R. Korponay-Szabó, Knut E.A. Lundin, Gustavo A. de Souza, Ludvig M. Sollid
Mucosal antigens induce generation of lamina propria plasma cells (PCs) that secrete dimeric immunoglobulin A (IgA) destined for transport across the epithelium. In addition, blood contains monomeric IgA. To study the relationship between mucosal and systemic antibody responses, we took advantage of celiac disease patient samples for isolation of gut PCs as well as serum IgA and IgG reactive with a gluten-derived peptide or the autoantigen transglutaminase 2. Proteomic analysis of serum IgA revealed antigen-specific V-gene preferences, which matched those found in gut PCs. Further, gut PC CDR-H3 sequences were abundant in serum IgA but also detectable in serum IgG. Our data indicate that the same B cell clones that give rise to gut PCs also contribute to the serum antibody pool. However, serum IgA antibodies had a molecular composition distinct from that of IgA antibodies secreted in the gut, suggesting that individual B cell clones give rise to different PC populations.
Graphical abstract
Teaser
The relationship between mucosal antibody responses and antibodies in blood is not clearly understood. Iversen et al. use proteomics to characterize antibodies in serum and gut biopsy specimens obtained from celiac disease patients. Serum and gut IgA are derived from the same B cell clones but produced by different plasma cells.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJXKio
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KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Tirtha Kamal Das, Ross Leigh Cagan
Gene fusions are increasingly recognized as important cancer drivers. The KIF5B-RET gene has been identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation, including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. The KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation, including invadopodia-like processes. Through a combination of genetic and biochemical studies, we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB-vesicle-dependent RET-SRC-EGFR-FGFR signaling hub. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR, microtubules, or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility of exploring the full biology of fusions to identify rational therapeutic strategies.
Graphical abstract
Teaser
Das and Cagan find that each portion of the KIF5B-RET fusion oncoprotein recruits different components to assemble a multi-kinase oncogenic signaling hub that promotes invadopodia formation. This suggests that multiple kinase components of this KIF5B-RET hub need to be simultaneously targeted therapeutically.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJOWsO
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ALPK1- and TIFA-Dependent Innate Immune Response Triggered by the Helicobacter pylori Type IV Secretion System
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Stephanie Zimmermann, Lennart Pfannkuch, Munir A. Al-Zeer, Sina Bartfeld, Manuel Koch, Jianping Liu, Cindy Rechner, Meike Soerensen, Olga Sokolova, Alla Zamyatina, Paul Kosma, André P. Mäurer, Frithjof Glowinski, Klaus-Peter Pleissner, Monika Schmid, Volker Brinkmann, Alexander Karlas, Michael Naumann, Marion Rother, Nikolaus Machuy, Thomas F. Meyer
Activation of transcription factor NF-κB is a hallmark of infection with the gastric pathogen Helicobacter pylori, associated with inflammation and carcinogenesis. Genome-wide RNAi screening revealed numerous host factors involved in H. pylori-, but not IL-1β- and TNF-α-dependent NF-κB regulation. Pathway analysis including CRISPR/Cas9-knockout and recombinant protein technology, immunofluorescence microscopy, immunoblotting, mass spectrometry, and mutant H. pylori strains identified the H. pylori metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (βHBP) as a cagPAI type IV secretion system (T4SS)-dependent effector of NF-κB activation in infected cells. Upon pathogen-host cell contact, TIFA forms large complexes (TIFAsomes) including interacting host factors, such as TRAF2. NF-κB activation, TIFA phosphorylation, and TIFAsome formation depend on a functional ALPK1 kinase, highlighting the ALPK1-TIFA axis as a core innate immune pathway. ALPK1-TIFA-mediated NF-κB activation was independent of CagA protein translocation, indicating that CagA translocation and HBP delivery to host cells are distinct features of the pathogen's T4SS.
Graphical abstract
Teaser
Zimmermann et al. identify pathogen and host factors involved in NF-κB activation after infection with type IV secretion-proficient Helicobacter pylori. Central hits are ALPK1 and TIFA. ALPK1 is necessary for phosphorylation-dependent formation of TIFA complexes (TIFAsomes) with TRAF2. This yields HBP-ALPK1-TIFA-TRAF2-NF-κB as the core-regulon of H. pylori-induced innate immune activation.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gKSUBt
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Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Florine E.M. Scholte, Marko Zivcec, John V. Dzimianski, Michelle K. Deaton, Jessica R. Spengler, Stephen R. Welch, Stuart T. Nichol, Scott D. Pegan, Christina F. Spiropoulou, Éric Bergeron
Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines.
Graphical abstract
Teaser
Using reverse genetics, Scholte et al. report that OTU catalytic activity is critical for Crimean-Congo hemorrhagic fever virus replication, and deubiquitinase activity suppresses the antiviral response to infection. These findings provide insights in the multifunctional properties of viral OTUs and support development of OTU-specific therapeutics.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJXH6c
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Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Xiao Ling Li, Murugan Subramanian, Matthew F. Jones, Ritu Chaudhary, Deepak K. Singh, Xinying Zong, Berkley Gryder, Sivasish Sindri, Min Mo, Aaron Schetter, Xinyu Wen, Swetha Parvathaneni, Dickran Kazandjian, Lisa M. Jenkins, Wei Tang, Fathi Elloumi, Jennifer L. Martindale, Maite Huarte, Yuelin Zhu, Ana I. Robles, Susan M. Frier, Frank Rigo, Maggie Cam, Stefan Ambs, Sudha Sharma, Curtis C. Harris, Mary Dasso, Kannanganattu V. Prasanth, Ashish Lal
Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.
Graphical abstract
Teaser
For a cell to divide, the tumor suppressor protein p53 must be kept at low levels. Li et al. find that a long noncoding RNA PURPL allows cancer cells to divide by keeping p53 levels low. PURPL binds to the p53 regulator MYBBP1A to suppress p53 levels and facilitate cell proliferation.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gLW741
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A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Steven Moreira, Enio Polena, Victor Gordon, Solen Abdulla, Sujeivan Mahendram, Jiayi Cao, Alexandre Blais, Geoffrey A. Wood, Anna Dvorkin-Gheva, Bradley W. Doble
Co-expression and cross-regulation of the four TCF/LEFs render their redundant and unique functions ambiguous. Here, we describe quadruple-knockout (QKO) mouse ESCs lacking all full-length TCF/LEFs and cell lines rescued with TCF7 or TCF7L1. QKO cells self-renew, despite gene expression patterns that differ significantly from WT, and display delayed, neurectoderm-biased, embryoid body (EB) differentiation. QKO EBs have no contracting cardiomyocytes and differentiate poorly into mesendoderm but readily generate neuronal cells. QKO cells and TCF7L1-rescued cells cannot efficiently activate TCF reporters, whereas TCF7-rescued cells exhibit significant reporter responsiveness. Surprisingly, despite dramatically different transactivation capacities, re-expression of TCF7L1 or TCF7 in QKO cells restores their tri-lineage differentiation ability, with similar lineage marker expression patterns and beating cardiomyocyte frequencies observed in EBs. Both factors also similarly affect the transcriptome of QKO cells. Our data reveal that a single TCF, regardless of its activation capacity, is sufficient for effective trilineage differentiation of ESCs.
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Teaser
Moreira et al. describe the generation and characterization of mouse ESCs lacking all four full-length TCF/LEF factors. By knocking in single epitope-tagged TCF/LEFs, they reveal redundancies in the abilities of "activating" and "repressive" TCFs to rescue the differentiation deficits of the quadruple-knockout cells.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJXG28
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mTORC2 Signaling Selectively Regulates the Generation and Function of Tissue-Resident Peritoneal Macrophages
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Min-Hee Oh, Samuel L. Collins, Im-Hong Sun, Ada J. Tam, Chirag H. Patel, Matthew L. Arwood, Yee Chan-Li, Jonathan D. Powell, Maureen R. Horton
Tissue-resident macrophages play critical roles in sentinel and homeostatic functions as well as in promoting inflammation and immunity. It has become clear that the generation of these cells is highly dependent upon tissue-specific cues derived from the microenvironment that, in turn, regulate unique differentiation programs. Recently, a role for GATA6 has emerged in the differentiation programming of resident peritoneal macrophages. We identify a critical role for mTOR in integrating cues from the tissue microenvironment in regulating differentiation and metabolic reprogramming. Specifically, inhibition of mTORC2 leads to enhanced GATA6 expression in a FOXO1 dependent fashion. Functionally, inhibition of mTORC2 promotes peritoneal resident macrophage generation in the resolution phase during zymosan-induced peritonitis. Also, mTORC2-deficient peritoneal resident macrophages displayed increased functionality and metabolic reprogramming. Notably, mTORC2 activation distinguishes tissue-resident macrophage proliferation and differentiation from that of M2 macrophages. Overall, our data implicate a selective role for mTORC2 in the differentiation of tissue-resident macrophages.
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Teaser
Oh et al. identify the mTORC2-FOXO1 axis as playing a critical role in integrating cues from the microenvironment to regulate metabolic reprogramming, differentiation, and function of peritoneal tissue-resident macrophages.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gJS8EZ
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Heparin Increases Food Intake through AgRP Neurons
Publication date: 5 September 2017
Source:Cell Reports, Volume 20, Issue 10
Author(s): Canjun Zhu, Pingwen Xu, Yanlin He, Yexian Yuan, Tao Wang, Xingcai Cai, Lulu Yu, Liusong Yang, Junguo Wu, Lina Wang, Xiaotong Zhu, Songbo Wang, Ping Gao, Qianyun Xi, Yongliang Zhang, Yong Xu, Qingyan Jiang, Gang Shu
Although the widely used anticoagulant drug heparin has been shown to have many other biological functions independent of its anticoagulant role, its effects on energy homeostasis are unknown. Here, we demonstrate that heparin level is negatively associated with nutritional states and that heparin treatment increases food intake and body weight gain. By using electrophysiological, pharmacological, molecular biological, and chemogenetic approaches, we provide evidence that heparin increases food intake by stimulating AgRP neurons and increasing AgRP release. Our results support a model whereby heparin competes with insulin for insulin receptor binding on AgRP neurons, and by doing so it inhibits FoxO1 activity to promote AgRP release and feeding. Heparin may be a potential drug target for food intake regulation and body weight control.
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Teaser
Zhu et al. demonstrate that heparin competes with insulin for insulin receptor binding on AgRP neurons, and by doing so it inhibits FoxO1 activity to promote AgRP release and feeding. Heparin is identified as a potential drug target for food intake regulation and body weight control.from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2gKpVhc
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Unusual glycosylation of proteins: Beyond the universal sequon and other amino acids
Publication date: Available online 5 September 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Devawati Dutta, Chhabinath Mandal, Chitra Mandal
BackgroundGlycosylation of proteins is the most common, multifaceted co- and post-translational modification responsible for many biological processes and cellular functions. Significant alterations and aberrations of these processes are related to various pathological conditions, and often turn out to be disease biomarkers. Conventional N-glycosylation occurs through the recognition of the consensus sequon, asparagine (Asn)-X-serine (Ser)/threonine (Thr), where X is any amino acid except for proline, with N-acetylglucosamine (GlcNAc) as the first glycosidic linkage. Usually, O-glycosylation adds a glycan to the hydroxyl group of Ser or Thr beginning with N-acetylgalactosamine (GalNAc).Scope of reviewProtein glycosylation is further governed by additional diversifications in sequon and structure, which are yet to be fully explored. This review mainly focuses on the occurrence of N-glycosylation in non-consensus motifs, where Ser/Thr at the +2 position is substituted by other amino acids. Additionally, N-glycosylation is also observed in other amide/amine group-containing amino acids. Similarly, O-glycosylation occurs at hydroxyl group-containing amino acids other than serine/threonine. The neighbouring amino acids and local structural features around the potential glycosylation site also play a significant role in determining the extent of glycosylation. All of these phenomena that yield glycosylation at the atypical sites are reported in a variety of biological systems, including different pathological conditions.Conclusion and SignificanceTherefore, the discovery of more novel sequence patterns for N- and O-glycosylation may help in understanding the functions of complex biological processes and cellular functions. Taken together, all these information provided in this review would be helpful for the biological readers.
Graphical abstract
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Tripeptides Restore the Number of Neuronal Spines under Conditions of In Vitro Modeled Alzheimer’s Disease
In primary culture of mouse hippocampal neurons, peptide EDR (200 ng/ml) under conditions of amyloid synaptotoxicity (a model of Alzheimer's disease) increased the number of mushroom spines by 71% and returned this parameter to the normal level. Under the same conditions, tripeptide KED (200 ng/ml) increased the number of mushroom spines in hippocampal neurons by 20%. Tripeptide EDR can be recommended for further experimental study as a candidate neuroprotective agent for prevention and treatment of Alzheimer's disease.
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p38 МАРK is Involved in Regulation of Epigenetic Mechanisms of Food Aversion Learning
Consolidation of the conditioned food aversion response in Helix lucorum was associated with induction of histone H3 acetylation and methylation. We hypothesized that not only activatory, but also inhibitory p38 MARK-mediated pathways are involved in these processes. To assess the contribution of p38 MAPK to epigenetic processes, we studied the effect p38 MAPK inhibitor SB203580 on acetylation of histone H3 during training of Helix lucorum. Administration of SB203580 decreased learning-induced enhancement of histone H3 acetylation in the CNS of Helix lucorum, which was accompanied by long-term memory impairment. Thus, p38 MAPK is involved in the regulation of epigenetic mechanisms of long-term memory.
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Blue-Shifted Aggregation-Induced Emission of Siloles by Simple Structural Modification and Their Application as Nitro Explosive Chemosensor
Photochem. Photobiol. Sci., 2017, Accepted Manuscript
DOI: 10.1039/C7PP00268H, Paper
DOI: 10.1039/C7PP00268H, Paper
Jiwon Lee, Yoona Park, Joori Jung, Won-Sik Han
To induce blue-shifted emission of silole, two tolyl-substituted derivatives - 1,1-diphenyl-2,3,4,5-tetra(m-tolyl)-1H-silole (m-TS) and 1,1-diphenyl-2,3,4,5-tetra(o-tolyl)-1H-silole (o-TS) - were prepared, and their photophysical properties were compared with those of a reference compound,...
The content of this RSS Feed (c) The Royal Society of Chemistry
To induce blue-shifted emission of silole, two tolyl-substituted derivatives - 1,1-diphenyl-2,3,4,5-tetra(m-tolyl)-1H-silole (m-TS) and 1,1-diphenyl-2,3,4,5-tetra(o-tolyl)-1H-silole (o-TS) - were prepared, and their photophysical properties were compared with those of a reference compound,...
The content of this RSS Feed (c) The Royal Society of Chemistry
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Satisfaction with facial profile aesthetics: are norms overrated?
This study aimed to explore to what extent adults perceive deviations from the norm of a balanced profile with normal occlusion as reducing satisfaction with facial appearance and having a psychosocial impact. This cross-sectional study included 225 Caucasian subjects (64% women) aged 18–42 years. Their facial profiles were analyzed photogrammetrically and they were classified into three categories: within, below, or above the standard range for the Croatian population with a normal occlusion. Psychosocial issues were assessed by self-reported satisfaction with facial appearance and domains from the Orthognathic Quality of Life Questionnaire: social aspects of dentofacial aesthetics (SA), facial aesthetics concern (FA), and awareness of dentofacial aesthetics (AW).
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The action of anti-inflammatory agents in healthy temporomandibular joint synovial tissues is sex-dependent
This study evaluated the effects of dexamethasone, parecoxib, and glucosamine on cartilage thickness and cytokine levels in the temporomandibular joint (TMJ). Forty-eight rats (24 female, 24 male) were assigned to four treatments administered once daily for 7 days: control (saline intramuscularly), parecoxib (0.3mg/kg intramuscularly), dexamethasone (0.1mg/kg intramuscularly), and glucosamine (80mg/kg orally). The thickness of TMJ cartilage and levels of four cytokines were measured. Median cartilage thickness was higher in males than in females in the control (253.2 vs.
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IJMS, Vol. 18, Pages 1629: Overview of β-Glucans from Laminaria spp.: Immunomodulation Properties and Applications on Biologic Models
IJMS, Vol. 18, Pages 1629: Overview of β-Glucans from Laminaria spp.: Immunomodulation Properties and Applications on Biologic Models
International Journal of Molecular Sciences doi: 10.3390/ijms18091629
Authors: Patrícia Bonfim-Mendonça Isis Capoci Flávia Tobaldini-Valerio Melyssa Negri Terezinha Svidzinski
Glucans are a group of glucose polymers that are found in bacteria, algae, fungi, and plants. While their properties are well known, their biochemical and solubility characteristics vary considerably, and glucans obtained from different sources can have different applications. Research has described the bioactivity of β-glucans extracted from the algae of the Laminaria genus, including in vivo and in vitro studies assessing pro- and anti-inflammatory cytokines, vaccine production, inhibition of cell proliferation, and anti- and pro-oxidant activity. Thus, the objective of this article was to review the potential application of β-glucans from Laminaria spp. in terms of their immunomodulatory properties, microorganism host interaction, anti-cancer activity and vaccine development.
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Non-uraemic calciphylaxis: a diagnostic and management challenge for the burns team
Abstract
Calciphylaxis is a rare systemic condition usually seen in patients with end-stage renal disease. It is characterised by pathological calcification of dermal blood vessels, causing ischaemia and necrosis in the skin and subcutaneous fat. The lesions are usually small but, in extreme cases, may be very extensive and may mimic necrotising fasciitis, prompting extensive surgical debridement. We describe the challenges faced in managing such a case. A 38-year-old female patient was admitted to another hospital with widespread progressive truncal skin necrosis. A provisional diagnosis of necrotising fasciitis was made, and she underwent debridement of 32% of her total body surface area (TBSA). However, her condition rapidly deteriorated and she was transferred to our burn centre for further management. Diagnosis of calciphylaxis was based on clinical features and confirmed by tissue biopsy. Characteristic findings of progressive skin and fat necrosis at the wound margins with healthy underlying fascia and muscle were recognised from previously treated cases of calciphylaxis; however, the absence of renal disease proved misleading. Non-uraemic calciphylaxis is very rare but can, as in this case, be associated with alcoholic liver disease. At our centre, the patient required prolonged ventilation and supportive treatment in burns critical care, combined with intensive wound management, repeated episodes of debridement, temporary wound cover using human skin allografts and reconstruction using split-thickness autograft. We report this case to alert others to this rare condition as a possible diagnosis in patients presenting with extensive panniculitis. We discuss associations, diagnostic difficulties, novel therapies and the importance of multidisciplinary care in managing these complex cases.
Level of evidence: Level V, diagnostic study.
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Design of Oxygen Vacancy Configuration for Memristive Systems
ACS Nano
DOI: 10.1021/acsnano.7b03116
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UTHealth ORL & Hurricane Harvey
Hurricane Harvey brought catastrophic flooding to the 6 million inhabitants of the greater Houston region. We are happy to report... Read the full article...
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How Ohio's New Prescription Opioid Rules Will Impact Dentists
Dentists who typically prescribe opioids for wisdom teeth extractions or other surgeries will now have to use more caution. The new state rule for dentists limits prescribing opioids for acute pain to only 7 days, according to the Ohio Dental Board.
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Local Dentist To Help Low-Income Residents
For the 7th year, their dentist office, Smiles For Life Dental Care in Bridgewater, plans to offer free dental care to low-income residents later this month as part of the Dentistry From The Heart program. A Florida dentist looking for a way to give back to his community and to help the growing number of Americans without dental insurance started Dentistry From The Heart in 2001.
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The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions [Research]
The tumor necrosis factor receptor–associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF-α-mediated signaling pathways. Modulation of TRAF2 activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down-regulation of USP48 increases K48-linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels. Interestingly, USP48 only targets the TRAF2 related to JNK pathway, not the TRAF2 related to NF-B and p38 pathways. USP48 is serine phosphorylated in response to TNF-α. The phosphorylation is catalyzed by glycogen synthase kinase 3β (GSK3β), ultimately resulting in increases in USP48 DUB activity. Furthermore, we reveal a new biologic function of TRAF2 that contributes to epithelial barrier dysfunction, which is attenuated by knockdown of USP48. Inhibition of TRAF2/JNK pathway increases E-cadherin expression and enhances epithelial barrier integrity, while knockdown of USP48 attenuates TNF-α/JNK pathway and increases E-cadherin expression and cell–cell junction in epithelial cells. These data, taken together, indicate that USP48 stabilizes TRAF2, which is promoted by GSK3β-mediated phosphorylation. Further, down-regulation of USP48 increases E-cadherin expression and epithelial barrier integrity through reducing TRAF2 stability.—Li, S., Wang, D., Zhao, J., Weathington, N. M., Shang, D., Zhao, Y. The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions.
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Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating [Research]
Mucociliary clearance, driven by the engine of ciliary beating, is the primary physical airway defense against inhaled pathogens and irritants. A better understanding of the regulation of ciliary beating and mucociliary transport is necessary for identifying new receptor targets to stimulate improved clearance in airway diseases, such as cystic fibrosis and chronic rhinosinusitis. In this study, we examined the protease-activated receptor (PAR)-2, a GPCR previously shown to regulate airway cell cytokine and mucus secretion, and transepithelial Cl– current. PAR-2 is activated by proteases secreted by airway neutrophils and pathogens. We cultured various airway cell lines, primary human and mouse sinonasal cells, and human bronchial cells at air–liquid interface and examined them using molecular biology, biochemistry, and live-cell imaging. We found that PAR-2 is expressed basolaterally, where it stimulates both intracellular Ca2+ release and Ca2+ influx, which activates low-level nitric oxide production, increases apical membrane Cl– permeability ~3–5-fold, and increases ciliary beating ~20–50%. No molecular or functional evidence of PAR-4 was observed. These data suggest a novel and previously overlooked role of PAR-2 in airway physiology, adding to our understanding of the role of this receptor in airway Ca2+ signaling and innate immunity.—McMahon, D. B., Workman, A. D., Kohanski, M. A., Carey, R. M., Freund, J. R., Hariri, B. M., Chen, B., Doghramji, L. J., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Lee, R. J. Protease-activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating.
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Computational modeling and validation of human nasal airflow under various breathing conditions
Publication date: Available online 5 September 2017
Source:Journal of Biomechanics
Author(s): Chengyu Li, Jianbo Jiang, Haibo Dong, Kai Zhao
The human nose serves vital physiological functions, including warming, filtration, humidification, and olfaction. These functions are based on transport phenomena that depend on nasal airflow patterns and turbulence. Accurate prediction of these airflow properties requires careful selection of computational fluid dynamics models and rigorous validation. The validation studies in the past have been limited by poor representations of the complex nasal geometry, lack of detailed airflow comparisons, and restricted ranges of flow rate. The objective of this study is to validate various numerical methods based on an anatomically accurate nasal model against published experimentally measured data under breathing flow rates from 180 to 1100 ml/s. The numerical results of velocity profiles and turbulence intensities were obtained using the laminar model, four widely used Reynolds-averaged Navier-Stokes (RANS) turbulence models (i.e., k-e, standard k-w, Shear Stress Transport k-w, and Reynolds Stress Model), large eddy simulation (LES) model, and direct numerical simulation (DNS). It was found that, despite certain irregularity in the flow field, the laminar model achieved good agreement with experimental results under restful breathing condition (180 ml/s) and performed better than the RANS models. As the breathing flow rate increased, the RANS models achieved more accurate predictions but still performed worse than LES and DNS. As expected, LES and DNS can provide accurate predictions of the nasal airflow under all flow conditions but have an approximately 100-fold higher computational cost. Among all the RANS models tested, the standard k-? model agrees most closely with the experimental values in terms of velocity profile and turbulence intensity.
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The Influence of ligament Modelling Strategies on the Predictive Capability of Finite Element Models of the Human Knee Joint
Publication date: Available online 5 September 2017
Source:Journal of Biomechanics
Author(s): Hamid Naghibi Beidokhti, Dennis Janssen, Sebastiaan van de Groes, Javad Hazrati, Ton Van den Boogaard, Nico Verdonschot
In finite element (FE) models knee ligaments can represented either by a group of one-dimensional springs, or by three-dimensional continuum elements based on segmentations. Continuum models closer approximate the anatomy, and facilitate ligament wrapping, while spring models are computationally less expensive. The mechanical properties of ligaments can be based on literature, or adjusted specifically for the subject. In the current study we investigated the effect of ligament modelling strategy on the predictive capability of FE models of the human knee joint. The effect of literature-based versus specimen-specific optimized material parameters was evaluated. Experiments were performed on three human cadaver knees, which were modelled in FE models with ligaments represented either using springs, or using continuum representations. In spring representation collateral ligaments were each modelled with three and cruciate ligaments with two single-element bundles. Stiffness parameters and pre-strains were optimized based on laxity tests for both approaches. Validation experiments were conducted to evaluate the outcomes of the FE models.Models (both spring and continuum) with subject-specific properties improved the predicted kinematics and contact outcome parameters. Models incorporating literature-based parameters, and particularly the spring models (with the representations implemented in this study), led to relatively high errors in kinematics and contact pressures. Using a continuum modelling approach resulted in more accurate contact outcome variables than the spring representation with two (cruciate ligaments) and three (collateral ligaments) single-element-bundle representations. However, when the prediction of joint kinematics is of main interest, spring ligament models provide a faster option with acceptable outcome.
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Ultrafine Particle Transport and Deposition in a Large Scale 17-Generation Lung Model
Publication date: Available online 5 September 2017
Source:Journal of Biomechanics
Author(s): Mohammad S. Islam, Suvash C. Saha, Emilie Sauret, Tevfik Gemci, Ian A. Yang, YT Gu
To understand how to assess optimally the risks of inhaled particles on respiratory health, it is necessary to comprehend the uptake of ultrafine particulate matter by inhalation during the complex transport process through a non-dichotomously bifurcating network of conduit airways. It is evident that the highly toxic ultrafine particles damage the respiratory epithelium in the terminal bronchioles. The wide range of in silico available and the limited realistic model for the extrathoracic region of the lung have improved understanding of the ultrafine particle transport and deposition (TD) in the upper airways. However, comprehensive ultrafine particle TD data for the real and entire lung model are still unavailable in the literature. Therefore, this study is aimed to provide an understanding of the ultrafine particle TD in the terminal bronchioles for the development of future therapeutics. The Euler-Lagrange (E-L) approach and ANSYS fluent (17.2) solver were used to investigate ultrafine particle TD. The physical conditions of sleeping, resting, and light activity were considered in this modelling study. A comprehensive pressure-drop along five selected path lines in different lobes was calculated. The non-linear behaviour of pressure-drops is observed, which could aid the health risk assessment system for patients with respiratory diseases. Numerical results also showed that ultrafine particle-deposition efficiency (DE) in different lobes is different for various physical activities. Moreover, the numerical results showed hot spots in various locations among the different lobes for different flow rates, which could be helpful for targeted therapeutical aerosol transport to terminal bronchioles and the alveolar region.
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Is bone density associated with intervertebral disc pressure in healthy and degenerated discs?
Publication date: Available online 4 September 2017
Source:Journal of Biomechanics
Author(s): Paul M. Fein, Alexander DelMonaco, Timothy M. Jackman, Cameron Curtiss, Ali Guermazi, Glenn D. Barest, Elise F. Morgan
The coupling of the intervertebral disc (IVD) and vertebra as a biomechanical unit suggests that changes in the distribution of pressure within the IVD (intradiscal pressure, IDP) as a result of disc degeneration can influence the distribution of bone density within the vertebra, and vice versa. The goal of this study was to assess the correspondence between IDP and bone density in the adjacent vertebrae, with emphasis on how this correspondence differs between healthy and degenerated IVDs. Bone density of the endplates and subchondral bone in regions adjacent to the anterior and posterior annulus fibrosus (aAF and pAF, respectively) and nucleus pulposus (NP) was measured via quantitative computed tomography (QCT) in 61 spine segments (T7-9, T9-11, T10-12; 71±14 years). IDP was measured in the aAF, NP, and pAF regions in 26 of the spine segments (68±16 years) while they were tested in flexed (5°) or erect postures. Disc degeneration was assessed by multiple grading schemes. No correlation was found between bone density and IDP in either posture (p>0.104). Regional variations in IDP and, to a greater extent bone density, were found to change with advancing degeneration: both IDP (p=0.045) and bone density (p=0.024) decreased in the NP region relative to the aAF region. The finding of only a modest correspondence between degeneration-associated changes in IDP and bone density may arise from complexity in how IDP relates to mechanical force transmission through the endplate and from limitations of the available IVD grading schemes in estimating the mechanical behavior of the IVD.
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The effects of early stages of aging on postural sway: a multiple domain balance assessment using a force platform
Publication date: Available online 5 September 2017
Source:Journal of Biomechanics
Author(s): Adriana M. Degani, Charles T. Leonard, Alessander Danna-dos-Santos
Technical advancements in instrumentation and analytical methods have improved the ability of assessing balance control. This study investigated the effects of early stages of aging on postural sway using traditional and contemporary postural indices from different domains. Eleven healthy young adults and fourteen healthy non-faller older adults performed two postural tasks: (a) functional limits of stability and (b) unperturbed bipedal stance for 120 seconds. Postural indices from spatial, temporal, frequency, and structural domains were extracted from the body's center of pressure (COP) signals and its Rambling and Trembling components. Results revealed a preservation of functional limits of upright stability in older adults accompanied by larger, faster, and shakier body sway in both anterior-posterior and medio-lateral directions; increased medio-lateral sway frequency; increased irregularity of body sway pattern in time in both directions; and increased area, variability, velocity, and jerkiness of both rambling and trembling components of the COP displacement in the anterior-posterior direction (p < .02). Such changes might be interpreted as compensatory adjustments to the age-related decline of sensory, neural, and motor functions. In conclusion, balance assessment using postural indices from different domains extracted from the COP displacement was able to capture subtle effects of the natural process of aging on the mechanisms of postural control. Our findings suggest the use of such indices as potential markers for postural instability and fall risk in older adults.
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ESMO 2017: ALEX and ALUR trials of alectinib show CNS benefit in NSCLC
Data from two separate phase 3 studies to be presented at the ESMO 2017 Congress in Madrid, show alectinib's particular central nervous system (CNS) activity in patients with advanced non-small cell lung cancer involving a mutation of the anaplastic...
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Alcohol consumption and bladder cancer risk with or without the flushing response: The Japan Public Health Center-based Prospective Study
ABSTRACT
The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95915 subjects (45649 men and 50266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non- and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (P for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted. This article is protected by copyright. All rights reserved.
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G protein-coupled receptor GPR55 promotes colorectal cancer and has opposing effects to cannabinoid receptor 1
Abstract
The putative cannabinoid receptor GPR55 has been shown to play a tumor-promoting role in various cancers, and is involved in many physiological and pathological processes of the gastrointestinal (GI) tract. While the cannabinoid receptor 1 (CB1) has been reported to suppress intestinal tumor growth, the role of GPR55 in the development of GI cancers is unclear. We, therefore, aimed at elucidating the role of GPR55 in colorectal cancer (CRC), the third most common cancer worldwide.
Using azoxymethane (AOM)- and dextran sulfate sodium (DSS)-driven CRC mouse models, we found that GPR55 plays a tumor-promoting role that involves alterations of leukocyte populations, i.e. myeloid-derived suppressor cells and T lymphocytes, within the tumor tissues. Concomitantly, expression levels of COX-2 and STAT3 were reduced in tumor tissue of GPR55 knockout mice, indicating reduced presence of tumor-promoting factors. By employing the experimental CRC models to CB1 knockout and CB1/GPR55 double knockout mice, we can further show that GPR55 plays an opposing role to CB1. We report that GPR55 and CB1 mRNA expression are differentially regulated in the experimental models and in a cohort of 86 CRC patients. Epigenetic methylation of CNR1 and GPR55 was also differentially regulated in human CRC tissue compared to control samples.
Collectively, our data suggest that GPR55 and CB1 play differential roles in colon carcinogenesis where the former seems to act as oncogene and the latter as tumor suppressor. This article is protected by copyright. All rights reserved.
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