bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitric oxide in rostral ventrolateral medulla regulates cardiac-sympathetic reflexes: role of synthase isoforms
Authors: Guo Zhi-Ling , Tjen-A-Looi Stephanie C. , Fu Liang-Wu , Longhurst John C.
Published: August 2009

Our previous studies have shown that nitric oxide (NO) synthase (NOS)-containing neurons in the rostral ventrolateral medulla (rVLM) are activated during cardiac sympathoexcitatory reflexes (Refs. 12 and 13 ). However, the precise function of NO in the rVLM in regulation of these reflexes has not been defined. Three isoforms of NOS, including neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS), are located in the rVLM. We explored the role of NO, derived from different NOS isoforms in the rVLM, in processing cardiac-sympathetic reflexes using whole animal reflex and electrophysiological approaches. We found that, in anesthetized cats, increased mean arterial blood pressure and renal sympathetic nerve activity elicited by epicardial application of bradykinin (BK; 1–10 μg/ml, 50 μl) were significantly attenuated following unilateral rVLM microinjection of the nonselective NOS inhibitor, Nω-nitro-l-arginine methyl ester (50 nmol/50 nl), or a specific nNOS inhibitor, 7-nitroindazole (7-NI; 5–10 pmol/50 nl; both P < 0.05). In contrast, the responses of mean arterial blood pressure and renal sympathetic nerve activity to cardiac BK stimulation were unchanged by unilateral rVLM microinjection of Nω-nitro-d-arginine methyl ester (inactive isomer of Nω-nitro-l-arginine methyl ester, 50 nmol/50 nl), 3–6% methanol (7-NI vehicle), N6-(1-iminoethyl)-l-lysine (250 pmol/50 nl; iNOS inhibitor), or N5-(1-iminoethyl)-l-ornithine (250 nmol/50 nl; eNOS inhibitor). Furthermore, in separate cats, we noted that iontophoresis of 7-NI (0.1 mM) reduced the increased discharge of cardiovascular sympathoexcitatory rVLM neurons in response to cardiac stimulation with BK ( P < 0.05). These neurons were characterized by their responses to inputs from baroreceptors, and their cardiac rhythmicity was determined through frequency and time domain analyses, correlating their discharge to arterial blood pressure and cardiac sympathetic efferent nerve activity. These data suggest that NO, specifically nNOS, mediates sympathetic cardiac-cardiovascular responses through its action in the rVLM.
Galvanic vestibular stimulation counteracts hypergravity-induced plastic alteration of vestibulo-cardiovascular reflex in rats
Authors: Abe Chikara , Tanaka Kunihiko , Awazu Chihiro , Morita Hironobu
Published: August 2009

Recent data from our laboratory demonstrated that, when rats are raised in a hypergravity environment, the sensitivity of the vestibulo-cardiovascular reflex decreases. In a hypergravity environment, static input to the vestibular system is increased; however, because of decreased daily activity, phasic input to the vestibular system may decrease. This decrease may induce use-dependent plasticity of the vestibulo-cardiovascular reflex. Accordingly, we hypothesized that galvanic vestibular stimulation (GVS) may compensate the decrease in phasic input to the vestibular system, thereby preserving the vestibulo-cardiovascular reflex. To examine this hypothesis, we measured horizontal and vertical movements of rats under 1-G or 3-G environments as an index of the phasic input to the vestibular system. We then raised rats in a 3-G environment with or without GVS for 6 days and measured the pressor response to linear acceleration to examine the sensitivity of the vestibulo-cardiovascular reflex. The horizontal and vertical movement of 3-G rats was significantly less than that of 1-G rats. The pressor response to forward acceleration was also significantly lower in 3-G rats (23 ± 1 mmHg in 1-G rats vs. 12 ± 1 mmHg in 3-G rats). The pressor response was preserved in 3-G rats with GVS (20 ± 1 mmHg). GVS stimulated Fos expression in the medial vestibular nucleus. These results suggest that GVS stimulated vestibular primary neurons and prevent hypergravity-induced decrease in sensitivity of the vestibulo-cardiovascular reflex.
Moderate intensity of regular exercise improves cardiac SR Ca2+ uptake activity in ovariectomized rats
Authors: Bupha-Intr Tepmanas , Laosiripisan Jitanan , Wattanapermpool Jonggonnee
Published: August 2009

The impact of regular exercise in protecting cardiac deteriorating results of female sex hormone deprivation was evaluated by measuring changes in intracellular Ca2+ removal activity of sarcoplasmic reticulum (SR) in ovariectomized rats following 9-wk treadmill running exercise at moderate intensity. Despite induction of cardiac hypertrophy in exercised groups of both sham-operated and ovariectomized rats, exercise training had no effect on SR Ca2+ uptake and SR Ca2+-ATPase (SERCA) in hormone intact rat heart. However, exercise training normalized the suppressed maximum SR Ca2+ uptake and SERCA activity in ovariectomized rat heart. While exercise training normalized the leftward shift in pCa (−log[Ca2+])-SR Ca2+ uptake relation in ovariectomized rats, no effect was detected in exercised sham-operated rats. Similar phenomena were also observed on SERCA and on phospholamban (PLB) phosphorylation levels; exercise training in ovariectomized rats enhanced SERCA expression to reach the level as that in sham-operated rats, in which there were no differences in SERCA and phospho-PLB levels between sedentary and exercised groups. In addition, the reduction in phospho-Thr17 PLB in myocardium of ovariectomized rats was abolished by exercise training. These results showed that regular exercise maintains the molecular activation of cardiac SR Ca2+ uptake under normal physiological conditions and is able to induce a protective impact on cardiac SR Ca2+ uptake in ovarian sex hormone-deprived status.
The phenotype and potential origin of nestin+cardiac myocyte-like cells following infarction
Authors: Béguin Pauline C. , El-Helou Viviane , Assimakopoulos John , Clément Robert , Gosselin Hugues , Brugada Ramon , Villeneuve Louis , Rohlicek Charles V. , Del Duca Danny , Lapointe Nathalie , Rouleau Jean L. , Calderone Angelino
Published: August 2009

Nestin+cardiac myocyte-like cells were detected in the peri-infarct/infarct region of the ischemically damaged heart. The present study was undertaken to elucidate the phenotype and potential origin of nestin+cardiac myocyte-like cells and identify stimuli implicated in their appearance. In the infarcted human and rat heart, nestin+cardiac myocyte-like cells were morphologically and structurally immature, exhibited a desmin-immunoreactive striated phenotype, expressed the β1-adrenergic receptor, and associated with an aberrant pattern of connexin-43 expression and/or organization. Nestin+cardiac myocyte-like cells were detected 24 h postischemic injury and persisted in the infarcted rat heart for 9 mo. In the normal rat heart, cardiac progenitor transcriptional factors Nkx2.5/GATA4 were detected in a subpopulation of nestin+neural stem cells. Following an ischemic insult, nestin+/Nkx2.5+neural stem cells migrated to the peri-infarct/infarct region and appeared to be in a primordial state of differentiation to a nestin+cardiac myocyte-like cell. The exposure of adult male rats to normobaric hypoxia (12% O2) for 10 days failed to promote the appearance of nestin+cardiac myocyte-like cells. Following osmotic pump delivery of isoproterenol to normal adult rats, nestin+cardiac myocyte-like cells were detected, albeit the response was modest and secondary to tissue loss. Thus ischemia-induced appearance of nestin+cardiac myocyte-like cells apparently represents an adaptive response to heal the infarcted heart. Nkx2.5/GATA4 expression in a subpopulation of resident neural stem cells provides the appropriate phenotype for their potential differentiation to a nestin+cardiac myocyte-like cell.
Aging affects the cardiovascular responses to cold stress in humans
Authors: Hess Kari L. , Wilson Thad E. , Sauder Charity L. , Gao Zhaohui , Ray Chester A. , Monahan Kevin D.
Published: August 2009

Cardiovascular-related mortality peaks during cold winter months, particularly in older adults. Acute physiological responses, such as increases in blood pressure, in response to cold exposure may contribute to these associations. To determine whether the blood pressure-raising effect (pressor response) of non-internal body temperature-reducing cold stress is greater with age, we measured physiological responses to 20 min of superficial skin cooling, via water-perfused suit, in 12 younger [25 ± 1 (SE) yr old] and 12 older (65 ± 2 yr old) adults. We found that superficial skin cooling elicited an increase in blood pressure from resting levels (pressor response; P < 0.05) in younger and older adults. However, the magnitude of this pressor response (systolic and mean blood pressure) was more than twofold higher in older adults ( P < 0.05 vs. younger adults). The magnitude of the pressor response was similar at peripheral (brachial) and central (estimated in the aorta) measurement sites. Regression analysis revealed that aortic pulse wave velocity, a measure of central arterial stiffness obtained before cooling, was the best predictor of the increased pressor response to superficial skin cooling in older adults, explaining ∼63% of its variability. These results indicate that there is a greater pressor response to non-internal body temperature-reducing cold stress with age in humans that may be mediated by increased levels of central arterial stiffness.
Fatigue and Its Correlates in Chronic Hemodialysis Patients
Authors: Bossola Maurizio , Luciani Giovanna , Tazza Luigi
Published: August 2009

Background: The present study aimed at evaluating the possible correlation between fatigue and demographic, clinical and laboratory variables in chronic HD patients. Methods: Sixty-two chronic HD patients were assessed for the presence of fatigue through the SF-36 Vitality subscale and were administered the Beck Depression Inventory (BDI), the Hamilton Anxiety Rating Scale (HARS), and the Mini-Mental State Examination. In all, the number/severity of comorbidities was assessed through the Charlson Comorbidity Index and laboratory parameters were measured. Results: Correlations among the SF-36 Vitality subscale and age, dialytic age, BDI, HARS and the Charlson Comorbidity Index were statistically significant. Correlations between the SF-36 vitality score and the serum creatinine, albumin and IL-6 levels were also significant. Twenty-six and 36 patients constituted the fatigued and nonfatigued groups, respectively. The age and the scores of the Charlson Comorbidity Index, BDI and HARS of fatigued patients were significantly higher than those of nonfatigued subjects. Serum IL-6 levels were significantly higher in the fatigued than in the nonfatigued group, whereas serum albumin and creatinine levels were significantly lower. Conclusions: We found that depression, anxiety, number and severity of comorbidities and IL-6 levels are significantly correlated with fatigue in end-stage renal disease patients receiving chronic hemodialysis.
Stress in Pregnancy: A Role for Neuroactive Steroids in Protecting the Fetal and Neonatal Brain
Authors: Hirst Jonathan J. , Walker David W. , Yawno Tamara , Palliser Hannah K.
Published: August 2009

Stressors during pregnancy can lead to perinatal brain injury resulting in serious neurological impairment. Neuroactive steroid concentrations are elevated during pregnancy and are remarkably high in the fetal brain. In long-gestation species, including humans, these steroids enhance GABAergic inhibition and reduce the possibility of cerebral excitotoxicity during the last third of gestation. The fetal brain responds to acute hypoxia/ischemia by increasing steroid concentrations further as protection against excitotoxic cell death. The placenta has a key role in maintaining neuroactive steroid concentrations in the brain by acting as a source of precursors for neuroactive steroid synthesis. Gestational neuroactive steroid concentrations are needed for normal cell proliferation and cell death in the late gestation brain and a loss of these steroids at preterm birth may adversely affect development and vulnerability to injury.
The Role of the Extracorporeal Circuit in the Trapping and Degranulation of Platelets
Authors: Gritters-van den Oever Mareille , Schoorl Marianne , Schoorl Margreet , Bartels Piet C.M. , Grooteman Muriel P.C. , Nubé Menso J.
Published: August 2009

Background: Although platelet (PLT) activation and degranulation are well-known phenomena during hemodialysis (HD), controversies still exist about their nature and origin. Methods: PLT characteristics [PLT numbers, mean PLT volume (MPV), PLT distribution width (PDW), PLT large cell ratio (p-LCR), immature PLT fraction] and activation status [CD62p expression, platelet factor 4 (PF4) and β-thromboglobulin (BTG) plasma levels] were estimated in 19 patients before and during HD. Blood was sampled from both the afferent and efferent lines. Additionally, the influence of low-molecular-weight heparin (LMWH) on PF4 and BTG concentrations was analyzed. Results: CD62p expression increased in the extracorporeal circuit (ECC) in the first 30 min. Simultaneously, PLT numbers dropped markedly within the ECC. MPV, PDW and p-LCR decreased over time. Like CD62p expression, BTG reached peak values at t30, was exclusively released within the ECC and was not influenced by the application of LMWH. In contrast, PF4 was significantly released outside the ECC in response to LMWH. Conclusions: PLTs are predominantly activated within the ECC and not on a remote distance. PLTs stick to the ECC, particularly after first passage. BTG is an appropriate marker for HD-induced PLT degranulation, whereas PF4 originates from both activated PLTs and LMWH-induced detachment from the endothelium. PLTs are not exhausted due to the repetitive stimulation of clinical HD. Hence, dialysis modalities with longer duration or greater frequency may be associated with a less beneficial PLT activation profile, which may counteract their clinical benefits.
Effects of Nigella sativa Oil and Thymoquinone on Oxidative Stress and Neuropathy in Streptozotocin-Induced Diabetic Rats
Authors: Hamdy Nadia M. , Taha Ragia A.
Published: August 2009

We examined whether Nigella sativa (NS) oil and its active constituent thymoquinone (TQ) attenuate oxidative stress in the heart and brain in an experimental model of diabetes mellitus using streptozotocin (STZ). Oxidative stress was assessed by measuring cardiac and brain nitric oxide (NO), lipid peroxide levels, glutathione (GSH) and antioxidant enzyme activities, i.e. glutathione-S-transferase (GST) and catalase. Cardiac metabolic damage was estimated by measuring cardiac creatine kinase muscle and brain types (CK-MB). Brain monoamine levels were also evaluated. STZ diabetes induced a significant increase in heart and brain NO and malondialdehyde concentrations compared with the control group. These changes were attenuated by posttreatment of rats with NS oil and TQ. STZ diabetes induced oxidative stress via a significant decrease in GST, GSH and catalase. These lowered levels were improved by either NS oil or TQ administration. Serum CK-MB was decreased in the diabetic rats, which recovered with NS oil and TQ administration. During the course of diabetes, there was a marked increase in norepinephrine and dopamine concentrations and a marked decrease in serotonin concentration compared to the control group. These findings were partly reversed by oral administration of either NS oil or TQ. It is concluded that NS and TQ correct STZ-diabetes-induced alterations in CK-MB and brain monoamines due to their antioxidant properties.
Auditory Sensory Gating in the Neonatal Ventral Hippocampal Lesion Model of Schizophrenia
Authors: Vohs Jenifer L. , Chambers R. Andrew , Krishnan Giri P. , O’Donnell Brian F. , Hetrick William P. , Kaiser Samuel T. , Berg Sarah , Morzorati Sandra L.
Published: August 2009

Background/Aims: The neonatal ventral hippocampal lesion (NVHL) rat model shows biological and behavioral abnormalities similar to schizophrenia. Disturbed sensory gating reflects a consistent neurobiological abnormality in schizophrenia. Although of critical interest, sensory gating has not been evaluated in the NVHL model. Methods: The N40 rat analog of the human P50 was measured to assess sensory response and gating in NVHL and sham rats. Epidural electrodes recorded evoked potentials (EPs), from which amplitudes, latencies, difference scores (S1–S2) and gating ratios (S2/S1) were assessed. Power and phase locking were computed for evoked EEG activity, to test for frequency-specific abnormalities. Results: Prolonged S1 N40 latency was detected in the NVHL group, but amplitude and power measures did not differ. NVHL rats demonstrated disturbed phase-locked sensory gating at theta and beta frequencies, as well as reduced phase-locked gamma activity across stimuli, most robustly at S1. Conclusions: While measures of sensory gating obtained from the EP were relatively insensitive to the NVHL model, phase locking across trials was affected. NVHL rats may have increased evoked response temporal variability, similar to patients with schizophrenia. This pattern of findings likely reflects core developmental NVHL disturbances in dorsal hippocampal circuits associated with temporal and frontal areas.
Experimental Comparison of Meshes for Rectal Prolapse Surgery
Authors: Caliskan C. , Denizli A. , Makay O. , Firat O. , Tanyalcin T. , Alkanat M. , Korkut M.A.
Published: August 2009

Aim: The aim of this experimental study is to investigate the foreign body tissue created by the meshes that are used for rectopexy. Method: Sixty rats were divided equally into 5 groups. Four mesh types (Surgipro®, Ivalon®, Gore-Tex® and Vypro®) were implanted into the retroperitoneal area except for the sham group. After a 5-week follow-up period, all animals were sacrificed. Specimens were evaluated macroscopically by using scoring systems and biochemically by determining tissue hydroxyproline and nitric oxide levels. Results: The most evident foreign body reaction was observed in the Ivalon group, which showed higher ‘macroscopic adhesion’ scores (p < 0.005), although there were no significant differences in tissue hydroxyproline and nitric oxide levels between the groups (p > 0.05). Conclusion: In rectal prolapse surgery, selecting the ideal mesh type is unclear, depending on evidence-based results. In the present study, we could not prove which mesh was definitely superior to the other, macroscopically, histologically and biochemically. The findings of this experimental rat model suggest that implantation of all 4 types of meshes are suitable for posterior rectopexy.
Tubulo-Glomerular Feedback Activation in Humans before and after Nephrectomy
Authors: Guidi Ettore , Cozzi Maria Grazia
Published: August 2009

Background/Aims: Tubulo-glomerular feedback (TGF) is a key mechanism for controlling glomerular filtration. Nephrectomy for kidney donation provides a good opportunity for studying TGF status before and after a defined loss of renal function. Methods: A total of 22 kidney donors were studied before and one year after nephrectomy. Effective renal plasma flow and glomerular filtration rate were measured by means of para-amino-hippurate and inulin plasma clearances before and after intravenous acetazolamide. Results: TGF activation was not dependent on sex, age or familiality for hypertension either before or after nephrectomy, however, it increased the filtration fraction before, but not after nephrectomy. Nephrectomy did not affect TGF response, but elicited a correlation between TGF response and renal plasma flow, not present in the intact state. Donors with a more activated TGF before nephrectomy had a lower filtration fraction that increased after nephrectomy, while subjects with a less activated TGF before nephrectomy had a higher basal filtration fraction that showed a blunted increase after nephrectomy. Conclusion: TGF is a stable mechanism quantitatively unaltered by nephrectomy, age, sex, menopausal status or family history of hypertension. However, its degree of activation before nephrectomy determines different responses to the loss of a kidney.
Plasma Cell-Free DNA Levels in Children on Peritoneal Dialysis
Authors: Ozkaya O. , Bek K. , Bedir A. , Açıkgöz Y. , Özdemir T.
Published: August 2009

Background/Aims: Plasma levels of cell-free DNA (cfDNA) are elevated in various clinical conditions including cancer, stroke, trauma, myocardial infarction, autoimmune disorders, and pregnancy-associated complications. Previously, increased cfDNA levels were reported during hemodialysis. However, there is limited data regarding cfDNA levels in peritoneal dialysis (PD) patients. The aim of this study was to investigate the levels of cfDNA in children on PD. Methods: Twenty-one children on PD (median age: 12; range: 4–18 years) and 21 healthy children (median age: 10; range: 6–16 years) were enrolled into the study. Plasma cfDNA was measured using a real-time quantitative PCR for the beta-globin gene. Results: The median concentrations of cfDNA in the plasma of PD patients and healthy controls were 2,205 genome-equivalents/ml of plasma (range: 39–5,845) and 1,033 genome-equivalents/ml of plasma (range: 254–5,116), respectively (p = 0.026). A significant positive correlation was observed between C-reactive protein levels and plasma cfDNA levels (r: 0.52, p < 0.0001). Conclusion: Our data have demonstrated for the first time that cfDNA is increased in children on PD treatment. However, the mechanism by which the levels of cfDNA is increased and the clinical significance of this finding in PD patients is unclear. Further studies are warranted to clarify the precise mechanism and clinical significance of elevated cfDNA in children on PD.
Measurement of Donor Kidney Functional Renal Volume and Glomerular Filtration Rate to Predict Allograft Function during the Post-Transplantation Period
Authors: Huh Kyu Ha , Yun Mijin , Kim Tae Sung , Cho Arthur , Lee Jong Doo , Myoung Sung Min , Kim Yu Seun , Kim Myoung Soo
Published: August 2009

Background: We measured donor kidney weight (D-KW), functional renal volume (D-FRV), and single-kidney glomerular filtration rate (D-SKGFR), and then evaluated the impact of the indices to recipient body weight (R-BW) on graft function. Methods: This study included 44 recipients of live donor transplants without delayed graft function or acute rejection within 2 years of transplantation. Results: There was a statistically significant difference in serum creatinine between recipients with a D-KW/R-BW ratio of ≤4.25, D-FRV/R-BW ratio of ≤5.14, or D-SKGFR/R-BW ratio of ≤1.06 and recipients with a D-KW/R-BW ratio of >4.25, D-FRV/R-BW ratio of >5.14, or D-SKGFR/R-BW ratio of >1.06, respectively. D-KW/R-BW, D-FRV/R-BW, and D-SKGFR/R-BW strongly correlated with serum creatinine at 1 year and 2 years post-transplantation. In multivariate analysis, D-FRV and donor age were statistically significant risk factors which influenced serum creatinine at 1 year and 2 years post-transplantation. Conclusion: D-FRV/R-BW and donor age have significant impact on graft function. D-FRV/R-BW can be measured ahead of surgery. Therefore, measuring the D-FRV is useful to select a more optimal donor kidney among otherwise similar candidates during preoperative evaluation to improve posttransplant graft function.
Divergent Effects on Phagocytosis by Macrophage-Derived Oxygen Radicals
Authors: Brown Kelly L. , Christenson Karin , Karlsson Anna , Dahlgren Claes , Bylund Johan
Published: August 2009

Clearance of senescent cells from damaged tissue is a crucial step to successfully resolve an inflammatory response. Poor clearance has been attributed to defects in neutrophil apoptosis, a process that is regulated in part by reactive oxygen species (ROS) produced by activated neutrophils. Using ROS-deficient and wild-type macrophages treated with extracellular ROS scavengers we demonstrate that macrophage-derived ROS also influence phagocytosis and do so by direct and indirect mechanisms.
Estradiol Increases the Bax/Bcl-2 Ratio and Induces Apoptosis in the Anterior Pituitary Gland
Authors: Zaldivar Verónica , Magri María Laura , Zárate Sandra , Jaita Gabriela , Eijo Guadalupe , Radl Daniela , Ferraris Jimena , Pisera Daniel , Seilicovich Adriana
Published: August 2009

Background: Estrogens are recognized as acting as modulators of pituitary cell renewal, sensitizing cells to mitogenic and apoptotic signals, thus participating in anterior pituitary homeostasis during the estrous cycle. The balance of pro- and antiapoptotic proteins of the Bcl-2 family is known to regulate cell survival and apoptosis. Aims: In order to understand the mechanisms underlying apoptosis during the estrous cycle, we evaluated the expression of the proapoptotic protein Bax and the antiapoptotic proteins Bcl-2 and Bcl-xL in the anterior pituitary gland in cycling female rats as well as the influence of estradiol on the expression of these proteins in anterior pituitary cells of ovariectomized rats. Methods/Results: As determined by Western blot, the expression of Bax was higher in anterior pituitary glands from rats at proestrus than at diestrus I, Bcl-2 protein levels showed no difference and Bcl-xL expression was lower, thus increasing the Bax/Bcl-2 ratio at proestrus. Assessed by annexin V binding and flow cytometry, the percentage of apoptotic anterior pituitary cells was higher in rats at proestrus than at diestrus I. Chronic estrogen treatment in ovariectomized rats enhanced the Bax/Bcl-2 ratio and induced apoptosis. Moreover, incubation of cultured anterior pituitary cells from ovariectomized rats with 17β-estradiol for 24 h increased the Bax/Bcl-2 ratio, decreased Bcl-xL expression and induced apoptosis. Conclusion: Our results demonstrate that estradiol increases the ratio between proapoptotic and antiapoptotic proteins of the Bcl-2 family. This effect could participate in the sensitizing action of estrogens to proapoptotic stimuli and therefore be involved in the high apoptotic rate observed at proestrus in the anterior pituitary gland.
Effects of Salmeterol on Sleeping Oxygen Saturation in Chronic Obstructive Pulmonary Disease
Authors: Ryan Silke , Doherty Liam S. , Rock Clare , Nolan Geraldine M. , McNicholas Walter T.
Published: August 2009

Background: Sleep is associated with important adverse effects in patients with chronic obstructive pulmonary disease (COPD), such as disturbed sleep quality and gas exchange, including hypoxemia and hypercapnia. The effects of inhaled long-acting β2-agonist therapy (LABA) on these disturbances are unclear. Objectives: The aim of the study was to assess the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation (SaO2) and sleep quality. Methods: In a randomized, double-blind, placebo-controlled, crossover study of moderate/severe stable COPD patients, we compared the effects of 4 weeks of treatment with salmeterol 50 µg b.d. and matching placebo on sleeping SaO2 and sleep quality. Overnight polysomnography (PSG) was performed at baseline, and after 4 and 8 weeks in addition to detailed pulmonary function testing. Of 15 patients included, 12 completed the trial (median age 69 years, forced expiratory volume in 1 s, FEV1: 39%). Results: Both mean SaO2 [salmeterol vs. placebo: 92.9% (91.2, 94.7) vs. 91.0% (88.9, 94.8); p = 0.016] and the percentage of sleep spent below 90% of SaO2 [1.8% (0.0, 10.8) vs. 25.6% (0.5, 53.5); p = 0.005] improved significantly with salmeterol. Sleep quality was similar with both salmeterol and placebo on PSG. Static lung volumes, particularly trapped gas volume, tended to improve with salmeterol. Conclusion: We conclude that inhaled LABA therapy improves sleeping SaO2 without significant change in sleep quality.
Dysfunctional HDL as a Diagnostic and Therapeutic Target
Authors: Smith Jonathan D.
Published: August 2009

The atheroprotective effects of HDL are mediated by several mechanisms, including its role in reverse cholesterol transport and via its antiinflammatory properties. However, not all HDL is functionally similar. HDL and apolipoprotein A-I may become dysfunctional or even proinflammatory and thus promote atherosclerosis. ApoAI posttranslational modification can have a large impact on its function. Myeloperoxidase modification of apoAI impairs its function as a cholesterol acceptor, and the molecular changes induced by myeloperoxidase have been studied in detail. These studies provide the basis for the development of an oxidant-resistant form of apoAI and clinical measures of HDL modification and dysfunction, which may be useful as a treatment criterion.
Therapeutic Potential of Unrestricted Somatic Stem Cells Isolated from Placental Cord Blood for Cardiac Repair Post Myocardial Infarction
Authors: Iwasaki Hiroto , Kawamoto Atsuhiko , Willwerth Christina , Horii Miki , Oyamada Akira , Akimaru Hiroshi , Shibata Toshihiko , Hirai Hidekazu , Suehiro Shigefumi , Wnendt Stephan , Fodor William L. , Asahara Takayuki
Published: August 2009

Objective—

Unrestricted somatic stem cells (USSCs) were successfully identified from human cord blood. However, the efficacy of USSC transplantation for improving left ventricular (LV) function post myocardial infarction (MI) is still controversial.

Methods and Results—

PBS, 1×10
6
human fibroblasts (Fbr), 1×10
5
USSCs (LD), or 1×10
6
USSCs (HD) were transplanted intramyocardially 20 minutes after ligating the LAD of nude rats. Echocardiography and a microtip conductance catheter at day 28 revealed a dose-dependent improvement of LV function after USSC transplantation. Necropsy examination revealed dose-dependent augmentation of capillary density and inhibition of LV fibrosis. Dual-label immunohistochemistry for cardiac troponin-I and human nuclear antigen (HNA) demonstrated that human cardiomyocytes (CMCs) were dose-dependently generated in ischemic myocardium 28 days after USSC transplantation. Similarly, dual-label immunostaining for smooth muscle actin and class I human leukocyte antigen or that for von Willebrand factor and HNA also revealed a dose-dependent vasculogenesis after USSC transplantation. RT-PCR indicated that expression of human-specific genes of CMCs, smooth muscle cells, and endothelial cell markers in infarcted myocardium were significantly augmented in USSC-treated animals compared with control groups.

Conclusions—

USSC transplantation leads to functional improvement and recovery from MI and exhibits a significant and dose-dependent potential for concurrent cardiomyogenesis and vasculogenesis.
Lack of Tyrosylprotein Sulfotransferase Activity in Hematopoietic Cells Drastically Attenuates Atherosclerosis in
Ldlr
−/−
Mice
Authors: Westmuckett Andrew D. , Moore Kevin L.
Published: August 2009

Objective—

Leukocyte recruitment is a major contributor in the development of atherosclerosis and requires a variety of proteins such as adhesion molecules, chemokines, and chemokine receptors. Several key molecular players implicated in this process are expressed on monocytes and require protein-tyrosine sulfation for optimal function in vitro, including human CCR2, CCR5, CX3CR1, and PSGL-1. We therefore hypothesized that protein-tyrosine sulfation in hematopoietic cells plays an important role in the development of atherosclerosis.

Methods and Results—

Lethally-irradiated
Ldlr
−/−
mice were rescued with hematopoietic progenitors lacking tyrosylprotein sulfotransferase (TPST) activity attributable to deletion of the
Tpst1
and
Tpst2
genes. TPST deficient progenitors efficiently reconstituted hematopoiesis in
Ldlr
−/−
recipients and transplantation had no effect on plasma lipids on a standard or atherogenic diet. However, we observed a substantial reduction in the size of atherosclerotic lesions and the number of macrophages in lesions from hyperlipidemic
Ldlr
−/−
recipients transplanted with TPST deficient progenitors compared to wild-type progenitors. We also document for the first time that murine Psgl-1 and Cx3cr1 are tyrosine-sulfated.

Conclusions—

These data demonstrate that protein-tyrosine sulfation is an important contributor to monocytes/macrophage recruitment and/or retention in a mouse model of atherosclerosis.
LIM Kinase 1 Promotes Endothelial Barrier Disruption and Neutrophil Infiltration in Mouse Lungs
Authors: Gorovoy Matvey , Han Jingyan , Pan Haiyun , Welch Emily , Neamu Radu , Jia Zhengping , Predescu Dan , Vogel Stephen , Minshall Richard D. , Ye Richard D. , Malik Asrar B. , Voyno-Yasenetskaya Tatyana
Published: August 2009

Rationale:

Disruption of endothelial barrier function and neutrophil-mediated injury are two major mechanisms underlying the pathophysiology of sepsis-induced acute lung injury (ALI). Recently we reported that endotoxin induced activation of RhoA in mice lungs that led to the disruption of endothelial barrier and lung edema formation; however, the molecular mechanism of this phenomenon remained unknown.

Objective:

We reasoned that LIMK1, which participates in the regulation of endothelial cell contractility and is activated by RhoA/Rho kinase pathway, could mediate RhoA-dependent disruption of endothelial barrier function in mouse lungs during ALI. And if that is the case, then attenuation of endothelial cell contractility by downregulating LIMK1 may lead to the enhancement of endothelial barrier function, which could protect mice from endotoxin-induced ALI.

Methods and Results:

Here we report that LIMK1 deficiency in mice significantly reduced mortality induced by endotoxin. Data showed that lung edema formation, lung microvascular permeability, and neutrophil infiltration into the lungs were suppressed in
limk1
−/−
mice.

Conclusions:

We identified that improvement of endothelial barrier function along with impaired neutrophil chemotaxis were the underlying mechanisms that reduced severity of ALI in
limk1
−/−
mice, pointing to a new therapeutic target for diseases associated with acute inflammation of the lungs.
PKC Phosphorylation of Titin’s PEVK Element
Authors: Hidalgo Carlos , Hudson Bryan , Bogomolovas Julius , Zhu Yi , Anderson Brian , Greaser Marion , Labeit Siegfried , Granzier Henk
Published: August 2009

Rationale
:

Protein kinase C (PKC) regulates contractility of cardiac muscle cells by phosphorylating thin- and thick- filament-based proteins. Myocardial sarcomeres also contain a third myofilament, titin, and it is unknown whether titin can be phosphorylated by PKC and whether it affects passive tension.

Objective
:

The purpose of this study was to examine the effect of PKC on titin phosphorylation and titin-based passive tension.

Methods and Results
:

Phosphorylation assays with PKCα revealed that titin is phosphorylated in skinned myocardial tissues; this effect is exacerbated by pretreating with protein phosphatase 1. In vitro phosphorylation of recombinant protein representing titin’s spring elements showed that PKCα targets the proline – glutamate – valine – lysine (PEVK) spring element. Furthermore, mass spectrometry in combination with site-directed mutagenesis identified 2 highly conserved sites in the PEVK region that are phosphorylated by PKCα (S11878 and S12022); when these 2 sites are mutated to alanine, phosphorylation is effectively abolished. Mechanical experiments with skinned left ventricular myocardium revealed that PKCα significantly increases titin-based passive tension, an effect that is reversed by protein phosphatase 1. Single molecule force-extension curves show that PKCα decreases the PEVK persistence length (from 1.20 nm to 0.55 nm), without altering the contour length, and using a serially-linked wormlike chain model we show that this increases titin-based passive force with a sarcomere length dependence that is similar to that measured in skinned myocardium after PKCα phosphorylation.

Conclusions
:

PKC phosphorylation of titin is a novel and conserved pathway that links myocardial signaling and myocardial stiffness.
NADPH Oxidase Nox2 Is Required for Hypoxia-Induced Mobilization of Endothelial Progenitor Cells
Authors: Schröder Katrin , Kohnen Andreas , Aicher Alexandra , Liehn Elisa A. , Büchse Tom , Stein Stefan , Weber Christian , Dimmeler Stefanie , Brandes Ralf P.
Published: August 2009

Rationale:

Endothelial progenitor cells (EPCs, defined as sca-1
+
flk-1
+
lin
−
mononuclear blood cells) contribute to vascular repair. The role of hypoxia and reactive oxygen species (ROS) in mobilization and function of these cells is incompletely understood.

Objective:

We studied the contribution of the NADPH oxidase Nox2, an important vascular source of ROS in this context.

Methods and Results:

Hypoxia (10% oxygen) induced the mobilization of EPCs in wild-type (WT) and Nox1 but not in Nox2 knockout (Nox2
y/−
) mice. As erythropoietin (EPO) is known to induce EPC mobilization, we focused on this hormone. EPO induced the mobilization of EPCs in WT and Nox1
y/−
but not Nox2
y/−
animals. Transplantation of bone marrow from Nox2
y/−
mice into WT-mice blocked mobilization in response to hypoxia and EPO, whereas transplantation of WT bone marrow into Nox2
y/−
mice restored mobilization. Reendothelialization of the injured mouse carotid artery was enhanced by hypoxia as well as by EPO, and this effect was not observed in Nox2
y/−
mice or after transplantation of Nox2
y/−
bone marrow. In cultured EPCs from WT but not Nox2
y/−
mice, EPO induced ROS production, migration, and proliferation. EPO signaling involves the STAT5 transcription factor. EPO-induced STAT5-dependent reporter gene expression was absent in Nox2-deficient cells. siRNA against the redox-sensitive phosphatase SHP-2 restored EPO-mediated STAT5 induction and inhibition of SHP-2 restored EPO-induced migration in Nox2-deficient cells

Conclusions:

We conclude that Nox2-derived ROS inactivate SHP-2 and thereby facilitate EPO signaling in EPCs to promote hypoxia-induced mobilization and vascular repair by these cells.
Defeating Normal Thermoregulatory Defenses
Authors: Sessler Daniel I.
Published: August 2009

Therapeutic hypothermia may be useful in various circumstances including stroke. However, core body temperature is normally tightly regulated. Even mild hypothermia in conscious subjects thus provokes vigorous thermoregulatory defenses which are potentially harmful in fragile patients. Furthermore, thermoregulatory responses are effective, which reduces the rate at which hypothermia can be induced. Drugs are thus often given to blunt normal thermoregulatory defenses. General anesthetics profoundly impair thermoregulatory control, but prolonged general anesthesia is rarely practical or appropriate. A variety of other drugs have therefore been evaluated. Most opioids only slightly impair thermoregulatory defenses, but meperidine is considerably more effective than equipotent doses of other opioids. The central α-2 agonists clonidine and dexmedetomidine are also useful. However, the best overall approach to inducing thermal tolerance appears to be a combination of buspirone and meperidine, which reduces the core temperature triggering shivering to about 33.5°C in doses that maintain adequate ventilation.
Multi-Ethnic Genetic Association Study of Carotid Intima-Media Thickness Using a Targeted Cardiovascular SNP Microarray
Authors: Lanktree Matthew B. , Hegele Robert A. , Yusuf Salim , Anand Sonia S.
Published: August 2009

Background and Purpose—

Identification of subclinical atherosclerosis by ultrasonographic measurement of carotid intima-media thickness (IMT) is a validated tool, in conjunction with traditional risk factors, for clinical assessment of cardiovascular disease risk. IMT has also been recognized as a quantitative measure of cardiovascular disease progression in asymptomatic individuals, and many candidate gene association studies have attempted to identify genetic variants associated with interindividual differences in IMT with limited success. We sought to test the association between subclinical atherosclerosis measured by IMT and ≈50 000 SNPs, densely mapping ≈2100 genes found on the gene-centric Illumina cardiovascular disease beadchip in a multi-ethnic population-based sample.

Methods—

IMT was measured by B-mode ultrasound and DNA was collected from a population-based sample of South Asian (n=328), Chinese (n=302), and European Caucasian (n=268) participants. Genetic association was measured using multivariate linear regression including adjustment for covariates.

Results—

The most robust association across all models tested was observed for a SNP (rs3791398) in histone deacetylase 4 (
HDAC4
;
P
=1.8e-5 to
P
=3.6e-5), while another strong association signal was observed with natriuretic peptide receptor a/guanylate cyclase A (
NPR1
) (rs10082235,
P
=5.4e-5). Seven of 13 previously reported functional candidate genes contained a SNP that was marginally associated (0.01<
P
≤0.05).

Conclusion—

This initial multi-ethnic high-density association study of carotid IMT suggests some novel loci requiring further evaluation in follow-up studies.
Geography, Structure, and Evolution of Diffusion and Perfusion Lesions in Diffusion and Perfusion Imaging Evaluation For Understanding Stroke Evolution (DEFUSE)
Authors: Olivot Jean-Marc , Mlynash Michael , Thijs Vincent N. , Purushotham Archana , Kemp Stephanie , Lansberg Maarten G. , Wechsler Lawrence , Gold Garry E. , Bammer Roland , Marks Michael P. , Albers Gregory W.
Published: August 2009

Background and Purpose—

The classical representation of acute ischemic lesions on MRI is a central diffusion-weighted imaging (DWI) lesion embedded in a perfusion-weighted imaging (PWI) lesion. We investigated spatial relationships between final infarcts and early DWI/PWI lesions before and after intravenous thrombolysis in the Diffusion and perfusion imaging Evaluation For Understanding Stroke Evolution (DEFUSE) study.

Methods—

Baseline and follow-up DWI and PWI lesions and 30-day fluid-attenuated inversion recovery scans of 32 patients were coregistered. Lesion geography was defined by the proportion of the DWI lesion superimposed by a T
max
(time when the residue function reaches its maximum) >4 seconds PWI lesion; Type 1: >50% overlap and Type 2: ≤50% overlap. Three-dimensional structure was dichotomized into a single lesion (one DWI and one PWI lesion) versus multiple lesions. Lesion reversal was defined by the percentage of the baseline DWI or PWI lesion not superimposed by the early follow-up DWI or PWI lesion. Final infarct prediction was estimated by the proportion of the final infarct superimposed on the union of the DWI and PWI lesions.

Results—

Single lesion structure with Type 1 geography was present in only 9 patients (28%) at baseline and 4 (12%) on early follow-up. In these patients, PWI and DWI lesions were more likely to correspond with the final infarcts. DWI reversal was greater among patients with Type 2 geography at baseline. Patients with multiple lesions and Type 2 geography at early follow-up were more likely to have early reperfusion.

Conclusion—

Before thrombolytic therapy in the 3- to 6-hour time window, Type 2 geography is predominant and is associated with DWI reversal. After thrombolysis, both Type 2 geography and multiple lesion structure are associated with reperfusion.
Factors Explaining Excess Stroke Prevalence in the US Stroke Belt
Authors: Liao Youlian , Greenlund Kurt J. , Croft Janet B. , Keenan Nora L. , Giles Wayne H.
Published: August 2009

Background and Purpose—

Higher risk and burden of stroke have been observed within the southeastern states (the Stroke Belt) compared with elsewhere in the United States. We examined reasons for these disparities using a large data set from a nationwide cross-sectional study.

Methods—

Self-reported data from the 2005 and 2007 Behavioral Risk Factor Surveillance System were used (n=765 368). The potential contributors for self-reported stroke prevalence (n=27 962) were demographics (age, sex, geography, and race/ethnicity), socioeconomic status (education and income), common risk factors (smoking and obesity), and chronic diseases (hypertension, diabetes, and coronary heart disease). Multivariate logistic regression was used in the analysis.

Results—

The age- and sex-adjusted OR comparing self-reported stroke prevalence in the 11-state Stroke Belt versus non-Stroke Belt region was 1.25 (95% CI, 1.19 to 1.31). Unequal black/white distribution by region accounted for 20% of the excess prevalence in the Stroke Belt (OR reduced to 1.20; 1.15 to 1.26). Approximately one third (32%) of the excess prevalence was accounted either by socioeconomic status alone or by risk factors and chronic disease alone (OR, 1.12). The OR was further reduced to 1.07 (1.02 to 1.13) in the fully adjusted logistic model, a 72% reduction.

Conclusions–

Differences in socioeconomic status, risk factors, and prevalence of common chronic diseases account for most of the regional differences in stroke prevalence.
The Redemption of State Securities: The Intersection of Civil and Budgetary Legislation in Russia
Authors: Ishutina Olga
Published: August 2009

The author discusses the inter-relationship of Russia's civil and budgetary legislation in light of the rules and regulations governing obligations arising from state securities under conditions of a financial crisis. She argues that the redemption of state bonds (treasury bills) by exchanging them for other state debt instrument bonds does not conform to the conditions for debt novation. However, the author does not rule out the possibility for the state to make unilateral changes to the terms and conditions of a loan and, in addition, offers alternative means of resolving this (legal) issue.
Receivables Financing in Lithuania: Is the Legal Regulation Suited to Accommodate the Practical Needs of Industry?
Authors: Aleknaitė Lina
Published: August 2009

This article examines the provisions of the 2000 Lithuanian Civil Code regarding the use of receivables for the purpose of raising finance. It starts by discussing the mechanism that the Code provides for the transfer of receivables—i.e., cession. Also, limitations on cession without debtor approval and the extent of rights that can be ceded are noted. The author then turns to the two main techniques of using receivables for financing. First, she examines the legal provisions on factoring and their practical application, as well as the structure of the industry. She presents some observations on the present structure of the industry, which precludes smaller companies from entering the market. Thereafter, she focuses on the possibilities under the Code of creating a security interest in receivables. Here, she reveals that the mechanism, although it does exist, is not a viable alternative to factoring, as it imposes additional burdens upon economic actors. Finally, the author presents her suggestions to the Lithuanian legislator, specifying the amendments that she believes should be made to the Code in order to encourage wider use of receivables financing in different ways (both by selling and by creating a security interest in receivables), as well as the further development of the industry.
The Effects of Hypothyroidism on the Mechanical Properties and Histomorphological Structure of the Thoracic Aorta
Authors: Moulakakis Konstantinos G. , Sokolis Dimitrios P. , Perrea Despina N. , Dontas Ismene , Dosios Theodosios , Poulakou Maria V. , Mylonas Spyridon N. , Dimitriou Constantinos A. , Karayannacos Panayotis E.
Published: August 2009

This experimental study investigates the effects of hypothyroidism on the descending thoracic aorta. Hypothyroidism was induced in 20 male Wistar rats by administering 0.05% of 6-n propyl 2-thiouracil (PTU) in their drinking water for 8 weeks. Euthyroid rats were used as controls. Animals were sacrificed and longitudinal strips of the descending aorta were subjected to various preselected levels of stress in a uniaxial tensile-testing device. Analysis of stress—strain, elastic modulus—strain curves disclosed significant differences between groups, indicative of stiffer aortas in hypothyroid animals at the upper physiologic and higher levels of pressure. Remodeling of the aortic wall of hypothyroid animals revealed significant histological changes. The thoracic aorta of hypothyroid rats compared with that of euthyroid ones became stiffer at high strains, including the upper physiologic range, loosing part of its distensibility. Hypothyroidism was also associated with diameter enlargement and substantial lengthening of the aorta.