bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical implementation of a new antibiotic prophylaxis regimen for percutaneous endoscopic gastrostomy
Authors: Lagergren Jesper , Mattsson Fredrik , Lagergren Pernilla
Published: June 2013

Objectives

This study was undertaken to test the extent to which a new antibiotic prophylaxis regimen for percutaneous endoscopic gastrostomy (PEG), identified as a justified and simpler alternative to conventional regimen in a randomised clinical trial, has been adopted in clinical practice.

Design

A Swedish nationwide implementation survey, conducted in February 2013, assessed the level of clinical implementation of a 20 ml dose of oral solution of sulfamethoxazole and trimethoprim deposited in the PEG catheter immediately after insertion. All hospitals inserting at least five PEGs annually were identified from the Swedish Patient Registry. A clinician involved in the PEG insertions at each hospital participated in a structured telephone interview addressing their routine use of antibiotic prophylaxis.

Setting

All Swedish hospitals inserting PEGs (n=60).

Participants

Representatives of PEG insertions at each of the 60 eligible hospitals participated (100% participation).

Main outcome measures

Use of routine antibiotic prophylaxis for PEG.

Results

A total of 32 (53%) of the 60 hospitals had adopted the new regimen. It was more frequently adopted in university hospitals (67%) than in community hospitals (41%). An annual total of 1813 (70%) of 2573 patients received the new regimen. Higher annual hospital volume was associated with a higher level of adoption of the new regimen (80% in the highest vs 31% in the lowest).

Conclusions

The clinical implementation of the new antibiotic prophylaxis regimen for PEG was high and rapid (70% of all patients within 3 years), particularly in large hospitals.
Would increasing centre volumes improve patient outcomes in peritoneal dialysis? A registry-based cohort and Monte Carlo simulation study
Authors: Evans David , Lobbedez Thierry , Verger Christian , Flahault Antoine
Published: June 2013

Objective

To estimate the association between centre volume and patient outcomes in peritoneal dialysis, explore robustness to residual confounding and predict the impact of policies to increase centre volumes.

Design

Registry-based cohort study with probabilistic sensitivity analysis and Monte Carlo simulation of (hypothetical) intervention effects.

Setting

112 secondary-care centres in France.

Participants

9602 adult patients initiating peritoneal dialysis.

Main outcome measures

Technique failure (ie, permanent transfer to haemodialysis), renal transplantation and death while on peritoneal dialysis within 5 years of initiating treatment. Associations with underlying risk measured by cause-specific HRs (cs-HRs) and with cumulative incidence by subdistribution HRs (sd-HRs). Intervention effects measured by predicted mean change in cumulative incidences.

Results

Higher volume centres had more patients with diabetes and were more frequently academic centres or associative groupings of private physicians. Patients in higher volume centres had a reduced risk of technique failure (>60 patients vs 0–10 patients: adjusted cs-HR 0.46; 95% CI 0.43 to 0.69), with no changed risk of death or transplantation. Sensitivity analyses mitigated the cs-HRs without changing the findings. In higher volume centres, the cumulative incidence was reduced for technique failure (>60 patients vs 0–10 patients: adjusted sd-HR 0.49; 95% CI 0.29 to 0.85) but was increased for transplantation and death (>60 patients vs 0–10 patients: transplantation—adjusted sd-HR 1.53; 95% CI 1.04 to 2.24; death—adjusted sd-HR 1.28; 95% CI 1.00 to 1.63). The predicted reduction in cumulative incidence of technique failure was largest under a scenario of shifting all patients to the two highest volume centre groups (0.091 reduction) but lower for three more realistic interventions (around 0.06 reduction).

Conclusions

Patients initiating peritoneal dialysis in high-volume centres had a considerably reduced risk of technique failure but simulations of interventions to increase exposure to high-volume centres yielded only modest improvements.
What is the best strategy for investigating abnormal liver function tests in primary care? Implications from a prospective study
Authors: Lilford Richard J , Bentham Louise M , Armstrong Matthew J , Neuberger James , Girling Alan J
Published: June 2013

Objective

Evaluation of predictive value of liver function tests (LFTs) for the detection of liver-related disease in primary care.

Design

A prospective observational study.

Setting

11 UK primary care practices.

Participants

Patients (n=1290) with an abnormal eight-panel LFT (but no previously diagnosed liver disease).

Main outcome measures

Patients were investigated by recording clinical features, and repeating LFTs, specific tests for individual liver diseases, and abdominal ultrasound scan. Patients were characterised as having: hepatocellular disease; biliary disease; tumours of the hepato-biliary system and none of the above. The relationship between LFT results and disease categories was evaluated by stepwise regression and logistic discrimination, with adjustment for demographic and clinical factors. True and False Positives generated by all possible LFT combinations were compared with a view towards optimising the choice of analytes in the routine LFT panel.

Results

Regression methods showed that alanine aminotransferase (ALT) was associated with hepatocellular disease (32 patients), while alkaline phosphatase (ALP) was associated with biliary disease (12 patients) and tumours of the hepatobiliary system (9 patients). A restricted panel of ALT and ALP was an efficient choice of analytes, comparing favourably with the complete panel of eight analytes, provided that 48 False Positives can be tolerated to obtain one additional True Positive. Repeating a complete panel in response to an abnormal reading is not the optimal strategy.

Conclusions

The LFT panel can be restricted to ALT and ALP when the purpose of testing is to exclude liver disease in primary care.
The effect of weekly short message service communication on patient retention in care in the first year after HIV diagnosis: study protocol for a randomised controlled trial (WelTel Retain)
Authors: van der Kop Mia L , Ojakaa David I , Patel Anik , Thabane Lehana , Kinagwi Koki , Ekström Anna Mia , Smillie Kirsten , Karanja Sarah , Awiti Patricia , Mills Edward , Marra Carlo , Kyomuhangi Lennie Bazira , Lester Richard T
Published: June 2013

Introduction

Interventions to improve retention in care after HIV diagnosis are necessary to optimise the timely initiation of antiretroviral therapy (ART) and HIV/AIDS control outcomes. Widespread mobile phone use presents new opportunities to engage patients in care. A randomised controlled trial (RCT), WelTel Kenya1, demonstrated that weekly text messages led to improved ART adherence and viral load suppression among those initiating ART. The aim of this study was to determine whether the WelTel intervention is an effective and cost-effective method of improving retention in care in the first year of care following HIV diagnosis.

Methods and analysis

WelTel Retain is an open, parallel group RCT that will be conducted at the Kibera Community Health Centre in Nairobi, Kenya. Over a 1-year period, we aim to recruit 686 individuals newly diagnosed with HIV who will be randomly allocated to an intervention or control arm (standard care) at a 1:1 ratio. Intervention arm participants will receive the weekly WelTel SMS ‘check-in’ to which they will be instructed to respond within 48 h. An HIV clinician will follow-up and triage any problems that are identified. Participants will be followed for 1 year, with a primary endpoint of retention in care at 12 months. Secondary outcomes include retention in stage 1 HIV care (patients return to the clinic to receive their first CD4 results) and timely ART initiation. Cost-effectiveness will be analysed through decision-analytic modelling.

Ethics and dissemination

Ethical approval has been obtained from the University of British Columbia and the African Medical and Research Foundation. This trial will test the effectiveness and cost-effectiveness of the WelTel intervention to engage patients during the first year of HIV care. Trial results and economic evaluation will help inform policy and practice on the use of WelTel in the early stages of HIV care.

Trial registration

ClinicalTrials.govNCT01630304.
The developmental origins of ageing: study protocol for the Dutch famine birth cohort study on ageing
Authors: de Rooij Susanne R , Roseboom Tessa J
Published: June 2013

Introduction

Evidence from animal studies suggest that the rate of ageing may be influenced not only by genetic and lifestyle factors, but also by the prenatal environment. We have previously shown that people who were exposed to famine during early gestation performed worse on a selective attention task, which may be a first sign of cognitive decline, and were on average 3 years younger at the time of coronary artery disease diagnosis. Women in this group seem to die at a younger age. We hypothesise that an accelerated ageing process, set in motion by the poor prenatal environment, underlies these findings.

Methods and analysis

The Dutch Famine Birth Cohort consists of 2414 men and women born in Amsterdam as term singletons around the time of the Dutch famine. In a subsample of 150 cohort members, who now are about 68 years of age, we are currently measuring cognitive decline and the incidence of white matter hyperintensities and cerebral microbleeds (through MRI), incidence of fractures, grip strength and physical performance, visual acuity and incidence of cataract operations. In this same subgroup, we will assess telomere length, oxidative stress and inflammatory status as potential underlying mechanisms. Furthermore, in the entire cohort, we will assess mortality as well as hospital admissions for age-related diseases up to the age of 68 years.

Ethics and dissemination

The study was approved by the local medical ethics committee (Academic Medical Centre, University of Amsterdam) and is being carried out in agreement with the Declaration of Helsinki. All participants give written informed consent. Study findings will be widely disseminated to the scientific public as well as to the medical society and general public.
The effects of a multisite aerobic exercise intervention on asthma morbidity in sedentary adults with asthma: the Ex-asthma study randomised controlled trial protocol
Authors: Bacon Simon L , Lavoie Kim L , Bourbeau Jean , Ernst Pierre , Maghni Karim , Gautrin Denyse , Labrecque Manon , Pepin Veronique , Pedersen Bente Klarlund
Published: June 2013

Objective

Aerobic exercise can improve cardiovascular fitness and does not seem to be detrimental to patients with asthma, though its role in changing asthma control and inflammatory profiles is unclear. The main hypothesis of the current randomised controlled trial is that aerobic exercise will be superior to usual care in improving asthma control. Key secondary outcomes are asthma quality of life and inflammatory profiles.

Design

A total of 104 sedentary adults with physician-diagnosed asthma will be recruited. Eligible participants will undergo a series of baseline assessments including: the asthma control questionnaire; the asthma quality-of-life questionnaire and the inflammatory profile (assessed from both the blood and sputum samples). On completion of the assessments, participants will be randomised (1:1 allocation) to either 12-weeks of usual care or usual care plus aerobic exercise. Aerobic exercise will consist of three supervised training sessions per week. Each session will consist of taking a short-acting bronchodilator, 10 min of warm-up, 40 min of aerobic exercise (50–75% of heart rate reserve for weeks 1–4, then 70–85% for weeks 5–12) and a 10 min cool-down. Within 1 week of completion, participants will be reassessed (same battery as at baseline). Analyses will assess the difference between the two intervention arms on postintervention levels of asthma control, quality of life and inflammation, adjusting for age, baseline inhaled corticosteroid prescription, body weight change and pretreatment dependent variable level. Missing data will be handled using standard multiple imputation techniques.

Ethics and dissemination

The study has been approved by all relevant research ethics boards. Written consent will be obtained from all participants who will be able to withdraw at any time.

Results

The result will be disseminated to three groups of stakeholder groups: (1) the scientific and professional community; (2) the research participants and (3) the general public.

Registration Details ClinicalTrials.gov Identifier

NCT00953342
A retrospective review of the palliative surgical management of malignant pleural effusions
Authors: Bell David , Wright Gavin
Published: June 2013

Background

A malignant pleural effusion (MPE) can be associated with debilitating dyspnoea. Determining optimal surgical management involves balancing the quality of palliation, degree of short-term dysfunction and expected duration of patient survival.

Objective

To examine differences in postoperative survival after different surgical approaches to MPEs and to analyse the relationship between primary tumour site and duration of postoperative survival.

Design, setting and subjects

Data from patients who underwent implantation of a tunnelled pleural catheter, video-assisted thoracoscopic surgery (VATS) pleurodesis or decortication at a thoracic surgical service from February 2001 to October 2010 were retrospectively reviewed.

Measurements and results

291 procedures were performed in 283 patients. The three most common primary malignancies were non-small cell lung cancer (NSCLC) (n=69), breast (n=62) and mesothelioma (n=49). Median postoperative survival was 184 days for NSCLC patients, 221 days for breast cancer patients and 595 days for mesothelioma patients. Tunnelled pleural catheters were implanted in 33 patients with a median survival of 92 days. VATS pleurodeses were performed in 224 patients with a median survival of 227 days. Decortications were performed in 26 patients with a median survival of 379 days.

Conclusions

Results reflect that procedures can be successfully matched to projected survival, although prognosis is not informed by primary tumour site, age or sex. Further to this, results are consistent with the policy that the procedures resulting in the shortest hospital stay and lowest peri-operative morbidity should be reserved for patients with the shortest predicted survival.
Is home-based palliative care cost-effective? An economic evaluation of the Palliative Care Extended Packages at Home (PEACH) pilot
Authors: McCaffrey Nikki , Agar Meera , Harlum Janeane , Karnon Jonathon , Currow David , Eckermann Simon
Published: June 2013

Objective

The aim of this study was to evaluate the cost-effectiveness of a home-based palliative care model relative to usual care in expediting discharge or enabling patients to remain at home.

Design

Economic evaluation of a pilot randomised controlled trial with 28 days follow-up.

Methods

Mean costs and effectiveness were calculated for the Palliative Care Extended Packages at Home (PEACH) and usual care arms including: days at home; place of death; PEACH intervention costs; specialist palliative care service use; acute hospital and palliative care unit inpatient stays; and outpatient visits.

Results

PEACH mean intervention costs per patient ($3489) were largely offset by lower mean inpatient care costs ($2450) and in this arm, participants were at home for one additional day on average. Consequently, PEACH is cost-effective relative to usual care when the threshold value for one extra day at home exceeds $1068, or $2547 if only within-study days of hospital admission are costed. All estimates are high uncertainty.

Conclusions

The results of this small pilot study point to the potential of PEACH as a cost-effective end-of-life care model relative to usual care. Findings support the feasibility of conducting a definitive, fully powered study with longer follow-up and comprehensive economic evaluation.
Teaching the difficult-to-teach topics
Authors: MacPherson Anna , Lawrie Iain , Collins Sarah , Forman Louise
Published: June 2013

It is now accepted that teaching in palliative medicine should be integrated throughout the medical undergraduate curriculum. Recommendations suggest the inclusion of knowledge areas such as symptom control, as well as more attitudinal aspects such as teamwork and understanding patient and carer perspectives on illness. These subjects should be taught on a stepwise basis, introducing concepts at an early stage and then be built on throughout training. However, how this is done and how effectively all aspects are taught vary considerably. This article outlines one way of using patient and carer experiences of significant illness, and multi-disciplinary teams, to teach attitudinal concepts behind palliative care to medical students early in their undergraduate careers. Palliative care is considered here in a broad sense, with the relevance to all healthcare professionals emphasised, and specialist palliative care used as an example of holistic care. The sessions consisted of small group discussions with patient and carer representatives as well as discussions with various members of the multi-disciplinary team. These were led by the patient/carer/professionals’ experiences and further explored with facilitated questions by the students. The sessions have been evaluated well by all involved, including patients, carers, multi-disciplinary team members and palliative medicine doctors. The learning objectives (to understand patient perspectives, multi-disciplinary working and holistic care) were achieved, along with discussion of professionalism.
Sports facilities in Madrid explain the relationship between neighbourhood economic context and physical inactivity in older people, but not in younger adults: a case study
Authors: Pascual Cruz , Regidor Enrique , Álvarez-del Arco Débora , Alejos Belén , Santos Juana M , Calle María E , Martínez David
Published: June 2013

Background

Neighbourhood characteristics may contribute to differences in physical inactivity.

Purpose

To evaluate whether the availability of sports facilities helps explain the differences in physical inactivity according to the economic context of the neighbourhood.

Methods

6607 participants representative of the population aged 16–74 years, resident in Madrid (Spain) in 2005, were analysed. Using ORs calculated by multilevel logistic regression, the association between per capita income of the neighbourhood of residence and physical inactivity was estimated, after adjusting for age, population density, individual socioeconomic characteristics and the availability of green spaces. The analysis was repeated after further adjustment for the availability of sports facilities to determine if this reduced the magnitude of the association.

Results

Residents in the neighbourhoods with the lowest per capita income had the highest OR for the prevalence of physical inactivity. In participants aged 16–49 years, after adjusting for the availability of sports facilities, the magnitude of the OR in the poorest neighbourhoods with respect to the richest neighbourhoods increased in men (from 2.22 to 2.35) and declined by 13% in women (from 2.13 to 1.98). In contrast, in the population aged 50–74 years, this adjustment reduced the magnitude of the OR by 21% in men (from 2.00 to 1.80) and by 53% in women (from 2.03 to 1.48).

Conclusions

The poorest neighbourhoods show the highest prevalence of physical inactivity. The availability of sports facilities explains an important part of this excess prevalence in participants aged 50–74 years, but not in younger individuals.
Use of emergency contraceptive pills among female sex workers in Swaziland
Authors: Yam Eileen A , Mnisi Zandile , Maziya Sibusiso , Kennedy Caitlin , Baral Stefan
Published: June 2013

Objectives

Female sex workers (FSW) often have unprotected sex. Emergency contraceptive pills (ECP) are an important back-up method to prevent unwanted pregnancy among FSW. We examine ECP use among FSW in Swaziland.

Methods

Using data from a 2011 respondent-driven sampling survey of 325 Swazi FSW, we explored the association between individual characteristics and ever having used ECP.

Results

In weighted analyses, 27.5% of FSW had ever used ECP. Most (77.8%) had ever been pregnant, among whom 48.7% had had an unwanted pregnancy and 11.7% had had an abortion. Nearly half (47.5%) had experienced condom failure in the past month. Significant independent correlates of ECP use were younger age, higher education, higher income, having two or more children, and never having been married.

Conclusions

FSW who are older or of lower socioeconomic status may not have adequate access to ECP. By better addressing these women's family planning needs, the dual goals of preventing unwanted pregnancy and preventing vertical transmission of HIV can be achieved.
Herpes simplex virus type 2 cross-sectional seroprevalence and the estimated rate of neonatal infections among a cohort of rural Malawian female adolescents
Authors: Sudfeld Christopher R , Hewett Paul C , Abuelezam Nadia N , Chalasani Satvika , Soler-Hampejsek Erica , Kelly Christine A , Mensch Barbara S
Published: June 2013

Objective

To assess herpes simplex virus type 2 (HSV-2) seroprevalence among rural Malawian adolescent women and estimate the number of neonatal herpes infections among infants of these adolescents.

Methods

A longitudinal cohort study of adolescents (14–16 years at entry) residing in rural Malawi was initiated in 2007 with annual observation. HSV-2 testing was introduced in 2010. In this study, we (1) determined, using cross-sectional analysis, risk factors for positive serostatus, (2) adjusted for non-response bias with imputation methods and (3) estimated the incidence of neonatal herpes infection using mathematical models.

Results

A total of 1195 female adolescents (age 17–20 years) were interviewed in 2010, with an observed HSV-2 seroprevalence of 15.2% among the 955 women tested. From a multivariate analysis, risk factors for HSV-2 seropositivity include older age (p=0.037), moving from the baseline village (p=0.020) and report of sexual activity with increasing number of partners (p<0.021). Adjusting for non-response bias, the estimated HSV-2 seroprevalence among the total female cohort (composed of all women interviewed in 2007) was 18.0% (95% CI 16.0% to 20.2%). HSV-2 seropositivity was estimated to be 25.6% (95% CI 19.6% to 32.5%) for women who refused to provide a blood sample. The estimated number of neonatal herpes infections among the total female cohort was 71.8 (95% CI 57.3 to 86.3) per 100 000 live births.

Conclusions

The risk of HSV-2 seroconversion is high during adolescence, when childbearing is beginning, among rural Malawian women. Research on interventions to reduce horizontal and vertical HSV-2 transmission during adolescence in resource-limited settings is needed.
Anticancer effects of crocetin in both human adenocarcinoma gastric cancer cells and rat model of gastric cancer
Authors: Bathaie S. Zahra , Hoshyar Reyhane , Miri Hamidreza , Sadeghizadeh Majid
Published: June 2013

This study investigated the therapeutic effect of crocetin, a carotenoid derived from saffron, on gastric adenocarcinoma (AGS) cells and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced gastric cancer in rats. An MTT assay showed a significant dose- and time-dependent inhibition of AGS cell proliferation as a result of crocetin administration. Flow cytometry and caspases activity assays revealed apoptosis had been induced in these cells; RT-PCR and Western blot analyses revealed the suppression of Bcl-2 and up-regulation of Bax expression in AGS cells treated with crocetin. These changes were not observed in normal human fibroblast (HFSF-PI3) cells. Pathological study of the tumor tissue in MNNG-induced gastric cancer in rats indicated the dose-dependent inhibition of tumor progression. In addition, crocetin reversed some changed biochemical parameters, including serum antioxidant activity and lactate dehydrogenase in rat serum. The present study demonstrates the antioxidant, anti-proliferative, and apoptotic activities of crocetin against gastric cancer that may benefit human stomach cancer treatment.
Metamorphic grade of source rocks revealed by chemical fingerprints of detrital amphibole and garnet
Authors: Andò Sergio , Morton Andrew , Garzanti Eduardo
Published: June 2013

Amphibole and garnet are among the most widespread heavy minerals in orogenic sediments. Their chemical composition and optical properties vary markedly and systematically with temperature and pressure conditions during growth, and thus provide important information on the metamorphic evolution of source areas that is crucial in palaeotectonic and palaeogeodynamic reconstructions. This study investigates the chemical composition of detrital amphiboles and garnets derived from parent rocks of progressively increasing metamorphic grade through a well-studied composite section across the Central and Southern Alps, including the granulite-facies core of the Late Palaeozoic orogen exposed in the Ivrea–Verbano Zone and the amphibolite-facies core of the Cenozoic orogen exposed in the Lepontine Dome. We specifically focus on metamorphic grade because it represents the best proxy for tectono-stratigraphic crustal level, and hence degree of unroofing of source areas. In river sands collected between metamorphic isograds corresponding to crystallization temperatures ranging from
c.
500 °C to
c.
850 °C, TiO
2
gradually increases in detrital amphibole while its colour progressively changes from blue-green in the lower amphibolite-facies where actinolite, hornblende and tschermakite are most abundant, to brown in the granulite facies where pargasite is dominant. Detrital garnets display moderate gradual changes across the amphibolite-facies Lepontine Dome, where low-Mg ‘type B’ garnets predominate. Almandine-spessartine is spatially associated with abundance of pegmatites while entering the zone of anatexis (Southern Steep Belt), where grossular or grossular-andradite-spessartine are occasionally found. A sharp change occurs while reaching granulite-facies in the Ivrea–Verbano Zone, where high-Mn garnets disappear and ‘type A’ almandine-pyrope (from ‘stronalite’ metasediments) and ‘type C’ almandine-pyrope-grossular (from metagabbros of the Mafic Complex) predominate. Also redefined in this article are a series of numerical indices based on amphibole colour and relative abundances of diverse key minerals (chloritoid, staurolite, andalusite, kyanite, fibrolitic and prismatic sillimanite), useful to accurately assess the average metamorphic grade of meta-igneous and metasedimentary source rocks.

Supplementary material:

Chemical composition of detrital amphiboles and garnets and full information on the location and mineralogical composition of studied samples is available at
http://www.geolsoc.org.uk/SUP18618
.
STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology
Authors: Collins Helen E. , Zhu-Mauldin Xiaoyuan , Marchase Richard B. , Chatham John C.
Published: June 2013

Store-operated Ca2+entry (SOCE) is critical for Ca2+signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca2+homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca2+handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca2+overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.
Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus
Authors: Reichelt Melissa E. , Mellor Kimberley M. , Bell James R. , Chandramouli Chanchal , Headrick John P. , Delbridge Lea M. D.
Published: June 2013

More than three decades ago, the Framingham study revealed that cardiovascular risk is elevated for all diabetics and that this jeopardy is substantially accentuated for women in particular. Numerous studies have subsequently documented worsened cardiac outcomes for women. Given that estrogen and insulin exert major regulatory effects through common intracellular signaling pathways prominent in maintenance of cardiomyocyte function, a sex-hormone:diabetic-disease interaction is plausible. Underlying aspects of female cardiovascular pathophysiology that exaggerate cardiovascular diabetic risk may be identified, including increased vulnerability to coronary microvascular disease, age-dependent impairment of insulin-sensitivity, and differential susceptibility to hyperglycemia. Since Framingham, considerable progress has been made in the development of experimental models of diabetic disease states, including a diversity of genetic rodent models. Ample evidence indicates that animal models of both type 1 and 2 diabetes variably recapitulate aspects of diabetic cardiomyopathy including diastolic and systolic dysfunction, and cardiac structural pathology including fibrosis, loss of compliance, and in some instances ventricular hypertrophy. Perplexingly, little of this work has explored the relevance and mechanisms of sexual dimorphism in diabetic cardiomyopathy. Only a small number of experimental studies have addressed this question, yet the prospects for gaining important mechanistic insights from further experimental enquiry are considerable. The case for experimental interrogation of sex differences, and of sex steroid influences in the aetiology of diabetic cardiomyopathy, is particularly compelling—providing incentive for future investigation with ultimate therapeutic potential.
Strong linear relationship between heart rate and mean pulmonary artery pressure in exercising patients with severe precapillary pulmonary hypertension
Authors: Chemla Denis , Castelain Vincent , Hoette Susana , Creuzé Nicolas , Provencher Steeve , Zhu Kaixian , Humbert Marc , Herve Philippe
Published: June 2013

The contribution of heart rate (HR) to pulmonary artery hemodynamics has been suggested in pulmonary hypertension (PH). Our high-fidelity pressure, retrospective study tested the hypothesis that HR explained the majority of mean pulmonary artery pressure (mPAP) and pulse pressure (PApp) variation in 12 severe precapillary PH patients who performed incremental-load cycling while in the supine position. Seven idiopathic pulmonary arterial hypertension patients and five chronic thromboembolic PH patients were studied. Four to five PAP-thermodilution cardiac output (CO) points (mean: 4.4) were obtained. At rest, mPAP was 57 ± 9 mmHg, PApp was 51 ± 11 mmHg, HR was 90 ± 12 beats/min, and stroke volume (SV) was 50 ± 22 ml. At peak exercise, mPAP was 76 ± 10 mmHg, PApp was 67 ± 11 mmHg, and HR was 123 ± 18 beats/min (i.e., 71 ± 10% of maximum HR, each P < 0.05), whereas SV was 51 ± 20 ml ( P = not significant). The input resistance did not change (mPAP/CO = 14.1 ± 4.1 vs. 13.5 ± 4.4 mmHg·min·l−1). The relative increase in mPAP was related to the relative increase in HR ( n = 12, r2= 0.74) but not in CO. mPAP was linearly related to CO in 8 of 12 patients (median r2= 0.83) and to HR in 12 of 12 patients (median r2= 0.985). The parsimony principle favored the latter fit. PApp was linearly related to mPAP in 12 of 12 patients (median r2= 0.985), HR in 10 of 12 patients (median r2= 0.97), CO in 7 of 12 patients (median r2= 0.87), and SV in 1 of 12 patients. A strong linear relationship between HR and mPAP was consistently documented in severe precapillary PH patients who performed supine exercise. The limited value of thermodilution CO to predict mPAP could be explained by unavoidable precision errors in CO measurements, unchanged/decreased SV on exercise, curvilinearity of the mPAP-CO relationship at high flow, or flow-independent additional mechanisms increasing mPAP on exercise.
Size-dependent predilections of cardiogenic embolic transport
Authors: Carr Ian A. , Nemoto Naohiko , Schwartz Robert S. , Shadden Shawn C.
Published: June 2013

While it is intuitively clear that aortic anatomy and embolus size could be important determinants for cardiogenic embolic stroke risk and stroke location, few data exist confirming or characterizing this hypothesis. The objective of this study is to use medical imaging and computational modeling to better understand if aortic anatomy and embolus size influence predilections for cardiogenic embolic transport and right vs. left hemisphere propensity. Anatomically accurate models of the human aorta and branch arteries to the head were reconstructed from computed tomography (CT) angiography of 10 patients. Blood flow was modeled by the Navier-Stokes equations using a well-validated flow solver with physiologic inflow and boundary conditions. Embolic particulate was released from the aortic root and tracked through the common carotid and vertebral arteries for a range of particle sizes. Cardiogenic emboli reaching the carotid and vertebral arteries appeared to have a strong size-destination relationship that varied markedly from expectations based on blood distribution. Observed trends were robust to modeling parameters. A patient's aortic anatomy appeared to significantly influence the probability a cardiogenic particle becomes embolic to the head. Right hemisphere propensity appeared dominant for cardiogenic emboli, which has been confirmed clinically. The predilections discovered through this modeling could represent an important mechanism underlying cardiogenic embolic stroke etiology.
Astrocyte regulation of cerebral vascular tone
Authors: Filosa Jessica A. , Iddings Jennifer A.
Published: June 2013

Cerebral blood flow is controlled by two crucial processes, cerebral autoregulation (CA) and neurovascular coupling (NVC) or functional hyperemia. Whereas CA ensures constant blood flow over a wide range of systemic pressures, NVC ensures rapid spatial and temporal increases in cerebral blood flow in response to neuronal activation. The focus of this review is to discuss the cellular mechanisms by which astrocytes contribute to the regulation of vascular tone in terms of their participation in NVC and, to a lesser extent, CA. We discuss evidence for the various signaling modalities by which astrocytic activation leads to vasodilation and vasoconstriction of parenchymal arterioles. Moreover, we provide a rationale for the contribution of astrocytes to pressure-induced increases in vascular tone via the vasoconstrictor 20-HETE (a downstream metabolite of arachidonic acid). Along these lines, we highlight the importance of the transient receptor potential channel of the vanilloid family (TRPV4) as a key molecular determinant in the regulation of vascular tone in cerebral arterioles. Finally, we discuss current advances in the technical tools available to study NVC mechanisms in the brain as it relates to the participation of astrocytes.
Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging
Authors: Bolduc Virginie , Thorin-Trescases Nathalie , Thorin Eric
Published: June 2013

Cognitive performances are tightly associated with the maximal aerobic exercise capacity, both of which decline with age. The benefits on mental health of regular exercise, which slows the age-dependent decline in maximal aerobic exercise capacity, have been established for centuries. In addition, the maintenance of an optimal cerebrovascular endothelial function through regular exercise, part of a healthy lifestyle, emerges as one of the key and primary elements of successful brain aging. Physical exercise requires the activation of specific brain areas that trigger a local increase in cerebral blood flow to match neuronal metabolic needs. In this review, we propose three ways by which exercise could maintain the cerebrovascular endothelial function, a premise to a healthy cerebrovascular function and an optimal regulation of cerebral blood flow. First, exercise increases blood flow locally and increases shear stress temporarily, a known stimulus for endothelial cell maintenance of Akt-dependent expression of endothelial nitric oxide synthase, nitric oxide generation, and the expression of antioxidant defenses. Second, the rise in circulating catecholamines during exercise not only facilitates adequate blood and nutrient delivery by stimulating heart function and mobilizing energy supplies but also enhances endothelial repair mechanisms and angiogenesis. Third, in the long term, regular exercise sustains a low resting heart rate that reduces the mechanical stress imposed to the endothelium of cerebral arteries by the cardiac cycle. Any chronic variation from a healthy environment will perturb metabolism and thus hasten endothelial damage, favoring hypoperfusion and neuronal stress.
Laminar shear stress upregulates endothelial Ca2+-activated K+channels KCa2.3 and KCa3.1 via a Ca2+/calmodulin-dependent protein kinase kinase/Akt/p300 cascade
Authors: Takai Jun , Santu Alexandra , Zheng Haifeng , Koh Sang Don , Ohta Masanori , Filimban Linda M. , Lemaître Vincent , Teraoka Ryutaro , Jo Hanjoong , Miura Hiroto
Published: June 2013

In endothelial cells (ECs), Ca2+-activated K+channels KCa2.3 and KCa3.1 play a crucial role in the regulation of arterial tone via producing NO and endothelium-derived hyperpolarizing factors. Since a rise in intracellular Ca2+levels and activation of p300 histone acetyltransferase are early EC responses to laminar shear stress (LS) for the transcriptional activation of genes, we examined the role of Ca2+/calmodulin-dependent kinase kinase (CaMKK), the most upstream element of a Ca2+/calmodulin-kinase cascade, and p300 in LS-dependent regulation of KCa2.3 and KCa3.1 in ECs. Exposure to LS (15 dyn/cm2) for 24 h markedly increased KCa2.3 and KCa3.1 mRNA expression in cultured human coronary artery ECs (3.2 ± 0.4 and 45 ± 10 fold increase, respectively; P < 0.05 vs. static condition; n = 8–30), whereas oscillatory shear (OS; ± 5 dyn/cm2× 1 Hz) moderately increased KCa3.1 but did not affect KCa2.3. Expression of KCa2.1 and KCa2.2 was suppressed under both LS and OS conditions, whereas KCa1.1 was slightly elevated in LS and unchanged in OS. Inhibition of CaMKK attenuated LS-induced increases in the expression and channel activity of KCa2.3 and KCa3.1, and in phosphorylation of Akt (Ser473) and p300 (Ser1834). Inhibition of Akt abolished the upregulation of these channels by diminishing p300 phosphorylation. Consistently, disruption of the interaction of p300 with transcription factors eliminated the induction of these channels. Thus a CaMKK/Akt/p300 cascade plays an important role in LS-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes.
Insights into the arginine paradox: evidence against the importance of subcellular location of arginase and eNOS
Authors: Elms Shawn , Chen Feng , Wang Yusi , Qian Jin , Askari Bardia , Yu Yanfang , Pandey Deepesh , Iddings Jennifer , Caldwell Ruth B. , Fulton David J. R.
Published: June 2013

Reduced production of nitric oxide (NO) is one of the first indications of endothelial dysfunction and precedes overt cardiovascular disease. Increased expression of Arginase has been proposed as a mechanism to account for diminished NO production. Arginases consume l-arginine, the substrate for endothelial nitric oxide synthase (eNOS), and l-arginine depletion is thought to competitively reduce eNOS-derived NO. However, this simple relationship is complicated by the paradox that l-arginine concentrations in endothelial cells remain sufficiently high to support NO synthesis. One mechanism proposed to explain this is compartmentalization of intracellular l-arginine into distinct, poorly interchangeable pools. In the current study, we investigated this concept by targeting eNOS and Arginase to different intracellular locations within COS-7 cells and also BAEC. We found that supplemental l-arginine and l-citrulline dose-dependently increased NO production in a manner independent of the intracellular location of eNOS. Cytosolic arginase I and mitochondrial arginase II reduced eNOS activity equally regardless of where in the cell eNOS was expressed. Similarly, targeting arginase I to disparate regions of the cell did not differentially modify eNOS activity. Arginase-dependent suppression of eNOS activity was reversed by pharmacological inhibitors and absent in a catalytically inactive mutant. Arginase did not directly interact with eNOS, and the metabolic products of arginase or downstream enzymes did not contribute to eNOS inhibition. Cells expressing arginase had significantly lower levels of intracellular l-arginine and higher levels of ornithine. These results suggest that arginases inhibit eNOS activity by depletion of substrate and that the compartmentalization of l-arginine does not play a major role.
Altered ventricular torsion and transmural patterns of myocyte relaxation precede heart failure in aging F344 rats
Authors: Campbell Stuart G. , Haynes Premi , Kelsey Snapp W. , Nava Kristofer E. , Campbell Kenneth S.
Published: June 2013

The purpose of this study was to identify and explain changes in ventricular and cellular function that contribute to aging-associated cardiovascular disease in aging F344 rats. Three groups of female F344 rats, aged 6, 18, and 22 mo, were studied. Echocardiographic measurements in isoflurane-anesthetized animals showed an increase in peak left ventricular torsion between the 6- and the 18-mo-old groups that was partially reversed in the 22-mo-old animals ( P < 0.05). Epicardial, midmyocardial, and endocardial myocytes were subsequently isolated from the left ventricles of each group of rats. Unloaded sarcomere shortening and Ca2+transients were then measured in these cells ( n = >75 cells for each of the nine age-region groups). The decay time of the Ca2+transient and the time required for 50% length relaxation both increased with age but not uniformly across the three regions ( P < 0.02). Further analysis revealed a significant shift in the transmural distribution of these properties between 18 and 22 mo of age, with the largest changes occurring in epicardial myocytes. Computational modeling suggested that these changes were due in part to slower Ca2+dissociation from troponin in aging epicardial myocytes. Subsequent biochemical assays revealed a >50% reduction in troponin I phosphoprotein content in 22-mo-old epicardium relative to the other regions. These data suggest that between 18 and 22 mo of age (before the onset of heart failure), F344 rats display epicardial-specific myofilament-level modifications that 1) break from the progression observed between 6 and 18 mo and 2) coincide with aberrant patterns of cardiac torsion.
Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart
Authors: Shimura Daisuke , Nakai Gaku , Jiao Qibin , Osanai Kota , Kashikura Kasumi , Endo Keiko , Soga Tomoyoshi , Goda Nobuhito , Minamisawa Susumu
Published: June 2013

Energy of the cardiac muscle largely depends on fatty acid oxidation. It is known that the atrium and ventricle have chamber-specific functions, structures, gene expressions, and pathologies. The left ventricle works as a high-pressure chamber to pump blood toward the body, and its muscle wall is thicker than those of the other chambers, suggesting that energy utilization in each of the chambers should be different. However, a chamber-specific pattern of metabolism remains incompletely understood. Recently, innovative techniques have enabled the comprehensive analysis of metabolites. Therefore, we aimed to clarify differences in metabolic patterns among the chambers. Male C57BL6 mice at 6 wk old were subject to a comprehensive measurement of metabolites in the atria and ventricles by capillary electrophoresis and mass spectrometry. We found that overall metabolic profiles, including nucleotides and amino acids, were similar between the right and left ventricles. On the other hand, the atria exhibited a distinct metabolic pattern from those of the ventricles. Importantly, the high-energy phosphate pool (the total concentration of ATP, ADP, and AMP) was higher in both ventricles. In addition, the levels of lactate, acetyl CoA, and tricarboxylic acid cycle contents were higher in the ventricles. Accordingly, the activities and/or expression levels of key enzymes were higher in the ventricles to produce more energy. The present study provides a basis for understanding the chamber-specific metabolism underlining pathophysiology in the heart.
Unchanged mitochondrial organization and compartmentation of high-energy phosphates in creatine-deficient GAMT−/−mouse hearts
Authors: Branovets Jelena , Sepp Mervi , Kotlyarova Svetlana , Jepihhina Natalja , Sokolova Niina , Aksentijevic Dunja , Lygate Craig A. , Neubauer Stefan , Vendelin Marko , Birkedal Rikke
Published: June 2013

Disruption of the creatine kinase (CK) system in hearts of CK-deficient mice leads to changes in the ultrastructure and regulation of mitochondrial respiration. We expected to see similar changes in creatine-deficient mice, which lack the enzyme guanidinoacetate methyltransferase (GAMT) to produce creatine. The aim of this study was to characterize the changes in cardiomyocyte mitochondrial organization, regulation of respiration, and intracellular compartmentation associated with GAMT deficiency. Three-dimensional mitochondrial organization was assessed by confocal microscopy. On populations of permeabilized cardiomyocytes, we recorded ADP and ATP kinetics of respiration, competition between mitochondria and pyruvate kinase for ADP produced by ATPases, ADP kinetics of endogenous pyruvate kinase, and ATP kinetics of ATPases. These data were analyzed by mathematical models to estimate intracellular compartmentation. Quantitative analysis of morphological and kinetic data as well as derived model fits showed no difference between GAMT-deficient and wild-type mice. We conclude that inactivation of the CK system by GAMT deficiency does not alter mitochondrial organization and intracellular compartmentation in relaxed cardiomyocytes. Thus, our results suggest that the healthy heart is able to preserve cardiac function at a basal level in the absence of CK-facilitated energy transfer without compromising intracellular organization and the regulation of mitochondrial energy homeostasis. This raises questions on the importance of the CK system as a spatial energy buffer in unstressed cardiomyocytes.