bluuebunny/crossref_metadata_2025 huggingface dataset:
Heat shock protein modulation of KATPand KCachannel cerebrovasodilation after brain injury
Authors: Armstead William M. , Hecker James G.
Published: May 2005

Fluid percussion brain injury (FPI) impairs pial artery dilation to activators of the ATP-sensitive (KATP) and calcium-activated (KCa) K+channels. This study investigated the role of heat shock protein (HSP) in the modulation of K+channel-induced pial artery dilation after FPI in newborn pigs equipped with a closed cranial window. Under nonbrain injury conditions, topical coadministration of exogenous HSP-27 (1 μg/ml) blunted dilation to cromakalim, CGRP, and NS-1619 (10−8and 10−6M; cromakalim and CGRP are KATPagonists and NS-1619 is a KCaagonist). In contrast, coadministration of exogenous HSP-70 (1 μg/ml) potentiated dilation to cromakalim, CGRP, and NS-1619. FPI increased the cerebrospinal fluid (CSF) concentration of HSP-27 from 0.051 ± 0.012 to 0.113 ± 0.035 ng/ml but decreased the CSF concentration of HSP-70 from 50.42 ± 8.96 to 30.9 ± 9.9 ng/ml at 1 h postinsult. Pretreatment with topical exogenous HSP-70 (1 μg/ml) before FPI fully blocked injury-induced impairment of cromakalim and CGRP dilation and partially blocked injury-induced impairment of dilation to NS-1619. These data indicate that HSP-27 and HSP-70 contribute to modulation of K+channel-induced pial artery dilation. These data suggest that HSP-70 is an endogenous protectant of which its actions may be unmasked and/or potentiated with exogenous administration before brain injury.
Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats
Authors: Matsumoto Takayuki , Kobayashi Tsuneo , Wakabayashi Kentaro , Kamata Katsuo
Published: May 2005

We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats that 1) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283–H291, 2003) and that 2) PKA activity is decreased (Matsumoto T, Wakabayashi K, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 287: H1064–H1071, 2004). Here we investigated whether chronic treatment with cilostazol, a PDE3 inhibitor, improves EDHF-type relaxation in mesenteric arteries isolated from STZ rats. We found that in such arteries 1) cilostazol treatment (2 wk) improved ACh-, A-23187-, and cyclopiazonic acid-induced EDHF-type relaxations; 2) the ACh-induced cAMP accumulation was transient and sustained in arteries from cilostazol-treated STZ rats; 3) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group; 4) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level; and 5) PKA catalytic subunit (Cat-α) protein was significantly decreased, but the regulatory subunit RII-β was increased (and the latter effect was significantly decreased by cilostazol treatment). These results strongly suggest that cilostazol improves EDHF-type relaxations in STZ rats via an increase in cAMP and PKA signaling.
AIDS-related vasculopathy: evidence for oxidative and inflammatory pathways in murine and human AIDS
Authors: Baliga Reshma S. , Chaves Alysia A. , Jing Liang , Ayers Leona W. , Bauer John A.
Published: May 2005

Increased life expectancy of human immunodeficiency virus (HIV)-positive patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in the murine acquired immune deficiency syndrome (AIDS) model and evaluated potential mechanisms in murine AIDS tissues and relevant human HIV/AIDS vascular tissues. We also investigated endothelial activation and/or endothelial protein nitration and their association with time-dependent vascular dysfunction. At 1 and 5 wk of murine AIDS, statistically significant decreases in KCl contractility and time-dependent contractile deficits in response to phenylephrine were observed. The maximal response (Emax) was reduced by ∼40% at 10 wk, and EC50 values were significantly changed: 102 ± 7.3 ng for control vs. 190 ± 37 and 130 ± 22 ng at 5 and 10 wk, respectively ( P < 0.05). Endothelium-dependent relaxation to ACh was decreased (EC50 = 120 ± 27 and 343 ± 94 nM for control and at 10 wk, respectively), whereas the response to an exogenous nitric oxide donor, sodium nitroprusside, remained unchanged, suggesting a specific endothelial dysfunction. Histochemical investigations of the same vascular tissues as well as corresponding coronary endothelium showed an increase in protein 3-nitrotyrosine, intercellular adhesion molecule, and nitric oxide synthase isoforms 2 and 3. These findings were corroborated in concurrent experiments in a cohort of well-cataloged human cardiac microvascular tissues. We have demonstrated, for the first time, a specific functional vasculopathy with endothelial involvement in a murine model of AIDS that was also associated with and correlated to increased oxidative stress and specific endothelial activation. This finding was echoed in a relevant population of human HIV/AIDS patients. Research into sources and intracellular targets of oxidants in this disease could provide important mechanistic insights and may reveal new therapeutic opportunities for this increasingly important cardiovascular disease state.
Modulation of myosin phosphatase targeting subunit and protein phosphatase 1 in the heart
Authors: Rajashree Ravi , Blunt Bradford C. , Hofmann Polly A.
Published: May 2005

Myosin light chain 2 (LC2) phosphorylation is of both physiological and pathological importance to myocardial function. The phosphatase that directly dephosphorylates LC2 is a type 1 protein phosphatase (PP1) that contains a catalytic subunit that complexes with a myosin-binding phosphatase targeting subunit (MYPT). The goal of the present study was to examine the role of MYPT in the regulation of PP1 in ventricular myocytes. In the first part of the study, regional distribution of MYPT expression and phosphorylation were determined in unstimulated hearts. The pattern of MYPT phosphorylation was inversely related to the LC2 phosphorylation spatial gradient as described by Epstein and colleagues (Davis JS, Hassanzadeh S, Winitsky S, Lin H, Satorius C, Vemuri R, Aletras AH, Wen H, and Epstein ND. Cell 107: 631–641, 2001). In the second part of the study, adult rat isolated ventricular myocytes were exposed to an α-adrenergic receptor agonist, and properties of MYPT, PP1, and LC2 were studied. We found MYPT associates with cardiac myofilaments, and this association increases upon α-adrenergic receptor stimulation. Activation of α-adrenergic receptors also led to a decrease in the PP1-myofilament association. Furthermore, α-adrenergic receptor stimulation results in phosphorylation of MYPT and LC2 and an increase in myocyte Ca2+ sensitivity of tension that all depend on Rho kinase activation. These data support the hypothesis that α-adrenergic receptor activation works through Rho kinase to phosphorylate MYPT, and phosphorylated MYPT dissociates from PP1 so that PP1 is no longer physically associated with LC2. Hence, we propose a pathway for the dynamic modulation of LC2 phosphorylation through receptor-dependent phosphorylation of MYPT, and a spatial gradient of LC2 phosphorylation under basal conditions that occurs due to varied levels of phosphorylation of MYPT in ventricles.
Electromechanical analysis of infarct border zone in chronic myocardial infarction
Authors: Ashikaga Hiroshi , Mickelsen Steven R. , Ennis Daniel B. , Rodriguez Ignacio , Kellman Peter , Wen Han , McVeigh Elliot R.
Published: May 2005

To test the hypothesis that alterations in electrical activation sequence contribute to depressed systolic function in the infarct border zone, we examined the anatomic correlation of abnormal electromechanics and infarct geometry in the canine post-myocardial infarction (MI) heart, using a high-resolution MR-based cardiac electromechanical mapping technique. Three to eight weeks after an MI was created in six dogs, a 247-electrode epicardial sock was placed over the ventricular epicardium under thoracotomy. MI location and geometry were evaluated with delayed hyperenhancement MRI. Three-dimensional systolic strains in epicardial and endocardial layers were measured in five short-axis slices with motion-tracking MRI (displacement encoding with stimulated echoes). Epicardial electrical activation was determined from sock recordings immediately before and after the MR scans. The electrodes and MR images were spatially registered to create a total of 160 nodes per heart that contained mechanical, transmural infarct extent, and electrical data. The average depth of the infarct was 55% (SD 11), and the infarct covered 28% (SD 6) of the left ventricular mass. Significantly delayed activation (>mean + 2SD) was observed within the infarct zone. The strain map showed abnormal mechanics, including abnormal stretch and loss of the transmural gradient of radial, circumferential, and longitudinal strains, in the region extending far beyond the infarct zone. We conclude that the border zone is characterized by abnormal mechanics directly coupled with normal electrical depolarization. This indicates that impaired function in the border zone is not contributed by electrical factors but results from mechanical interaction between ischemic and normal myocardium.
Biomechanical proprieties of decellularized porcine common carotid arteries
Authors: Roy Sylvain , Silacci Paolo , Stergiopulos Nikolaos
Published: May 2005

To analyze the effects of decellularization on the biomechanical properties of porcine common carotid arteries, decellularization was performed by a detergent-enzymatic procedure that preserves extracellular matrix scaffold. Internal diameter, external diameter, and wall thickness were measured by optical microscopy on neighboring histological sections before and after decellularization. Rupture tests were conducted. Inner diameter and wall thickness were measured by echo tracking during pressure inflation from 10 to 145 mmHg. Distensibility and incremental elastic modulus were computed. At 10 mmHg, mean diameter of decellularized arteries was 5.38 mm, substantially higher than controls (4.1 mm), whereas decellularized and control arteries reached the same internal diameter (6.7 mm) at 145 mmHg. Wall thickness decreased 16% for decellularized and 32% for normal arteries after pressure was increased from 10 to 145 mmHg. Decellularized arteries withstood pressure >2,200 mmHg before rupture. At 145 mmHg, decellularization reduced compliance by 66% and increased incremental elastic modulus by 54%. Removal of cellular elements from media led to changes in arterial dimensions. Collagen fibers engaged more rapidly during inflation, yielding a stiffer vessel. Distensibility was therefore significantly lower (by a factor of 3) in decellularized than in normal vessels: reduced in the physiological range of pressures. In conclusion, decellularization yields vessels that can withstand high inflation pressures with, however, markedly different geometrical and biomechanical properties. This may mean that the potential use of a decellularized artery as a scaffold for the creation of xenografts may be compromised because of geometrical and compliance mismatch.
Angiotensin II mediates glutathione depletion, transforming growth factor-β1 expression, and epithelial barrier dysfunction in the alcoholic rat lung
Authors: Bechara Rabih I. , Pelaez Andres , Palacio Andres , Joshi Pratibha C. , Hart C. Michael , Brown Lou Ann S. , Raynor Robert , Guidot David M.
Published: May 2005

Alcohol abuse markedly increases the risk of sepsis-mediated acute lung injury. In a rat model, ethanol ingestion alone (in the absence of any other stress) causes pulmonary glutathione depletion, increased expression of transforming growth factor-β1 (TGF-β1), and alveolar epithelial barrier dysfunction, even though the lung appears grossly normal. However, during endotoxemia, ethanol-fed rats release more activated TGF-β1 into the alveolar space where it can exacerbate epithelial barrier dysfunction and lung edema. Ethanol ingestion activates the renin-angiotensin system, and angiotensin II is capable of inducing oxidative stress and TGF-β1 expression. We determined that lisinopril, an angiotensin-converting enzyme inhibitor that decreases angiotensin II formation, limited lung glutathione depletion, and treatment with either lisinopril or losartan, a selective angiotensin II type 1 receptor blocker, normalized TGF-β1 expression. The glutathione precursor procysteine also prevented TGF-β1 expression, suggesting that TGF-β1 may be induced indirectly by angiotensin II-mediated oxidative stress and glutathione depletion. Importantly, lisinopril treatment normalized barrier function in alveolar epithelial cell monolayers from ethanol-fed rats, and treatment with either lisinopril or losartan normalized alveolar epithelial barrier function in ethanol-fed rats in vivo, as reflected by lung liquid clearance of an intratracheal saline challenge, even during endotoxemia. In parallel, lisinopril treatment limited TGF-β1 protein release into the alveolar space during endotoxemia. Together, these results suggest that angiotensin II mediates oxidative stress and the consequent TGF-β1 expression and alveolar epithelial barrier dysfunction that characterize the alcoholic lung.
Divalent metal transporter-1 decreases metal-related injury in the lung
Authors: Ghio Andrew J. , Piantadosi Claude A. , Wang Xinchao , Dailey Lisa A. , Stonehuerner Jacqueline D. , Madden Michael C. , Yang Funmei , Dolan Kevin G. , Garrick Michael D. , Garrick Laura M.
Published: May 2005

Exposure to airborne particulates makes the detoxification of metals a continuous challenge for the lungs. Based on the fate of iron in airway epithelial cells, we postulated that divalent metal transporter-1 (DMT1) participates in detoxification of metal associated with air pollution particles. Homozygous Belgrade rats, which are functionally deficient in DMT1, exhibited diminished metal transport from the lower respiratory tract and greater lung injury than control littermates when exposed to oil fly ash. Preexposure of normal rats to iron in vivo increased expression of the isoform of DMT1 protein that lacked an iron-response element (−IRE), accelerated metal transport out of the lung, and decreased injury after particle exposure. In contrast, normal rats preexposed to vanadium showed less expression of the −IRE isoform of DMT1, decreased metal transport, and greater pulmonary injury after particle instillation. Respiratory epithelial cells in culture gave similar results. Also, DMT1 mRNA and protein expression for the −IRE isoform increased or decreased in these cells when exposed to iron or vanadium, respectively. These results thus demonstrate for the first time a primary role for DMT1 in lung metal transport and detoxification.
Thyroid hormone modulates renin and ANG II receptor expression in fetal sheep
Authors: Chen Kai , Carey Luke C. , Valego Nancy K. , Liu Jingfang , Rose James C.
Published: May 2005

Fetal renin-angiotensin system (RAS) activity is developmentally regulated, increasing in late gestation toward term. At the same time, fetal hemodynamic parameters change, with blood pressure increasing and heart rate decreasing. During this period, fetal plasma thyroid hormone concentrations also increase significantly. In this study we utilized the technique of thyroidectomy (TX), which removes thyroid hormone from the circulation, to investigate the importance of thyroid hormone on the developmental changes in the RAS (in plasma, kidney, heart, and lung) and hemodynamic regulation in fetal sheep. TX was performed at 120 days of gestational age (dGA), and control fetuses were sham operated. Immediately before necropsy (∼137 dGA), fetuses were infused with isoproterenol and the hemodynamic responses were noted. TX significantly decreased plasma thyroid hormone concentrations and renal renin mRNA and renal active renin levels but did not change fetal plasma active renin levels. TX decreased both angiotensin II receptor subtype 1 (AT1) mRNA and protein levels in kidney and lung but not in the left ventricle. TX also was associated with increased ANG II receptor subtype 2 (AT2) mRNA and protein at the 44-kDa band in kidney, whereas AT2 protein was decreased at the 78-kDa level in kidney and lung tissue only. TX fetuses had significantly lower basal mean arterial blood pressures (MAP) and heart rates than controls. Isoproterenol infusion decreased MAP in TX fetuses. These findings support the hypothesis that thyroid hormone is important in modulating maturation of RAS and cardiovascular function in the late-gestation fetal sheep.
Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats
Authors: Cordaillat Magali , Rugale Caroline , Casellas Daniel , Mimran Albert , Jover Bernard
Published: May 2005

Reversal by the mineralocorticoid receptor antagonist spironolactone on cardiac and renal abnormalities, associated with long-term (since weaning) administration of a high (2 and 8% NaCl chow, HS2 and HS8) sodium diet, was assessed in Sprague-Dawley rats. At the age of 5 mo, spironolactone (20 or 100 mg/kg, gavage) or placebo were given for 14 days to HS2 and HS8 rats. A group fed a regular diet (0.8% NaCl, NS) remained untreated. High sodium intake had no detectable effect on blood pressure; however, cardiac mass index and cross-sectional area of the carotid artery, as well as albuminuria, were increased only in the HS8 group compared with the control group on NS diet. In addition, a marked reduction in glomerular filtration rate (by 40%), associated with a nonproportional fall in renal plasma flow (thus resulting in a decrease in filtration fraction), was observed only in the HS8 group. No change in cardiac and renal fibrosis was detected. Production of the reactive oxygen species (ROS) by aortic tissue was increased in HS8 rats, whereas ROS production by the heart was unaffected. Only the high dose of spironolactone was effective, as it markedly reversed the cardiac hypertrophy and renal hypofiltration associated with the HS8 feeding. The changes were observed in the absence of any effect on systemic blood pressure and production of ROS. These observations favor aldosterone’s role in the deleterious effects of marked and prolonged increases in sodium intake.
Differential role of the paraventricular nucleus of the hypothalamus in modulating the sympathoexcitatory component of peripheral and central chemoreflexes
Authors: Reddy Maram K. , Patel Kaushik P. , Schultz Harold D.
Published: May 2005

In the present study we investigated the involvement of the hypothalamic paraventricular nucleus (PVN) in the modulation of sympathoexcitatory reflex activated by peripheral and central chemoreceptors. We measured mean arterial blood pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) before and after blocking neurotransmission within the PVN by bilateral microinjection of 2% lidocaine (100 nl) during specific stimulation of peripheral chemoreceptors by potassium cyanide (KCN, 75 μg/kg iv, bolus dose) or stimulation of central chemoreceptors with hypercapnia (10% CO2). Typically stimulation of peripheral chemoreceptors evoked a reflex response characterized by an increase in MAP, RSNA, and PNA and a decrease in HR. Bilateral microinjection of 2% lidocaine into the PVN had no effect on basal sympathetic and cardiorespiratory variables; however, the RSNA and PNA responses evoked by peripheral chemoreceptor stimulation were attenuated ( P < 0.05). Bilateral microinjection of bicuculline (50 pmol/50 nl, n = 5) into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation ( P < 0.05). Conversely, the GABA agonist muscimol (0.2 nmol/50 nl, n = 5) injected into the PVN attenuated these reflex responses ( P < 0.05). Blocking neurotransmission within the PVN had no effect on the hypercapnia-induced central chemoreflex responses in carotid body denervated animals. These results suggest a selective role of the PVN in processing the sympathoexcitatory and ventilatory component of the peripheral, but not central, chemoreflex.
Molecular Study on Cloned Endoglucanase Gene from Rumen Bacterium
Authors: Ozkose Emin , Akyol Ismail , Ekinci Mehmet Sait
Published: May 2005

An endoglucanase gene was subcloned from anaerobic rumen bacterium Ruminococcus flavefaciens strain 17. To express endoglucanase gene in Escherichia coli and Streptococcus bovis JB1, an endoglucanase gene fragment was inserted into pVA838-based shuttle vectors. Removal of endoglucanase gene promoter and expression of endoglucanase by promoter of S. bovis JB1 α-amylase gene (pACMCS) was also achieved. Survival of constructs pVACMCI, pTACMC and pACMCS, which carry endoglucanase gene, and stability of endoglucanase gene in S. bovis JB1, were observed. Maximal endoglucanase activities from S. bovis JB1/pVACMCI were 2- to 3-fold higher than from E. coli/pVACMCI. Specific cell activity of E. coli/pACMCS was found to be approximately 2- to -3 fold higher than the both E. coli/pVACMCI and E. coli/pTACMC. Specific cell activity of S. bovis JB1/pACMCS was also found to be approximately 2-fold higher than the both S. bovis/pVACMCI and S. bovis JB1/pTACMC.
Atypical Poorly Differentiated Cutaneous T-Cell Lymphoma with an Angiocentric Growth Pattern Presenting Histologically as Vasculitis
Authors: Laetsch B. , Hofbauer G. , Kempf W. , Burg G. , Dummer R.
Published: May 2005

We report the case of a 41-year-old patient with an aggressive cutaneous T-cell lymphoma (CTCL) initially presenting on histology as lymphocytic vasculitis. On repeated histological examination and by molecular biology work-up, the diagnosis of an unclassifiable CTCL could eventually be established. This atypical poorly differentiated lymphoma was of a CD4+ CD8– CD56– phenotype and followed an unfavourable course. The patient died despite chemo- and immunotherapy 7 months after the first consideration of lymphoma as diagnosis.
The Spontaneous Regression of Tufted Angioma
Authors: Ishikawa Kazushi , Hatano Yutaka , Ichikawa Hiroki , Hashimoto Hiroyuki , Fujiwara Sakuhei
Published: May 2005

Background: Tufted angioma, a peculiar angioma that is characterized by tufts of capillary-sized vessels scattered ‘cannonball fashion’ within the dermis, is known, on occasion, to regress spontaneously. However, the appropriate waiting period for spontaneous regression has remained unclear. Objective: To know the appropriate waiting period for spontaneous regression of tufted angioma. Methods: We report here a case of tufted angioma that regressed spontaneously after the lesions had recurred twice. We also review previously reported cases of tufted angioma with spontaneous regression, including cases in the Japanese and non-Japanese literature. Results: In 18 (86%) of the 21 cases, the waiting period was more than 6 months and in 20 cases (95%) it was less than 2 years. Conclusion: The appropriate wait for spontaneous regression might be between 6 months and 2 years.
A Pilot Study of Spatial Patterns in Referrals to a Multicentre Cancer Genetics Service
Authors: Tempest Vanessa , Higgs Gary , McDonald Kevin , Iredale Rachel , Bater Tony , Gray Jonathon
Published: May 2005

Objectives: To analyse spatial and temporal patterns in patients referred to a cancer genetics service in order to monitor service utilization and accessibility. Methods: Postcodes of patients during a 4-year period were used to examine spatial patterns using a Geographical Information System (GIS). Referral rates were compared visually and statistically to explore yearly variation for administrative areas in Wales. Results: There has been a four-fold increase in actual referrals to the service over the period of study. The variance between unitary authority referral rates has decreased from the inception of the service from an almost ten-fold difference between lowest and highest in year 1 to less than a three-fold difference in year 4. Conclusions: This study shows the potential of GIS to highlight spatial variations in referral rates across Wales. Although the disparity in referral rates has decreased, trends in referral rates are not consistent. Ongoing research will examine those referral and referrer characteristics affecting uptake.
Parental Attitudes and Beliefs regarding the Genetic Testing of Children
Authors: Campbell Elizabeth , Ross Lainie Friedman
Published: May 2005

Objectives: To explore parental attitudes and beliefs about genetic testing of children for conditions that present throughout the life cycle. Methods: Twelve semi-structured focus groups with black and white parents were conducted. Results: Across racial groups, most respondents want access to genetic testing and believe that parents should be the final decision-makers. While most respondents believe it is important to share genetic information with relatives, white respondents want physicians to respect confidentiality absolutely, whereas some black respondents accept physician disclosures in specific situations. Conclusions: Professional policy statements are restrictive about access to predictive genetic testing of children. This conflicts with parental attitudes about who should have decisional authority. While there is consensus among respondents that genetic information should be shared with relatives, respondents disagree as to who should be responsible for disclosure, and when professionals should breach patient confidentiality.
High Distress in Parents Whose Children Undergo Predictive Testing for Long QT Syndrome
Authors: Hendriks Karin S.W.H. , Grosfeld F.J.M. , Wilde A.A.M. , van den Bout J. , van Langen I.M. , van Tintelen J.P. , ten Kroode H.F.J.
Published: May 2005

Objectives: To assess the psychological effect of predictive testing in parents of children at risk for long QT syndrome (LQTS) in a prospective study.Methods: After their child was clinically screened by electrocardiography and blood was taken for DNA analysis, and shortly after delivery of the DNA test result, 36 parents completed measures of psychological distress. Results: 24 parents were informed that at least one of their children is a mutation carrier. Up to 50% of the parents of carrier children showed clinically relevant high levels of distress. Parents who were familiar with the disease for a longer time, who had more experiences with the disease in their family and who received positive test results for all their children were most distressed. Conclusions: Predictive ECG testing together with DNA testing has a profound impact on parents whose minors undergo predictive testing for LQTS.
Increased Prevalence of Mediterranean and Muslim Populations in Mutation-Related Research Literature
Authors: Birenbaum-Carmeli Daphna
Published: May 2005

This paper assesses the prevalence of 569 population groups in mutation-related research literature by means of prevalence scores, calculated on the basis of a systematic search of the PubMed database. The main finding is that Mediterranean and Muslim populations are mentioned more often than other groups. The observed overrepresentation is attributed to the pervasiveness of hemoglobin disorders in these populations, the early decoding of hemoglobin and the relative commonness of consanguineous marriage in some of these populations. The paper points at potential benefits as well as predicaments that the intensive targeting of these populations for mutation research may entail.
Cloxacillin versus Pristinamycin for Superficial Pyodermas: A Randomized, Open-Label, Non-Inferiority Study
Authors: Chosidow O. , Bernard P. , Berbis P. , Humbert P. , Crickx B. , Jarlier V.
Published: May 2005

Background: Superficial pyodermas may require systemic antibiotics. In a previous open-label trial, oxacillin and pristinamycin achieved similar cure rates, but its design was not truly that of a non-inferiority study. Objectives: To assess the efficacy and safety of oral cloxacillin versus pristinamycin (both 2 g/day) to treat superficial pyodermas. Methods: Multicentre, parallel-group, open-label, randomized non-inferiority trial. Results: French general practitioners in private practice included 334 out-patients (mean age: 42 years). At the follow-up (day 14), the cure rates (primary efficacy end point) for the intent-to-treat populations were 80.7% (138/171) for cloxacillin and 82.8% (135/163) for pristinamycin. The observed difference between cure rates was –2.1%, with the lower limit of the two-sided 95% confidence interval higher than the non-inferiority threshold of –15%. The per-protocol analysis yielded similar results. Therapy was discontinued for 10 patients (cloxacillin: 1, pristinamycin: 9; p = 0.01). Conclusion: Cloxacillin could be an alternative to pristinamycin in out-patients with superficial pyodermas.
Association of Dyslipidemia and Concomitant Risk Factors with In-Hospital Mortality in Acute Coronary Syndrome in Switzerland
Authors: Radovanovic Dragana , Erne Paul , Schilling Julian , Noseda Giorgio , Gutzwiller Felix
Published: May 2005

Background: Although dyslipidemia is one of the main risk factors for cardiovascular diseases, very few randomized trials have provided data on the association of dyslipidemia and in-hospital mortality in patients with acute coronary syndrome (ACS). Objective: The study assessed the association of dyslipidemia and concomitant risk factors, and early lipid-lowering therapy (LLD) on in-hospital mortality in patients admitted for ACS. Methods: Using AMIS Plus registry data, 13,482 patients admitted between January 1997 and October 2003 were analyzed, and logistic regression was used for predicting in-hospital mortality. Results: Baseline characteristics of patients with dyslipidemia (n = 6,079) significantly differed from those without, and in-hospital mortality was lower (5.5 vs. 9.4%; p < 0.001). Subgroup analyses of 9,383 patients with one or more of four preexisting main risk factors (hypertension, diabetes, coronary heart disease, CHD, or dyslipidemia) showed that whenever dyslipidemia was combined with another risk factor, the mortality rate clearly decreased. Patients with dyslipidemia were, in all subgroups, significantly younger (p < 0.001) and predominantly male, and they had more frequently primary percutaneous coronary intervention (PCI). However, this was only significant in patients with hypertension or hypertension and CHD. Independent in-hospital mortality predictors were age (odds ratio, OR: 1.08 per year, 95% confidence interval, CI, 1.07–1.09), diabetes (OR: 1.96, 95% CI: 1.56–2.46, p < 0.0001) and primary PCI (OR: 0.62, 95% CI: 0.44–0.86, p < 0.0001). In patients who received LLD, mortality was significantly lower regardless of the total cholesterol level measured within 24 h after symptom onset. Conclusion: Patients with dyslipidemia admitted for ACS had significantly lower in-hospital mortality than patients without dyslipidemia, mainly but not only due to the younger age of these patients. Early administration of LLD was associated with lower in-hospital mortality.
Arrhythmogenic Right Ventricular Cardiomyopathy: A Presentation of Thirty Consecutive Patients
Authors: Nielsen H.B. , Thomsen C. , Chen X. , Andersen C.B. , Toft G.G. , Søndergaard L. , Haunsø S. , Svendsen J.H.
Published: May 2005

Background: There is a limited number of studies of consecutive patients suspected of having arrhythmogenic right ventricular cardiomyopathy (ARVC) as established by the Task Force report [Br Heart J 1994;71:215–218]. Objective: The aim of this study was to describe a population of ARVC patients who were referred to a university hospital for thorough clinical evaluation of right ventricle arrhythmia using both noninvasive and invasive procedures. Methods: In a prospective design 48 patients suspected of having ARVC underwent cardiac magnetic resonance imaging (MRi), contrast ventriculography, an electrophysiological test and endomyocardial biopsies from the lower septum. Results: A diagnosis of ARVC was established in 30 patients (age 40 ± 2 years, mean ± SEM) and in one third of the patients, intense running, cycling or rowing provoked palpitations and syncope. Arrhythmias were frequent premature contractions of RV origin and/or ventricular tachycardia with a left bundle branch configuration. In 14 ARVC patients the ECG trace showed right bundle branch block or inverted T waves in right precordial leads. Contrast ventriculography demonstrated RV dilatation in 11 ARVC patients and in 18 patients the septal biopsies showed fatty tissue myocardial infiltration. In 25 patients cardiac MRi showed islands of high signal intensity indicative of RV fatty infiltration. Conclusions: ARVC is a heterogeneous syndrome and an abnormal right ventricle and arrhythmias of right ventricle origin must lead to a clinical evaluation. Cardiac MRi appears to be an important diagnostic tool in patients suspected of ARVC and should be used to guide invasive procedures.
Haplotype Reconstruction for Diploid Populations
Authors: Zhang Jian , Vingron Martin , Hoehe Margret R.
Published: May 2005

The inference of haplotype pairs directly from unphased genotype data is a key step in the analysis of genetic variation in relation to disease and pharmacogenetically relevant traits. Most popular methods such as Phase and PL do require either the coalescence assumption or the assumption of linkage between the single-nucleotide polymorphisms (SNPs). We have now developed novel approaches that are independent of these assumptions. First, we introduce a new optimization criterion in combination with a block-wise evolutionary Monte Carlo algorithm. Based on this criterion, the ‘haplotype likelihood’, we develop two kinds of estimators, the maximum haplotype-likelihood (MHL) estimator and its empirical Bayesian (EB) version. Using both real and simulated data sets, we demonstrate that our proposed estimators allow substantial improvements over both the expectation-maximization (EM) algorithm and Clark’s procedure in terms of capacity/scalability and error rate. Thus, hundreds and more ambiguous loci and potentially very large sample sizes can be processed. Moreover, applying our proposed EB estimator can result in significant reductions of error rate in the case of unlinked or only weakly linked SNPs.
Parcellation and Area-Area Connectivity as a Function of Neocortex Size
Authors: Changizi Mark A. , Shimojo Shinsuke
Published: May 2005

Via the accumulation of data from across the neuroanatomy literature, we estimate the manner in which (i) the number of neocortical areas varies with neocortex size, and (ii) the number of area-area connections varies with neocortex size. Concerning parcellation, we find that the number of areas scales approximately as the 1/3 power of gray matter volume, or, equivalently, as the square root of the total number of neocortical neurons. A consequence of this is that the average number of neurons per area also scales approximately as the square root of the total number of areas. Concerning area-area connectivity, we find evidence that the total number of area-area connections scales as the square of the number of areas. These scaling results help constrain theories about the principles underlying neocortical organization.
High-Grade Endometrial Stromal Sarcoma after Tamoxifen Therapy for Breast Cancer
Authors: Sesti Francesco , Patrizi Lodovico , Ermini Beatrice , Palmieri Giampiero , Orlandi Augusto , Piccione Emilio
Published: May 2005

A case of high-grade endometrial stromal sarcoma, confined into an intrauterine polypoid growth, in a woman with a history of breast cancer who was treated with adjuvant tamoxifen. Based on the findings, a high-grade endometrial stromal sarcoma was diagnosed. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy with multiple omental biopsies. Pathological examination on multiple uterine sections showed the absence of residual tumor cells in the uterus. The endometrium showed patterns of glandular cystic hyperplasia. After 14 months of follow-up, the patient is well and free of disease. In deciding if tamoxifen therapy is warranted, all potentially life-threatening adverse events associated with tamoxifen should be considered, including endometrial adenocarcinoma or uterine sarcoma.
Protective Effects of Ginkgo biloba Leaf Extracts on Trichloroethylene-Induced Human Keratinocyte Cytotoxicity and Apoptosis
Authors: Zhu Q.-X. , Shen T. , Tu D.-Y. , Ding R. , Liang Z.-Z. , Zhang X.-J.
Published: May 2005

The objective of this study was to assess the protective effects of Ginkgo biloba leaf extracts (EGb) on trichloroethylene (TCE)-induced cytotoxicity and apoptosis in normal human epidermal keratinocytes (NHEK). Cytotoxicity was determined by neutral red uptake, and lipid peroxidation of the cells was assessed by malondialdehyde (MDA) and superoxide dismutase (SOD). Electron microscopy and flow cytometry were used to evaluate NHEK apoptosis. Treatment of NHEK with various concentrations of TCE caused a substantial decrease in cell viability. NR50 from the cytotoxicity assay was found to be 4.53 mM. TCE caused an increase in MDA, while an inhibition of SOD activity, in a concentration-dependent manner. Electron microscopic examination revealed typical morphologic changes of apoptosis in cells treated with TCE. Incubation of NHEK with TCE (0, 0.125, 0.5, 2.0 mM) for 4 h increased the proportion of apoptotic cells from control of 19.23% to nearly 44.35%. Pretreatment of EGb at 10–200 mg/l dose-dependently attenuated the cytotoxic effect of TCE, prevented TCE-induced elevation of lipid peroxidation and decline of antioxidant enzyme activities. Similar inhibition by EGb on TCE-mediated NHEK apoptosis was also observed. These results suggest that EGb can protect NHEK from TCE-induced cytotoxicity and apoptosis, which may be associated with the superoxide scavenging effect and enhancement of antioxidant enzyme activities.
BAPTA Induces Frequency Shifts in vivo of Spontaneous Otoacoustic Emissions of the Bobtail Lizard
Authors: Manley Geoffrey A. , Kirk Desmond L.
Published: May 2005

Spontaneous otoacoustic emissions (SOAEs) are indicators of active processes in the inner ear and are found in all classes of land vertebrates. In the Australian bobtail lizard, earlier work showed that otoacoustic emissions are generated by an active motility process in the hair-cell bundle. This is likely to be driven by calcium-sensitive mechanisms implicated in other non-mammalian hair cell systems. If so, it should be fundamentally influenced by the extracellular calcium concentration. In in vitro studies, the rate of force generation in hair cell stereovilli is linked to the extracellular calcium concentration. In such preparations, low-calcium solutions, buffered by the calcium chelator BAPTA, were reported to change the frequency of hair cell bundle oscillations. In the present study, BAPTA was iontophoresed into the endolymph of the bobtail skink in vivo, and SOAEs were monitored. Application of BAPTA resulted in a prolonged downward shift in the frequency of individual SOAE spectral peaks. Recovery took more than 1 h, consistent with a slow clearance of BAPTA from endolymph. SOAE peak amplitudes were most often enhanced, suggesting there was no functional disruption of tip links. The direction and degree of frequency shifts were consistent with in vitroand in vivo data showing the effects of changing calcium concentrations in the endolymph directly.
Procoagulant Soluble Tissue Factor Is Released From Endothelial Cells in Response to Inflammatory Cytokines
Authors: Szotowski Björn , Antoniak Silvio , Poller Wolfgang , Schultheiss Heinz-Peter , Rauch Ursula
Published: May 2005

Inflammatory cytokines alter the hemostatic balance of endothelial cells (ECs). Alternatively spliced human tissue factor (asHTF), a soluble isoform of tissue factor (TF), has recently been detected in ECs, possibly contributing to procoagulability. Agonists regulating asHTF expression and release are yet unknown. This study examines the effect of TNF-α and IL-6 on the endothelial expression of both TF variants and delineates the impact of asHTF on the procoagulability of extracellular fluids. asHTF and TF mRNA were assessed by real-time PCR, and asHTF, TF, and tissue factor pathway inhibitor (TFPI) proteins by Western blot and fluorescence microscopy before and after stimulation with TNF-α (10 ng/mL) or IL-6 (10 ng/L). The procoagulability of cell supernatant was analyzed by a chromogenic assay with or without phospholipid vesicles. We found asHTF mRNA to be maximally increased 10 minutes after TNF-α and 40 minutes after IL-6 treatment (asHTF/GAPDH ratio 0.0223±0.0069 versus 0.0012±0.0006 for control,
P
<0.001 and 0.0022±0.0004 versus 0.0012±0.0007,
P
<0.05, respectively). Not only was asHTF increased, but also TFPI decreased after cytokine treatment. asHTF was found in the supernatant as early as 5 hours after TNF-α stimulation, supporting factor Xa generation after relipidation (6.55±1.13 U versus 2.99±0.59 U in control supernatant,
P
<0.00001). Removal of asHTF from supernatants by immunoprecipitation diminished its procoagulability to baseline. The soluble TF isoform expressed and released from ECs in response to inflammatory cytokines becomes procoagulant in the presence of phospholipids. Thus, asHTF released from ECs is a marker for and a contributor to imbalanced hemostasis.
Angiopoietin-1 Opposes VEGF-Induced Increase in Endothelial Permeability by Inhibiting TRPC1-Dependent Ca
2
Influx
Authors: Jho David , Mehta Dolly , Ahmmed Gias , Gao Xiao-Pei , Tiruppathi Chinnaswamy , Broman Michael , Malik Asrar B.
Published: May 2005

Angiopoietin-1 (Ang1) exerts a vascular endothelial barrier protective effect by blocking the action of permeability-increasing mediators such as vascular endothelial growth factor (VEGF) through unclear mechanisms. Because VEGF may signal endothelial hyperpermeability through the phospholipase C (PLC)-IP
3
pathway that activates extracellular Ca
2+
entry via the plasmalemmal store-operated channel transient receptor potential canonical-1 (TRPC1), we addressed the possibility that Ang1 acts by inhibiting this Ca
2+
entry mechanism in endothelial cells. Studies in endothelial cell monolayers demonstrated that Ang1 inhibited the VEGF-induced Ca
2+
influx and increase in endothelial permeability in a concentration-dependent manner. Inhibitors of the PLC-IP
3
Ca
2+
signaling pathway prevented the VEGF-induced Ca
2+
influx and hyperpermeability similar to the inhibitory effects seen with Ang1. Ang1 had no effect on PLC phosphorylation and IP
3
production, thus its permeability-decreasing effect could not be ascribed to inhibition of PLC activation. However, Ang1 interfered with downstream IP
3
-dependent plasmalemmal Ca
2+
entry without affecting the release of intracellular Ca
2+
stores. Anti-TRPC1 antibody inhibited the VEGF-induced Ca
2+
entry and the increased endothelial permeability. TRPC1 overexpression in endothelial cells augmented the VEGF-induced Ca
2+
entry, and application of Ang1 opposed this effect. In immunoprecipitation studies, Ang1 inhibited the association of IP
3
receptor (IP
3
R) and TRPC1, consistent with the coupling hypothesis of Ca
2+
entry. These results demonstrate that Ang1 blocks the TRPC1-dependent Ca
2+
influx induced by VEGF by interfering with the interaction of IP
3
R with TRPC1, and thereby abrogates the increase in endothelial permeability.
Changes in Shear Stress–Related Gene Expression After Experimentally Altered Venous Return in the Chicken Embryo
Authors: Groenendijk Bianca C.W. , Hierck Beerend P. , Vrolijk Johannes , Baiker Martin , Pourquie Mathieu J.B.M. , Gittenberger-de Groot Adriana C. , Poelmann Robert E.
Published: May 2005

Hemodynamics play an important role in cardiovascular development, and changes in blood flow can cause congenital heart malformations. The endothelium and endocardium are subjected to mechanical forces, of which fluid shear stress is correlated to blood flow velocity. The shear stress responsive genes lung Krüppel-like factor (KLF2), endothelin-1 (ET-1), and endothelial nitric oxide synthase (NOS-3) display specific expression patterns in vivo during chicken cardiovascular development. Nonoverlapping patterns of these genes were demonstrated in the endocardium at structural lumen constrictions that are subjected to high blood flow velocities. Previously, we described in chicken embryos a dynamic flow model (the venous clip) in which the venous return to the heart is altered and cardiac blood flow patterns are disturbed, causing the formation of congenital cardiac malformations. In the present study we test the hypothesis that disturbed blood flow can induce altered gene expression. In situ hybridizations indeed show a change in gene expression after venous clip. The level of expression of ET-1 in the heart is locally decreased, whereas KLF2 and NOS-3 are both upregulated. We conclude that venous obstruction results in altered expression patterns of KLF2, ET-1, and NOS-3, suggestive for increased cardiac shear stress.
Body Mass Index and Mortality From Cardiovascular Disease Among Japanese Men and Women
Authors: Cui Renzhe , Iso Hiroyasu , Toyoshima Hideaki , Date Chigusa , Yamamoto Akio , Kikuchi Shogo , Kondo Takaaki , Watanabe Yoshiyuki , Koizumi Akio , Wada Yasuhiko , Inaba Yutaka , Tamakoshi Akiko ,   JACC Study Group
Published: May 2005

Background and Purpose—

Although overweight is an important risk factor for cardiovascular disease in Western countries, the impact of overweight has not been well elucidated in Japan, where its prevalence is low.

Methods—

A total of 104 928 Japanese (43 889 men and 61 039 women) aged 40 to 79 years, free of stroke, coronary heart disease, and cancer at entry participated in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk Sponsored by Monbusho (JACC Study) between 1988 and 1990. Systematic surveillance was completed until the end of 1999, with 1 042 835 person years of follow-up, and the underlying causes of death were determined based on the International Classification of Diseases.

Results—

There were 765 total strokes (191 intraparenchymal hemorrhages), 379 coronary heart diseases, and 1707 total cardiovascular diseases for men; and for women, there were 685 (145), 256, and 1432, respectively. Compared with persons with body mass index (BMI) 23.0 to 24.9, those with BMI ≥27.0 kg/m
2
had a higher risk of coronary heart disease; for men and women, the respective multivariate relative risk (95% CI) was 2.05 (1.35 to 3.13) and 1.58 (0.95 to 2.62). Persons with BMI <18.5 kg/m
2
had higher risk of total stroke and intraparenchymal hemorrhage, for men and women, the respective multivariate relative risk was 1.29 (1.01 to 1.49) and 1.92 (1.49 to 2.47) for total stroke and 1.96 (1.16 to 3.31) and 2.32 (1.36 to 3.97) for intraparenchymal hemorrhage. These excess risks did not alter materially when deaths within 5 years were excluded or when smoking status was taken into account.

Conclusions—

For Japanese men and women, high BMI was associated with increased risk of coronary heart disease, whereas low BMI was associated with intraparenchymal hemorrhage.
Meredith Monk: Four Decades by Design and by Invention
Authors: Smithner Nancy Putnam
Published: May 2005

This account of Meredith Monk's directorial, compositional, and performance processes over the past 40 years describes a body of work that spans the multidisciplinary continuum.
Romani Performance and Heritage Tourism: The Pilgrimage of the Gypsies at Les Saintes-Maries-de-la-Mer
Authors: Wiley Eric
Published: May 2005

Every May some ten thousand Romanies (aka Gypsies) perform a pilgrimage to Les Saintes-Maries-de-le-Mer, a remote fishing village in the south of France. Their annual gathering has developed into a popular festival of Romani culture that spawns its own pilgrimage of tourists and journalists—as well as some tension between the townspeople and the Romani.