bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Expression Analysis of Human Epidermal Keratinocytes after N-Acetyl L-Cysteine Treatment Demonstrates Cell Cycle Arrest and Increased Differentiation
Authors: Edlundh-Rose Esther , Kupershmidt Ilya , Gustafsson Anna C. , Parasassi Tiziana , Serafino Annalucia , Bracci-Laudiero Luisa , Greco Giulia , Krasnowska Ewa K. , Romano Maria-Concetta , Lundeberg Thomas , Nilsson Peter , Lundeberg Joakim
Published: August 2005

Objectives: Several cancer prevention programmes have previously been executed using treatment of antioxidant compounds. The antioxidant N-acetyl L-cysteine (NAC), a membrane-permeable aminothiol, is a sulfhydryl reductant reducing oxidised glutathione, as well as being a precursor of intracellular cysteine and glutathione. A previous report based on the cellular response to NAC treatment showed that NAC induced a 10-fold more rapid differentiation in normal primary keratinocytes as well as a reversion of a colon carcinoma cell line from neoplastic proliferation to apical-basolateral differentiation. In order to investigate molecular events underlying thechanges in proliferation and differentiation induced by NAC treatment, we performed global gene expression analysis of normal human epidermal keratinocytes in a time series. Methods: Treated samples were compared to untreated samples through a reference design using a spotted cDNA array comprising approximately 30,000 features. B statistics was used to identify differentially expressed genes, and RT-PCR of a selected set of genes was performed to verify differential expression. Results: The number of differentially expressed genes increased over time, starting with 0 at 30 min, 73 at 3 h and increasing to 952 genes at 48 h. Results of the expression analysis showed arrest of the cell cycle and an upregulation of cytoskeletal reorganisation, implicating increased differentiation. A comparison to gene ontology groups indicated downregulation of a large number of genes involved in cell proliferation and regulation of the cell cycle. Conclusions: A significant fraction of the differentially expressed genes could be classified according to their role in the differentiation process, demonstrating that NAC regulates the conversion from proliferation to differentiation at a transcriptional level.
Anxiety and P Wave Dispersion in a Healthy Young Population
Authors: Uyarel Hüseyin , Kasıkcıoglu Hülya , Dayi Sennur Unal , Tartan Zeynep , Karabulut Ahmet , Uzunlar Bülent , Samur Hasan , Sarı Ibrahim , Okmen Ertan , Cam Nese
Published: August 2005

Background: P wave dispersion (Pd), defined as the difference between the maximum (Pmax) and the minimum P wave duration (Pmin), and Pmax are electrocardiographic (ECG) markers that have been used to evaluate the discontinuous propagation of sinus impulses and the prolongation of atrial conduction time. Pd in normal subjects has been reported to be influenced by the autonomic tone, which induces changes in atrial size and the velocity of impulse propagation. However, the association between Pd and anxiety has not been studied in normal subjects. Methods and Results: Pmax, Pmin and Pd were measured in 726 physically and mentally healthy young male volunteers, aged 21.23 ± 1.25 years (range 20–26). The Spielberger State-Trait Anxiety Inventory (STAI) was scored concomitantly. Blinded intra- and interobserver reproducibility of the P wave duration and Pd measurement were evaluated, and comparison revealed a Pearson correlation coefficient of 0.87 and 0.89 for the P wave duration, and 0.93 and 0.90 for Pd, respectively (p < 0.001). Pmax and Pd were significantly correlated with the state anxiety (STAI-1) subscale (r = 0.662, p < 0.001, and r = 0.540, p < 0.001, respectively) and the trait anxiety (STAI-2) subscale (r = 0.583, p < 0.001, and r = 0.479, p < 0.001, respectively). Pmin did not show any significant correlation with anxiety. Across 3 variables included in a multiple linear regression analysis, STAI-1 and STAI-2 were the significant independent determinants of Pmax and Pd. Beta coefficients indicated that the contribution of STAI-1 to Pmax (66.3 and 33.7%) and Pd (65 and 35%) was much greater than that of STAI-2. Conclusions: STAI-1 and STAI-2are associated with an increase in Pmax and Pd. The association of Pd resulted from an augmentation of Pmax. This is the first study to show the relation between Pmax, Pd and anxiety.
Two Successful Pregnancies after in vitro Fertilization and Embryo Transfer in a Patient with Endometrial Atypical Hyperplasia Bordering on Adenocarcinoma Treated Conservatively with High-Dose Progesterone
Authors: Piura Benjamin
Published: August 2005

Women suffering from anovulatory infertility may develop endometrial hyperplasia and adenocarcinoma due to the unopposed estrogen effect. We present the case of a young infertile woman with endometrial atypical hyperplasia bordering on adenocarcinoma who refused hysterectomy and bilateral salpingo-oophorectomy and achieved two successful pregnancies after conservative treatment with high-dose progesterone followed by in vitro fertilization and embryo transfer. It is concluded that conservative treatment with high-dose progesterone for endometrial hyperplasia and well-differentiated early-stage adenocarcinoma followed by assisted reproductive technologies is an appropriate means for achieving pregnancy. However, the issue of hysterectomy and bilateral salpingo-oophorectomy after delivery or after fertility being no longer required is controversial. If surgery is not performed, close observation with endometrial sampling every 6 months is advisable.
Effects of New Peritoneal Dialysis Solutions on Leukocyte Recruitment in the Rat Peritoneal Membrane
Authors: Mortier Siska , Faict Dirk , Gericke Marion , Lameire Norbert , De Vriese An
Published: August 2005

Objectives: Peritonitis remains a principal cause of dropout in peritoneal dialysis (PD). The physiological host response to a peritoneal infection involves a rise in numbers of circulating leukocytes to the peritoneal cavity. We evaluated the effects of (1) conventional peritoneal dialysis fluid (PDF), (2) bicarbonate-based PDF, low in glucose degradation products, and (3) non-glucose PDF on peritoneal leukocyte recruitment in response to an inflammatory stimulus using intravital microscopy. Methods: The visceral peritoneum was exposed to EBSS, conventional lactate-buffered and bicarbonate/lactate-buffered glucose-based PDF and three lactate-buffered non-glucose PDF – icodextrin, amino acid-based PDF and amino acid/glycerol-based PDF. The number of rolling, adhering and extravasated leukocytes and leukocyte rolling velocity was assessed at different time intervals after stimulation with lipopolysaccharide (LPS). Results: Exposure to LPS dissolved in EBSS dramatically increased the number of rolling, adhering and extravasated leukocytes and decreased leukocyte rolling velocity. Conventional PDF completely abolished LPS-induced leukocyte recruitment. Bicarbonate/lactate-buffered PDF only minimally affected the process of leukocyte recruitment, whereas icodextrin PDF resulted in partial inhibition of the immune response. The amino acid-based and the amino acid/glycerol-based PDF inhibited leukocyte recruitment to a similar extent as conventional PDF. Conclusions: Bicarbonate/lactate-buffered PDF has superior biocompatibility towards peritoneal host defense, in spite of its high glucose concentrations. Lactate-buffered non-glucose containing PDF has substantial inhibitory effects on leukocyte recruitment, indicating that the bioincompatibility of high lactate concentrations and/or low pH may not be underestimated.
Innate Antiviral Immunity Is Not Impaired in Patients with Chronic Renal Failure on Hemodialysis
Authors: Zaczyńska E. , Magott-Procelewska M. , Rybka K. , Siemieniec I. , Błach-Olszewska Z. , Klinger M.
Published: August 2005

Although it is well documented that chronic renal failure patients are susceptible to infectious diseases, the reason for this has not been clarified. The aim of the study was to assess the antiviral natural (innate) immunity of peripheral leukocytes in 37 hemodialysis patients and compare it with that of a of control group (70 blood donors). We investigated 16 patients with anti-hepatitis C virus (HCV) antibodies, anti-HCV(+) and 21 patients without anti-HCV antibodies, anti-HCV(–). Methods: Innate immunity was measured using the method of direct infection of peripheral blood leukocytes with indicatory VS virus. The VS virus did not replicate in leukocytes with strong innate immunity, whereas by impaired immunity the virus multiplied to high titer. Results: Patients on hemodialysis expressed the same levels of nonspecific antiviral immunity as the control group. We found complete, partial or deficient of innate immunity respectively in 33, 52.5, 14.5% of anti-HCV(–) patients, 43, 43 and 14% of anti-HCV(+) patients, and 44, 40 and 16% of controls. Conclusions: Innate antiviral immunity was not impaired (disturbed) in chronic HD patients. The categories of innate immunity disposition in dialysis patients and the healthy population did not differ.
Patterns of Pulmonary Complications Associated with Sirolimus
Authors: Chhajed Prashant N. , Dickenmann Michael , Bubendorf Lukas , Mayr Michael , Steiger Jürg , Tamm Michael
Published: August 2005

Sirolimus inhibits human fibroblast cell proliferation in cell cultures from transbronchial biopsies of lung transplant recipients. However, a few cases of interstitial pneumonitis and bronchiolitis obliterans organizing pneumonia have been recently described in solid organ transplant recipients, including a fatality in a heart transplant recipient. We studied the patterns of pulmonary adverse effects associated with sirolimus in 4 renal transplant recipients who developed pulmonary opacities on chest radiograph, which were proved to be noninfectious in origin. Lung biopsy was performed to obtain histological diagnosis (3 interstitial pneumonitis, 1 necrotizing vasculitis). Symptoms were dyspnea (4), cough (2), hemoptysis (1), fever (1) and eyelid edema (1). Those with interstitial pneumonitis had bilateral basal opacities on chest X-ray, and histopathology showed mild lymphoplasmocytic interstitial inflammation, scattered intraalveolar epitheloid granulomas and a focal pattern of organizing pneumonia. Serum C-reactive protein (CRP) was elevated and bronchoalveolar lavage revealed lymphocytosis (77, 79.5 and 31%). The fourth patient had an opacity localized in the upper lobe, which progressed to both the lower lobes, and histopathology showed multifocal necroses of lung tissue with lymphoplasmocytic vasculitis and scattered granulomas. In this patient, the serum CRP level was not elevated and bronchoalveolar lavage was normal. Pulmonary symptoms and opacities on chest radiograph resolved and the serum CRP level became normal after sirolimus was stopped in all patients. Sirolimus may be a cause of interstitial pneumonitis or pulmonary vasculitis, and withdrawal of sirolimus is therapeutic.
N-Terminal Pro Brain Natriuretic Peptide Is Inversely Related to Metabolic Cardiovascular Risk Factors and the Metabolic Syndrome
Authors: Olsen Michael H. , Hansen Tine W. , Christensen Marina K. , Gustafsson Finn , Rasmussen Susanne , Wachtell Kristian , Borch-Johnsen Knut , Ibsen Hans , Jørgensen Torben , Hildebrandt Per
Published: August 2005

We wanted to investigate the relationship of N-terminal pro brain natriuretic peptide (Nt-proBNP) to metabolic and hemodynamic cardiovascular (CV) risk factors in the general population. From a population-based sample of 2656 people 41, 51, 61, or 71 years of age, we selected 2070 patients without previous stroke or myocardial infarction who did not receive any CV, antidiabetic, or lipid-lowering treatment in 1993 to 1994. Traditional CV risk factors, 24-hour blood pressures, left ventricular (LV) mass, and ejection fraction by echocardiography, pulse wave velocity, urine albumin/creatinine ratio (UACR), and serum Nt-proBNP were measured in 1993 to 1994. The metabolic syndrome was defined in accordance with the definition of the European Group for the Study of Insulin Resistance (EGIR). Higher log(Nt-proBNP) was in multiple regression analysis related to female gender (β=−0.37), older age (β=0.32), higher clinic pulse pressure (β=0.20), lower serum total cholesterol (β=−0.15), lower LVEF (β=−0.08, all
P
<0.001), lower log(serum insulin) (β=−0.07), lower log(plasma glucose) (β=−0.06, both
P
<0.01, lower log(serum triglyceride) (β=−0.06), lower body mass index (β=−0.05); lower heart rate (β=−0.05), higher logUACR (β=0.04, all
P
<0.05) and higher log(LV mass index) (β=0.04,
P
=0.07), adjusted
R
2
=0.35,
P
<0.001). The metabolic syndrome was associated with lower Nt-proBNP (35 pg/mL versus 48 pg/mL;
P
<0.001) and shifted the positive relationship between pulse pressure and Nt-proBNP to the right (ie, higher blood pressure for a given level of Nt-proBNP). The metabolic syndrome was associated with lower Nt-proBNP levels and shifted the positive relationship between Nt-proBNP and pulse pressure to the right, creating a possible link between the metabolic syndrome and hypertension.
Slow Breathing Improves Arterial Baroreflex Sensitivity and Decreases Blood Pressure in Essential Hypertension
Authors: Joseph Chacko N. , Porta Cesare , Casucci Gaia , Casiraghi Nadia , Maffeis Mara , Rossi Marco , Bernardi Luciano
Published: August 2005

Sympathetic hyperactivity and parasympathetic withdrawal may cause and sustain hypertension. This autonomic imbalance is in turn related to a reduced or reset arterial baroreflex sensitivity and chemoreflex-induced hyperventilation. Slow breathing at 6 breaths/min increases baroreflex sensitivity and reduces sympathetic activity and chemoreflex activation, suggesting a potentially beneficial effect in hypertension. We tested whether slow breathing was capable of modifying blood pressure in hypertensive and control subjects and improving baroreflex sensitivity. Continuous noninvasive blood pressure, RR interval, respiration, and end-tidal CO
2
(CO
2
-et) were monitored in 20 subjects with essential hypertension (56.4±1.9 years) and in 26 controls (52.3±1.4 years) in sitting position during spontaneous breathing and controlled breathing at slower (6/min) and faster (15/min) breathing rate. Baroreflex sensitivity was measured by autoregressive spectral analysis and “alpha angle” method. Slow breathing decreased systolic and diastolic pressures in hypertensive subjects (from 149.7±3.7 to 141.1±4 mm Hg,
P
<0.05; and from 82.7±3 to 77.8±3.7 mm Hg,
P
<0.01, respectively). Controlled breathing (15/min) decreased systolic (to 142.8±3.9 mm Hg;
P
<0.05) but not diastolic blood pressure and decreased RR interval (
P
<0.05) without altering the baroreflex. Similar findings were seen in controls for RR interval. Slow breathing increased baroreflex sensitivity in hypertensives (from 5.8±0.7 to 10.3±2.0 ms/mm Hg;
P
<0.01) and controls (from 10.9±1.0 to 16.0±1.5 ms/mm Hg;
P
<0.001) without inducing hyperventilation. During spontaneous breathing, hypertensive subjects showed lower CO
2
and faster breathing rate, suggesting hyperventilation and reduced baroreflex sensitivity (
P
<0.001 versus controls). Slow breathing reduces blood pressure and enhances baroreflex sensitivity in hypertensive patients. These effects appear potentially beneficial in the management of hypertension.
Risk Factors Identified in Childhood and Decreased Carotid Artery Elasticity in Adulthood
Authors: Juonala Markus , Järvisalo Mikko J. , Mäki-Torkko Noora , Kähönen Mika , Viikari Jorma S.A. , Raitakari Olli T.
Published: August 2005

Background—

Exposure to risk factors in childhood may have long-term influences on vascular function. We examined the relationship between risk factors identified in childhood and arterial elasticity assessed in adulthood.

Methods and Results—

Carotid artery compliance (CAC), Young’s elastic modulus (YEM), and stiffness index (SI), 3 measures of large-artery elasticity, were assessed with noninvasive ultrasound in 2255 healthy white adults aged 24 to 39 years participating in a population-based cohort study and who had risk factor data available since childhood. In multivariate models, childhood obesity (skinfold thickness) predicted decreased CAC (
P
<0.001), increased YEM (
P
<0.01), and increased SI (
P
<0.01) in adulthood. Childhood blood pressure was inversely associated with CAC (
P
<0.001) and directly associated with YEM (
P
<0.001). The number of risk factors identified in childhood, which included high LDL cholesterol (at or above 80th percentile), elevated blood pressure, skinfold thickness, low HDL cholesterol (at or below 20th percentile), and smoking, was related inversely with CAC (
P
<0.001) and directly with YEM (
P
<0.001). These associations remained highly significant after adjustment for the number of risk factors identified in adulthood (
P
=0.005 for CAC and
P
<0.001 for YEM).

Conclusions—

Cardiovascular risk factors identified in childhood and adolescence predict decreased carotid artery elasticity in adulthood. These data suggest that risk factors operating in early life may have sustained deleterious effects on arterial elasticity.
C-Reactive Protein in Heart Failure
Authors: Anand Inder S. , Latini Roberto , Florea Viorel G. , Kuskowski Michael A. , Rector Thomas , Masson Serge , Signorini Stefano , Mocarelli Paolo , Hester Allen , Glazer Robert , Cohn Jay N.
Published: August 2005

Background—

The role of C-reactive protein (CRP) in heart failure is not well studied. We assessed the prognostic value of CRP in patients randomized in Val-HeFT (Valsartan Heart Failure Trial) and studied changes in CRP that were associated with valsartan.

Methods and Results—

Characteristics of patients with baseline CRP levels above and below the median value were compared. Univariable and multivariable Cox proportional hazards regression models were used to examine the relationship of CRP to mortality and morbidity. Interactions were tested to determine whether differences in CRP changes from baseline to 4 and 12 months between groups randomly assigned to valsartan or placebo depended on baseline ACE inhibitor use. Median plasma CRP was 3.23 mg/L (interquartile range 1.42 to 7.56 mg/L), which is higher than in the general population. Patients with CRP above the median had features of more severe heart failure than those with CRP levels below the median. The cumulative likelihood of death and first morbid event increased with increasing quartile of CRP. Relative to the lowest CRP quartile, the risk of mortality (hazard ratio 1.51, 95% CI 1.2 to 1.9) and first morbid event (hazard ratio 1.53, 95% CI 1.28 to 1.84) was increased in the highest CRP quartile in multivariable models. CRP added incremental prognostic information to that provided by brain natriuretic peptide alone. CRP did not change significantly over time in the placebo group; however, after 12 months, valsartan was associated with a decrease in CRP in patients not receiving ACE inhibitors but not in those receiving ACE inhibitors at 12 months.

Conclusions—

CRP is increased in heart failure. Higher levels are associated with features of more severe heart failure and are independently associated with mortality and morbidity. The ability of treatments to reduce CRP levels and the prognostic importance of reducing CRP require further study.
Lack of JunD Promotes Pressure Overload–Induced Apoptosis, Hypertrophic Growth, and Angiogenesis in the Heart
Authors: Hilfiker-Kleiner Denise , Hilfiker Andres , Kaminski Karol , Schaefer Arnd , Park Joon-Keun , Michel Kim , Quint Anja , Yaniv Moshe , Weitzman Jonathan B. , Drexler Helmut
Published: August 2005

Background—

The Jun family of activator protein 1 (AP-1) transcription factors (c-Jun, JunB, and JunD) is involved in fundamental biological processes such as proliferation, apoptosis, tumor angiogenesis, and hypertrophy. The role of individual AP-1 transcription factors in the stressed heart is not clear. In the present study we analyzed the role of JunD in survival, hypertrophy, and angiogenesis in the pressure-overloaded mouse heart after thoracic aortic constriction.

Methods and Results—

Mice lacking JunD (knockout [KO]) showed increased mortality and enhanced cardiomyocyte apoptosis and fibrosis associated with increased levels of hypoxia-induced factor-1α, vascular endothelial growth factor (VEGF), p53, and Bax protein and reduced levels of Bcl-2 protein after 7 days of severe pressure overload compared with wild-type (WT) siblings. Cardiomyocyte hypertrophy in surviving KO mice was enhanced compared with that in WT mice. Chronic moderate pressure overload for 12 weeks caused enhanced left ventricular hypertrophy in KO mice, and survival and interstitial fibrosis were comparable with WT mice. Cardiac function, 12 weeks after operation, was comparable among shams and pressure-overloaded mice of both genotypes. In addition, KO mice exposed to chronic pressure overload showed higher cardiac capillary density associated with increased protein levels of VEGF.

Conclusions—

Thus, JunD limits cardiomyocyte hypertrophy and protects the pressure-overloaded heart from cardiac apoptosis. These beneficial effects of JunD, however, are associated with antiangiogenic properties.
Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction
Authors: Kraitchman Dara L. , Tatsumi Mitsuaki , Gilson Wesley D. , Ishimori Takayoshi , Kedziorek Dorota , Walczak Piotr , Segars W. Paul , H. Chen Hunter , Fritzges Danielle , Izbudak Izlem , Young Randell G. , Marcelino Michelle , Pittenger Mark F. , Solaiyappan Meiyappan , Boston Raymond C. , Tsui Benjamin M.W. , Wahl Richard L. , Bulte Jeff W.M.
Published: August 2005

Background—

Recent results from animal studies suggest that stem cells may be able to home to sites of myocardial injury to assist in tissue regeneration. However, the histological interpretation of postmortem tissue, on which many of these studies are based, has recently been widely debated.

Methods and Results—

With the use of the high sensitivity of a combined single-photon emission CT (SPECT)/CT scanner, the in vivo trafficking of allogeneic mesenchymal stem cells (MSCs) colabeled with a radiotracer and MR contrast agent to acute myocardial infarction was dynamically determined. Redistribution of the labeled MSCs after intravenous injection from initial localization in the lungs to nontarget organs such as the liver, kidney, and spleen was observed within 24 to 48 hours after injection. Focal and diffuse uptake of MSCs in the infarcted myocardium was already visible in SPECT/CT images in the first 24 hours after injection and persisted until 7 days after injection and was validated by tissue counts of radioactivity. In contrast, MRI was unable to demonstrate targeted cardiac localization of MSCs in part because of the lower sensitivity of MRI.

Conclusions—

Noninvasive radionuclide imaging is well suited to dynamically track the biodistribution and trafficking of mesenchymal stem cells to both target and nontarget organs.
Drinking Frequency, Mediating Biomarkers, and Risk of Myocardial Infarction in Women and Men
Authors: Mukamal Kenneth J. , Jensen Majken K. , Grønbæk Morten , Stampfer Meir J. , Manson JoAnn E. , Pischon Tobias , Rimm Eric B.
Published: August 2005

Background—

The associations of drinking frequency and quantity with risk of myocardial infarction have not been studied among women, and the degree to which specific risk factors mediate the inverse association of drinking frequency with risk of myocardial infarction is uncertain.

Methods and Results—

We conducted nested case-control studies of 32 826 women enrolled in the Nurses Health Study followed up from 1990 to 1998 and 18 225 men enrolled in the Health Professionals Follow-Up Study followed up from 1994 to 2000. A total of 249 women and 266 men with incident myocardial infarction were matched on age, smoking, and date of entry to 498 female and 532 male control participants. We determined the risk of myocardial infarction related to frequency and quantity of alcohol intake and the change in risk before and after adjustment for putative cardiovascular risk factors. Among both women and men, drinking frequency tended to be associated with lower risk of myocardial infarction, with the lowest risks among those who drank 3 to 7 days per week. Further adjustment for levels of high-density lipoprotein cholesterol, hemoglobin A
1c
, and fibrinogen attenuated 75% of the association of frequent drinking with risk among women and fully attenuated the association among men.

Conclusions—

Alcohol intake at least 3 to 4 days per week is associated with a lower risk of myocardial infarction among women and men, an association apparently attributable to the relationship of alcohol with HDL cholesterol, fibrinogen, and hemoglobin A
1c
. Because the effects of alcohol on HDL cholesterol, fibrinogen, and insulin sensitivity have been confirmed in randomized trials, our findings support the hypothesis that the inverse relation of alcohol use and myocardial infarction is causal.
Revised Adult Treatment Panel III Guidelines and Cardiovascular Disease Mortality in Men Attending a Preventive Medical Clinic
Authors: Ardern Chris I. , Katzmarzyk Peter T. , Janssen Ian , Church Timothy S. , Blair Steven N.
Published: August 2005

Background—

National Cholesterol Education Program Adult Treatment Panel III guidelines recommend therapeutic lifestyle changes (TLC) and drug therapy to reduce cardiovascular disease (CVD) risk. These guidelines have been revised recently (ATP III-R); however, the risk of CVD mortality within each intervention window and the effects of cardiorespiratory fitness (CRF) and metabolic syndrome on CVD mortality within the framework of the guidelines are unknown.

Methods and Results—

Risk factor and CRF data from 19 125 men (aged 20 to 79 years) who attended a preventive medical clinic between 1979 and 1995 were used. Mortality follow-up was completed until December 31, 1996. Participants were assigned to ATP III-R groups (LDL-C goal, TLC initiation, and drug consideration), and risk of CVD mortality was assessed by Cox proportional hazards regression. There were 179 CVD deaths over an average 10.2 years of follow-up. Compared with the LDL-C goal group, men in the TLC initiation and drug consideration groups had an elevated risk of CVD mortality (TLC initiation: HR=2.65, 95% CI 1.67 to 4.19; drug consideration: HR=6.44, 95% CI 4.49 to 9.25). Compared with LDL-C goal/fit, CVD mortality risk was higher in the LDL-C goal/unfit (4.8, 2.5 to 9.1), TLC initiation/fit (3.0, 1.7 to 5.3), TLC initiation/unfit (7.5, 3.7 to 15.2), drug consideration/fit (7.2, 4.6 to 11.4), and drug consideration/unfit (14.9, 9.1 to 24.4) groups. A similar gradient was observed for metabolic syndrome across intervention windows.

Conclusions—

Men eligible for TLC or drug consideration under ATP III-R were at elevated risk of CVD mortality compared with men who met the LDL-C goal. Furthermore, men who were physically fit or who did not have the metabolic syndrome had a lower risk of CVD mortality.
Restricting Excessive Cardiac Action Potential and QT Prolongation
Authors: Jost Norbert , Virág László , Bitay Miklós , Takács János , Lengyel Csaba , Biliczki Péter , Nagy Zsolt , Bogáts Gábor , Lathrop David A. , Papp Julius G. , Varró András
Published: August 2005

Background—

Although pharmacological block of the slow, delayed rectifier potassium current (
I
Ks
) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of
I
Ks
block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of
I
Ks
in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline.

Methods and Results—

Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 μmol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 μmol/L) produced a <12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the
I
Kr
blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L-735,821 and chromanol 293B each blocked
I
Ks
in the presence of E-4031 to block
I
Kr
. The E-4031–sensitive current (
I
Kr
) at the end of a 150-ms-long test pulse to 30 mV was 32.9±6.7 pA (n=8); the L-735,821–sensitive current (
I
Ks
) magnitude was 17.8±2.94 pA (n=10). During a longer 500-ms test pulse,
I
Kr
was not substantially changed (33.6±6.1 pA; n=8), and
I
Ks
was significantly increased (49.6±7.24 pA; n=10). On application of an “action potential–like” test pulse,
I
Kr
increased as voltage became more negative, whereas
I
Ks
remained small throughout all phases of the action potential–like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 μmol/L adrenaline, 1 μmol/L HMR-1556 significantly increased APD by 14.7±3.2% (
P
<0.05; n=3).

Conclusions—

Pharmacological
I
Ks
block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated,
I
Ks
plays an increasingly important role in limiting action potential prolongation.
Anatomic Relations Between the Esophagus and Left Atrium and Relevance for Ablation of Atrial Fibrillation
Authors: Sánchez-Quintana Damian , Cabrera José Angel , Climent Vicente , Farré Jerónimo , de Mendonça Maria Cristina , Ho Siew Yen
Published: August 2005

Background—

Esophageal injury is a potential complication after intraoperative or percutaneous transcatheter ablation of the posterior aspect of the left atrium. Understanding the spatial relations between the esophagus and the left atrium is essential to reduce risks.

Methods and Results—

We examined by gross dissection the course of the esophagus in 15 cadavers. We measured the minimal distance of the esophageal wall to the endocardium of the left atrium with histological studies in 12 specimens. To measure the transmural thickness of the atrial wall, we sectioned another 30 human heart specimens in the sagittal plane at 3 different regions of the left atrium. The esophagus follows a variable course along the posterior aspect of the left atrium; its wall was <5 mm from the endocardium in 40% of specimens. The posterior left atrial wall has a variable thickness, being thickest adjacent to the coronary sinus and thinnest more superiorly. Behind is a layer of fibrous pericardium and fibrofatty tissue of irregular thickness that contains esophageal arteries of 0.4±0.2-mm external diameters.

Conclusions—

The nonuniform thickness of the posterior left atrial wall and the variable fibrofatty layer between the wall and the esophagus are risk factors that must be considered during ablation procedure. Esophageal arteries and vagus nerve plexus on the anterior surface of the esophagus may be affected by ablative procedures.
Pergolide Is an Inhibitor of Voltage-Gated Potassium Channels, Including Kv1.5, and Causes Pulmonary Vasoconstriction
Authors: Hong Zhigang , Smith Andrew J. , Archer Stephen L. , Wu Xi-Chen , Nelson Daniel P. , Peterson Douglas , Johnson Gerhard , Weir E. Kenneth
Published: August 2005

Background—Pergolide produces clinical benefit in Parkinson disease by stimulating dopamine D1and D2receptors. An increased incidence of carcinoid-like heart valve disease (CLHVD) has been noted in pergolide users, reminiscent of that induced by certain anorexigens used for weight reduction. Anorexigens that modulate serotonin release and reuptake, such as dexfenfluramine, were withdrawn from sale because of CLHVD. Interestingly, the anorexigens also caused pulmonary arterial hypertension (PAH). Anorexigens were shown to enhance hypoxic pulmonary vasoconstriction, in part by inhibiting voltage-gated K+channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). Although PAH has not been associated with pergolide use, we hypothesized that pergolide might have similar effects on hypoxic pulmonary vasoconstriction and Kv channels.

Methods and Results—Pergolide enhanced hypoxic pulmonary vasoconstriction in the isolated perfused rat lung compared with control lungs (mean pulmonary artery pressure 32±3 versus 21±2 mm Hg;P<0.01). Pergolide also caused vasoconstriction in rat pulmonary artery rings. Pergolide inhibited PASMC potassium current density, resulting in membrane depolarization (from −51±2 to −44±1 mV) and increased cytosolic calcium in both rat and human PASMCs. Pergolide directly inhibited heterologously expressed Kv1.5 and KCachannels.

Conclusions—Pergolide causes Kv channel inhibition and, despite being from a different class of drugs, has pulmonary vascular effects reminiscent of dexfenfluramine. Coupled with their shared proclivity to induce CLHVD, these findings suggest that clinical monitoring for pergolide-induced PAH should be considered.
Using a Multilevel Approach to Examine the Relationship between Task Cohesion and Team Task Satisfaction in Elite Ice Hockey Players
Authors: Spink Kevin S. , Nickel Darren , Wilson Kathleen , Odnokon Pat
Published: August 2005

Of numerous studies conducted over the years examining cohesion in the sport setting, very few have acknowledged that participants are nested within teams, which has resulted in analysis of data at the individual level. Given that members of sport teams are interdependent, valuable information might be lost if constructs such as cohesion are examined only at an individual level. The purpose of this study was to illustrate how multilevel modeling could be used to handle this interdependence among observations within teams when examining the relationship between task cohesion and team satisfaction. Male ice hockey players (N = 194) on 10 teams completed the cohesion and satisfaction measures near the end of the regular season. Using multilevel analysis, task cohesion predicted variance in team task satisfaction at the individual (33%) and group (55%) levels. Results highlight the value of multilevel models as well as extend research finding a relationship between cohesion and individual satisfaction to team satisfaction.
Is there a “Big Five” in Teamwork?
Authors: Salas Eduardo , Sims Dana E. , Burke C. Shawn
Published: August 2005

The study of teamwork has been fragmented through the years, and the findings are generally unable to be used practically. This article argues that it is possible to boil down what researchers know about teamwork into five core components that the authors submit as the “Big Five” in teamwork. The core components of teamwork include team leadership, mutual performance monitoring, backup behavior, adaptability, and team orientation. Furthermore, the authors examine how these core components require supporting coordinating mechanisms (e.g., shared mental modes, closed-loop communication, and mutual trust) and vary in their importance during the life of the team and the team task. Finally, the authors submit a set of propositions for future research.
A New Method for Analyzing Sequential Processes
Authors: Chiu Ming Ming , Khoo Lawrence
Published: August 2005

Researchers studying sequential processes (e.g., marital conflicts, teacher-student interactions, etc.) often try to model how recent events affect current events. A researcher doing so faces several difficulties: the threat of combinatorial explosion due to comprehensive coding, continuous and discrete variables, and differences across time (nonstationarity) and across groups (group heterogeneity). The authors discuss three often-used methods of analyzing time-series data (conditional probabilities, sequential analysis, and Logit with lag variables) and the problems inherent in them. The authors then introduce a new method that addresses the above problems: dynamic multilevel analysis. To highlight the similarities and differences between these methods, the authors apply them to data from student group problem-solving sessions in an algebra class. The authors use the various methods to show how likelihood of agreement was affected by other recent speakers’ correct ideas, mathematics status, agreement, and rudeness.
Hypoxia-activated genes from early placenta are elevated in Preeclampsia, but not in Intra-Uterine Growth Retardation
Authors: Vaiman Daniel , Mondon Françoise , Garcès-Duran Alexandra , Mignot Thérèse-Marie , Robert Brigitte , Rebourcet Régis , Jammes Hélène , Chelbi Sonia T , Quetin Frédérique , Marceau Geoffrey , Sapin Vincent , Piumi François , Danan Jean-Louis , Rigourd Virginie , Carbonne Bruno , Ferré Françoise
Published: August 2005

Background

As a first step to explore the possible relationships existing between the effects of low oxygen pressure in the first trimester placenta and placental pathologies developing from mid-gestation, two subtracted libraries totaling 2304 cDNA clones were constructed. For achieving this, two reciprocal suppressive/subtractive hybridization procedures (SSH) were applied to early (11 weeks) human placental villi after incubation either in normoxic or in hypoxic conditions. The clones from both libraries (1440 hypoxia-specific and 864 normoxia-specific) were spotted on nylon macroarrays. Complex cDNAs probes prepared from placental villi (either from early pregnancy, after hypoxic or normoxic culture conditions, or near term for controls or pathological placentas) were hybridized to the membranes.

Results

Three hundred and fifty nine clones presenting a hybridization signal above the background were sequenced and shown to correspond to 276 different genes. Nine of these genes are mitochondrial, while 267 are nuclear. Specific expression profiles characteristic of preeclampsia (PE) could be identified, as well as profiles specific of intra-uterine growth retardation (IUGR).

Focusing on the chromosomal distribution of the fraction of genes that responded in at least one hybridization experiment, we could observe a highly significant chromosomal clustering of 54 genes into 8 chromosomal regions, four of which containing imprinted genes. Comparative mapping data indicate that these imprinted clusters are maintained in synteny in mice, and apparently in cattle and pigs, suggesting that the maintenance of such syntenies is requested for achieving a normal placental physiology in eutherian mammals.

Conclusion

We could demonstrate that genes induced in PE were also genes highly expressed under hypoxic conditions (P = 5.10-5), which was not the case for isolated IUGR. Highly expressed placental genes may be in syntenies conserved interspecifically, suggesting that the maintenance of such clusters is requested for achieving a normal placental physiology in eutherian mammals.
GH97 is a new family of glycoside hydrolases, which is related to the α-galactosidase superfamily
Authors: Naumoff Daniil G
Published: August 2005

Background

As a rule, about 1% of genes in a given genome encode glycoside hydrolases and their homologues. On the basis of sequence similarity they have been grouped into more than ninety GH families during the last 15 years. The GH97 family has been established very recently and initially included only 18 bacterial proteins. However, the evolutionary relationship of the genes encoding proteins of this family remains unclear, as well as their distribution among main groups of the living organisms.

Results

The extensive search of the current databases allowed us to double the number of GH97 family proteins. Five subfamilies were distinguished on the basis of pairwise sequence comparison and phylogenetic analysis. Iterative sequence analysis revealed the relationship of the GH97 family with the GH27, GH31, and GH36 families of glycosidases, which belong to the α-galactosidase superfamily, as well as a more distant relationship with some other glycosidase families (GH13 and GH20).

Conclusion

The results of this study show an unexpected sequence similarity of GH97 family proteins with glycoside hydrolases from several other families, that have (β/α)8-barrel fold of the catalytic domain and a retaining mechanism of the glycoside bond hydrolysis. These data suggest a common evolutionary origin of glycosidases representing different families and clans.
Epidermal growth factor (EGF) withdrawal masks gene expression differences in the study of pituitary adenylate cyclase-activating polypeptide (PACAP) activation of primary neural stem cell proliferation
Authors: Sievertzon Maria , Wirta Valtteri , Mercer Alex , Frisén Jonas , Lundeberg Joakim
Published: August 2005

Background

The recently discovered adult neural stem cells, which maintain continuous generation of new neuronal and glial cells throughout adulthood, are a promising and expandable source of cells for use in cell replacement therapies within the central nervous system. These cells could either be induced to proliferate and differentiate endogenously, or expanded and differentiated in culture before being transplanted into the damaged site of the brain. In order to achieve these goals effective strategies to isolate, expand and differentiate neural stem cells into the desired specific phenotypes must be developed. However, little is known as yet about the factors and mechanisms influencing these processes. It has recently been reported that pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neural stem cell proliferation both in vivo and in vitro.

Results

We used cDNA microarrays with the aim of analysing the transcriptional changes underlying PACAP induced proliferation of neural stem cells. The primary neural stem/progenitor cells used were neurospheres, generated from the lateral ventricle wall of the adult mouse brain. The results were compared to both differentiation and proliferation controls, which revealed an unexpected and significant differential expression relating to withdrawal of epidermal growth factor (EGF) from the neurosphere growth medium. The effect of EGF removal was so pronounced that it masked the changes in gene expression patterns produced by the addition of PACAP.

Conclusion

Experimental models aiming at transcriptional analysis of induced proliferation in primary neural stem cells need to take into consideration the significant effect on transcription caused by removal of EGF. Alternatively, EGF-free culture conditions need to be developed.
The cost-effectiveness of early noninvasive ventilation for ALS patients
Authors: Gruis Kirsten L , Chernew Michael E , Brown Devin L
Published: August 2005

Background

Optimal timing of noninvasive positive pressure ventilation (NIPPV) initiation in patients with amyotrophic lateral sclerosis (ALS) is unknown, but NIPPV appears to benefit ALS patients who are symptomatic from pulmonary insufficiency. This has prompted research proposals of earlier NIPPV initiation in the ALS disease course in an attempt to further improve ALS patient quality of life and perhaps survival. We therefore used a cost-utility analysis to determine a priori what magnitude of health-related quality of life (HRQL) improvement early NIPPV initiation would need to achieve to be cost-effective in a future clinical trial.

Methods

Using a Markov decision analytic model we calculated the benefit in health-state utility that NIPPV initiated at ALS diagnosis must achieve to be cost-effective. The primary outcome was the percent utility gained through NIPPV in relation to two common willingness-to-pay thresholds: $50,000 and $100,000 per quality-adjusted life year (QALY).

Results

Our results indicate that if NIPPV begun at the time of diagnosis improves ALS patient HRQL as little as 13.5%, it would be a cost-effective treatment. Tolerance of NIPPV (assuming a 20% improvement in HRQL) would only need to exceed 18% in our model for treatment to remain cost-effective using a conservative willingness-to-pay threshold of $50,000 per QALY.

Conclusion

If early use of NIPPV in ALS patients is shown to improve HRQL in future studies, it is likely to be a cost-effective treatment. Clinical trials of NIPPV begun at the time of ALS diagnosis are therefore warranted from a cost-effectiveness standpoint.
Hazardous waste sites and stroke in New York State
Authors: Shcherbatykh Ivan , Huang Xiaoyu , Lessner Lawrence , Carpenter David O
Published: August 2005

Background -

Environmental exposure to persistent organic pollutants (POPs) may lead to elevation of serum lipids, increasing risk of atherosclerosis with thromboembolism, a recognized cause of stroke. We tested the hypothesis that exposure to contaminants from residence near hazardous waste sites in New York State influences the occurrence of stroke.

Methods -

The rates of stroke hospital discharges were compared among residents of zip codes containing hazardous waste sites with POPs, other pollutants or without any waste sites using information for 1993–2000 from the New York Statewide Planning and Research Cooperative System (SPARCS) database, containing the records of all discharge diagnoses for patients admitted to state-regulated hospitals.

Results -

After adjustment for age and race, the hospitalization rate for stroke in zip codes with POPs-contaminated sites was 15% higher than in zip codes without any documented hazardous waste sites (RR 1.15, 95% CI, 1.05, 1.26). For ischemic stroke only, the RR was 1.17 (95% CI 1.04, 1.31). Residents of zip codes containing other waste sites showed a RR of 1.13 (95% CI, 1.02, 1.24) as compared to zip codes without an identified waste site.

Conclusion -

These results suggest that living near a source of POPs contamination constitutes a risk of exposure and an increased risk of acquiring cerebrovascular disease. However further research with better control of individual risk factors and direct measurement of exposure is necessary for providing additional support for this hypothesis.