bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Resolution Functional Profiling of a Gammaherpesvirus
RTA
Locus in the Context of the Viral Genome
Authors: Arumugaswami Vaithilingaraja , Sitapara Ronika , Hwang Seungmin , Song Moon Jung , Ho Tuyet Ngoc , Su Nancy Qi , Sue Eric Y. , Kanagavel Vidhya , Xing Fangfang , Zhang Xiaolin , Zhao Minglei , Deng Hongyu , Wu Ting-Ting , Kanagavel Sudhakar , Zhang LuLu , Dandekar Sugandha , Papp Jeanette , Sun Ren
Published: December 2008

Gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus are associated with multiple human cancers. Our goal was to develop a quantitative, high-throughput functional profiling system to identify viral
cis
-elements and protein subdomains critical for virus replication in the context of the herpesvirus genome. In gamma-2 herpesviruses, the transactivating factor RTA is essential for initiation of lytic gene expression and viral reactivation. We used the
RTA
locus as a model to develop the functional profiling approach. The mutant murine gammaherpesvirus 68 viral library, containing 15-bp random insertions in the
RTA
locus, was passaged in murine fibroblast cells for multiple rounds of selection. The effect of each 15-bp insertion was characterized using fluorescent-PCR profiling. We identified 1,229 insertions in the 3,845-bp
RTA
locus, of which 393, 282, and 554 were critically impaired, attenuated, and tolerated, respectively, for viral growth. The functional profiling phenotypes were verified by examining several individual RTA mutant clones for transactivating function of the RTA promoter and transcomplementing function of the RTA-null virus. Thus, the profiling approach enabled us to identify several novel functional domains in the
RTA
locus in the context of the herpesvirus genome. Importantly, our study has demonstrated a novel system to conduct high-density functional genetic mapping. The genome-scale expansion of the genetic profiling approach will expedite the functional genomics research on herpesvirus.
Expression of GATA-6 transcription factor in pleural malignant mesothelioma and metastatic pulmonary adenocarcinoma
Authors: Lindholm P M , Soini Y , Myllärniemi M , Knuutila S , Heikinheimo M , Kinnula V L , Salmenkivi K
Published: December 2008

Background:

Malignant mesothelioma (MM) is a highly aggressive tumour with poor prognosis and limited response to therapy. New markers for the prediction of prognosis in MM and in pulmonary adenocarcinoma of the pleura are valuable. GATA-6 belongs to a six member zinc finger transcription factor family named after their recognition motif W-GATA-R.

Aim:

To clarify the distribution and possible function of GATA-6 transcription factor in MM and in pleural metastasis of lung adenocarcinomas.

Methods:

63 pleural MM and 36 pleural metastatic pulmonary adenocarcinomas were studied for GATA-6 expression by immunohistochemistry using tissue microarrays. Expression of GATA-6 was examined in relation to thyroid transcription factor-1 expression, survival, proliferation and apoptosis.

Results:

Nuclear immunoreactivity for GATA-6 was stronger and more frequent in MM than in metastatic pleural adenocarcinoma. Prognosis was better in patients with GATA-6 expression when compared to those with no GATA-6 expression (p = 0.002); in the subgroup analysis the difference was significant in epithelial and sarcomatous mesothelioma. GATA-6 was not associated with spontaneous proliferation or apoptosis of the tumour cells in situ.

Conclusion:

Results suggest that GATA-6 plays a role in pleural malignancies, predicting longer survival in subgroups of MM.
Geographic density of landfill sites and risk of congenital anomalies in England
Authors: Elliott P , Richardson S , Abellan J J , Thomson A , de Hoogh C , Jarup L , Briggs D J
Published: December 2008

Objective:

To investigate the risk of congenital anomalies in relation to an index of geographic density of landfill sites across 5×5 km grid squares in England.

Methods:

2 km zones were constructed in a geographical information system around 8804 landfill sites, including 607 that handled special (hazardous) wastes, and intersected with postcode coordinates of over 10 million births (136 821 with congenital anomalies), 1983–98. A landfill exposure index was calculated to represent the geographic density of landfill sites within 2 km of births for each 5×5 km grid square, calculated separately for landfill sites handling special, and non-special or unknown, waste. For each group of landfills, the index was classified into four categories of intensity, and risks for the second, third and top categories were compared to the bottom category, comprising areas with no such landfill sites within 2 km (index of zero). We used hierarchical logistic regression modelling in a Bayesian framework, with adjustment for potential confounding.

Results:

For special waste sites, adjusted odds ratios were significant for the third category of the landfill exposure index for all anomalies combined and cardiovascular defects (OR 1.08 (95% credible interval 1.02 to 1.13) and 1.16 (1.00 to 1.33), respectively) and for hypospadias and epispadias for the third and top categories (OR 1.11 (1.02 to 1.21) and 1.12 (1.02 to 1.22), respectively). After adjustment, there were no excess risks in relation to sites handling non-special or unknown waste types.

Conclusions:

There was a weak spatial association between risk of certain congenital anomalies and geographic density of special (hazardous) waste sites at the level of 5×5 km grid squares. Exposure pathways and mechanisms to help interpret these findings are not well-established.
A retrospective assessment of occupational noise exposures for a longitudinal epidemiological study
Authors: Davies H W , Teschke K , Kennedy S M , Hodgson M R , Demers P A
Published: December 2008

Objectives:

Chronic exposure to high levels of noise may be associated with increased risk of cardiovascular disease. We therefore undertook a quantitative retrospective exposure assessment using predictive statistical modelling to estimate historical exposures to noise among a cohort of 27 499 sawmill workers as part of an investigation of acute myocardial infarction mortality.

Methods:

Noise exposure data were gathered from research, industry and regulatory sources. An exposure data matrix was defined and exposure level estimated for job title/mill/time period combinations utilising regression analysis to model determinants of noise exposure. Cumulative exposure and duration of exposure metrics were calculated for each subject. These were merged with work history data, and exposure–response associations were tested in subsequent epidemiological studies, reported elsewhere.

Results:

Over 14 000 noise measurements were obtained from British Columbia sawmills. A subset, comprising 1901 full-shift dosimetry measurements from cohort mills was used in producing a predictive model (R2 = 0.51). The model was then used to estimate noise exposures for 3809 “cells” of an exposure data matrix representing 81 jobs at 14 mills over several decades. Various exposure metrics were then calculated for subjects; mean cumulative exposure was 101 dBA*year. Mean durations of employment in jobs with exposure above thresholds of 85, 90 and 95 dBA, were 9.9, 7.0 and 3.2 years, respectively.

Conclusions:

The utility of predictive statistical modelling for occupational noise exposure was demonstrated. The model required input data that were relatively easily obtained, even retrospectively. Remaining issues include adequate handling of the use of hearing protectors that likely bias exposure estimation.
Maternal levels of dichlorodiphenyl-dichloroethylene (DDE) may increase weight and body mass index in adult female offspring
Authors: Karmaus W , Osuch J R , Eneli I , Mudd L M , Zhang J , Mikucki D , Haan P , Davis S
Published: December 2008

Objectives:

To investigate the effect of prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyl-dichloroethylene (DDE) on weight, height and body mass index (BMI) in adult female offspring of the Michigan fisheater cohort examined between 1973 and 1991.

Methods:

259 mothers from the Michigan fisheater cohort were studied. Prenatal exposure to PCBs and DDE was estimated by extrapolating maternal measurements to the time that the women gave birth. 213 daughters aged 20–50 years in 2000 were identified and 83% of them participated in at least one of two repeated investigations in 2001/02 (n = 151) and 2006/07 (n = 129). To assess the effect of prenatal PCB and DDE exposure on anthropometric measurements, generalised estimating equations nested for repeated measurements (2001/02 and 2006/07) and for sharing the same mother were used. We controlled for maternal height and BMI and for daughters’ age, birth weight, having been breastfed and number of pregnancies.

Results:

Maternal height and BMI were significant predictors of the daughters’ height, weight and BMI. Low birth weight (<2500 g) was significantly associated with reduced adult offspring weight and BMI. The weight and BMI of adult offspring were statistically significantly associated with the extrapolated prenatal DDE levels of their mothers. Controlling for confounders and compared to maternal DDE levels of <1.503 μg/l, offspring BMI was increased by 1.65 when prenatal DDE levels were 1.503–2.9 μg/l and by 2.88 if levels were >2.9 μg/l. Prenatal PCB levels showed no effect.

Conclusion:

Prenatal exposure to the oestrogenic endocrine-disrupting chemical DDE may contribute to the obesity epidemic in women.
Physical workload, low back pain and neck–shoulder pain: a Swedish twin study
Authors: Nyman T , Mulder M , Iliadou A , Svartengren M , Wiktorin C
Published: December 2008

Objectives:

To investigate if high physical workload is associated with low back pain (LBP) and/or neck–shoulder pain (NSP) when taking into account the influence of genetic and shared environmental factors. Further, the study aims to explore the potential influence of genetic and shared environmental factors in the associations between high physical workload and the three disorder subgroups: solely LBP, solely NSP, and concurrent LBP and NSP.

Methods:

Data on 16 107 monozygotic and dizygotic twins, born during 1959–1985, were obtained from a cross-sectional study, performed in 2005–2006 by the Swedish Twin Registry. Odds ratios (ORs) calculated in cohort analyses and co-twin control analyses were used to assess the associations between high physical workload and LBP and NSP when controlling for genetic and shared environmental factors.

Results:

In the cohort analysis, the association between high physical workload and the group with any one symptom (LBP and/or NSP) was OR 1.47 (95% CI 1.37 to 1.57). The co-twin control analyses indicated that the association was not confounded by genetic and shared environmental factors with OR 1.34 (95% CI 1.02 to 1.75) for dizygotic twins and OR 1.44 (95% CI 1.06 to 1.95) for monozygotic twins.

In the cohort analyses the association with high physical workload was higher for concurrent LBP and NSP (OR 1.80 (95% CI 1.62 to 1.99)) than for solely LBP (OR 1.41 (95% CI 1.27 to 1.57)) and solely NSP (OR 1.31 (95% CI 1.20 to 1.43)). Concurrent LBP and NSP was the only group that showed a stepwise decrease of the point estimates between the cohort analysis and the co-twin control analyses, OR 1.71 (95% CI 1.00 to 2.94) for dizygotic twins, and OR 1.29 (95% CI 0.64 to 2.59) for monozygotic twins indicating confounding by genetic and shared environmental factors.

Conclusions:

High physical workload was associated with LBP and/or NSP even after adjusting for genetic or shared environmental factors. Only for concurrent LBP and NSP, genetic and shared environmental factors seemed to have an influence on the association with high physical workload.
Exhaled nitric oxide in endotoxin-exposed adults: effect modification by smoking and atopy
Authors: Smit L A M , Heederik D , Doekes G , Wouters I M
Published: December 2008

Objectives:

Occupational exposure to endotoxin is associated with non-allergic asthma and other airway inflammatory reactions. Little is known about the role of mucosal nitric oxide (NO) production in endotoxin-induced airway inflammation. The objective was to explore exposure–response relationships between occupational endotoxin exposure and fractional concentrations of exhaled NO (FENO) and study the role of FENOas an intermediate factor in the relationship between endotoxin exposure and asthma-like symptoms.

Methods:

FENOwas measured online in 425 farmers and agricultural processing workers. For each participant (cumulative) endotoxin level was modelled on the basis of 249 personal measurements and job history. Atopy was assessed as specific serum IgE to common inhalant allergens, and other health data and personal characteristics by standardised questionnaires.

Results:

A significant positive exposure–response relationship was found between endotoxin and FENO, but only in non-atopic, non-smoking subjects (p = 0.001). FENOwas significantly associated with current wheeze and other asthma-like symptoms irrespective of atopy and current smoking. Associations between endotoxin exposure and symptoms changed slightly after adjusting for FENO.

Conclusions:

A positive association was found between occupational endotoxin exposure and exhaled nitric oxide in non-smoking, non-atopic adults. Increased FENOwas associated with asthma-like symptoms, but the role of FENOas an intermediate factor between endotoxin exposure and airway symptoms appears to be limited.
Bayesian modelling of lung cancer risk and bitumen fume exposure adjusted for unmeasured confounding by smoking
Authors: de Vocht F , Kromhout H , Ferro G , Boffetta P , Burstyn I
Published: December 2008

Objectives:

Residual confounding can be present in epidemiological studies because information on confounding factors was not collected. A Bayesian framework, which has the advantage over frequentist methods that the uncertainty in the association between the confounding factor and exposure and disease can be reflected in the credible intervals of the risk parameter, is proposed to assess the magnitude and direction of this bias.

Methods:

To illustrate this method, bias from smoking as an unmeasured confounder in a cohort study of lung cancer risk in the European asphalt industry was assessed. A Poisson disease model was specified to assess lung cancer risk associated with career average, cumulative and lagged bitumen fume exposure. Prior distributions for the exposure strata, as well as for other covariates, were specified as uninformative normal distributions. The priors on smoking habits were specified as Dirichlet distributions based on smoking prevalence estimates available for a sub-cohort and assumptions about precision of these estimates.

Results:

Median bias in this example was estimated at 13%, and suggested an attenuating effect on the original exposure–disease associations. Nonetheless, the results still implied an increased lung cancer risk, especially for average exposure.

Conclusions:

This Bayesian framework provides a method to assess the bias from an unmeasured confounding factor taking into account the uncertainty surrounding the estimate and from random sampling error. Specifically for this example, the bias arising from unmeasured smoking history in this asphalt workers’ cohort is unlikely to explain the increased lung cancer risk associated with average bitumen fume exposure found in the original study.
Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes
Authors: Suarez Jorge , Hu Yong , Makino Ayako , Fricovsky Eduardo , Wang Hong , Dillmann Wolfgang H.
Published: December 2008

Mitochondrial transcription factor A (TFAM) is essential for mitochondrial DNA transcription and replication. TFAM transcriptional activity is decreased in diabetic cardiomyopathy; however, the functional implications are unknown. We hypothesized that a reduced TFAM activity may be responsible for some of the alterations caused by hyperglycemia. Therefore, we investigated the effect of TFAM overexpression on hyperglycemia-induced cytosolic calcium handling and mitochondrial abnormalities. Neonatal rat cardiomyocytes were exposed to high glucose (30 mM) for 48 h, and we examined whether TFAM overexpression, by protecting mitochondrial DNA, could reestablish calcium fluxes and mitochondrial alterations toward normal. Our results shown that TFAM overexpression increased to more than twofold mitochondria copy number in cells treated either with normal (5.5 mM) or high glucose. ATP content was reduced by 30% and mitochondrial calcium decreased by 40% after high glucose. TFAM overexpression returned these parameters to even higher than control values. Calcium transients were prolonged by 70% after high glucose, which was associated with diminished sarco(endo)plasmic reticulum Ca2+-ATPase 2a and cytochrome- c oxidase subunit 1 expression. These parameters were returned to control values after TFAM overexpression. High glucose-induced protein oxidation was reduced by TFAM overexpression, indicating a reduction of the high glucose-induced oxidative stress. In addition, we found that TFAM activity can be modulated by O-linked β- N-acetylglucosamine glycosylation. In conclusion, TFAM overexpression protected cell function against the damage induced by high glucose in cardiomyocytes.
Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis
Authors: Malhotra Ashwani , Vashistha Himanshu , Yadav Virendra S. , Dube Michael G. , Kalra Satya P. , Abdellatif Maha , Meggs Leonard G.
Published: December 2008

Apoptotic myocyte cell death, diastolic dysfunction, and progressive deterioration in left ventricular pump function characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG) transmits danger signals in cardiac muscle cells. The growth factor adapter protein p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here we demonstrate that interventions which attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser36) inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes obtained by enzymatic dissociation were transduced with mutant-36 p66ShcA (mu-36) dominant-negative expression vector and plated in serum-free media containing 5 or 25 mM glucose. At HG, adult rat ventricular myocytes exhibit a marked increase in reactive oxygen species production, upregulation of phospho-Ser36, collapse of mitochondrial transmembrane potential, and increased formation of p66ShcA/cytochrome- c complexes. These indexes of oxidative stress were accompanied by a 40% increase in apoptosis and the upregulation of cleaved caspase-3 and the apoptosis-related proteins p53 and Bax. To test whether p66ShcA functions as a redox-sensitive molecular switch in vivo, we examined the hearts of male Akita diabetic nonobese (C57BL/6J) mice. Western blot analysis detected the upregulation of phospho-Ser36, the translocation of p66ShcA to mitochondria, and the formation of p66ShcA/cytochrome- c complexes. Conversely, the correction of HG by recombinant adeno-associated viral delivery of leptin reversed these alterations. We conclude that p66ShcA is a molecular switch whose redox function is turned on by phospho-Ser36 and turned off by interventions that prevent this modification.
Distinct phosphodiesterase-4D variants integrate into protein kinase A-based signaling complexes in cardiac and vascular myocytes
Authors: Raymond Daniel R. , Carter Rhonda L. , Ward Christopher A. , Maurice Donald H.
Published: December 2008

Numerous cAMP-elevating agents regulate events required for efficient migration of arterial vascular smooth muscle cells (VSMCs). Interestingly, when the impact of cAMP-elevating agents on individual migration-related events is studied, these agents have been shown to have distinct, and sometimes unexpected, effects. For example, although cAMP-elevating agents inhibit overall migration, they promote VSMC adhesion to extracellular matrix proteins and the formation of membrane extensions, which are both events that are essential for and promote migration. Herein, we extend previous observations that identified phosphodiesterase-4D3 (PDE4D3) as an integral component of a PKA/A kinase-anchoring protein (AKAP) complex in cultured/hypertrophied rat cardiac myocytes to the case for nonhypertrophied cardiac myocytes. Moreover, we show that while rat aortic VSMCs also express PDE4D3, this protein is not detected in PKA/AKAP complexes isolated from these cells. In contrast, we show that another PDE4D splice variant expressed in arterial vascular myocytes, namely, PDE4D8, integrates into PKA/AKAP-based signaling complexes in VSMCs. Consistent with the idea that a PDE4D8/PKA/AKAP complex regulates specific VSMC functions, PKA and PDE4D8 were each recruited to leading-edge structures in migrating VSMCs, and inhibition of PDE4D8 recruitment to pseudopodia of migrating cells caused localized changes in actin dynamics. Our data are presented in the context that cardiac myocytes and arterial VSMCs may use distinct PDE4D variants to regulate selected pools of targeted PKA activity and that disruption of this complex may allow selective regulation of cAMP-dependent events between these two cardiovascular cell types.
Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations
Authors: Dabkowski Erinne R. , Williamson Courtney L. , Bukowski Valerie C. , Chapman Rebecca S. , Leonard Stephen S. , Peer Cody J. , Callery Patrick S. , Hollander John M.
Published: December 2008

Diabetic cardiomyopathy is the leading cause of heart failure among diabetic patients, and mitochondrial dysfunction has been implicated as an underlying cause in the pathogenesis. Cardiac mitochondria consist of two spatially, functionally, and morphologically distinct subpopulations, termed subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). SSM are situated beneath the plasma membrane, whereas IFM are embedded between myofibrils. The goal of this study was to determine whether spatially distinct cardiac mitochondrial subpopulations respond differently to a diabetic phenotype. Swiss-Webster mice were subjected to intraperitoneal injections of streptozotocin or citrate saline vehicle. Five weeks after injections, diabetic hearts displayed decreased rates of contraction, relaxation, and left ventricular developed pressures ( P < 0.05 for all three). Both mitochondrial size (forward scatter, P < 0.01) and complexity (side scatter, P < 0.01) were decreased in diabetic IFM but not diabetic SSM. Electron transport chain complex II respiration was decreased in diabetic SSM ( P < 0.05) and diabetic IFM ( P < 0.01), with the decrease being greater in IFM. Furthermore, IFM complex I respiration and complex III activity were decreased with diabetes ( P < 0.01) but were unchanged in SSM. Superoxide production was increased only in diabetic IFM ( P < 0.01). Oxidative damage to proteins and lipids, indexed through nitrotyrosine residues and lipid peroxidation, were higher in diabetic IFM ( P < 0.05 and P < 0.01, respectively). The mitochondria-specific phospholipid cardiolipin was decreased in diabetic IFM ( P < 0.01) but not SSM. These results indicate that diabetes mellitus imposes a greater stress on the IFM subpopulation, which is associated, in part, with increased superoxide generation and oxidative damage, resulting in morphological and functional abnormalities that may contribute to the pathogenesis of diabetic cardiomyopathy.
Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes
Authors: Kellogg Aaron P. , Converso Kimber , Wiggin Tim , Stevens Martin , Pop-Busui Rodica
Published: December 2008

Glucose-mediated oxidative stress and the upregulation of cyclooxygenase (COX)-2 pathway activity have been implicated in the pathogenesis of several vascular complications of diabetes including diabetic neuropathy. However, in nondiabetic subjects, the cardiovascular safety of selective COX-2 inhibition is controversial. The aim of this study was to explore the links between hyperglycemia, oxidative stress, activation of the COX-2 pathway, cardiac sympathetic integrity, and the development of left ventricular (LV) dysfunction in experimental diabetes. R wave-to-R wave interval (R-R interval) and parameters of LV function measured by echocardiography using 1% isoflurane, LV sympathetic nerve fiber density, LV collagen content, and markers of myocardial oxidative stress, inflammation, and PG content were assessed after 6 mo in control and diabetic COX-2-deficient (COX-2−/−) and littermate, wild-type (COX-2+/+) mice. There were no differences in blood glucose, LV echocardiographic measures, collagen content, sympathetic nerve fiber density, and markers of oxidative stress and inflammation between nondiabetic (ND) COX-2+/+ and COX-2−/− mice at baseline and thereafter. After 6 mo, diabetic COX-2+/+ mice developed significant deteriorations in the R-R interval and signs of LV dysfunction. These were associated with a loss of LV sympathetic nerve fiber density, increased LV collagen content, and a significant increase in myocardial oxidative stress and inflammation compared with those of ND mice. Diabetic COX-2−/− mice were protected against all these biochemical, structural, and functional deficits. These data suggest that in experimental diabetes, selective COX-2 inactivation confers protection against sympathetic denervation and LV dysfunction by reducing intramyocardial oxidative stress, inflammation, and myocardial fibrosis.
Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction
Authors: Takenaka Hiroharu , Horiba Mitsuru , Ishiguro Hisaaki , Sumida Arihiro , Hojo Mayumi , Usui Akihiko , Akita Toshiaki , Sakuma Sadatoshi , Ueda Yuichi , Kodama Itsuo , Kadomatsu Kenji
Published: December 2008

Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.
Cardiac phase-dependent time normalization reduces load dependence of time-varying elastance
Authors: Kind Taco , Westerhof Nico , Faes Theo J. C. , Lankhaar Jan-Willem , Steendijk Paul , Vonk-Noordegraaf Anton
Published: December 2008

The time-varying elastance concept provides a comprehensive description of the intrinsic mechanical properties of the left ventricle that are assumed to be load independent. Based on pressure-volume measurements obtained with combined pressure conductance catheterization in six open-chest anesthetized sheep, we show that the time to reach end systole (defined as maximal elastance) is progressively prolonged for increasing ventricle pressures, which challenges the original (load-independent) time-varying elastance concept. Therefore, we developed a method that takes into account load dependency by normalization of time course of the four cardiac phases (isovolumic contraction, ejection, isovolumic relaxation, filling) individually. With this normalization, isophase lines are obtained that connect points in pressure-volume loops of different beats at the same relative time in each of the four cardiac phases, instead of isochrones that share points at the same time in a cardiac cycle. The results demonstrate that pressure curves can be predicted with higher accuracy, if elastance curves are estimated using isophase lines instead of using isochrones [root-mean-square error (RMSE): 3.8 ± 1.0 vs. 14.0 ± 7.4 mmHg ( P < 0.001), and variance accounted for (VAF): 94.8 ± 1.3 vs. 78.6 ± 14.8% ( P < 0.001)]. Similar results were found when the intercept volume was assumed to be time varying [RMSE: 1.7 ± 0.3 vs. 13.4 ± 7.4 mmHg ( P < 0.001), and VAF: 97.4 ± 0.5 vs. 81.8 ± 15.5% ( P < 0.001)]. In conclusion, phase-dependent time normalization reduces cardiac load dependency of timing and increases accuracy in estimating time-varying elastance.
A computational study of mother rotor VF in the human ventricles
Authors: Keldermann R. H. , ten Tusscher K. H. W. J. , Nash M. P. , Bradley C. P. , Hren R. , Taggart P. , Panfilov A. V.
Published: December 2008

Sudden cardiac death is one of the major causes of death in the industrialized world. It is most often caused by a cardiac arrhythmia called ventricular fibrillation (VF). Despite its large social and economical impact, the mechanisms for VF in the human heart yet remain to be identified. Two of the most frequently discussed mechanisms observed in experiments with animal hearts are the multiple wavelet and mother rotor hypotheses. Most recordings of VF in animal hearts are consistent with the multiple wavelet mechanism. However, in animal hearts, mother rotor fibrillation has also been observed. For both multiple wavelet and mother rotor VF, cardiac heterogeneity plays an important role. Clinical data of action potential restitution measured from the surface of human hearts have been recently published. These in vivo data show a substantial degree of spatial heterogeneity. Using these clinical restitution data, we studied the dynamics of VF in the human heart using a heterogeneous computational model of human ventricles. We hypothesized that this observed heterogeneity can serve as a substrate for mother rotor fibrillation. We found that, based on these data, mother rotor VF can occur in the human heart and that ablation of the mother rotor terminates VF. Furthermore, we found that both mother rotor and multiple wavelet VF can occur in the same heart depending on the initial conditions at the onset of VF. We studied the organization of these two types of VF in terms of filament numbers, excitation periods, and frequency domains. We conclude that mother rotor fibrillation is a possible mechanism in the human heart.
Role of α1-adrenergic vasoconstriction in the regulation of skeletal muscle blood flow with advancing age
Authors: Wray D. Walter , Nishiyama Steven K. , Richardson Russell S.
Published: December 2008

α1-Adrenergic vasoconstriction during dynamic leg exercise is diminished in younger individuals, although the extent of this exercise-induced “sympatholysis” in the elderly remains uncertain. Thus, in nine young (25 ± 1 yr) and six older (72 ± 2 yr) healthy volunteers, we evaluated changes in leg blood flow (ultrasound Doppler) during blood flow-adjusted intra-arterial infusion of phenylephrine (PE; a selective α1-adrenergic agonist) at rest and during knee-extensor leg exercise at 20, 40, and 60% of maximal work rate (WRmax). To probe the potential contributors to exercise-induced changes in α1-adrenergic receptor sensitivity, exercising leg O2 consumption (V̇o2) and lactate efflux were also evaluated ( n = 10). At rest, the PE-induced vasoconstriction (i.e., decrease in leg blood flow) was diminished in older (−37 ± 3%) compared with young (−54 ± 4%) subjects. During exercise, the magnitude of α1-adrenergic vasoconstriction in the active leg decreased in both groups. However, compared with young, older subjects maintained a greater vasoconstrictor response to PE at 40% WRmax (−14 ± 3%, older; −7 ± 2%, young) and 60% WRmax (−11 ± 3%, older; −4 ± 3%, young). It is possible that this observation may be attributed to lower absolute work rates in the older group, because, for a similar absolute work rate (≈10 W) and leg V̇o2 (≈0.36 l/min), vasoconstriction to PE was not different between groups (−14 ± 3%; older; −17 ± 5%, young). Together, these data challenge the concept of reduced sympatholysis in the elderly, suggesting instead that the inhibition of α1-adrenergic vasoconstriction in the exercising leg is associated with work performed and, therefore, more closely related to the rate of oxidative metabolism than to age per se.
Cardiovascular responses to incremental and sustained submaximal exercise in heart transplant recipients
Authors: Scott Jessica M. , Esch Ben T. A. , Haykowsky Mark J. , Warburton Darren E. R. , Toma Mustafa , Jelani Anwar , Taylor Dylan , Paterson Ian , Poppe Delores , Liang Yuanyuan , Thompson Richard
Published: December 2008

The cardiovascular response to exercise in heart transplant recipients (HTR) has been compared with that of healthy individuals matched to the recipient age (RM controls). However, no study has compared HTR with donor age-matched (DM) controls. Moreover, the cardiovascular response to sustained submaximal exercise in HTR requires further evaluation. We therefore examined cardiovascular responses during incremental exercise and sustained (1 h) submaximal aerobic exercise in 9 clinically stable HTR [63 ± 10 yr of age, 24.2 ± 10.9 ml·kg−1·min−1 peak O2 uptake (V̇o2peak)] and 11 healthy age-matched controls (60 ± 11 yr of age and 36.3 ± 10.7 ml·kg−1·min−1 V̇o2peak for 6 RM controls and 35 ± 8 yr of age and 51.1 ± 10.4 ml·kg−1·min−1 V̇o2peak for 5 DM controls). Heart rate (HR) and left ventricular systolic and diastolic volumes (2-dimensional echocardiography) indexed to body surface area [end-systolic and end-diastolic volume indexes (EDVI and ESVI)], cardiac output (CI), ejection fraction (EF), systemic vascular resistance (SVRI), end-systolic elastance index, and arterial elastance index were determined. Although systolic function was maintained during incremental exercise, peak CI was significantly reduced (6.7 ± 2.4 vs. 11.6 ± 1.4 l·min−1·m−2), secondary to blunted HR, EDVI, and increased peak SVRI, in HTR compared with DM controls. The lower peak CI in HTR than in RM controls was due to blunted peak EDVI (54.1 ± 13.2 vs. 68.6 ± 5.7 ml/m2). During sustained submaximal exercise, HTR exhausted their preload reserve, a response for which changes in ESVI, HR, or EF did not fully compensate. Thus it appears that HTR are limited by impaired preload reserve, HR reserve, and vascular reserve during exercise conditions.
MMP dependence of fibroblast contraction and collagen production induced by human mast cell activation in a three-dimensional collagen lattice
Authors: Margulis Alexander , Nocka Karl H. , Wood Nancy L. , Wolf Stanley F. , Goldman Samuel J. , Kasaian Marion T.
Published: December 2008

Mast cell-fibroblast interactions may contribute to fibrosis in asthma and other disease states. Fibroblast contraction is known to be stimulated by coculture with the human mast cell line, HMC-1, or by mast cell-derived agents. Matrix metalloproteinases (MMPs) can also mediate contraction, but the MMP-dependence of mast cell-induced fibroblast contractility is not established, and the consequences of mast cell activation within the coculture system have not been fully explored. We demonstrate that activation of primary human mast cells (pHMC) with IgE receptor cross-linking, or activation of HMC-1 with C5a, enhanced contractility of human lung fibroblasts in a three-dimensional collagen lattice system. This enhanced contractility was inhibited by the pan-MMP antagonist, batimastat, and was transferrable in the conditioned medium of activated mast cells. Exogenously added MMPs promoted gel contraction by mediating the proteolytic activation of latent transforming growth factor-β (TGF-β). Consistent with this, fibroblast contraction induced by mast cell activation was enhanced by addition of excess latent TGF-β to the cultures. Batimastat inhibited this response, suggesting that MMPs capable of activating latent TGF-β were released following mast cell activation in coculture with fibroblasts. Collagen production was also stimulated by activated mast cells in an MMP-dependent manner. MMP-2 and MMP-3 content of the gels increased in the presence of activated mast cells, and inhibition of these enzymes blocked the contractile response. These findings demonstrate the MMP dependence of mast cell-induced fibroblast contraction and collagen production.
Neither fibrin nor plasminogen activator inhibitor-1 deficiency protects lung function in a mouse model of acute lung injury
Authors: Allen Gilman B. , Cloutier Mary E. , Larrabee Yuna C. , Tetenev Konstantin , Smiley Stephen T. , Bates Jason H. T.
Published: December 2008

Fibrin impairs surfactant function in vitro, and inhibition of fibrinolysis by plasminogen activator inhibitor (PAI-1) is thought to promote fibrin accumulation in acute lung injury (ALI). This has led to speculation that impaired PAI-1 and fibrin accumulation should protect lung function in ALI. We tested this hypothesis by investigating ALI severity in fibrinogen-deficient (Fgn−/−) and PAI-1-deficient (PAI-1−/−) mice. PAI-1−/−, C57BL/6, Fgn−/−, and Fgn+/− females were anesthetized and allowed to aspirate 4 μl/g of hydrochloric acid (pH 1.0) and then reanesthetized and connected to a ventilator 48 h later. Naive C57BL/6 and Fgn+/− females served as controls. Following deep inflation (DI), forced oscillations were delivered periodically over 8 min to measure changes in elastance ( H) as a surrogate of lung derecruitment, at positive end-expiratory pressures (PEEP) of 6, 3, and 1 cmH2O. Increases in H following DI in acid-injured mice were greater than naive strain-matched controls. Increases in H were no different between injured PAI-1−/− and C57BL/6, or between injured Fgn−/− and +/− mice, at any PEEP. Pressure-volume curves were no different between injured groups. Total lung fibrin was lower in injured PAI-1−/− and Fgn−/− mice relative to injured C57BL/6 and Fgn+/− mice, respectively, but indices of permeability were no different between strains. Unexpectedly, neither fibrin nor PAI-1 deficiency protects lung mechanical function in mice with acid-induced ALI. We speculate that in vivo lung function may be more closely tied to permeability and alveolar protein in general, rather than being linked specifically to fibrin.
Effects of dietary glutamine supplementation on lung injury induced by lipopolysaccharide administration
Authors: Hou Yu-Chen , Pai Man-Hui , Chiu Wan-Chun , Hu Ya-Mei , Yeh Sung-Ling
Published: December 2008

Acute lung injury (ALI) is a critical syndrome associated with respiratory dysfunction, and neutrophils are considered to be central to the pathogenesis of ALI. This study investigated the effects of glutamine (Gln) on neutrophil recruitment in a model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 mice were fed a standard diet either with casein as the nitrogen source or with 25% of total nitrogen replaced by Gln. After 10 days, intratracheal instillation of LPS was used to induce ALI. Mice were killed at 0, 6, 12, and 24 h after LPS administration ( n = 10/group). Bronchoalveolar lavage fluid and lung tissues were collected for further analysis. The results showed that, compared with the control group, lipid peroxide levels in the lungs were higher at 12 and 24 h after LPS administration in the Gln group. CXC chemokines as well as tumor necrosis factor-α were significantly elevated and reached peaks at 6 h in the Gln group, which was earlier than in the control group. Histopathological findings showed that the thickening of alveolar septal space was extensive in the Gln group 24 h and 2 wk after LPS. Also, greater amounts of collagen had accumulated in lung tissue in the Gln group. This study indicates that dietary Gln administration resulted in higher inflammatory cytokine production, with more neutrophils recruited at the early stage of ALI. These results were consistent with the histopathological findings that Gln supplementation causes more severe interstitial inflammation and fibrosis in a model of ALI induced by LPS.
Molecular diversity and function of K+channels in airway and alveolar epithelial cells
Authors: Bardou Olivier , Trinh Nguyen Thu Ngan , Brochiero Emmanuelle
Published: December 2008

Multiple K+channels are expressed in the respiratory epithelium lining airways and alveoli. Of the three main classes [ 1) voltage-dependent or Ca2+-activated, 6-transmembrane domains (TMD), 2) 2-pores 4-TMD, and 3) inward-rectified 2-TMD K+channels], almost 40 different transcripts have already been detected in the lung. The physiological and functional significance of this high molecular diversity of lung epithelial K+channels is intriguing. As detailed in the present review, K+channels are located at both the apical and basolateral membranes in the respiratory epithelium, where they mediate K+currents of diverse electrophysiological and regulatory properties. The main recognized function of K+channels is to control membrane potential and to maintain the driving force for transepithelial ion and liquid transport. In this manner, KvLQT1, KCa and KATPchannels, for example, contribute to the control of airway and alveolar surface liquid composition and volume. Thus, K+channel activation has been identified as a potential therapeutic strategy for the resolution of pathologies characterized by ion transport dysfunction. K+channels are also involved in other key functions in lung physiology, such as oxygen-sensing, inflammatory responses and respiratory epithelia repair after injury. The purpose of this review is to summarize and discuss what is presently known about the molecular identity of lung K+channels with emphasis on their role in lung epithelial physiology.
CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling
Authors: Doherty Taylor A. , Soroosh Pejman , Broide David H. , Croft Michael
Published: December 2008

The contribution of CD4 T cells and other CD4+ cells to lung inflammation and airway remodeling remains unclear during bouts of chronic exposure to airborne allergen. Previously, murine models have shown that CD4 T cells are required for initiation of acute inflammation and the remodeling process. However, it is unknown whether CD4 T cells or other CD4+ cells continue to be required for remodeling during ongoing allergen challenges after the development of acute eosinophilic lung inflammation. To test this, mice were sensitized and challenged with ovalbumin (OVA). After acute airway inflammation was established, a CD4 depleting antibody was administered for 4 wk during a period of chronic exposure to intranasal OVA, resulting in effective depletion of CD4+ cells from all organs, including the lung, lung-draining lymph nodes, and spleen. In these mice, levels of peribronchial inflammation, bronchoalveolar (BAL) eosinophils, and lung CD11c+, CD8+, and Siglec-F+CD11c- cells were significantly reduced. However, mucus metaplasia, peribronchial subepithelial fibrosis, and smooth muscle mass were not affected. Additionally, depletion of CD4+ cells before the last week of chronic allergen challenges also led to significant reductions in BAL eosinophils, peribronchial inflammation, and lung CD11c+, CD8+, and Siglec-F+CD11c- cells. These results show that CD4 T cells, and other CD4+ cells including subsets of dendritic cells, iNKT cells, and LTi cells, play a role in ongoing eosinophilic lung inflammation during periods of chronic allergen challenge, but are not required for progressive airway remodeling that develops after initial acute inflammation.
Neuromechanics of Muscle Synergies During Cycling
Authors: Wakeling James M. , Horn Tamara
Published: December 2008

Muscle synergies have been proposed as building blocks that could simplify the construction of motor behaviors. However, the muscles within synergistic groups may have different architectures, mechanical linkages to the skeleton, and biochemical properties, and these put competing demands on the most appropriate way to activate them for different mechanical tasks. This study identifies the extent to which synergistic patterns of muscle activity vary when the mechanical demands on a limb were altered, and additionally identifies how consistent the spectral profiles of the electromyographic (EMG) intensities were across the different movement tasks. The muscle activities were measured with surface EMG across 10 muscles in the leg during cycling at a range of loads and velocities. The EMGs were quantified by their intensities in time-frequency space using wavelet analysis; the instantaneous patterns of activity identified using principal component analysis, statistically compared and further visualized using the varimax rotation. Variability (35.7%) in the patterns of activity between the muscles were correlated with the torque and velocity of the pedal crank. Anatomic groups of muscles share a common mechanical action across a joint; uncoupling between such muscles was identified in 68.8% of the varimax patterns that encompassed all 10 muscles and 20.8–29.5% of the activity patterns when the anatomic groups were analyzed separately. The EMG spectra showed greatest heterogeneity for the gastrocnemii. These results show that the activity of muscles within anatomic groups is partially uncoupled in response to altered mechanical demands on the limb.
The Prognostic Significance of Pathologic Stage T0 on Organ-Confined Bladder Transitional Cell Carcinoma following Radical Cystectomy
Authors: Cho Kang Su , Seo Joo Wan , Park Sung Yul , Cho Nam Hoon , Choi Young Deuk , Yang Seung Choul , Hong Sung Joon
Published: December 2008

Introduction: We evaluated the prognostic significance of pT0 stage on organ-confined transitional cell carcinoma of the bladder following radical cystectomy. Patients and Methods: We retrospectively reviewed the medical records of consecutive patients who underwent radical cystectomy for organ-confined transitional cell carcinoma of the bladder between 1986 and 2004. Patients who were treated with neoadjuvant or adjuvant therapy were excluded. A total of 197 patients were enrolled in this study. We investigated the impact of pathologic T stage on disease-specific survival. Results: Overall disease-specific survival rate was 84.1% after 5 years. Five-year disease-specific survival rates according to pathologic stage were 88.7% in pT0, 92.2% in pTis-1 and 65.4% in pT2 disease. Overall disease-specific survival rate with pTis-1 or pT0 tumors was significantly higher than with pT2 tumors (p = 0.001, pT2 vs. pT0; p < 0.001, pT2 vs. pTis-1), but there was no difference in disease-specific survival between pTis-1 and pT0 tumors (p > 0.05). In the muscle-invasive tumor group, pT0 tumors had a more favorable prognosis than pT2 tumors (p = 0.042), but there was no difference in prognosis between pT0 and pTis-1 tumors. Conclusions: Pathologic stage T0 cystectomy can be considered a curative therapy in most cases, including pT0cT2 tumors, but there is a substantial risk of tumor recurrence.