bluuebunny/crossref_metadata_2025 huggingface dataset:
A mistaken case of tension pneumothorax
Authors: Newman Michael Joseph
Published: May 2014

The patient was an otherwise usually fit and well 25-year-old man who presented to A&E department in extremis. The initial working diagnosis was a tension pneumothorax, and he was subsequently treated with needle thoracocentesis causing a release of air. A chest radiograph was taken, after which a chest drain was inserted. Bilious fluid was drained from the chest drain. The patient was taken for an emergency CT, which demonstrated a Bochdalek diaphragmatic hernia, with the spleen and bowel found to be causing a near total left lung collapse. He was taken to the theatre to return the bowel to the correct anatomical position, in addition to undergoing a sleeve gastrectomy, and diaphragmatic defect repair. The patient has had a complex and protracted recovery in the intensive therapy unit (ITU) with complications including wound dehiscence, gastrectomy leak requiring additional surgical repair, fluid overload and bilateral pleural empyema.
Did the 2000 Sydney Olympics increase physical activity among adult Australians?
Authors: Bauman Adrian , Bellew Bill , Craig Cora L
Published: May 2014

Background

The Olympic Games’ (OG) organisers typically hope that a diverse range of health legacies, including increases in physical activity and sport participation will result from their hosting of the OG. Despite these aspirations, the effects of the Olympics on physical activity levels remain to be demonstrated in large-scale population studies.

Methods

This study examined the short-term impact of the Sydney 2000 OG, using serial cross-sectional population physical activity surveys of Australian adults in November 1999 and November 2000. Random sample surveys of adults asked about physical activity participation, intention to be more active, and in 2000, response to the OG.

Results

There were no significant effects of the Olympics on physical activity participation among adult Australians, measured 6 weeks after the end of the Games. Total minutes of leisure-time physical activity did not change significantly between 1999 and 2000 (295–303 min/week), and the proportion reaching the recommended levels of 150 min/week did not change (56.6% and 56.8%, respectively, in 1999 and 2000). The intention to be active in the next month increased after the Games (adjusted OR 1.12, 95% CI 1.01 to 1.24), but was not associated with physical activity behaviour change.

Conclusions

The legacy of the OG may be apparent through new infrastructure and other urban improvements, but evidence of their influence on physical activity levels remains elusive. Without multiyear integrated and well-funded programmes to promote physical activity, the Olympic legacy of a more active community may remain more rhetoric than reality.
Incidence of road traffic disabilities trending upwards in transitional China: a retrospective analysis from 1980 to 2005
Authors: Liu Lan , Du Wei , Pang Lihua , Chen Gong , Zheng Xiaoying
Published: May 2014

Objective

To evaluate the change in incidence rates of road traffic disabilities from 1980 to 2005 in China.

Methods

We employed the 2006 China National Sample Survey on Disability to derive weighted number of persons with disabilities resulting from road crashes and weighted age-gender-specific population at risk by disability occurrence year. The annual incidence rate of road traffic disabilities and corresponding 95% CI were estimated. We used the World Population Prospects (WPP) and the death rate of people with disabilities (PWD) to estimate potential earlier loss of lives before 2006. Both WPP-adjusted and PWD-adjusted incidence rates of road traffic disabilities were further adjusted using the life table analysis.

Results

The WPP-adjusted incidence rate for road traffic disabilities increased over time from 1.50 (95% CI 1.47 to 1.52) in 1980 to 11.19 (95% CI 11.13 to 11.25) per 100 000 persons in 2005. The PWD-adjusted incidence rate also increased from 1.71 (95% CI 1.68 to 1.73) to 11.51 (95% CI 11.45 to 11.57) per 100 000 persons.

Conclusions

Road crashes disable thousands of Chinese and remain a significant population health and development problem. The increasing burden of road traffic disabilities calls for more efforts and specific strategies to improve road safety in China.
Balance and walking after three different models of stroke rehabilitation: early supported discharge in a day unit or at home, and traditional treatment (control)
Authors: Gjelsvik Bente Elisabeth Bassøe , Hofstad Håkon , Smedal Tori , Eide Geir Egil , Næss Halvor , Skouen Jan Sture , Frisk Bente , Daltveit Silje , Strand Liv Inger
Published: May 2014

Objective

To compare the effects on balance and walking of three models of stroke rehabilitation: early supported discharge with rehabilitation in a day unit or at home, and traditional uncoordinated treatment (control).

Design

Group comparison study within a randomised controlled trial.

Setting

Hospital stroke unit and primary healthcare.

Participants

Inclusion criteria: a score of 2–26 on National Institutes of Health Stroke Scale, assessed with Postural Assessment Scale for Stroke (PASS), and discharge directly home from the hospital stroke unit.

Interventions

Two intervention groups were given early supported discharge with treatment in either a day unit or the patient's own home. The controls were offered traditional, uncoordinated treatment.

Outcome measures

Primary: PASS. Secondary: Trunk Impairment Scale—modified Norwegian version; timed Up-and-Go; 5 m timed walk; self-reports on problems with walking, balance, ADL, physical activity, pain and tiredness. The patients were tested before randomisation and 3 months after inclusion.

Results

From a total of 306 randomised patients, 167 were tested with PASS at baseline and discharged directly home. 105 were retested at 3 months: mean age 69 years, 63 men, 27 patients in day unit rehabilitation, 43 in home rehabilitation and 35 in a control group. There were no group differences, either at baseline for demographic and test data or for length of stroke unit stay. At 3 months, there was no group difference in change on PASS (p>0.05). Some secondary measures tended to show better outcome for the intervention groups, that is, trunk control, median (95% CI): day unit, 2 (0.28 to 2.31); home rehabilitation, 4 (1.80 to 3.78); control, 1 (0.56 to 2.53), p=0.044; and for self-report on walking, p=0.021 and ADL, p=0.016.

Conclusions

There was no difference in change between the groups for postural balance, but the secondary outcomes indicated that improvement of trunk control and walking was better in the intervention groups than in the control group.

Trial registration

This study is part of the Early Supported Discharge after Stroke in Bergen, ClinicalTrials.gov (NCT00771771).
Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis
Authors: Narum Sigrid , Westergren Tone , Klemp Marianne
Published: May 2014

Objective

To assess whether corticosteroids are associated with increased risk of gastrointestinal bleeding or perforation.

Design

Systematic review and meta-analysis of randomised, double-blind, controlled trials comparing a corticosteroid to placebo for any medical condition or in healthy participants. Studies with steroids given either locally, as a single dose, or in crossover studies were excluded.

Data sources

Literature search using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews between 1983 and 22 May 2013.

Outcome measure

Outcome measures were the occurrence of gastrointestinal bleeding or perforation. Predefined subgroup analyses were carried out for disease severity, use of non-steroidal anti-inflammatory drugs (NSAIDs) or gastroprotective drugs, and history of peptic ulcer.

Results

159 studies (N=33 253) were included. In total, 804 (2.4%) patients had a gastrointestinal bleeding or perforation (2.9% and 2.0% for corticosteroids and placebo). Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66). For patients in ambulatory care, the increased risk was not statistically significant (OR 1.63, 95% CI 0.42 to 6.34). Only 11 gastrointestinal bleeds or perforations occurred among 8651 patients in ambulatory care (0.13%). Increased risk was still present in subgroup analyses (studies with NSAID use excluded; OR 1.44, 95% CI 1.20 to 1.71, peptic ulcer as an exclusion criterion excluded; OR 1.47, 95% CI 1.21 to 1.78, and use of gastroprotective drugs excluded; OR 1.42, 95% CI 1.21 to 1.67).

Conclusions

Corticosteroid use was associated with increased risk of gastrointestinal bleeding and perforation. The increased risk was statistically significant for hospitalised patients only. For patients in ambulatory care, the total occurrence of bleeding or perforation was very low, and the increased risk was not statistically significant.
Patient punctuality and clinic performance: observations from an academic-based private practice pain centre: a prospective quality improvement study
Authors: Williams Kayode A , Chambers Chester G , Dada Maqbool , McLeod Julia C , Ulatowski John A
Published: May 2014

Objectives

The aim of this study was to examine the effects of an intervention to alter patient unpunctuality. The major hypothesis was that the intervention will change the distribution of patient unpunctuality by decreasing patient tardiness and increasing patient earliness.

Design

Prospective Quality Improvement.

Setting

Specialty Pain Clinic in suburban Baltimore, Maryland, USA.

Participants

The patient population ranged in age from 18 to 93 years. All patients presenting to the clinic during the study period were included in the study. The average monthly volume was 86.2 (SD=13) patients. A total of 1500 patient visits were included in this study.

Interventions

We tracked appointment times and patient arrival times at an ambulatory pain clinic. An intervention was made in which patients were informed that tardy patients would not be seen and would be rescheduled. This policy was enforced over a 12-month period.

Primary and secondary outcome measures

The distribution of patient unpunctuality was developed preintervention and at 12 months after implementation. Distribution parameters were used as inputs to a discrete event simulation to determine effects of the change in patient unpunctuality on clinic delay.

Results

Data regarding patient unpunctuality were gathered by direct observation before and after implementation of the intervention. The mean unpunctuality changed from −20.5 min (110 observations, SD=1.7) preintervention to −23.2 (169, 1.2) at 1 month after the intervention, −23.8 min (69, 1.8) at 6 months and −25.0 min (71, 1.2) after 1 year. The unpunctuality 12 months after initiation of the intervention was significantly different from that prior to the intervention (p<0.05).

Conclusions

Physicians and staff are able to alter patient arrival patterns to reduce patient unpunctuality. Reducing tardiness improves some measures of clinic performance, but may not always improve waiting times. Accommodating early arriving patients does serve to improve clinic performance.
Evidence-informed recommendations for rehabilitation with older adults living with HIV: a knowledge synthesis
Authors: O'Brien Kelly K , Solomon Patricia , Trentham Barry , MacLachlan Duncan , MacDermid Joy , Tynan Anne-Marie , Baxter Larry , Casey Alan , Chegwidden William , Robinson Greg , Tran Todd , Wu Janet , Zack Elisse
Published: May 2014

Objective

Our aim was to develop evidence-informed recommendations for rehabilitation with older adults living with HIV.

Design

We conducted a knowledge synthesis, combining research evidence specific to HIV, rehabilitation and ageing, with evidence on rehabilitation interventions for common comorbidities experienced by older adults with HIV.

Methods

We included highly relevant HIV-specific research addressing rehabilitation and ageing (stream A) and high-quality evidence on the effectiveness of rehabilitation interventions for common comorbidities experienced by older adults ageing with HIV (stream B). We extracted and synthesised relevant data from the evidence to draft evidence-informed recommendations for rehabilitation. Draft recommendations were refined based on people living with HIV (PLHIV) and clinician experience, values and preferences, reviewed by an interprofessional team for Grading of Recommendations Assessment, Development, and Evaluation (GRADE) (quality) rating and revision and then circulated to PLHIV and clinicians for external endorsement and final refinement. We then devised overarching recommendations to broadly guide rehabilitation with older adults living with HIV.

Results

This synthesis yielded 8 overarching and 52 specific recommendations. Thirty-six specific recommendations were derived from 108 moderate-level or high-level research articles (meta-analyses and systematic reviews) that described the effectiveness of rehabilitation interventions for comorbidities that may be experienced by older adults with HIV. Recommendations addressed rehabilitation interventions across eight health conditions: bone and joint disorders, cancer, stroke, cardiovascular disease, mental health challenges, cognitive impairments, chronic obstructive pulmonary disease and diabetes. Sixteen specific recommendations were derived from 42 research articles specific to rehabilitation with older adults with HIV. The quality of evidence from which these recommendations were derived was either low or very low, consisting primarily of narrative reviews or descriptive studies with small sample sizes. Recommendations addressed approaches to rehabilitation assessment and interventions, and contextual factors to consider for rehabilitation with older adults living with HIV.

Conclusions

These evidence-informed recommendations provide a guide for rehabilitation with older adults living with HIV.
Longitudinal cohort survey of women's smoking behaviour and attitudes in pregnancy: study methods and baseline data
Authors: Orton Sophie , Bowker Katharine , Cooper Sue , Naughton Felix , Ussher Michael , Pickett Kate E , Leonardi-Bee Jo , Sutton Stephen , Dhalwani Nafeesa N , Coleman Tim
Published: May 2014

Objectives

To report the methods used to assemble a contemporary pregnancy cohort for investigating influences on smoking behaviour before, during and after pregnancy and to report characteristics of women recruited.

Design

Longitudinal cohort survey.

Setting

Two maternity hospitals, Nottingham, England.

Participants

3265 women who attended antenatal ultrasound scan clinics were offered cohort enrolment; those who were 8–26 weeks pregnant and were currently smoking or had recently stopped smoking were eligible. Cohort enrollment took place between August 2011 and August 2012.

Primary and secondary outcome measures

Prevalence of smoking at cohort entry and at two follow-up time points (34–36 weeks gestation and 3 months postnatally); response rate, participants’ sociodemographic characteristics.

Results

1101 (33.7%, 95% CI 32.1% to 35.4%) women were eligible for inclusion in the cohort, and of these 850 (77.2%, 95% CI 74.6% to 79.6%) were recruited. Within the cohort, 57.4% (N=488, 95% CI 54.1% to 60.7%) reported to be current smokers. Current smokers were significantly younger than ex-smokers (p<0.05), more likely to have no formal qualifications and to not be in current paid employment compared to recent ex-smokers (p<0.001).

Conclusions

This contemporary cohort, which seeks very detailed information on smoking in pregnancy and its determinants, includes women with comparable sociodemographic characteristics to those in other UK cross-sectional studies and cohorts. This suggests that future analyses using this cohort and aimed at understanding smoking behaviour in pregnancy may produce findings that are broadly generalisable.
Mode of delivery at birth and the metabolic syndrome in midlife: the role of the birth environment in a prospective birth cohort study
Authors: Bouhanick Béatrice , Ehlinger Virginie , Delpierre Cyrille , Chamontin Bernard , Lang Thierry , Kelly-Irving Michelle
Published: May 2014

Objectives

The aim of this study is to examine the hypothesis that mode of delivery at birth may be associated with metabolic disorders in adult midlife.

Setting

Population cohort study

Participants

The National Child Development Study consists of individuals born during 1 week in 1958 in Great Britain. Respondents with biomedical data on the metabolic syndrome at age 45 were included.

Outcome measure

The metabolic syndrome was defined based on the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III classification.

Results

7156 were born naturally; among the caesarean births, 106 were non-elective and 85 were elective caesareans. The metabolic syndrome is present in 37.7% of those born by non-elective caesareans, 25.9% of those born by elective caesarean and 27.5% of those born by vaginal delivery. In a multivariate logistic regression model adjusted for antenatal factors, birth history, mother's characteristics and the socioeconomic environment at birth, only birth by non-elective caesarean remained associated with the metabolic syndrome in adulthood compared with vaginal delivery (OR 1.51, 95% CI 1.00 to 2.30). Mother's obesity (OR 1.61, 95% CI 1.12 to 2.34) and low maternal education level (OR 1.47, 95% CI 1.30 to 1.67) were also independently associated with midlife metabolic syndrome.

Conclusions

Birth by non-elective caesarean in 1958 may be associated with metabolic syndrome in adulthood after adjusting for prior confounding factors. We suggest that the birth context of emergency caesareans in 1958 is suggestive of a ‘fetal stress’ mechanism affecting health across the lifecourse.
Doing challenging research studies in a patient-centred way: a qualitative study to inform a randomised controlled trial in the paediatric emergency care setting
Authors: Woolfall Kerry , Young Bridget , Frith Lucy , Appleton Richard , Iyer Anand , Messahel Shrouk , Hickey Helen , Gamble Carrol
Published: May 2014

Objective

To inform the design of a randomised controlled trial (called EcLiPSE) to improve the treatment of children with convulsive status epilepticus (CSE). EcLiPSE requires the use of a controversial deferred consent process.

Design

Qualitative interview and focus group study.

Setting

8 UK support groups for parents of children who have chronic or acute health conditions and experience of paediatric emergency care.

Participants

17 parents, of whom 11 participated in telephone interviews (10 mothers, 1 father) and 6 in a focus group (5 mothers, 1 father). 6 parents (35%) were bereaved and 7 (41%) had children who had experienced seizures, including CSE.

Results

Most parents had not heard of deferred consent, yet they supported its use to enable the progress of emergency care research providing a child's safety was not compromised by the research. Parents were reassured by tailored explanation, which focused their attention on aspects of EcLiPSE that addressed their priorities and concerns. These aspects included the safety of the interventions under investigation and how both EcLiPSE interventions are used in routine clinical practice. Parents made recommendations about the appropriate timing of a recruitment discussion, the need to individualise approaches to recruiting bereaved parents and the use of clear written information.

Conclusions

Our study provided information to help ensure that a challenging trial was patient centred in its design. We will use our findings to help EcLiPSE practitioners to: discuss potentially threatening trial safety information with parents, use open-ended questions and prompts to identify their priorities and concerns and clarify related aspects of written trial information to assist understanding and decision-making.
Patient Reporting of Safety experiences in Organisational Care Transfers (PRoSOCT): a feasibility study of a patient reporting tool as a proactive approach to identifying latent conditions within healthcare systems
Authors: Scott Jason , Waring Justin , Heavey Emily , Dawson Pamela
Published: May 2014

Background

It is increasingly recognised that patients can play a role in reporting safety incidents. Studies have tended to focus on patients within hospital settings, and on the reporting of patient safety incidents as defined within a medical model of safety. This study aims to determine the feasibility of collecting and using patient experiences of safety as a proactive approach to identifying latent conditions of safety as patients undergo organisational care transfers.

Methods and analysis

The study comprises three components: (1) patients’ experiences of safety relating to a care transfer, (2) patients’ receptiveness to reporting experiences of safety, (3) quality improvement using patient experiences of safety. (1) A safety survey and evaluation form will be distributed to patients discharged from 15 wards across four clinical areas (cardiac, care of older people, orthopaedics and stroke) over 1 year. Healthcare professionals involved in the care transfer will be provided with a regular summary of patient feedback. (2) Patients (n=36) who return an evaluation form will be sampled representatively based on the four clinical areas and interviewed about their experiences of healthcare and safety and completing the survey. (3) Healthcare professionals (n=75) will be invited to participate in semistructured interviews and focus groups to discuss their experiences with and perceptions of receiving and using patient feedback. Data analysis will explore the relationship between patient experiences of safety and other indicators and measures of quality and safety. Interview and focus group data will be thematically analysed and triangulated with all other data sources using a convergence coding matrix.

Ethics and dissemination

The study has been granted National Health Service (NHS) Research Ethics Committee approval. Patient experiences of safety will be disseminated to healthcare teams for the purpose of organisational development and quality improvement. Results will be disseminated to study participants as well as through peer-reviewed outputs.
The OxVALVE population cohort study (OxVALVE-PCS)—population screening for undiagnosed valvular heart disease in the elderly: study design and objectives
Authors: Coffey Sean , d'Arcy Joanna L , Loudon Margaret A , Mant David , Farmer Andrew J , Prendergast Bernard D ,   for the OxVALVE-PCS group
Published: May 2014

Introduction

Valvular heart disease (VHD) is an increasingly important cardiac condition, driven by an ageing population and lack of progress in the development of medical therapies. There is a dearth of accurate information to guide decision-makers in the development of strategies to combat VHD, and no population-based study has been performed specifically to investigate its contemporary epidemiology. This document describes the design and methodology of the OxVALVE population cohort study (OxVALVE-PCS), which was conceived to address this need.

Methods and analysis

Participants aged 65 years and older attending a participating general practice in Oxfordshire, UK, are invited to attend a screening examination. Exclusion criteria include previously diagnosed VHD, inability to provide consent, terminal illness or excessive frailty. Demographics, a focused cardiovascular history and vital signs are recorded at the initial screening examination, accompanied by an echocardiogram. Any finding of significant VHD triggers a separate, more formal echocardiographic assessment (including acquisition of a three-dimensional dataset) and collection of blood samples for future genetic and biomarker analysis. Participants provide consent for longitudinal follow-up and enrolment in future cohort substudies. We also assess the acceptability of community-based echocardiographic examination and compare self-assessed quality of life between those with and without VHD.

Conclusions

OxVALVE-PCS will provide contemporary epidemiological data concerning the community prevalence of undiagnosed VHD, facilitate accurate deployment of scarce resources to meet the anticipated increase in demand for VHD-associated healthcare and create a series of subcohorts with carefully defined genotypes and echocardiographic phenotypes for long overdue clinical studies.

Ethics and dissemination

This study was approved by the local research ethics committee (Southampton, UK; REC Ref: 09/H0502/58).

Results

Results will be submitted for publication in peer-reviewed scientific journals.
Extracting structural requirements for activity of GPR119 agonists: a hologram quantitative structure activity relationship (HQSAR) study
Authors: Ugarkar Apoorva G. , Ambre Premlata K. , Coutinho Evans C. , Nandan Santosh , Pissurlenkar Raghuvir R.S.
Published: May 2014

GPR119 is a potential target for the treatment of diabetes mellitus. GPR119 agonists minimize the side-effects observed with sulphonyl ureas and glucagon-like peptide 1 analogs. Various reported GPR119 agonists from various patents were selected for the study and a 2D-QSAR study (HQSAR) was carried out. Fifty-five molecules were selected for the study. The study was performed on a training set of 40 structurally diverse molecules with reported biological activity. The most significant HQSAR model (q2 = 0.87, r2 = 0.99) was obtained using atoms, bond, connection, and acceptor and donor as fragment distinction. The fragment size was kept at 4–7. The predictive ability of the model was evaluated by an external test set containing 15 molecules not included in the training set, and the predicted values were in good agreement with the experimental values. The important fragments determined by the study were used to design new drug candidates having increased biological activity and comparable physicochemical properties.
Thomas precession and the Bacry paradox
Authors: Kholmetskii Alexander L. , Missevitch Oleg V. , Yarman Tolga
Published: May 2014

We show that in the derivation of the frequency of Thomas precession, the fact of implementation of rotation-free Lorentz transformations between a laboratory frame, KL, and Lorentz frames K(t) co-moving with a particle with spin at any time moments, t, has principal importance. Choosing for the observation of the particle’s motion any other inertial frame, K, related with KL by the rotation-free transformation, we have to realize that the transformations between K and K(t) at any t are no longer rotation-free. This way we provide a resolution of the known paradox by Bacry (H. Bacry. Nuovo Cimento, 26, 1164 (1962)) and suggest a reinterpretation of the Thomas precession, which is further discussed.
MODELING CICADA SOUND PRODUCTION AND PROPAGATION
Authors: EDOH KOSSI
Published: May 2014

The paper investigates the sound signals radiated by cicadas and study why their "songs" are so loud. The sound pulses emanating from a class of insects are believed to come from small oscillators such as cicada tymbals, a vibrating drum-like membrane with some initially stored energy and a resonating air sac — the abdomen. The system is very efficient in a way that the resulting sound is very loud. The paper determines a region close to the cicada where the sound signals have strong nonlinear characteristics. Just outside this region the propagation of the sound signals are modeled by the Mendousse–Burgers' equation. The sound production mechanism is investigated in terms of "buckling" phenomenon to determine the sound pulses in atmospheric air medium. The resulting numerical results are very encouraging when compared with the data from the microphone readings.
UTILITY THEORY FRONT TO BACK — INFERRING UTILITY FROM AGENTS' CHOICES
Authors: COX ALEXANDER M. G. , HOBSON DAVID , OBłÓJ JAN
Published: May 2014

We pursue an inverse approach to utility theory and associated consumption and investment problems. Instead of specifying a utility function and deriving the actions of an agent, we assume that we observe the actions of the agent (i.e. consumption and investment strategies) and ask if it is possible to derive a utility function for which the observed behavior is optimal. We work in continuous time both in a deterministic and stochastic setting. In the deterministic setup, we find that there are infinitely many utility functions generating a given consumption pattern. In the stochastic setting of a geometric Brownian motion market it turns out that the consumption and investment strategies have to satisfy a consistency condition (PDE) if they are to come from a classical utility maximization problem. We show further that important characteristics of the agent such as risk attitudes (e.g., DARA) can be deduced directly from the agent's consumption and investment choices.
The inhibitory effect of ethanol on Sestrin3 in the pathogenesis of ethanol-induced liver injury
Authors: Kang Xinqin , Petyaykina Kateryna , Tao Rongya , Xiong Xiwen , Dong X. Charlie , Liangpunsakul Suthat
Published: May 2014

Sestrins ( Sesns) are a family of stress-sensitive genes that have been suggested to regulate lipid metabolism. Chronic ethanol feeding is known to cause lipid accumulation in hepatocytes. This study was designed to investigate the role of S esn3 in the pathogenesis of alcohol-induced hepatic steatosis. We demonstrated that ethanol inhibited the expression of Sesn3 in VL-17A cells. Overexpression of Sesn3 ameliorated triglyceride accumulation; downregulation using short hairpin RNA significantly deteriorated triglyceride accumulation in these cells. The expression of Sesn3 was also reduced in mice fed with ethanol for 4 wk. Overexpression of Sesn3 prevented hepatic steatosis, whereas knockdown of Sesn3 worsened hepatic steatosis in ethanol-fed mice. Overexpression of Sesn3 significantly reduced the expression of genes encoding for lipid synthesis through AMPK pathway. Overexpression of Sesn3 augmented the effect of ethanol on phospho-p70 S6 kinase. The levels of hepatic light chain 3, a marker for autophagy, expression were significantly decreased in ethanol-fed mice after Sesn3 gene was knocked down. Our findings suggest that inhibitory effect of ethanol on Sesn3 may play an important role in the development of ethanol-induced fatty liver.
Defining the role of albumin infusion in cirrhosis-associated hyponatremia
Authors: Nguyen Minhtri K. , Ornekian Vahram , Kao Liyo , Butch Anthony W. , Kurtz Ira
Published: May 2014

The presence of negatively charged, impermeant proteins in the plasma space alters the distribution of diffusible ions in the plasma and interstitial fluid (ISF) compartments to preserve electroneutrality and is known as Gibbs-Donnan equilibrium. In patients with hypoalbuminemia due to underlying cirrhosis, the decrease in the plasma water albumin concentration ([Alb−]pw) would be expected to result in a decrease in the plasma water sodium concentration ([Na+]pw) due to an alteration in the distribution of Na+ between the plasma and ISF. In addition, cirrhosis-associated hyponatremia may be due to the renal diluting defect resulting from the intravascular volume depletion due to gastrointestinal losses and overdiuresis and/or decreased effective circulatory volume secondary to splanchnic vasodilatation. Therefore, albumin infusion may result in correction of the hyponatremia in cirrhotic patients either by modulating the Gibbs-Donnan effect due to hypoalbuminemia or by restoring intravascular volume in patients with intravascular volume depletion due to gastrointestinal losses and overdiuresis. However, the differential role of albumin infusion in modulating the [Na+]pw in these patients has not previously been analyzed quantitatively. In the present study, we developed an in vitro assay system to examine for the first time the quantitative effect of changes in albumin concentration on the distribution of Na+ between two compartments separated by a membrane that allows the free diffusion of Na+. Our findings demonstrated that changes in [Alb−]pw are linearly related to changes in [Na+]pw as predicted by Gibbs-Donnan equilibrium. However, based on our findings, we predict that the improvement in cirrhosis-associated hyponatremia due to intravascular volume depletion results predominantly from the restoration of intravascular volume rather than alterations in Gibbs-Donnan equilibrium.
Recruitment and plasticity in diaphragm, intercostal, and abdominal muscles in unanesthetized rats
Authors: Navarrete-Opazo A. , Mitchell G. S.
Published: May 2014

Although rats are a frequent model for studies of plasticity in respiratory motor control, the relative capacity of rat accessory respiratory muscles to express plasticity is not well known, particularly in unanesthetized animals. Here, we characterized external intercostal (T2, T4, T5, T6, T7, T8, T9 EIC) and abdominal muscle (external oblique and rectus abdominis) electromyogram (EMG) activity in unanesthetized rats via radiotelemetry during normoxia (Nx: 21% O2) and following acute intermittent hypoxia (AIH: 10 × 5-min, 10.5% O2; 5-min intervals). Diaphragm and T2–T5 EIC EMG activity, and ventilation were also assessed during maximal chemoreceptor stimulation (MCS: 7% CO2, 10.5% O2) and sustained hypoxia (SH: 10.5% O2). In Nx, T2 EIC exhibits prominent inspiratory activity, whereas T4, T5, T6, and T7 EIC inspiratory activity decreases in a caudal direction. T8 and T9 EIC and abdominal muscles show only tonic or sporadic activity, without consistent respiratory activity. MCS increases diaphragm and T2 EIC EMG amplitude and tidal volume more than SH (0.94 ± 0.10 vs. 0.68 ± 0.05 ml/100 g; P < 0.001). Following AIH, T2 EIC EMG amplitude remained above baseline for more than 60 min post-AIH (i.e., EIC long-term facilitation, LTF), and was greater than diaphragm LTF (41.5 ± 1.3% vs. 19.1 ± 2.0% baseline; P < 0.001). We conclude that 1) diaphragm and rostral T2–T5 EIC muscles exhibit inspiratory activity during Nx; 2) MCS elicits greater ventilatory, diaphragm, and rostral T2–T5 EIC muscle activity vs. SH; and 3) AIH induces greater rostral EIC LTF than diaphragm LTF.
The TGFβ–miR200–MIG6 Pathway Orchestrates the EMT-Associated Kinase Switch That Induces Resistance to EGFR Inhibitors
Authors: Izumchenko Evgeny , Chang Xiaofei , Michailidi Christina , Kagohara Luciane , Ravi Rajani , Paz Keren , Brait Mariana , Hoque Mohammad O. , Ling Shizhang , Bedi Atul , Sidransky David
Published: May 2014

Although specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKI), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial–mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here, we show that during transforming growth factor β (TGFβ)–mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of the mitogen-inducible gene 6 (MIG6), a negative regulator of EGFR. The MIG6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of MIG6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild-type EGFR showed that the tumor MIG6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ–miR200–MIG6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of MIG6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs. Cancer Res; 74(14); 3995–4005. ©2014 AACR.
Pooling Prospective Studies to Investigate the Etiology of Second Cancers
Authors: Black Amanda , Gibson Todd M. , Shiels Meredith S. , Park Yikyung , Robien Kim , Albanes Demetrius , Weinstein Stephanie J. , Freeman Laura E. Beane , Andreotti Gabriella , Purdue Mark P. , Fraumeni Joseph F. , Hartge Patricia , Tucker Margaret A. , Hoover Robert N. , Cerhan James R. , Zeleniuch-Jacquotte Anne , Curtis Rochelle E. , Elena Joanne , Sampson Joshua N. , de Gonzalez Amy Berrington , Morton Lindsay M.
Published: May 2014

Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology.

Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements.

Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers.

Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention.

Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.
NADPH Oxidases as Therapeutic Targets in Chronic Myelogenous Leukemia
Authors: Sánchez-Sánchez Beatriz , Gutiérrez-Herrero Sara , López-Ruano Guillermo , Prieto-Bermejo Rodrigo , Romo-González Marta , Llanillo Marcial , Pandiella Atanasio , Guerrero Carmen , Miguel Jesús F. San , Sánchez-Guijo Fermín , del Cañizo Consuelo , Hernández-Hernández Angel
Published: May 2014

Purpose: Cancer cells show higher levels of reactive oxygen species (ROS) than normal cells and increasing intracellular ROS levels are becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myelogenous leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here, we assessed NADPH oxidases as therapeutic targets in CML.

Experimental Design: We have analyzed the effect of different NADPH oxidase inhibitors, either alone or in combination with BCR-ABL inhibitors, in CML cells and in two different animal models for CML.

Results: NADPH oxidase inhibition dramatically impaired the proliferation and viability of BCR-ABL–expressing cells due to the attenuation of BCR-ABL signaling and a pronounced cell-cycle arrest. Moreover, the combination of NADPH oxidase inhibitors with BCR-ABL inhibitors was highly synergistic. Two different animal models underscore the effectiveness of NADPH oxidase inhibitors and their combination with BCR-ABL inhibitors for CML targeting in vivo.

Conclusion: Our results offer further therapeutic opportunities for CML, by targeting NADPH oxidases. In the future, it would be worthwhile conducting further experiments to ascertain the feasibility of translating such therapies to clinical practice. Clin Cancer Res; 20(15); 4014–25. ©2014 AACR.
Neural Autoantibody Clusters Aid Diagnosis of Cancer
Authors: Horta Erika S. , Lennon Vanda A. , Lachance Daniel H. , Jenkins Sarah M. , Smith Carin Y. , McKeon Andrew , Klein Christopher , Pittock Sean J.
Published: May 2014

Purpose: Clustering of neural autoantibodies in patients with paraneoplastic neurologic disorders may predict tumor type. A mathematical analysis of neural autoantibody clusters was performed in 78,889 patients undergoing evaluation for a suspected paraneoplastic autoimmune neurologic disorder. Tumor predictive autoantibody profiles were confirmed in sera from patients with histologically proven tonsillar cancer, thymoma, and lung cancer.

Patients and Methods: Of note, 78,889 patient sera were tested for 15 defined neural autoantibodies (1.2 million tests). The observed and hypothesized frequencies of autoantibody clusters were compared and their tumor associations defined. A tumor validation study comprised serum from 368 patients with a variety of tumors (thymoma, lung, or tonsil).

Results: Informative oncological associations included (i) thymoma in 85% of patients with muscle striational, acetylcholine receptor antibodies plus CRMP5 autoantibodies; (ii) lung carcinoma in 80% with both P/Q-type and N-type calcium channel antibodies plus SOX1-IgG; and (iii) in men, prostate carcinoma frequency more than doubled when striational and muscle AChR specificities were accompanied by ganglionic AChR antibody. In women, amphiphysin-IgG alone was associated commonly with breast carcinoma, but amphiphysin-IgG, coexisting with antineuronal nuclear autoantibody-type 1 or CRMP5-IgG, was associated with lung cancer (P < 0.0001). In the validation cohorts, many tumor-associated profiles were encountered that matched the clusters identified in the screening study (e.g., 15% of thymoma patients had striational, acetylcholine receptor antibodies plus collapsin response-mediator protein-5 autoantibodies).

Conclusions: Neural autoantibodies commonly coexist in specific clusters that are identifiable by comprehensive screening. Signature autoantibody clusters may predict a patient's cancer risk and type. Clin Cancer Res; 20(14); 3862–9. ©2014 AACR.
Rescue of Notch-1 Signaling in Antigen-Specific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer
Authors: Sierra Rosa A. , Thevenot Paul , Raber Patrick L. , Cui Yan , Parsons Chris , Ochoa Augusto C. , Trillo-Tinoco Jimena , Valle Luis Del , Rodriguez Paulo C.
Published: May 2014

An impaired antitumor immunity is found in patients with cancer and represents a major obstacle in the successful development of different forms of immunotherapy. Signaling through Notch receptors regulates the differentiation and function of many cell types, including immune cells. However, the effect of Notch in CD8+ T-cell responses in tumors remains unclear. Thus, we aimed to determine the role of Notch signaling in CD8+ T cells in the induction of tumor-induced suppression. Our results using conditional knockout mice show that Notch-1 and Notch-2 were critical for the proliferation and IFNγ production of activated CD8+ T cells and were significantly decreased in tumor-infiltrating T cells. Conditional transgenic expression of Notch-1 intracellular domain (N1IC) in antigen-specific CD8+ T cells did not affect activation or proliferation of CD8+ T cells, but induced a central memory phenotype and increased cytotoxicity effects and granzyme B levels. Consequently, a higher antitumor response and resistance to tumor-induced tolerance were found after adoptive transfer of N1IC-transgenic CD8+ T cells into tumor-bearing mice. Additional results showed that myeloid-derived suppressor cells (MDSC) blocked the expression of Notch-1 and Notch-2 in T cells through nitric oxide–dependent mechanisms. Interestingly, N1IC overexpression rendered CD8+ T cells resistant to the tolerogenic effect induced by MDSC in vivo. Together, the results suggest the key role of Notch in the suppression of CD8+ T-cell responses in tumors and the therapeutic potential of N1IC in antigen-specific CD8+ T cells to reverse T-cell suppression and increase the efficacy of T cell–based immunotherapies in cancer. Cancer Immunol Res; 2(8); 800–11. ©2014 AACR.
Anti-VEGF Therapy in Myopic Choroidal Neovascularization: Long-Term Results
Authors: Freitas-da-Costa Paulo , Pinheiro-Costa João , Carvalho Beatriz , Falcão Manuel , Brandão Elisete , Falcão-Reis Fernando , Carneiro Ângela
Published: May 2014

Purpose: To evaluate the medium- and long-term efficacy of anti-VEGF agents in the treatment of choroidal neovascularization secondary to pathologic myopia (mCNV). Methods: We performed a retrospective analysis of patients with mCNV who had been treated with intravitreous anti-VEGF for at least 2 years. The best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were compared before and after the treatment. The number of injections per year was also assessed. Results: The results were analysed at 2 years for 67 eyes, at 3 years for 52 eyes, at 4 years for 28 eyes and at 5 years for 13 eyes. The mean change from baseline BCVA was significant at 2 years (+8.6 letters; p < 0.001) and this gain remained significantly stable for a period of 5 years. The mean CRT showed a significant decrease over time, with a nadir at 2 years (-104.0 μm; p < 0.001). The mean number of injections performed during the first year was 5.2, being lower in subsequent years (p < 0.001). Conclusion: In this subset of patients with mCNV, an intravitreous therapy with anti-VEGF agents proved to have effective results over 5 years, with a sustained increase in BCVA.