Decoupling between sulfate reduction and the anaerobic oxidation of methane in the shallow methane seep of the Black sea

ABSTRACT

Methane seepages are widespread in the Black Sea. However, microbiological research has been carried out only at the continental shelf seeps. The present work dealt with coastal gas seepages of the Kalamit Bay (Black Sea). High-throughput 16S rRNA gene sequencing and radiotracer analysis (¹⁴С and ³⁵S) were used to determine the composition of the microbial community and the rates of microbial sulfate reduction and methane oxidation. The phylum Proteobacteria, represented mainly by sulfate reducers of the class Deltaproteobacteria, was the predominant in sequence dataset. Bacteroidetes and Planctomycetes were other numerous phyla. Among archaea, the phylum Woesearchaeota and Marine Benthic Group B were predominant in the upper horizons. Relative abundance of Euryarchaeota of the families Methanomicrobiaceae and Methanosarcinaceae (including ANME-3 archaea) increased in deeper sediment layers. Sulfate reduction rate (up to 2.9 mmol/L × day) was considerably higher than the rate of anaerobic methane oxidation (up to 43.4 μmol/L × day), which indicated insignificant contribution of anaerobic methane oxidation to the total sulfide production.

https://ift.tt/2AcQ0gb

Volatile phenols are produced by strains of Dekkera bruxellensis under Brazilian fuel ethanol industry-like conditions

ABSTRACT

Dekkera bruxellensis is a spoilage yeast in wine and fuel ethanol fermentations able to produce volatile phenols from hydroxycinnamic acids by the action of the enzymes cinnamate decarboxylase (CD) and vinyphenol reductase (VR) in wine. However, there is no information about this ability in the bioethanol industry. This work evaluated CD and VR activities and 4-ethylphenol production from p-coumaric acid by three strains of D. bruxellensis and PE-2, an industrial Saccharomyces cerevisiae strain. Single and multiple-cycle batch fermentations in molasses and sugarcane juice were carried out. Dekkera bruxellensis strains showed similar CD activity but differences in VR activity. No production of 4-ethylphenol by S. cerevisiae in any fermentation system or media was observed. The concentrations of 4-ethylphenol peaked during active growth of D. bruxellensis in single-cycle fermentation but they were lower than in multiple-cycle fermentation. Higher concentrations were observed in molasses with molar conversion (p-coumaric acid to 4-ethylphenol) ranging from 45% to 85%. As the first report on 4-ethylphenol production in sugarcane musts by D. bruxellensis in industry-like conditions, it opens up a new avenue to investigate its effect on the viability and fermentative capacity of S. cerevisiae as well as to understand the interaction between the yeasts in the bioethanol industry.

https://ift.tt/2QTuNgD

Cancers, Vol. 10, Pages 385: SPARC Inhibits Metabolic Plasticity in Ovarian Cancer

Cancers, Vol. 10, Pages 385: SPARC Inhibits Metabolic Plasticity in Ovarian Cancer

Cancers doi: 10.3390/cancers10100385

Authors: Christine Naczki Bincy John Chirayu Patel Ashlyn Lafferty Alia Ghoneum Hesham Afify Michael White Amanda Davis Guangxu Jin Steven Kridel Neveen Said

The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy.

https://ift.tt/2CLLEir

PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β–catenin axis

PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β–catenin axis

PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β–catenin axis, Published online: 15 October 2018; doi:10.1038/s41419-018-1082-z

PHF19 promotes the proliferation, migration, and chemosensitivity of glioblastoma to doxorubicin through modulation of the SIAH1/β–catenin axis

https://ift.tt/2pUyNlH

C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event

C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event

C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event, Published online: 15 October 2018; doi:10.1038/s41419-018-1103-y

C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event

https://ift.tt/2NJj3vk

Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells

Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells

Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells, Published online: 15 October 2018; doi:10.1038/s41419-018-1083-y

Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells

https://ift.tt/2pUyLKB

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription, Published online: 15 October 2018; doi:10.1038/s41419-018-1108-6

PARP1 promote autophagy in cardiomyocytes via modulating FoxO3a transcription

https://ift.tt/2NJbQLZ

The thiosemicarbazone Me2NNMe2 induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

The thiosemicarbazone Me₂NNMe₂ induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

The thiosemicarbazone Me₂NNMe₂ induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition, Published online: 15 October 2018; doi:10.1038/s41419-018-1102-z

The thiosemicarbazone Me₂NNMe₂ induces paraptosis by disrupting the ER thiol redox homeostasis based on protein disulfide isomerase inhibition

https://ift.tt/2pWg4pQ

Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: key role of ATM in the differential radiation response

Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: key role of ATM in the differential radiation response

Sensitivity of CD3/CD28-stimulated <i>versus</i> non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: key role of ATM in the differential radiation response, Published online: 15 October 2018; doi:10.1038/s41419-018-1095-7

Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: key role of ATM in the differential radiation response

https://ift.tt/2NH3cNP

Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells

Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells

Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells, Published online: 15 October 2018; doi:10.1038/s41419-018-1006-y

Novel dihydroartemisinin derivative DHA-37 induces autophagic cell death through upregulation of HMGB1 in A549 cells

https://ift.tt/2pUyCXz

Validation of a prediction model for long-term outcome of aphasia after stroke

About 30% of stroke patients suffer from aphasia. As aphasia strongly affects daily life, most patients request a prediction of outcome of their language function. Prognostic models provide predictions of outc...

https://ift.tt/2pUyzel

How do specialist trainee doctors acquire skills to practice patient-centred care? A qualitative exploration

Objectives

The importance of patient-centred care (PCC) has been increasingly recognised. However, there is limited work exploring what doctors actually understand by PCC, and how they perceive they acquire PCC skills in the workplace. The objectives of our study were to explore (1) what UK doctors, in specialist training, perceive to be the essential components of PCC, (2) if/how they acquire these skills, (3) any facilitators/barriers for engaging in PCC and (4) views on their PCC training.

Design

Qualitative study using in-depth individual semi-structured interviews with UK specialist trainees. Interview transcripts were thematically analysed.

Setting and participants

Thirty-one specialist trainee doctors, with at least 4 years postgraduate experience, were interviewed. Participants worked in various medical specialities within the Medical Directorate of an acute hospital in the East Midlands of England.

Results

Interview data were transcribed verbatim and categorised into three main themes. The first theme was 'Understanding PCC' where the doctors gave varied perspectives on what they understood by PCC. Although many were able to highlight key components of PCC, there were also some accounts which demonstrated a lack of understanding. The second theme was 'Learning PCC skills: A work in progress'. Learning to be patient-centred was perceived to be an ongoing process. Within this, trainee doctors reported 'on-the-job' learning as the main means of acquiring PCC skills, but they also saw a place for formal training (eg, educational sessions focussing on PCC, role play). 'Delivering PCC: Beyond the physician' referred to the many influences the doctors reported in learning and delivering PCC including patients, the organisation and colleagues. Observing consultants taking a patient-centred approach was cited as an important learning tool.

Conclusions

Our findings may assist clinical educators in understanding how trainee doctors perceive PCC, and the factors that influence their learning, thereby helping them shape PCC skills training.

https://ift.tt/2IYkIMV

Proficiency-based progression training: an 'end to end model for decreasing error applied to achievement of effective epidural analgesia during labour: a randomised control study

Background

Training procedural skills using proficiency-based progression (PBP) methodology has consistently resulted in error reduction. We hypothesised that implementation of metric-based PBP training and a valid assessment tool would decrease the failure rate of epidural analgesia during labour when compared to standard simulation-based training.

Methods

Detailed, procedure-specific metrics for labour epidural catheter placement were developed based on carefully elicited expert input. Proficiency was defined using criteria derived from clinical performance of experienced practitioners. A PBP curriculum was developed to train medical personnel on these specific metrics and to eliminate errors in a simulation environment.

Seventeen novice anaesthetic trainees were randomly allocated to undergo PBP training (Group P) or simulation only training (Group S). Following training, data from the first 10 labour epidurals performed by each participant were recorded. The primary outcome measure was epidural failure rate.

Results

A total of 74 metrics were developed and validated. The inter-rater reliability (IRR) of the derived assessment tool was 0.88. Of 17 trainees recruited, eight were randomly allocated to group S and six to group P (three trainees did not complete the study). Data from 140 clinical procedures were collected. The incidence of epidural failure was reduced by 54% with PBP training (28.7% in Group S vs 13.3% in Group P, absolute risk reduction 15.4% with 95% CI 2% to 28.8%, p=0.04).

Conclusion

Procedure-specific metrics developed for labour epidural catheter placement discriminated the performance of experts and novices with an IRR of 0.88. Proficiency-based progression training resulted in a lower incidence of epidural failure compared to simulation only training.

Trial registration number

NCT02179879. NCT02185079; Post-results.

https://ift.tt/2OsqUTq

Scoping review of systematic reviews of complementary medicine for musculoskeletal and mental health conditions

Objective

To identify potentially effective complementary approaches for musculoskeletal (MSK)–mental health (MH) comorbidity, by synthesising evidence on effectiveness, cost-effectiveness and safety from systematic reviews (SRs).

Design

Scoping review of SRs.

Methods

We searched literature databases, registries and reference lists, and contacted key authors and professional organisations to identify SRs of randomised controlled trials for complementary medicine for MSK or MH. Inclusion criteria were: published after 2004, studying adults, in English and scoring >50% on Assessing the Methodological Quality of Systematic Reviews (AMSTAR); quality appraisal checklist). SRs were synthesised to identify research priorities, based on moderate/good quality evidence, sample size and indication of cost-effectiveness and safety.

Results

We included 84 MSK SRs and 27 MH SRs. Only one focused on MSK–MH comorbidity. Meditative approaches and yoga may improve MH outcomes in MSK populations. Yoga and tai chi had moderate/good evidence for MSK and MH conditions. SRs reported moderate/good quality evidence (any comparator) in a moderate/large population for: low back pain (LBP) (yoga, acupuncture, spinal manipulation/mobilisation, osteopathy), osteoarthritis (OA) (acupuncture, tai chi), neck pain (acupuncture, manipulation/manual therapy), myofascial trigger point pain (acupuncture), depression (mindfulness-based stress reduction (MBSR), meditation, tai chi, relaxation), anxiety (meditation/MBSR, moving meditation, yoga), sleep disorders (meditative/mind–body movement) and stress/distress (mindfulness). The majority of these complementary approaches had some evidence of safety—only three had evidence of harm. There was some evidence of cost-effectiveness for spinal manipulation/mobilisation and acupuncture for LBP, and manual therapy/manipulation for neck pain, but few SRs reviewed cost-effectiveness and many found no data.

Conclusions

Only one SR studied MSK–MH comorbidity. Research priorities for complementary medicine for both MSK and MH (LBP, OA, depression, anxiety and sleep problems) are yoga, mindfulness and tai chi. Despite the large number of SRs and the prevalence of comorbidity, more high-quality, large randomised controlled trials in comorbid populations are needed.

https://ift.tt/2Otaryf

Obstructive sleep apnoea and the risk for coronary heart disease and type 2 diabetes: a longitudinal population-based study in Finland

Objective

To evaluate if obstructive sleep apnoea (OSA) modifies the risk of coronary heart disease, type 2 diabetes (T2D) and diabetic complications in a gender-specific fashion.

Design and setting

A longitudinal population-based study with up to 25-year follow-up data on 36 963 individuals (>500 000 person years) from three population-based cohorts: the FINRISK study, the Health 2000 Cohort Study and the Botnia Study.

Main outcome measures

Incident coronary heart disease, diabetic kidney disease, T2D and all-cause mortality from the Finnish National Hospital Discharge Register and the Finnish National Causes-of-Death Register.

Results

After adjustments for age, sex, region, high-density lipoprotein (HDL) and total cholesterol, current cigarette smoking, body mass index, hypertension, T2D baseline and family history of stroke or myocardial infarction, OSA increased the risk for coronary heart disease (HR=1.36, p=0.0014, 95% CI 1.12 to 1.64), particularly in women (HR=2.01, 95% CI 1.31 to 3.07, p=0.0012). T2D clustered with OSA independently of obesity (HR=1.48, 95% CI 1.26 to 1.73, p=9.11x10–7). The risk of diabetic kidney disease increased 1.75-fold in patients with OSA (95% CI 1.13 to 2.71, p=0.013). OSA increased the risk for coronary heart disease similarly among patients with T2D and in general population (HR=1.36). All-cause mortality was increased by OSA in diabetic individuals (HR=1.35, 95% CI 1.06 to 1.71, p=0.016).

Conclusion

OSA is an independent risk factor for coronary heart disease, T2D and diabetic kidney disease. This effect is more pronounced even in women, who until now have received less attention in diagnosis and treatment of OSA than men.

https://ift.tt/2IZcfsW

Protocol for the STRONG trial: stereotactic body radiation therapy following chemotherapy for unresectable perihilar cholangiocarcinoma, a phase I feasibility study

Introduction

For patients with perihilar cholangiocarcinoma (CCA), surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients, the tumours are found to be unresectable at presentation due to either local invasive tumour growth or the presence of distant metastases. For patients with unresectable CCA, palliative chemotherapy is the standard treatment yielding an estimated median overall survival (OS) of 12–15.2 months. There is no evidence from randomised trials to support the use of stereotactic body radiation therapy (SBRT) for CCA. However, small and most often retrospective studies combining chemotherapy with SBRT have shown promising results with OS reaching up to 33–35 months.

Methods and analysis

This study has been designed as a single-centre phase I feasibility trial and will investigate the addition of SBRT after standard chemotherapy in patients with unresectable perihilar CCA (T1-4 N0-1 M0). A total of six patients will be included. SBRT will be delivered in 15 fractions of 3–4.5 Gy (risk adapted). The primary objective of this study is to determine feasibility and toxicity. Secondary outcomes include local tumour control, progression-free survival (PFS), OS and quality of life. Length of follow-up will be 2 years. As an ancillary study, the personalised effects of radiotherapy will be measured in vitro, in patient-derived tumour and bile duct organoid cultures.

Ethics and dissemination

Ethics approval for the STRONG trial has been granted by the Medical Ethics Committee of Erasmus MC Rotterdam, the Netherlands. It is estimated that all patients will be included between October 2017 and October 2018. The results of this study will be published in a peer-reviewed journal, and presented at national and international conferences.

Trial registration number

NCT03307538; Pre-results.

https://ift.tt/2OrUzvS

Factors influencing rapid progress in child health in post-conflict Liberia: a mixed methods country case study on progress in child survival, 2000-2013

Objectives

Only 12 countries in the WHO's African region met Millennium Development Goal 4 (MDG 4) to reduce under-five mortality by two-thirds by 2015. Given the variability across the African region, a four-country mixed methods study was undertaken to examine barriers and facilitators of child survival prior to 2015. Liberia was selected for an in-depth case study due to its success in reducing under-five mortality by 73% and thus successfully meeting MDG 4. Liberia's success was particularly notable given the civil war that ended in 2003. We examined some factors contributing to their reductions in under-five mortality.

Design

A case study mixed methods approach drawing on data from quantitative indicators, national documents and qualitative interviews was used to describe factors that enabled Liberia to rebuild their maternal, neonatal and child health (MNCH) programmes and reduce under-five mortality following the country's civil war.

Setting

The interviews were conducted in Monrovia (Montserrado County) and the areas in and around Gbarnga, Liberia (Bong County, North Central region).

Participants

Key informant interviews were conducted with Ministry of Health officials, donor organisations, community-based organisations involved in MNCH and healthcare workers. Focus group discussions were conducted with women who have experience accessing MNCH services.

Results

Three prominent factors contributed to the reduction in under-five mortality: national prioritisation of MNCH after the civil war; implementation of integrated packages of services that expanded access to key interventions and promoted intersectoral collaborations; and use of outreach campaigns, community health workers and trained traditional midwives to expand access to care and improve referrals.

Conclusions

Although Liberia experiences continued challenges related to limited resources, Liberia's effective strategies and rapid progress may provide insights for reducing under-five mortality in other post-conflict settings.

https://ift.tt/2IYhVmZ

Diagnostic, preventive and therapeutic evidence in obstetrics for the implementation of patient blood management: a systematic review protocol

Introduction

Patientblood management (PBM) is defined as the application of evidence-based diagnostic, preventive and therapeutic approaches designed to maintain haemoglobin concentration, optimise haemostasis and minimise blood loss in an effort to improve patient outcome. We propose a protocol for the assessment of the evidence of diagnostic, preventive and therapeutic approaches for the management of relevant outcomes in obstetrics with the aim to create a framework for PBM implementation.

Methods and analysis

Diagnostic, preventive and therapeutic tools will be considered in the gynaecological conditions and obstetrics setting (antenatal care, peripartum care and maternity care). For each condition, (1) clinical questions based on prioritised outcomes will be developed; (2) evidence will be retrieved systematically from electronic medical literature (MEDLINE, EMBASE, the Cochrane Library, Web of Science, and CINAHL); (3) quality of the reviews will be assessed using the AMSTAR (A Measurement Tool to Assess Systematic Reviews) checklist; quality of primary intervention studies will be assessed using the risk of bias tool (Cochrane method); quality of diagnostic primary studies will be assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies); (4) the Grading of Recommendations Assessment, Development and Evaluation method will be applied to rate the quality of the evidence and to develop recommendations.

Ethics and dissemination

For each diagnostic, preventive or therapeutic intervention evaluated, a manuscript comprising the evidence retrieved and the recommendation produced will be provided and published in peer-reviewed journals. Ethical approval is not required.

https://ift.tt/2OsjcIZ

Cost-effectiveness of exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: protocol for an economic evaluation alongside the SITLESS three-armed pragmatic randomised controlled trial

Introduction

Promoting physical activity (PA) and reducing sedentary behaviour (SB) may exert beneficial effects on the older adult population, improving behavioural, functional, health and psychosocial outcomes in addition to reducing health, social care and personal costs. This paper describes the planned economic evaluation of SITLESS, a multicountry three-armed pragmatic randomised controlled trial (RCT) which aims to assess the short-term and long-term effectiveness and cost-effectiveness of a complex intervention on SB and PA in community-dwelling older adults, based on exercise referral schemes enhanced by a group intervention providing self-management strategies to encourage lifestyle change.

Methods and analysis

A within-trial economic evaluation and long-term model from both a National Health Service/personal social services perspective and a broader societal perspective will be undertaken alongside the SITLESS multinational RCT. Healthcare costs (hospitalisations, accident and emergency visits, appointment with health professionals) and social care costs (eg, community care) will be included in the economic evaluation. For the cost-utility analysis, quality-adjusted life-years will be measured using the EQ-5D-5L and capability well-being measured using the ICEpop CAPability measure for Older people (ICECAP-O) questionnaire. Other effectiveness outcomes (health related, behavioural, functional) will be incorporated into a cost-effectiveness analysis and cost-consequence analysis.

The multinational nature of this RCT implies a hierarchical structure of the data and unobserved heterogeneity between clusters that needs to be adequately modelled with appropriate statistical and econometric techniques. In addition, a long-term population health economic model will be developed and will synthesise and extrapolate within-trial data with additional data extracted from the literature linking PA and SB outcomes with longer term health states.

Methods guidance for population health economic evaluation will be adopted including the use of a long-time horizon, 1.5% discount rate for costs and benefits, cost consequence analysis framework and a multisector perspective.

Ethics and dissemination

The study design was approved by the ethics and research committee of each intervention site: the Ethics and Research Committee of Ramon Llull University (reference number: 1314001P) (Fundació Blanquerna, Spain), the Regional Committees on Health Research Ethics for Southern Denmark (reference number: S-20150186) (University of Southern Denmark, Denmark), Office for Research Ethics Committees in Northern Ireland (ORECNI reference number: 16/NI/0185) (Queen's University of Belfast) and the Ethical Review Board of Ulm University (reference number: 354/15) (Ulm, Germany). Participation is voluntary and all participants will be asked to sign informed consent before the start of the study.

This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 634 270. This article reflects only the authors' view and the Commission is not responsible for any use that may be made of the information it contains.

The findings of the study will be disseminated to different target groups (academia, policymakers, end users) through different means following the national ethical guidelines and the dissemination regulation of the Horizon 2020 funding agency.

Use of the EuroQol was registered with the EuroQol Group in 2016.

Use of the ICECAP-O was registered with the University of Birmingham in March 2017.

Trial registration number

NCT02629666; Pre-results.

https://ift.tt/2IZceFo

Ten-year risk prediction models of complications and mortality of Chinese patients with diabetes mellitus in primary care in Hong Kong: a study protocol

Introduction

Diabetes mellitus (DM) is a major disease burden worldwide because it is associated with disabling and lethal complications. DM complication risk assessment and stratification is key to cost-effective management and tertiary prevention for patients with diabetes in primary care. Existing risk prediction functions were found to be inaccurate in Chinese patients with diabetes in primary care. This study aims to develop 10-year risk prediction models for total cardiovascular diseases (CVD) and all-cause mortality among Chinese patients with DM in primary care.

Methods and analysis

A 10-year cohort study on a population-based primary care cohort of Chinese patients with diabetes, who were receiving care in the Hospital Authority General Outpatient Clinic on or before 1 January 2008, were identified from the clinical management system database of the Hospital Authority. All patients with complete baseline risk factors will be included and followed from 1 January 2008 to 31 December 2017 for the development and validation of prediction models. The analyses will be carried out separately for men and women. Two-thirds of subjects will be randomly selected as the training sample for model development. Cox regressions will be used to develop 10-year risk prediction models of total CVD and all-cause mortality. The validity of models will be tested on the remaining one-third of subjects by Harrell's C-statistics and calibration plot. Risk prediction models for diabetic complications specific to Chinese patients in primary care will enable accurate risk stratification, prioritisation of resources and more cost-effective interventions for patients with DM in primary care.

Ethics and dissemination

The study was approved by the Institutional Review Board of the University of Hong Kong—the Hospital Authority Hong Kong West Cluster (reference number: UW 15–258).

Trial registration number

NCT03299010; Pre-results.

https://ift.tt/2OuKHBC

Prevalence and risk factors of physical inactivity among middle-aged and older Chinese in Shenzhen: a cross-sectional study

Objective

Investigations on physical inactivity are common around the world; however, little is known about the status of physical inactivity in mainland China. The aim of this study was to examine the prevalence and risk factors associated with physical inactivity in Shenzhen in Southern China.

Design

A community-based, cross-sectional study.

Setting

A multistage-stratified, random cluster survey was conducted in Xixiang Street, Bao'an District of Shenzhen in Southeast China.

Participants

3920 adults aged 40 years or more were recruited to the study and completed the International Physical Activity Questionnaire Short Form between 1 March 2015 and 30 July 2016.

Main outcome measures

Physical inactivity was defined as engaging in physical activity levels insufficient to reach the current guidelines. Bivariate and multivariate analyses were undertaken to assess the prevalence and risk factors associated with physical inactivity.

Results

The prevalence of physical inactivity was 63.1% for all participants, 63.9% for women and 61.9% for men, respectively. Participants who were older (OR=1.31, 95% CI 1.11 to 1.54), who were female (OR=1.22, 95% CI 1.04 to 1.43), who had higher education experience (OR=1.38, 95% CI 1.19 to 1.61), who are under economic pressure (OR=2.17, 95% CI 1.48 to 3.17), who ever smoked a cigarette (OR=1.44, 95% CI 1.13 to 1.82) and drank alcohol (OR=1.42, 95% CI 1.14 to 1.77), and participants in the lowest body mass index category (OR=1.40, 95% CI 1.03 to 1.89), were more likely to report physical inactivity.

Conclusions

These findings indicate that physical inactivity is prevalent in Southern China. Interventions and programmes aimed at increasing physical activity among middle-aged and older Chinese adults may also be tailored to participants under economic pressure and those with unhealthy behaviours such as smoking and drinking.

https://ift.tt/2J4BpXb

Protocol for a multicentre, dual prospective and retrospective cohort study investigating timing of ileostomy closure after anterior resection for rectal cancer: The CLOSurE of Ileostomy Timing (CLOSE-IT) study

Introduction

A defunctioning ileostomy is often formed during rectal cancer surgery to reduce the potentially fatal sequelae of anastomotic leak. Once the ileostomy is closed and bowel continuity restored, many patients can suffer poor bowel function, that is, low anterior resection syndrome (LARS). It has been suggested that delay to closure can increase incidence of LARS which is known to significantly reduce quality of life. Despite this, within the UK, time to closure of ileostomy is not subject to national targets within the National Health Service and delay to closure exceeds 18 months in one-third of patients. Clinical factors, surgeon and patient preference or service pressures may all impact time to closure, yet to date no study has investigated this. The aim of this UK-wide study is to assess time to ileostomy closure and identify reasons for delays.

Methods and analysis

A UK-wide multicentre prospective snapshot study, together with retrospective analysis of ileostomy closure through The Dukes' Club Research Collaborative including patients undergoing ileostomy closure in a 3-month period (April to June 2018) and all patients who underwent anterior resection and ileostomy formation over a historical 12-month period (2015). Time to closure and incidence of 'non-closure' will be calculated. Units will be surveyed to determine local clinical and management protocols and barriers to timely closure. Multivariate linear regression analysis will be used to determine factors significantly associated with delay to ileostomy closure.

Ethics and dissemination

Study approved by the South West-Exeter Research Ethics Committee and the Health Research Authority. Study results will be submitted for presentation at international conferences and for publication in peer-reviewed journals. Results will be presented to and discussed with the patient and public representatives and relevant national bodies to facilitate the development of consensus guidelines on optimum treatment pathways.

https://ift.tt/2Oqx5qR

Effects of the Namaste Care Family programme on quality of life of nursing home residents with advanced dementia and on family caregiving experiences: study protocol of a cluster-randomised controlled trial

Introduction

Quality of life of people with advanced dementia living in nursing homes is often suboptimal. Family caregivers can feel frustrated with limited contact with their relatives, which results in visits that are perceived as stressful and not very meaningful. Few psychosocial interventions are specifically developed for people with advanced dementia, and actively involve family caregivers or volunteers. Also, interventions usually stop when it becomes difficult for people to participate. The Namaste Care Family programme aims to increase the quality of life of people with advanced dementia, and improve family caregiving experiences through connecting to people and making them comfortable.

Methods and analysis

Our study will evaluate the effects of the Namaste Care Family programme on quality of life of people with advanced dementia living in nursing homes and family caregiving experiences using a cluster-randomised controlled trial. Longitudinal analyses will be performed taking into account clustering at the nursing home level. Both a cost-effectiveness and a cost-utility analysis from a societal perspective will be performed. We will modify the Namaste Care Family programme to increase family and volunteer involvement in ongoing and end-of-life care. Data collection involves assessments by family caregivers, nursing staff and elderly care physicians using questionnaires, and observations by the researchers at baseline and multiple times over 12 months. The last questionnaire will be sent up to month 24 after the death of the person with dementia. During semistructured interviews, the feasibility, accessibility and sustainability of the Namaste Care Family programme will be assessed.

Ethics and dissemination

The study protocol is approved by the Medical Ethics Review Committee of the VU University Medical Center in Amsterdam (protocol no. 2016.399) and registered with the Nederlands Trial Register (NTR5692). The findings will be disseminated via publications in peer-reviewed journals, conference presentations and presentations for healthcare professionals where appropriate.

Trial registration number

NTR5692.

https://ift.tt/2IYgKnj

La orientación comunitaria de nuestra práctica: hacer y no hacer [Gratuito]

Carmen Belén Benedé Azagra, Marta Sastre Paz, Jesús Sepúlveda
Aten Primaria.2018;50:451-4

Texto Completo - PDF

https://ift.tt/2J01sP5

Diagnóstico en hipertensión arterial: cuando las técnicas no son accesibles en atención primaria y además se producen inequidades [Gratuito]

Enrique Martín Rioboó, Jose Ramón Banegas, Luis Angel Pérula de Torres, Jose María Lobos Bejarano
Aten Primaria.2018;50:455-8

Texto Completo - PDF

https://ift.tt/2pVvTNN

Tendencias sobre los parámetros del grado de control de los pacientes con diabetes tipo 2 desde el año 2010 al año 2015 [Gratuito]

Ana María Herrero Gil, Javier Pinillos Robles, Patricia Sabio Repiso, José Luis Martín Maldonado, Gerardo Garzón González, Ángel Gil de Miguel
Aten Primaria.2018;50:459-66

Resumen - Texto Completo - PDF

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Impacto de los resultados a medio plazo de la prescripción inadecuada en los pacientes ancianos dados de alta desde una unidad de corta estancia [Gratuito]

Elena Rodríguez del Río, Javier Perdigones, Manuel Fuentes Ferrer, Juan González del Castillo, Juan González Armengol, M. Isabel Borrego Hernando, M. Lourdes Arias Fernández, Francisco Javier Martín-Sánchez
Aten Primaria.2018;50:467-76

Resumen - Texto Completo - PDF

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Abandono precoz y retención en servicios ambulatorios de drogodependencias: análisis transversal comparativo de factores que aumentan o disminuyen la adherencia [Gratuito]

Fran Calvo, Xavier Carbonell, Ramón Valero, Jordi Costa, Oriol Turró, Cristina Giralt, Marissa Ramírez
Aten Primaria.2018;50:477-85

Resumen - Texto Completo - PDF

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Descripción de factores contribuyentes en sucesos adversos relacionados con la seguridad del paciente y su evitabilidad [Gratuito]

María Mercedes Guerra-García, Beatriz Campos-Rivas, Alexandra Sanmarful-Schwarz, Alicia Vírseda-Sacristán, M. Aránzazu Dorrego-López, Ángeles Charle-Crespo
Aten Primaria.2018;50:486-92

Resumen - Texto Completo - PDF

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Síntomas psicosomáticos como expresión del deterioro de la calidad de vida relacionada con la salud en adolescentes [Gratuito]

Rosa M. Fuentes Chacón, M. José Simón Saiz, Margarita Garrido Abejar, M. Dolores Serrano Parra, M. Elisa Larrañaga Rubio, Santiago Yubero Jiménez
Aten Primaria.2018;50:493-9

Resumen - Texto Completo - PDF

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Modelo Point-of-Care Ultrasound en Atención Primaria: ¿herramienta de alta resolución? [Gratuito]

Antonio Calvo Cebrián, Alberto López García-Franco, Jorge Short Apellaniz
Aten Primaria.2018;50:500-8

Resumen - Texto Completo - PDF

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Hemorragia gastrointestinal en paciente con púrpura de Schönlein-Henoch [Gratuito]

Miguel Fraile López, Mónica García Espiga, Gustavo Pérez Álvarez
Aten Primaria.2018;50:509-10

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Patología crónica, fragilidad y funcionalidad en adultos mayores de Guadalajara. México [Gratuito]

Ana L. Salcedo Rocha, Javier E. García de Alba García, Susana de la Rosa Hernández
Aten Primaria.2018;50:511-3

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Cribado oportunista de arteriopatía periférica en pacientes hipertensos de mediana edad que acuden al centro de salud☆ [Gratuito]

María Isabel Rosell Malchirant, María Antonia Cantallops Borràs, Julio Francisco Fóthy, Antonia Fe Pascual, Catalina Picornell Yanes, Josep Maria Mendez Guillaumet
Aten Primaria.2018;50:513-4

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Precisión sobre respuesta a estandarización ortográfica [Gratuito]

Hugo González Aguilar
Aten Primaria.2018;50:515

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What you want and what you get from your PhD supervisor in primary care

Filipe Prazeres
Aten Primaria.2018;50:515-6

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Stage III melanoma incidence and impact of transitioning to the 8th AJCC staging system: a US population-based study

Future Oncology, Ahead of Print.


https://ift.tt/2ElKhso

Cost-utility of afatinib and gefitinib as first-line treatment for EGFR-mutated advanced non-small-cell lung cancer

Future Oncology, Ahead of Print.


https://ift.tt/2RSG7ef

Re: “High Altitude and Cancer Mortality” by Thiersch and Swenson (High Alt Med Biol 2018;19:116–123)

High Altitude Medicine &Biology, Ahead of Print.


https://ift.tt/2EoSNqR

Female Questionnaire of Trait Self-Objectification: Initial Development and Validation in China

Abstract

The present research involved the initial development and validation of the 17-item Female Questionnaire of Trait Self-Objectification (FQSO), which measures Chinese women's trait self-objectification. In Study 1 (n = 663), an exploratory factor analysis identified two dimensions underpinning the FQSO: Physical Appearance and Physical Competence. In Study 2 (n = 421), results from a confirmatory factor analyses indicated that the two-factor model of the FQSO was superior to a one-factor model. Further, in Study 3 (n = 421), the validity of all FQSO dimensions was supported via their relationship with the Revised Self-Objectification Questionnaire and other body-image measures. Lastly, the results of the Study 4 (n = 32) supported the stability of the FQSO over a 1-month period. Collectively, results indicate that the FQSO demonstrates adequate validity and reliability in assessing self-objectification in Chinese women who express more concerns about facial appearance and skin than about sex appeal, firm/sculpted muscles, or measurements.

https://ift.tt/2P0M62a

Reducing a Male Bias in Language? Establishing the Efficiency of Three Different Gender-Fair Language Strategies

Abstract

Different strategies of gender-fair language have been applied to reduce a male bias, which means the implicit belief that a word describing an undefined person describes a man. This male bias might be caused by the words themselves in terms of generic masculine or masculine forms or by androcentrism (the conflation of men with humanity). In two experiments, we tested how different gender-fair strategies used as labels of an unknown social target (an applicant in a recruitment situation) could eliminate the male bias. The three types of gender-fair strategies tested were: (a) paired forms (he/she), (b) traditional neutral words (e.g., singular they, "the applicant"), or (c) gender-neutral third-person pronouns actively created to challenge the binary gender system (ze, Swedish hen). The two experiments were performed in Swedish with 417 undergraduates in Sweden and in English with 411 U.S. participants recruited online. In Swedish, the third-person gender-neutral pronoun singular (hen) was used. In English, several forms of such gender-neutral pronouns have been suggested (e.g., ze). In both experiments, results indicated that paired forms and actively created gender-neutral pronouns eliminated the male bias, whereas traditional neutral words contained a male bias. Thus, gender-fair language strategies should avoid using traditional words. Consequences of using paired forms and creating new gender-neutral words are discussed. We argue that an actively created gender-neutral pronoun is of highest value because it is more inclusive.

https://ift.tt/2Pz58tu

When Seeing Is Not Believing: An Examination of the Mechanisms Accounting for the Protective Effect of Media Literacy on Body Image

Abstract

The present study aimed to explore the moderating role of three dimensions of media literacy on the relationship between media exposure and body dissatisfaction, mediated by thin-ideal internalization and appearance comparison among early female adolescents. A sample of 284 Australian female adolescents in single-sex schools (M_age = 13.15 years, range 11–16) reported on their media exposure, thin-ideal internalization, appearance comparison, body dissatisfaction, and three dimensions of media literacy: realism scepticism (scepticism regarding the extent to which media images portray reality, similarity scepticism (scepticism regarding the extent to which images portray a reality that is compatible with one's personal experience), and critical thinking (with regard to the intention of the message, its meaning, and influence). Moderated mediation analyses were conducted. Findings revealed different patterns of relationships for the different dimensions of media literacy, with similarity scepticism moderating the mediated relationship between media exposure and body dissatisfaction via both thin-ideal internalization and appearance comparison. In contrast, reality scepticism and critical thinking revealed negative associations with body dissatisfaction but were not found to serve as moderators. Findings suggest that the mechanisms of action may vary for different dimensions of media literacy, and they highlight the importance of targeting media literacy in intervention and prevention efforts.

https://ift.tt/2P2Mk8Z

Does Traditional Stereotyping of Career as Male Affect College Women’s, but Not College Men’s, Career Decision Self-Efficacy and Ultimately Their Career Adaptability?

Abstract

In South Korea, strong beliefs about traditional gender roles in accordance with Confucian and patriarchic atmosphere still strongly influence daily life and the career development process. Cultural and contextual factors impact the development of gender role socialization, which influences an individual's career decision self-efficacy (CDSE) and adaptability to manage the challenging career decision-making process. In our study, we recruited 291 South Korean undergraduate students (138 women, 153 men) and investigated how an implicit gender-career stereotyping impacts career adaptability via CDSE and whether there is a gender difference on the direct and indirect effects of implicit gender-career stereotyping on career adaptability. The Implicit Association Test (IAT) was implemented to measure implicit gender-career stereotyping. By testing a moderated mediation model, we found a mediated effect of CDSE in the link between implicit gender-career stereotyping and career adaptability in the female students. Moreover, the direct relationship between implicit gender-career stereotyping and CDSE was significant only for female students. Given the findings, practitioners and educators who work with South Korean women need to explore the degree of clients' traditional gender role stereotyping and provide tailored interventions to increase their level of career adaptability by minimizing the negative impacts of gender role stereotyping and by increasing CDSE.

https://ift.tt/2PBwnUo

Mutations in the MAB_2299c TetR regulator confer cross-resistance to clofazimine and bedaquiline in Mycobacterium abscessus [Mechanisms of Resistance]

New therapeutic approaches are needed against Mycobacterium abscessus, a respiratory mycobacterial pathogen that evades efforts to successfully treat infected patients. Clofazimine and bedaquiline, two drugs used for the treatment of multi-drug resistant tuberculosis, are being considered as alternatives for the treatment in lung diseases caused by M. abscessus. With the aim to understand the mechanism of action of these agents in M. abscessus, we sought herein to determine the means by which M. abscessus can develop resistance. Spontaneous resistant strains selected on clofazimine, followed by whole-genome sequencing, identified mutations in MAB_2299c, encoding a putative TetR transcriptional regulator. Unexpectedly, these mutants were also cross-resistant to bedaquiline. MAB_2299c was found to bind to its target DNA located upstream of the divergently orientated MAB_2300/MAB_2301 gene cluster, encoding MmpS/MmpL membrane proteins. Point mutations or deletion of MAB_2299c were associated with concomitant up-regulation of the mmpS/mmpL transcripts and accounted for this cross-resistance. Strikingly, deletion of MAB_2300/MAB_2301 in the MAB_2299c mutant strain restored susceptibility to bedaquiline and clofazimine. Overall, these results expand our knowledge with respect to the regulatory mechanisms of the MmpL family of proteins and on a novel mechanism of drug resistance in this difficult-to-treat respiratory mycobacterial pathogen. Therefore, MAB_2299c may represent an important marker of resistance to be considered for the treatment of M. abscessus diseases with clofazimine and bedaquiline in clinical settings.

https://ift.tt/2OV8Vo7

Activity of Meropenem-Vaborbactam Against Pseudomonas aeruginosa and Acinetobacter baumannii in a Neutropenic Mouse Thigh Infection Model [Experimental Therapeutics]

We have evaluated the activity of meropenem-vaborbactam against clinical isolates of Pseudomonas aeruginosa and Acinetobacter baumannii in a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-hour infusions every 8 hours with 2g meropenem-2g vaborbactam produced bacterial killing against strains with MICs of 2 – 16 mg/L and suggests that this combination may have utility in the treatment of infections caused by P. aeruginosa and A. baumannii.

https://ift.tt/2P0Ku8C

Loss of C-5 sterol desaturase activity in Candida albicans - azole resistance or merely trailing growth? [Susceptibility]

Increased expression of drug efflux pumps and changes in the target enzyme, Erg11p, are known to contribute to azole resistance in Candida albicans, one of the most prevalent fungal pathogens. Mutations that inactivate ERG3, which encodes sterol ^5,6-desaturase also confer in vitro azole resistance. However, it is unclear if loss of Erg3p activity is sufficient to confer resistance within the mammalian host, and relatively few erg3 deficient mutants have been reported among azole-resistant clinical isolates. 'Trailing growth' (residual growth in the presence of the azoles) is a phenotype observed with many C. albicans isolates, and in its extreme form can be mistaken for resistance. The purpose of this study was to determine if growth of Erg3p-deficient C. albicans mutants in the presence of the azoles possesses the characteristics of azole resistance, or of an exaggerated form of trailing growth. Our results demonstrate that similar to trailing isolates, the capacity of an erg3/ mutant to endure the consequences of azole exposure is at least partly dependent upon both temperature and pH. This contrasts with true azole resistance that results from enhanced drug efflux and/or changes in the target enzyme. The erg3/ mutant and trailing isolates also appear to sustain significant membrane damage upon azole treatment, further distinguishing them from resistant isolates. However, the erg3/ mutant's insensitivity to the azoles is unaffected by the calcineurin inhibitor cyclosporin A, distinguishing it from trailing isolates. In conclusion, the erg3 mutant phenotype is qualitatively and quantitatively distinct from both azole resistance and trailing growth.

https://ift.tt/2PBEKzk

The Utility of Urine Cultures in Predicting Blood Culture Susceptibilities in Patients with Bacteremic Urinary Tract Infection [Susceptibility]

In a review of 428 patients with bacteremic urinary tract infection, urine culture susceptibility results accurately predicted blood culture results when the same organism was isolated from both cultures. Early targeted therapy using urine culture results can potentially reduce broad-spectrum antibiotic exposure, its associated adverse effects, and length of hospitalization.

https://ift.tt/2OWtZun

Comparison of Pharmacist-Directed Management of Multiplex PCR Blood Culture Results with Conventional Microbiology Methods on Effective and Optimal Therapy within a Community Hospital [Clinical Therapeutics]

Multiplex PCR combined with a pharmacist-driven reporting protocol was compared to standard-of-care within a community hospital to evaluate initial changes after notification of a positive blood culture. The intervention group demonstrated decreased time-to-change in antimicrobial therapy (p=0.0081), increased change to optimal antimicrobial therapy (p=0.013) and decreased vancomycin use for coagulase negative staphylococci contaminants (p<0.01) with multiplex PCR implementation and pharmacist intervention.

https://ift.tt/2PvWkEB

Acquisition of extended-spectrum ss-lactamase GES-6 leading to resistance to ceftolozane-tazobactam combination in Pseudomonas aeruginosa [Mechanisms of Resistance]

A clinical Pseudomonas aeruginosa isolate resistant to all β-lactams including ceftolozane-tazobactam and carbapenems was recovered. It belonged to the Sequence Type ST235 and produced the extended-spectrum β-lactamase (ESBL) GES-6 differing from GES-1 by two amino-acid substitutions (E104K and G170S). GES-6 possessed an increased hydrolytic activity toward carbapenems and to ceftolozane, and a decreased susceptibility to β-lactamase inhibitors as compared to GES-1, except for avibactam. We showed here that resistance to ceftolozane-tazobactam may occur through acquisition of a specific ESBL in P. aeruginosa, but that ceftazidime-avibactam combination remained an effective alternative.

https://ift.tt/2P3kQA4

Effects of ivermectin and oxantel pamoate on tribendimidine: in vitro and in vivo drug-drug interaction study [Experimental Therapeutics]

Soil-transmitted helminth (STH) infections still remain a major health problem in poor rural settings. The lack of efficacious drugs against all STH species raises the interest in drug combinations. Drug-drug interactions are, however, of major concern so that careful in vitro and in vivo characterization is needed. The combination of tribendimidine with either ivermectin or oxantel pamoate targets a broad range of STH and thus, represents a promising treatment alternative. Drug-drug interactions, however, have not yet been investigated. Therefore, the effect of combinations of ivermectin, oxantel pamoate and tribendimidine's active metabolite deacylated amidantel (dADT) on the CYP450 metabolism was evaluated followed by a pharmacokinetic analysis of tribendimidine and ivermectin alone and in combination in healthy rats. Oxantel pamoate is only poorly absorbed and was therefore excluded from pharmacokinetic analysis. No evident effect was observed for tribendimidine-oxantel pamoate at CYP450 metabolism level, whereas a combination of tribendimidine and ivermectin led to a moderately increased CYP2D6 inhibition as compared to ivermectin or tribendimidine alone. Co-administration of tribendimidine with ivermectin altered neither the T_max nor elimination half-lives of dADT, adADT and ivermectin. While the AUCs and C_max of dADT, adADT and ivermectin are reduced by co-administration, the change is insufficient to declare that a DDI has been detected. Further studies are necessary to understand the observed interaction of tribendimidine and ivermectin, which is not related to P450 metabolism, and its significance for the situation in human.

https://ift.tt/2PxPHln

A Novel Actin Binding Drug with In Vivo Efficacy [Mechanisms of Action]

Occidiofungin is produced by the soil bacterium Burkholderia contaminans MS14 likely as an antifungal agent. This study identified the primary cellular target of occidiofungin, which was determined to be actin. Occidiofungin modified with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers an apoptotic cell death. We demonstrate highly specific localization of occidiofungin to cellular regions rich in actin in yeast and binding of occidiofungin to purified actin in vitro. Further, disruption of actin mediated cellular processes such as endocytosis, nuclear segregation, and hyphae formation were observed. All these processes require the formation of stable actin cables, which are disrupted following the addition of a subinhibitory concentration of occidiofungin. We were also able to demonstrate the effectiveness of occidiofungin in treating a vulvovaginal yeast infection in a murine model. The results of this study are important for the development of an efficacious novel class of actin binding drugs that could fill the existing gap in treatment options for fungal infections or in the treatment of different types of cancer.

https://ift.tt/2OZmjaE

Daptomycin pore formation and stoichiometry depends on membrane potential of target membrane [Mechanisms of Action]

Daptomycin is a calcium-dependent lipodepsipeptide antibiotic clinically used to treat serious infections caused by Gram-positive pathogens. Its precise mode of action is somewhat controversial; the biggest issue is daptomycin pore formation, which we directly investigated here. We first performed a screening experiment using propidium iodide (PI) entry to Bacillus subtilis cells and chose the optimum and therapeutically relevant conditions (10 µg/mL daptomycin and 1.25 mM CaCl₂) for the subsequent analyses. Using conductance measurements on planar lipid bilayers, we show that daptomycin forms non-uniform oligomeric pores with conductance ranging from 120 pS up to 14 nS. The smallest conductance unit is probably a dimer, however tetramers and pentamers occur in the membrane most frequently. Moreover, daptomycin pore-forming activity is exponentially dependent on the applied membrane voltage. We further analyzed the membrane permeabilizing activity in B. subtilis cells using fluorescence methods (PI, DiSC₃(5)). Daptomycin most rapidly permeabilizes cells with high initial membrane potential and dissipates it within a few minutes. Low initial membrane potential hinders daptomycin pore formation.

https://ift.tt/2PBHoou

Comparison of the Superpolymyxin™ and CHROMID(R) Colistin R screening media for the detection of colistin-resistant Enterobacteriaceae from spiked rectal swabs [Analytical Procedures]

The dissemination of carbapenemase-producing Enterobacteriaceae (CPE), has led to the increased use of colistin, which resulted in the emergence of colistin-resistant Enterobacteriaceae worldwide. One of the most threatening scenarios is the dissemination of colistin-resistance in CPE, particularly the plasmid-encoded resistance MCR. Thus, it becomes now mandatory to possess reliable media to screen for colistin-resistant Gram-negative isolates, especially Enterobacteriaceae. In this study we evaluated the performances of the Superpolymyxin™medium (ELITechGroup) and the CHROMID® Colistin R (bioMérieux) to screen for colistin-resistant Enterobacteriaceae from spiked rectal swabs. Stools were spiked with a total of 94 enterobacterial isolates (Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Enterobacter cloacae), including 53 colistin-resistant isolates. ESwabs™(Copan Diagnostics) were then inoculated with those spiked fecal suspensions and proceed as recommended by both manufacturers. The sensitivity of detection colistin-resistant Enterobacteriaceae were of 86.8% [95% confidence interval (CI95) 74.0 – 94.0] using both the Superpolymyxin™medium and the CHROMID® Colistin R plates. Surprisingly, the isolates that were not detected were not the same for both media. The specificities were high for both media, at 97.9% [CI95 = 87.3% - 99.9%] for Superpolymyxin™medium and 100% [CI95 = 90.4% - 100%] for the CHROMID® Colistin R medium. Both commercially-available media, CHROMID® Colistin R and Superpolymyxin™, provide a useful tool to screen for colistin-resistant Enterobacteriaceae from patient samples (rectal swabs) regardless of the level and mechanism of colistin resistance.

https://ift.tt/2Pz2rbm

Pse-T2, an antimicrobial peptide with High-Level, Broad-Spectrum Antimicrobial Potency and Skin Biocompatibility against Multidrug-resistant Pseudomonas aeruginosa infection [Experimental Therapeutics]

Pseudin-2, isolated from the frog Pseudis paradoxa, exhibits potent antibacterial activity but also cytotoxicity. In an effort to develop clinically applicable AMPs, we designed pseudin-2 analogs with Lys substitutions, resulting in elevated amphipathic α-helical structure and cationicity. In addition, truncated analogs of pseudin-2 and Lys-substituted peptides were synthesized to produce linear 18-residue amphipathic α-helices, which were further investigated for their mechanism and functions. These truncated analogs exhibited higher antimicrobial activity and lower cytotoxicity than pseudin-2. In particular, Pse-T2 showed marked pore formation, permeabilization of the outer/inner bacterial membranes, and DNA binding. Fluorescence spectroscopy and scanning electron microscopy showed that Pse-T2 kills bacterial cells by disrupting membrane integrity. In vivo, wounds infected with MDR Pseudomonas aeruginosa healed significantly faster when treated Pse-T2 than did untreated wounds or wounds treated with ciprofloxacin. Moreover, Pse-T2 facilitated infected wound closure by reducing inflammation through suppression of IL-1β, IL-6, and TNF-α. These data suggest the small antimicrobial peptide Pse-T2 could be useful for future development of therapeutic agents effective against MDR bacterial strains.

https://ift.tt/2P0Ktl4

A pathway-directed screen for inhibitors of the bacterial cell elongation machinery [Mechanisms of Action]

New antibiotics are needed to combat the growing problem of resistant bacterial infections. An attractive avenue towards the discovery of such next generation therapies is to identify novel inhibitors of clinically validated targets like cell wall biogenesis. We have therefore developed a pathway-directed, whole-cell screen for small molecules that block the activity of the Rod system of Escherichia coli. This conserved multi-protein complex is required for cell elongation and the morphogenesis of rod-shaped bacteria. It is composed of cell wall synthases and membrane proteins of unknown function that are organized by filaments of the actin-like MreB protein. Our screen takes advantage of the conditional essentiality of the Rod system and the ability of the beta-lactam mecillinam to cause a toxic malfunctioning of the machinery. Rod system inhibitors can therefore be identified as molecules that promote growth in the presence of mecillinam under conditions permissive for the growth of Rod^– cells. A screen of ~690,000 identified 1,300 compounds active against E. coli. Pathway-directed screening of a majority of this subset of compounds for Rod inhibitors successfully identified eight analogs of the MreB-antagonist A22. Further characterization of the A22 analogs identified showed that their antibiotic activity under conditions where the Rod system is essential was strongly correlated with their ability to suppress mecillinam toxicity. This result combined with additional biological studies reinforce the notion that A22-like molecules are relatively specific for MreB and suggest that the lipoprotein transport factor LolA is unlikely to be a physiologically relevant target as previously proposed.

https://ift.tt/2PCBN1w

Method-dependent epidemiological cutoff values (ECVs) for detection of triazole resistance in Candida and Aspergillus species for the SYO colorimetric broth and Etest agar diffusion methods [Susceptibility]

Although the Sensitrite Yeast-One (SYO) and Etest methods are widely utilized, interpretive criteria are not available for triazole susceptibility testing of Candida or Aspergillus species. We collected fluconazole, itraconazole, posaconazole and voriconazole SYO and Etest MICs from 39 laboratories representing all continents for (method-agent-dependent): 11,171 Candida albicans, 215 C. dubliniensis, 4,418 C. glabrata species complex (SC), 157 C. (Meyerozyma) guilliermondii, 676 C. krusei (Pichia kudriavzevii), 298 C. (Clavispora) lusitaniae, 911 and 3,691 C. parapsilosis sensu stricto (SS) and C. parapsilosis SC, respectively, 36 C. metapsilosis, 110 C. orthopsilosis, 1,854 C. tropicalis, 244 Saccharomyces cerevisiae, 1,409 Aspergillus fumigatus, 389 A. flavus, 130 A. nidulans, 233 A. niger, and 302 A. terreus complexes. SYO/Etest MICs for 282 confirmed non-WT isolates were included: ERG11 (C. albicans), ERG11 and MRR1 (C. parapsilosis), cyp51A (A. fumigatus), and CDR2, CDR1 overexpression (C. albicans and C. glabrata, respectively). Interlaboratory modal agreement was superior by SYO for yeast spp., and by the Etest for Aspergillus spp. Distributions fulfilling CLSI criteria for ECV definition were pooled and we proposed SYO ECVs for S. cerevisiae, 9 yeast and 3 Aspergillus species, and Etest ECVs for 5 yeast and 4 Aspergillus species. The posaconazole SYO ECV of 0.06 µg/ml for C. albicans and the Etest itraconazole ECV of 2 µg/ml for A. fumigatus were the best predictors of non-WT isolates. These findings support the need for method-dependent ECVs, as overall, the SYO appears to perform better for susceptibility testing of yeast spp. and the Etest for Aspergillus spp. Further evaluations should be conducted with more Candida mutants.

https://ift.tt/2OY2NeO

Genomic Characterization of Carbapenemase-producing Klebsiella pneumoniae with Chromosomally Encoded blaNDM-1 [Epidemiology and Surveillance]

We report here the K. pneumoniae strains carrying chromosomal bla_NDM-1 in Thailand. The genomes of these two isolates include a 160-kbp insertion containing bla_NDM-1, which is almost identical to that in the IncHI1B-like plasmid. Further analysis indicated that IS5-mediated intermolecular transposition and Tn3-transposase-mediated homologous recombination resulted in the integration of bla_NDM-1 into the chromosome from an IncHI1B-like plasmid. The spread of this type of carbapenem-resistant Enterobacteriaceae may threaten public health and warrants further monitoring.

https://ift.tt/2PF7Iyp

Activation of 2,4-diaminoquinazoline in Mycobacterium tuberculosis by Rv3161c, a putative dioxygenase [Mechanisms of Resistance]

The diaminoquinazoline series has good potency against Mycobacterium tuberculosis. Resistant isolates have mutations in Rv3161c, a putative dioxygenase. We carried out metabolite analysis on wild-type and an Rv3161c mutant strain after exposure to a diaminoquinazoline. The parental compound was found in intracellular extracts from the mutant, but not the wild-type. A metabolite consistent with a mono-hydroxylated form was identified in the wild-type. These data support the hypothesis that Rv3161c metabolizes diaminoquinazolines in M. tuberculosis.

https://ift.tt/2PBUySs

New Treatment Options Against Carbapenem-Resistant Acinetobacter baumannii Infections [Minireviews]

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late stage pre-clinical studies for the treatment of CRAB and evaluates their expected benefits and potential shortcomings.

https://ift.tt/2OV8R7R

No evidence for acquired mutations associated with cytochrome bc1-inhibitor resistance in 13,559 clinical Mycobacterium tuberculosis complex isolates [Letters]

In 2016, tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) was responsible for an estimated 1.7 million deaths (1)....

https://ift.tt/2PzmOoP

Regulation of Root Angle and Gravitropism

Regulation of plant root angle is critical for obtaining nutrients and water and is an important trait for plant breeding. A plant's final, long-term root angle is the net result of a complex series of decisions made by a root tip in response to changes in nutrient availability, impediments, the gravity vector and other stimuli. When a root tip is displaced from the gravity vector, the short-term process of gravitropism results in rapid reorientation of the root toward the vertical. Here, we explore both short- and long-term regulation of root growth angle, using natural variation in tomato to identify shared and separate genetic features of the two responses. Mapping of expression quantitative trait loci mapping and leveraging natural variation between and within species including Arabidopsis suggest a role for PURPLE ACID PHOSPHATASE 27 and CELL DIVISION CYCLE 73 in determining root angle.

https://ift.tt/2IY7P5j

Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy

Purpose: Pediatric diffuse midline glioma (DMG) are highly malignant tumors with poor clinical outcomes. Over 70% of patients with DMG harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but rebiopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost nonexistent. To overcome these hurdles, we examined whether liquid biopsy allows measurement of disease response to precision therapy.

Experimental Design: We established a sensitive and specific methodology that detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n = 48 subjects, n = 110 specimens). Quantification of circulating tumor DNA (ctDNA) for H3K27M was used for longitudinal assessment of disease response compared with centrally reviewed MRI data.

Results: H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient's tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients.

Conclusions: Our liquid biopsy approach provides a molecularly based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs. Clin Cancer Res; 1–10. ©2018 AACR.

https://ift.tt/2yKtDwy

Ketoconazole and Posaconazole Selectively Target HK2 Expressing Glioblastoma Cells

Purpose: HK2 is elevated in GBM and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient derived glioma stem cells, and mouse models of GBM. Experimental Design: We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2 associated gene signature. We next determined the EC₅₀ of the compounds by treating glioma cell lines and glioma stem cells. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on tumor cell metabolic activity was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, Ketoconazole and Posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo. Treatment of mice bearing GBM with Ketoconazole and Posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. Additionally, treatment with azoles resulted in increased proportion of apoptotic cells. Conclusions: Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM., Combined with existing literature and pre-clinical results these data support the value of repurposing azoles in GBM clinical trials.

https://ift.tt/2ym3ghg

Regulation of eIF4F translation initiation complex by the peptidyl prolyl isomerase FKBP7 in taxane-resistant prostate cancer

Purpose:Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance. Experimental Design:We established four chemoresistant prostate cancer cell lines and used image-based high-content siRNA functional screening, based on gene-expression signature, to explore mechanisms of chemoresistance and identify new potential targets with potential roles in taxane resistance. The functional role of a new target was assessed by in vitro and in vivo silencing, and mass spectrometry analysis was used to identify its downstream effectors. Results:We identified FKBP7, a prolyl-peptidyl isomerase overexpressed in docetaxel-resistant and in cabazitaxel-resistant prostate cancer cells. This is the first study to characterize the function of human FKBP7 and explore its role in cancer. We discovered that FKBP7 was upregulated in human prostate cancers and its expression correlated with the recurrence observed in patients receiving docetaxel. FKBP7 silencing showed that FKBP7 is required to maintain the growth of chemoresistant cell lines and chemoresistant tumors in mice. Mass spectrometry analysis revealed that FKBP7 interacts with eIF4G, a component of the eIF4F translation initiation complex, to mediate the survival of chemoresistant cells. Using small molecule inhibitors of eIF4A, the RNA helicase component of eIF4F, we were able to kill docetaxel and cabazitaxel-resistant cells. Conclusions:Targeting FKBP7 or the eIF4G-containing eIF4F translation initiation complex could be novel therapeutic strategies to eradicate taxane-resistant prostate cancer cells.

https://ift.tt/2yDnO48

Plasma exchange can be an alternative therapeutic modality for severe cytokine release syndrome after chimeric antigen receptor-T cell infusion: a case report

Background: Tumor immunotherapy with chimeric antigen receptor T cells (CAR-T) is a promising new treatment for B-cell malignancies and has produced exciting results. However, cytokine release syndrome (CRS) is the most significant toxicity associated with this treatment and can be life-threatening. Case presentation: A 23-year-old male patient had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia. The patient was recruited into our CAR-T clinical trial, and 1x10⁶/kg of engineered anti-CD19 CAR-T cells was administered. After infusion of CAR-T cells (day 0), the patient underwent a typical CRS reaction, with increases in fever, muscle soreness and inflammatory cytokines. He was treated with antiallergic and antipyretic drugs, glucocorticoids and tocilizumab (4mg/kg, day 3 and day 5). However, CRS was not under control, and his condition rapidly deteriorated, He was transferred to the intensive care unit, where dexamethasone10 mg q6h was administered and plasma exchange was performed, with 3000 ml of plasma replaced by fresh frozen plasma per day for three consecutive days. His symptoms gradually improved, and the CRS-related symptoms were relieved. Additionally, a bone marrow smear showed no lymphoblast cells and minimal residual disease was negative on day 28. The patient was eventually discharged in a normal condition. Conclusion: CRS is caused by an exaggerated systemic immune response, potentially resulting in organ damage that can be fatal. Although therapeutic plasma exchange is not included in CRS management guidelines, this case shows that plasma exchange is feasible in at least some patients with severe CRS.

https://ift.tt/2yjsE74

The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC)

Purpose: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PC) mortality by PSA-based screening. The aim of the study is to evaluate screening effect on PC incidence and mortality in relation to number of screening rounds attended. Experimental Design: The participants of the Finnish ERSPC trial (31,867 men) were classified according to screening attendance. All men were regarded as non-attenders until the first screening attendance, then remained once-screened until the second screen and similarly for the third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration or end of 2013. PC incidence and mortality, lung cancer and overall mortality were evaluated. Results: PC mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times (HR:0.17, 95% CI:0.09-0.33). However, a reduction was also seen in lung cancer (HR:0.59, 95% CI:0.47-0.73) and overall mortality (HR:0.56, 95% CI:0.52-0.60). Conclusions: Assuming a similar relative reduction being due to selection bias and screening in PC as other causes of death (40% reduction), approximately half of the observed PC mortality reduction by repeated screening is likely to be non-causal and a real screening effect may account for up to 40% reduction in men screened three times. PC mortality reduction can only be achieved by repeated screening cycles.

https://ift.tt/2yFv0wK

SERUM- AND GLUCOCORTICOID-INDUCED KINASE SGK1 DIRECTLY PROMOTES THE DIFFERENTIATION OF COLORECTAL CANCER CELLS AND RESTRAINS METASTASIS

Background and Aims: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, since in colorectal cancer (CRC), the degree of differentiation of a tumour is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer (CRC), there is marked downregulation of SGK1 compared to normal tissue. Methods: An inducible SGK1 viral overexpression system was utilised to induce re-expression of SGK1 in CRC cell lines. Transcriptomic and phenotypic analyses of these CRC lines was performed and validation in mouse and human cohorts was performed. Results: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Re-expression of SGK1 in CRC cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated in part by SGK1-induced PKP3 expression and increased degradation of MYC. Conclusions: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit CRC metastasis.

https://ift.tt/2yiCFkX

FAL1 regulates endothelial cell proliferation in diabetic arteriosclerosis through PTEN/AKT pathway

OBJECTIVE: This study aims to investigate the role of FAL1 in the occurrence and progression of diabetic arteriosclerosis and its underlying mechanism.

PATIENTS AND METHODS: FAL1 expression in coronary artery disease (CAD) tissues, normal artery tissues, and tumor necrosis factor-α (TNF-α)-induced endothelial cells was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The regulatory effects of FAL1 on cell proliferation, migration, and cell cycle were examined by cell counting kit-8 (CCK-8) assay, transwell assay, and flow cytometry, respectively. Western blot was used to detect protein expressions of proliferation-related gene PCNA (proliferating cell nuclear antigen), cell cycle-related genes cyclin D1, PTEN (phosphatase and tensin homolog deleted on chromosome ten) and AKT (protein kinase B) in HUVECs. Subsequently, rescue experiments were performed to assess whether PTEN/AKT signaling pathway is activated during the process of FAL1-regulated proliferation and migration of HUVECs.

RESULTS: FAL1 was highly expressed in CAD tissues and TNF-α-induced endothelial cells compared with that of controls. Overexpression of FAL1 in HUVECs promoted cell cycle, proliferation, and migration. FAL1 activated PTEN/AKT pathway in HUVECs, which was partially reversed by PTEN overexpression.

CONCLUSIONS: Highly expressed FAL1 can promote proliferation and migration of endothelial cells through activating PTEN/AKT signaling pathway.

L'articolo FAL1 regulates endothelial cell proliferation in diabetic arteriosclerosis through PTEN/AKT pathway sembra essere il primo su European Review.

https://ift.tt/2OZYy23

The added value of genetic information in colorectal cancer risk prediction models: development and evaluation in the UK Biobank prospective cohort study

The added value of genetic information in colorectal cancer risk prediction models: development and evaluation in the UK Biobank prospective cohort study

The added value of genetic information in colorectal cancer risk prediction models: development and evaluation in the UK Biobank prospective cohort study, Published online: 16 October 2018; doi:10.1038/s41416-018-0282-8

The added value of genetic information in colorectal cancer risk prediction models: development and evaluation in the UK Biobank prospective cohort study

https://ift.tt/2pUq7f6

Urinary Metabolomics Study of Patients with Gout Using Gas Chromatography-Mass Spectrometry

Objectives. Gout is a common type of inflammatory arthritis. The aim of this study was to detect urinary metabolic changes in gout patients which may contribute to understanding the pathological mechanism of gout and discovering potential metabolite markers. Methods. Urine samples from 35 gout patients and 29 healthy volunteers were analyzed by gas chromatography–mass spectrometry (GC–MS). Orthogonal partial least-squares discriminant analysis (OPLS-DA) was performed to screen differential metabolites between two groups, and the variable importance for projection (VIP) values and Student's t-test results were combined to define the significant metabolic changes caused by gout. Further, binary logistic regression analysis was performed to establish a model to distinguish gout patients from healthy people, and receiver operating characteristic (ROC) curve was made to evaluate the potential for diagnosis of gout. Result. A total of 30 characteristic metabolites were significantly different between gout patients and controls, mainly including amino acids, carbohydrates, organic acids, and their derivatives, associated with perturbations in purine nucleotide synthesis, amino acid metabolism, purine metabolism, lipid metabolism, carbohydrate metabolism, and tricarboxylic acid cycle. Binary logistic regression and ROC curve analysis showed the combination of urate and isoxanthopterin can effectively discriminate the gout patients from controls with the area under the curve (AUC) of 0.879. Conclusion. Thus, the urinary metabolomics study is an efficient tool for a better understanding of the metabolic changes of gout, which may support the clinical diagnosis and pathological mechanism study of gout.

https://ift.tt/2RS8rxp

Safety of Natural Insecticides: Toxic Effects on Experimental Animals

Long-term application and extensive use of synthetic insecticides have resulted in accumulating their residues in food, milk, water, and soil and cause adverse health effects to human and ecosystems. Therefore, application of natural insecticides in agriculture and public health sectors has been increased as alternative to synthetic insecticides. The question here is, are all natural insecticides safe. Therefore, the review presented here focuses on the safety of natural insecticides. Natural insecticides contain chemical, mineral, and biological materials and some products are available commercially, e.g., pyrethrum, neem, spinosad, rotenone, abamectin, Bacillus thuringiensis (Bt), garlic, cinnamon, pepper, and essential oil products. It can induce hepatotoxicity, renal toxicity, hematotoxicity, reproductive toxicity, neurotoxicity, and oxidative stress. It can induce mutagenicity, genotoxicity, and carcinogenicity in mammals. Some natural insecticides and active compounds from essential oils are classified in categories Ib (Highly hazardous) to U (unlikely toxic). Therefore, the selectivity and safety of natural insecticides not absolute and some natural compounds are toxic and induce adverse effects to experimental animals. In concussion, all natural insecticides are not safe and the term "natural" does not mean that compounds are safe. In this respect, the term "natural" is not synonymous with "organic" and not all-natural insecticide products are acceptable in organic farmers.

https://ift.tt/2EmR2u1

Number of Children Not Receiving Vaccines Slightly Increased

MONDAY, Oct. 15, 2018 -- Overall, vaccine coverage for children aged 19 to 35 months remained high and stable from 2013 to 2017; however, a small, but growing number of children received no vaccinations, according to research published in the Oct....

https://ift.tt/2PBxMKG

American College of Gastroenterology, Oct. 5-10

The American College of Gastroenterology's 83rd Annual Scientific Meeting The annual meeting of the American College of Gastroenterology was held from Oct. 5 to 10 in Philadelphia and attracted approximately 5,000 participants from around the world,...

https://ift.tt/2P3dyfG

β-Blockers in 1st Trimester Do Not Up Congenital Malformations

MONDAY, Oct. 15, 2018 -- Maternal use of β-blockers in the first trimester of pregnancy is not associated with a large increase in the risk for overall or cardiac congenital malformations, according to a study published online Oct. 16 in the Annals...

https://ift.tt/2PBxG5M

In NSCLC, Longer Survival With Brigatinib Than Crizotinib

MONDAY, Oct. 15, 2018 -- Among patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) who have not previously received an ALK inhibitor, progression-free survival is significantly longer in those who receive...

https://ift.tt/2OZpkrC

Without Medicaid Expansion, Poor Patients Forgo Medical Care

MONDAY, Oct. 15, 2018 -- Doing without medical care is much more common among low-income residents of states that have not expanded Medicaid than among low-income people in other states, according to a Government Accountability Office report. The...

https://ift.tt/2PBxCmy

Pneumococcal Meningitis Complicated by Cerebral Vasculitis, Abscess, Hydrocephalus, and Hearing Loss

Intracranial abscesses, postinfectious vasculitis, and hydrocephalus are rare complications of Streptococcus pneumoniae (S. pneumoniae) meningitis, and to our knowledge, there have been no case reports where all these 3 complications occurred in a single patient with Streptococcus pneumoniae meningitis. Here, we report a case of a 48-year-old male who developed postinfectious vasculitis, abscess, hydrocephalus, and hearing loss after S. pneumoniae meningitis. Clinicians ought to be aware of the possible adverse outcomes of S. pneumoniae meningitis and the limitations of current treatment options.

https://ift.tt/2Ae6ncx

Endocrine Modulation in Long-Term Karate Practitioners

Purpose. Karate is a martial arts discipline which is widely practiced in the Western world as a form of self-defense, as well as a discipline to achieve physical and mental balance. However, little is known with respect to its specific psychobiological effects, particularly in relation to the influence that it may exert on the endocrine system. Thus, in the present study, we examined the effects of karate on several hormonal parameters of the Hypothalamic-Pituitary-Adrenal and Hypothalamic-Pituitary-Thyroid axes in long-time practitioners. Methods. Twenty-two healthy volunteer subjects (12 experimental and 10 controls) participated in the study. Experimental subjects were karate players with a minimum of 3 years of practice in this discipline. Blood samples for the quantification of hormonal parameters were taken in both groups. The Mann-Whitney U test was performed for each variable in order to analyze the differences between groups. Results. Statistically significant differences were found in cortisol and thyroid hormones, with the karate group showing lower levels of these hormones as compared to control. Conclusions. These findings, therefore, reveal that long-term karate practice is associated with a significant endocrine modulation, which suggests interesting psychobiological and clinical implications. Further research is needed to verify these preliminary results, as well as properly assessing its possible use as a psychosomatic intervention tool.

https://ift.tt/2Ov5sgF

A Network Pharmacology Approach to Uncover the Molecular Mechanisms of Herbal Formula Ban-Xia-Xie-Xin-Tang

Ban-Xia-Xie-Xin-Tang (BXXXT) is a classical formula from Shang-Han-Lun which is one of the earliest books of TCM clinical practice. In this work, we investigated the therapeutic mechanisms of BXXXT for the treatment of multiple diseases using a network pharmacology approach. Here three BXXXT representative diseases (colitis, diabetes mellitus, and gastric cancer) were discussed, and we focus on in silico methods that integrate drug-likeness screening, target prioritizing, and multilayer network extending. A total of 140 core targets and 72 representative compounds were finally identified to elucidate the pharmacology of BXXXT formula. After constructing multilayer networks, a good overlap between BXXXT nodes and disease nodes was observed at each level, and the network-based proximity analysis shows that the relevance between the formula targets and disease genes was significant according to the shortest path distance (SPD) and a random walk with restart (RWR) based scores for each disease. We found that there were 22 key pathways significantly associated with BXXXT, and the therapeutic effects of BXXXT were likely addressed by regulating a combination of targets in a modular pattern. Furthermore, the synergistic effects among BXXXT herbs were highlighted by elucidating the molecular mechanisms of individual herbs, and the traditional theory of "Jun-Chen-Zuo-Shi" of TCM formula was effectively interpreted from a network perspective. The proposed approach provides an effective strategy to uncover the mechanisms of action and combinatorial rules of BXXXT formula in a holistic manner.

https://ift.tt/2J30cLa

Successful Management of Giant Placental Chorangioma by Microcoil Embolization

AJP Rep 2018; 08: e230-e233
DOI: 10.1055/s-0038-1669944

Optimal prenatal management of giant placental chorangioma (also known as chorioangioma, angiomyxoma, fibroangiomyxoma, or fibroma) has yet to be determined. Interventions intended to devascularize the tumor such as interstitial laser, bipolar coagulation, fetoscopic laser photocoagulation, and chemical embolization have met mixed results. We report a minimally invasive, extra-amniotic approach, technically similar to cordocentesis, of microcoil embolization of the feeding vessel. These percutaneously placed microcoils initiate clot formation at the site of insertion and are unable to migrate through the tumor, thereby minimizing fetal harm by downstream embolic phenomena. Intervention at 26 and 22 weeks resulted in intraoperative fetal loss in the former and vaginal delivery at term of a healthy neonate in the latter. Preoperative, intraoperative, and placental findings are highlighted. The ease and safety of this procedure may alter the risk–benefit equation toward earlier intervention with potentially better clinical outcomes.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

https://ift.tt/2Oo6VoG

Progressive Devascularization: A Novel Surgical Approach for Placenta Previa

AJP Rep 2018; 08: e223-e226
DOI: 10.1055/s-0038-1673373

Background The gold standard for antenatal diagnosis of placenta previa is the transvaginal ultrasonography. In placenta previa cases, separation of placental and uterine tissues is challenging even for the most experienced surgeons. Life-threatening obstetrical complications from cesarean deliveries with placenta previa include peripartum hemorrhage, coagulopathy, blood transfusion, peripartum hysterectomy, and multiple organ failure. Cases We detailed the 3 cases of placenta previa that underwent bilateral uterine artery ligation; if hemostasis was not achieved, horizontal mattress sutures were placed in the lower uterine segment. All patients were discharged with minimal morbidity. Conclusion For patients with placenta previa and low risk for placenta creta, counseling should include the risk for maternal morbidity and criteria for pursuing peripartum hysterectomy. Our devascularization, a stepwise surgical approach, shows promising outcomes in placenta previa cases. Précis We propose a novel surgical approach, using a progressive devascularization surgical technique, for management of women with placenta previa, undergoing cesarean delivery.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

https://ift.tt/2IXX57f

Sildenafil Use in the Treatment of Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: A Case Series

AJP Rep 2018; 08: e219-e222
DOI: 10.1055/s-0038-1673343

Objective This article studies the role of sildenafil in reducing myocardial stress (measured by serial N-terminal pro b-type natriuretic peptide [NTproBNP] levels) secondary to bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH). Study Design This is a case series of three extremely low birth weight infants with severe BPD at 36 weeks' postmenstrual age. All infants had very elevated NTproBNP (> 2,000 ng/dL) levels and echocardiographic evidence of BPD-PH. Sildenafil was started and infants were followed up every 2 weeks clinically along with NTproBNP levels and echocardiograms. Results After 4 weeks of sildenafil treatment, NTproBNP levels decreased significantly in all infants, echocardiograms showed significant improvement in one infant, and respiratory severity score improved significantly in one infant. All infants tolerated sildenafil. Conclusion Sildenafil reduced NTproBNP levels in all infants with BPD-PH but the echocardiographic findings and respiratory scores did not improve consistently. We speculate that this may be due to a delay in diagnosis and initiation of therapy after irreversible pulmonary changes have set in.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

https://ift.tt/2IZElEe

DUODENAL TUMOR RISK IN LYNCH SYNDROME

Lynch syndrome (LS) is associated with an increased risk of small bowel tumors but routine screening is not recommended in international guidelines. The aim of our study was to determinate the prevalence of duodenal tumors in a French cohort of LS patients.

https://ift.tt/2Ac0vjI

Population Trends in Intensive Care Unit Admissions in the United States Among Medicare Beneficiaries, 2006–2015

https://ift.tt/2CLh0G2

Mechanisms That Contribute to a Profound Reduction of the HIV-1 Reservoir After Allogeneic Stem Cell Transplant

Background:

The multifactorial mechanisms associated with radical reductions in HIV-1 reservoirs after allogeneic hematopoietic stem cell transplant (allo-HSCT), including a case of HIV cure, are not fully understood.

Objective:

To investigate the mechanism of HIV-1 eradication associated with allo-HSCT.

Design:

Nested case series within the IciStem observational cohort.

Setting:

Multicenter European study.

Participants:

6 HIV-infected, antiretroviral-treated participants who survived more than 2 years after allo-HSCT with CCR5 wild-type donor cells.

Measurements:

HIV DNA analysis, HIV RNA analysis, and quantitative viral outgrowth assay were performed in blood, and HIV DNA was also measured in lymph nodes, ilea, bone marrow, and cerebrospinal fluid. A humanized mouse model was used for in vivo detection of the replication-competent blood cell reservoir. HIV-specific antibodies were measured in plasma.

Results:

Analysis of the viral reservoir showed that 5 of 6 participants had full donor chimera in T cells within the first year after transplant, undetectable proviral HIV DNA in blood and tissue, and undetectable replication-competent virus (<0.006 infectious unit per million cells). The only participant with detectable virus received cord blood stem cells with an antithymocyte globulin–containing conditioning regimen, did not develop graft-versus-host disease, and had delayed complete standard chimerism in T cells (18 months) with mixed ultrasensitive chimera. Adoptive transfer of peripheral CD4⁺ T cells to immunosuppressed mice resulted in no viral rebound. HIV antibody levels decreased over time, with 1 case of seroreversion.

Limitation:

Few participants.

Conclusion:

Allo-HSCT resulted in a profound long-term reduction in the HIV reservoir. Such factors as stem cell source, conditioning, and a possible "graft-versus-HIV-reservoir" effect may have contributed. Understanding the mechanisms involved in HIV eradication after allo-HSCT can enable design of new curative strategies.

Primary Funding Source:

The Foundation for AIDS Research (amFAR).

https://ift.tt/2CiZnMP

To β or Not to β? Very Likely OK to β

In their article, Bateman and colleagues report a study that provides reassurance regarding the safety of β-blocker use during pregnancy. The editorialist discusses the findings and their clinical implications for caring for pregnant women who have hypertension or other conditions that require the use of β-blockers.

https://ift.tt/2CMo8Ca