A cost of illness study of hypoglycaemic events in insulin-treated diabetes in the Netherlands

Objectives

Patients with diabetes mellitus are at a risk for hypoglycaemia. Besides the burden of hypoglycaemia for patients, hypoglycaemia poses an economic burden to society. The aim of this study was to calculate the per patient societal costs of hypoglycaemia among patients with type1 diabetes (T1DM) and type 2 diabetes (T2DM) on insulin therapy in the Netherlands.

Methods

To calculate the costs of hypoglycaemia, data from the Global Hypoglycaemia Assessment Tool (HAT) study were used. Dutch patients were selected from the HAT study database and data regarding healthcare resource use, informal care use and productivity losses were combined with Dutch unit costs to calculate the per patient 4-week costs of patients experiencing hypoglycaemia. Besides these 4-week costs, costs per hypoglycaemic event were calculated by dividing the study population total 4-week costs by the total number of events in this period.

Results

Mean 4-week total costs of hypoglycaemia amounted to 163 (SD, 870) in T1DM and 134 (SD, 364) in T2DM. While productivity costs were the most important cost driver of hypoglycaemia in patients with T1DM (accounting for 72% of the total costs), costs of hypoglycaemia in patients with T2DM were almost entirely driven by costs within the healthcare sector (accounting for 98% of the total costs). Mean costs of a severe hypoglycaemic event were 828 and 508 in T1DM and T2DM, respectively, whereas mean costs of a non-severe event were almost zero.

Conclusions

This study showed that the economic burden of severe hypoglycaemia is substantial. The prevention of hypoglycaemia could therefore not only reduce the burden for patients, but also the economic burden to society.

https://ift.tt/2pH4aQp

Index coronary angiography use in Manitoba, Canada: a population-level descriptive analysis of First Nations and non-First Nations recipients

Objectives

To investigate recipient characteristics and rates of index angiography among First Nations (FN) and non-FN populations in Manitoba, Canada.

Setting

Population-based, secondary analysis of provincial administrative health data.

Participants

All adults 18 years or older who received an index angiogram between 2000/2001 and 2008/2009.

Primary and secondary outcome measures

(1) Descriptive statistics for age, sex, income quintile by rural and urban residency and Charlson Comorbidity Index for FN and non-FN recipients. (2) Annual index angiogram rates for FN and non-FN populations and among those rates of 'urgent' angiograms based on acute myocardial infarction (AMI)-related hospitalisations during the previous 7 days. (3) Proportions of people who did not receive an angiogram in the 20 years preceding an ischaemic heart disease (IHD) diagnosis or a cardiovascular death; stratified by age (<65 or ≥65 years old).

Results

FN recipients were younger (56.3vs63.8 years; p<0.0001) and had higher Charlson Comorbidity scores (1.32vs0.78; p<0.001). During all years examined, index angiography rates were lower among FN people (2.67vs3.33 per 1000 population per year; p<0.001) with no notable temporal trends. Among the index angiogram recipients, a higher proportion was associated with an AMI-related hospitalisation in the FN group (28.8%vs25.0%; p<0.01) and in both groups rates significantly increased over time. FN people who died from cardiovascular disease or were older (65+years old) diagnosed with IHD were more likely to have received an angiogram in the preceding 20–30 years (17.8%vs12.5%; p<0.01 and 50.9%vs49.5%; p<0.03, respectively). FN people diagnosed with IHD who were under the age of 65 were less likely to have received an angiogram (47.8%vs53.1%; p<0.01)

Conclusions

Index angiogram use differences are suggested between FN and non-FN populations, which may contribute to reported IHD disparities. Investigating factors driving these rates will determine any association between ethnicity and angiography services.

https://ift.tt/2Gs3Yig

Is exposure to ionising radiation associated with childhood cardiac arrhythmia in the Russian territories contaminated by the Chernobyl fallout? A cross-sectional population-based study

Objective

To investigate childhood cardiac arrhythmia and chronic exposure to caesium-137 (¹³⁷Cs) resulting from the Chernobyl accident.

Design

Prospective cross-sectional study using exposed/unexposed design conducted in the Bryansk region from May 2009 to May 2013 on children selected on the basis of ¹³⁷Cs soil deposition: control territories ([¹³⁷Cs]<37 kBq per square metre, where children were considered as unexposed) and contaminated territories ([¹³⁷Cs]>555 kBq per square metre, where children were considered as exposed).

Setting

Russian territories affected by the Chernobyl fallout (Bryansk region).

Participants

This cross-sectional study included 18 152 children aged 2–18 years and living in the Bryansk region (Russia).

Main outcome measures

All children received three medical examinations (ECG, echocardiography and ¹³⁷Cs whole-body activity measurement) and some of them were given with a 24-hour Holter monitoring and blood tests.

Results

Cardiac arrhythmia was diagnosed in 1172 children living in contaminated territories and 1354 children living in control territories. The crude prevalence estimated to 13.3% in contaminated territories was significantly lower than in control territories with 15.2% over the period 2009–2013 (P<0.001). Considering ¹³⁷Cs whole-body burden as exposure, cardiac arrhythmia was found in 449 contaminated children and 2077 uncontaminated children, corresponding to an estimated crude prevalence of 14.5% and 14.2%, respectively, which does not differ significantly (P=0.74). Also, we investigated the association between territory, exposure to ¹³⁷Cs and cardiac arrhythmia: the adjusted OR was not significant (0.90 with 95% CI 0.81 to 1.00; P=0.06) for the territory. For ¹³⁷Cs whole-body burden, the ORs close to 1 did not reach statistical significance (P for trend=0.97).

Conclusion

This study does not observe an association between cardiac arrhythmia and ¹³⁷Cs deposition levels in the Bryansk region exposed to Chernobyl fallout. The suspected increase of cardiac arrhythmia in children exposed to Chernobyl fallout is not confirmed.

https://ift.tt/2GcFC8G

Cross-sectional associations of objectively assessed neighbourhood attributes with depressive symptoms in older adults of an ultra-dense urban environment: the Hong Kong ALECS study

Objectives

This study aimed to examine the associations between objectively assessed neighbourhood environmental attributes and depressive symptoms in Hong Kong Chinese older adults and the moderating effects of neighbourhood environmental attributes on the associations between living arrangements and depressive symptoms.

Design

Cross-sectional observational study.

Setting

Hong Kong.

Participants

909 Hong Kong Chinese community dwellers aged 65+ years residing in preselected areas stratified by walkability and socioeconomic status.

Exposure and outcome measures

Attributes of participants' neighbourhood environment were objectively assessed using geographic information systems and environmental audits. Depressive symptoms were measured using the Geriatric Depression Scale.

Results

Overall, pedestrian infrastructure (OR=1.025; P=0.008), connectivity (OR=1.039; P=0.002) and prevalence of public transport stops (OR=1.056; P=0.012) were positively associated with the odds of reporting depressive symptoms. Older adults living alone were at higher risk of reporting any depressive symptoms than those living with others (OR=1.497; P=0.039). This association was moderated by neighbourhood crowdedness, perceptible pollution, access to destinations and presence of people. Residing in neighbourhoods with lower levels of these attributes was associated with increased deleterious effects of living alone. Living in neighbourhoods with lower public transport density also increased the deleterious effects of living alone on the number of depressive symptoms. Those living alone and residing in neighbourhoods with higher levels of connectivity tended to report more depressive symptoms than their counterparts.

Conclusions

The level of access to destinations and social networks across Hong Kong may be sufficiently high to reduce the risk of depressive symptoms in older adults. Yet, exposure to extreme levels of public transport density and associated traffic volumes may increase the risk of depressive symptoms. The provision of good access to a variety of destinations, public transport and public open spaces for socialising in the neighbourhood may help reduce the risk of depressive symptoms in older adults who live alone.

https://ift.tt/2Gt5wZc

Effectiveness of the 13-valent pneumococcal conjugate vaccine against adult pneumonia in Italy: a case-control study in a 2-year prospective cohort

Objectives

Current strategies to prevent adult pneumococcal disease have been recently reviewed in Italy. We did a postlicensure study to estimate the direct vaccine effectiveness (VE) of the 13-valent pneumococcal conjugate vaccine (PCV13) against adult pneumococcal community-acquired pneumonia (pCAP).

Study design

Between 2013 and 2015, a 2-year prospective cohort study of adults with CAP was conducted in the Apulia region of Italy where the average vaccine uptake of PCV13 was 32% among adults ≥65 years. The test-negative design was used to estimate VE against all episodes of confirmed pCAP and vaccine-type (VT)-CAP. VE in a subgroup of patients managed in the community was also estimated using a matched case–control design. VE was calculated as one minus the OR times 100%.

Results

The overall VE of PCV13 was 33.2% (95% CI –106.6% to 82%) against pCAP irrespective of serotype and 38.1% (95% CI –131.9% to 89%) against VT-CAP in the cohort of adults ≥65 years. The VE was 42.3% (95% CI –244.1% to 94.7%) against VT-CAP in the age group at higher vaccine uptake. For the subgroup of cases managed in the community, the overall VE against disease due to any pneumococcal strain was 88.1% (95% CI 4.2% to 98.5%) and 91.7% (95% CI 13.1% to 99.2%) when we controlled for underlying conditions.

Conclusions

Although our results are non-significant, PCV13 promises to be effective against all confirmed pCAP already with modest levels of uptake in the population of adults ≥65 years of age. Larger studies are needed to confirm the direct vaccine benefits.

https://ift.tt/2G9SZ9G

Glycaemic control in type 2 diabetes patients and its predictors: a retrospective database study at a tertiary care diabetes centre in Ningbo, China

Objectives

The objectives of the study were to assess glycaemic control in patients with type 2 diabetes (T2DM) at a tertiary care diabetes centre in Ningbo, China and to determine factors that independently predict their glycaemic control.

Design

Retrospective cross-sectional study using an existing database, the Diabetes Information Management System.

Setting

Tertiary care diabetes centre in Ningbo, China.

Participants

The study included adult patients with T2DM, registered and received treatment at the diabetes centre for at least six consecutive months. The study inclusion criteria were satisfied by 1387 patients, from 1 July 2012 to 30 June 2017.

Primary outcome measure

Glycaemic control (poor was defined as glycated haemoglobin (HbA1c)>=7% or fasting blood glucose (FBG)>7.0 mmol/L).

Results

In terms of HbA1c and FBG, the 5-year period prevalence of poor glycaemic control was 50.3% and 57.3%, respectively. In terms of HbA1c and FBG, the odds of poor glycaemic control increased with the duration of T2DM (>1 to 2 years: OR 1.84, 95% CI 1.06 to 3.19; >2 to 4 years: 3.32, 1.88 to 5.85 and >4 years: 5.98, 4.09 to 8.75 and >1 to 2 years: 2.10, 1.22 to 3.62; >2 to 4 years: 2.48, 1.42 to 4.34 and >4 years: 3.34, 2.32 to 4.80) and were higher in patients residing in rural areas (1.68, 1.24 to 2.28 and 1.42, 1.06 to 1.91), with hyperlipidaemia (1.57, 1.12 to 2.19 and 1.68, 1.21 to 2.33), on diet, physical activity and oral hypoglycaemic drug (OHD) as part of their T2DM therapeutic regimen (1.80, 1.01 to 3.23 and 2.40, 1.36 to 4.26) and on diet, physical activity, OHD and insulin (2.47, 1.38 to 4.41 and 2.78, 1.58 to 4.92), respectively.

Conclusions

More than half of patients with T2DM at the diabetes centre in Ningbo, China have poor glycaemic control, and the predictors of glycaemic control were identified. The study findings could be taken into consideration in future interventional studies aimed at improving glycaemic control in these patients.

https://ift.tt/2Gt5aSm

Voices from low-income and middle-income countries: a systematic review protocol of primary healthcare interventions within public health systems addressing intimate partner violence against women

Introduction

Intimate partner violence (IPV) considerably harms the health, safety and well-being of women. In response, public health systems around the globe have been gradually implementing strategies. In particular, low-income and middle-income countries (LMIC) have been developing innovative interventions in primary healthcare (PHC) addressing the problem. This paper describes a protocol for a systematic review of studies addressing the impacts and outcomes of PHC centre interventions addressing IPV against women from LMIC.

Methods and analysis

A systematic search for studies will be conducted in African Index Medicus, Africa Portal Digital Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Index Medicus for the Southeast Asia Region, IndMed, Latin American and Caribbean Health Science Literature Database (LILACS), Medecins Sans Frontieres, MEDLINE, Minority Health and Health Equity Archive, ProQuest, PsycINFO, Scientific Electronic Library Online, (SciELO) and Social Policy and Practice. Studies will be in English, Spanish and Portuguese, published between 2007 and 2017, addressing IPV against women from LMIC, whose data quantitatively report on the impacts and outcomes for survivors and/or workers and/or public health systems preintervention and postintervention. Two trilingual reviewers will independently screen for study eligibility and data extraction, and a librarian will cross-check for compliance. Risk of bias and quality assessment of studies will be measured according to: (1) the Cochrane Collaboration's tool for assessing risk of bias for randomised controlled trials and (2) the Methodological Index for Non-Randomised Studies (MINORS). Data will be analysed and summarised using meta-analysis and narrative description of the evidence across studies. This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols(PRISMA P) guidelines.

Ethics and dissemination

This systematic review will be based on published studies, thus not requiring ethical approval. Findings will be presented in conferences and published in a peer-reviewed journal.

PROSPERO registration number

CRD42017069261.

https://ift.tt/2Gc29Td

Validation of an algorithm to identify heart failure hospitalisations in patients with diabetes within the veterans health administration

Objectives

We aimed to validate an algorithm using both primary discharge diagnosis (International Classification of Diseases Ninth Revision (ICD-9)) and diagnosis-related group (DRG) codes to identify hospitalisations due to decompensated heart failure (HF) in a population of patients with diabetes within the Veterans Health Administration (VHA) system.

Design

Validation study.

Setting

Veterans Health Administration—Tennessee Valley Healthcare System

Participants

We identified and reviewed a stratified, random sample of hospitalisations between 2001 and 2012 within a single VHA healthcare system of adults who received regular VHA care and were initiated on an antidiabetic medication between 2001 and 2008. We sampled 500 hospitalisations; 400 hospitalisations that fulfilled algorithm criteria, 100 that did not. Of these, 497 had adequate information for inclusion. The mean patient age was 66.1 years (SD 11.4). Majority of patients were male (98.8%); 75% were white and 20% were black.

Primary and secondary outcome measures

To determine if a hospitalisation was due to HF, we performed chart abstraction using Framingham criteria as the referent standard. We calculated the positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity for the overall algorithm and each component (primary diagnosis code (ICD-9), DRG code or both).

Results

The algorithm had a PPV of 89.7% (95% CI 86.8 to 92.7), NPV of 93.9% (89.1 to 98.6), sensitivity of 45.1% (25.1 to 65.1) and specificity of 99.4% (99.2 to 99.6). The PPV was highest for hospitalisations that fulfilled both the ICD-9 and DRG algorithm criteria (92.1% (89.1 to 95.1)) and lowest for hospitalisations that fulfilled only DRG algorithm criteria (62.5% (28.4 to 96.6)).

Conclusions

Our algorithm, which included primary discharge diagnosis and DRG codes, demonstrated excellent PPV for identification of hospitalisations due to decompensated HF among patients with diabetes in the VHA system.

https://ift.tt/2GsESQs

Real-world effects of medications for chronic obstructive pulmonary disease: protocol for a UK population-based non-interventional cohort study with validation against randomised trial results

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disease affecting 3 million people in the UK, in which patients exhibit airflow obstruction that is not fully reversible. COPD treatment guidelines are largely informed by randomised controlled trial results, but it is unclear if these findings apply to large patient populations not studied in trials. Non-interventional studies could be used to study patient groups excluded from trials, but the use of these studies to estimate treatment effectiveness is in its infancy. In this study, we will use individual trial data to validate non-interventional methods for assessing COPD treatment effectiveness, before applying these methods to the analysis of treatment effectiveness within people excluded from, or under-represented in COPD trials.

Methods and analysis

Using individual patient data from the landmark COPD Towards a Revolution in COPD Health (TORCH) trial and validated methods for detecting COPD and exacerbations in routinely collected primary care data, we will assemble a cohort in the UK Clinical Practice Research Datalink (selecting people between 1 January 2004 and 1 January 2017) with similar characteristics to TORCH participants and test whether non-interventional data can generate comparable results to trials, using cohort methodology with propensity score techniques to adjust for potential confounding. We will then use the methodological template we have developed to determine risks and benefits of COPD treatments in people excluded from TORCH. Outcomes are pneumonia, COPD exacerbation, mortality and time to treatment change. Groups to be studied include the elderly (>80 years), people with substantial comorbidity, people with and without underlying cardiovascular disease and people with mild COPD.

Ethics and dissemination

Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 11997). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 17_114R). An application to use the TORCH trial data made to clinicalstudydatarequest.com has been approved. In addition to scientific publications, dissemination methods will be developed based on discussions with patient groups with COPD.

https://ift.tt/2pGRzfV

Omega-3 polyunsaturated fatty acid supplementation for improving peripheral nerve health: protocol for a systematic review

Introduction

Damage to peripheral nerves occurs in a variety of health conditions. Preserving nerve integrity, to prevent progressive nerve damage, remains a clinical challenge. Omega-3 polyunsaturated fatty acids (PUFAs) are implicated in the development and maintenance of healthy nerves and may be beneficial for promoting peripheral nerve health. The aim of this systematic review is to assess the effects of oral omega-3 PUFA supplementation on peripheral nerve integrity, including both subjective and objective measures of peripheral nerve structure and/or function.

Methods and analysis

A systematic review of randomised controlled trials that have evaluated the effects of omega-3 PUFA supplementation on peripheral nerve assessments will be conducted. Comprehensive electronic database searches will be performed in Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), US National Institutes of Health Clinical Trials Registry and the WHO International Clinical Trials Registry Platform. The title, abstract and keywords of identified articles will be assessed for eligibility by two reviewers. Full-text articles will be obtained for all studies judged as eligible or potentially eligible; these studies will be independently assessed by two reviewers to determine eligibility. Disagreements will be resolved by consensus. Risk of bias assessment will be performed using the Cochrane Collaboration risk of bias tool to appraise the quality of included studies. If clinically meaningful, and there are a sufficient number of eligible studies, a meta-analysis will be conducted and a summary of findings table will be provided.

Ethics and dissemination

This is a systematic review that will involve the analysis of previously published data, and therefore ethics approval is not required. A manuscript reporting the results of this systematic review will be published in a peer-reviewed journal and may also be presented at relevant scientific conferences.

PROSPERO registration number

CRD42018086297.

https://ift.tt/2Gs3MQ4

A systematic assessment of Cochrane reviews and systematic reviews published in high-impact medical journals related to cancer

Objective

To compare cancer-related systematic reviews (SRs) published in the Cochrane Database of SRs (CDSR) and high-impact journals, with respect to type, content, quality and citation rates.

Design

Methodological SR with assessment and comparison of SRs and meta-analyses. Two authors independently assessed methodological quality using an Assessment of Multiple Systematic Reviews (AMSTAR)-based extraction form. Both authors independently screened search results, extracted content-relevant characteristics and retrieved citation numbers of the included reviews using the Clarivate Analytics Web of Science database.

Data sources

Cancer-related SRs were retrieved from the CDSR, as well as from the 10 journals which publish oncological SRs and had the highest impact factors, using a comprehensive search in both the CDSR and MEDLINE.

Eligibility criteria for selecting studies

We included all cancer-related SRs and meta-analyses published from January 2011 to May 2016. Methodological SRs were excluded.

Results

We included 346 applicable Cochrane reviews and 215 SRs from high-impact journals. Cochrane reviews consistently met more individual AMSTAR criteria, notably with regard to an a priori design (risk ratio (RR) 3.89; 95% CI 3.10 to 4.88), inclusion of the grey literature and trial registries (RR 3.52; 95% CI 2.84 to 4.37) in their searches, and the reporting of excluded studies (RR 8.80; 95% CI 6.06 to 12.78). Cochrane reviews were less likely to address questions of prognosis (RR 0.04; 95% CI 0.02 to 0.09), use individual patient data (RR 0.03; 95% CI 0.01 to 0.09) or be based on non-randomised controlled trials (RR 0.04; 95% CI 0.02 to 0.09). Citation rates of Cochrane reviews were notably lower than those for high-impact journals (Cochrane reviews: mean number of citations 6.52 (range 0–143); high-impact journal SRs: 74.45 (0–652)).

Conclusions

When comparing cancer-related SRs published in the CDSR versus those published in high-impact medical journals, Cochrane reviews were consistently of higher methodological quality, but cited less frequently.

https://ift.tt/2pGRrNt

Study protocol for a self-controlled cluster randomised trial of the Alert Program to improve self-regulation and executive function in Australian Aboriginal children with fetal alcohol spectrum disorder

Introduction

While research highlights the benefits of early diagnosis and intervention for children with fetal alcohol spectrum disorders (FASD), there are limited data documenting effective interventions for Australian children living in remote communities.

Methods and analysis

This self-controlled cluster randomised trial is evaluating the effectiveness of an 8-week Alert Program school curriculum for improving self-regulation and executive function in children living in remote Australian Aboriginal communities. Children in grades 1–6 attending any of the eight participating schools across the Fitzroy Valley in remote North-West Australia (N 363) were invited to participate. Each school was assigned to one of four clusters with clusters randomly assigned to receive the intervention at one of four time points. Clusters two, three and four had extended control conditions where students received regular schooling before later receiving the intervention. Trained classroom teachers delivered the Alert Program to students in discrete, weekly, 1-hour lessons. Student outcomes were assessed at three time points. For the intervention condition, data collection occurred 2 weeks immediately before and after the intervention, with a follow-up 8 weeks later. For control conditions in clusters two to four, the control data collection matched that of the data collection for the intervention condition in the preceding cluster. The primary outcome is change in self-regulation. FASD diagnoses will be determined via medical record review after the completion of data collection. The results will be analysed using generalised linear mixed modelling and reported in accordance with Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Ethics and dissemination

Ethical approval was obtained from the University of Western Australia (WA) (RA/4/1/7234), WA Aboriginal Health Ethics Committee (601) and WA Country Health Service (2015:04). The Kimberley Aboriginal Health Planning Forum Research Sub-Committee and WA Department of Education also provided approval. The results will be disseminated through peer-reviewed journals, conference presentations, the media and at forums.

Trial registration number

ACTRN12615000733572; Pre-results.

https://ift.tt/2GnJvej

Effects of vaccines in patients with sickle cell disease: a systematic review protocol

Introduction

Sickle cell disease (SCD) is an inherited haematological disorder caused by a single point mutation (Glub6Val) that promotes polymerisation of haemoglobin S and sickling of erythrocytes. Inflammation, haemolysis, microvascular obstruction and organ damage characterise the highly variable clinical expression of SCD. People with SCD are at increased risk of severe infections, hence the need for vaccination against common disease-causing organisms in this population. We aim to review the evidence on the efficacy and safety of vaccines in people with SCD.

Methods and analysis

The present systematic review will examine the current data as indexed in PubMed, CENTRAL, EMBASE and EBSCOHost. We will consult Strategic Advisory Group of Experts practice statements, conference abstracts, reference lists of relevant articles, WHO ICTRP trial registry and experts in the field. Two authors will independently screen search outputs, select studies, extract data and assess risk of bias; resolving discrepancies by discussion and consensus between the two authors or arbitration by a third author when necessary. We will perform a meta-analysis for clinically homogenous studies. Evidence from clinically diverse studies will be aggregated using narrative synthesis of the findings. In either case, we will use the GRADE approach to assess the strength of the available evidence.

Ethics and dissemination

The study draws on data that are readily available in the public domain, hence no formal ethical review and approval is required. The findings of this review will be disseminated through conference presentations and a publication in a peer-reviewed journal.

PROSPERO registration number

CRD42018084051.

https://ift.tt/2Ga15yZ

Care home services at the vanguard: a qualitative study exploring stakeholder views on the development and evaluation of novel, integrated approaches to enhancing healthcare in care homes

Objectives

To explore stakeholders' understanding of novel integrated approaches to enhancing care in care homes (a care home 'vanguard') and identify priorities for evaluation.

Design

A qualitative study, using semistructured interviews with commissioners and service providers to/within care homes, and third sector organisations with thematic analysis.

Setting

A Clinical Commissioning Group (CCG) area in England.

Participants

Thirty interviewees from care homes, the National Health Service (NHS; England) and local authority, third sector (10 care home managers, 5 general practitioners, 4 CCG employees, 4 local authority employees, 1 national (NHS England) vanguard lead, 2 specialist nurses, 2 geriatricians, 1 third sector and 1 health manager).

Results

Four higher level themes emerged from the data: understanding of proposed changes, communication, evaluation of outcome measures of success, and trust and complexity. The vision for the new programme was shared by stakeholders, with importance attached to equitable access to high-quality care. Support for the programme was described as being 'the right thing to do', inferring a moral imperative. However, the practical implications of key aspects, such as integrated working, were not clearly understood and the programme was perceived by some as being imposed, top down, from the health service. Barriers and facilitators to change were identified across themes of communication, outcomes, trust and complexity. Importance was attached to the measurement of intangible aspects of success, such as collaboration. Interviewees understood that outcome-based commissioning was one element of the new programme, but discussion of their aspirations and practices revealed values and beliefs more compatible with a system based on trust.

Conclusions

Innovation in service delivery requires organisations to adopt common priorities and share responsibility for success. The vanguard programme is working to ensure health and local authorities have this commitment, but engaging care homes that may feel isolated from the welfare system needs sustained dialogue over the longer term. Evaluation of the programme needs to measure what is important to stakeholders, and not focus too closely on resource consumption.

https://ift.tt/2GsEMIA

Fueling the culture of distrust in physicians [Letters]

https://ift.tt/2G99OWs

Are provincial medical associations taking physician mental health seriously enough? [News]

https://ift.tt/2I0I0A3

Smoking abstinence 1 year after acute coronary syndrome: follow-up from a randomized controlled trial of varenicline in patients admitted to hospital [Research]

BACKGROUND:

Patients who continue to smoke after acute coronary syndrome are at increased risk of reinfarction and death. We previously found use of varenicline to increase abstinence 24 weeks after acute coronary syndrome; here we report results through 52 weeks.

METHODS:

The EVITA trial was a multicentre, double-blind, randomized, placebo-controlled trial of varenicline for smoking cessation in patients admitted to hospital with acute coronary syndrome. Participants were randomly assigned (1:1) to receive varenicline or placebo for 12 weeks, in conjunction with low-intensity counselling. Smoking abstinence was assessed via 7-day recall, with biochemical validation using exhaled carbon monoxide. Participants lost to follow-up or withdrawn were assumed to have returned to smoking.

RESULTS:

Among the 302 participants, abstinence declined over the course of the trial, with 34.4% abstinent 52 weeks after acute coronary syndrome. Compared with placebo, point estimates suggest use of varenicline increased point-prevalence abstinence (39.9% v. 29.1%, difference 10.7%, 95% confidence interval [CI] 0.01% to 21.44%; number needed to treat 10), continuous abstinence (31.1% v. 21.2%, difference 9.9%, 95% CI –0.01% to 19.8%) and reduction in daily cigarette smoking by 50% or greater (57.8% v. 49.7%, difference 8.1%, 95% CI –3.1% to 19.4%). Varenicline and placebo groups had similar occurrence of serious adverse events (24.5% v. 21.9%, risk difference 2.7%, 95% CI –7.3% to 12.6%) and major adverse cardiovascular events (8.6% v. 9.3%, risk difference –0.7%, 95% CI –7.8% to 6.5%).

INTERPRETATION:

Varenicline was efficacious for smoking cessation in this high-risk patient population. However, 60% of patients who received treatment with varenicline still returned to smoking. Trial registration: ClinicalTrials.gov, no. NCT00794573

https://ift.tt/2G99GGs

Most Quebec medical residents show signs of burnout [News]

https://ift.tt/2I6Soq6

Person-level changes in oxycodone use after the introduction of a tamper-resistant formulation in Australia [Research]

BACKGROUND:

Australia introduced tamper-resistant controlled-release (CR) oxycodone in April 2014. We quantified the impact of the reformulation on dispensing, switching and poisonings.

METHODS:

We performed interrupted time-series analyses using population-representative national dispensing data from 2012 to 2016. We measured dispensing of oxycodone CR (≥ 10 mg), discontinuation of use of strong opioids and switching to other strong opioids after the reformulation compared with a historical control period. Similarly, we compared calls about intentional opioid poisoning using data from a regional poisons information centre.

RESULTS:

After the reformulation, dispensing decreased for 10–30 mg (total level shift –11.1%, 95% confidence interval [CI], –17.2% to –4.6%) and 40–80 mg oxycodone CR (total level shift –31.5%, 95% CI –37.5% to –24.9%) in participants less than 65 years of age but was unchanged in people 65 years of age or older. Compared with the previous year, discontinuation of use of strong opioids did not increase (adjusted hazard ratio [HR] 0.95, 95% CI 0.91 to 1.00), but switching to oxycodone/naloxone did increase (adjusted HR 1.54, 95% CI 1.32 to 1.79). Switching to morphine varied by age (p < 0.001), and the greatest increase was in participants less than 45 years of age (adjusted HR 4.33, 95% CI 2.13 to 8.80). Participants switching after the reformulation were more likely to be dispensed a tablet strength of 40 mg or more (adjusted odds ratio [OR] 1.40, 95% CI 1.09 to 1.79). Calls for intentional poisoning that involved oxycodone taken orally increased immediately after the reformulation (incidence rate ratio (IRR) 1.31, 95% CI 1.05–1.64), but there was no change for injected oxycodone.

INTERPRETATION:

The reformulation had a greater impact on opioid access patterns of people less than 65 years of age who were using higher strengths of oxycodone CR. This group has been identified as having an increased risk of problematic opioid use and warrants closer monitoring in clinical practice.

https://ift.tt/2G99y9W

Tackling smoking cessation systematically among inpatients with heart disease [Commentary]

https://ift.tt/2pFazvc

Human granulocytic anaplasmosis acquired from a blacklegged tick in Ontario [Practice]

https://ift.tt/2G99pmU

Creating the conditions that allow health for all to emerge [Letters]

https://ift.tt/2I2Jnhw

Low-risk ankle injuries in children [Practice]

https://ift.tt/2G99erK

Medical trainees want benefit of doubt when reporting harassment [News]

https://ift.tt/2pGRHw1

Seeking graphic medicine narratives [Humanities]

https://ift.tt/2G4ZXAM

Public health in the Anthropocene [Coda]

https://ift.tt/2I4zBeU

Hematopoietic Stem Cell Transplantation for Adult Philadelphia-Negative Acute Lymphoblastic Leukemia in the First Complete Remission in the Era of Minimal Residual Disease

Abstract

Purpose of Review

The purpose of this review is to discuss the potential role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for Philadelphia-negative (Ph⁻) adult acute lymphoblastic leukemia (ALL) in first complete remission (CR1) in the era of minimal residual disease (MRD).

Recent Findings

Allo-HSCT continues to have a role in the therapy of a selected group of high-risk adult patients with ALL in CR1. Although the clinical significance of MRD has been studied less extensively in adults with ALL than in children, recent studies support its role as the strongest prognostic factor that can identify patients that are unlikely to be cured by standard chemotherapy and benefit from undergoing allo-HSCT. In addition, MRD status both pre- and post-HSCT has been found to correlate directly with the risk of relapse.

Summary

Currently, the clinical challenge consists on applying MRD and molecular failure to integrate novel agents and immunotherapy to lower MRD before allo-HSCT and to modulate the graft versus leukemia (GVL) effect after transplant.

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Assessment of Cardiac Vegetative Control during Acute Graduated Exogenous Normobaric Hypoxia in Rats

The effects of exogenous normobaric hypoxic hypoxia on vegetative control of the heart and BP were examined in Wistar rats. The reference ranges of variation pulsometry parameters were determined in rats with normoxemia for 3 physiological variants of autonomic homeostasis: eutony, sympathicotony, and vagotony. Most rats (80%) demonstrated autonomic eutony. The study showed that saturation of arterial blood with oxygen is the most adequate assessment of severity of acute exogenous normobaric hypoxic hypoxia progressing within a closed hypoxic chamber, which standardizes this method and minimizes inaccuracies resulting from individual sensitivity to hypoxic stress. The changes in functional activity of systems that control the heart rhythm closely correlated with the drop in arterial blood oxygenation. While a small arterial hypoxemia activated the ergotropic elements of autonomic nervous system central subdivision accompanied by elevation of systolic BP, the moderate hypoxemia augmented the cholinergic influences and moderated the adrenergic ones under maintaining mobilization of the central autonomic nervous system-control loop and normotension. Severe hypoxemia was manifested by augmented influences from autonomic nervous system central subdivisions on the heart rate, disadaptation of the control systems, and systolic-diastolic arterial hypotension.

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Compounds of IL-6 Receptor Complex during Acute Lung Injury

Soluble receptor of IL-6 (sIL-6R) and antagonist of the receptor complex, soluble glycoprotein 130 (sgp130) mediate opposite effects during inflammation. We measured the levels of these cytokines and their ratio in rat blood on the model of acute lung injury. The injury was modeled by the intratracheal administration of LPS. The levels of sgp130 and sIL-6R increased during the inflammatory process in the injured lungs. The sgp130/sIL-6R ratio increased or decreased depending on the intensity of the inflammatory process. sgp130/sIL-6R ratio might reflect the intensity of inflammation during lung injury.

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Experimental Analysis of the Efficacy of Dihydroquercetin on the Model of Chronic Nonbacterial Inflammation of the Prostatic Gland

We studied the efficiency of dihydroquercetin on the model of chronic nonbacterial inflammation of the prostatic gland in rats. It was found that administration of dihydroquercetin was followed by a significant decrease in the area of the connective tissue in the prostatic gland to initial levels, which attested to antifibrotic properties of this oxidant. Additionally, the substance prevented the development of atrophy of acinus epithelium. After administration of reference drug Prostamol Uno, only moderate antifibrotic effects were observed.

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Role of Copper Dyshomeostasis in the Pathogenesis of Parkinson’s Disease

Serum concentration of copper, immunoreactive polypeptides of ceruloplasmin and its oxidase activity, and the number of copper atoms per ceruloplasmin molecule were decreased in patients with Parkinson's disease in comparison with the corresponding parameters in age-matched healthy individuals, but the ratio of apoceruloplasmin to holoceruloplasmin in patients with Parkinson's disease was similar in both groups. Treatment of blood serum with Helex 100, a high-affinity copper chelator, revealed reduced content of labile copper atoms per ceruloplasmin molecule in patients with Parkinson's disease in comparison with that in healthy controls. The mechanism underlying impaired metabolic incorporation of labile copper atoms into CP molecule is discussed as a possible cause of copper dyshomeostasis associated with Parkinson's disease.

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Effects of Fluoxetine and Potential Antidepressant 8-Trifluoromethyl 1,2,3,4,5-Benzopentathiepin-6-Amine Hydrochloride (TC-2153) on Behavior of Danio rerio Fish in the Novel Tank Test and Brain Content of Biogenic Amines and Their Metabolites

We compared the effect of a new potential antidepressant 8-trifluoromethyl 1,2,3,4,5-benzopentathiepine-6-amine hydrochloride (TC-2153) and classical antidepressant fluoxetine in a dose of 0.25 mg/liter on the behavior of Danio rerio in the "novel tank" test and content of biogenic amines and their metabolites in the brain. Fluoxetine alone and TC-2153 alone significantly increased the time spent in the upper part of the tank and insignificantly reduced motor activity. Combined exposure of fishes in the solution containing potential and classical antidepressants potentiated their effects on both parameters. The compounds did not affect brain contents of serotonin, dopamine, and norepinephrine. At the same time, fluoxetine, but not TC-2153, reduced brain content of the main serotonin metabolite 5-hydroxyindole acetic acid.

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Cytokine Production by Splenic Cells in C57BL/6J Mice with Depression-Like Behavior Depends on the Duration of Social Stress

We studied the influence of depression-like behavior developed in C57BL/6J mice under conditions of social stress of different duration on cytokine production by splenic cells. Imbalance of the pro- and anti-inflammatory cytokines was detected at the early stage of depression-like behavior (10-day experience of defeats): increased production of proinflammatory IL-2 and IL-6 cytokines along with a decrease in anti-inflammatory IL-10 level; the levels of IL-1β, TNFα, IFNγ, and IL-4 remained unaffected. At later terms (20 days of confrontations), we revealed more pronounced changes in spontaneous production of proinflammatory cytokines that were not detected after shorter social stress. These findings suggest that cytokine profile depends on duration of social stress. Possible mechanisms of cytokine production during formation of depression-like state are discussed.

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Effects of Electromagnetic Fields Modulated by Infralow Frequencies on the Production of Stem Cells

Experimental validation of the method for regulation of stem cell proliferation and differentiation is carried out. The method consists in exposure to ultrahigh frequency electromagnetic radiation, modulated by infralow frequencies with variable parameters. A specially designed programmer, setting up the parameters of exposure, is connected to the source of radiation. The zones of anatomical location of the red bone marrow of rats were exposed for 15 min to the amplitude-modulated electromagnetic radiation of ultrahigh frequency range. The parameters of exposure were determined in previous studies. The red bone marrow was collected from the sternum and head of the femur. The cellular composition of the red bone marrow was evaluated 1, 2, 3, and 6 days after the exposure. The optimal therapeutic mode of irradiation was then chosen, leading to stem cell activation with subsequent proliferation and differentiation into mature red bone marrow cells.

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Microscopic Study of Nervous System Plasticity: Interactions of Sympathetic Nerves with Neurons of Intraocular Hippocampal Transplants

Functional interactions of sympathetic fibers innervating the iris with the neurons of central origin in intraocular transplants of the rat hippocampus were studied by optic, confocal, and electron microscopy. After formaldehyde fixation, fluorescent dye Dil was applied to the upper cervical ganglion; the dye migrated to the transplant by lateral diffusion via axons. Sympathetic nerves labeled with fluorescent dye grew into the neurotransplants along perivascular membranes of blood vessels. In addition, some fluorescent axons were identified in the transplant parenchyma. Electron microscopy showed large bundles of the peripheral type axons in the vascular adventitia and Schwann-axonal complexes in the transplant neuropil. Autonomic axons formed synaptic contacts with transplanted neurons.

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Study of the Oxime-induced Reactivation of Acetyl- and Butyrylcholinesterase of Human with Inhibition of Organophosphorus Insecticide In Vitro

The efficiency of different reactivators of cholinesterase (toxogonin, dipiroxime, pralidoxime, carboxim, HI-6, and methoxime) at inhibition of butyrylcholinesterase and human acetylcholinesterase by organophosphate insecticide malathion was evaluated in in vitro experiments. Most reactivators increased inhibition of butyrylcholinesterase in comparison with the control, but HI-6 in a concentration of 10^—3 mol/liter partially (10%) restored activity of the enzyme. Oxime-induced reactivation of acetylcholinesterase was most pronounced in dipyroxime and toxogonin: parameters of the kinetics of reduction of the phosphorylated enzyme differed by more than 2 times from the values received with the use of other reactivators.

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Modulation of GABA- and Glycine-Activated Ionic Currents with Semax in Isolated Cerebral Neurons

The concentration-clamp experiments with neurons isolated from the rat brain showed that nootropic and neuroprotective drug Semax added to perfusion solution at concentration of 1 μM augmented the amplitude of GABA-activated ionic currents in cerebellum Purkinje cells by 147±13%. In addition, Semax in perfusion solution (0.1 and 1 μM) diminished the amplitude of glycine-activated chloride currents in hippocampal pyramidal neurons down to 68 and 43% control level, respectively. Both potentiating and inhibitory effects developed slowly, and they were poorly reversible, which indicated a probable implication of second messengers in the observed phenomena. Semax accelerated the falling edge of glycine-activated current both after a short-term co-application with agonist and after addition of this peptide into perfusion solution.

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Combined Action of PGRPs-Hsp70 Cytotoxic Complex with Paclitaxel Improves Outcomes of Melanoma Treatment in Mice

We studied the effect of PGRPs-Hsp70 cytotoxic complex that is analogous to natural complex secreted by cytotoxic lymphocytes and the antitumor drug paclitaxel on the development of M3 melanoma in DBA mice. Significant inhibition of tumor growth was observed in all experimental groups by days 20 and 35 of observation; paclitaxel monotherapy was less effective than administration of PGRPs-Hsp70 cytotoxic complex and its combination with paclitaxel. Pairwise comparison of Kaplan—Meier curves showed that survival was maximum in the group receiving combined therapy with PGRPs-Hsp70 cytotoxic complex and paclitaxel in comparison with groups receiving monotherapy.

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Role of IGFBP6 Protein in the Regulation of Epithelial-Mesenchymal Transition Genes

Protein IGFBP6 plays an important role in the pathogenesis of many malignant tumors, including breast cancer. The relationship between IGFBP6 protein and the expression of genes associated with the epithelial-mesenchymal transition is studied. Gene IGFBP6 knockdown does not trigger the epithelial-mesenchymal transition in MDA-MB-231 cells, but modifies significantly the expression of many genes involved in this process. A decrease of IGFBP6 expression can involve a decrease in the expression of N-cadherin and transcription factor Slug.

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Changes in the Expression of Immune Proteasomes in the Liver after the Induction of Portal Tolerance Depending on Donor—Recipient Differences in Rats

Induction of donor-specific tolerance in outbred Wistar rats (RT1^u) and inbred August rats (RT1^c) increased the expression of immune proteasome subunits in liver with a peak on day 7 after beginning of the induction. The increase in the level of immune subunits LMP2 and LMP7 was more pronounced in the liver of August rats in comparison with Wistar rats (by 2 and 6 times, respectively), which was associated with higher concentrations of monoamines in the CNS of August rats. After induction of donor-specific tolerance in August and Wistar rats, the immune subunits were in cells of sinusoidal lining and in cells located in sinusoid lumens. It can be suggested that immune proteasomes in these cells producing antigenic peptides for presentation to immunocompetent participate in the suppression of their activity and form the molecular basis for the development of donor-specific tolerance at very early stages of this process.

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Effect of Various Treatment Modes of Experimental Mammary Gland Tumor on Structure of Anterior Mediastinal Lymph Nodes

The effects of various treatment modes on the morphology of anterior mediastinal lymph nodes were examined in female Wistar rats with chemically provoked breast cancer. Adjuvant chemotherapy impaired filtration barrier potential of the anterior mediastinal lymph nodes, which manifested in increased volume of sinuses, reduced volumes of lymphoid nodules with germinal centers and thymus-dependent regions, down-regulated proliferative activity of lymphoid cells in B-cell zone and paracortex, and diminished macrophage score in all zones. Intraperitoneal injection of double-stranded DNA preparation (5 mg/kg) activated the humoral and cellular immune responses manifested by morphological alterations in anterior mediastinal lymph nodes observed in parallel with a decrease of medullary sinuses volume: enhancement of lymphocyte volume and lymphocyte score in paracortex, mantle zone expansion, and an increase of volume of the light centers in lymphoid nodules paralleled with diminished proliferative activity in them.

https://ift.tt/2G5lKbH

fMRI Responses in Healthy Individuals and in Patients with Mild Depression to Presentation of Pleasant and Unpleasant Images

Patients with mild depression and apparently healthy individuals were presented images and asked to sort them into "pleasant" and "unpleasant" subsets. In both groups, the main differences between brain activation patterns during presentation of pleasant and unpleasant images were localized in the motor regions (precentral and postcentral gyrus) and in the cerebellum (p<0.05 with FWE correction). Most likely, these clusters are associated with motion (pressing a button in accordance with the instruction). According to the data of intergroup contrasts, patients with depression had less pronounced activation of frontal structures (middle frontal gyrus and other areas, including the white matter) in response to both positive and negative images (p<0.001). In healthy subjects, the response of the temporo-occipital areas (lingual and fusiform gyrus) to unpleasant stimuli was more intensive than in patients (p<0.001). This can be due to differences in the semantic image processing. Thus, in case of mild depression, the response of the amygdaloid complex, the key structure in the development in affective disorder, was not always observed. At the same time, the response of frontal and temporo-occipital regions has a certain potential as a biomarker of mild depression, although the reliability of the obtained data requires additional confirmation.

https://ift.tt/2DU6w36

Evaluation of DNA Damage in Experimental Preeclampsia by Comet Assay

Experimental preeclampsia induced by substitution of drinking water with 1.8% NaCl during pregnancy was associated with an increase in the level of DNA damage in fetal brain and placenta measured by DNA comet assay by 35.7 and 27.8 times, respectively, in comparison with physiological pregnancy.

https://ift.tt/2G91ZQk

Stress Response to Physical Exercise in Rats with Alimentary Obesity

Stress response to physical exercise was studied in rats with alimentary obesity with and without caloric diet restriction. Daily excretion of corticosterone, progesterone, and testosterone, weights of internal organs, and serum levels of glucose, free fatty acids, triglycerides, corticosterone, and testosterone were estimated. Stress response to moderate exercise in rats with alimentary obesity was associated with predominance of anabolic influence of testosterone over the catabolic effects of corticosterone, which promoted the increase in the weight of reproductive organs. Exposure to physical loads against the background of restricted ration potentiated the response of the adrenocortical system and reduced the concentration and anabolic effects of testosterone.

https://ift.tt/2I6994n

Re-Examination of the Esophageal Squamous Cell Carcinoma Model in Rats Induced by N-Nitrososarcosine Ethyl Ester Precursors

Studies of the molecular mechanisms of esophageal cancer development have to be carried out on sufficient amount of tumor material, obtained under conditions of controlled exposure to carcinogenic factors. Esophageal cancer models on laboratory animals serve an indispensable source of this material. One of these models is esophageal cancer induction in rats by N-nitroso compound precursors. Despite adequate reproduction of human esophageal cancer, this model in fact has not been used since the 1990ies. Re-examination of esophageal cancer model, induced by N-nitrososarcosine ethyl ester precursors, is carried out and its efficiency in induction of squamous cell carcinoma is confirmed.

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Decrease in Bcl-2 Protein Level during the Development of Lewis Carcinosarcome

We studied the development of Lewis carcinoma and possible antitumor effect of preliminary administered antioxidant anphen. The tumor was intramuscularly transplanted to C57Bl×DBA mice (7×10⁶ cells per mouse). According to immunoblotting results, the content of anti-apoptotic Bcl-2 protein steadily decreased starting from post-transplantation day 11. In few days, its content decreased by 15-20% and soon the animals died. After administration of anphen, the content of Bcl-2 decreased more rapidly than in the control. Atomic force microscopy revealed a decrease in the mean volume of erythrocytes and then increase in this parameter at the terminal stage of tumor growth. These findings suggest that anphen does not affect the tumor growth rate and mouse lifespan, but enhances apoptosis of blood cells of animals with Lewis carcinoma at the terminal stages of tumor growth.

https://ift.tt/2I32vMu

Variability of the Expression of Reference Genes in Samples of Human Olfactory Epithelium

We analyzed variability of the expression of three reference genes in biopsy samples of the olfactory epithelium obtained from healthy volunteers. The expression of B2M, HPRT1, and CASC3 genes was analyzed by real-time PCR. The pairs of genes B2M—HPRT1 and B2M—CASC3 were found to possess minimum individual variability of expression and can be reliable candidates for the reference genes in analysis of gene expression in neural cells.

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Toward eradicating misconceptions on matching in etiological studies

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Assessment of CTNNB1 gene mutations and β-catenin immunoexpression in salivary gland pleomorphic adenomas and adenoid cystic carcinomas

Abstract

β-Catenin exerts multiple functions in several neoplasms, playing a major role in cell signaling and tumor progression. This study analyzed possible CTNNB1 mutations in salivary gland pleomorphic adenomas (PAs) and adenoid cystic carcinomas (ACCs), and determined possible differences in β-catenin immunoexpression in relation to these mutations, as well as histopathological aspects of these tumors. Twenty-four PAs (15 cell-rich and 9 cell-poor tumors) and 24 ACCs (10 tubular, 8 cribriform, and 6 solid tumors) were selected for the analysis of β-catenin distribution and cellular localization. Furthermore, β-catenin expression was evaluated using the H-score scoring system. Mutations in CTNNB1 exon 3 were investigated by the single-strand conformational polymorphism test. Diffuse β-catenin expression was more frequently observed in ACCs compared to PAs (P = 0.008). No significant difference in β-catenin cellular localization was observed between these tumors (P = 0.098). Comparisons between PA and ACC cases revealed a higher median H-score in the latter (P = 0.036). Cell-rich PAs exhibited a trend for higher H-score than cell-poor tumors (P = 0.060), whereas lower H-scores were observed in cribriform ACCs when compared to tubular and solid ACCs (P = 0.042). Mutations in CTNNB1 were observed in 6 PAs and 7 ACCs, with no significant difference in H-scores for β-catenin according to mutation status (P = 0.135). β-Catenin is important in the pathogenesis of salivary gland PAs and ACCs. In addition, CTNNB1 exon 3 mutations do not seem to significantly influence β-catenin cytoplasmic/membranous expression or nuclear translocation in these tumors.

https://ift.tt/2Gme587

Chemokines and cancer: new immune checkpoints for cancer therapy

Nathan Karin

https://ift.tt/2I6cbWD

Engineering T cells for adoptive therapy: outsmarting the tumor

Andre Kunert | Reno Debets

https://ift.tt/2IOpBYm

The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin

The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin

The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin, Published online: 26 March 2018; doi:10.1038/s41416-018-0043-8

The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin

https://ift.tt/2DXlJkk

Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry

Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry

Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry, Published online: 26 March 2018; doi:10.1038/s41416-018-0033-x

Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry

https://ift.tt/2G6rSfF

Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma

Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma

Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma, Published online: 26 March 2018; doi:10.1038/s41416-018-0061-6

Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma

https://ift.tt/2Gnz62l

Predicting cumulative incidence of adverse events in older patients with cancer undergoing first-line palliative chemotherapy: Korean Cancer Study Group (KCSG) multicentre prospective study

Predicting cumulative incidence of adverse events in older patients with cancer undergoing first-line palliative chemotherapy: Korean Cancer Study Group (KCSG) multicentre prospective study

Predicting cumulative incidence of adverse events in older patients with cancer undergoing first-line palliative chemotherapy: Korean Cancer Study Group (KCSG) multicentre prospective study, Published online: 26 March 2018; doi:10.1038/s41416-018-0037-6

Predicting cumulative incidence of adverse events in older patients with cancer undergoing first-line palliative chemotherapy: Korean Cancer Study Group (KCSG) multicentre prospective study

https://ift.tt/2GawMIu

Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

Targeting glutaminolysis in chondrosarcoma in context of the <i>IDH1/2</i> mutation, Published online: 26 March 2018; doi:10.1038/s41416-018-0050-9

Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

https://ift.tt/2Gla0RE

Effect of Formaldehyde on Human Middle Ear Epithelial Cells

Formaldehyde (FA) is a familiar indoor air pollutant found in everything from cosmetics to clothing, but its impact on the middle ear is unknown. This study investigated whether FA causes cytotoxicity, inflammation, or induction of apoptosis in human middle ear epithelial cells (HMEECs). Cell viability was investigated using the trypan blue assay and a cell counting kit (CCK-8) in HMEECs treated with FA for 4 or 24 h. The expression of genes encoding the inflammatory cytokine tumor necrosis factor alpha (TNF-α) and mucin (MUC5AC) was analyzed using RT-PCR. Activation of the apoptosis pathway was determined by measuring mitochondrial membrane potential (MMP), cytochrome oxidase, caspase-9/Mch6/Apaf 3, and Caspase-Glo® 3/7 activities. The CCK-8 assay and trypan blue assay results showed a reduction in cell viability in FA-treated HMEECs. FA also increased the cellular expression of TNF-α and MUC5AC and reduced the activities of MMP and cytochrome oxidase. Caspase-9 activity increased in cells stimulated for 4 h, as well as caspase-3/7 activity in cells stimulated for 24 h. The decreased cell viability, the induction of inflammation and mucin gene expression, and the activation of the apoptosis pathway together indicate a link between environmental FA exposure and the development of otitis media.

https://ift.tt/2GjG7kT

Does Uterine Fibroid Adversely Affect Obstetric Outcome of Pregnancy?

Background. Fibroid is the most common benign tumor of the uterus and if associated with pregnancy may adversely affect the outcome of pregnancy. Objective of the present study was to assess the obstetric outcome (maternal and fetal) in pregnancy with fibroid. Methods. A prospective observational study was performed over a period from May 2015 to August 2017 at Obstetrics and Gynecology Department in Zagazig University Hospitals, Egypt. 64 pregnant patients with >2 cm fibroid were taken in the study. Routine fundamental investigations were done for all. They were followed during antenatal period clinically and scanned by ultrasonogram which was done at booking visit and during subsequent visits to assess the change in the size of the fibroid and other obstetric complications. Maternal age, parity, size of fibroid, complications during pregnancy, and mode of delivery were noted. Results. 64 pregnant patients with uterine fibroids were recruited; 47 of them completed the study to the end. The average age was years, body mass index (BMI) [calculated as weight in kilograms divided by the square of height in meters] was , primigravida was 23.4%, multigravida was 76.6%, duration of menstrual cycle/day was , and duration of menstrual period/day was . The percentage of spontaneous conception was 59.57% and 40.43% for using assisted reproductive technology. The results of obstetric outcome were spontaneous abortion in 2%, premature delivery in 27.7%, and delivery at 37–41 weeks of pregnancy in 70.2%. The mode of delivery was vaginal delivery in 15% and cesarean sections in 85%. Also, 34% had threatened miscarriage, 21% had preterm labor, 2% had antepartum bleeding in the form of placenta previa, 4% had abdominal pain needing admission, one of them underwent laparotomy and was diagnosed as red degeneration, 2 (4%) had postpartum hemorrhage, and only one needed blood transfusion. Cesarean sections were done in 85%. Neonatal outcome was acceptable with no perinatal mortality. There were no significant differences between patients with single or multiple fibroids as regards the obstetric outcome or type of fibroid either intramural or subserosal. The obstetric outcomes were not significantly affected by the number, size, or type of fibroids. Conclusions. Even most of fibroids in pregnancy are asymptomatic but may be associated with some complications affecting the course of pregnancy and labor. So, pregnancy has to be cautiously screened in the antenatal period, through regular follow-up, to detect any adverse obstetric complications and so improve the outcome.

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Sentinel Lymph Node Biopsy in Breast Cancer Patients by Means of Indocyanine Green Using the Karl Storz VITOM® Fluorescence Camera

Currently, the use of radioisotope and blue dye for sentinel lymph node biopsy (SLNB) for axillary staging in breast cancer is common. Recently, indocyanine green (ICG) has been proposed as an alternative sentinel lymph node (SLN) tracking agent. We evaluated the clinical value of ICG as an additional tracer in combination with Technetium99m and as an alternative to Technetium99m for the identification of SLN in 104 breast cancer patients. 21 patients had at least 1 histologically tumor-positive SLN. All 21 patients were detected by ICG; in one of these 21 sentinel-positive patients, Technetium99m was unable to identify lymph node involvement. Our results show that ICG is as effective as the radioisotope for SLNB. In addition, as a near-infrared dye, it has the advantages of real-time visualization, lower cost, and wider availability, since no radioactive material needs to be handled. This trial is registered with German Clinical Trial Register Main ID: DRKS00013606.

https://ift.tt/2GlqwRE

American Journal of Medical Genetics Part A, Ahead of Print.

American Journal of Medical Genetics Part A, Ahead of Print.


https://ift.tt/2pDLq3W

Targeting glutaminolysis in chondrosarcoma in context of the IDH1/2 mutation

https://ift.tt/2pEMwNI

Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma

https://ift.tt/2pJAXEv

Predicting cumulative incidence of adverse events in older patients with cancer undergoing first-line palliative chemotherapy: Korean Cancer Study Group (KCSG) multicentre prospective study

https://ift.tt/2pDPoKH

The mechanism study of lentiviral vector carrying methioninase enhances the sensitivity of drug-resistant gastric cancer cells to Cisplatin

https://ift.tt/2HZIk1V

Optoacoustics delineates murine breast cancer models displaying angiogenesis and vascular mimicry

https://ift.tt/2pGZafh

What Faces Reveal: A Novel Method to Identify Patients at Risk of Deterioration Using Facial Expressions

Objectives: To identify facial expressions occurring in patients at risk of deterioration in hospital wards. Design: Prospective observational feasibility study. Setting: General ward patients in a London Community Hospital, United Kingdom. Patients: Thirty-four patients at risk of clinical deterioration. Interventions: A 5-minute video (25 frames/s; 7,500 images) was recorded, encrypted, and subsequently analyzed for action units by a trained facial action coding system psychologist blinded to outcome. Measurements and Main Results: Action units of the upper face, head position, eyes position, lips and jaw position, and lower face were analyzed in conjunction with clinical measures collected within the National Early Warning Score. The most frequently detected action units were action unit 43 (73%) for upper face, action unit 51 (11.7%) for head position, action unit 62 (5.8%) for eyes position, action unit 25 (44.1%) for lips and jaw, and action unit 15 (67.6%) for lower face. The presence of certain combined face displays was increased in patients requiring admission to intensive care, namely, action units 43 + 15 + 25 (face display 1, p

https://ift.tt/2ISD0hV

Intra-Abdominal Hypertension Is More Common Than Previously Thought: A Prospective Study in a Mixed Medical-Surgical ICU

Objectives: To determine the prevalence of intra-abdominal hypertension in mixed medical-surgical critically ill patients using modern definitions and measurement techniques. Secondarily to determine variables associated with intra-abdominal hypertension and ICU mortality. Design: A prospective observational study. Setting: Single institution trauma, medical and surgical ICU in Canada. Patients: Consecutive adult patients admitted to the ICU (n = 285). Intervention: Intra-abdominal pressure measurements twice a day during admission to the ICU. Measurements and Main Results: In 285 patients who met inclusion criteria, 30% were diagnosed with intra-abdominal hypertension at admission and a further 15% developed intra-abdominal hypertension during admission. The prevalence of abdominal compartment syndrome was 3%. Obesity, sepsis, mechanical ventilation, and 24-hour fluid balance (> 3 L) were all independent predictors for intra-abdominal hypertension. Intra-abdominal hypertension occurred in 28% of nonventilated patients. Admission type (medical vs surgical vs trauma) was not a significant predictor of intra-abdominal hypertension. Overall ICU mortality was 20% and was significantly higher for patients with intra-abdominal hypertension (30%) compared with patients without intra-abdominal hypertension (11%). Intra-abdominal hypertension of any grade was an independent predictor of mortality (odds ratio, 3.33; 95% CI, 1.46–7.57). Conclusions: Intra-abdominal hypertension is common in both surgical and nonsurgical patients in the intensive care setting and was found to be independently associated with mortality. Despite prior reports to the contrary, intra-abdominal hypertension develops in nonventilated patients and in patients who do not have intra-abdominal hypertension at admission. Intra-abdominal pressure monitoring is inexpensive, provides valuable clinical information, and there may be a role for its routine measurement in the ICU. Future work should evaluate the impact of early interventions for patients with intra-abdominal hypertension. This work was performed at the London Health Sciences Centre and Western University. Trial Registration: ClinicalTrials.gov NCT02514135. Drs. Murphy, Parry, Leslie, Vogt, and Ball participated in study design and served as content experts in the field. Data collection was performed by Drs. Murphy and Sela, and analysis was performed by Dr. Murphy. Dr. Vogt also reviewed and repeated the data analysis. All authors contributed to and reviewed the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by resident research grant from the Department of Surgery, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada. Presented, in part, at the 2016 American Association for the Surgery of Trauma Conference, Hawaii, HI, September 14, 2016. Dr. Murphy received funding from Western University. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: patrick.murphy@londonhospitals.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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BioEssays, Ahead of Print.

BioEssays, Ahead of Print.


https://ift.tt/2DTrWgN

Epilepsia, Ahead of Print.

Epilepsia, Ahead of Print.


https://ift.tt/2G7aqrn

Bauhinia variegata candida Fraction Induces Tumor Cell Death by Activation of Caspase-3, RIP, and TNF-R1 and Inhibits Cell Migration and Invasion In Vitro

Metastasis remains the most common cause of death in cancer patients. Inhibition of metalloproteinases (MMPs) is an interesting approach to cancer therapy because of their role in the degradation of extracellular matrix (ECM), cell-cell, and cell-ECM interactions, modulating key events in cell migration and invasion. Herein, we show the cytotoxic and antimetastatic effects of the third fraction (FR3) from Bauhinia variegata candida (Bvc) stem on human cervical tumor cells (HeLa) and human peripheral blood mononuclear cells (PBMCs). FR3 inhibited MMP-2 and MMP-9 activity, indicated by zymogram. This fraction was cytotoxic to HeLa cells and noncytotoxic to PBMCs and decreased HeLa cell migration and invasion. FR3 is believed to stimulate extrinsic apoptosis together with necroptosis, assessed by western blotting. FR3 inhibited MMP-2 activity in the HeLa supernatant, differently from the control. The atomic mass spectrometry (ESI-MS) characterization suggested the presence of glucopyranosides, D-pinitol, fatty acids, and phenolic acid. These findings provide insight suggesting that FR3 contains components with potential tumor-selective cytotoxic action in addition to the action on the migration of tumor cells, which may be due to inhibition of MMPs.

https://ift.tt/2GodXoQ

Basic Fibroblast Growth Factor Fused with Tandem Collagen-Binding Domains from Clostridium histolyticum Collagenase ColG Increases Bone Formation

Basic fibroblast growth factor 2 (bFGF) accelerates bone formation during fracture healing. Because the efficacy of bFGF decreases rapidly following its diffusion from fracture sites, however, repeated dosing is required to ensure a sustained therapeutic effect. We previously developed a fusion protein comprising bFGF, a polycystic kidney disease domain (PKD; s2b), and collagen-binding domain (CBD; s3) sourced from the Clostridium histolyticum class II collagenase, ColH, and reported that the combination of this fusion protein with a collagen-like peptide, poly(Pro-Hyp-Gly)10, induced mesenchymal cell proliferation and callus formation at fracture sites. In addition, C. histolyticum produces class I collagenase (ColG) with tandem CBDs (s3a and s3b) at the C-terminus. We therefore hypothesized that a bFGF fusion protein containing ColG-derived tandem CBDs (s3a and s3b) would show enhanced collagen-binding activity, leading to improved bone formation. Here, we examined the binding affinity of four collagen anchors derived from the two clostridial collagenases to H-Gly-Pro-Arg-Gly-(Pro-Hyp-Gly)12-NH2, a collagenous peptide, by surface plasmon resonance and found that tandem CBDs (s3a-s3b) have the highest affinity for the collagenous peptide. We also constructed four fusion proteins consisting of bFGF and s3 (bFGF-s3), s2b-s3b (bFGF-s2b-s3), s3b (bFGF-s3b), and s3a-s3b (bFGF-s3a-s3b) and compared their biological activities to those of a previous fusion construct (bFGF-s2b-s3) using a cell proliferation assay in vitro and a mouse femoral fracture model in vivo. Among these CB-bFGFs, bFGF-s3a-s3b showed the highest capacity to induce mesenchymal cell proliferation and callus formation in the mice fracture model. The poly(Pro-Hyp-Gly)10/bFGF-s3a-s3b construct may therefore have the potential to promote bone formation in clinical settings.

https://ift.tt/2DRSeQT

Herniation of Hoffa's Fat Pad Through the Lateral Retinaculum: Usefulness of Dynamic Ultrasonography to Diagnose a Lateral Knee Mass

No abstract available

https://ift.tt/2pIFqHw

Diagnosis and Incidence of Spondylosis and Cervical Disc Disorders in the University Clinical Hospital in Olsztyn, in Years 2011–2015

Background. Disorders connected with the musculoskeletal and central nervous system dysfunction are the most significant clinical problem worldwide. Our earlier research has shown that back and spinal disorders and lumbar disc disorders were most frequently diagnosed using MRI scanner at the University Clinical Hospital (UCH) in Olsztyn in years 2011–2015. We have also observed that another two diseases of spinal column, spondylosis and cervical disc disorders, were also very prevalent. The main objective of this work was to analyze the prevalence of spondylosis and cervical disc disorders in the study population diagnosed at UCH in years 2011–2015. Methods. The digital database including patients' diagnostic and demographic information was generated based on MRI reports from years 2011–2015 and analyzed using SPSS software. Results. Within the study group () the most frequently MRI-diagnosed diseases were musculoskeletal group (M00–M99; ; 57,98%) and cervical disc disorders (M50; ; 12,47%) and spondylosis (M47, ; 4,59%). More women (67%) than men (33%) were enrolled in the study, and the largest fraction of the study population was in the range of 51–60 years, with about 1/3 of cases of both diseases diagnosed in early age range of 31–40 years. Conclusion. Significant number of patients presenting with either of the spine disorders at the young age of 31–40 years points to the necessity of introducing methods preventing disorders of the vertebral column at younger age, preferably at school age.

https://ift.tt/2G9hOTo

Epigallocatechin-3-Gallate Reduces Neuronal Apoptosis in Rats after Middle Cerebral Artery Occlusion Injury via PI3K/AKT/eNOS Signaling Pathway

Background/Aims. Epigallocatechin-3-gallate (EGCG) has neuroprotective effects and the ability to resist amyloidosis. This study observed the protective effect of EGCG against neuronal injury in rat models of middle cerebral artery occlusion (MCAO) and investigated the mechanism of action of PI3K/AKT/eNOS signaling pathway. Methods. Rat models of permanent MCAO were established using the suture method. Rat behavior was measured using neurological deficit score. Pathology and apoptosis were measured using HE staining and TUNEL. Oxidative stress and brain injury markers were examined using ELISA. Apoptosis-related proteins and PI3K/AKT/eNOS signaling pathway were determined using western blot assay and immunohistochemistry. Results. EGCG decreased neurological function score, protected nerve cells, inhibited neuronal apoptosis, and inhibited oxidative stress injury and brain injury markers level after MCAO. EGCG reduced the apoptotic rate of neurons, increased the expression of Bcl-2, and decreased the expression of Caspase-3 and Bax. After LY294002 suppressed the PI3K pathway, the protective effect of EGCG decreased after administration of PI3K inhibitors. Conclusion. EGCG has a protective effect on rat brain injury induced by MCAO, possibly by modulating the PI3K/AKT/eNOS signaling pathway.

https://ift.tt/2GrpR0W

Second Blood Meal by Female Lutzomyia longipalpis: Enhancement by Oviposition and Its Effects on Digestion, Longevity, and Leishmania Infection

Lutzomyia longipalpis is the main vector of visceral leishmaniasis (VL) in America. Physiological and molecular mechanisms of Leishmania infection in sand flies have been studied during the first gonotrophic cycle. There are few studies about these interactions during the second gonotrophic cycle mainly because of the difficulties maintaining sand flies through sequential feeds. Here we standardized conditions to perform the second blood feed efficiently, and our results show that oviposition is an essential factor for the success of multiple feeds. We evaluated the impact of the second blood meal on longevity, protein digestion, trypsin activity, and Leishmania mexicana development within L. longipalpis gut. Mortality of blood-fed females increases after second blood meal as compared to sugar-fed females. Trypsin activity was lower during the second gonotrophic cycle. However, no difference in protein intake was observed between blood meals. There was no difference in the population size of Leishmania in the gut after both blood meals. In this work, we presented an optimized protocol for obtaining sufficient numbers of sand fly females fed on a second blood meal, and we described some physiological and parasitological aspects of the second gonotrophic cycle which might influence the vectorial competence of sand flies.

https://ift.tt/2DS24lL

The Significance of Scalp Involvement in Pemphigus: A Literature Review

Scalp is a unique location for pemphigus because of the abundance of desmogleins localized in hair follicles. Scalp involvement is observed in up to 60% of patients in the course of pemphigus. The lesions may occasionally lead to alopecia. Unforced removal of anagen hairs in a pull test is a sign of high disease activity. Direct immunofluorescence of plucked hair bulbs is considered a reliable diagnostic method in patients with pemphigus. Follicular acantholysis is a characteristic histopathological feature of pemphigus lesions localized on the scalp. Trichoscopy may serve as a supplementary method in the diagnosis of pemphigus. This review summarizes the most recent data concerning scalp involvement in pemphigus vulgaris and pemphigus foliaceus. A systematic literature search was conducted in three medical databases: PubMed, Embase, and Web of Science. The analysis included literature data about desmoglein distribution in hair follicles, as well as information about clinical manifestations, histopathology, immunopathology, and trichoscopy of scalp lesions in pemphigus and their response to treatment.

https://ift.tt/2Gql6Vq

A Case of Congenital Syphilis Presenting with Unusual Skin Eruptions

Once believed to be a rare disease in developed countries, recent data suggest that there is a surge in incidence of congenital syphilis in many developed countries. Diagnosis of congenital syphilis can be difficult because more than two-thirds of affected infants are asymptomatic at birth, and signs of symptomatic infants may be nonspecific or subtle. On top of this, some affected infants may have atypical presentations. Familiarity with the diverse presentations is essential to diagnosis. We report a 2-week-old male infant with congenital syphilis whose cutaneous manifestations included diffuse, erythematous keratoderma with desquamation and fissures on his hands and feet, multiple linear scaly fissures at the angles of his mouth, and onychauxis of the fingernails and toenails To our knowledge, diffuse, erythematous keratoderma of the hands and feet and thick nails have not been reported previously in congenital syphilis.

https://ift.tt/2G3Ixo7

Evaluation of immune responses in mice and sheep inoculated with a live attenuated Brucella melitensis REV1 vaccine produced in bioreactor.

Evaluation of immune responses in mice and sheep inoculated with a live attenuated Brucella melitensis REV1 vaccine produced in bioreactor.

Vet Immunol Immunopathol. 2018 Apr;198:44-53

Authors: Curina G, Nardini R, Corneli S, D'Avino N, Tentellini M, Montagnoli C, Severi G, Forti K, Paternesi B, Coletti M, Cagiola M

Abstract
The Brucella melitensis REV1 vaccine is the most widely employed vaccine for prophylaxis against brucellosis in sheep and goats. The objective of vaccination is disease control in herds or preventing infection in farms. In this study, we produced REV1 vaccine with a protocol, based on the use of liquid medium in a bioreactor, that resulted efficient, safe, relatively fast, and cost-effective. The live attenuated vaccine produced was tested in mice and sheep to investigate its immunogenicity and efficacy. Seventy-two female BALB/c mice were obtained and subdivided in 2 groups, one was stimulated with 1 × 106 colony-forming units (CFUs) of B. melitensis while the other with physiological solution alone and acting as control group. Furthermore, 25 sheep were subdivided into 5 groups: four were inoculated with a B. melitensis dose, ranging from 0.6 × 109 and 3.2 × 109 CFUs and the other was the control group. In addition, a serological diagnosis was performed for sheep by rapid serum agglutination and the complement-fixation test. Immunocompetent cells from both experiment were collected at different times post vaccination and immunostained to evaluate innate and adaptive-immune responses. In mice flow cytometry was used to detect macrophages, T lymphocytes, dendritic cells, memory cells, naïve cells, natural killer cells, major histocompatibility complex type II, B lymphocytes, regulatory T lymphocytes, T helper lymphocytes, cytotoxic T lymphocytes and recently activated CD4+ and CD8+ lymphocytes. In sheep, macrophages, T helper cells, cytotoxic T lymphocytes, regulatory T lymphocytes, dendritic cells, memory cells and naïve lymphocytes, by the same method, were analyzed. The results showed, both in mice and sheep, that the live, attenuated REV1 vaccine stimulated all immunocompetent cells tested, with a balanced innate and adaptive response. In the sheep experiment, the administered vaccine dose was very important because, at the lower doses, immunological tolerance tended to disappear, while, at the highest dose, the immunological tolerance remained active for a long period. In our experimental conditions, the optimal vaccine dose for sheep was 3.2 × 109 CFUs, although a good immune response was found using a dose of 1.6 × 109 CFUs. The vaccine produced in this study could be extensively employed in developing countries to control the brucellosis in sheep and goats.

PMID: 29571517 [PubMed - in process]

https://ift.tt/2ue0D1u

Optimum Antithrombotic Therapy in Patients Requiring Long-Term Anticoagulation and Undergoing Percutaneous Coronary Intervention

Management of patients on long-term anticoagulation requiring percutaneous coronary intervention is challenging. Triple therapy with oral anticoagulant and dual antiplatelet therapy is the standard of care. However, there is no strong evidence to support this strategy. There is emerging data regarding the safety and efficacy of dual therapy with oral anticoagulant and single antiplatelet therapy in these patients. In this comprehensive review we highlight available evidence regarding various antithrombotic regimens' efficacy and safety in patient with coronary artery disease undergoing percutaneous coronary intervention with long-term anticoagulation therapy requirements.

https://ift.tt/2ujNZOo

AEG-1 Contributes to Metastasis in Hypoxia-Related Ovarian Cancer by Modulating the HIF-1alpha/NF-kappaB/VEGF Pathway

Objective. Ovarian carcinoma represents one of the deadliest malignancies among female cancer patients. Astrocyte-elevated gene-1 (AEG-1) participates in the ontogenesis of multiple human malignant diseases. Here we evaluated AEG-1, hypoxia-inducible factor- (HIF-) 1α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF) amounts in hypoxia induced ovarian carcinoma cells. This study aimed to explore the mechanism by which AEG-1 regulates metastasis in hypoxia induced ovarian carcinoma. Patients and Methods. AEG-1, HIF-1α, and VEGF protein amounts were evaluated by immunohistochemistry in 40 and 170 normal ovary and ovarian cancer tissue specimens, respectively. In addition, AEG-1, HIF-1α, NF-κB, and VEGF mRNA and protein levels were determined by reverse quantified RT-PCR and WB, respectively, at different time periods (0–24 h) in epithelial ovarian cancer (EOC) SKOV3 cells treated in a hypoxia incubator. Furthermore, NF-κB and VEGF gene and protein expression levels in AEG-1 knockdown EOC cells were quantitated by RT-PCR and WB, respectively. Results. AEG-1, HIF-1α, and VEGF amounts were significantly elevated in EOC tissue samples compared with normal ovary specimens (). Positive expression of HIF-1α and AEG-1 was associated with higher metastatic rate (), lower FIGO stage (), and degree of differentiation (). Meanwhile, EOC SKOV3 cells grew upon exposure to hypoxia for 8 h (); at this time point, AEG-1, HIF-1α, NF-κB, and VEGF amounts peaked (), at both the gene and the protein levels. After AEG-1 knockdown, HIF-1α, NF-κB, and VEGF amounts were significantly decreased in EOC SKOV3 cells, also under hypoxic conditions (). Conclusions. As an independent prognostic factor, AEG-1 was found to be significantly associated with hypoxia in ovarian cancer by regulating the HIF-1alpha/NF-kappaB/VEGF pathway. Therefore, AEG-1 may be useful in determining disease stage and prognosis in ovarian cancer.

https://ift.tt/2pBH9Ps

Characterization and Comparative Analysis of the Complete Chloroplast Genome of the Critically Endangered Species Streptocarpus teitensis (Gesneriaceae)

Streptocarpus teitensis (Gesneriaceae) is an endemic species listed as critically endangered in the International Union for Conservation of Nature (IUCN) red list of threatened species. However, the sequence and genome information of this species remains to be limited. In this article, we present the complete chloroplast genome structure of Streptocarpus teitensis and its evolution inferred through comparative studies with other related species. S. teitensis displayed a chloroplast genome size of 153,207 bp, sheltering a pair of inverted repeats (IR) of 25,402 bp each split by small and large single-copy (SSC and LSC) regions of 18,300 and 84,103 bp, respectively. The chloroplast genome was observed to contain 116 unique genes, of which 80 are protein-coding, 32 are transfer RNAs, and four are ribosomal RNAs. In addition, a total of 196 SSR markers were detected in the chloroplast genome of Streptocarpus teitensis with mononucleotides (57.1%) being the majority, followed by trinucleotides (33.2%) and dinucleotides and tetranucleotides (both 4.1%), and pentanucleotides being the least (1.5%). Genome alignment indicated that this genome was comparable to other sequenced members of order Lamiales. The phylogenetic analysis suggested that Streptocarpus teitensis is closely related to Lysionotus pauciflorus and Dorcoceras hygrometricum.

https://ift.tt/2ujidkw

PARP1-Targeted Radiotherapy in Mouse Models of Glioblastoma.

PARP1-Targeted Radiotherapy in Mouse Models of Glioblastoma.

J Nucl Med. 2018 Mar 23;:

Authors: Jannetti SA, Carlucci G, Carney B, Kossatz S, Shenker L, Carter LM, Salinas B, Brand C, Sadique A, Donabedian PL, Cunanan KM, Gönen M, Ponomarev V, Zeglis BM, Souweidane MM, Lewis JS, Weber WA, Humm JL, Reiner T

Abstract
The DNA repair enzyme PARP1 is over-expressed in glioblastoma, with overall low expression in healthy brain tissue. Paired with the availability of specific molecularly targeted small molecules for this biomarker, PARP1 is a near-ideal target for novel radiotherapeutics. A successful PARP1-targeted radiotherapeutic would induce DNA damage and apoptosis in cancer cells, while sparing healthy brain tissue. We synthesized a 131I-labeled poly(ADP-ribose) polymerase 1 (PARP1) therapeutic and investigated its pharmacology using in vitro and in vivo methodologies. A subcutaneous mouse model was used to quantify retention times and therapeutic efficacy. A potential clinical scenario, intratumoral convection-enhanced delivery (CED), was mimicked using an orthotopic glioblastoma model combined with an implanted osmotic pump system to study local administration of [131I]PARPi. [131I]PARPi is a 1(2H)-phthalazinone, similar in structure to the FDA-approved PARP inhibitor Olaparib (Lynparza, Astra-Zeneca). In vitro studies have shown that [131I]PARPi and Olaparib share similar pharmacologic profiles. [131I]PARPi delivers 134.1 cGy/MBq intratumoral injected activity; doses to non-target tissues, including liver and kidney, were significantly lower. Radiation damage and cell death could be shown by p53 activation via bioluminescence imaging in U87 MG cells transfected with a p53-bioluminescent reporter in treated tumors. Treated mice had significantly longer survival than mice receiving only vehicle (29 vs. 22 days, P < 0.005) in a subcutaneous model. CED demonstrated efficient retention of [131I]PARPi in orthotopic brain tumors, while quickly clearing from healthy brain tissue. We validated the novel PARP1-targeted radiotherapeutic [131I]PARPi, studying its performance in mouse models. Our results demonstrate [131I]PARPi's high potential as a therapeutic, and highlight PARP's relevance as a target for radionuclide therapy. Radiation plays an integral role in brain tumor therapy, and radiolabeled PARP therapeutics could ultimately lead to improvements in the standard of care.

PMID: 29572254 [PubMed - as supplied by publisher]

https://ift.tt/2IMFMpb

Chlamydia pneumoniae Infection Exacerbates Atherosclerosis in ApoB100only/LDLR−/− Mouse Strain

Aims. Hyperlipidaemia model animals have been used to elucidate the role of Chlamydia pneumoniae (Cpn) infection in atherosclerosis. The aims of this study were to investigate the proatherogenic effect of multiple Cpn infections in ApoB100only/LDLR−/− mice which based on lipid profile can be regarded as the most suitable mouse model of human hypercholesterolemia and to compare the lesion development to that in a major atherosclerosis model ApoE−/− mice. Methods and Results. Aorta samples of ApoB100only/LDLR−/− mice infected three times with Cpn were subjected to morphometric analyses. Morphometric evaluation disclosed that Cpn infections exacerbated atherosclerosis development in the aortic root and descending aorta of the mice fed with normal diet. Viable Cpn was detected in the ascending aorta by RT-PCR. Chlamydial 16SrRNA expression showed the presence of viable Cpn in the aorta of infected animals. A similar rate of acceleration of atherosclerosis was observed when the infection protocol was applied in ApoB100only/LDLR−/− and in ApoE−/− mice. Conclusion. Similar to ApoE−/− mice, ApoB100only/LDLR−/− mice with more human-relevant serum lipoprotein composition develop increased atherosclerosis after Cpn infections; thus this mouse strain can be used as a model of infection-related atherosclerosis enhancement and can provide further evidence for the proatherogenic influence of Cpn in mice.

https://ift.tt/2G9UzZ6

The Prediction of Drug-Disease Correlation Based on Gene Expression Data

The explosive growth of high-throughput experimental methods and resulting data yields both opportunity and challenge for selecting the correct drug to treat both a specific patient and their individual disease. Ideally, it would be useful and efficient if computational approaches could be applied to help achieve optimal drug-patient-disease matching but current efforts have met with limited success. Current approaches have primarily utilized the measureable effect of a specific drug on target tissue or cell lines to identify the potential biological effect of such treatment. While these efforts have met with some level of success, there exists much opportunity for improvement. This specifically follows the observation that, for many diseases in light of actual patient response, there is increasing need for treatment with combinations of drugs rather than single drug therapies. Only a few previous studies have yielded computational approaches for predicting the synergy of drug combinations by analyzing high-throughput molecular datasets. However, these computational approaches focused on the characteristics of the drug itself, without fully accounting for disease factors. Here, we propose an algorithm to specifically predict synergistic effects of drug combinations on various diseases, by integrating the data characteristics of disease-related gene expression profiles with drug-treated gene expression profiles. We have demonstrated utility through its application to transcriptome data, including microarray and RNASeq data, and the drug-disease prediction results were validated using existing publications and drug databases. It is also applicable to other quantitative profiling data such as proteomics data. We also provide an interactive web interface to allow our Prediction of Drug-Disease method to be readily applied to user data. While our studies represent a preliminary exploration of this critical problem, we believe that the algorithm can provide the basis for further refinement towards addressing a large clinical need.

https://ift.tt/2G1sdEB

Anticancer Properties of Essential Oils and Other Natural Products

Essential oils are secondary metabolites with a key-role in plants protection, consisting primarily of terpenes with a volatile nature and a diverse array of chemical structures. Essential oils exhibit a wide range of bioactivities, especially antimicrobial activity, and have long been utilized for treating various human ailments and diseases. Cancer cell prevention and cytotoxicity are exhibited through a wide range of mechanisms of action, with more recent research focusing on synergistic and antagonistic activity between specific essential oils major and minor components. Essential oils have been shown to possess cancer cell targeting activity and are able to increase the efficacy of commonly used chemotherapy drugs including paclitaxel and docetaxel, having also shown proimmune functions when administered to the cancer patient. The present review represents a state-of-the-art review of the research behind the application of EOs as anticancer agents both in vitro and in vivo. Cancer cell target specificity and the use of EOs in combination with conventional chemotherapeutic strategies are also explored.

https://ift.tt/2G5tpqo

In Vitro Cytotoxicity and In Vivo Antimammary Tumor Effects of the Hydroethanolic Extract of Acacia seyal (Mimosaceae) Stem Bark

The present study was designed to evaluate the in vitro and in vivo antitumor effects of A. seyal hydroethanolic extract on breast cancer. The cytotoxicity of A. seyal extract was evaluated using resazurin reduction assay in 9 cell lines. Further, the protective effect of the hydroethanolic extract of A. seyal stem barks was evaluated on 7,12-dimethylbenz(a)anthracene- (DMBA-) induced breast cancer rat model. Incidence, burden, volume, and histological analysis of mammary tumors were measured. The Acacia seyal extract exhibited CC50 of 100 in MCF-7 cells after 24 h. In vivo, no tumors were detected in rats from the control group, while 11 rats out of 12 (91.66%) developed mammary tumors in the DMBA-exposed group receiving only the vehicle. Acacia seyal extract significantly () and in the dose-dependent manner reduced tumor incidence (3 rats out of 12 at the dose of 300 mg/kg), burden [62.1% (150 mg/kg) and 65.8% (300 mg/kg)], and mass. It protected rats against DMBA-induced breast hyperplasia, with an optimal effect at the dose of 300 mg/kg. Taken altogether, these results suggest that the hydroethanolic extract of Acacia seyal might contain phytoconstituents endowed with antitumoral properties, which could protect against the breast cancer induced in rats.

https://ift.tt/2pDJ9a3

Incidence and Extent of Graft Extrusion following Meniscus Allograft Transplantation

Background. The incidence and extent of graft extrusion after meniscus allograft transplantation (MAT) may differ in patients undergoing medial and lateral meniscus transplantation due to the use of different surgical techniques. This meta-analysis was therefore designed to quantify the extent and incidence of graft extrusion after meniscus allograft transplantation. Methods. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, all studies reporting absolute extrusion, relative percentage of extrusion (RPE), or frequency of major extrusions (>3 mm) on magnetic resonance imaging in patients undergoing medial or lateral MAT were included. Results. The pooled mean absolute extrusion following all MATs was 3.15 mm but was significantly greater following medial than lateral MAT (3.26 versus 3.01 mm; ). The pooled mean RPE following all MATs was 32.79% and was significantly greater after medial than lateral MAT (32.69% versus 28.81%; ). The pooled mean proportion of knees with major (>3 mm) extrusion was 53% (95% CI: 49% to 58%) and was significantly greater after medial than lateral MAT (61% versus 39%; ). Conclusion. Mean graft extrusion after arthroscopic assisted MAT using bony fixation was 3.2 mm, with major graft extrusion > 3 mm occurring in about 50% of transplanted menisci. Graft extrusion was significantly greater after medial than lateral MAT.

https://ift.tt/2ufeOTT

Cytomorphometric analysis of exfoliated cells in patients with oral lichen planus

Abstract

Lichen planus is a mucocutaneous chronic inflammatory lesion with a potential for malignant transformation. Exfoliative cytology is a cheaper and less aggressive method for early diagnosis. The study was conducted to evaluate cytomorphometric changes of exfoliated cells of oral lichen planus lesions. This case-control study was accomplished on 33 patients with oral lichen planus and 50 patients who did not have any lesions as the control group. Buccal mucosa cells which were provided by five to ten reciprocating motion of hard toothbrush with constant tolerable pressure were spread on a slide; then, the samples were fixed within an hour and stained with papanicolau method. The cytomorphometric parameters including the diameter of the nucleus (ND), the diameter of cytoplasm (CD), and nuclear-cytoplasmic diameter ratio of each cell were measured. Our findings showed a significant increase in nuclear diameter of case group cells and a significant decrease in cytoplasmic diameter of the same group; so, the N/C ratio in this group was clearly higher than the control group. Oral mucosa brush biopsy can be an inexpensive, sensitive, simple, and safe method of screening the dysplastic and malignant changes. It serves as an adjuvant method which is precise, objective, and repeatable.

https://ift.tt/2DT6jgJ

Mitochondrial T16189C Polymorphism Is Associated with Metabolic Syndrome in the Mexican Population

Genetic factors, such as the mitochondrial DNA (mtDNA) T16189C polymorphism, have been associated with metabolic syndrome (MetS), but this association has not been studied in Mexico to date. The aim of the present study was to determine whether this polymorphism contributes to MetS in the Mexican population. We recruited 100 unrelated volunteer subjects who were divided into 2 groups: with MetS (MetS group) and without MetS (control group). All subjects were genotyped for the mtDNA T16189C polymorphism by polymerase chain reaction and sequencing. The mitochondrial T16189C polymorphism was detected in 24 (24%) of 100 subjects analyzed. The frequency of the mtDNA T16189C polymorphism was higher in the MetS group with 21 (32.3%) of 65 testing positive compared to 3 (8.5%) of 35 in the control group, indicating that this polymorphism is a probable risk factor for MetS in the Mexican population (odds ratio 5.0909, 95% CI 1.3977–18.5424, ). Our results may contribute to early diagnosis of MetS, which is essential for establishing changes in early stages of the disease to avoid further complications and pathologies, thereby preventing the development of type 2 diabetes and cardiovascular disease in Mexico.

https://ift.tt/2pB5lAG

Object Discernment by “A Difference Which Makes a Difference”

Abstract

Gregory Bateson is well known for defining information by stating "In fact what we mean by information – the elementary unit of information – is a difference which makes a difference…" This conceptual perspective has the merit of simplicity and generality. Simplicity, in addressing the complexity of information. Generality, in seeking applicability to any and every field of human experience. The purpose of this paper is to focus the applicability of this conceptual approach by Bateson and use it to perform a calculation of taking the difference between two grey-level digital images that are shifted one relative to the other. The digital images take the place of the field of view that a human being would have access through her sense of vision at two different spatial/temporal instances. The results show that it is possible to highlight the edges of the objects under scrutiny, as well as to highlight other differences within the object. Bateson's "difference that makes a difference" would seem to provide a first step in the elusive meaning making process of humans.

https://ift.tt/2I33IUb