Setting the baseline to fight Gram-negative bacteraemia: the necessity of epidemiological insights

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https://ift.tt/2LlnCzL

Effects of retinopathy and chronic kidney disease on long-term mortality in type 2 diabetic inpatients with normal urinary albumin or protein: a retrospective cohort study

Objective

Normoalbuminuric chronic kidney disease (NA-CKD) is recognised as a distinct phenotype of diabetic kidney disease, but the role of diabetic retinopathy (DR) in predicting long-term mortality among these patients remains unclear. Here, we aimed to investigate the effects of DR and CKD on mortality in type 2 diabetic patients with normoalbuminuria.

Design

We conducted this study as a retrospective cohort study.

Setting

We collected clinical information from the medical records of a public medical centre in central Taiwan.

Participants

Patients with type 2 diabetes (n=665) who were hospitalised due to poor glucose control were consecutively enrolled and followed for a median of 6.7 years (IQR 4.1-9.6 years). Patients with either urinary protein excretion >150 mg/day or urine albumin excretion >30 mg/day were excluded.

Primary outcome measure

All-cause mortality served as the primary follow-up outcome, and the mortality data were obtained from the national registry in Taiwan.

Results

The patients with CKD and DR showed the highest mortality rate (log-rank p<0.001). The risks of all-cause mortality (HR 2.263; 95% CI 1.551 to 3.302) and cardiovascular mortality (HR 2.471; 95% CI 1.421 to 4.297) were significantly greater in patients with CKD and DR than in those without CKD or DR, after adjusting for the associated risk factors.

Conclusions

DR is an independent predictor for all-cause and cardiovascular mortality in type 2 diabetic inpatients with normoalbuminuria. Moreover, DR with CKD shows the highest risks of all-cause and cardiovascular mortality among these patients. Funduscopy screening can provide additive information on mortality in patients with type 2 diabetes, even among those with NA-CKD.

https://ift.tt/2LGzRWM

Cohort profile: the Martinique Cancer Registry and the quality of life prostate cancer cohort (QoL Prostate-MQ): challenges and prospects for reducing disparities in the Caribbean

Purpose

Recording cancer data in cancer registries is essential for producing reliable population-based data for service planning, monitoring and evaluation. Prostate cancer (PCa) remains the most frequent type of cancer in terms of incidence and mortality in men in the Caribbean. The quality of life PCa cohort will assess quality of life and patient outcomes in Martinique using a digital platform for patient-reported outcome measures.

Participants

The Martinique Cancer Registry database is the largest clinical database among the French population-based cancer registries in the Caribbean, including more than 38 000 cancer cases, with 1650 new cancer cases per year, including 550 new PCa cases per year (2010–2014 latest period). In 2018, follow-up will include vital status, assessment of quality of life with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core 30 and the Prostate cancer module QLQ-PR25. Urinary incontinence and erectile dysfunction recorded prior to treatment will be analysed 1 and 5 years after treatment.

Findings to date

The registry includes data on circumstances of diagnosis, clinical stage at diagnosis. For PCa, the registry includes blood prostate-specific antigen level at the time of diagnosis, Gleason score and primary treatment.

Future plans

Further studies will provide detailed data regarding the quality of diagnosis and management of patients with PCa in Martinique; analysing quality of care will be the next challenge.

Quality of life and patient outcomes will be evaluated using a digital platform for patient-reported outcome measurement and electronic records.

https://ift.tt/2uRveQ7

Cohort study evaluating pressure ulcer management in clinical practice in the UK following initial presentation in the community: costs and outcomes

Objectives

The aim of this study was to estimate the patterns of care and annual levels of healthcare resource use attributable to managing pressure ulcers (PUs) in clinical practice in the community by the UK's National Health Service (NHS), and the associated costs of patient management.

Methods

This was a retrospective cohort analysis of the records of 209 patients identified within a randomly selected population of 6000 patients with any type of wound obtained from The Health Improvement Network (THIN) Database, who developed a PU in the community and excluded hospital-acquired PUs. Patients' characteristics, wound-related health outcomes and healthcare resource use were quantified over 12 months from initial presentation, and the corresponding total NHS cost of patient management was estimated at 2015/2016 prices.

Results

50% of all the PUs healed within 12 months from initial presentation, but this varied between 100% for category 1 ulcers and 21% for category 4 ulcers. The mean time to healing ranged from 1.0 month for a category 1 ulcer to 8 months for a category 3/4 ulcer and 10 months for an unstageable ulcer. Patients were predominantly managed in the community by nurses with minimal clinical involvement of specialist clinicians. Up to 53% of all the ulcers may have been clinically infected at the time of presentation, and 35% of patients subsequently developed a putative wound infection a mean 4.7 months after initial presentation. The mean NHS cost of wound care over 12 months ranged from £1400 for a category 1 ulcer to >£8500 for the other categories of ulcer. Additionally, the cost of managing an unhealed ulcer was 2.4 times more than that of managing a healed ulcer (mean of £5140 vs £12 300 per ulcer).

Conclusion

This study provides important insights into a number of aspects of PU management in clinical practice in the community that have been difficult to ascertain from other studies, and provides the best estimate available of NHS resource use and costs with which to inform policy and budgetary decisions.

https://ift.tt/2uOEDrK

Acceptability and experience of a functional training programme (ReTrain) in community-dwelling stroke survivors in South West England: a qualitative study

Rehabilitation Training (ReTrain) is a group-based approach to functional training post stroke. ReTrain has recently been evaluated through a pilot randomised controlled trial.

Objective

This article reports on the acceptability of the intervention as described by trial participants.

Design

A qualitative approach was undertaken. Of the 45 participants recruited into the trial, 23 were randomised to receive ReTrain. Following a sampling strategy, 10 participants undertook 1:1 semistructured audio-recorded interviews. Transcripts were analysed following a modified Framework Approach.

Results

Six themes were developed including exploration of: the physical and psychological impacts of training,the perceived mechanisms of change, the interaction of the group and approach of the trainer. A further theme considered the reported longer term impact of participation. Overall, the results indicated the acceptability of the intervention, but also key areas for potential modification in the definitive trial. These include a need to consider potential impact on both physical and psychological function, careful consideration of dosing and fatigue and the interpersonal factors that facilitate appropriate level of delivery, the trainer to participant ratio, and enhancing features that support continuation of activity postintervention.

Conclusion

Overall, this study supports the acceptability of ReTrain and the development of a definitive trial evaluation of this intervention to full.

Trial registration number

NCT02429180.

https://ift.tt/2LT0zsp

Prehospital trauma death review in the State of Victoria, Australia: a study protocol

Introduction

Regionalised trauma systems have been shown to improve outcomes for trauma patients. However, the evaluation of these trauma systems has been oriented towards in-hospital care. Therefore, the epidemiology and care delivered to the injured patients who died in the prehospital setting remain poorly studied. This study aims to provide an overview of a methodological approach to reviewing trauma deaths in order to assess the preventability, identify areas for improvements in the system of care provided to these patients and evaluate the potential for novel interventions to improve outcomes for seriously injured trauma patients.

Methods and analysis

The planned study is a retrospective review of prehospital and early in-hospital (<24 hours) deaths following traumatic out-of-hospital cardiac arrest that were attended by Ambulance Victoria between 2008 and 2014. Eligible patients will be identified from the Victorian Ambulance Cardiac Arrest Registry and linked with the National Coronial Information System. For patients who were transported to hospital, data will be linked the Victoria State Trauma Registry. The project will be undertaken in four phases: (1) survivability assessment; (2) preventability assessment; (3) identification of potential areas for improvement; and (4) identification of potentially useful novel technologies. Survivability assessment will be based on predetermined anatomical injuries considered unsurvivable. For patients with potentially survivable injuries, multidisciplinary expert panel reviews will be conducted to assess the preventability as well as the identification of potential areas for improvement and the utility of novel technologies.

Ethics and dissemination

The present study was approved by the Victorian Department of Justice and Regulation HREC (CF/16/272) and the Monash University HREC (CF16/532 – 2016000259). Results of the study will be published in peer-reviewed journals and reports provided to Ambulance Victoria, the Victorian State Trauma Committee and the Victorian State Government Department of Health and Human Services.

https://ift.tt/2LMe2Sy

Deciding on behalf of others: a population survey on procedural preferences for surrogate decision-making

Objectives

To assess people's procedural preferences for making medical surrogate decisions, from the perspectives of both a potential surrogate and an incapacitated patient.

Design

Computer-assisted telephone interviews. Respondents were randomly assigned either the role of an incapacitated patient or that of a potential surrogate for an incapacitated family member. They were asked to rate six approaches to making a surrogate decision: patient-designated surrogate, discussion among family members, majority vote of family members' individual judgements, legally assigned surrogate, population-based treatment indicator and delegating the decision to a physician.

Setting

Germany and German-speaking and French-speaking parts of Switzerland.

Participants

2010 respondents were quota sampled from a panel (representative for the German and German-speaking and French-speaking Swiss populations, respectively, in terms of age, sex and regions).

Main outcome measures

Endorsement of each approach (rated on a scale from 1 to 10). Degree to which preferences overlap between the perspective of potential surrogates and potential patients.

Results

Respondents' endorsement of the six different approaches varied markedly (from Mdn=9.3 to Mdn=2.6). Yet the preferences of respondents taking the perspective of incapacitated patients corresponded closely with those of respondents taking the perspective of a potential surrogate (absolute differences ranging from 0.1 to 1.3). The preferred approaches were a patient-designated surrogate (Mdn=9.3) and all family members making a collective decision by means of group discussion (Mdn=9.3). The two least-preferred approaches were relying on a statistical prediction rule (Mdn=3.0) and delegating the decision to a physician (Mdn=2.6).

Conclusions

Although respondents taking the perspective of an incapacitated patient preferred a patient-designated surrogate, few people have designated such a surrogate in practice. Policy-makers may thus consider implementing active choice, that is, identifying institutional settings in which many people can be reached (eg, when obtaining a driver's licence) and requesting them to complete advance directives and to designate a specific surrogate. Moreover, potential patients and surrogates alike highly valued shared surrogate decisions among family members. Policy-makers may consider acknowledging this possibility explicitly in future legislation, and caregivers and physicians may consider promoting shared surrogate decisions in practice.

https://ift.tt/2uPEeFi

Bibliometric analysis of gaps in research on asbestos-related diseases: declining emphasis on public health over 26 years

Objectives

The global burden of asbestos-related diseases (ARDs) is significant, and most of the world's population live in countries where asbestos use continues. We examined the gaps between ARD research and suggestions of WHO and the International Labour Organization on prevention.

Methods

From the Web of Science, we collected data on all articles published during 1991–2016 and identified a subset of ARD-related articles. We classified articles into three research areas—laboratory, clinical and public health—and examined their time trends. For all and the top 11 countries publishing ARD-related articles, we calculated the proportions of all ARD-related articles that were in each of the three areas, the average rates of ARD-related articles over all articles, and the average annual per cent changes of rates.

Results

ARD-related articles (n=14 284) accounted for 1.3 of all articles in 1991, but this had declined to 0.8 by 2016. Among the three research areas, the clinical area accounted for the largest proportion (65.0%), followed by laboratory (26.5%) and public health (24.9%). The public health area declined faster than the other areas, at –5.7% per year. Discrepancies were also observed among the top 11 countries regarding emphasis on public health research, with Finland and Italy having higher, and China and the Netherlands lower, emphases.

Conclusions

There is declining emphasis on the public health area in the ARD-related literature. Under the ongoing global situation of ARD, primary prevention will remain key for some time, warranting efforts to rectify the current trend in ARD-related research.

https://ift.tt/2LPuKjS

Determinants of adherence and consequences of the transition from adolescence to adulthood among young people with severe haemophilia (TRANSHEMO): study protocol for a multicentric French national observational cross-sectional study

Introduction

Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life.

Methods and analysis

We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14–17 years) with those from a group of young adults (aged 20–29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag.

Ethics and dissemination

The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public.

Trial registration number

NCT02866526; Pre-results.

https://ift.tt/2LDkv5q

Patent foramen ovale closure, antiplatelet therapy or anticoagulation in patients with patent foramen ovale and cryptogenic stroke: a systematic review and network meta-analysis incorporating complementary external evidence

Objective

To examine the relative impact of three management options in patients aged <60 years with cryptogenic stroke and a patent foramen ovale (PFO): PFO closure plus antiplatelet therapy, antiplatelet therapy alone and anticoagulation alone.

Design

Systematic review and network meta-analysis (NMA) supported by complementary external evidence.

Data sources

Medline, EMBASE and Cochrane CENTRAL.

Study selection

Randomised controlled trials (RCTs) addressing PFO closure and/or medical therapies in patients with PFO and cryptogenic stroke.

Review methods

We conducted an NMA complemented with external evidence and rated certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Results

Ten RCTs in eight studies proved eligible (n=4416). Seven RCTs (n=3913) addressed PFO closure versus medical therapy. Of these, three (n=1257) addressed PFO closure versus antiplatelet therapy, three (n=2303) addressed PFO closure versus mixed antiplatelet and anticoagulation therapies and one (n=353) addressed PFO closure versus anticoagulation. The remaining three RCTs (n=503) addressed anticoagulant versus antiplatelet therapy. PFO closure versus antiplatelet therapy probably results in substantial reduction in ischaemic stroke recurrence (risk difference per 1000 patients over 5 years (RD): –87, 95% credible interval (CrI) –100 to –33; moderate certainty). Compared with anticoagulation, PFO closure may confer little or no difference in ischaemic stroke recurrence (low certainty) but probably has a lower risk of major bleeding (RD –20, 95% CrI –27 to –2, moderate certainty). Relative to either medical therapy, PFO closure probably increases the risk of persistent atrial fibrillation (RD 18, 95% CI +5 to +56, moderate certainty) and device-related adverse events (RD +36, 95% CI +23 to +50, high certainty). Anticoagulation, compared with antiplatelet therapy, may reduce the risk of ischaemic stroke recurrence (RD –71, 95% CrI –100 to +17, low certainty), but probably increases the risk of major bleeding (RD +12, 95% CrI –5 to +65, moderate certainty).

Conclusions

In patients aged <60 years, PFO closure probably confers an important reduction in ischaemic stroke recurrence compared with antiplatelet therapy alone but may make no difference compared with anticoagulation. PFO closure incurs a risk of persistent atrial fibrillation and device-related adverse events. Compared with alternatives, anticoagulation probably increases major bleeding.

PROSPERO registration number

CRD42017081567.

https://ift.tt/2LQeP59

Can a bothersome course of pelvic pain from mid-pregnancy to birth be predicted? A Norwegian prospective longitudinal SMS-Track study

Objective

To explore if pregnant women with pelvic girdle pain (PGP), subgrouped following the results from two clinical tests with high validity and reliability, differ in demographic characteristics and weekly amount of days with bothersome symptoms through the second half of pregnancy.

Design

A prospective longitudinal cohort study.

Participants

Pregnant women with pelvic and lumbopelvic pain due for their second-trimester routine ultrasound examination.

Setting

Obstetric outpatient clinic at Stavanger University Hospital, Norway.

Methods

Women reporting pelvic and lumbopelvic pain completed a questionnaire on demographic and clinical features. They were clinically examined following a test procedure recommended in the European guidelines for the diagnosis and treatment of PGP. Women without pain symptoms completed a questionnaire on demographic data. All women were followed weekly through an SMS-Track survey until delivery.

Primary and secondary outcome measures

The outcome measures were the results from clinical diagnostic tests for PGP and the number of days per week with bothersome pelvic pain.

Results

503 women participated. 42% (212/503) reported pain in the lumbopelvic region and 39% (196/503) fulfilled the criteria for a probable PGP diagnosis. 27% (137/503) reported both the posterior pelvic pain provocation (P4) and the active straight leg raise (ASLR) tests positive at baseline in week 18, revealing 7.55 (95% CI 5.54 to 10.29) times higher mean number of days with bothersome pelvic pain compared with women with both tests negative. They presented the highest scores for workload, depressed mood, pain level, body mass index, Oswestry Disability Index and the number of previous pregnancies. Exercising regularly before and during pregnancy was more common in women with negative tests.

Conclusion

If both P4 and ASLR tests were positive mid-pregnancy, a persistent bothersome pelvic pain of more than 5 days per week throughout the remainder of pregnancy could be predicted. Increased individual control over work situation and an active lifestyle, including regular exercise before and during pregnancy, may serve as a PGP prophylactic.

https://ift.tt/2NLivFL

Prevalence and associated factors of post-traumatic stress disorder among emergency responders of Addis Ababa Fire and Emergency Control and Prevention Service Authority, Ethiopia: institution-based, cross-sectional study

Objective

To assess the prevalence and associated factors of post-traumatic stress disorder (PTSD) among emergency responders at Addis Ababa Fire and Emergency Control and Prevention Service Authority, Ethiopia.

Design

Institution-based, cross-sectional design.

Setting

The study was conducted at the Fire and Emergency Control and Prevention Service Authority, Addis Ababa, Ethiopia.

Participants

603 emergency responders who worked in the Fire and Emergency Control and Prevention Authority during the study period.

Measurement

Data were collected using a self-administered questionnaire: an adaptation of the standardised PTSD Checklist–Civilian Version. The questionnaire was administered to subjects on duty. Social support was measured using the Oslo 3-Item Social Support Scale, while other stressful life events were measured using the List of Threatening Experiences, that is, experiencing one or more stressful life events in the last 6 months. Reliability and construct validity were verified. To be diagnosed with PTSD, a subject must display at least three different types of symptoms at once. Coded variables were entered into Epi Info V.3.5.1 and then exported to SPSS V.20 for analysis. Descriptive and bivariate and multivariate logistic regressions and 95% CI were employed to establish and test statistically significant associations.

Results

A total of 603 subjects participated in the study, with 19.9% prevalence rate of PTSD (95% CI 16.9 to 23.1). The study found family history of mental illness (adjusted OR (AOR)=2.82; 95% CI 1.65 to 4.84), longer years of service (AOR=2.67; 95% CI 1.54 to 4.63), as well as prolonged exposure to emergency situations (AOR=0.44; 95% CI 0.24 to 0.84) and road traffic accidents (AOR=2.71; 95% CI 1.67 to 4.42) as significant predictors of PTSD among emergency responders.

Conclusion

The prevalence of PTSD was high among the study population. Family history of mental illness, length of service, duration of exposure and type of exposure were found to be associated with PTSD. Mental health education and linking emergency responders with available mental health services/facilities should be prioritised to mitigate the problem.

https://ift.tt/2uRv9fh

Establishment of blood pressure nomograms representative for Egyptian children and adolescents: a cross-sectional study

Objective

To define nomograms for blood pressure in Egyptian children and adolescents.

Methods and study design

A total of 60 025 Egyptian children from birth to 19 years were enrolled in this cross-sectional randomised study from December 2015 to March 2017. They were selected from diverse geographical districts in Egypt. Healthy children who fulfilled the inclusion criteria, which included good nutritional history, absence of fever or documented underlying disease at the time of examination, no evidence of haemodynamically significant illness, and no antihypertensive drugs or other chronic drug administration, were included in the study. Body weight, recumbent length (for less than 24 months) and height (from 2 years to 19 years), and blood pressure were measured using standard mercury sphygmomanometers.

Results

Blood pressure increases with age in both boys and girls. The 90th percentile of systolic and diastolic blood pressure among Egyptian children was different from other ethnic populations (American and Turkish children) in both sexes. Systolic and diastolic blood pressure showed a positive correlation with weight and height in both sexes (p<0.001).

Conclusion

We assumed that normal blood pressure curves should be used cautiously during childhood, and it is recommended that every population have its own normal standard curve to define measured blood pressure levels in children. These centiles increased our knowledge and awareness of normal blood pressure among Egyptian children and adolescents. The percentiles will distinguish children and young adolescents with increased blood pressure and will be of value to both medical practice and scientific research.

https://ift.tt/2LPuukU

Patient-reported outcome (PRO) measure-based algorithm for clinical decision support in epilepsy outpatient follow-up: a test-retest reliability study

Objectives

Patient-reported outcome (PRO) measures have been used in epilepsy outpatient clinics in Denmark since 2011. The patients' self-reported PRO data are used by clinicians as a decision aid to support whether a patient needs contact with the outpatient clinic or not based on a PRO algorithm. Validity and reliability are fundamental to any PRO measurement used at the individual level in clinical practice. The aim of this study was to evaluate the test–retest reliability of the PRO algorithm used in epilepsy outpatient clinics and to analyse whether the method of administration (web and paper) would influence the result.

Design and setting

Test–retest reliability study conducted in three epilepsy outpatient clinics in Central Denmark Region, Denmark.

Participants

A total of 554 epilepsy outpatients aged 15 years or more were included from August 2016 to April 2017. The participants completed questionnaires at two time points and were randomly divided into four test–retest groups: web–web, paper–paper, web–paper and paper–web. In total, 166 patients completed web–web, 112 paper–paper, 239 web–paper and 37 paper–web.

Results

Weighted kappa with squared weight was 0.67 (95% CI 0.60 to 0.74) for the pooled PRO algorithm, and perfect agreement was observed in 82% (95% CI 78% to 85%) of the cases. There was a tendency towards higher test–retest reliability and agreement estimates within same method of administration (web–web or paper–paper) compared with a mixture of methods (web–paper and paper–web).

Conclusions

The PRO algorithm used for clinical decision support in epilepsy outpatient clinics showed moderate to substantial test–retest reliability. Different methods of administration produced similar results, but an influence of change in administration method cannot be ruled out.

https://ift.tt/2uQ2VS3

Femoral neuropathy following a psoas hitch vesicopexy

A 68-year-old man classified as III on the American Society of Anaesthesiologists (ASA) physical status classification system, with a high-grade papillary urothelial cell carcinoma of the left distal ureter, underwent open retroperitoneal distal ureterectomy followed by a ureteroneocystostomy with a vesico-psoas hitch. Postoperatively, the patient complained of left proximal lower limb weakness, severe pain and hypaesthesia of the ventral left thigh suggestive of femoral neuropathy. After excluding common causes for postsurgical pain, a surgical re-exploration was eventually performed during which the sutures used in the vesicopexy were removed, resulting in almost complete resolution of the symptoms. Electromyographic analysis 4 weeks after discharge confirmed the diagnosis of femoral neuropathy, most likely caused by the sutures used in the vesicopexy. This is a rare complication with major consequences for postoperative recovery.

https://ift.tt/2vdy0yL

Avoiding diagnostic delay for mucopolysaccharidosis IIIB: do not overlook common clues such as wheezing and otitis media

Mucopolysaccharidosis IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disorder. In comparison to Hurler syndrome (MPS I) and Hunter syndrome (MPS II), characteristic facial and physical features tend to be milder and progression of neurological symptoms may initially be slower. Obvious neurological and behavioural symptoms may not appear until age 2–6 years, but once they begin, progression is relentless, leading to death by the early 20s. Although there is currently no known cure for MPS IIIB, enzyme replacement clinical trials are showing hope for delay in the progression of symptoms. Early diagnosis is therefore necessary before neurological symptoms have progressed. In our case, MPS IIIB was diagnosed at an early age because recurrent wheezing and otitis media in conjunction with hepatomegaly were recognised as more than trivial findings. A thorough examination and a definitive proactive decision to perform a liver biopsy resulted in early diagnosis of a rare disease.

https://ift.tt/2LnXeoQ

Frey syndrome following herpes zoster in an otherwise healthy girl

A 12-year-old girl presented with red spots appearing on the left side of her face. The girl was usually healthy and fully vaccinated, including varicella vaccination.

Six years prior to her presentation, she had suffered an episode of blister rash on the left side of her face, including lesions in the ear canal and buccal mucous membrane. A diagnosis of herpes zoster was made, and she was treated with acyclovir with complete skin recovery. A hearing examination demonstrated mild-to-moderate left neurosensory hearing loss.

Since then, she is having short episodes of redness on her face without pain or sweating at the exact distribution of the zoster blisters 6 years ago. The appearance of spots is related to sour foods, such as sour flavoured candies, yoghourt and green apples. The diagnosis of postherpetic Frey syndrome was made, and observational approach was adopted due to the benign character of symptoms.

https://ift.tt/2v0CBEa

Hepatitis C virus infection: 'beyond the liver

There are rare reports of association between hepatitis C virus (HCV) infection and dermatomyositis although cause and effect remains to be proven. We present a clinical case with a probable cause and effect association between these two entities. A 71-year-old woman developed an erythematous exanthem with pruritic and scaly lesions located at the torso and upper limbs associated with heliotrope and Gottron's papules. At the same time, she notice a significant loss of muscular strength. Skin and muscular biopsies made the diagnosis of dermatomyositis and the patient started with prednisolone (60 mg/day) with poor symptoms control. Paraneoplastic syndrome, HIV, hepatitis B virus and syphilis infections were excluded. HCV serology was positive, with a viral load of 58 159 IU/mL (genotype 1a). Therefore, the patient underwent a 12-week treatment with grazoprevir 100 mg and elbasvir 50 mg achieving a sustained virological response with regression of skin lesions and complete recovery of muscular strength (photodocumented before/after treatment). Additionally it was possible to reduce prednisolone dosage to 5 mg/day.

https://ift.tt/2LogO4q

Stroke-induced resolution of primary blepharospasm: evidence for the lenticular nucleus as a control candidate

Primary blepharospasm is an adult-onset focal dystonia characterised by involuntary contractions of the orbicularis oculi, leading to bilateral spasmodic closure of the eyelids. While spasms of this muscle constitute the hallmark of disease, other motor manifestations include increased spontaneous blinking and apraxia of eyelid opening. Originally misdiagnosed as a psychiatric condition, blepharospasm is now well established as being of neurological origin although questions remain as to its pathophysiological mechanisms.

We report a 66-year-old woman who had a 14-year history of primary blepharospasm which completely resolved following a left medial cerebral artery thromboembolic infarct of the lenticular nucleus. This report provides supporting evidence of the lenticular nucleus as a key structure mediating the disease which can lead to functional blindness.

https://ift.tt/2v7R94T

Correction to: Pulmonary nocardiosis masquerading renascence of tuberculosis in an immunocompetent host: a case report from Nepal

Following publication of the original article [1], a typesetting mistake is reported. The captions of Figure 2 and Figure 3 were interchanged. The incorrect and correct combination of the figures and captions ...

https://ift.tt/2OhsOm4

Systemic Delivery of AAVB1-GAA Clears Glycogen and Prolongs Survival in a Mouse Model of Pompe Disease

Human Gene Therapy, Ahead of Print.


https://ift.tt/2Lrr8Zz

Evaluation of a multi-slice spiral computed tomography perfusion for the prediction of the recurrence of gastric cancer

Future Oncology, Ahead of Print.


https://ift.tt/2Lqdju0

Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR , and WNT10A in four Turkish families with tooth agenesis

Abstract

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM #150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM #614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM #104530; Epidermolysis bullosa, junctional, MIMs #226700 and #226650), and BCOR (Microphthalmia, syndromic 2, MIM #300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype–phenotype relationship in the common complex trait of TA.

https://ift.tt/2LJzf2Y

Human liver spheroids in chemically defined conditions for studies of gene–drug, drug–drug and disease–drug interactions

Pharmacogenomics, Ahead of Print.


https://ift.tt/2LC4Mnj

Genomic markers of resistance to targeted treatments in gastric cancer: potential new treatment strategies

Pharmacogenomics, Ahead of Print.


https://ift.tt/2JSbuAF

Editorial: Polar and Alpine Microbiology

https://ift.tt/2OftPuJ

Daily variation in the prokaryotic community during a spring bloom in shelf waters of the East China Sea

ABSTRACT

To understand prokaryotic responses during a spring bloom in offshore shelf waters, prokaryotic parameters were measured daily at a station located in the middle of the East China Sea over a six-week period from March 25 to May 19. The site experienced a phytoplankton bloom in late April, triggering changes in prokaryotic abundance and production after a lag of approximately one week. Before the bloom, changes in prokaryotic composition were small. Both during the bloom and in the post-bloom period, successive changes among bacterial groups were apparent. A SAR11 group became more dominant during the bloom period, and diverse groups belonging to the Flavobacteriia occurred dominantly during both the bloom and post-bloom periods. However, bacterial community changes at the species level during the bloom and post-bloom periods occurred rapidly in a time scale of a few days. Especially, NS5, NS4 and Formosa bacteria belonging to Flavobacteriia and bacteria belonging to Halieaceae and Arenicellaceae families of Gammaproteobacteria showed a successive pattern with large short-term variation during the period. The changes in prokaryotic composition were found to be related to phytoplankton biomass and composition, as well as seawater temperature and variations in nutrients.

https://ift.tt/2A8rGOH

Gut microbial and metabolomic profiles after fecal microbiota transplantation in pediatric ulcerative colitis patients

ABSTRACT

Ulcerative colitis is a chronic inflammatory disease of the colon that carries a significant disease burden in children. Therefore, new therapeutic approaches are being explored to help children living with this disease. Fecal microbiota transplantation (FMT) has been successful in some children with ulcerative colitis. However, the mechanism of its therapeutic effect in this patient population is not well understood. To characterize changes in gut microbial and metabolomic profiles after FMT, we performed 16S rRNA gene sequencing, shotgun metagenomic sequencing, virome analysis and untargeted metabolomics by gas chromatography-time of flight-mass spectrometry on stool samples collected before and after FMT from four children with ulcerative colitis who responded to this treatment. Alpha diversity of the gut microbiota increased after intervention, with species richness rising from 251 (S.D. 125) to 358 (S.D. 27). In responders, the mean relative abundance of bacteria in the class Clostridia shifted toward donor levels, increasing from 33% (S.D. 11%) to 54% (S.D. 16%). Patient metabolomic and viromic profiles exhibited a similar but less pronounced shift toward donor profiles after FMT. The fecal concentrations of several metabolites were altered after FMT, correlating with clinical improvement. Larger studies using a similar multi-omics approach may suggest novel strategies for the treatment of pediatric ulcerative colitis.

https://ift.tt/2mIEf9B

Effect of spatial origin and hydrocarbon composition on bacterial consortia community structure and hydrocarbon biodegradation rates

Abstract

Oil reserves in deep-sea sediments are currently subject to intense exploration, with associated risks of oil spills. Previous research suggests that microbial communities from deep-sea sediment (>1000m) can degrade hydrocarbons (HCs), but have a lower degradation ability than shallow (<200m) communities, probably due to in situ temperature. This study aimed to assess the effect of marine origin on microbial HC degradation potential while separating the influence of temperature, and to characterise associated HC-degrading bacterial communities. Microbial communities from 135 and 1000 m deep sediments were selectively enriched on crude oil at in situ temperatures and both consortia were subsequently incubated for 42 days at 20°C with two HC mixtures: diesel fuel or model oil. Significant HC biodegradation occurred rapidly in the presence of both consortia, especially of low molecular weight HCs and was concomitant with microbial community changes. Further, oil degradation was higher with the shallow consortium than with the deep one. Dominant HC-degrading bacteria differed based on both spatial origin of the consortia and supplemented HC types. This study provides evidence for influence of sediment spatial origin and HC composition on the selection and activity of marine HC-degrading bacterial communities and is relevant for future bioremediationdevelopments.

https://ift.tt/2A8MXaN

CAP2 is a Valuable Biomarker for Diagnosis and Prognostic in Patients with Gastric Cancer

Abstract

Cyclase-associated protein 2 (CAP2) protein is reported to be upregulated in hepatocellular carcinoma (HCC), human breast cancer, and malignant melanoma. However, its expression in gastric cancer remains unknown, this study was to investigate CAP2 expression and its prognostic significance in gastric cancer. Firstly, we analyzed the Oncomine databases to compare CAP2 mRNA expression in gastric cancer and normal tissues. CAP2 protein expression was analyzed in gastric cancer samples and non-tumor mucosa by RT-PCR and immunohistochemical analysis. Consequently, statistical analyses were performed to evaluate the clinicopathological significance of CAP2 expression in gastric cancer. CAP2 expression was significant higher in gastric cancer tissues than that in non-tumor mucosa at protein levels. CAP2 was up-regulated in 57.8% (252/436) of gastric cancer samples, while detected in only 10.9% (10/92) of non-tumor mucosa. Statistical analysis shows that the expression of CAP2 was correlated with tumor size, Lauren's classification, depth of invasion, lymph node and distant metastases, and regional lymph node stage, TNM stage, but not with age, sex, histology classification, and histologic differentiation. Kaplan-Meier analysis indicated that high CAP2 expression was associated with poor overall survival (78.7%) in 203 of 252 gastic cancer patients. In stage I, II, and III tumors, the 5-year survival rate was lower in those with high expression of CAP2 than those with low expression. In stage IV tumors, the expression of CAP2 did not correlate with the 5-year survival rate. Multiple Cox regression analysis indicated CAP2 as an independent predictor for overall survival [hazard ratio (HR) = 2.045, 95% confidence interval: 1.445–2.895, p < 0.01], while Lauren's classification, TNM stage, and expression of CAP2 were independent prognostic factors in patients with gastric cancer. For the first time, we found that CAP2 was upregulated in gastic cancer, and was associated with lymph node and distant metastases. CAP2 may serve as a prognostic indicator for patients with gastic cancer.

https://ift.tt/2NMnx4N

The Republican War on Obamacare — What Has It Achieved?

For nearly a decade, Republicans have opposed the Affordable Care Act (ACA). They have fought Obamacare in Congress, the courts, and the states and, since 2017, from the White House. Given the scope, intensity, and duration of this campaign, it is worth considering what it has achieved. Opposition…

https://ift.tt/2AbQOE7

SHP2 Inhibition Prevents Adaptive Resistance to MEK inhibitors in Multiple Cancer Models [Research Briefs]

Adaptive resistance to MEK inhibitors (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs, and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEK-I inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEK-I treatment had similar effects, while expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancer and in wild type RAS-expressing triple negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEK-Is and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEK-I combinations could have therapeutic utility in multiple malignancies.

https://ift.tt/2Ac9KCD

Tickborne Diseases — Confronting a Growing Threat

Every spring, public health officials prepare for an upsurge in vectorborne diseases. As mosquito-borne illnesses have notoriously surged in the Americas, the U.S. incidence of tickborne infections has risen insidiously, triggering heightened attention from clinicians and researchers. According to…

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Crossing Borders

By my third time caring for John, there was a certain familiarity in our interactions. An overweight white man with salt-and-pepper hair, John was in his early 50s and lived with his father. He'd been a successful chef but struggled with an addiction to injection methamphetamines that had left him…

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Tickborne Diseases — Confronting a Growing Threat

Every spring, public health officials prepare for an upsurge in vectorborne diseases. As mosquito-borne illnesses have notoriously surged in the Americas, the U.S. incidence of tickborne infections has risen insidiously, triggering heightened attention from clinicians and researchers. According to…

https://ift.tt/2NKCt3j

Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study

Abstract

Cognitive decline is common in multiple sclerosis and strongly affects overall quality of life. Despite the identification of cross-sectional MRI correlates of cognitive impairment, predictors of future cognitive decline remain unclear. The objective of this study was to identify which MRI measures of structural damage, demographic and/or clinical measures at baseline best predict cognitive decline, during a 5-year follow-up period. A total of 234 patients with clinically definite multiple sclerosis and 60 healthy control subjects were examined twice, with a 5-year interval (mean = 4.9 years, standard deviation = 0.9). An extensive neuropsychological evaluation was performed at both time points and the reliable change index was computed to evaluate cognitive decline. Both whole-brain and regional MRI (3 T) measures were assessed at baseline, including white matter lesion volume, diffusion-based white matter integrity, cortical and deep grey matter volume. Logistic regression analyses were performed to determine which baseline measures best predicted cognitive decline in the entire sample as well as in early relapsing-remitting (symptom duration <10 years), late relapsing-remitting (symptom duration ≥10 years) and progressive phenotypes. At baseline, patients with multiple sclerosis had a mean disease duration of 14.8 (standard deviation = 8.4) years and 96/234 patients (41%) were classified as cognitively impaired. A total of 66/234 patients (28%) demonstrated cognitive decline during follow-up, with higher frequencies in progressive compared to relapsing-remitting patients: 18/33 secondary progressive patients (55%), 10/19 primary progressive patients (53%) and 38/182 relapsing-remitting patients (21%). A prediction model that included only whole-brain MRI measures (Nagelkerke R² = 0.22, P < 0.001) showed cortical grey matter volume as the only significant MRI predictor of cognitive decline, while a prediction model that assessed regional MRI measures (Nagelkerke R² = 0.35, P < 0.001) indicated integrity loss of the anterior thalamic radiation, lesions in the superior longitudinal fasciculus and temporal atrophy as significant MRI predictors for cognitive decline. Disease stage specific regressions showed that cognitive decline in early relapsing-remitting multiple sclerosis was predicted by white matter integrity damage, while cognitive decline in late relapsing-remitting and progressive multiple sclerosis was predicted by cortical atrophy. These results indicate that patients with more severe structural damage at baseline, and especially cortical atrophy, are more prone to suffer from cognitive decline. New studies now need to further elucidate the underlying mechanisms leading to cortical atrophy, evaluate the value of including cortical atrophy as a possible outcome marker in clinical trials as well as study its potential use in individual patient management.

https://ift.tt/2LIsNca

Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers.

Purpose: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. Experimental Design: We identified all patients with metastatic EGFR exon19del or L858R mutant lung cancers treated with first/second generation EGFR tyrosine kinase inhibitors (TKIs) with pre-treatment large panel next generation sequencing data (MSK-IMPACT assay). The effect of TMB on time to treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type (WT) lung adenocarcinoma samples were used for comparison. Results: Among 153 patients with EGFR mutant lung cancer, TMB was lower compared to EGFR wild-type (n=1849) (median 3.77 vs. 6.12 mutations/Mb, p<0.0001) with a broad range (0.82-17.9). EGFR mutant lung cancer patients whose tumors had TMB in the upper tertile had shorter TTD (HR=0.46, p=0.0008) and OS (HR=0.40, p=0.006) compared to patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD p=0.006, OS p=0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared to high TMB (HR=0.57, p=0.01; HR=0.50, p=0.02, respectively). In paired pre-treatment and post-progression samples, TMB was increased at resistance (median 6.56 vs 3.42 mutations/Mb, p=0.008). Conclusions: TMB is negatively associated with clinical outcomes in metastatic EGFR mutant lung cancer patients treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.

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Phase I Trial of ALT-803, a Novel Recombinant Interleukin-15 Complex, in Patients with Advanced Solid Tumors

Background: IL-15 induces the activation and proliferation of NK and memory CD8+ T cells and has preclinical antitumor activity. Given the superior activity and favorable kinetics of ALT-803 (IL-15N72D:IL-15RαSu/IgG1 Fc complex) over recombinant human IL-15 (rhIL-15) in animal models, we performed this first-in-human Phase I trial of ALT-803 in patients with advanced solid tumors. Methods: Patients with incurable advanced melanoma, renal cell, non-small cell lung, and head and neck cancer were treated with ALT-803 0.3-6 mg/kg weekly i.v. or 6-20 mg/kg weekly s.c. for 4 consecutive weeks, every 6 weeks. Immune correlates included pharmacokinetics, immunogenicity, lymphocyte expansion and function. Clinical endpoints were toxicity and antitumor activity. Results: Twenty-four patients were enrolled; eleven received i.v. and 13 received s.c. ALT-803. Of these patients, 9 had melanoma, 6 renal, 3 head and neck, and 6 lung cancer. Although total lymphocyte and CD8+ T cell expansion were modest, NK cell numbers rose significantly. Neither anti-ALT-803 antibodies nor clinical activity were observed. Overall, ALT-803 was well-tolerated, with adverse effects including fatigue and nausea most commonly with i.v. administration, while painful injection site wheal was reported most commonly with s.c. ALT-803. Conclusions: Subcutaneous ALT-803 produced the expected NK cell expansion and was well-tolerated with minimal cytokine toxicities and a strong local inflammatory reaction at injection sites in advanced cancer patients. These data, together with compelling evidence of synergy in preclinical and clinical studies, provide the rationale for combining ALT-803 with other anti-cancer agents.

https://ift.tt/2v6NN27

Real-time Tumor Gene Expression Profiling to Direct Gastric Cancer Chemotherapy: Proof-of-Concept '3G' Trial

Background The oxaliplatin plus S-1 and cisplatin plus S-1 regimens are interchangeably used in the management of advanced gastric cancer. The previously-reported G-intestinal ('G1') and G-diffuse ('G2') intrinsic gene expression signatures showed promise for stratifying patients according to their tumour sensitivity to oxaliplatin or cisplatin. Methods The proof-of-concept, multicentre, open-label phase 2 '3G' trial was done to prospectively evaluate the feasibility and efficacy of using genomic classifiers to tailor treatment in gastric cancer. Patients' tumours were classified as 'G1' or 'G2' using a nearest-prediction template method, or 'G3' (unclear assignment) when FDR≥0·05. The first thirty patients in the 'G1' cohort were assigned oxaliplatin plus S-1 (SOX) chemotherapy, thereafter, subsequently-recruited 'G1' patients were treated with cisplatin plus S-1 (SP) chemotherapy. 'G2' patients and 'G3' patients were treated with SP and SOX chemotherapy respectively. Results 48, 21 and 12 patients respectively were given 'G1', 'G2' and 'G3' genomic assignments. Median turnaround time was 7 days (IQR 5-9). Response rates were 44·8%, 8·3%, 26·7% and 55·6% for the 'G1-SOX', 'G1-SP', 'G2', 'G3' cohorts respectively; and was higher in G1 patients treated with SOX compared with SP (p=0·033). Exploratory analyses using the genomic classifier of Lei et al validated the utility of the metabolic signature as a biomarker for predicting benefit from chemotherapy (log-rank p=0·004 for PFS), whereas the Asian Cancer Research Group (ACRG) classifier did not demonstrate any predictive value. Conclusions This bench-to-bedside effort establishes a reasonable turnaround time for gene expression profiling and possible utility of genomic classifiers in gastric cancer treatment stratification.

https://ift.tt/2LnzP6Y

The effect of icariin on immunity and its potential application.

Related Articles

The effect of icariin on immunity and its potential application.

Am J Clin Exp Immunol. 2018;7(3):50-56

Authors: Shen R, Wang JH

Abstract
Icariin (ICA) is a major bioactive monomer belonging to flavonoid glycosides attracted from Epimedium, being a classic tonic agent in traditional Chinese medicine. ICA commonly presents multiple effects such as regulating sex hormones, relieving atherosclerosis and antioxidant activity, etc. Recently, more and more studies have demonstrated the application of ICA in autoimmune diseases such as rheumatoid arthritis, bronchial asthma, multiple sclerosis and systemic lupus erythematosus due to its anti-inflammatory. Additionally, ICA also has the anti-tumor activities. Multiple targets and mechanisms of ICA are reported which relates to regulate lymphocytes balance, anti-inflammatory/inflammatory cytokines, signal pathways like NF-kappaβ and Erk-p38-JNK, lymphocyte transcription factors and other targets such as TLRs, STAT and PTEN, etc. In this review, we have updated the advance in this field and these studies have suggested that ICA has a potential to treat immunological and inflammatory diseases.

PMID: 30038846 [PubMed]

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FDA Approves Magnetic System for Guiding Lymph Node Biopsies

WEDNESDAY, July 25, 2018 -- A magnetic system for guiding lymph node biopsies in patients with breast cancer undergoing mastectomy has been approved by the U.S. Food and Drug Administration. The Sentimag System uses magnetic detection during a...

https://ift.tt/2mKkzCy

WHO: Congo Ebola Outbreak Over

WEDNESDAY, July 25, 2018 -- The latest Ebola outbreak in the Democratic Republic of Congo is over, according to the World Health Organization. The outbreak began in April and was the first in which a new vaccine was quickly utilized, The New York...

https://ift.tt/2Ab6qb3

Regulations Restrict Providers' Ability to Offer Info on Abortions

WEDNESDAY, July 25, 2018 -- Proposed regulations restrict providers' ability to deliver unbiased patient care for individuals wanting to know about or undergo abortion, according to a perspective piece published online July 18 in the New England...

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One-Third of Hep C Rx Receive Absolute Denial From Insurers

WEDNESDAY, July 25, 2018 -- Insurers are increasingly denying prescriptions of direct-acting antiviral (DAA) drugs for hepatitis C virus treatment, according to a study published online June 7 in Open Forum Infectious Diseases. Charitha Gowda, M.D.,...

https://ift.tt/2OgTqU8

First IVF Baby Louise Brown Turns 40

WEDNESDAY, July 25, 2018 -- It's been 40 years since the birth of the first baby conceived through in vitro fertilization (IVF), and there have been more than eight million born since. Louise Joy Brown, who was 5 pounds 12 ounces when she was born...

https://ift.tt/2AdTmSc

Anti-inflammatory effects of Phyllanthus amarus Schum. & Thonn. through inhibition of NF-κB, MAPK, and PI3K-Akt signaling pathways in LPS-induced human macrophages

Phyllanthus amarus has been used widely in various traditional medicines to treat swelling, sores, jaundice, inflammatory diseases, kidney disorders, diabetes and viral hepatitis, while its pharmacological and bi...

https://ift.tt/2LOYNIs

Cross-sectional survey of the amount of sugar and energy in cakes and biscuits on sale in the UK for the evaluation of the sugar-reduction programme

Objectives

To investigate the variation in sugar and energy content of cakes and biscuits available in the UK.

Design

We carried out a cross-sectional survey in 2016 of 381 cakes and 481 biscuits available in nine main UK supermarkets.

Methods

The sugar and energy content was collected from product packaging and nutrition labelling of cake and biscuit products.

Results

The average sugar content in cakes and biscuits was 36.6±7.6 and 30.0±9.2 g/100 g, respectively. The mean energy content was 406±37 for cakes and 484±38 kcal/100 g for biscuits. There was a large variation in sugar and energy content between different cake and biscuit categories and within the same category. 97% of cakes and 74% of biscuits would receive a 'red' (high) label for sugar.

Conclusions

This research makes available baseline data of the cakes and biscuits market in the UK for future evaluation of the recently launched sugar-reduction programme. The study showed that reductions in sugar and energy content of cakes and biscuits are possible, since there was a large variation in sugar and energy content between different cake and biscuit categories and within the same category. A reduction in sugar and energy content, and overall cake and biscuit consumption, can help reduce overall sugar and energy intake in the UK and thus reduce the risk of obesity and dental caries.

https://ift.tt/2AdLXCo

Endoscopic ultrasound FNA: An illustrated review of spindle cell neoplasms of the upper gastrointestinal tract including a novel case of gastric plexiform fibromyxoma

Diagnostic Cytopathology, EarlyView.


https://ift.tt/2NHMsqk

Liesegang structures and pseudofungi in a cystic renal cell carcinoma aspirate

Diagnostic Cytopathology, EarlyView.


https://ift.tt/2LBDBch

Quantitative INTERSPECIMEN variability during biphasic pleural fluid cytological sampling in adenocarcinoma effusions

Diagnostic Cytopathology, EarlyView.


https://ift.tt/2LMDZBn

“Triple hit” lymphomas: A retrospective cytology case series of an uncommon high grade B‐cell malignancy with C‐MYC, BCL‐2 and BCL‐6 rearrangements

Diagnostic Cytopathology, EarlyView.


https://ift.tt/2LFpWAO

Expression of p63 immunostaining in liquid‐based cytology (BD SurePath) of breast fine‐needle aspiration

Diagnostic Cytopathology, EarlyView.


https://ift.tt/2LORHDO

Fecal Microbiota Transplantation: Current Status in Treatment of GI and Liver Disease

Fecal microbiota transplantation was originally introduced as a method to repair intestinal microbiota following failure of multiple treatments of recurrent Clostridium difficile infection with antibiotics. However, it is hypothesized that intestinal dysbiosis may contribute to pathogenesis of many diseases, especially those involving the gastrointestinal tract. Therefore, fecal microbiota transplantation is increasingly being explored as a potential treatment that aims to optimize microbiota composition and functionality.

https://ift.tt/2OfRDyw

Multidisciplinary treatment of pediatric functional gastrointestinal disorders results in improved pain and functioning

https://ift.tt/2LPFajB

Is Endoscopic Submucosal Dissection of Early Esophageal Cancer ready for prime time?

https://ift.tt/2OeWtfL

STING agonist therapy in combination with PD-1 immune checkpoint blockade enhances response to carboplatin chemotherapy in high-grade serous ovarian cancer

https://ift.tt/2JTL7KJ

The theranostic target prostate-specific membrane antigen is expressed in medullary thyroid Cancer

Medullary thyroid cancer (MTC) accounts for 4% of all thyroid cancers and originates from the parafollicular C-cells. Prostate-Specific Membrane Antigen (PSMA) is known for its expression in the epithelium of prostate cancer and has been demonstrated to be useful both for therapeutic and diagnostic purposes as a so-called theranostic target. As PSMA is also expressed in the neovasculature of other solid tumor types, our aim was to assess PSMA expression and its prognostic role in MTC. Tissues from patients that underwent surgery for MTC between 1988 and 2014 in five tertiary referral centers in The Netherlands were included in a tissue microarray.

https://ift.tt/2LBAKA0

Clinical impact of closure of the mucosal defect after duodenal endoscopic submucosal dissection

Delayed adverse events (bleeding or perforation) are major concerns associated with duodenal endoscopic submucosal dissection (ESD). The aim of this study was to assess the efficacy of prophylactic closure of the mucosal defect after duodenal ESD.

https://ift.tt/2JWIVlo

Detection of mesenteric ischemia by means of endoscopic visible light spectroscopy after luminal feeding

Endoscopic visible light spectroscopy (VLS) enables measurement of mucosal oxygen saturation during upper GI endoscopy and is used in the diagnostic work-up of chronic mesenteric ischemia (CMI). Currently, VLS is performed when the patient has fasted. We aimed to determine whether food challenge improves the diagnostic performance of VLS measurements for the diagnosis of CMI.

https://ift.tt/2LFSGcE

Epinephrine and the Paramedic-2 trial: Is it time to pull our starting pitcher?

New research questions whether pharmacotherapy in cardiac arrest is effective at ROSC and long-term survival

https://ift.tt/2LpC9KP

Concurrent daily Cisplatin and high dose radiotherapy in patients with stage III non-small cell lung cancer.

Concurrent chemoradiotherapy (CCRT) including low-dose daily cisplatin (6mg/m2) and high dose radiotherapy (24 fractions of 2,75 Gy to a total dose of 66 Gy) for locally advanced stage III NSCLC resulted in good overall survival (3-year survival rate of 52%(95%CI: 43%-60%) with low toxicity. Prognostic factors for overall survival include GTV lymph nodes and Gender. GTV lymph nodes is the prognostic factor for toxicity. Prognostic factor for distant metastasis is the GTV of the tumor. The incidence of gastrointestinal disorders(grade 3-5) was 11% among which radiation esophagitis grade 3 was 8,4%. The incidence of respiratory, thoracic and mediastinal disorders (grade 3-5) was 8% among which radiation pneumonitis grade 3 was 1,3%.

https://ift.tt/2JRKwco

Intra-treatment response assessment with 18F-FDG PET: Correlation of semi-quantitative PET features with pathologic response of esophageal cancer to neoadjuvant chemoradiotherapy

We extracted semi-quantitative PET features from 18F-FDG PET scans performed before and during neoadjuvant chemoradiotherapy for esophageal cancer and compared their accuracy in predicting histopathologic response. Volumetric PET features including metabolic tumor volume and total lesion glycolysis from the intra-treatment PET were the most accurate predictors of histopathologic response.

https://ift.tt/2mHPkb6

What is the best kind of toothpaste to use?

To choose the best toothpaste, people need to consider a range of factors. These include fluoride content and whether or not the American Dental Association (ADA) have approved the toothpaste. People should pick a product that is suitable for their specific dental needs. Learn how to choose the best toothpaste here.

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Alkylating Agents in the Treatment of Waldenström Macroglobulinemia

The introduction of ibrutinib has grossly changed the treatment landscape in patients with Waldenström's Macroglobulinemia. Nevertheless, chemotherapy in combination with rituximab is still a cornerstone treatment. Among chemotherapeutics, alkylating agents are most frequently used. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a highly effective but potentially neurotoxic regimen. Dexamethasone, rituximab, and cyclophosphamide (DRC) induces long responses and has a favorable toxicity profile. Bendamustine was shown to be among the most potent chemotherapeutics in combination with rituximab. Future studies must define the role of alkylating agents, which compete with highly effective chemotherapy-free targeted therapies.

https://ift.tt/2OfTgMN

Genomic Landscape of Waldenström Macroglobulinemia

Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM). Common mutations include MYD88 (95%–97%), as well as CXCR4 (30%–40%), ARID1A (17%), and CD79B (8%–15%), which are typically found in MYD88-mutated patients. The genomic findings provide important insights into the pathogenesis, prognostication, and treatment outcome in WM. We discuss the genomic landscape of WM, and the impact of underlying genomics on disease presentation, transcriptional changes, treatment outcome, and overall survival impact.

https://ift.tt/2AaXCBS

The Bone Marrow Microenvironment in Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) is an indolent B-cell lymphoma defined predominantly by infiltration of lymphoplasmacytic cells into the bone marrow (BM) and increased production of monoclonal immunoglobulin M (IgM) by lymphoplasmacytic cells, and the secretion of IgM is enhanced by cytokines in the bone marrow microenvironment. This article highlights the available data regarding the interaction of WM cells with both the cellular and noncellular compartments of the BM microenvironment and discusses how the BM promotes malignant cell growth and increases IgM production in this disease.

https://ift.tt/2mK2dla

Proteasome Inhibitors in Waldenström Macroglobulinemia

Waldenström macroglobulinemia (WM) remains an incurable B-cell lymphoproliferative disorder, yet therapy is only considered for patients with symptomatic disease. Primary therapy options for WM include combinations based on anti-CD20 monoclonal antibodies, mainly rituximab. However, proteasome inhibitors have become an important part of WM therapy both as primary therapy and as salvage option. Bortezomib is the proteasome inhibitor most studied and with extensive clinical experience, but new proteasome inhibitors (carfilzomib, ixazomib, oprozomib), with different toxicity profiles, routes of administration, and probably with preserved or improved activity, have become available and may also find their way into WM therapy.

https://ift.tt/2Aa4nnH

Donor’s APOL1 Risk Genotype and “Second Hits” Associated With De Novo Collapsing Glomerulopathy in Deceased Donor Kidney Transplant Recipients: A Report of 5 Cases

The presence of 2 APOL1 risk variants (G1/G1, G1/G2, or G2/G2) is an important predictor of focal segmental glomerulosclerosis (FSGS) and chronic kidney disease in individuals of African descent. Although recipient APOL1 genotype is not associated with allograft survival, kidneys from deceased African American donors with 2 APOL1 risk variants demonstrate shorter graft survival. We present a series of cases of presumed de novo collapsing FSGS in 5 transplanted kidneys from 3 deceased donors later identified as carrying 2 APOL1 risk alleles, including 2 recipients from the same donor whose kidneys were transplanted in 2 different institutions.

https://ift.tt/2LF7Mz8

Elevated levels of matrix metalloproteinases reflect severity and extent of disease in tuberculosis-diabetes co-morbidity and are predominantly reversed following standard anti-tuberculosis or metformin treatment

Matrix metalloproteinases (MMPs) are considered to be key mediators of tuberculosis (TB) pathology but their role in tuberculosis – diabetes comorbidity (TB-DM) is not well understood.

https://ift.tt/2LNXs4Q

Responses to hypothetical health scenarios overestimate healthcare utilization for common infectious syndromes: a cross-sectional survey, South Africa, 2012

Asking people how they would seek healthcare in a hypothetical situation can be an efficient way to estimate healthcare utilization, but it is unclear how intended healthcare use corresponds to actual healthca...

https://ift.tt/2uQ0OxL

Safety of Adalimumab in Pediatric Patients with Polyarticular Juvenile Idiopathic Arthritis, Enthesitis-Related Arthritis, Psoriasis, and Crohn's Disease

To evaluate the safety of adalimumab in pediatric patients who participated in clinical trials of juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and pediatric enthesitis-related arthritis), psoriasis, and Crohn's disease.

https://ift.tt/2LD5651

Language Trajectories of Children Born Very Preterm and Full Term from Early to Late Childhood

To identify distinct language trajectories of children born very preterm and full term from 2 to 13 years of age and examine predictors for the identified trajectories.

https://ift.tt/2uPfRaP

Enhancing the Development and Retention of Physician-Scientists in Academic Pediatrics: Strategies for Success

The physician-scientist, defined as an individual with a doctor of medicine (MD) degree who devotes significant effort to biomedical inquiry, plays an essential role in the translation of laboratory discoveries into novel therapies to improve outcomes of human disease, yet the "vanishing physician-scientist" remains a persistent problem.1-5 Despite much discussion on approaches to enhance the development, recruitment, and retention of physician-scientists, decreasing numbers in this vital group continue to be a major challenge within academic medicine.

https://ift.tt/2NKBEYa

Long-Term Outcomes of Free Gracilis Muscle Transfer for Smile Reanimation in Children

To evaluate long-term outcomes of free gracilis muscle transfer (FGMT) for smile reanimation on smile excursion, facial symmetry, and quality of life in a cohort of children with facial palsy.

https://ift.tt/2uNNppW

The Imperative to Vaccinate

Human beings are almost certainly the most diseased species on earth. By one accounting, there are at least 1400 human pathogens, including bacteria, fungi, prions, protozoa, viruses, and worms, and of these, 100-150 appear capable of causing human epidemics.1,2 Even this is likely to be an underestimate, as new and sensitive sequencing techniques continue to uncover new viruses at a steady rate.3 We human beings are remarkable in many ways, but why are we remarkable for playing host to so many infectious agents? Why is it that we must maintain high levels of vaccine coverage to prevent infectious agents from sickening or even killing large swaths of the population? The answers lie in the story of human disease epidemics, and it begins with human cultural and technological ascendance and what we now understand to be its inevitable consequences for pestilence and death.

https://ift.tt/2NGM630

Behavioral Evidence and Neural Correlates of Perceptual Grouping by Motion in the Barn Owl

Perceiving an object as salient from its surround often requires a preceding process of grouping the object and background elements as perceptual wholes. In humans, motion homogeneity provides a strong cue for grouping, yet it is unknown to what extent this occurs in nonprimate species. To explore this question, we studied the effects of visual motion homogeneity in barn owls of both genders, at the behavioral as well as the neural level. Our data show that the coherency of the background motion modulates the perceived saliency of the target object. An object moving in an odd direction relative to other objects attracted more attention when the other objects moved homogeneously compared with when moved in a variety of directions. A possible neural correlate of this effect may arise in the population activity of the intermediate/deep layers of the optic tectum. In these layers, the neural responses to a moving element in the receptive field were suppressed when additional elements moved in the surround. However, when the surrounding elements all moved in one direction (homogeneously moving), they induced less suppression of the response compared with nonhomogeneously moving elements. Moreover, neural responses were more sensitive to the homogeneity of the background motion than to motion-direction contrasts between the receptive field and the surround. The findings suggest similar principles of saliency-by-motion in an avian species as in humans and show a locus in the optic tectum where the underlying neural circuitry may exist.

SIGNIFICANCE STATEMENT A critical task of the visual system is to arrange incoming visual information to a meaningful scene of objects and background. In humans, elements that move homogeneously are grouped perceptually to form a categorical whole object. We discovered a similar principle in the barn owl's visual system, whereby the homogeneity of the motion of elements in the scene allows perceptually distinguishing an object from its surround. The novel findings of these visual effects in an avian species, which lacks neocortical structure, suggest that our basic visual perception shares more universal principles across species than presently thought, and shed light on possible brain mechanisms for perceptual grouping.

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Differential Representation of Landmark and Self-Motion Information along the CA1 Radial Axis: Self-Motion Generated Place Fields Shift toward Landmarks during Septal Inactivation

Spatial location in the environment can be defined in relation to specific landmarks or in relation to the global context, and is estimated from both the sensing of landmarks and the inner sense of cumulated locomotion referred to as path-integration. The respective contribution of landmark and path-integration to place-cell activity in the hippocampus is still unclear and complicated by the fact that the two mechanisms usually overlap. To bias spatial mechanisms toward landmark or path-integration, we use a treadmill equipped with a long belt on which male mice run sequentially through a zone enriched and a zone impoverished in visual-tactile cues. We show that inactivation of the medial septum (MS), which is known to disrupt the periodic activity of grid cells, impairs mice ability to anticipate the delivery of a reward in the cue-impoverished zone and transiently alter the spatial configuration of place fields in the cue-impoverished zone selectively: following MS inactivation, place fields in the cue-impoverished zone progressively shift backward and stabilize near the cues, resulting in the contraction of the spatial representation around cues; following MS recovery, the initial spatial representation is progressively restored. Furthermore, we found that place fields in the cue-rich and cue-impoverished zones are preferentially generated by cells from the deep and superficial sublayers of CA1, respectively. These findings demonstrate with mechanistic insights the contribution of MS to the spread of spatial representations in cue-impoverished zones, and indicate a segregation of landmark-based and path-integration-assisted spatial mechanisms into deep and superficial CA1, respectively.

SIGNIFICANCE STATEMENT Cells encoding a cue-impoverished zone and the vicinity of landmarks responded differentially to septal inactivation and resided in distinct sublayers of CA1. These findings provide new insights on place field mechanisms: septal activity is critical for maintaining the spread of place fields in cue-impoverished areas, but not for the generation of place fields; Following MS inactivation, trial-by-trial network modifications by activity-dependent mechanisms are responsible for the gradual collapse of spatial representations. Furthermore, the findings suggest parallel coding streams for landmark and self-motion information. Superficial CA1 cells are better suited for encoding global position via the assist of path-integration, whereas deep CA1 cells can support spatial memory processes on an object-specific basis.

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Escitalopram Cuts MACE Risk in Depressed Patients With ACS

WEDNESDAY, July 25, 2018 -- For patients with depression following recent acute coronary syndrome (ACS), escitalopram results in lower risk of major adverse cardiac events (MACE) versus placebo, according to a study published in the July 24/31 issue...

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Modifiable Midlife Risk Factors Linked to Late-Onset Epilepsy

WEDNESDAY, July 25, 2018 -- Potentially modifiable risk factors in midlife are associated with the risk of developing late-onset epilepsy, according to a study published online July 23 in JAMA Neurology. Emily L. Johnson, M.D., from the Johns...

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Tools, Methods of RCTs Can Be Adapted to Real-World Settings

WEDNESDAY, July 25, 2018 -- Use of appropriate statistical methodology can allow for the synthesis of data collected as part of traditional clinical trials with real-world data, according to an Ideas and Opinions piece published online July 24 in...

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Prevalence of Depression 4.4 Percent Among Dads of Infants

WEDNESDAY, July 25, 2018 -- The prevalence of depression is 4.4 percent among fathers of children age 15 months or younger attending a well-child care clinic visit, according to a research letter published online July 23 in JAMA Pediatrics. Erika R....

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HerbList App Launched to Provide Information on Herbal Products

WEDNESDAY, July 25, 2018 -- The National Institutes of Health's National Center for Complementary and Integrative Health (NCCIH) has announced the launch of an app for easy access to research-based information on the safety and effectiveness of...

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Coal and Oil Power Plant Pollution May Lower Fertility Rates

WEDNESDAY, July 25, 2018 -- Fertility rates among nearby populations appear to increase after coal and oil power plant retirements, according to a study published recently in Environmental Health. Joan A. Casey, Ph.D., from the University of...

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Majority of Those in Residential Care Have Advance Directives

WEDNESDAY, July 25, 2018 -- More than three-quarters of those living in residential care facilities have an advance directive, according to a QuickStats report published in the July 20 issue of the U.S. Centers for Disease Control and Prevention's...

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Diabetes Diagnosis May Impact Health Behaviors of Family

WEDNESDAY, July 25, 2018 -- Partners of people with newly diagnosed diabetes have small but significant differences in health-related behavioral changes compared with partners of people without diabetes, according to a study published in the...

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Many U.S. Adults View Marijuana Use Positively

WEDNESDAY, July 25, 2018 -- Most U.S. adults believe that marijuana has at least one benefit, according to a study published online July 24 in the Annals of Internal Medicine. Salomeh Keyhani, M.D., M.P.H., from the University of California in San...

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Guidelines for ART Updated for Those With or at Risk for HIV

WEDNESDAY, July 25, 2018 -- Recommendations for antiretroviral therapy (ART) have been updated for individuals at risk of or living with HIV; the 2018 recommendations of the International Antiviral Society-USA Panel are published in the July 24/31...

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Critical role of FOXO3a in carcinogenesis

Abstract

FOXO3a is a member of the FOXO subfamily of forkhead transcription factors that mediate a variety of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage and tumorigenesis. It also responds to several cellular stresses such as UV irradiation and oxidative stress. The function of FOXO3a is regulated by a complex network of processes, including post-transcriptional suppression by microRNAs (miRNAs), post-translational modifications (PTMs) and protein–protein interactions. FOXO3a is widely implicated in a variety of diseases, particularly in malignancy of breast, liver, colon, prostate, bladder, and nasopharyngeal cancers. Emerging evidences indicate that FOXO3a acts as a tumor suppressor in cancer. FOXO3a is frequently inactivated in cancer cell lines by mutation of the FOXO3a gene or cytoplasmic sequestration of FOXO3a protein. And its inactivation is associated with the initiation and progression of cancer. In experimental studies, overexpression of FOXO3a inhibits the proliferation, tumorigenic potential, and invasiveness of cancer cells, while silencing of FOXO3a results in marked attenuation in protection against tumorigenesis. The role of FOXO3a in both normal physiology as well as in cancer development have presented a great challenge to formulating an effective therapeutic strategy for cancer. In this review, we summarize the recent findings and overview of the current understanding of the influence of FOXO3a in cancer development and progression.

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Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice

The human 16p11.2 microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the 16p11.2 deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the 16p11.2 deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in 16p11.2 deletion carriers.

SIGNIFICANCE STATEMENT The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the 16p11.2 chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the 16p11.2del mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult 16p11.2del mice. These data provide a strong rationale for therapeutic approaches to this disorder.

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PTP{sigma} Drives Excitatory Presynaptic Assembly via Various Extracellular and Intracellular Mechanisms

Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are hub proteins that organize excitatory and inhibitory synapse development through binding to various extracellular ligands. Here, we report that knockdown (KD) of the LAR-RPTP family member PTP reduced excitatory synapse number and transmission in cultured rat hippocampal neurons, whereas KD of PTP produced comparable decreases at inhibitory synapses, in both cases without altering expression levels of interacting proteins. An extensive series of rescue experiments revealed that extracellular interactions of PTP with Slitrks are important for excitatory synapse development. These experiments further showed that the intracellular D2 domain of PTP is required for induction of heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic machinery assembly. Consistent with this, double-KD of liprin-α2 and -α3 or KD of PTP substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, PTP-mediated heterologous synapse formation activity. We propose a synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized retrograde signaling cascades, in which both extracellular and intracellular mechanisms are critical in orchestrating distinct synapse types.

SIGNIFICANCE STATEMENT In this study, we sought to test the unproven hypothesis that PTP and PTP are required for excitatory and inhibitory synapse formation/transmission, respectively, in cultured hippocampal neurons, using knockdown-based loss-of-function analyses. We further performed extensive structure–function analyses, focusing on PTP-mediated actions, to address the mechanisms of presynaptic assembly at excitatory synaptic sites. Using interdisciplinary approaches, we systematically applied a varied set of PTP deletion variants, point mutants, and splice variants to demonstrate that both extracellular and intracellular mechanisms are involved in organizing presynaptic assembly. Strikingly, extracellular interactions of PTP with heparan sulfates and Slitrks, intracellular interactions of PTP with liprin-α and its associated proteins through the D2 domain, as well as distinct substrates are all critical.

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Prostaglandin Signaling Governs Spike Timing-Dependent Plasticity at Sensory Synapses onto Mouse Spinal Projection Neurons

Highly correlated presynaptic and postsynaptic activity evokes spike timing-dependent long-term potentiation (t-LTP) at primary afferent synapses onto spinal projection neurons. While prior evidence indicates that t-LTP depends upon an elevation in intracellular Ca²⁺ within projection neurons, the downstream signaling pathways that trigger the observed increase in glutamate release from sensory neurons remain poorly understood. Using in vitro patch-clamp recordings from female mouse lamina I spino-parabrachial neurons, the present study demonstrates a critical role for prostaglandin synthesis in the generation of t-LTP. Bath application of the selective phospholipase A₂ (PLA₂) inhibitor arachidonyl trifluoromethyl ketone (AACOCF₃) or the cyclooxygenase 2 (Cox-2) inhibitor nimesulide prevented t-LTP at sensory synapses onto spino-parabrachial neurons. Similar results were observed following the block of the EP2 subtype of prostaglandin E₂ (PGE₂) receptor with PF 04418948. Meanwhile, perfusion with PGE₂ or the EP2 agonist butaprost potentiated the amplitude of monosynaptic primary afferent-evoked EPSCs while decreasing the paired-pulse ratio, suggesting a presynaptic site of action. Cox-2 was constitutively expressed in both spinal microglia and lamina I projection neurons within the superficial dorsal horn (SDH). Suppression of microglial activation with minocycline had no effect on the production of t-LTP, suggesting the possibility that prostaglandins produced within projection neurons could contribute to an enhanced probability of glutamate release at primary afferent synapses. Collectively, the results suggest that the amplification of ascending nociceptive transmission by the spinal SDH network is governed by PLA₂–Cox-2–PGE₂ signaling.

SIGNIFICANCE STATEMENT Long-term potentiation (LTP) of primary afferent synapses contributes to the sensitization of spinal nociceptive circuits and has been linked to greater pain sensation in humans. Prior work has implicated elevated glutamate release in the generation of spike timing-dependent LTP (t-LTP) at sensory synapses onto ascending spinal projection neurons, but the underlying mechanisms remain unknown. Here we provide evidence that the activation of EP2 prostaglandin receptors by prostaglandin E₂, occurring downstream of phospholipase A₂ and cyclooxygenase 2 activation, mediates t-LTP at these synapses via changes in presynaptic function. This suggests that prostaglandins can increase the flow of nociceptive information from the spinal cord to the brain independently of their known ability to suppress synaptic inhibition within the dorsal horn.

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Why transitions of care are an important patient safety opportunity

Transitions of care are critical opportunities to communicate patient assessment and treatment information to other healthcare providers

https://ift.tt/2NHB8KK

Epinephrine and the paramedic-2 trial: Is it time to pull our starting pitcher?

New research questions whether pharmacotherapy in cardiac arrest is effective at ROSC and long-term survival

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EMS leaders challenged ‘to make tomorrow better than today’

John O'Leary, a survivor of 100 percent TBSA burn as a child, delivered an inspiring opening keynote to Pinnacle EMS conference attendees

https://ift.tt/2LNJZda

Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma

Objective

To characterise gut microbiome in patients with hepatocellular carcinoma (HCC) and evaluate the potential of microbiome as non-invasive biomarkers for HCC.

Design

We collected 486 faecal samples from East China, Central China and Northwest China prospectively and finally 419 samples completed Miseq sequencing. We characterised gut microbiome, identified microbial markers and constructed HCC classifier in 75 early HCC, 40 cirrhosis and 75 healthy controls. We validated the results in 56 controls, 30 early HCC and 45 advanced HCC. We further verified diagnosis potential in 18 HCC from Xinjiang and 80 HCC from Zhengzhou.

Results

Faecal microbial diversity was increased from cirrhosis to early HCC with cirrhosis. Phylum Actinobacteria was increased in early HCC versus cirrhosis. Correspondingly, 13 genera including Gemmiger and Parabacteroides were enriched in early HCC versus cirrhosis. Butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early HCC versus controls. The optimal 30 microbial markers were identified through a fivefold cross-validation on a random forest model and achieved an area under the curve of 80.64% between 75 early HCC and 105 non-HCC samples. Notably, gut microbial markers validated strong diagnosis potential for early HCC and even advanced HCC. Importantly, microbial markers successfully achieved a cross-region validation of HCC from Northwest China and Central China.

Conclusions

This study is the first to characterise gut microbiome in patients with HCC and to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC.

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Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice

Objective

Chronic pancreatitis is a progressive, relapsing inflammatory disorder of the pancreas, which often develops in the background of genetic susceptibility. Recently, loss-of-function mutations in CPA1, which encodes the digestive enzyme carboxypeptidase A1, were described in sporadic early onset cases and in hereditary pancreatitis. Mutationinduced misfolding of CPA1 and associated endoplasmic reticulum (ER) stress was suggested as potential disease mechanism; however, in vivo evidence has been lacking. The objective of the present study was to create a mouse model that recapitulates features of CPA1-associated chronic pancreatitis.

Design

We knocked-in the most frequently occurring p.N256K human CPA1 mutation to the mouse Cpa1 locus. Mutant mice were with respect to pancreas pathology and ER stress and C57BL/ and CPA1 null control mice.

Results

In the CPA1 N256K mutant mice, we observed hallmarks of chronic pancreatitis that included progressive acinar cell atrophy, inflammatory cell infiltration, fibrosis and acinar-ductal metaplasia. In contrast, similarly to the C57BL/6N mice, the CPA1 null control strain exhibited no signs of pancreatic disease. Mutation p.N256K induced misfolding of mouse CPA1 and resulted in elevated expression of ER stress markers Hspa5 (BiP) and Ddit3 (CHOP) both in cell culture and mutant mice.

Conclusion

The results offer categorical evidence that CPA1 mutations elicit enzyme misfolding and cause chronic pancreatitis via an ER stress-related mechanism.

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Intermittent Fasting (Alternate Day Fasting) in Healthy, Non-obese Adults: Protocol for a Cohort Trial with an Embedded Randomized Controlled Pilot Trial

Abstract

Background/objectives

Alternate day fasting (ADF) is a subtype of intermittent fasting and is defined as a continuous sequence of a fast day (100% energy restriction, zero calories) and a feed day (ad libitum food consumption), resulting in roughly 36-h fasting periods. Previous studies demonstrated weight reductions and improvements of cardiovascular risk factors with ADF in obese subjects. However, rigorous data on potential endocrine, metabolic and cardiovascular effects, besides weight loss, are lacking. Therefore we aim to investigate the short- and mid- to long-term clinical and molecular effects of ADF in healthy non-obese subjects.

Methods

We will perform a prospective cohort study with an embedded randomized controlled trial (RCT) including 90 healthy subjects. Thirty of them will have performed ADF for at least 6 months (mid-term group). Sixty healthy subjects without a particular diet before enrolment will serve as the control group. These subjects will be 1:1 randomized to either continuing their current diet or performing ADF for 4 weeks. All subjects will undergo study procedures that will be repeated in RCT participants after 4 weeks. These procedures will include assessment of outcome parameters, dual-energy X-ray absorptiometry, measurement of endothelial function, an oral glucose tolerance test, 24-h blood pressure measurement, retinal vessel analysis, echocardiography and physical activity measurement by an accelerometer. Blood, sputum, buccal mucosa and faeces will be collected for laboratory analyses. Participants in the RCT will wear a continuous glucose monitor to verify adherence to the study intervention.

Planned outcomes

The aim of this project is to investigate the effects of ADF on human physiology and molecular cellular processes. This investigation should gain in-depth mechanistic insights into the concept of ADF and form the basis for larger subsequent cohort recruitment and consecutive intervention studies.

Trial registration

NCT02673515; registered 24 November 2015. Current protocol date/version: 7 February 2017/version 1.8.

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Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease

Abstract

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated α-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key neuropathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with α-synuclein, is present in the α-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we observed that silencing of Syn III gene could prevent α-synuclein fibrillary aggregation in vitro. This evidence suggests that Syn III might be crucially involved in α-synuclein pathological deposition. To test this hypothesis, we studied whether mice knock-out (ko) for Syn III might be protected from α-synuclein aggregation and nigrostriatal neuron degeneration resulting from the unilateral injection of adeno-associated viral vectors (AAV)-mediating human wild-type (wt) α-synuclein overexpression (AAV-hαsyn). We found that Syn III ko mice injected with AAV-hαsyn did not develop fibrillary insoluble α-synuclein aggregates, showed reduced amount of α-synuclein oligomers detected by in situ proximity ligation assay (PLA) and lower levels of Ser129-phosphorylated α-synuclein. Moreover, the nigrostriatal neurons of Syn III ko mice were protected from both synaptic damage and degeneration triggered by the AAV-hαsyn injection. Our observations indicate that Syn III constitutes a crucial mediator of α-synuclein aggregation and toxicity and identify Syn III as a novel therapeutic target for PD.

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Why transitions of care are an important patient safety opportunity

Transitions of care are critical opportunities to communicate patient assessment and treatment information to other healthcare providers

https://ift.tt/2NHB8KK

[ 18 F]Fluciclovine PET discrimination between high- and low-grade gliomas

Abstract

Background

The ability to accurately and non-invasively distinguish high-grade glioma from low-grade glioma remains a challenge despite advances in molecular and magnetic resonance imaging. We investigated the ability of fluciclovine (¹⁸F) PET as a means to identify and distinguish these lesions in patients with known gliomas and to correlate uptake with Ki-67.

Results

Sixteen patients with a total of 18 newly diagnosed low-grade gliomas (n = 6) and high grade gliomas (n = 12) underwent fluciclovine PET imaging after histopathologic assessment. Fluciclovine PET analysis comprised tumor SUV_max and SUV_mean, as well as metabolic tumor thresholds (1.3*, 1.6*, 1.9*) to normal brain background (TB_max, and TB_mean). Comparison was additionally made to the proliferative status of the tumor as indicated by Ki-67 values.

Fluciclovine uptake greater than normal brain parenchyma was found in all lesions studied. Time activity curves demonstrated statistically apparent flattening of the curves for both high-grade gliomas and low-grade gliomas starting 30 min after injection, suggesting an influx/efflux equilibrium. The best semiquantitative metric in discriminating HGG from LGG was obtained utilizing a metabolic 1 tumor threshold of 1.3* contralateral normal brain parenchyma uptake to create a tumor: background (TB_mean1.3) cutoff of 2.15 with an overall sensitivity of 97.5% and specificity of 95.5%. Additionally, using a SUV_max > 4.3 cutoff gave a sensitivity of 90.9% and specificity of 97.5%. Tumor SUV_mean and tumor SUV_max as a ratio to mean normal contralateral brain were both found to be less relevant predictors of tumor grade. Both SUV_max (R = 0.71, p = 0.0227) and TB_mean (TB_mean1.3: R = 0.81, p = 0.00081) had a high correlation with the tumor proliferative index Ki-67.

Conclusions

Fluciclovine PET produces high-contrast images between both low-grade and high grade gliomas and normal brain by visual and semiquantitative analysis. Fluciclovine PET appears to discriminate between low-grade glioma and high-grade glioma, but must be validated with a larger sample size.

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SWATH-MS based quantitative proteomics analysis reveals that curcumin alters the metabolic enzyme profile of CML cells by affecting the activity of miR-22/IPO7/HIF-1α axis

Abstract

Background

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, resulting from the t(9;22) chromosomal translocation. Imatinib (gleevec, STI-571) is a selective inhibitor of BCR-ABL activity highly effective in the treatment of CML. However, even though almost all CML patients respond to treatment with imatinib or third generation inhibitors, these drugs are not curative and need to be taken indefinitely or until patients become resistant. Therefore, to get a definitive eradication of leukemic cells, it is necessary to find novel therapeutic combinations, for achieving greater efficacy and fewer side effects.

Curcumin is an Indian spice with several therapeutic properties: anti-oxidant, analgesic, anti-inflammatory, antiseptic and anti-cancer. In cancer disease, it acts by blocking cell transformation, proliferation, and invasion and by inducing cell apoptosis.

Methods

In the present study, the effect of a sub-toxic dose of curcumin on K562 cells was evaluated by using the technique of Sequential Window Activation of All Theoretical Mass Spectra (SWATH-MS). Bioinformatic analysis of proteomic data was performed to highlight the pathways mostly affected by the treatment. The involvement of Hypoxia inducible factor 1 α (HIF-1α) was assayed by evaluating its activation status and the modulation of importin 7 (IPO7) and miR-22 was assessed by quantitative PCR and western blot analysis. Finally, K562 cells transfected with miR-22 inhibitor were used to confirm the ability of curcumin to elicit miR-22 expression.

Results

Our findings revealed that the most relevant effect induced by curcumin was a consistent decrease of several proteins involved in glucose metabolism, most of which were HIF-1α targets, concomitant with the up-regulation of functional and structural mitochondrial proteins. The mechanism by which curcumin affects metabolic enzyme profile was associated with the reduction of HIF-1α activity, due to the miR-22-mediated down-regulation of IPO7 expression. Finally, the ability of curcumin to enhance in vitro the efficiency of imatinib was reported.

Conclusions

In summary, our data indicates that the miR-22/IPO7/HIF-1α axis may be considered as a novel molecular target of curcumin adding new insights to better define therapeutic activity and anticancer properties of this natural compound. The MS proteomic data have been deposited to the ProteomeXchange with identifier <PXD007771>.

https://ift.tt/2v2VVAQ

Responders thank woman for paying breakfast bill

A woman left a note, simply signed "Recovering addict," for a group of Toms River First Aid Squad members and paid their tab

https://ift.tt/2v4TuxA

Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors

Abstract

Background

Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs.

Methods

The analysis was conducted using 40 primary tumors and corresponding 47 metastases. The level of 5hmC, TET1 and TET2 was analyzed by DNA immune-dot blot assay and immunohistochemistry. Other methods included a colony forming assay, western blotting analysis, and quantitative bisulfite pyrosequencing analysis. The effect of the exportin-1 nuclear transport machinery inhibitors on cell proliferation and apoptosis was also explored using two SI-NET cell lines.

Results

Variable levels of 5hmC and a mosaic staining appearance with a mixture of positive and negative cell nuclei, regardless of cell number and staining strength, was observed overall both in primary tumors and metastases. Similarly aberrant staining pattern was observed for TET1 and TET2. In a number of tumors (15/32) mosaic pattern together with areas of negative staining was also observed for TET1. Abolished expression of TET1 in the tumors did not seem to involve hypermethylation of the TET1 promoter region. Overexpression of TET1 in a colony forming assay supported a function as cell growth regulator. In contrast to 5hmC and TET1, TET2 was also observed in the cytoplasm of all the analyzed SI-NETs regardless of nuclear localization. Treatment of CNDT2.5 and KRJ-I cells with the exportin-1 (XPO1/CRM1) inhibitor, leptomycin B, induced reduction in the cytoplasm and nuclear retention of TET2. Aberrant partitioning of TET2 from the nucleus to the cytoplasm seemed therefore to involve the exportin-1 nuclear transport machinery. Reduced cell proliferation and induction of apoptosis were observed after treatment of CNDT2.5 and KRJ-I cells with leptomycin B or KPT-330 (selinexor).

Conclusions

SI-NETs are epigenetically dysregulated at the level of 5-hydroxymethylcytosine/ TET1/TET2. We suggest that KPT-330/selinexor or future developments should be considered and evaluated for single treatment of patients with SI-NET disease and also in combinations with somatostatin analogues, peptide receptor radiotherapy, or everolimus.

https://ift.tt/2Lyojoy