bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful endoscopic treatment of an intestinal diospyrobezoar migrated from the stomach
Authors: Qin Bin , Wan Xiao Long , Guo Xiao Yan , Dong Lei
Published: July 2014

Diospyrobezoars are a rare cause of small intestinal obstruction. A 78-year-old man, with a history of persimmons ingestion and gastrectomy, presented with upper abdominal pain and weight loss. The upper gastrointestinal endoscopy showed a huge bezoar in the stomach. After initial endoscopic fragmentation, the abdominal X-ray revealed intestinal obstruction and the colonoscopy showed large fragments of the bezoar filling the terminal ileum. The migrated bezoar pieces were successfully removed by endoscopic fragmentation with a cutting lithotripter.
Pre-existing type 2 diabetes and risk of lung cancer: a report from two prospective cohort studies of 133 024 Chinese adults in urban Shanghai
Authors: Yang Wan-Shui , Yang Yang , Yang Gong , Chow Wong-Ho , Li Hong-Lan , Gao Yu-Tang , Ji Bu-Tian , Rothman Nat , Zheng Wei , Shu Xiao-Ou , Xiang Yong-Bing
Published: July 2014

Objectives

Observational studies of type 2 diabetes (T2D) and lung cancer risk are limited and controversial. We thus examined the association between T2D and risk of incident lung cancer using a cohort design.

Setting

Data from two ongoing population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002–2006 and the Shanghai Women's Health Study, SWHS, 1996–2000) were used. Cox proportional-hazards regression models with T2D as a time-varying exposure were modelled to estimate HRs and 95% CIs.

Participants

The study population included 61 491 male participants aged 40–74 years from SMHS and 74 941 female participants aged 40–70 years from SWHS.

Outcome measure

Lung cancer cases were identified through annual record linkage to the Shanghai Cancer Registry and Shanghai Municipal Registry of Vital Statistics, and were further verified through home visits and a review of medical charts by clinical and/or pathological experts. Outcome data until 31 December 2010 for men and women were used for the present analysis.

Results

After a median follow-up of 6.3 years for SMHS and 12.2 years for SWHS, incident lung cancer cases were detected in 492 men and 525 women. A null association between T2D and lung cancer risk was observed in men (HR=0.87, 95% CI 0.62 to 1.21) and women (HR=0.92, 95% CI 0.69 to 1.24) after adjustments for potential confounders. Similar results were observed among never smokers.

Conclusions

There is little evidence that pre-existing T2D may influence the incidence of lung cancer.
Rapid paediatric fluid resuscitation: a randomised controlled trial comparing the efficiency of two provider-endorsed manual paediatric fluid resuscitation techniques in a simulated setting
Authors: Cole Evan T , Harvey Greg , Urbanski Sara , Foster Gary , Thabane Lehana , Parker Melissa J
Published: July 2014

Objectives

Manual techniques of intravascular fluid administration are commonly used during paediatric resuscitation, although it is unclear which technique is most efficient in the hands of typical healthcare providers. We compared the rate of fluid administration achieved with the disconnect–reconnect and push–pull manual syringe techniques for paediatric fluid resuscitation in a simulated setting.

Methods

This study utilised a randomised crossover trial design and enrolled 16 consenting healthcare provider participants from a Canadian paediatric tertiary care centre. The study was conducted in a non-clinical setting using a model simulating a 15 kg child in decompensated shock. Participants administered 900 mL (60 mL/kg) of normal saline to the simulated patient using each of the two techniques under study. The primary outcome was the rate of fluid administration, as determined by two blinded independent video reviewers. We also collected participant demographic data and evaluated other secondary outcomes including total volume administered, number of catheter dislodgements, number of technical errors, and subjective and objective measures of provider fatigue.

Results

All 16 participants completed the trial. The mean (SD) rate of fluid administration (mL/s) was greater for the disconnect–reconnect technique at 1.77 (0.145) than it was for the push–pull technique at 1.62 (0.226), with a mean difference of 0.15 (95% CI 0.055 to 0.251; p=0.005). There was no difference in mean volume administered (p=0.778) or participant self-reported fatigue (p=0.736) between techniques. No catheter dislodgement events occurred.

Conclusions

The disconnect–reconnect technique allowed for the fastest rate of fluid administration, suggesting that use of this technique may be preferable in situations requiring rapid resuscitation. These findings may help to inform future iterations of paediatric resuscitation guidelines.

Trial registration number

This trial was registered at ClinicalTrials.gov [NCT01774214] prior to enrolling the first participant.
Prevalence and severity of patient harm in a sample of UK-hospitalised children detected by the Paediatric Trigger Tool
Authors: Chapman Susan M , Fitzsimons John , Davey Nicola , Lachman Peter
Published: July 2014

The measurement and examination of adverse events (AEs) that occur in children during hospital admissions is essential if we are to prevent, reduce or ameliorate the harm experienced. The UK Paediatric Trigger Tool (UKPTT) is a method of retrospective case note review that measures harm in hospitalised children.

Objectives

To examine the harm resulting from the processes of healthcare in hospitalised children from centres providing data to the National Health Service (NHS) Institute UKPTT data portal, to understand the positive predictive values of triggers and to make recommendations for the further development of the trigger tool.

Setting

25 hospitals across the UK, including secondary, tertiary and quaternary paediatric centres.

Participants

Randomly selected children who were admitted to hospital for longer than 24 h.

Outcome measures

The primary outcome measure was the rate of harm (the percentage of children experiencing one or more AEs during a hospital admission). Secondary measures were the severity of harm and performance of triggers.

Results

Data from 3992 patient admissions were reviewed across the hospitals and submitted to the trigger tool portal from February 2008 to November 2011. At least one AE was reported for 567 (14.2%) patients, with 211 (5.3%) experiencing more than one event. There were 1001 AEs identified. Where harm occurred, it was considered temporary for 923 (92.2%) AEs; however, 43 (4.3%) AEs resulted in the need for life-sustaining interventions, 18 (1.8%) AEs led to permanent harm and for 17 children (1.7% of AEs) the AE was believed to have contributed to death.

Conclusions

There is a significant, measurable level of harm experienced by children admitted to hospitals in the UK. While most of this harm is temporary, some of it is serious. The UKPTT offers organisations the means to measure and examine the AEs occurring in their hospital in order to reduce harm.
Rationale, design and baseline results of the Guangxi manganese-exposed workers healthy cohort (GXMEWHC) study
Authors: Lv Yingnan , Zou Yunfeng , Liu Jing , Chen Kangcheng , Huang Damin , Shen Yuefei , Zhong Yaoqiu , Liu Zhihao , Jiang Bei , Li Qin , Qing Li , Zhang Wei , Chen Lang , Wang Fenfen , Xia Bing , Yang Li , Yang Xiaobo
Published: July 2014

Objective

To determine the relationship between biomarkers of exposure, disease and susceptibility, and early health effects and long-term diseases related to occupational manganese (Mn) exposure.

Design

Baseline survey of a longitudinal cohort study of workers in a ferromanganese refinery.

Participants

A total of 1888 individuals (1197 men, 691 women; average seniority 15.34 years) were enrolled in the Guangxi manganese-exposed workers healthy cohort (GXMEWHC) study. Participants were between 18 and 60 years of age (mean 40.31 years), had worked in the ferromanganese refinery for at least 1 year and lived in the local area.

Results

The GXMEWHC study included a baseline survey. Participants were divided into four groups according to manganese (Mn) cumulative exposure index (Mn-CEI) levels: an internal control group (Mn-CEI <1.0 mg/m3 year), a low exposure group (1.0 mg/m3 year≤Mn-CEI<2.0 mg/m3 year), a medium exposure group (2.0 mg/m3 year≤Mn-CEI<5.0 mg/m3 year) and a high exposure group (Mn-CEI≥5.0 mg/m3 year). Genome-wide association studies of quantitative trait loci and binary trait loci in 500 Mn-exposed workers were performed using Illumina Infinium HumanExome BeadChip arrays. Stored plasma, DNA, hair and urine are available for further study. Participants will be followed up every 3 years.

Conclusions

The GXMEWHC study provides abundant data for exploring the systemic health effects of occupational Mn exposure using biomarkers of exposure, disease and susceptibility.
Comparing the clinical-effectiveness and cost-effectiveness of an internet-delivered Acceptance and Commitment Therapy (ACT) intervention with a waiting list control among adults with chronic pain: study protocol for a randomised controlled trial
Authors: Hayes Sara , Hogan Michael , Dowd Haulie , Doherty Edel , O'Higgins Siobhan , Nic Gabhainn Saoirse , MacNeela Padraig , Murphy Andrew W , Kropmans Thomas , O'Neill Ciaran , Newell John , McGuire Brian E
Published: July 2014

Introduction

Internet-delivered psychological interventions among people with chronic pain have the potential to overcome environmental and economic barriers to the provision of evidence-based psychological treatment in the Irish health service context. While the use of internet-delivered cognitive–behavioural therapy programmes has been consistently shown to have small-to-moderate effects in the management of chronic pain, there is a paucity in the research regarding the effectiveness of an internet-delivered Acceptance and Commitment Therapy (ACT) programme among people with chronic pain. The current study will compare the clinical-effectiveness and cost-effectiveness of an online ACT intervention with a waitlist control condition in terms of the management of pain-related functional interference among people with chronic pain.

Methods and analysis

Participants with non-malignant pain that persists for at least 3 months will be randomised to one of two study conditions. The experimental group will undergo an eight-session internet-delivered ACT programme over an 8-week period. The control group will be a waiting list group and will be offered the ACT intervention after the 3-month follow-up period. Participants will be assessed preintervention, postintervention and at a 3-month follow-up. The primary outcome will be pain-related functional interference. Secondary outcomes will include: pain intensity, depression, global impression of change, acceptance of chronic pain and quality of life. A qualitative evaluation of the perspectives of the participants regarding the ACT intervention will be completed after the trial.

Ethics and dissemination

The study will be performed in agreement with the Declaration of Helsinki and is approved by the National University of Ireland Galway Research Ethics Committee (12/05/05). The results of the trial will be published according to the CONSORT statement and will be presented at conferences and reported in peer-reviewed journals.

Trial registration number

ISRCTN18166896.
Treatment effect of memantine on survival in dementia with Lewy bodies and Parkinson's disease with dementia: a prospective study
Authors: Stubendorff Kajsa , Larsson Victoria , Ballard Clive , Minthon Lennart , Aarsland Dag , Londos Elisabet
Published: July 2014

Objective

To investigate the effect on survival of treatment with memantine in patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD).

Methods

75 patients with DLB and PDD were included in a prospective double-blinded randomised placebo-controlled trial (RCT) of memantine, of whom long-term follow-up was available for 42. Treatment response was recorded 24 weeks from baseline and measured by Clinical Global Impression of Change (CGIC). The participants were grouped as responders (CGIC 1–3) or non-responders (CGIC 4–7). The 24-week RCT was followed by open-label treatment and survival was recorded at 36 months.

Results

After 36-month follow-up, patients in the memantine group had a longer length of survival compared with patients in the placebo group (log rank x²=4.02, p=0.045). Within the active treatment group, survival analysis 36 months from baseline showed that the memantine responders, based on CGIC, had higher rates of survival compared with the non-responders (log rank x²=6.595, p=0.010). Similar results were not seen in the placebo group.

Conclusions

Early treatment with memantine and a positive clinical response to memantine predicted longer survival in patients with DLB and PDD. This suggests a possible disease-modifying effect and also has implications for health economic analysis. However, owing to the small study sample, our results should merely be considered as generating a hypothesis which needs to be evaluated in larger studies.

Trial registration number

ISRCTN89624516.
Doctors admitted to a Physicians’ Health Program: a comparison of self-referrals versus directed referrals
Authors: Braquehais María Dolores , Valero Sergi , Bel Miquel Jordi , Navarro María Cecilia , Matalí Josep Lluís , Nasillo Viviana , Padrós Jaume , Arteman Antoni , Bruguera Eugeni , Casas Miquel
Published: July 2014

Objective

To compare the profile of doctors with mental disorders admitted to a Physicians’ Health Program (PHP) depending on their type of referral.

Design

Retrospective chart review.

Method

We analysed 1545 medical records of doctors admitted to the Barcelona PHP (PAIMM) from 1 February 1998 to 31 December 2012.

Results

Most doctors (83.2%) were self-referred to the programme. Patients non-self-referred were older (=55 vs=49.6 years; t=6.96, p<0.01) than those self-referred and there were more men (68.3%) than women (45.8%; OR=0.39; 95% CI 0.29 to 0.52). Self-referrals were more frequent among patients with non-addictive disorders (84.6% vs 15.4%; OR=4.52; 95% CI 3.23 to 28.45). Self-referred patients needed less inpatient admissions (16.8% vs30.9%; OR=2.22; 95% CI 1.63 to 3.01) and the length of their treatment episodes was shorter (=24.3 vs = 32.4 months; t=3.34; p<0.01). Logistic regression showed a significant model (χ2=67.52; df=3; p<0.001). Age, gender and diagnosis were statistically associated with type of referral to the programme.

Conclusions

Type of referral to a PHP may be influenced not only by sick doctors’ personal traits but also by each programme's design and how it is perceived by service users. Our findings should be taken into account when designing treatment and preventive interventions for this professional group.
The health of the Role 1 doctor
Authors: Parsons Iain T
Published: July 2014

Many pitfalls are evident in the event that a doctor becomes a patient requiring investigation or treatment. The military environment theoretically creates an added dimension to difficulties such as self-treatment, insight and objectivity, vulnerability, mental health and medication abuse, confidentiality and the kerb-side consultation. These are explored with the military and civilian perspectives contrasted. Further qualitative research is required to formally assess what barriers military doctors face in accessing military healthcare. This, along with national guidelines should be incorporated into formal policy.
Observed and predicted behaviour of rail ballast under monotonic loading capturing particle breakage
Authors: Indraratna Buddhima , Sun Qi Deng , Nimbalkar Sanjay
Published: July 2014

A substantial amount of experimental evidence suggests that the critical state envelope for ballast is nonlinear, especially at low confining pressure. To study the implications of this nonlinearity and the associated role of particle breakage, monotonically loaded drained triaxial tests were conducted using a large-scale cylindrical triaxial apparatus. A nonlinear critical state envelope is determined in the q–p′ and υ–lnp′ planes. Mathematical expressions for critical state stress ratio and specific volume are proposed to incorporate the evolution of particle breakage during monotonic shearing. In this paper, an elastoplastic constitutive model based on the critical state soil mechanics framework is presented to capture the salient aspects of stress–strain behaviour and degradation of ballast. Constitutive parameters were conveniently determined from large-scale laboratory tests. The model is able to predict the monotonic shear behaviour of ballast corroborating with the laboratory measurements. The proposed model is further validated using experimental results available from past independent studies.
IDENTIFYING RELIABLE POSTS AND USERS IN ONLINE SOCIAL NETWORKS
Authors: XIE SIFA , WENG WEI , CHEN KE , LIU XIANGRONG
Published: July 2014

In the age of Web 2.0, generalizing concepts are mainly based on information sharing and user cooperation. The user-centric Internet mode encourages more users to participate in the Internet. However, this mode causes the flooding of social networks with low-quality information. Thus, identifying trusted information in online social networks (OSNs) so as to enable the Internet to serve humans better has gradually become a research hotspot. However, most studies evaluate the quality of user-created content or discriminate reliable users in isolation. These results are specific to particular social networks and lack generality. Intuitively, reliable content and users are closely related. In this study, the authors attempt to combine these two types of reliable data by separately identifying reliable posts and users in a social network. Posts and users are found to improve each other based on the preliminary identification results. To deal with imbalanced data, an algorithm that combines oversampling and undersampling is used to build balanced data. An ensemble classifier is adopted for data classification. Experiments show that the proposed framework is both effective and efficient for most types of OSNs. The contributions of this study are two-fold: (i) a framework combining user-created content and reliable user recognition is proposed, and (ii) an ensemble classifier is built for use in data classification.
Securing Vehicle Communication Systems by the KLJN Key Exchange Protocol
Authors: Saez Y. , Cao X. , Kish L. B. , Pesti G.
Published: July 2014

We review the security requirements for vehicular communication networks and provide a critical assessment of some typical communication security solutions. We also propose a novel unconditionally secure vehicular communication architecture that utilizes the Kirchhoff-law–Johnson-noise (KLJN) key distribution scheme.
Beneficial Effect of Noise in Suppression of Self-Excited Vibrations
Authors: Bobryk R. V. , Yurchenko D.
Published: July 2014

We discuss the possibility of full suppressions of self-excited vibrations by noise. Recently, periodic excitations have been intensively studied for this aim. We compare the used periodic and random noise excitations in the case of a two-mass system. It is shown that the random noise excitations can be more efficient under certain conditions. The telegraphic process is used as the source of noise. The mean-square (energetic) asymptotic stability of the system is a tool in study of the suppression. The stability charts are presented for different values of the transition rate of the telegraphic noise.
Comparative theoretical synthesis of high-energy explosive 1,4,5,8-tetranitro-1,4,5,8-tetraazadecalin
Authors: Cheng Ken-Fa , Liu Min-Hsien
Published: July 2014

Reaction mechanisms were proposed in this study for the theoretical synthesis of high-energy 1,4,5,8-tetranitro-1,4,5,8-tetraazadecalin (TNAD). Corresponding computations were performed using density functional theory (DFT) and the Hartree Fock (HF) method with the same 6-31G(d,p) base function. Glyoxal and ethylenediamine were used as the raw materials and were placed into respective gaseous and solvated (water or ethanol) environments to proceed the condensation reaction to form the precursor 1,4,5,8-tetraazadecalin, which subsequently underwent four stages of nitro-group substitution to obtain the target TNAD compound. A whole reaction scheme closely related to the experimental processes was successfully constructed, and the corresponding energy barriers were estimated for each elementary reaction. The findings revealed that the overall activation energy by B3LYP/6-31G(d,p) calculation is 2660.4 kJ/mol, which is lower than the 2832.1 kJ/mol calculated by HF/6-31G(d,p) computation. Furthermore, the reaction has a lower overall energy barrier in the solvated environment than in the gaseous system, being 2389.6 kJ/mol in ethanol, 2428.7 kJ/mol in water and 2660.4 kJ/mol in the gaseous phase. The ethanol-solvated system is suggested to be the most suitable medium for the synthesis of TNAD.
Allergen-induced resistin-like molecule-α promotes esophageal epithelial cell hyperplasia in eosinophilic esophagitis
Authors: Mavi Parm , Niranjan Rituraj , Dutt Parmesh , Zaidi Asifa , Shukla Jai Shankar , Korfhagen Thomas , Mishra Anil
Published: July 2014

Resistin-like molecule (Relm)-α is a secreted, cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-β, and Relm-γ. Although resistin was initially defined based on its insulin-resistance activity, the family members are highly induced in various inflammatory states. Earlier studies implicated Relm-α in insulin resistance, asthmatic responses, and intestinal inflammation; however, its function still remains an enigma. We now report that Relm-α is strongly induced in the esophagus in an allergen-challenged murine model of eosinophilic esophagitis (EoE). Furthermore, to understand the in vivo role of Relm-α, we generated Relm-α gene-inducible bitransgenic mice by using lung-specific CC-10 promoter (CC10-rtTA- Relm-α). We found Relm-α protein is significantly induced in the esophagus of CC10-rtTA- Relm-α bitransgenic mice exposed to doxycycline food. The most prominent effect observed by the induction of Relm-α is epithelial cell hyperplasia, basal layer thickness, accumulation of activated CD4+and CD4−T cell subsets, and eosinophilic inflammation in the esophagus. The in vitro experiments further confirm that Relm-α promotes primary epithelial cell proliferation but has no chemotactic activity for eosinophils. Taken together, our studies report for the first time that Relm-α induction in the esophagus has a major role in promoting epithelial cell hyperplasia and basal layer thickness, and the accumulation of activated CD4+and CD4−T cell subsets may be responsible for partial esophageal eosinophilia in the mouse models of EoE. Notably, the epithelial cell hyperplasia and basal layer thickness are the characteristic features commonly observed in human EoE.
TCF-1-mediated Wnt signaling regulates Paneth cell innate immune defense effectors HD-5 and -6: implications for Crohn's disease
Authors: Beisner Julia , Teltschik Zora , Ostaff Maureen J. , Tiemessen Machteld M. , Staal Frank J. T. , Wang Guoxing , Gersemann Michael , Perminow Gori , Vatn Morten H. , Schwab Matthias , Stange Eduard F. , Wehkamp Jan
Published: July 2014

Wnt signaling regulates small intestinal stem cell maintenance and Paneth cell differentiation. In patients with ileal Crohn's disease (CD), a decrease of Paneth cell α-defensins has been observed that is partially caused by impaired TCF-4 and LRP6 function. Here we show reduced expression of the Wnt signaling effector TCF-1 (also known as TCF-7) in patients with ileal CD. Reporter gene assays and in vitro promoter binding analysis revealed that TCF-1 activates α-defensin HD-5 and HD-6 transcription in cooperation with β-catenin and that activation is mediated by three distinct TCF binding sites. EMSA analysis showed binding of TCF-1 to the respective motifs. In ileal CD patients, TCF-1 mRNA expression levels were significantly reduced. Moreover, we found specifically reduced expression of active TCF-1 mRNA isoforms. Tcf-1 knockout mice exhibited reduced cryptdin expression in the jejunum, which was not consistently seen at other small intestinal locations. Our data provide evidence that TCF-1-mediated Wnt signaling is disturbed in small intestinal CD, which might contribute to the observed barrier dysfunction in the disease.
Intestinal sweet-sensing pathways and metabolic changes after Roux-en-Y gastric bypass surgery
Authors: Bhutta Hina Y. , Deelman Tara E. , le Roux Carel W. , Ashley Stanley W. , Rhoads David B. , Tavakkoli Ali
Published: July 2014

Studies suggest that improvements in type 2 diabetes (T2D) post- Roux-en-Y gastric bypass (RYGB) surgery are attributable to decreased intestinal glucose absorption capacity mediated by exclusion of sweet taste-sensing pathways in isolated proximal bowel. We probed these pathways in rat models that had undergone RYGB with catheter placement in the biliopancreatic (BP) limb to permit post-RYGB exposure of isolated bowel to sweet taste stimulants. Lean Sprague Dawley ( n = 13) and obese Zucker diabetic fatty rats ( n = 15) underwent RYGB with BP catheter placement. On postoperative day 11 (POD 11), rats received catheter infusions of saccharin [sweet taste receptor (T1R2/3) agonist] or saline (control). Jejunum was analyzed for changes in glucose transporter/sensor mRNA expression and functional sodium-glucose transporter 1 (SGLT1)-mediated glucose uptake. Saccharin infusion did not alter glucose uptake in the Roux limb of RYGB rats. Intestinal expression of the glucose sensor T1R2 and transporters (SGLT1, glucose transporter 2) was similar in saccharin- vs. saline-infused rats of both strains. However, the abundance of SGLT3b mRNA, a putative glucose sensor, was higher in the common limb vs. BP/Roux limb in both strains of bypassed rats and was significantly decreased in the Roux limb after saccharin infusion. We concluded that failure of BP limb exposure to saccharin to increase Roux limb glucose uptake suggests that isolation of T1R2/3 is unlikely to be involved in metabolic benefits of RYGB, as restimulation failed to reverse changes in intestinal glucose absorption capacity. The altered expression pattern of SGLT3 after RYGB warrants further investigation of its potential involvement in resolution of T2D after RYGB.
Cardiac-restricted overexpression or deletion of tissue inhibitor of matrix metalloproteinase-4: differential effects on left ventricular structure and function following pressure overload-induced hypertrophy
Authors: Yarbrough William M. , Baicu Catalin , Mukherjee Rupak , Van Laer An , Rivers William T. , McKinney Richard A. , Prescott Corey B. , Stroud Robert E. , Freels Parker D. , Zellars Kia N. , Zile Michael R. , Spinale Francis G.
Published: July 2014

Historically, the tissue inhibitors of matrix metalloproteinases (TIMPs) were considered monochromatic in function. However, differential TIMP profiles more recently observed with left ventricular (LV) dysfunction and matrix remodeling suggest more diverse biological roles for individual TIMPs. This study tested the hypothesis that cardiac-specific overexpression (TIMP-4OE) or deletion (knockout; TIMP-4KO) would differentially affect LV function and structure following pressure overload (LVPO). LVPO (transverse aortic constriction) was induced in mice (3.5 ± 0.1 mo of age, equal sex distribution) with TIMP-4OE ( n = 38), TIMP-4KO ( n = 24), as well as age/strain-matched wild type (WT, n = 25), whereby indexes of LV remodeling and function such as LV mass and ejection fraction (LVEF) were determined at 28 days following LVPO. Following LVPO, both early (7 days) and late (28 days) survival was ∼25% lower in the TIMP-4KO group ( P < 0.05). While LVPO increased LV mass in all groups, the relative hypertrophic response was attenuated with TIMP-4OE. With LVPO, LVEF was similar between WT and TIMP-4KO (48 ± 2% and 45 ± 3%, respectively) but was higher with TIMP-4OE (57 ± 2%, P < 0.05). With LVPO, LV myocardial collagen expression (type I, III) increased by threefold in all groups ( P < 0.05), but surprisingly this response was most robust in the TIMP-4KO group. These unique findings suggest that increased myocardial TIMP-4 in the context of a LVPO stimulus may actually provide protective effects with respect to survival, LV function, and extracellular matrix (ECM) remodeling. These findings challenge the canonical belief that increased levels of specific myocardial TIMPs, such as TIMP-4 in and of themselves, contribute to adverse ECM accumulation following a pathological stimulus, such as LVPO.
Disease-specific differences of left ventricular rotational mechanics between cardiac amyloidosis and hypertrophic cardiomyopathy
Authors: Nucifora Gaetano , Muser Daniele , Morocutti Giorgio , Piccoli Gianluca , Zanuttini Davide , Gianfagna Pasquale , Proclemer Alessandro
Published: July 2014

Left ventricular (LV) twist (LVT) and untwisting (LVUT) rate are global and thorough parameters of LV function. The aim of the present study was to investigate the differences in LV rotational mechanics between patients with cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM). Twenty consecutive patients with CA, 20 consecutive patients with HCM, and 20 consecutive subjects without evidence of structural heart disease were included. Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging was performed to evaluate biventricular function, LV mass index, and presence/extent of LGE. Feature-tracking analysis was applied to LV basal and apical short-axis images to determine peak LVT, time to peak LVT, peak LVUT rate, and time to peak LVUT rate. Peak LVT and peak LVUT rate were significantly impaired in patients with CA compared with controls ( P < 0.05 for both). In patients with HCM, peak LVT was increased ( P < 0.05) compared with controls, whereas peak LVUT rate was preserved ( P > 0.05). Time to peak LVUT rate was significantly prolonged in patients with CA and in patients with HCM compared with controls (ANOVA P < 0.001). At multivariate analysis, age ( P = 0.007), LV ejection fraction ( P = 0.035) and extent of LGE ( P < 0.001) were independently related to peak LVT, and LV mass index ( P = 0.015) and extent of LGE ( P = 0.004) were independently related to peak LVUT rate, whereas extent of LGE ( P < 0.001) was the only variable independently related to time to peak LVUT rate. In conclusion, CA and HCM have specific behavior of LV rotational mechanics. The extent of LGE significantly influences the LV rotational mechanics.
BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy
Authors: Urbina Princess , Singla Dinender K.
Published: July 2014

The main objective of this study was to determine whether or not monocyte infiltration occurs in the prediabetic (PD) heart and its role in PD cardiomyopathy. We hypothesized that the PD heart is significantly populated with monocytes and that bone morphogenetic protein (BMP)-7, a novel mediator of monocyte polarization, activates infiltrated monocytes into anti-inflammatory M2 macrophages, thereby inhibiting apoptosis and fibrosis and improving cardiac function. C57Bl6 mice were assigned to control, PD, or PD + BMP-7 groups. PD and PD + BMP-7 groups were administered streptozotocin (50 mg/kg), whereas control animals received sodium citrate buffer. Afterward, the PD + BMP-7 group was administered BMP-7 (200 μg/kg) for 3 days. Our data showed significantly increased infiltrated monocytes and associated pro-inflammatory cytokines, adverse cardiac remodeling, and heart dysfunction in the PD group ( P < 0.05). Interestingly, M2 macrophage differentiation and associated anti-inflammatory cytokines were enhanced and there were reduced adverse cardiac remodeling and improved cardiac function in the PD + BMP-7 group ( P < 0.05). In conclusion, our data suggest that PD cardiomyopathy is associated with increased monocyte infiltration and released proinflammatory cytokines, which contributes to adverse cardiac remodeling and cardiac dysfunction. Moreover, we report that BMP-7 possesses novel therapeutic potential in its ability to differentiate monocytes into M2 macrophages and confer cardiac protection in the PD heart.
Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle
Authors: Plomaritas Danielle R. , Herbert Lindsay M. , Yellowhair Tracylyn R. , Resta Thomas C. , Gonzalez Bosc Laura V. , Walker Benjimen R. , Jernigan Nikki L.
Published: July 2014

Our laboratory shows that acid-sensing ion channel 1 (ASIC1) contributes to the development of hypoxic pulmonary hypertension by augmenting store-operated Ca2+ entry (SOCE) that is associated with enhanced agonist-induced vasoconstriction and arterial remodeling. However, this enhanced Ca2+ influx following chronic hypoxia (CH) is not dependent on an increased ASIC1 protein expression in pulmonary arterial smooth muscle cells (PASMC). It is well documented that hypoxic pulmonary hypertension is associated with changes in redox potential and reactive oxygen species homeostasis. ASIC1 is a redox-sensitive channel showing increased activity in response to reducing agents, representing an alternative mechanism of regulation. We hypothesize that the enhanced SOCE following CH results from removal of an inhibitory effect of hydrogen peroxide (H2O2) on ASIC1. We found that CH increased PASMC superoxide (O2·−) and decreased rat pulmonary arterial H2O2 levels. This decrease in H2O2 is a result of decreased Cu/Zn superoxide dismutase expression and activity, as well as increased glutathione peroxidase (GPx) expression and activity following CH. Whereas H2O2 inhibited ASIC1-dependent SOCE in PASMC from control and CH animals, addition of catalase augmented ASIC1-mediated SOCE in PASMC from control rats but had no further effect in PASMC from CH rats. These data suggest that, under control conditions, H2O2 inhibits ASIC1-dependent SOCE. Furthermore, H2O2 levels are decreased following CH as a result of diminished dismutation of O2·− and increased H2O2 catalysis through GPx-1, leading to augmented ASIC1-dependent SOCE.
Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl− channels in Calu-3 airway epithelial cells
Authors: Hendrick Siobhán M. , Mroz Magdalena S. , Greene Catherine M. , Keely Stephen J. , Harvey Brian J.
Published: July 2014

Bile acids resulting from the aspiration of gastroesophageal refluxate are often present in the lower airways of people with cystic fibrosis and other respiratory distress diseases. Surprisingly, there is little or no information on the modulation of airway epithelial ion transport by bile acids. The secretory effect of a variety of conjugated and unconjugated secondary bile acids was investigated in Calu-3 airway epithelial cells grown under an air-liquid interface and mounted in Ussing chambers. Electrogenic transepithelial ion transport was measured as short-circuit current ( Isc). The taurine-conjugated secondary bile acid, taurodeoxycholic acid (TDCA), was found to be the most potent modulator of basal ion transport. Acute treatment (5 min) of Calu-3 cells with TDCA (25 μM) on the basolateral side caused a stimulation of Isc, and removal of extracellular Cl− abolished this response. TDCA produced an increase in the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent current that was abolished by pretreatment with the CFTR inhibitor CFTRinh172. TDCA treatment also increased Cl− secretion through calcium-activated chloride (CaCC) channels and increased the Na+/K+ pump current. Acute treatment with TDCA resulted in a rapid cellular influx of Ca2+ and increased cAMP levels in Calu-3 cells. Bile acid receptor-selective activation with INT-777 revealed TGR5 localized at the basolateral membrane as the receptor involved in TDCA-induced Cl− secretion. In summary, we demonstrate for the first time that low concentrations of bile acids can modulate Cl− secretion in airway epithelial cells, and this effect is dependent on both the duration and sidedness of exposure to the bile acid.
Effects of pole compliance and step frequency on the biomechanics and economy of pole carrying during human walking
Authors: Castillo Eric R. , Lieberman Graham M. , McCarty Logan S. , Lieberman Daniel E.
Published: July 2014

This study investigates whether a flexible pole can be used as an energy-saving method for humans carrying loads. We model the carrier and pole system as a driven damped harmonic oscillator and predict that the energy expended by the carrier is affected by the compliance of the pole and the ratio between the pole's natural frequency and the carrier's step frequency. We tested the model by measuring oxygen consumption in 16 previously untrained male participants walking on a treadmill at four step frequencies using two loaded poles: one made of bamboo and one of steel. We found that when the bamboo pole was carried at a step frequency 20% greater than its natural frequency, the motions of the centers of mass of the load and carrier were approximately equal in amplitude and opposite in phase, which we predicted would save energy for the carrier. Carrying the steel pole, however, resulted in the carrier and loads oscillating in phase and with roughly equal amplitude. Although participants were less economical using poles than predicted costs using conventional fixed-load techniques (such as backpacks), the bamboo pole was on average 5.0% less costly than the steel pole. When allowed to select their cadence, participants also preferred to carry the bamboo pole at step frequencies of ∼2.0 Hz. This frequency, which is significantly higher than the preferred unloaded step frequency, is most economical. These experiments suggest that pole carriers can intuitively adjust their gaits, or choose poles with appropriate compliance, to increase energetic savings.
Impact of skin temperature and hydration on plasma volume responses during exercise
Authors: Kenefick Robert W. , Sollanek Kurt J. , Charkoudian Nisha , Sawka Michael N.
Published: July 2014

Heat stress and hydration may both alter plasma volume (PV) responses during acute exercise; potential interactions have not been fully studied. The purpose of this study was to determine the effect of graded elevations in skin temperature (Tsk) on PV changes during steady-state exercise under conditions of euhydration (EU) and hypohydration (HYPO, −4% of body mass). Thirty-two men (22 ± 4 yr) were divided into four cohorts ( n = 8 each) and completed EU and HYPO trials in one environment [ambient temperature (Ta) 10, 20, 30, and 40°C]. Thirty minutes of cycle ergometry (50% V̇o2peak) was performed. Core (Tre) and mean skin (Tsk) temperatures were measured; changes in PV, total circulating protein (TCP), and mean arterial pressure (MAP) were calculated; and skin blood flow (SkBF) was estimated. Hypohydration decreased ( P < 0.05) PV by 200 ml (−5.7%) but did not alter TCP. Plasma loss was not different between EU and HYPO during exercise at any Ta. Plasma losses were greater ( P < 0.05) with elevated Ta with an average −130, −174, −294, and −445 ml losses during the 10, 20, 30, and 40°C trials, respectively. Significant ( P < 0.05) correlations ( r = 0.50 to 0.84) were found between ΔTCP and ΔPV during exercise when Tsk was cool/warm (<33°C; Ta 10, 20, and 30°C), but not at 40°C (high Tsk). We conclude that 1) graded skin warming proportionally accentuated plasma loss; 2) plasma loss was associated with plasma protein efflux at lower Tsk and SkBF; 3) at high Tsk, additional plasma loss likely results from increased net filtration at the capillaries; and 4) HYPO did not alter vascular fluid loss during exercise in any environment.
PTEN Deficiency Mediates a Reciprocal Response to IGFI and mTOR Inhibition
Authors: Patel Mukund , Gomez Nicholas C. , McFadden Andrew W. , Moats-Staats Billie M. , Wu Sam , Rojas Andres , Sapp Travis , Simon Jeremy M. , Smith Scott V. , Kaiser-Rogers Kathleen , Davis Ian J.
Published: July 2014

Recent evidence implicates the insulin-like growth factor (IGF) pathway in development of Ewing sarcoma, a highly malignant bone and soft-tissue tumor that primarily affects children and young adults. Despite promising results from preclinical studies of therapies that target this pathway, early-phase clinical trials have shown that a significant fraction of patients do not benefit, suggesting that cellular factors determine tumor sensitivity. Using FAIRE-seq, a chromosomal deletion of the PTEN locus in a Ewing sarcoma cell line was identified. In primary tumors, PTEN deficiency was observed in a large subset of cases, although not mediated by large chromosomal deletions. PTEN loss resulted in hyperactivation of the AKT signaling pathway. PTEN rescue led to decreased proliferation, inhibition of colony formation, and increased apoptosis. Strikingly, PTEN loss decreased sensitivity to IGF1R inhibitors but increased responsiveness to temsirolimus, a potent mTOR inhibitor, as marked by induction of autophagy. These results suggest that PTEN is lost in a significant fraction of primary tumors, and this deficiency may have therapeutic consequences by concurrently attenuating responsiveness to IGF1R inhibition while increasing activity of mTOR inhibitors. The identification of PTEN status in the tumors of patients with recurrent disease could help guide the selection of therapies.

Implications: PTEN status in Ewing sarcoma affects cellular responses to IGFI and mTOR-directed therapy, thus justifying its consideration as a biomarker in future clinical trials. Mol Cancer Res; 12(11); 1610–20. ©2014 AACR.
Viral Oncogene Expression in the Stem/Progenitor Cell Compartment of the Mouse Intestine Induces Adenomatous Polyps
Authors: Sáenz Robles Maria Teresa , Chong Jean Leon , Koivisto Christopher , Trimboli Anthony , Liu Huayang , Leone Gustavo , Pipas James M.
Published: July 2014

Genetic and epigenetic events that alter gene expression and/or protein function or localization are thought to be the primary mechanism that drives tumorigenesis and governs the clinical behavior of cancers. Yet, a number of studies have shown that the effects of oncogene expression or tumor suppressor ablation are highly dependent on cell type. The molecular basis for this cell-type specificity and how it contributes to tumorigenesis are unknown. Here, expression of a truncated SV40 large T antigen in murine intestinal crypts promoted the formation of numerous adenomatous polyps in the colon and small intestine. In contrast, when the same T-antigen construct is expressed in villous enterocytes, the consequences are limited to hyperplasia and dysplasia. The T-antigen–induced polyps show high levels of the proto-oncogene c-Myc protein even though there is no transport of β-catenin to the nucleus. Targeting the expression of viral oncogenes to intestinal crypts or villi provides a murine model system for studying cell-type specific effects in tumorigenesis, and is particularly relevant to the study of APC/β-catenin–independent pathways contributing to the generation of intestinal polyps.

Implications: This mouse model system describes the formation of colon polyps in the absence of Wnt/β-catenin signaling. Mol Cancer Res; 12(10); 1355–64. ©2014 AACR.
Kaempferol Targets RSK2 and MSK1 to Suppress UV Radiation-Induced Skin Cancer
Authors: Yao Ke , Chen Hanyong , Liu Kangdong , Langfald Alyssa , Yang Ge , Zhang Yi , Yu Dong Hoon , Kim Myoung Ok , Lee Mee-Hyun , Li Haitao , Bae Ki Beom , Kim Hong-Gyum , Ma Wei-Ya , Bode Ann M. , Dong Ziming , Dong Zigang
Published: July 2014

Solar UV (SUV) irradiation is a major factor in skin carcinogenesis, the most common form of cancer in the United States. The MAPK cascades are activated by SUV irradiation. The 90 kDa ribosomal S6 kinase (RSK) and mitogen and stress-activated protein kinase (MSK) proteins constitute a family of protein kinases that mediate signal transduction downstream of the MAPK cascades. In this study, phosphorylation of RSK and MSK1 was upregulated in human squamous cell carcinoma (SCC) and SUV-treated mouse skin. Kaempferol, a natural flavonol, found in tea, broccoli, grapes, apples, and other plant sources, is known to have anticancer activity, but its mechanisms and direct target(s) in cancer chemoprevention are unclear. Kinase array results revealed that kaempferol inhibited RSK2 and MSK1. Pull-down assay results, ATP competition, and in vitro kinase assay data revealed that kaempferol interacts with RSK2 and MSK1 at the ATP-binding pocket and inhibits their respective kinase activities. Mechanistic investigations showed that kaempferol suppresses RSK2 and MSK1 kinase activities to attenuate SUV-induced phosphorylation of cAMP-responsive element binding protein (CREB) and histone H3 in mouse skin cells. Kaempferol was a potent inhibitor of SUV-induced mouse skin carcinogenesis. Further analysis showed that skin from the kaempferol-treated group exhibited a substantial reduction in SUV-induced phosphorylation of CREB, c-Fos, and histone H3. Overall, our results identify kaempferol as a safe and novel chemopreventive agent against SUV-induced skin carcinogenesis that acts by targeting RSK2 and MSK1. Cancer Prev Res; 7(9); 958–67. ©2014 AACR.
Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
Authors: Chonghaile Triona Ni , Roderick Justine E. , Glenfield Cian , Ryan Jeremy , Sallan Stephen E. , Silverman Lewis B. , Loh Mignon L. , Hunger Stephen P. , Wood Brent , DeAngelo Daniel J. , Stone Richard , Harris Marian , Gutierrez Alejandro , Kelliher Michelle A. , Letai Anthony
Published: July 2014

Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears an ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199, both in vitro and in vivo. We thus describe for the first time a change of antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.

Significance: ETP T-ALL is a treatment-resistant subtype of T-ALL for which novel targeted therapies are urgently needed. We have discovered, through BH3 profiling, that ETP-ALL is BCL-2 dependent and is very sensitive to in vitro and in vivo treatment with ABT-199, a drug well tolerated in clinical trials. Cancer Discov; 4(9); 1074–87. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 973