bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension
Authors: Konduri Girija G. , Bakhutashvili Ivane , Eis Annie , Pritchard Kirkwood
Published: December 2006

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•−scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•−in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•−in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.
Enhanced AT1receptor-mediated vasocontractile response to ANG II in endothelium-denuded aorta of obese Zucker rats
Authors: Siddiqui Athar H. , Hussain Tahir
Published: December 2006

In the present study, we tested the hypothesis that ANG II causes a greater vasoconstriction in obese Zucker rats, a model of type 2 diabetes, with mild hypertension. Measurement of isometric tension in isolated aortic rings with intact endothelium revealed a modest but not significantly greater ANG II-induced contraction in obese than lean rats. Removal of endothelium or inhibition of nitric oxide (NO) synthase by NG-nitro-l-arginine methyl ester (l-NAME) enhanced 1) ANG II-induced contraction in both lean and obese rats, being significantly greater in obese rats (Emaxg/g tissue, denuded: lean 572 ± 40 vs. obese 664 ± 16; l-NAME: lean 535 ± 14 vs. obese 818 ± 23) and 2) ANG II sensitivity in obese compared with lean rats, as revealed by the pD2values. Endothelin-1 and KCl elicited similar contractions in the aortic rings of lean and obese rats. ACh, a NO-dependent relaxing hormone, produced greater relaxation in the aortic rings of obese than lean rats, whereas sodium nitroprusside, an NO donor, elicited similar relaxations in both rat strains. The expression of the ANG type 1 (AT1) receptor protein and mRNA in the endothelium-intact aorta was significantly greater in obese than lean rats, whereas the endothelium-denuded rings expressed modest but not significantly greater levels of AT1receptors in obese than lean rats. The endothelial NO synthase protein and mRNA expression levels were higher in the aorta of obese than lean animals. We conclude that, although ANG II produces greater vasoconstriction in obese rat aortic rings, enhanced endothelial AT1receptor-mediated NO production appears to counteract the increased ANG II-induced vasoconstriction, suggesting that arterial AT1receptor may not be a contributing factor to hypertension in this model of obesity.
Myosin essential light chain in health and disease
Authors: Hernandez Olga M. , Jones Michelle , Guzman Georgianna , Szczesna-Cordary Danuta
Published: December 2006

The essential light chain of myosin (ELC) is known to be important for structural stability of the α-helical lever arm domain of the myosin head, but its function in striated muscle contraction is poorly understood. Two ELC isoforms are expressed in fast skeletal muscle, a long isoform and its NH2-terminal ∼40 amino acid shorter counterpart, whereas only the long ELC is observed in the heart. Biochemical and structural studies revealed that the NH2-terminus of the long ELC can make direct contacts with actin, but the effects of the ELC on the affinity of myosin for actin, ATPase, force, and the kinetics of force generating myosin cross-bridges are inconclusive. Myosin containing the long ELC has been shown to have slower cross-bridge kinetics than myosin with the short isoform. A difference was also reported among myosins with long isoforms. Increased shortening velocity was observed in atrial compared with ventricular muscle fibers. The common findings suggest that ELC provides the fine tuning of the myosin motor function, which is regulated in an isoform and tissue-dependent manner. The functional importance of the ELC is further implicated by the discovery of ELC mutations associated with Familial Hypertrophic Cardiomyopathy. The pathological phenotypes vary in severity, but more notably, almost all ELC mutations result in sudden cardiac death at a young age. This review summarizes the functional roles of striated muscle ELC in normal healthy muscle and in disease. Transgenic animal models and phenotypic characterization of ELC-mediated remodeling of the heart are also discussed.
IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits
Authors: Suto Fumiaki , Zhu Wei , Chan Alice , Gross Gil J.
Published: December 2006

Bradycardic ventricular electrical remodeling predisposes to lethal tachyarrhythmias. We investigated the early temporal sequence and reversibility of electrical remodeling in a rabbit complete heart block model subjected to bradycardic ventricular pacing for either 2 or 8 days, with a third group of animals undergoing 8 days of bradycardic pacing followed by 8 days of physiological-rate pacing. At specified time points after complete heart block induction and pacing initiation, steady-state QT interval measurements and variability as well as dynamic QT interval adaptation to abrupt heart rate acceleration were assessed in the absence and presence of isoproterenol. Rapidly ( IKr) and slowly ( IKs) activating delayed rectifier repolarizing K+ tail current densities were evaluated using whole cell patch clamp in isolated right ventricular myocytes. Steady-state QT interval prolongation at both 2 and 8 days was associated with moderate IKr reduction. IKs downregulation was apparent by day 2 but more profound at day 8. Dynamic QT interval adaptation was impaired under baseline conditions at day 8 but only during isoproterenol administration at day 2. Both in vivo and cellular manifestations of remodeling reverted toward control values after 8 days of physiological-rate pacing. In conclusion, in this bradycardic model, IKs downregulation 1) proceeds more gradually but more extensively than that of IKr and 2) is most prominently associated with impaired dynamic QT interval adaptation to heart rate acceleration. Isoproterenol blunts the dynamic QT interval response in animals with partially downregulated IKs, consistent with stress-related phenomena in known IKs-impaired states. Relative early sparing of IKs could explain the delay in the onset of lethal tachyarrhythmia predisposition in bradycardic electrical remodeling. Reversibility of remodeling supports the potential utility of preventive pacing intervention soon after bradycardia onset.
ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats
Authors: Rakusan Karel , Chvojkova Zuzana , Oliviero Patricia , Ostadalova Ivana , Kolar Frantisek , Chassagne Catherine , Samuel Jane-Lise , Ostadal Bohuslav
Published: December 2006

Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT1) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT1receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT1but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1α markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT1receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia.
Estrogen receptor-α mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice
Authors: Xue Baojian , Pamidimukkala Jaya , Lubahn Dennis B. , Hay Meredith
Published: December 2006

It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-α (ERα) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng·kg−1·min−1) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERα knockout (ERαKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 ± 1.0 mmHg) and ERαKO mice (23.8 ± 2.5 mmHg) than in intact WT mice (10.1 ± 4.5 mmHg). In OVX WT mice, central infusion of 17β-estradiol (E2; 30 μg·kg−1·day−1) attenuated the pressor effect of ANG II (7.0 ± 0.4 mmHg), and this protective effect of E2 was prevented by coadministration of ICI-182,780 (ICI; 1.5 μg·kg−1·day−1, 18.8 ± 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 ± 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E2-treated OVX ERαKO mice (19.0 ± 1.1 mmHg) or central ICI-treated intact ERαKO mice (19.6 ± 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E2 + ICI-treated OVX WT, ERαKO, and central E2- or ICI-treated ERαKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERα, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.
Direct demonstration of 25- and 50-μm arteriovenous pathways in healthy human and baboon lungs
Authors: Lovering Andrew T. , Stickland Michael K. , Kelso Amy J. , Eldridge Marlowe W.
Published: December 2006

Postmortem microsphere studies in adult human lungs have demonstrated the existence of intrapulmonary arteriovenous pathways using nonphysiological conditions. The aim of the current study was to determine whether large diameter (>25 and 50 μm) intrapulmonary arteriovenous pathways are functional in human and baboon lungs under physiological perfusion and ventilation pressures. We used fresh healthy human donor lungs obtained for transplantion and fresh lungs from baboons ( Papio c. anubis). Lungs were ventilated with room air by using a peak inflation pressure of 15 cmH2O and a positive end-expiratory pressure of 5 cmH2O. Lungs were perfused between 10 and 20 cmH2O by using a phosphate-buffered saline solution with 5% albumin. We infused a mixture of 25- and 50-μm microspheres (0.5 and 1 million total for baboons and human studies, respectively) into the pulmonary artery and collected the entire pulmonary venous outflow. Under these conditions, evidence of intrapulmonary arteriovenous anastomoses was found in baboon ( n = 3/4) and human ( n = 4/6) lungs. In those lungs showing evidence of arteriovenous pathways, 50-μm microspheres were always able to traverse the pulmonary circulation, and the fraction of transpulmonary passage ranged from 0.0003 to 0.42%. These data show that intrapulmonary arteriovenous pathways >50 μm in diameter are functional under physiological ventilation and perfusion pressures in the isolated lung. These pathways provide an alternative conduit for pulmonary blood flow that likely bypasses the areas of gas exchange at the capillary-alveolar interface that could compromise both gas exchange and the ability of the lung to filter out microemboli.
Adiponectin and cardiovascular disease: state of the art?
Authors: Szmitko Paul E. , Teoh Hwee , Stewart Duncan J. , Verma Subodh
Published: December 2006

The cardiometabolic syndrome, associated with increased cardiovascular disease risk in the industrialized world, is estimated to affect one in four adults. Although the mechanisms linking obesity and cardiovascular disease remain unclear, research continues to unravel the molecular pathways behind this pandemic. Adipose tissue has emerged as a metabolically active participant in mediating vascular complications, serving as an active endocrine and paracrine organ secreting adipokines, which participate in diverse metabolic processes. Among these adipokines is adiponectin, which seems to possess antiatherogenic and anti-inflammatory effects and may be protective against cardiovascular disease development. The current review describes the pathophysiology of adiponectin in atherosclerotic disease.
Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema
Authors: Shifren Adrian , Durmowicz Anthony G. , Knutsen Russell H. , Hirano Eiichi , Mecham Robert P.
Published: December 2006

Cigarette smoking is the strongest risk factor for emphysema. However, sensitivity to cigarette smoke-induced emphysema is highly variable, and numerous genetic and environmental factors are thought to mitigate lung response to injury. We report that the quantity of functional elastin in the lung is an important modifier of both lung development and response to injury. In mice with low levels of elastin, lung development is adversely affected, and mice manifest with congenital emphysema. Animals with intermediate elastin levels exhibit normal alveolar structure but develop worse emphysema than normal mice following cigarette smoke exposure. Mechanical testing demonstrates that lungs with low levels of elastin experience greater tissue strains for any given tissue stress compared with wild-type lungs, implying that force-mediated propagation of lung injury through alveolar wall failure may worsen the emphysema after an initial enzymatic insult. Our findings suggest that quantitative deficiencies in elastin predispose to smoke-induce emphysema in animal models and suggest that humans with altered levels of functional elastin could have relatively normal lung function while being more susceptible to smoke-induced lung injury.
Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet
Authors: Cambonie Gilles , Comte Blandine , Yzydorczyk Catherine , Ntimbane Thierry , Germain Nathalie , Lê Ngoc Loan Oanh , Pladys Patrick , Gauthier Cindy , Lahaie Isabelle , Abran Daniel , Lavoie Jean-Claude , Nuyt Anne Monique
Published: December 2006

Developmental programming of hypertension is associated with vascular dysfunction characterized by impaired vasodilatation to nitric oxide, exaggerated vasoconstriction to ANG II, and microvascular rarefaction appearing in the neonatal period. Hypertensive adults have indices of increased oxidative stress, and newborns that were nutrient depleted during fetal life have decreased antioxidant defenses and increased susceptibility to oxidant injury. To test the hypothesis that oxidative stress participates in early life programming of hypertension, vascular dysfunction, and microvascular rarefaction associated with maternal protein deprivation, pregnant rats were fed a normal, low protein (LP), or LP plus lazaroid (lipid peroxidation inhibitor) isocaloric diet from the day of conception until delivery. Lazaroid administered along with the LP diet prevented blood pressure elevation, enhanced vasomotor response to ANG II, impaired vasodilatation to sodium nitroprusside, and microvascular rarefaction in adult offspring. Liver total glutathione was significantly decreased in LP fetuses, and kidney eight-isoprostaglandin F2α (8-isoPGF2α) levels were significantly increased in adult LP offspring; these modifications were prevented by lazaroid. Renal nitrotyrosine abundance and blood levels of 1,4-dihydroxynonene and 4-hydroxynonenal-protein adducts were not modified by antenatal diet exposure. This study shows in adult offspring of LP-fed dams prevention of hypertension, vascular dysfunction, microvascular rarefaction, and of an increase in indices of oxidative stress by the administration of lazaroid during gestation. Lazaroid also prevented the decrease in antioxidant glutathione levels in fetuses, suggesting an antenatal mild oxidative stress in offspring of LP-fed dams. These studies support the concept that perinatal oxidative insult can lead to permanent alterations in the cardiovascular system development.
Interleukin-1 receptor antagonist as a modulator of gender differences in the febrile response to lipopolysaccharide in rats
Authors: Ashdown H. , Poole S. , Boksa P. , Luheshi G. N.
Published: December 2006

Febrile responses to bacterial pathogens are attenuated near term of pregnancy in several mammalian species. It is unknown, however, whether this reflects a fundamental physiological adaptation of female rats or whether it is specific to pregnancy. The aims of this study therefore were 1) to determine whether febrile responses to the bacterial endotoxin lipopolysaccharide (LPS) are attenuated in female vs. male rats and, if so, to identify possible mechanisms involved in modulating this and 2) to assess whether plasma concentrations of the anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), an important regulator of fever, are dependent on the physiological state of the female and could therefore be involved in modulating febrile responses. We found febrile responses were attenuated in cycling female vs. male rats and also in near-term pregnant dams vs. cycling females after intraperitoneal injection of LPS (0.05 mg/kg). Plasma levels of IL-1ra were significantly greater in female rats after injection of LPS, particularly during pregnancy, than in males. This was accompanied by attenuated levels of hypothalamic IL-1β and cyclooxygenase-2 mRNA, two key mediators of the febrile response, in female rats. Furthermore, increasing plasma levels of IL-1ra in male rats by intraperitoneal administration of the recombinant antagonist attenuated hypothalamic mRNA levels of these mediators after LPS. These data suggest that there is a fundamental difference in febrile response to LPS between the genders that is likely regulated by IL-1ra. This may be an important mechanism that protects the developing fetus from potentially deleterious consequences of maternal fever during pregnancy.
Carbon dioxide and pH effects on temperature-sensitive and -insensitive hypothalamic neurons
Authors: Wright Chadwick L. , Boulant Jack A.
Published: December 2006

The preoptic-anterior hypothalamus (POAH) controls body temperature, and thermoregulatory responses are impaired during hypercapnia. If increased CO2 or its accompanying acidosis inhibits warm-sensitive POAH neurons, this could provide an explanation for thermoregulatory impairment during hypercapnia. To test this possibility, extracellular electrophysiological recordings determined the effects of CO2 and pH on the firing rates of both temperature-sensitive and -insensitive neurons in hypothalamic tissue slices from 89 male Sprague-Dawley rats. Firing rate activity was recorded in 121 hypothalamic neurons before, during, and after changing the CO2 concentration aerating the tissue slice chamber or changing the pH of the solution bathing the tissue slices. Increasing the aeration CO2 concentration from 5% (control) to 10% (hypercapnic) had no effect on most (i.e., 69%) POAH temperature-insensitive neurons; however, this hypercapnia inhibited the majority (i.e., 59%) of warm-sensitive neurons. CO2 affected similar proportions of (non-POAH) neurons in other hypothalamic regions. These CO2 effects appear to be due to changes in pH since the CO2-affected neurons responded similarly to isocapnic acidosis (i.e., normal CO2 and decreased pH) but were not responsive to isohydric hypercapnia (i.e., increased CO2 and normal pH). These findings may offer a neural explanation for some heat-related illnesses (e.g., exertional heat stroke) where impaired heat loss is associated with acidosis.
Intensity of eccentric exercise, shift of optimum angle, and the magnitude of repeated-bout effect
Authors: Chen Trevor C. , Nosaka Kazunori , Sacco Paul
Published: December 2006

This study compared the effect of four different intensities of initial eccentric exercise (ECC1) on optimum angle shift and extent of muscle damage induced by subsequent maximal eccentric exercise. Fifty-two male students were placed into 100%, 80%, 60%, or 40% groups ( n = 13 per group), performing 30 eccentric actions of the elbow flexors of 100%, 80%, 60%, or 40% of maximal isometric strength [maximal voluntary contraction (MVC)] for ECC1, followed 2–3 wk later by a similar exercise (ECC2) that used 100% MVC load. MVC at six elbow joint angles, range of motion, upper arm circumference, serum creatine kinase activity, myoglobin concentration, and muscle soreness were measured before and for 5 days following ECC1 and ECC2. A rightward shift of optimum angle following ECC1 was significantly ( P < 0.05) greater for the 100% and 80% than for the 60% and 40% groups, and it decreased significantly ( P < 0.05) from immediately to 5 days postexercise. By the time ECC2 was performed, only the 100% group kept a significant shift (4°). Changes in most of the criterion measures following ECC1 were significantly greater for the 100% and 80% groups compared with the 60% and 40% groups. Changes in the criterion measures following ECC2 were significantly ( P < 0.05) greater for the 40% group compared with other groups. Although the magnitude of repeated bout effect following ECC2 was significantly ( P < 0.05) smaller for the 40% and 60% groups, all groups showed significantly ( P < 0.05) reduced changes in criterion measures following ECC2 compared with the ECC1 100% bout. We conclude that the repeated-bout effect was not dependent on the shift of optimum angle.
Left ventricular function during arm exercise: influence of leg cycling and lower body positive pressure
Authors: Goodman Jack M. , Freeman Michael R. , Goodman Leonard S.
Published: December 2006

The purpose of this study was to characterize left ventricular (LV) diastolic filling and systolic performance during graded arm exercise and to examine the effects of lower body positive pressure (LBPP) or concomitant leg exercise as means to enhance LV preload in aerobically trained individuals. Subjects were eight men with a mean age (±SE) of 26.8 ± 1.2 yr. Peak exercise testing was first performed for both legs [maximal oxygen uptake (V̇o2) = 4.21 ± 0.19 l/min] and arms (2.56 ± 0.16 l/min). On a separate occasion, LV filling and ejection parameters were acquired using non-imaging scintography using in vivo red blood cell labeling with technetium 99m first during leg exercise performed in succession for 2 min at increasing grades to peak effort. Graded arm exercise (at 30, 60, 80, and 100% peak V̇o2) was performed during three randomly assigned conditions: control (no intervention), with concurrent leg cycling (at a constant 15% leg maximal V̇o2) or with 60 mmHg of LBPP using an Anti G suit. Peak leg exercise LV ejection fraction was higher than arm exercise (60.9 ± 1.7% vs. 55.9 ± 2.7%; P < 0.05) as was peak LV end-diastolic volume was reported as % of resting value (110.3 ± 4.4% vs. 97 ± 3.7%; P < 0.05) and peak filling rate (end-diastolic volume/s; 6.4 ± 0.28% vs. 5.2 ± 0.25%). Concomitant use of either low-intensity leg exercise or LBPP during arm exercise failed to significantly increase LV filling or ejection parameters. These observations suggest that perturbations in preload fail to overcome the inherent hemodynamic conditions present during arm exercise that attenuate LV performance.
Factors Influencing Apnea and Bradycardia of Prematurity – Implications for Neurodevelopment
Authors: Pillekamp F. , Hermann C. , Keller T. , von Gontard A. , Kribs A. , Roth B.
Published: December 2006

Background: Apnea and bradycardia of prematurity (ABP) are possible risks towards damage of the developing brain. Objectives: To characterize the influence of neonatal factors on ABP and to determine the relationship of ABP to neurodevelopmental outcome. Methods: ABP was described in very low birth weight infants (n = 83) using the frequency and severity of ABP episodes with a clinical score considering heart rate, oxygenation, duration and interventions performed during each episode. Neonatal factors were analyzed for their relationship to ABP using regression analysis. Neurodevelopment was investigated using the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) of the Bayley Scales of Infant Development II at a corrected age of 13 months. Power of ABP parameters to predict outcome was assessed by logistic regression analysis. Results: ABP typically started within the first week after birth. Spontaneous resolution occurred at a postmenstrual age (PMA) of 36.0 ± 2.2 (31.1–44.1) weeks. A delayed resolution (>36 weeks PMA) and a higher average daily ABP score during a defined developmental period (31–37 weeks PMA) were associated with a higher incidence of unfavorable outcome (MDI or PDI <69 or death). Conclusion: ABP is an age-specific phenomenon. However, more severe courses than expected for PMA or the resolution at a later PMA indicated an increased risk of neurodevelopmental disturbances at a corrected age of 13 months.
Diagnosis of Gastro-Oesophageal Reflux in Preterm Infants: Sonography vs. pH-Monitoring
Authors: Pezzati Marco , Filippi Luca , Psaraki Margarita , Rossi Sauro , Dani Carlo , Tronchin Michele , Rubaltelli Firmino F.
Published: December 2006

Objectives: To compare the ultrasound examination with pH-metry in order to evaluate the diagnostic accuracy of sonography for diagnosis of gastro-oesophageal reflux (GOR) in preterm infants. Methods: A prospective study was conducted on 31 premature infants <34 weeks with clinically diagnosed GOR. First, they underwent 24-hour pH-monitoring; successively, the sonographic assessment was performed within 12 h after pH-monitoring. The two operators who performed the pH-monitoring and sonography respectively, were unaware of each other’s results. Results: Twenty-one patients (67.7%) had significant GOR with a reflux index >5 (GOR group). The median (range) reflux index in this group was 9.19% (6.04–20.1). Ten newborns (32.3%) did not have significant GOR with a reflux index <5. Sonography was positive for GOR in 8 patients (25.8%); all 8 infants with sonographic diagnosis of GOR had a reflux index >5. Therefore, sonographic diagnosis did not produce false positives. Sonography was negative in 23 newborns (74.2%); 13 of these were positive to pH-monitoring and may therefore be considered as false negatives. Respect to continuous 24-hour pH-monitoring, sonography showed a specificity of 100% but a very low sensitivity of 38% with a positive prediction value of 100% and a negative prediction value of 43%. Conclusions: Sonography should not replace 24-hour pH monitoring for detecting GOR in preterm infants. However, sonography has a very high specificity and a positive predictive value of 100%. When clinicians suspect GOR in preterm infants, it could be useful for selection of cases to refer for pH-metry.
Effects of Probiotics on Enteric Flora and Feeding Tolerance in Preterm Infants
Authors: Lee Soo Jeong , Cho Su Jin , Park Eun Ae
Published: December 2006

Background: Probiotics are live microbes that colonize the gastrointestinal tract and benefit the host. Preterm infants develop abnormal patterns of bowel colonization, and only a few clinical trials have reported the outcomes of preterm infants treated with probiotics. Purpose: We investigated the rate of colonization of Lactobacillus and the clinical variables affecting the colonization in preterm infants. Methods: Infants with gestational age less than 37 weeks treated at Ewha Womans University Hospital between March 2003 and July 2004 were eligible. Lactobacillus acidophilus (containing 108 CFU) was supplemented orally, mixed with breast milk or formula divided into three doses a day. Stool samples were collected before and 14 days after supplementation of the probiotic. Stool samples were anaerobically cultured on Rogosa agar and identified by Gram stain, catalase test and glucose fermentation test. Clinical characteristics were analyzed. Results: Seventy-three patients with an average gestational age of 33.0 ± 2.5 weeks were studied. Meconium was cultured in 46 patients and Lactobacillus was not detected. Probiotic supplementation began on 3.4 ± 6.8 days, and after 14 days of supplementation, Lactobacillus was cultured in an average of 3.01 × 108 CFU in the stool of 37.0% (27/73) of the patients. There was a tendency towards an increased incidence of sepsis in the Lactobacillus– group (p = 0.082). In the Lactobacillus+ group, a striking increase in feeding tolerance was detected. Conclusion: In preterm infants, with the administration of probiotics, 37% of the preterm infants had Lactobacillus colonized in the gastrointestinal tract and improved feeding tolerance. A double-blind study is in progress for further investigation into the effect on other systemic diseases in premature infants.
A Comparison of the Effect of Vitamin A on Cytokine Secretion by Mononuclear Cells of Preterm Newborns and Adults
Authors: Bessler H. , Wyshelesky G. , Osovsky M. , Prober V. , Sirota L.
Published: December 2006

Background: For a long time vitamin A has been known to be essential for immune defense of the organism and protection against infections. Vitamin A deficiency in children is associated with morbidity and mortality from infectious diseases which could be prevented and even alleviated by vitamin A supplementation. Moreover, this vitamin is involved in the modulation of immunological and inflammatory responses by regulation of cytokine production. The aim of the study was to compare the in vitro effect of vitamin A on the production of pro-inflammatory (IL-1β and IL-6) and anti-inflammatory (IL-1 receptor antagonist (ra) and IL-10) cytokines, as well as IL-2 and IFNγ by cord blood mononuclear cells (CBMC) of preterm newborns to that of peripheral blood mononuclear cells (PBMC) from adults. Methods: Mononuclear cells (MC) from individuals of the two age groups were incubated with vitamin A (retinyl palmitate) at various concentrations in the presence of phytohemagglutinin for IL-2 and IFNγ production or LPS for IL-1β, IL-1ra, IL-6 and IL-10 secretion. The level of the cytokines in the supernatants was tested by ELISA. Results: Vitamin A exerted an in vitro inhibitory effect on the production of the anti-inflammatory cytokine IL-1ra by MC of preterm newborns and adults, but did not affect the secretion of the pro-inflammatory cytokines IL-1β, IL-6 and IFNγ. Vitamin A caused inhibition of IL-10 secretion by cells from adults, but it did not significantly affect this function in cells from newborns except when high unphysiological doses were applied. In addition vitamin A stimulated the secretion of IL-2 by cells isolated from adults but had no effect on those derived from premature neonates. Conclusions: The results indicate that vitamin A may affect the immune function of premature infants via inhibition of IL-1ra secretion. It is suggested that the beneficial effect of vitamin A on the clinical course of bronchopulmonary dysplasia (BPD) may be due to the reduced production of anti-inflammatory cytokines by neonatal CBMC. This may indicate the importance of the pro-inflammatory cytokines in the management of severe lung diseases and BPD.
Comparison of Human Herpes Virus 8 Related Primary Effusion Lymphoma with Human Herpes Virus 8 Unrelated Primary Effusion Lymphoma-Like Lymphoma on the Basis of HIV: Report of 2 Cases and Review of 212 Cases in the Literature
Authors: Kobayashi Yutaka , Kamitsuji Yuri , Kuroda Junya , Tsunoda Sei , Uoshima Nobuhiko , Kimura Shinya , Wada Katsuya , Matsumoto Yosuke , Nomura Kenichi , Horiike Shigeo , Shimazaki Chihiro , Yoshikawa Toshikazu , Taniwaki Masafumi
Published: December 2006

Background: Primary lymphomatous effusion is a rare lymphoma that arises in the body cavity and has a peculiar proliferative form, lacking a tumor. This primary lymphomatous effusion includes human herpes virus 8 (HHV8)-related primary effusion lymphoma (PEL) and HHV8-unrelated PEL-like lymphoma. We attempted to clarify the nature of the primary lymphomatous effusion. Methods: Using ‘PEL’ and ‘body cavity-based lymphoma’ (BCBL) as key words, reports written in English were collected from PubMed. Primary lymphomatous effusion was defined as BCBL with primary effusion and without tumor at onset. Adding our 2 PEL-like lymphoma cases, each case was studied as to the patients’ and lymphomas’ characteristics, therapy and survival time. Moreover, each item was compared among four groups according to the presence of HHV8 and HIV. Results: In 214 cases investigated, there was no difference in proliferation, but an apparent difference in age, gender, phenotype, effectiveness and prognosis among the four groups. Conclusions: Both PEL and PEL-like lymphoma are thought to be characterized by a peculiar proliferation, regardless of the presence of HHV8. Dividing PEL or PEL-like lymphoma into two subgroups on the basis of HIV presentation might also be appropriate.
Epigallocatechin-3-Gallate Inhibits Secretion of TNF-α, IL-6 and IL-8 through the Attenuation of ERK and NF-κB in HMC-1 Cells
Authors: Shin Hye-Young , Kim Sang-Hyun , Jeong Hyun-Ja , Kim Sang-Yong , Shin Tae-Yong , Um Jae-Young , Hong Seung-Heon , Kim Hyung-Min
Published: December 2006

Background: Epigallocatechin-3-gallate (EGCG) is a major form of tea catechin and has a variety of biological activities. In the present study, we investigated the effect of EGCG on the secretion of TNF-α, IL-6 and IL-8, as well as its possible mechanism of action by using the human mast cell line (HMC-1). Methods: EGCG was treated before the activation of HMC-1 cells with phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore (A23187). To investigate the effect of EGCG on PMA+A23187-stimulated HMC-1 cells, ELISA, Western blot analysis, electrophorectic mobility shift assay and luciferase assay were used in this study. Results: EGCG (100 µM) inhibited PMA+A23187-induced TNF-α, IL-6 and IL-8 expression and production. EGCG inhibited the intracellular Ca2+ level. EGCG attenuated PMA+A23187-induced NF-ĸB and extracellular signal-regulated kinase (ERK1/2) activation, but not that of c-Jun N-terminal kinase or p38 mitogen-activated protein kinase. Conclusion: EGCG inhibited the production of TNF-α, IL-6 and IL-8 through the inhibition of the intracellular Ca2+ level, and of ERK1/2 and NF-ĸB activation. These results indicate that EGCG may be helpful in regulating mast-cell-mediated allergic inflammatory response.
An Inverse Correlation between Interleukin-6 and Select Gene Promoter Methylation in Patients with Gastric Cancer
Authors: Tang Li Ping , Cho Chi Hin , Hui Wai Mo , Huang Camy , Chu Kent Man , Xia Harry H.X. , Lam Shiu Kum , Rashid Asif , Wong Benjamin C.Y. , Chan Annie On On
Published: December 2006

Background: Both serum IL-6 levels and CpG island methylation have been shown to have prognostic significance in gastric cancer, it was suggested that an important link existed between IL-6 and methylation of cancers. Aim: To investigate the prognostic value of IL-6 serum level and the association between serum IL-6 levels and CpG island methylation at p16, DAPK, MGMT and E-cadherin in patients with gastric cancer. Patients and Methods: Methylation status was assessed by MSP in 75 surgical specimens of gastric adenocarcinoma. IL-6 serum levels were measured by chemiluminescent enzyme immunoassay (CLEIA). Results: Methylation of p16, DAPK, MGMT, and E-cadherin were present in 53, 48, 32, and 59% of patients. Patients with tumors methylated at p16 and DAPK had lower serum levels of IL-6 compared to unmethylated tumors (1.8 vs. 4.8 pg/ml, p = 0.01 for p16; 1.5 vs. 6.2 pg/ml, p = 0.0001 for DAPK). But there was no difference with MGMT and E-cadherin methylation status. Serum IL-6 levels were also associated with TNM stage (p = 0.001), depth of tumor invasion (p = 0.002), lymphatic invasion (p = 0.01), vascular invasion (p = 0.008), metastasis (p = 0.002) and signet cell histology (p = 0.001). Conclusion: IL-6 is of prognostic value for patients of gastric cancer. Low serum IL-6 levels were associated with p16 or DAPK gene methylation in patients with gastric cancer.
Vasopeptidase Inhibition Normalizes Blood Pressure and Restores Endothelial Function in Renovascular Hypertension
Authors: Quaschning Thomas , Hocher Berthold , Rühl Sabine , Kraemer-Guth Annette , Tilgner Johannes , Wanner Christoph , Galle Jan
Published: December 2006

Background/Aims: Vasopeptidase inhibitors by definition inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), therefore they may exceed the effect of ACE inhibitors in the treatment of hypertension. The present study investigated the effect of the vasopeptidase inhibitor AVE7688 in comparison to the ACE inhibitor ramipril on systolic blood pressure (SBP) and endothelial function in renovascular hypertension. Methods: Wistar-Kyoto rats with renovascular hypertension (two-kidney one-clamp-model) were randomized 2 weeks after unilateral clamping of the right renal artery for 3 weeks’ oral treatment with either AVE7688 (30 mg/kg/day), ramipril (1 mg/kg/day) or placebo. SBP was measured by the tail-cuff method and endothelium-dependent and -independent vascular function was assessed in isolated preconstricted (norepinephrine 10–7 mol/l) aortic rings as relaxation to acetylcholine (10–10–10–4 mol/l) and sodium nitroprusside (10–10–10–4 mol/l), respectively. Results: Two weeks after clamping, SBP was significantly elevated (196 ± 16 vs. 145 ± 8 mm Hg for sham-operated rats; p < 0.01) and further increased in placebo-treated animals to 208 ± 19 mm Hg. Treatment with AVE7688 and ramipril had a similar blood pressure-lowering effect (119 ± 8 and 124 ± 10 mm Hg, respectively; p < 0.01 vs. placebo). Maximum endothelium-dependent relaxation was reduced in hypertensive rats (72 ± 6 vs. 99 ± 7% in control rats; p < 0.05). Endothelium-dependent relaxation was restored by AVE7688 (101 ± 6%) and ramipril (94 ± 8%), respectively, whereas endothelium-independent relaxation was comparable in all groups. Conclusion: In renovascular hypertension the vasopeptidase inhibitor AVE7688 exhibited similar blood pressure-lowering and endothelial protective properties as compared to the ACE inhibitor ramipril. Therefore, in high renin models of hypertension, vasopeptidase inhibition may be considered an alternative treatment option to ACE inhibition.
Distinct Effects of Z-335, a New Thromboxane A2 Receptor Antagonist, on Rabbit Platelets and Aortic Smooth Muscle
Authors: Yoshida Makoto , Sato Yukari , Shimura Tokuro , Ohkubo Satoko , Honma Shigeyoshi , Tanaka Takao , Kurimoto Tadashi , Nakahata Norimichi
Published: December 2006

The effect of a novel thromboxane A2 receptor (TP) antagonist, (±)-sodium[2-(4-chlorophenylsulfonylaminomethyl)- indan-5-yl]acetate monohydrate (Z-335), on the U46619-induced responses was compared between rabbit platelets and aorta. Z-335 inhibited platelet shape change induced by U46619 with higher efficacy than SQ29548, a common TP antagonist. The U46619-induced platelet aggregation was inhibited by Z-335 in a noncompetitive manner, while it was competitively inhibited by SQ29548. Z-335 inhibited U46619-induced vasoconstriction of rabbit aorta with higher efficacy than SQ29548. The pA2 value of Z-335 in aortic vasoconstriction was significantly higher than in platelet shape change. The competitive binding study showed the higher pKi value of Z-335 against [3H]-SQ29548 binding in rabbit aortic smooth muscle cells than in platelets. These data suggest that Z-335 has useful characteristics of TP antagonism.
Ischemia-Modified Albumin in Acute Stroke
Authors: Abboud Halim , Labreuche Julien , Meseguer Elena , Lavallee Philippa C. , Simon Olivier , Olivot Jean-Marc , Mazighi Mikael , Dehoux Monique , Benessiano Joelle , Steg Philippe Gabriel , Amarenco Pierre
Published: December 2006

Background: Ischemia-modified albumin (IMA)is a new biological marker of ischemia. Previous studies have found increased serum IMA levels after myocardial ischemia, but no study has investigated the possibility that stroke modifies IMA blood levels. Materials and Methods: We studied 118 consecutive patients presenting within 3 h of the onset of an acute neurological deficit [84 brain infarctions (BI), 18 brain hemorrhages (ICH) and 16 transient ischemic attacks lasting less than 1 h or epileptic seizures]. Serum samples were obtained for all patients at initial presentation and repeated only in patients with stroke at 6, 12 and 24 h. IMA was measured by the albumin-cobalt-binding test (Ischemia Technologies, Denver, Colo., USA). Results: The initial median IMA (bootstrap 95% confidence interval, CI) was 83 U/ml (79–86) and 86 U/ml (75–90) in patients with BI and ICH, respectively (p = 0.76), and was 73 U/ml (58–79) in others (p = 0.003 compared with BI, and p = 0.017 with ICH). Baseline IMA levels correlated with the National Institutes of Health Stroke Scale [Spearman correlation coefficient: 0.34 (p = 0.002) in BI, 0.61 (p = 0.008) in ICH]. During the first 24 h, IMA levels increased in BI patients (median, 9.1%; bootstrap 95% CI, 5.2–11.5), whereas no change was observed in ICH patients (median, 1.2%; bootstrap 95% CI, –7.8 to 6.8). Conclusions: IMA blood levels may be a biomarker for early identification of acute stroke. Further studies are required to investigate the role of IMA in the early detection of acute stroke.
Ccr5 But Not Ccr1 Deficiency Reduces Development of Diet-Induced Atherosclerosis in Mice
Authors: Braunersreuther Vincent , Zernecke Alma , Arnaud Claire , Liehn Elisa A. , Steffens Sabine , Shagdarsuren Erdenechimeg , Bidzhekov Kiril , Burger Fabienne , Pelli Graziano , Luckow Bruno , Mach François , Weber Christian
Published: December 2006

Objective—Chemokines and their receptors are crucially involved in the development of atherosclerotic lesions by directing monocyte and T cell recruitment. The CC-chemokine receptors 1 (CCR1) and 5 (CCR5) expressed on these cells bind chemokines implicated in atherosclerosis, namely CCL5/RANTES. Although general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 have not been unequivocally determined.

Methods and Results—We provide two independent lines of investigation to dissect the effects of Ccr1 and Ccr5 deletion in apolipoprotein E–deficient (ApoE−/−) mice in a collaboration between Aachen/Germany and Geneva/Switzerland. Different strains of ApoE−/−Ccr5−/−mice, ApoE−/−Ccr1−/−mice or respective littermates, were fed a high-fat diet for 10 to 12 weeks. Plaque areas were quantified in the aortic roots and thoracoabdominal aortas. Concordantly, both laboratories found that lesion formation was reduced in ApoE−/−Ccr5−/−mice. Plaque quality and immune cells were assessed by immunohistochemistry or mRNA analysis. Whereas lesional macrophage content, aortic CD4, and Th1-related Tim3 expression were reduced, smooth muscle cell (SMC) content and expression of interleukin-10 in plaques, lesional SMCs, and splenocytes were elevated. Protection against lesion formation by Ccr5 deficiency was sustained over 22 weeks of high-fat diet or over 26 weeks of chow diet. Conversely, plaque area, T cell, and interferon-γ content were increased in ApoE−/−Ccr1−/−mice.

Conclusion—Genetic deletion of Ccr5 but not Ccr1 in ApoE−/−mice protects from diet-induced atherosclerosis, associated with a more stable plaque phenotype, reduced mononuclear cell infiltration, Th1-type immune responses, and increased interleukin-10 expression. This corroborates CCR5 as a promising therapeutic target.
Increased Body Iron Stores Are Associated With Poor Outcome After Thrombolytic Treatment in Acute Stroke
Authors: Millan Mónica , Sobrino Tomás , Castellanos Mar , Nombela Florentino , Arenillas Juan F. , Riva Elena , Cristobo Iván , García María M. , Vivancos José , Serena Joaquín , Moro María A. , Castillo José , Dávalos Antonio
Published: December 2006

Background and Purpose—

Iron overload has been associated with greater oxidative stress and brain injury in experimental cerebral ischemia and reperfusion. This study investigates whether high serum ferritin levels, as an index of increased cellular iron stores, are associated with poor outcome, hemorrhagic transformation, and brain edema after treatment with tissue plasminogen activator in patients with acute ischemic stroke.

Methods—

A total of 134 consecutive patients treated with intravenous tissue plasminogen activator were prospectively studied in four centers. Serum ferritin levels were determined at baseline, 24 and 72 hours after treatment. Cranial computed tomography was performed on admission and at 24 to 36 hours after tissue plasminogen activator infusion. Stroke severity and outcome were evaluated by using the National Institute of Health Stroke Scale and the modified Rankin Scale.

Results—

Computed tomography showed hemorrhagic transformation in 27 patients (hemorrhagic infarction in 15 and parenchymal hematoma in 12; symptomatic in four) and brain swelling with midline shift in 15. Poor outcome (modified Rankin Scale >2) at 90 days was observed in 54.5% of patients. Ferritin levels at baseline were higher in patients with poor outcome at 90 days (median [quartiles], 165 [98,307] versus 17 [12,37] ng/mL;
P
<0.001) and in those who developed parenchymal hematoma (
P
=0.006), symptomatic hemorrhagic transformation (
P
=0.008), and severe brain edema (
P
<0.001). Serum ferritin levels higher than 79 ng/mL before tissue plasminogen activator treatment were independently associated with poor outcome (OR, 117 [95% CI, 25 to 557]).

Conclusions—

Increased body iron stores are associated with poor outcome, symptomatic hemorrhagic transformation, and severe edema in patients treated with tissue plasminogen activator after ischemic stroke. These findings suggest that iron overload may offset the beneficial effect of thrombolytic therapies.