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Πέμπτη 16 Νοεμβρίου 2017

Sex hormone-binding globulin (SHBG) is a potential early diagnostic biomarker for gastric cancer

Abstract

The use of blood plasma biomarkers in gastric cancer (GC) management is limited due to a lack of reliable biomarkers. An LC-MS/MS assay and a bioinformatic analysis were performed to identify blood plasma biomarkers in a GC discovery cohort. The data obtained were verified and validated by western blotting and an ELISA in an independent study cohort. A label-free quantification analysis of the MS data using PEAKS7 software found that four plasma proteins of apolipoprotein C-1, gelsolin, sex hormone-binding globulin (SHBG), and complement component C4-A were significantly overexpressed in GC patients. A western blot assay of these plasma proteins showed that only SHBG was consistently overexpressed in the patient group. ELISA measurement of SHBG blood plasma levels confirmed that the patient group had significantly higher SHBG levels than the control group. SHBG levels in the patient group remained significantly higher after being stratified by gender, age, and disease stage. These findings show that LC-MS/MS is powerful and highly sensitive for plasma biomarker discovery, and SHBG could be a potential plasma biomarker for GC management.

Thumbnail image of graphical abstract

Discovery of plasma biomarker with powerfully and high sensitively LC-MS/MS analysis, SHBG could be a potential plasma biomarker for GC management.



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Baerveldt Scleral Patch Graft Abscess Secondary to Coagulase-Negative Staphylococcus

We report the case of a 69-year-old female who underwent a Baerveldt implant placement for severe-stage primary open-angle glaucoma and developed a bacterial infection of the conjunctiva and abscess of the scleral patch graft with subsequent tube exposure. The infection was identified 3 weeks postoperatively and a topical antibiotic was immediately initiated. A concurrent systemic staphylococcal infection was discovered by an outside physician and oral cephalexin was initiated. Despite antibiotic treatment, the conjunctival erosion progressed, and tube revision was required. Culture of the abscess revealed coagulase-negative Staphylococcus. As alluded to above, the patient also had multiple abscesses on the skin that cultured positive for Staphylococcus aureus. To our knowledge, this is the first case in the literature of coagulase-negative Staphylococcus causing an early postoperative abscess of the scleral patch graft following glaucoma drainage device placement.
Case Rep Ophthalmol 2017;8:521–526

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Genetic risk factors for perception of symptoms in GERD: an observational cohort study

Summary

Background

Genetic polymorphisms in G-protein beta-3 subunit (GNβ3) and beta-2 adrenergic receptor (ADRB2) are associated with pain and gut hypersensitivity, which can overlap with gastroesophageal reflux disease (GERD).

Aim

To evaluate relationships between single nucleotide polymorphisms (SNPs) within GNβ3 and ADRB2 systems, and reflux symptom burden, GERD phenotypes from ambulatory reflux monitoring, and quality of life.

Methods

Symptomatic adults undergoing ambulatory reflux testing were recruited and phenotyped based on acid burden and symptom reflux association; major oesophageal motor disorders and prior foregut surgery were exclusions. A comparison asymptomatic control cohort was also identified. Subjects and controls completed questionnaires assessing symptom burden on visual analog scales, short-form health survey-36 (SF-36), and Beck Anxiety and Depression Inventories (BAI and BDI). Genotyping was performed from saliva samples; 6 SNPs selected from each of the two genes of interest were compared.

Results

Saliva from 151 study subjects (55.3 ± 1.2 years, 63.6% F) and 60 control subjects (50.9 ± 2.2 years, 66.7%) had sufficient genetic material for genotyping. Study subjects had higher symptom burden, worse total and physical health, and higher anxiety scores compared to controls (P ≤ .002). Tested SNPs within ADRB2 were similar between study subjects and controls (P > .09). Study subjects with recessive alleles in 3 GNβ3 SNPs (Rs2301339, Rs5443, and Rs5446) had worse symptom severity (P = .011), worse mental health (P = .03), and higher depression scores (P = .005) despite no associations with GERD phenotypes or reflux metrics.

Conclusions

Genetic variation within GNβ3 predicts oesophageal symptom burden and affect, but not oesophageal acid burden or symptom association with reflux episodes.



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Adherence to Mediterranean diet and subjective cognitive function in men

Abstract

Benefits of a Mediterranean diet for cognition have been suggested, but epidemiologic studies have been relatively small and of limited duration. To prospectively assess the association between long-term adherence to a Mediterranean dietary pattern and self-reported subjective cognitive function (SCF). Prospective observational study. The Health Professionals' Follow-up Study, a prospective cohort of 51,529 men, 40–75 years of age when enrolled in 1986, of whom 27,842 were included in the primary analysis. Mediterranean diet (MD) score, computed from the mean of five food frequency questionnaires, assessed every 4 years from 1986 to 2002. Self-reported SCF assessed by a 6-item questionnaire in 2008 and 2012, and validated by association with genetic variants in apolipoprotein-4. Using the average of 2008 and 2012 SCF scores, 38.0% of men were considered to have moderate memory scores and 7.3% were considered to have poor scores. In a multivariate model, compared with men having a MD score in the lowest quintile, those in the highest quintile had a 36% lower odds of a poor SCF score (odds ratio 0.64, 95% CI 0.55–0.75; P, trend < 0.001) and a 24% lower odds of a moderate SCF score (OR 0.76, 95% CI 0.70–0.83; P, trend < 0.001). Both remote and more recent diet contributed to this relation. Associations were only slightly weaker using baseline dietary data and a lag of 22 years. Long-term adherence to the Mediterranean diet pattern was strongly related to lower subjective cognitive function. These findings provide further evidence that a healthy dietary pattern may prevent or delay cognitive decline.



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Physical activity across adulthood and subjective cognitive function in older men

Abstract

Low subjective cognitive function (SCF), which is associated with APOE4 genotype, adversely impacts quality of life and has predicted clinical dementia. We examined whether physical activity during early adulthood or mid-to-late life is associated with late-life SCF. We followed 28,481 US male health professionals aged 40–75 years who reported their physical activity in 1986 and biennially thereafter. SCF was reported in 2008 and 2012. The SCF score was averaged for the 2008 and 2012 assessments and categorized as "good", "moderate", and "poor". Men in the highest versus lowest quintile of mid-to-late life physical activity in 1986 had 38% lower odds of poor versus good SCF score (multivariable-adjusted odds ratio (OR) 0.62; 95% CI 0.53, 0.72; P for trend < 0.0001). Being physically active in early adulthood was also associated with a 23% lower odds of poor SCF, independent of later activity, and being active both in early and mid-to-late adulthood was associated with a 48% lower odds of poor SCF score compared with those who were always sedentary (OR 0.52; 95% CI 0.38, 0.71). Our results suggest that being physically active during early adulthood and mid-to-late life independently contribute to prevention of poor subjective cognitive function in late-life.



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Growth factors for diabetic foot ulcers: Mixed treatment comparison analysis of randomized clinical trials

Summary

Aims

Topical growth factors accelerate wound healing in patients with diabetic foot ulcers (DFU). Due to the absence of head to head comparisons, we carried out Bayesian network meta-analysis to compare the efficacy and safety of growth factors.

Methods

Using an appropriate search strategy, randomized controlled trials on topical growth factors compared with standard of care in patients with DFU, were included. Proportion of patients with complete healing was the primary outcome. Odds ratio [95% confidence interval] was used as the effect estimate and random effects model was used for both direct and indirect comparisons. Markov Chain Monte Carlo simulation was used to obtain pooled estimates. Rankogram was generated based on surface under the cumulative ranking curve (SUCRA).

Results

A total of 26 studies with 2088 participants and 1018 events were included. The pooled estimates for recombinant epidermal growth factor (rhEGF), autologous platelet rich plasma (PRP), recombinant human platelet-derived growth factor (rhPDGF) were 5.72 [3.34, 10.37], 2.65 [1.60, 4.54] and 1.97 [1.54, 2.55] respectively. SUCRA for rhEGF was 0.95. Sensitivity analyses did not reveal significant changes from the pooled estimates and rankogram. No differences were observed in the overall risk of adverse events between the growth factors. However, the growth factors were observed to lower the risk of wound infection, cellulitis, peripheral edema and lower limb amputation compared to standard of care.

Conclusion

To conclude, rhEGF, rhPDGF and autologous PRP significantly improved the healing rate when used as adjuvants to standard of care, of which rhEGF may perform better than other growth factors. The strength of most of the outcomes assessed was low and the findings may not be applicable for DFU with infection or osteomyelitis. The findings of this study needs to be considered with caution as the results might change with findings from head-to-head studies.



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Birth and death of a phantom

Abstract

Patients with supernumerary phantom limb report experiencing an additional limb duplicating its physical counterpart, usually following a stroke with sensorimotor disturbances. Here, we report a short-lasting case of a right upper supernumerary phantom limb with unusual visuomotor features in a healthy participant during a pure Jacksonian motor seizure unexpectedly induced by continuous Theta-Burst Stimulation over the left primary motor cortex. Electromyographic correlates of the event followed the phenomenological pattern of sudden appearance and brutal dissolution of the phantom, adding credit to the hypothesis that supernumerary phantom limb results from a dynamic resolution of conflictual multimodal information.



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Are food and drink retailers within NHS venues adhering to NICE Quality standard 94 guidance on childhood obesity? A cross-sectional study of two large secondary care NHS hospitals in England

Objective

To assess whether the food and drink retail outlets in two major National Health Service (NHS) district general hospitals in England adhere to quality statements 1–3 of the UK National Institute for Health and Care Excellence (NICE) quality standard 94.

Design

Cross-sectional, descriptive study to assess the food and drink options available in vending machines, restaurants, cafes and shops in two secondary care hospitals.

Main outcome measures

Adherence to quality statement 1 whereby the food and drink items available in the vending machines were classified as either healthy or less healthy using the Nutrient Profiling Model (NPM). Compliance with quality statements 2 and 3 was assessed through the measurement of how clearly the shops, cafes and restaurants displayed nutrition information on menus, and the availability and prominent display of healthy food and drink options in retail outlets, respectively.

Results

Adherence to quality statement 1 was poor. Of the 18 vending machines assessed, only 7 (39%) served both a healthy food and a healthy drink option. Neither hospital was compliant with quality statement 2 wherein nutritional information was not available on menus of food providers in either hospital. There was inconsistent compliance with quality standard 3 whereby healthy food and drink options were prominently displayed in the two main hospital restaurants, but all shops and cafes prioritised the display of unhealthy items.

Conclusions

Neither hospital was consistently compliant with quality statements 1–3 of the NICE quality standard 94. Improving the availability of healthy foods and drinks while reducing the display and accessibility to less healthy options in NHS venues may improve family awareness of healthy alternatives. Making it easier for parents to direct their children to healthier choices is an ostensibly central component of our healthcare system.



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Month of birth and risk of autism spectrum disorder: a retrospective cohort of male children born in Israel

Background

Increased incidence and prevalence of autism spectrum disorder (ASD) over the last two decades have prompted considerable efforts to investigate its aetiological factors. We examined an association between month of birth and ASD incidence.

Methods

In a retrospective cohort of male children born from January 1999 to December 2008 in a large health organisation in Israel (Maccabi Healthcare Services), ASD was followed from birth through December 2015.

Results

Of 108 548 boys, 975 cases of ASD were identified. The highest rates (10.3 and 10.2 per 1000 male live births) were recorded for children born in May and August, respectively, and the lowest rates for February (7.6 per 1000 male live births). Among lower socioeconomic status households, boys born in August were more likely (OR=1.71; 95% CI 1.06 to 2.74) of being diagnosed with ASD than children born in January. Significantly higher rates were not observed for other months.

Conclusions

In line with several previous studies, we found a modestly higher likelihood of autism occurrence among male children of lower socioeconomic levels born in August.



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Comprehensive analysis of vitreous specimens for uveitis classification: a prospective multicentre observational study

Purpose

To determine the clinical relevance of vitreous biomarkers in patients with uveitis.

Design

Multicentre, prospective, observational study.

Setting

Uveitis outpatient clinics of two academic medical centres in Japan.

Patient population

This study included 234 eyes of 191 patients with various uveitis aetiologies: definitive sarcoidosis (61 eyes of 46 patients), suspected sarcoidosis (60 eyes of 45 patients), intraocular tumour (34 eyes of 27 patients), viral infection (20 eyes of 18 patients), non-sarcoidosis (16 eyes of 16 patients) and unknown aetiology (43 eyes of 39 patients).

Observation procedure

Vitreous samples (taken by pars planta vitrectomy) were analysed with flow cytometry, cytology and multiplex PCR analysis.

Main outcome measures

The primary outcome measures were the diagnostic values of various biomarkers (T cells, B cells and pathogen DNA) in vitreous samples. The secondary outcome was visual acuity after vitrectomy.

Results

Sarcoidosis showed higher CD4/CD8 or CD4+ measurements than other aetiologies (p<0.01). In samples with viral infection, pathogen DNA was detected, and CD8+ counts were higher than the other aetiologies (p<0.01). Eyes with tumour had higher CD19+ (p<0.05). Non-sarcoidosis had lower CD4/CD8 than sarcoidosis, higher CD8+ than sarcoidosis and lower CD19+ than tumour (p<0.01). Unknown uveitis had lower CD4/CD8 than sarcoidosis (p<0.01), and higher CD4/CD8 than non-sarcoidosis, viral infection or tumour (p<0.001). Visual acuity improved after vitrectomy (p<0.001).

Conclusions

Uveitis aetiologies had distinct vitreous biomarker profiles, especially of infiltrating lymphocytes. Analyses of CD4/CD8 ratio, T-lymphocyte and B-lymphocyte subset, and pathogen DNA in vitreous samples have good safety profiles and high diagnostic value for uveitis classification.

Trial registration number

UMIN000004980; Pre-results.



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Testosterone therapy in hypogonadal men: a systematic review and network meta-analysis

Objective

To assess the relative effects of individual testosterone products among hypogonadal men.

Design

Systematic review and network meta-analysis.

Methods

We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (25 May 2017) for randomised-controlled trials (RCTs) and non-randomised studies (NRS) that involved hypogonadal men given testosterone replacement therapy (TRT) for ≥3 months. Comparators were placebo, another TRT, or the same product at a different dose. Outcomes were quality of life, depression, libido, erectile function, activities of daily living and testosterone levels, as well as cardiovascular death, myocardial infarction, stroke, prostate cancer, heart disease, diabetes, serious adverse events, withdrawals due to adverse events and erythrocytosis. RCT data were pooled via meta-analysis and network meta-analysis. Risk of bias was assessed using Cochrane's risk of bias tool (RCTs) andScottish Intercollegiate Guidelines Network (SIGN)50 (NRS).

Results

Eighty-seven RCTs and 51 NRS were included. Most were at high or unclear risk of bias, with short treatment duration and follow-up. When compared as a class against placebo, TRT improved quality of life (standardised mean difference (SMD) –0.26, 95% CI –0.41 to –0.11), libido (SMD 0.33, 95% CI 0.16 to 0.50), depression (SMD –0.23, 95% CI –0.44 to –0.01) and erectile function (SMD 0.25, 95% CI 0.10 to 0.41). Most individual TRTs were significantly better than placebo at improving libido (6/10). Only one TRT was better than placebo at improving quality of life, and no individual TRTs improved depression or erectile function. There was no increased risk of adverse events, with the exception of withdrawals due to adverse events with the use of some TRTs.

Conclusion

Despite a class effect of improving quality of life, depression, erectile function and libido, major improvements were not observed with the use of any individual product. We observed no statistically significant increase in the risk of adverse events; however, longer-term high-quality trials are needed to fully assess the risk of harm.

PROSPERO registration number

CRD42014009963.



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Core Outcome Sets in Miscarriage Trials (COSMisT) study: a study protocol

Introduction

'Core outcome sets' are an agreed, standardised set of outcomes based on what key stakeholders (clinicians, patients, their partners, researchers, service developers, funding organisations and so on) consider the important outcomes in the management or prevention of a condition. This paper describes the rationale and design for the development of Core Outcome Sets for Miscarriage Trials.

Methods and analysis

Systematic reviews, interviews and focus groups with patients and their partners will be conducted to identify potential core outcomes that will be introduced into a modified Delphi survey. To ensure all key stakeholders are included, patients, partners, clinicians, charities and researchers will be invited to take part in the modified Delphi survey. There will be three rounds of scoring and rescoring during the Delphi survey to reach consensus regarding outcomes to be included in the core set, which will be subsequently refined through face-to-face consensus discussions.

Ethics and dissemination

The use of core outcome sets allows results from different studies to be compared and combined, thereby reducing inconsistency and aiding interpretation of study findings. It also means research is more likely to report relevant outcomes and so can reduce reporting bias. Understanding which outcomes are important to patients has the potential to act as a driver to improve both the quality and cost-effectiveness of miscarriage services.



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Early versus Late Application of Subthalamic deep brain Stimulation to Parkinsons disease patients with motor complications (ELASS): protocol of a multicentre, prospective and observational study

Introduction

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established surgical treatment for Parkinson's disease (PD). However, there is currently no consensus on the best timing for this surgery. The aim of our study is to compare the therapeutic efficacy of bilateral STN DBS in patients with PD with early and late motor complications.

Methods and analysis

200 patients with PD will be enrolled in this multicentre, prospective, observational study, and will be followed up for 4 years. Patients with PD who meet the criteria for STN DBS surgery will be allocated to either the early stimulation group or the late stimulation group based on the duration of their motor complications. The primary outcome will be changes in quality of life from baseline to 4 years, measured using the 39-item Parkinson's Disease Questionnaire Summary Index. The secondary outcomes include changes in motor function measured using Movement Disorder Society-revised Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, self-reported experiences of daily living measured using MDS-UPDRS Part I B and Part II, good 'on' time recorded by the patients using a diary and safety profile of both groups.

Ethics and dissemination

The study received ethical approval from the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University. The results of this study will be published in peer-reviewed journals and presented at international conferences.

Trial registration number

NCT01922388; Pre-results.



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Biochemical monitoring after initiation of aldosterone antagonist therapy in users of renin-angiotensin system blockers: a UK primary care cohort study

Objective

To determine the frequency of biochemical monitoring after initiation of aldosterone antagonists(AA) in patients also using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB).

Setting

UK primary care.

Participants

ACEI/ARB users who initiated AA between 2004 and 2014.

Outcomes

We calculated the proportions with: (1) biochemical monitoring ≤2 weeks post initiation of AA, (2) adverse biochemical values ≤2 months (potassium ≥6 mmol/L, creatinine ≥220 µmol/L and ≥30% increase in creatinine from baseline) and (3) discontinuers of AA in those with an adverse biochemical value. We used logistic regression to study patient characteristics associated with monitoring and adverse biochemical values.

Results

In 10 546 initiators of AA, 3291 (31.2%) had a record of biochemical monitoring ≤2 weeks post initiation. A total of 2.0% and 2.7% of those with follow-up monitoring within 2 months of initiation experienced potassium ≥6 mmol/L and creatinine ≥220 µmol/L, respectively, whereas 13.5% had a ≥30% increase in creatinine. Baseline potassium (OR 3.59, 95% CI 2.43 to 5.32 for 5.0–5.5 mmol/L compared with <5.0 mmol/L) and estimated glomerular filtration rate 45-59 ml/min/1.73 m2 (OR 2.06, 95% CI 1.26 to 3.35 compared with ≥60 ml/min/1.73 m2) were independently predictive of potassium ≥6 mmol/L. Women and people with diabetes had higher odds of ≥30% increase in creatinine.

Conclusion

Less than one-third of patients taking ACEI/ARB had biochemical monitoring within 2 weeks of initiating AAs. Higher levels of monitoring may reduce adverse biochemical events.



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Interventions to improve adherence to reporting guidelines in health research: a scoping review protocol

Introduction

There is evidence that the use of some reporting guidelines, such as the Consolidated Standards for Reporting Trials, is associated with improved completeness of reporting in health research. However, the current levels of adherence to reporting guidelines are suboptimal. Over the last few years, several actions aiming to improve compliance with reporting guidelines have been taken and proposed. We will conduct a scoping review of interventions to improve adherence to reporting guidelines in health research that have been evaluated or suggested, in order to inform future interventions.

Methods and analysis

Our review will follow the Joanna Briggs Institute scoping review methods manual. We will search for relevant studies in MEDLINE, EMBASE and Cochrane Library databases. Moreover, we will carry out lateral searches from the reference lists of the included studies, as well as from the lists of articles citing the included ones. One reviewer will screen the full list, which will be randomly split into two halves and independently screened by the other two reviewers. Two reviewers will perform data extraction independently. Discrepancies will be solved through discussion. In addition, this search strategy will be supplemented by a grey literature search. The interventions found will be classified as assessed or suggested, as well as according to different criteria, in relation to their target (journal policies, journal editors, authors, reviewers, funders, ethical boards or others) or the research stage at which they are performed (design, conducting, reporting or peer review). Descriptive statistical analysis will be performed.

Ethics and dissemination

A paper summarising the findings from this review will be published in a peer-reviewed journal. This scoping review will contribute to a better understanding and a broader perspective on how the problem of adhering better to reporting guidelines has been tackled so far. This could be a major first step towards developing future strategies to improve compliance with reporting guidelines in health research.



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Patient-level and practice-level factors associated with consultation duration: a cross-sectional analysis of over one million consultations in English primary care

Objectives

Consultation duration has previously been shown to be associated with patient, practitioner and practice characteristics. However, previous studies were conducted outside the UK, considered only small numbers of general practitioner (GP) consultations or focused primarily on practitioner-level characteristics. We aimed to determine the patient-level and practice-level factors associated with duration of GP and nurse consultations in UK primary care.

Design and setting

Cross-sectional data were obtained from English general practices contributing to the Clinical Practice Research Datalink (CPRD) linked to data on patient deprivation and practice staffing, rurality and Quality and Outcomes Framework (QOF) achievement.

Participants

218 304 patients, from 316 English general practices, consulting from 1 April 2013 to 31 March 2014.

Analysis

Multilevel mixed-effects models described the association between consultation duration and patient-level and practice-level factors (patient age, gender, smoking status, ethnic group, deprivation and practice rurality, number of full-time equivalent GPs/nurses, list size, consultation rate, quintile of overall QOF achievement and training status).

Results

Mean duration of face-to-face GP consultations was 9.24 min and 5.32 min for telephone consultations. Nurse face-to-face and telephone consultations lasted 9.70 and 5.73 min on average, respectively. Longer GP consultation duration was associated with female patient gender, practice training status and older patient age. Shorter duration was associated with higher deprivation and consultation rate. Longer nurse consultation duration was associated with male patient gender, older patient age and ever smoking; and shorter duration with higher consultation rate. Observed differences in duration were small (eg, GP consultations with female patients compared with male patients were 8 s longer on average).

Conclusions

Small observed differences in consultation duration indicate that patients are treated similarly regardless of background. Increased consultation duration may be beneficial for older or comorbid patients, but the benefits and costs of increased consultation duration require further study.



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Prevalence and recognition of obesity and its associated comorbidities: cross-sectional analysis of electronic health record data from a large US integrated health system

Objective

To determine the prevalence of obesity and its related comorbidities among patients being actively managed at a US academic medical centre, and to examine the frequency of a formal diagnosis of obesity, via International Classification of Diseases, Ninth Revision (ICD-9) documentation among patients with body mass index (BMI) ≥30 kg/m2.

Design

The electronic health record system at Cleveland Clinic was used to create a cross-sectional summary of actively managed patients meeting minimum primary care physician visit frequency requirements. Eligible patients were stratified by BMI categories, based on most recent weight and median of all recorded heights obtained on or before the index date of 1July 2015. Relationships between patient characteristics and BMI categories were tested.

Setting

A large US integrated health system.

Results

A total of 324 199 active patients with a recorded BMI were identified. There were 121 287 (37.4%) patients found to be overweight (BMI ≥25 and <29.9), 75 199 (23.2%) had BMI 30–34.9, 34 152 (10.5%) had BMI 35–39.9 and 25 137 (7.8%) had BMI ≥40. There was a higher prevalence of type 2 diabetes, pre-diabetes, hypertension and cardiovascular disease (P value<0.0001) within higher BMI compared with lower BMI categories. In patients with a BMI >30 (n=134 488), only 48% (64 056) had documentation of an obesity ICD-9 code. In those patients with a BMI >40, only 75% had an obesity ICD-9 code.

Conclusions

This cross-sectional summary from a large US integrated health system found that three out of every four patients had overweight or obesity based on BMI. Patients within higher BMI categories had a higher prevalence of comorbidities. Less than half of patients who were identified as having obesity according to BMI received a formal diagnosis via ICD-9 documentation. The disease of obesity is very prevalent yet underdiagnosed in our clinics. The under diagnosing of obesity may serve as an important barrier to treatment initiation.



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UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey

Introduction

UpToDate is widely used by clinicians worldwide and includes more than 9400 recommendations that apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. GRADE guidance warns against strong recommendations when certainty of the evidence is low or very low (discordant recommendations) but has identified five paradigmatic situations in which discordant recommendations may be justified.

Objectives

Our objective was to document the strength of recommendations in UpToDate and assess the frequency and appropriateness of discordant recommendations.

Design

Analytical survey of all recommendations in UpToDate.

Methods

We identified all GRADE recommendations in UpToDate and examined their strength (strong or weak) and certainty of the evidence (high, moderate or low certainty). We identified all discordant recommendations as of January 2015, and pairs of reviewers independently classified them either into one of the five appropriate paradigms or into one of three categories inconsistent with GRADE guidance, based on the evidence presented in UpToDate.

Results

UpToDate included 9451 GRADE recommendations, of which 6501 (68.8%) were formulated as weak recommendations and 2950 (31.2%) as strong. Among the strong, 844 (28.6%) were based on high certainty in effect estimates, 1740 (59.0%) on moderate certainty and 366 (12.4%) on low certainty. Of the 349 discordant recommendations 204 (58.5%) were judged appropriately (consistent with one of the five paradigms); we classified 47 (13.5%) as good practice statements; 38 (10.9%) misclassified the evidence as low certainty when it was at least moderate and 60 (17.2%) warranted a weak rather than a strong recommendation.

Conclusion

The proportion of discordant recommendations in UpToDate is small (3.7% of all recommendations) and the proportion that is truly problematic (strong recommendations that would best have been weak) is very small (0.6%). Clinicians should nevertheless be cautious and look for clear explanations—in UpToDate and elsewhere—when guidelines offer strong recommendations based on low certainty evidence.



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Impact of preterm birth on parental separation: a French population-based longitudinal study

Objective

The objective of this study was to investigate both the effects of low gestational age and infant's neurodevelopmental outcome at 2 years of age on the risk of parental separation within 7 years of giving birth.

Design

Prospective.

Setting

24 maternity clinics in the Pays-de-la-Loire region.

Participants

This study included 5732 infants delivered at <35 weeks of gestation born between 2005 and 2013 who were enrolled in the population-based Loire Infant Follow-up Team cohort and who had a neurodevelopmental evaluation at 2 years. This neurodevelopmental evaluation was based on a physical examination, a psychomotor evaluation and a parent-completed questionnaire.

Outcome measure

Risk of parental separation (parents living together or parents living separately).

Results

Ten percent (572/5732) of the parents reported having undergone separation during the follow-up period. A mediation analysis showed that low gestational age had no direct effect on the risk of parental separation. Moreover, a non-optimal neurodevelopment at 2 years was associated with an increased risk of parental separation corresponding to a HR=1.49(1.23 to 1.80). Finally, the increased risk of parental separation was aggravated by low socioeconomic conditions.

Conclusions

The effect of low gestational age on the risk of parental separation was mediated by the infant's neurodevelopment.



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Risk factors for recurrent intussusception in children: a retrospective cohort study

Objective

The aim of this study was to assess the frequency of clinical features and pathological lead points in recurrent intussusception, with a special focus on the risk factors that lead to recurrent intussusception.

Design

This is a retrospective cohort study. A 5-year retrospective study was performed between January 2012 and July 2016 in the Children's Hospital of Soochow University, Suzhou, China, to determine the clinical features and pathological lead points of recurrent intussusception.

Setting

This is a retrospective chart review of recurrent intussusception cases in a large university teaching hospital.

Participants

The medical records were obtained for 1007 cases with intussusception, including demographics, clinical signs and symptoms, imaging and recurrence times if available.

Interventions

Univariate and multivariate logistic regression analyses were used to measure significant factors affecting recurrent intussusception and recurrent intussusception with pathological lead points.

Results

There were 481 total episodes of recurrence in 191 patients. Among these, 87 had one recurrence and 104 had multiple recurrences. After comparing recurrent and non-recurrent intussusception cases using univariate analysis, it was determined that the factors associated with recurrent intussusception were age (>1 year), duration of symptoms (≤12 hours), the lack of bloody stool, paroxysmal crying or vomiting, the mass location (right abdomen) and pathological lead point (P<0.05). Age (>1 year), duration of symptoms (≤12 hours), the absence of vomiting, mass location (right abdomen) and pathological lead point were significantly independently predictive of recurrent intussusception. The factors associated with recurrent intussusception with lead points present were vomiting and mass location in the right abdomen (P<0.05). Vomiting and mass location (left abdomen) were significantly predictive of recurrent intussusception with lead points.

Conclusions

Age (>1 year), symptom duration (≤12 hours), the absence of vomiting, mass location (right abdomen) and pathological lead points were significantly predictive of recurrent intussusception. Vomiting and mass location (left abdomen) were significantly predictive of recurrent intussusception with lead points.



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Platelet rich Plasma in Achilles Tendon Healing 2 (PATH-2) trial: protocol for a multicentre, participant and assessor-blinded, parallel-group randomised clinical trial comparing platelet-rich plasma (PRP) injection versus placebo injection for Achilles tendon rupture

Background

Achilles tendon injuries give rise to substantial long-lasting morbidity and pose considerable challenges for clinicians and patients during the lengthy healing period. Current treatment strategies struggle to curb the burden of this injury on health systems and society due to lengthy rehabilitation, work absence and reinjury risk. Platelet-rich plasma (PRP) is an autologous preparation that has been shown to improve the mechanobiological properties of tendons in laboratory and animal studies. The use of PRP in musculoskeletal injuries is on the increase despite the lack of adequately powered clinical studies.

Methods and design

This is a multicentre randomised controlled trial to evaluate the efficacy and mechanism of PRP in patients with acute Achilles tendon rupture (ATR). All adults with acute ATR presenting within 12 days of the injury who are to be treated non-operatively are eligible. A total of 230 consenting patients will be randomly allocated via a remote web-based service to receive PRP injection or placebo injection to the site of the injury. All participants will be blinded to the intervention and will receive standardised rehabilitation to reduce efficacy interference.

Participants will be followed up with blinded assessments of muscle–tendon function, quality of life, pain and overall patient's functional goals at 4, 7, 13, 24 weeks and 24 months post-treatment. The primary outcome is the heel-rise endurance test (HRET), which will be supervised by a blinded assessor at 24 weeks. A subgroup of 16 participants in one centre will have needle biopsy under ultrasound guidance at 6 weeks. Blood and PRP will be analysed for cell count, platelet activation and growth factor concentrations.

Ethics and dissemination

The protocol has been approved by the Oxfordshire Research Ethics Committee (Oxfordshire Research Ethics Committee A, reference no 14/SC/1333). The trial will be reported in accordance with the CONSORT statement and published in peer-reviewed scientific journals.

Trial registration number

ISRCTN: 54992179, assigned 12 January 2015. ClinicalTrials.gov: NCT02302664, received 18 November 2014. UK Clinical Research Network Study Portfolio Database: ID 17850.



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Impact of variation in functions and delivery on the effectiveness of behavioural and mood management interventions for smoking cessation in people with depression: protocol for a systematic review and meta-analysis

Introduction

Tobacco is the world's leading preventable cause of disease and death. People with depression are twice as likely to smoke and are less responsive to standard tobacco treatments as compared with the general population. A Cochrane systematic review of randomised controlled trials of smoking cessation treatment for smokers with current or historical depression found that adding mood management to usual smoking treatment improved quit rates. However, the review did not examine if variation in intervention delivery or intervention functions impacted on treatment effectiveness.

With the aim of providing information to develop tailored approaches to treating smoking for people with current depression, we will add-on to the Cochrane review in three ways: (1) use the Template for Intervention Description and Replication checklist to determine if variations in mood management delivery have impact on intervention effectiveness, (2) use the Taxonomy of Behaviour Change techniques for smoking cessation to examine which behaviour change functions are most effective for smoking cessation in people with current depression and (3) examine the difference in change in depression scores between intervention and control arms.

Methods and analysis

We will include randomised controlled trials of smokers with current depression as identified by a previous Cochrane review and the in-progress update of this Cochrane review. We will use meta-regression to examine (1) if variations in delivery of mood management impact on smoking cessation intervention effectiveness, (2) determine which behaviour change functions are most effective for smoking cessation and (3) use meta-analysis of the difference in change in depression scores between treatment arms from baseline to follow-up to determine if offering smoking cessation treatment causes psychological harm.

Ethics and dissemination

Ethical approval is not required for this study. We will disseminate the findings of this work at national and international conferences, and to relevant patient panels.

PROSPERO registration number

CRD42017070741.



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Function and mechanism of the pyrin inflammasome

Abstract

Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as Familial Mediterranean Fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease-causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogen- or host-derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as 'homeostasis-altering molecular processes' (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation.

This article is protected by copyright. All rights reserved



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Self-reported actual and desired proportion of sitting, standing, walking and physically demanding tasks of office employees in the workplace setting: do they fit together?

Occupational sitting time in white-collar workers represents a prominent contributor to overall daily sitting time, which is associated with various health risks. Workplace interventions intending to reduce si...

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U-CH17P, -M, and -S, a new cell culture system for tumour diversity and progression in chordoma

Abstract

Chordoma is a rare bone tumour with a known intrinsic heterogeneity. Here, we address this tumour heterogeneity in a new cell culture model for tumour diversity and progression in chordoma. The three cell lines U-CH17P, U-CH17M, and U-CH17S were established from a primary sacral chordoma and its derived metastases, a soft tissue and a skin metastasis, respectively. The lesions had divergent differentiation patterns which are conserved in the derived cell lines making them a suitable in vitro model for the analysis of tumorigenesis in chordoma. A common feature of the three cell lines is the expression of typical chordoma markers, such as Brachyury, vimentin, cytokeratins, EMA, and S100 protein. A comparison of the genomic aberrations by array comparative genomic hybridization of the cell lines and the corresponding parental tumour tissues revealed that the precursor cells of U-CH17P, U-CH17M, and U-CH17S were already present in the primary tumour. Therefore, we show that clonal diversity of this chordoma exists in the primary tumour and that not all of these subclones tend to metastasize. All cell lines had a CDKN2A loss. A comparison of the gene expression profiles of the cell lines revealed significant differences in the expression of several genes like MAGEC2 and SEMA6A known to be associated with the tendency to metastasize or proliferation and migration. Since the underlying mechanisms of tumour progression in chordoma are still largely unclear, the three U-CH17 cell lines are a suitable in vitro model for elucidating chordoma oncobiology. This article is protected by copyright. All rights reserved.



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What is in a Pronoun?: Why Gender-fair Language Matters

Mini Mounting evidence demonstrates that gender inequity is perpetuated by language. As such, understanding the ways in which linguistic bias reinforces gender and other stereotypes is paramount to creating a culture of inclusivity. This perspective reviews the science detailing the ways language reinforces gender inequality and offers strategies to reduce linguistic bias.

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Are We Ready for Our Close-up?: Why and How We Must Embrace Video in the OR

imageNo abstract available

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Rebranding “The Lab Years” as “Professional Development” in Order to Redefine the Modern Surgeon Scientist

No abstract available

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Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax [Review]

Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high-priority goal for cancer therapy. After decades of effort, drug-discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL2 biology, were essential to the development of BH3 mimetics such as the BCL2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL2 biology and facilitated the clinical development of venetoclax.

Significance: Basic research into the pathways governing programmed cell death have paved the way for the discovery of apoptosis-inducing agents such as venetoclax, a BCL2-selective inhibitor that was recently approved by the FDA and the European Medicines Agency. Preclinical studies aimed at identifying BCL2-dependent tumor types have translated well into the clinic thus far and will likely continue to inform the clinical development of venetoclax and other BCL2 family inhibitors. Cancer Discov; 7(12); 1–18. ©2017 AACR.



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Assessment of interleukin-1β, interleukin-6, and tumor necrosis factor-Α levels in the peri-implant sulcular fluid among waterpipe (narghile) smokers and never-smokers with peri-implantitis

Abstract

Background

It is hypothesized that levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α are significantly higher in the peri-implant sulcular fluid (PISF) of waterpipe-smokers (WS) compared with never-smokers with peri-implantitis.

Purpose

The aim of the present convenience sample case-control study was to compare the levels of IL-6, IL-1β, and TNF-α in the PISF of WS and never-smokers with peri-implantitis.

Materials and methods

Demographic data was collected using a questionnaire. Peri-implant probing depth (PPD) was measured and crestal bone loss (CBL) was measured on digital bitewing radiographs. PISF samples were collected using paper strips and the collected PISF volume was determined. levels of IL-6, IL-1β, and TNF-α were measured using enzyme linked immunosorbent assay. Study sample-size was estimated and statistical analysis was performed. P values less than .05 were considered statistically significant.

Results

Sixty-six individuals (33 individuals in group-1 and 33 in group-2) were included. In groups 1 and 2, 41 and 44 implants, respectively were placed. The mean total PPD (P < .001) and peri-implant CBL (P < .001) was statistically significantly higher around implants affected by peri-implantitis in group-1 compared with group-2. The PISF volume (P < .05) collected and levels of IL-1β (P < .01), IL-6 (P < .01), and TNF-α (P < .01) were statistically significantly higher among individuals in group-1 compared with group-2.

Conclusion

WS with peri-implantitis present increased expression of local proinflammatory cytokines in the PISF than never-smokers.



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Peri-implant parameters and C-reactive protein levels among patients with different obesity levels

Abstract

Background

It is hypothesized that peri-implant conditions are worse with increasing severity of obesity, because systemic low-grade inflammatory marker (C-reactive protein [CRP]) is higher in severe form of obese individuals.

Purpose

The aim of the cross-sectional retrospective study was to compare clinical and radiographic peri-implant inflammatory parameters in patients with different levels of obesity and correlate these parameters with CRP levels.

Materials and methods

Eighty-four patients who participated in this study were divided into 4 groups: class I obese (group 1), class II obese (group 2), class III obese (group 3), and nonobese individuals (group 4) were included. Clinical (plaque index [PI], bleeding on probing [BOP], probing depth [PD]) and radiographic (marginal bone loss [MBL]) peri-implant parameters were recorded. Serum CRP were quantified using enzyme-linked immunosorbent assay (ELISA). Clinical peri-implant parameters and serum CRP concentrations were analyzed using 1-way analysis of variance. The Pearson correlation coefficient was used to analyze correlations of CRP levels with any of the clinical and radiographic parameters assessed.

Results

Peri-implant PI, BOP, PD, and MBL were significantly higher in group-1, -2, and -3 patients as compared to nonobese individuals (P < .05). Peri-implant PI, BOP, PD, and MBL were significantly higher in obese patients of group-2 and group-3 as compared to obese patients in group-1 (P < .01). Mean PI, BOP, PD, and MBL were comparable between group-2 and group-3 patients (P > .05). A significant positive correlations were found between CRP levels and BOP (P = .0148) and PD (P = .0425); and significant negative correlation was found for MBL in group 3, respectively (P = .0212).

Conclusion

Clinical and radiographic peri-implant inflammatory parameters and serum CRP were significantly high in patients with severe form of obesity. Serum CRP levels correlated with peri-implant bleeding in obese patients. These findings are preliminary and long-term controlled trials are recommended to support these outcomes.



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LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity

LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity

LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity, Published online: 16 November 2017; doi:10.1038/bjc.2017.412



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Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in <i>ALK</i>-positive NSCLC, Published online: 16 November 2017; doi:10.1038/bjc.2017.395



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Reply to ‘Comment on ‘Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study’’

Reply to 'Comment on 'Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study''

Reply to 'Comment on 'Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study'', Published online: 16 November 2017; doi:10.1038/bjc.2017.406



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Comment on ‘Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study’

Comment on 'Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study'

Comment on 'Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study', Published online: 16 November 2017; doi:10.1038/bjc.2017.342



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Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation

Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation

<i>Treponema denticola</i> chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation, Published online: 16 November 2017; doi:10.1038/bjc.2017.409



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Comparison of ChIP-seq Data and a Reference Motif Set for Human KRAB C2H2 Zinc Finger Proteins

KRAB C2H2 zinc finger proteins (KZNFs) are the largest and most diverse family of human transcription factors, likely due to diversifying selection driven by novel endogenous retroelements (EREs), but the vast majority lack binding motifs or functional data. Two recent studies analyzed a majority of the human KZNFs using either ChIP-seq (60 proteins) or ChIP-exo (221 proteins) in the same cell type (HEK293). The ChIP-exo paper did not describe binding motifs, however. Thirty-nine proteins are represented in both studies, enabling the systematic comparison of the data sets presented here. Typically, only a minority of peaks overlap, but the two studies nonetheless display significant similarity in ERE binding for 32/39, and yield highly similar DNA binding motifs for 23 and related motifs for 34 (MoSBAT similarity score > 0.5 and > 0.2, respectively). Thus, there is overall (albeit imperfect) agreement between the two studies. For the 242 proteins represented in at least one study, we selected a highest-confidence motif for each protein, utilizing several motif-derivation approaches, and evaluating motifs within and across data sets. Peaks for the majority (158) are enriched (96% with AUC > 0.6 predicting peak vs non-peak) for a motif that is supported by the C2H2 "recognition code", consistent with intrinsic sequence specificity driving DNA binding in cells. An additional 63 yield motifs enriched in peaks, but not supported by the recognition code, which could reflect indirect binding. Altogether, these analyses validate both data sets, and provide a reference motif set with associated quality metrics.



http://ift.tt/2zKeduB

microRNA Tissue Atlas of the Malaria Mosquito Anopheles gambiae

Anopheles gambiae mosquitoes transmit the human malaria parasite Plasmodium falciparum, which causes the majority of fatal malaria cases worldwide. The hematophagous life style defines the mosquito reproductive biology and is exploited by P. falciparum for its own sexual reproduction and transmission. The two main phases of the mosquito reproductive cycle, pre-vitellogenic (PV) and post-blood meal (PBM) shape its capacity to transmit malaria. Transition between these phases is tightly coordinated to ensure homeostasis between mosquito tissues and successful reproduction. One layer of control is provided by microRNAs, well known regulators of blood meal digestion and egg development in Aedes mosquitoes. Here, we report a global overview of tissue-specific miRNA expression during the PV and PBM phases and identify miRNAs regulated during PV to PBM transition. The observed coordinated changes in the expression levels of a set of miRNAs in the energy-storing tissues suggest a role in the regulation of blood meal-induced metabolic changes.



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The NOTCH4-HEY1 pathway induces epithelial mesenchymal transition in head and neck squamous cell carcinoma

Background: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood. Methods: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell cycle assays. We also compared the relationships among NOTCH4, HEY1 and epithelial mesenchymal transition (EMT) related genes using the TCGA data set and in vitro assays. Results: HEY1 is specifically up-regulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison to other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell cycle dysregulation. Furthermore, NOTCH4 and HEY1 up-regulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression were associated with an EMT phenotypes as well as increased invasion and cell migration. Conclusion: In HNSCC the NOTCH4-HEY1 pathway is specifically up-regulated, induces proliferation and cisplatin resistance, and promotes EMT.



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Development of a function-blocking antibody against fibulin-3 as targeted reagent for glioblastoma

Purpose: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NF-kB signaling. Experimental Design: We used deletion constructs to identify a key signaling motif of fibulin-3. A monoclonal antibody (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3. mAb428.2 was tested in cultures to measure its inhibitory effect on fibulin-3 signaling. Nude mice carrying subcutaneous and intracranial GBM xenografts were treated with the maximum achievable dose of mAb428.2 to measure target engagement and anti-tumor efficacy. Results: We identified a critical 23-amino acid sequence of fibulin-3 that activates its signaling mechanisms. mAb428.2 binds to that epitope with nanomolar affinity and blocks the ability of fibulin-3 to activate ADAM17, Notch, and NF-kB signaling in GBM cells. mAb428.2 treatment of subcutaneous GBM xenografts inhibited fibulin-3, increased tumor cell apoptosis, and enhanced the infiltration of inflammatory macrophages. The antibody reduced tumor growth and extended survival of mice carrying GBMs as well as other fibulin-3-expressing tumors. Locally-infused mAb428.2 showed efficacy against intracranial GBMs, increasing tumor apoptosis and reducing tumor invasion and vascularization, which are enhanced by fibulin-3. Conclusions: To our knowledge this is the first rationally-developed, function-blocking antibody against an ECM target in GBM. Our results offer a proof of principle for using "anti-ECM" strategies towards more efficient targeted therapies for malignant glioma.



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Regulatory role of XynR (YagI) in catabolism of xylonate in Escherichia coli K-12

Abstract
The genome of Escherichia coli K-12 contains ten cryptic phages, altogether constituting about 3.6% of the genome in sequence. Among more than 200 predicted genes in these cryptic phages, 14 putative transcription factor (TF) genes exist, but their regulatory functions remain unidentified. As an initial attempt to make a breakthrough for understanding the regulatory roles of cryptic phage-encoded TFs, we tried to identify the regulatory function of CP4-6 cryptic prophage-encoded YagI with unknown function. After SELEX screening, YagI was found to bind mainly at a single site within the spacer of bidirectional transcription units, yagA (encoding another uncharacterized TF) and yagEF (encoding 2-keto-3-deoxy gluconate aldolase, and dehydratase, respectively) within this prophage region. YagEF enzymes are involved in the catabolism of xylose downstream from xylonate. We then designated YagI as XynR (regulator of xylonate catabolism), one of the rare single-target TFs. In agreement with this predicted regulatory function, the activity of XynR was suggested to be controlled by xylonate. Even though low-affinity binding sites of XynR were identified in the E. coli K-12 genome, they all were inside open reading frames, implying that the regulation network of XynR is still fixed within the CR4-6 prophage without significant influence over the host E. coli K-12.

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UV-based evaluation of ergosterol for monitoring the fungal exposure in Italian buffalo farms

Abstract
This study provided a reliable way to identify and estimate the ergosterol in farm environments, since it is renowned that it is a specific indicator for the occurrence of molds and yeasts. The quick valuation of exposure to airborne microorganisms is essential to assess the risk to which the health of employees is subjected in working places characterized by great humidity. From this view, it is worth estimating the total biomass of molds and yeast, including viable and non-viable forms, which may cause respiratory concerns to human. Air samples were collected with a passive method and the microbial growth was evaluated with a traditional counting method. At the same time, the ergosterol was quantified from yeasts and molds. In this way, the aerosol concentrations of molds and yeasts were compared by using the two methods, the cultivation on plates, as well as through ergosterol measurement by means of UV spectroscopy. Results showed, for the first time, a positive correlation between the amount of ergosterol and the yeast cells. Based on these outcomes, the ergosterol is a statistically significant biomarker to be used to control the air quality of indoor and outdoor farm spaces, by means of a simple and direct UV procedure.

http://ift.tt/2hDr0Iw

Molecular characterization of β-lactamase genes in clinical isolates of carbapenem-resistant Acinetobacter baumannii

Acinetobacter baumannii is a nosocomial pathogen which is establishing as a major cause of morbidity and mortality within the healthcare community. The success of this pathogen is larg...

http://ift.tt/2zH53zn

Multiple small hemorrhagic infarcts in cerebral air embolism: a case report

Cerebral air embolism is a rare cause of cerebral infarction. In cerebral air embolism, T2 star-weighted imaging shows numerous spotty hypointense signals. Previous reports have suggested that these signals re...

http://ift.tt/2yOaton

Bacillus anthracis gamma phage lysis among soil bacteria: an update on test specificity

Bacillus anthracis, which causes anthrax in humans and animals, is enzootic in parts of the U.S. state of Texas where cases are typically reported in animals annually. The gamma phage ...

http://ift.tt/2AV5F2a

The effect of increased intracranial EEG sampling rates in clinical practice

For the ∼1/3 of epilepsy patients who are not controlled by medications alone, epilepsy surgery or the possibility of implantable devices to treat their seizures may be the only therapeutic option. However, the success rates of epilepsy surgery vary broadly from 40-80%(Cohen-Gadol et al., 2006; Lee et al., 2005; Mohammed et al., 2012; de Tisi et al., 2011), and these numbers have not changed in many years. It is clear that the standard practice of evaluating epilepsy surgical candidates needs improvement.

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Cognitive impairment measured by event-related potentials during early and late postoperative period following intravenous or inhalation anaesthesia

Postoperative cognitive impairment, known as POCD (postoperative cognitive dysfunction), is not a diagnosis, but rather a clinical phenomenon. Development of POCD has not yet been clearly and unequivocally elucidated due to a lack of formal criteria for assessment and diagnosis. Some clinicians have challenged the importance of POCD because cognitive impairment seems to be transient, and long-term effects are unknown. It is likely that the cause of POCD is multifactorial and may include the preoperative health status of patients, perioperative events related to the surgery itself, and possible neurotoxic effects of anaesthetic agents (Machado et al.

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Correlating motor unit morphology with bioelectrical activity – a simulation study

Simulation studies on motor unit potentials (MUPs), apart from clinical experience, are important in understanding how the morphological features such as number of fibers, their diameters and distribution within the motor unit area influence the MUP waveform (Dumitru et al., 1997; Nandedkar et al., 1988b; Nandedkar and Sanders, 1989; Stålberg and Karlsson, 2000, 2001; Zalewska et al., 2004). Simulation enables the relationship between motor unit morphology and MUP shape variability to be determined.

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Treponema denticola chymotrypsin-like proteinase may contribute to orodigestive carcinogenesis through immunomodulation



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Reply to ‘Comment on ‘Efficacy of stereotactic body radiotherapy in oligorecurrent and in oligoprogressive prostate cancer: new evidence from a multicentric study’’



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LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity



http://ift.tt/2hFrePi

Cumulative incidence rates for CNS and non-CNS progression in two phase II studies of alectinib in ALK-positive NSCLC



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Is Primary Aldosteronism Still Largely Unrecognized?

Horm Metab Res
DOI: 10.1055/s-0043-119755

Primary aldosteronism (PA) was first reported by Jerome W. Conn in 1954 when it was considered a rare disorder, only suspected in cases of hypertension and spontaneous hypokalemia. Over the last 30 years, with the wide application of the plasma aldosterone to plasma renin activity ratio as screening test, the clinical spectrum of PA has dramatically changed. Different studies displayed significant differences in term of patients investigated, diagnostic criteria and hormonal assays; however, large prospective studies with robust diagnostic criteria indicated that the prevalence of PA is around 6% of the general hypertensive population and 11% of the patients referred to hypertension centers. In light of these epidemiological studies, the Endocrine Society Guideline recommends the screening for PA of around 50% of patients with hypertension, and identifies the categories of patients at high risk for the disease. However, clinical data obtained from "real-life" show that the screening rate is much lower and PA remains an under-diagnosed and under-treated cause of secondary hypertension with an associated increased risk of cardio- and cerebrovascular mortality and morbidity.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Blockade of nicotine sensitization by methanol extracts of Glycyrrhizae radix mediated via antagonism of accumbal oxidative stress

We previously reported that a methanol extract of Glycyrrhizae radix (MEGR) blocked methamphetamine-induced locomotor sensitization and conditioned place preference in rats. In the present study, the effects of M...

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Pharmacological potential of Bidens pilosa L. and determination of bioactive compounds using UHPLC-QqQLIT-MS/MS and GC/MS

Research of natural products from traditionally used medicinal plants to fight against the human ailments is fetching attention of researchers worldwide. Bidens pilosa Linn. var. Radiata (Asteraceae) is well know...

http://ift.tt/2zJAjha

Molecular network-based analysis of the mechanism of liver injury induced by volatile oils from Artemisiae argyi folium

Volatile oils from Artemisiae argyi folium (VOAAF) is reported with hepatotoxicity, but the underlying mechanism is still unclear.

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Clinical outcome of portal vein thrombosis in patients with digestive cancers: a large AGEO multicenter study

Management of portal vein thrombosis (PVT) in cancer patients remains discussed.

http://ift.tt/2z9xBlq

Molecular Ellipticity of Circulating Albumin-Bilirubin Complex Associates With Mortality in Patients With Severe Alcoholic Hepatitis

Hyperbilirubinemia and hypoalbuminemia are features of hepatic dysfunction that associate with disease severity. This is because hepatic insufficiency causes hypoalbuminemia, which indirectly increases the circulating levels of free bilirubin. Circular dichroism (CD) spectroscopy can be used to quantify the molecular ellipticity (ME) of the albumin–bilirubin complex, and might associate with the severity or outcome of severe alcoholic hepatitis (SAH).

http://ift.tt/2AOv8Jw

Incidence of gastric-to-pulmonary aspiration in patients undergoing elective upper gastrointestinal endoscopy



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Patient-Reported Outcomes Following Treatment of Chronic Hepatitis C Virus Infection With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir

Chronic infection with hepatitis C virus (HCV) has many hepatic and extrahepatic manifestations, measured by patient-reported outcomes (PROs). We measured changes in PROs during HCV treatment with recently developed pangenotypic regimens and from a sustained virologic response 12 weeks after treatment ended (SVR12).

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Invited Editorial: Advantages and Limitations of FAERS in Assessing Adverse Event Reporting for Eluxadoline



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Association of Gastric Intestinal Metaplasia and East Asian Ethnicity with the Risk of Gastric Adenocarcinoma in a U.S. Population

Although the incidence of gastric cancer is higher than esophageal cancer in the United States, no screening or surveillance guidelines exist. The aim of this study is to evaluate the association between gastric intestinal metaplasia and the risk of gastric cancer in a U.S. tertiary care system with a large immigrant population.

http://ift.tt/2zHYHjh

Incident Atrial Fibrillation and the Risk of Congestive Heart Failure, Myocardial Infarction, End-Stage Kidney Disease, and Mortality Among Patients With a Decreased Estimated GFR

The association of atrial fibrillation (AF), estimated glomerular filtration rate (eGFR), and adverse events.

http://ift.tt/2iozL6e

Longitudinal Estimated GFR Trajectories in Patients With and Without Type 2 Diabetes and Nephropathy

In clinical practice and clinical trials, changes in serum creatinine concentrations are used to evaluate changes in kidney function. It has been assumed that these changes follow a linear pattern when serum creatinine concentration is converted to estimated glomerular filtration rate (eGFR). However, the paradigm that kidney function declines linearly over time has been questioned by studies showing either linear or nonlinear patterns. To verify how this impacts on kidney end points in intervention trials, we analyzed eGFR trajectories in multiple clinical trials of patients with and without diabetes.

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Effectiveness of current and future regimens for treating genotype 3 hepatitis C virus infection: a large-scale systematic review

Six distinct genetic variants (genotypes 1 − 6) of hepatitis C virus (HCV) exist globally. Certain genotypes are more prevalent in particular countries or regions than in others but, globally, genotype 3 (GT3)...

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Recurrent tuberculosis in Finland 1995–2013: a clinical and epidemiological cohort study

We investigated the epidemiology and prevalence of potential risk factors of tuberculosis (TB) recurrence in a population-based registry cohort of 8084 TB cases between 1995 and 2013.

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Durability of switch regimens based on rilpivirine or on integrase inhibitors, both in association with tenofovir and emtricitabine, in HIV-infected, virologically suppressed patients

Switch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the stud...

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Tumor necrosis factor-α (TNF-α) −308 G/A and lymphotoxin-α (LT-α) +252 A/G genetic polymorphisms in Egyptian acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is one of the most hematological malignancies of lymphoid origin. It has been proposed that deregulation of cytokines could be linked with pathogenesis, progression, and survival in many diseases. Genetic polymorphisms in two important cytokines like tumor necrosis factor-α (TNF-α) −308 and lymphotoxin-α (LT-α) +252 can disturb both their transcription and expression and lead to their high plasma levels. A difference in the occurrence of the polymorphisms in TNF-α −308 G/A and LT-α +252 A/G in ALL cases among several populations with different ethnicities was observed. The study investigated the occurrence and the role of polymorphisms of tumor necrosis factor genes including TNF-α −308 G>A and LT-α +252 A>G in the development of ALL in Egypt. A case-control study was done on 126 newly diagnosed ALL patients (96 pediatric and 30 adult patients); 130 healthy subjects composed the control group. Polymorphism variants of TNF-α and LT-α genes were studied by PCR-RFLP on genomic DNA of all studied individuals. TNF-α −308 G/A polymorphism was statistically significant in ALL pediatric patients (P value = 0.008) with no association with ALL adult patients. TNF AA homozygous variant genotype and the A allele both showed significant risks of the development of pediatric ALL. However, there was no association between LT-α +252 A/G polymorphism in both pediatric and adult ALL. The results show that TNF AA homozygous variant genotype and A allele showed a significant risk of development of pediatric ALL.



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The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells

The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells

The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells, Published online: 16 November 2017; doi:10.1038/cddis.2017.521



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Soluble P-selectin promotes retinal ganglion cell survival through activation of Nrf2 signaling after ischemia injury

Soluble P-selectin promotes retinal ganglion cell survival through activation of Nrf2 signaling after ischemia injury

Soluble P-selectin promotes retinal ganglion cell survival through activation of Nrf2 signaling after ischemia injury, Published online: 16 November 2017; doi:10.1038/cddis.2017.566



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Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma

Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma

Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma, Published online: 16 November 2017; doi:10.1038/cddis.2017.556



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Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury

Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury

Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury, Published online: 16 November 2017; doi:10.1038/cddis.2017.549



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Alternative In Vitro Methods for the Determination of Viral Capsid Structural Integrity

Routine detection methods utilizing viral genome amplification are limited by their inability to discriminate infectious from non-infectious particles. The purpose of this article is to provide detailed protocols for alternative methods to aid in discrimination of infectious norovirus particles using aptamer binding, dynamic light scattering, and transmission electron microscopy.

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Women’s experiences of having depression during pregnancy and receiving acupuncture treatment—A qualitative study

Publication date: Available online 15 November 2017
Source:Women and Birth
Author(s): Simone M. Ormsby, Hannah G. Dahlen, Caroline A. Smith
BackgroundResearch indicates some women experiencing depression during pregnancy are dissatisfied with conventional depression treatments due to incomplete effectiveness, dislike of side effects, unsatisfactory experiences with providers and concerns regarding in-utero and breastfeeding safety. Consequently, many explore alternative options including acupuncture. To further understand women's views, preferences and motivations in this regard, as well as their experiences of receiving acupuncture as part of a three-armed pragmatic randomised controlled trial evaluating acupuncture for antenatal depression in Sydney, Australia, in-depth interviews were conducted with a group of acupuncture recipients.MethodsEight participants who had completed the eight-treatment intervention were interviewed. Data was analysed using thematic analysis.ResultsThe overarching theme to emerge was that women 'felt trapped between a rock and a hard place', in not wanting to feel the way they did, but also not knowing what else to do, as conventional treatments had been inadequate or unsatisfactory, or were now unacceptable during pregnancy. With a mixture of curiosity and open-mindedness, or scepticism and desperation, the women in this study decided to try acupuncture, to 'give it a go', in the hope of receiving benefits. After treatment, these women reported being surprised by 'gaining relief' from symptoms, that they also felt were cumulative and ongoing.ConclusionsThe women in this study described gaining benefits from acupuncture that they felt enabled them to better manage their lives and the changes that pregnancy brings. These findings provide new understanding regarding the possible role acupuncture could provide as a supportive treatment for antenatal depression.



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High-resolution Confocal Imaging of the Blood-brain Barrier: Imaging, 3D Reconstruction, and Quantification of Transcytosis

Here we present a microscopy-based protocol for high-resolution imaging and a three-dimensional reconstruction of the mouse neurovascular unit and blood-brain barrier using brain free-floating sections. This method allows for the visualization, analysis, and quantification of intracellular organelles at the BBB.

http://ift.tt/2AUtXcs

Iowa county donates AEDs to public sites

People at each location will be trained to use the devices, according to Wapello County Public Health director Lynelle Diers

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Dissection and Coronal Slice Preparation of Developing Mouse Pituitary Gland

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We present a protocol to dissect pituitary glands and prepare pituitary coronal sections from developing mice.

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Executive summary of the 12th HHT international scientific conference

Abstract

Hereditary hemorrhagic telangiectasia is an autosomal dominant trait affecting approximately 1 in 5000 people. A pathogenic DNA sequence variant in the ENG, ACVRL1 or SMAD4 genes, can be found in the majority of patients. The 12th International Scientific HHT Conference was held on June 8–11, 2017 in Dubrovnik, Croatia to present and discuss the latest scientific achievements, and was attended by over 200 scientific and clinical researchers. In total 174 abstracts were accepted of which 58 were selected for oral presentations. This article covers the basic science and clinical talks, and discussions from three theme-based workshops. We focus on significant emergent themes and unanswered questions. Understanding these topics and answering these questions will help to define the future of HHT research and therapeutics, and ultimately bring us closer to a cure.



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Epigenetic editing of the Dlg4 /PSD95 gene improves cognition in aged and Alzheimer’s disease mice

Abstract
The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer's disease and Huntington's disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer's disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.

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Induced cortical responses require developmental sensory experience

Abstract
Sensory areas of the cerebral cortex integrate the sensory inputs with the ongoing activity. We studied how complete absence of auditory experience affects this process in a higher mammal model of complete sensory deprivation, the congenitally deaf cat. Cortical responses were elicited by intracochlear electric stimulation using cochlear implants in adult hearing controls and deaf cats. Additionally, in hearing controls, acoustic stimuli were used to assess the effect of stimulus mode (electric versus acoustic) on the cortical responses. We evaluated time-frequency representations of local field potential recorded simultaneously in the primary auditory cortex and a higher-order area, the posterior auditory field, known to be differentially involved in cross-modal (visual) reorganization in deaf cats. The results showed the appearance of evoked (phase-locked) responses at early latencies (<100 ms post-stimulus) and more abundant induced (non-phase-locked) responses at later latencies (>150 ms post-stimulus). In deaf cats, substantially reduced induced responses were observed in overall power as well as duration in both investigated fields. Additionally, a reduction of ongoing alpha band activity was found in the posterior auditory field (but not in primary auditory cortex) of deaf cats. The present study demonstrates that induced activity requires developmental experience and suggests that higher-order areas involved in the cross-modal reorganization show more auditory deficits than primary areas.

http://ift.tt/2jwWBvS

Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity

Abstract
Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.

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Paramedic starts viral campaign to spread EMS positivity

By EMS1 Staff BRIERLEY HILL, England — Amidst recent stories of EMS abuse, a paramedic invited colleagues to share positive community experiences. BBC reported that West Midlands Ambulance Service paramedic Rob Moore created the campaign #BlueLightHappy to remind everyone of the positivity EMS providers experience. With so much negativity out there, Birmingham Paramedic @wmasRobMoore decided to ...

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Anti-aminoacyl-tRNA synthetase-related myositis and dermatomyositis: clues for differential diagnosis on muscle biopsy

Abstract

Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies toward amino acyl-tRNA synthetases (ARS), anti-Jo 1 being the most commonly detected. Muscle damage develops in up to 90% of ARS-positive patients, characterized by a necrotizing myositis restricted to the perifascicular region. This topographic distribution of muscle damage may lead to a misdiagnosis of dermatomyositis (DM) at muscle biopsy. We compared morphological, immunohistochemical, and histoenzymatic features of muscle from ARS-positive patients (n = 11) with those of DM (n = 7) providing clues for their differential diagnosis. In addition, we evaluated markers of mitochondrial damage to provide a further distinction between these two entities. Necrosis occurred in the majority of ARS patients, mainly located in the perifascicular region. It was often limited to small foci of fibers, always associated with myocyte regeneration. This last often overwhelmed necrosis, representing occasionally the main finding. In DM, necrosis/regeneration was scarce while the peculiar feature was a diffuse atrophy of perifascicular fibers. These last showed decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion, consistent with mitochondrial dysfunction. In contrast to DM, ARS displayed scattered COX-deficient fibers, not restricted to the perifascicular region. This feature occurred in up to 91% of patients, being prominent only in two.



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Central and Divided Visual Field Presentation of Emotional Images to Measure Hemispheric Differences in Motivated Attention

This study compared central versus divided visual field presentations of emotional images to assess differences in motivated attention between the two hemispheres. The late positive potential (LPP) was recorded using electroencephalography (EEG) and event-related potentials (ERPs) methodologies to assess motivated attention.

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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and not Always Lactate Elevation



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Reduction of Metallic Artifacts of the Post-treatment Intracranial Aneurysms: Effects of Single Energy Metal Artifact Reduction Algorithm

Abstract

Purpose

This study evaluated the quality of computed tomography (CT) and CT angiography images generated using the single-energy metal artifact reduction (SEMAR) algorithm during perfusion examination in patients who had undergone reconstruction with neurosurgical clipping or endovascular coiling for treatment of aneurysms.

Methods

A total of 55 patients with implanted intracranial clips or coils (24 men and 31 women; mean age 60.15 ± 15.86 years) underwent perfusion studies evaluated by CT and CT angiography with a 320-row CT scanner. Images were reconstructed with either the SEMAR algorithm combined with iterative reconstruction (SEMAR group), or by iterative reconstruction only (non-SEMAR group control). The SEMAR and control images were compared for artifacts (index and maximum diameter), image quality, cerebral perfusion parameters, noise (images with the worst artifacts), and contrast-to-noise ratio. The metallic artifacts were visually evaluated by two radiologists using a four-point scale in a double-blinded manner.

Results

The noise, artifact diameter, and artifact index of the SEMAR images were significantly lower than that of the control images, and the subjective image quality score and contrast-to-noise ratio were significantly higher (P < 0.01, all). The cerebral perfusion parameters of the SEMAR and control images were comparable (i. e. blood flow, blood volume, and mean transit time).

Conclusion

For imaging intracranial metallic implants, the SEMAR algorithm produced images with significantly fewer artifacts than the iterative reconstruction alone, with no statistical changes in perfusion parameters. Thus, SEMAR reconstruction can be instrumental in improving CT image quality and may ultimately improve the detection of postoperative complications and patient prognosis.



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Dallas fire dept. rolls out new 911 system

The new system cuts out the practice of "over triaging calls" and uses an algorithm to suggest to dispatchers what resources are needed

http://ift.tt/2hEvCOr

Penile warty-mucoepidermoid carcinoma with features of stratified mucin-producing intraepithelial lesion and invasive stratified mucin-producing carcinoma

Abstract

Aims

Stratified mucin-producing intraepithelial lesion (SMILE) and invasive stratified mucin-producing carcinoma (ISMC) are recently described cervical and penile lesions. We report an unusual case of mixed variant of penile squamous cell carcinomas with warty, usual and mucoepidermoid SMILE/ISMC features.

Methods and results

A 62-year-old Japanese man had a glans penis lesion of one and a half years duration, suggesting malignancy. Partial penectomy and left inguinal lymphadenectomy were performed. Pathological evaluation revealed a mixed squamous cell carcinoma with warty, mucinous and usual features. The mucinous component resembled mucoepidermoid carcinoma (MEC) and SMILE/ISMC. Glandular differentiation was absent. All the diverse tumour components were negative for p16 which was confirmed by negative human papillomavirus genotyping. The mucinous component was diffusely positive for cytokeratin 7 and largely negative for cytokeratin 5 and p63. Fluorescent in situ hybridization did not detect rearrangement in the MAML2 or EWSR1 genes. The tumour was pathologic stage pT2, pN1 (AJCC prognostic stage group IIIA) and was disease-free 26 months after surgery.

Conclusions

The lack of glands in the mucinous areas suggested that MEC should be separated from adenosquamous carcinoma (ASC) Penile SMILE/ISMC may occur without dependence on HPV status. Further studies will be necessary to determine the pathogenesis and definition of penile SMILE/ISMC, the presence of true MEC arising from the glans penis, and the clinicopathological differences of penile ASC, MEC, and SMILE/ISMC. Herein, we refer to the SMILE-like penile lesion as "mucinous penile intraepithelial neoplasia".

This article is protected by copyright. All rights reserved.



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Risk factors associated with the progression and metastases of hindgut neuroendocrine tumors: a retrospective study

Abstract

Background

The worldwide incidence of neuroendocrine tumors (NETs) has increased remarkably, with the hindgut being the second most common site for such tumors. However, the mechanisms underlying progression and metastasis of hindgut NETs are unclear. A retrospective study was conducted to elucidate these mechanisms.

Methods

Clinicopathological data of cases of hindgut NET between April 1996 and September 2015 were analyzed, retrospectively. Patients with neuroendocrine carcinoma were excluded. Formalin-fixed paraffin-embedded tissues of hindgut NET cases were subjected to detailed morphometric and immunohistochemical analyses. Statistical analyses were performed using the non-parametric Mann-Whitney U test, Spearman's correlation coefficient, and chi-squared test. Multivariate logistic regression analysis was conducted as appropriate for the data set.

Results

Fifty-six hindgut NET cases were considered. Microvessel density and lymphatic microvessel density were identified as significant risk factors for venous and lymphatic invasion. There was a positive correlation between microvessel density and the maximum tumor diameter. Multivariate logistic regression analysis revealed that the maximum tumor diameter alone was an independent predictor of lymph node metastasis, whereas lymphovascular invasion and MVD was not the predictor of lymph node metastasis. There were no significant correlations between the Ki-67 labeling index and any of the parameters evaluated including age, sex, the maximum tumor diameter, venous invasion, lymphatic invasion, microvessel density, lymphatic microvessel density, and lymph node metastasis.

Conclusions

Angiogenic mechanisms may play important roles in the progression of hindgut NET. Otherwise, the maximum tumor diameter alone was an independent predictor of lymph node metastasis in hindgut NETs. Moreover, our study raises the question of whether the presence of lymphovascular invasion, in endoscopically obtained hindgut NET tissues, is an absolute indication for additional surgery or not.



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Biospecimen donation among black and white breast cancer survivors: opportunities to promote precision medicine

Abstract

Purpose

Advances in precision medicine (PM) have potential to reduce and/or eliminate breast cancer disparities in both treatment and survivorship. However, compared to white Americans, black Americans are often underrepresented in genetic research. This report assessed factors that influence receipt of buccal cells via saliva kits.

Methods

This prospective study recruited women with confirmed hormonal-positive (HR+) breast cancer (BC). A standardized telephone survey collected sociodemographic, socio-cultural (e.g., religiosity), and healthcare process factors. Clinical information was abstracted from medical records. After the baseline survey, return postage-paid envelopes and mouthwash collection kits were mailed. Univariate and adjusted logistic regression models estimated the probability of biospecimen donation.

Results

Seventy percent of the sample provided buccal cells which were of good quality. No differences were noted by race or other demographic factors. In the multivariable logistic model, time spent with providers (OR 1.61 per 1-point increase; 95% CI 1.242, 2.088) and religiosity (OR 0.957 per 1-point increase; 95% CI 0.931, 0.984) remained associated with biospecimen provision. Women with lower-stage cancer (vs. higher stage III+) were more likely to donate biospecimens (p < 0.05).

Conclusions

Cancer care experiences predicted specimen donation. Understanding the contextual reasons for lower receipt among women with higher religiosity scores and higher stage warrants further examination.

Implications for cancer survivors

PM is relevant to cancer survivors because of its potential to inform targeted therapies, understand disease resistance, and aide in prediction of toxicity and/or recurrence. Future efforts to launch precision medicine trials with BC survivors may benefit from engaging medical oncologists and/or leveraging patient-provider encounters for trial participation.



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Downregulation of MiR-31 stimulates expression of LATS2 via the hippo pathway and promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma

Abstract

Background

Dysregulation of miRNAs is associated with cancer development by coordinately suppressing abundant target genes. Emerging evidence indicates that miR-31 plays a dual role in tumorigenicity. However, whether miR-31 plays as an oncogene in esophageal squamous cell carcinoma (ESCC) and the potential target molecules are still unclear. MiR-31 role in ESCC was investigated and an association of the target molecules with EMT was identified in the progression of ESCC.

Methods

Western blot assays and qRT-PCR was performed to detect the protein and mRNA levels. We investigated the role of miR-31 in the regulation of LATS2 expression in ESCC cell lines via functional assays both in vivo and in vitro. The luciferase reporter assays was conducted to confirm LATS2 is a potential target of miR-31. Immunohistochemistry was used to measure LATS2 and TAZ expression in normal and ESCC tissue.

Results

LATS2 is a component of the Hippo tumor-suppressive signaling pathway. Frequent loss of heterozygosity of LATS2 has been reported in esophageal cancer. We analyzed the reciprocal expression regulation of miR-31 and LATS2 and demonstrated that LATS2 expression was elevated by down-regulation of miR-31 at the post-transcriptional level in ESCC. Moreover, miR-31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3′-UTR, a key molecule in the Hippo pathway. Then, LATS2 consequently promoted the translocation of TAZ, which was examined using immunohistochemistry. Silencing of miR-31 significantly inhibited the cell proliferation, induced apoptosis and decreased the ability of migration/invasion in vitro. LATS2 impedes ESCC cell proliferation and invasion by suppressing miR-31, as well as mice xenograft model in vivo. Meanwhile, the nuclear localization of LATS2 constrained the phosphorylation of TAZ. Then, the expression level of TAZ was notably heightened with a high risk of recurrence compared to that observed in the low-risk patients, as well as, the higher expression associated with a poor survival.

Conclusions

Our study demonstrated that overexpression of miR-31 undertook an oncogenic role in ESCC by repressing expression of LATS2 via the Hippo Pathway and activating epithelial-mesenchymal transition. LATS2 and TAZ could be potential novel molecular markers for predicting the risk of recurrence and prognosis of ESCC.



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TGF-β2 initiates autophagy via Smad and non-Smad pathway to promote glioma cells’ invasion

Abstract

Background

Glioblastoma multiforme (GBM) is characterized by lethal aggressiveness and patients with GBM are in urgent need for new therapeutic avenues to improve quality of life. Current studies on tumor invasion focused on roles of cytokines in tumor microenvironment and numerous evidence suggests that TGF-β2 is abundant in glioma microenvironment and vital for glioma invasion. Autopagy is also emerging as a critical factor in aggressive behaviors of cancer cells; however, the relationship between TGF-β2 and autophagy in glioma has been poorly understood.

Methods

U251, T98 and U87 GBM cell lines as well as GBM cells from a primary human specimen were used in vitro and in vivo to evaluate the effect of TGF-β2 on autophagy. Western blot, qPCR, immunofluorescence and transmission-electron microscope were used to detect target molecular expression. Lentivirus and siRNA vehicle were introduced to establish cell lines, as well as mitotracker and seahorse experiment to study the metabolic process in glioma. Preclinical therapeutic efficacy was evaluated in orthotopic xenograft mouse models.

Results

Here we demonstrated that TGF-β2 activated autophagy in human glioma cell lines and knockdown of Smad2 or inhibition of c-Jun NH2-terminal kinase, attenuated TGF-β2-induced autophagy. TGF-β2-induced autophagy is important for glioma invasion due to the alteration of epithelial-mesenchymal transition and metabolism conversion, particularly influencing mitochondria trafficking and membrane potential (△Ψm). Autopaghy also initiated a feedback on TGF-β2 in glioma by keeping its autocrine loop and affecting Smad2/3/7 expression. A xenograft model provided additional confirmation on combination of TGF-β inhibitor (Galunisertib) and autophagy inhibitor (CQ) to better "turn off" tumor growth.

Conclusion

Our findings elucidated a potential mechanism of autophagy-associated glioma invasion that TGF-β2 could initiate autophagy via Smad and non-Smad pathway to promote glioma cells' invasion.



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“CHOP”ing intestinal stem cells on way to cholestatic liver injury



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Exercise alters the hepatic immunophenotype to protect against inflammatory liver disease



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Spanking Linked to Increase in Children’s Behavior Problems

Children who have been spanked by their parents by age 5 show an increase in behavior problems at age 6 and age 8 relative to children who have never been spanked, according to new findings in Psychological Science, a journal of the Association for Psychological Science.

The study, which uses a statistical technique to approximate random assignment, indicates that this increase in behavior problems cannot be attributed to various characteristics of the child, the parents, or the home environment – rather, it seems to be the specific result of spanking.

"Our findings suggest that spanking is not an effective technique and actually makes children's behavior worse not better," says psychological scientist Elizabeth T. Gershoff (University of Texas at Austin), lead author on the study.

Historically, trying to determine whether parents' use of spanking actually causes children to develop behavior problems has been difficult, because researchers cannot ethically conduct experiments that randomly assign parents to spank or not.

"Parents spank for many reasons, such as their educational or cultural background or how difficult their children's behavior is. These same reasons, which we call selection factors, can also predict children's behavior problems, making it difficult to determine whether spanking is in fact the cause of behavior problems," Gershoff explained. "We realized that the statistical method of propensity score matching could help us get as close to an experiment as possible."

Gershoff and coauthors Kierra M. P. Sattler (University of Texas at Austin) and Arya Ansari (University of Virginia) examined data from 12,112 children who participated in the nationally representative Early Childhood Longitudinal Study. When the children were 5 years old, their parents reported how many times they had spanked their child in the past week (if any). The researchers classified any child whose parent provided a number other than zero as having been spanked.

The researchers then matched children who had been spanked with those who hadn't according to 38 child- and family-related characteristics, including: the child's age, gender, overall health, and behavior problems at age 5; the parent's education, age, and marital status; the family socioeconomic status and household size; and factors related to parenting quality and conflict in the home.

Pairing the children in this way yielded two groups of children whose main difference was whether their parents had spanked them, effectively accounting for other factors that could plausibly influence the behavior of both parent and child. This approach allowed the researchers to approximate the random assignment of participants to groups, a hallmark of experimental design.

To gauge children's behavior problems over time, Gershoff, Sattler, and Ansari examined teachers' ratings when the children were 5, 6, and 8 years old. Children's teachers reported the frequency with which the children argued, fought, got angry, acted impulsively, and disturbed ongoing activities.

The results were clear: Children who had been spanked at age 5 showed greater increases in behavior problems by age 6 and also by age 8 when compared with children who had never been spanked.

Gershoff and colleagues conducted a similar analysis with only those children who had been spanked by their parents, comparing children who had been spanked in the week before the study (which suggests frequent spanking) and those who had not. Children spanked in the past week at age 5 also experienced greater increases in problem behavior at age 6 and 8 compared with children not spanked as frequently.

"The fact that knowing whether a child had ever been spanked was enough to predict their levels of behavior problems years later was a bit surprising," says Gershoff. "It suggests that spanking at any frequency is potentially harmful to children."

"Although dozens of studies have linked early spanking with later child behavior problems, this is the first to do so with a statistical method that approximates an experiment," she concluded.

This research was supported by grants awarded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24HD042849, Principal Investigator: D. J. Umberson; T32HD007081, Principal Investigators: R. K. Raley and E. T. Gershoff), by a grant from the National Science Foundation (1519686, Principal Investigators: E. T. Gershoff and R. Crosnoe), and by a grant from the Institute of Education Sciences, U.S. Department of Education (R305B130013, Principal Investigator: S. Rimm-Kaufman).



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