bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Maternal Blood Flow on the Placental Transfer of Three Opioids – FentanyI, Alfentanil, Sufentanil
Authors: Giroux M. , Teixera M.G. , Dumas J.C. , Desprats R. , Grandjean H. , Houin G.
Published: October 2009

The placental transfer of three opioids used in peridural analgesia, fentanyl, alfentanil and sufentanil, and two reference substances, antipyrine and *H2O, was determined ex vivo in the human placental cotyledon system. (1) In the first set of experiments, the infusion rates were constant and fixed at physiological flow rates. Under these conditions, the magnitude of the materno-fetal transfer was in the following order: *H2O = antipyrine = fentanyl > alfentanil > sufentanil. No particular influence of molecular weight, lipophilia, pKa or the degree of ionization could be discerned. (2) In the second set of experiments, the influence of different flow rates, reflecting various pathophysiological conditions, was examined. There was a linear relationship between the maternal flow and the materno-fetal transfer of the three opioids. On the other hand, for antipyrine and tritiated water, the relationship was logarithmic, a difference attributed to the marked lipophilia of the opioids. (3) At high maternal flow rates, saturation was observed for all five substances due to the short duration of contact with the membrane. There were logarithmic relationships between the maternal flow and the materno-fetal transfer. (4) These findings emphasize the importance of the lipophilic and hydrophilic characteristics of drugs on placental transfer, especially in the event of fluctuations in maternal flow.
In vitro Effect of Furosemide on the Chemiluminescence of Polymorphonuclear Neutrophils in Preterm Infants
Authors: Lakhani Mumtaz , Usmani Shaista S. , Wapnir Raul A. , Harper Rita G.
Published: October 2009

We tested the hypothesis that the phagocytic activity of polymorphonuclear neutrophils (PMNs) of neonates is more sensitive to furosemide (FU) in vitro than that of adults. Phagocytosis was monitored by chemiluminescence of PMNs in cord blood of full-term (n = 10) and preterm (n = 8) neonates in the presence of 0, 6, 9, and 12 μg/ml of FU. Venous blood from adults (n = 10) was used for comparison. Random motility and chemotaxis were also determined in the three groups. The peak chemiluminescence of PMNs in preterm neonates was significantly decreased at a FU concentration of either 6, 9, or 12 μg/ml when compared to full-term infants. In contrast, no difference was observed between full-term infants and adults. Random motility and chemotaxis were comparable in all groups, regardless of the FU concentration. The results of this study suggest that preterm infants may be more sensitive to FU, as indicated by the adverse effect of this drug on chemiluminescence activity of their PMNs, in vitro.
Longitudinal Study of Plasma Cortisol and 17-Hydroxyprogesterone in Very-Low-Birth-Weight Infants during the First 16 Weeks of Life
Authors: Arnold J. , Leslie G. , Bowen J. , Watters S. , Kreutzmann D. , Silink M.
Published: October 2009

There are few published data on plasma cortisol and 17-hydroxyprogesterone (17-OHP) in very-low-birth-weight (VLBW) infants beyond the 1st week of life. We therefore measured plasma cortisol and 17-OHP longitudinally in 26 infants (median birth weight 930 g, median gestational age 28 weeks) from 1 to 16 postnatal weeks to document normative values. We also examined the effect of clinical state on plasma cortisol and 17-OHP levels. Median plasma cortisol decreased with postnatal age from 1 to 8 weeks (110 vs. 60 nmol/l; p = 0.0007) and with postconceptional age from 25 to 36 weeks (104 vs. 47 nmol/l; p = 0.002). Median plasma 17-OHP decreased with postnatal age from 1 to 16 weeks (17.0 vs. 7.1 nmol/l; p < 0.0005) and also with postconceptional age from 25 to 42 weeks (21.1 vs. 7.1 nmol/l; p < 0.0005). Plasma cortisol was not influenced by the clinical state. Median plasma 17-OHP was significantly higher for ‘unwell’ versus ‘well’ infants at 5–8 weeks postnatal age (23.0 vs. 12.5 nmol/l; p = 0.012) but not at other postnatal age intervals. These data provide information on adrenocortical function in VLBW infants during the first 4 months of life.
Effect of Maternal Dietary n-3 Fatty Acids on the Accretion of Long-Chain Polyunsaturated Fatty Acids in the Tissues of Developing Chick Embryo
Authors: Cherian G. , Gopalakrishnan N. , Akiba Y. , Sim J.S.
Published: October 2009

The effect of maternal diets on the accretion of n–3 and n–6 polyunsaturated fatty acids in the brain and liver tissue of developing chick embryos was investigated. Hens were fed diets containing high (HLNA) or low levels of 18:3n–3 (LLNA). The HLNA diet increased (p < 0.05) the content of the 18:3n–3, 20:5n–3 and 22:6n–3 in the yolk lipids with a concomitant reduction (p < 0.005) in 20:4n–6. Diet and time significantly (p < 0.05) affected the transfer of 22:6n–3 (docosahexaenoic acid, DHA) and 20:4n–6 acid from the HLNA and LLNA yolk lipid. In the brain of HLNA chick embryos, a diet- and time-associated increase (p < 0.05) in the phospholipid content was observed. In the brain of HLNA and LLNA embryos, DHA levels increased (p < 0.05) from day 15 to the day of hatching, with a concomitant reduction (p < 0.05) in the liver. The accretion of arachidonic acid plateaued on day 15 in the brain of HLNA and LLNA embryos.
Measuring the Accentuation of the Brain Damage That Arises from Perinatal Cerebral Hypoxia-Ischemia
Authors: Vannucci Robert C. , Rossini Anthony , Towfighi Javad , Vannucci Susan J.
Published: October 2009

To ascertain the manner in which the severity of perinatal brain damage occurs as a result of hypoxia-ischemia, 7-day postnatal rats were subjected to unilateral common carotid artery ligation followed thereafter by exposure to 8% oxygen for up to 2.5 h. Following the hypoxic-ischemic exposure, the rat pups were reared with their dams until 30 days of postnatal age, at which time their brains underwent pathologic analysis. The severity of brain damage at each of four specific intervals of hypoxia-ischemia was determined and statistically compared by linear polynomial and nonparametric regression procedures. The data indicated that the accentuation of brain damage with increasing duration of hypoxia-ischemia was linear rather than curvilinear.
Effect of Post-Hypoxic-lschemic Inhibition of Nitric Oxide Synthesis on Cerebral Blood Flow, Metabolism and Electrocortical Brain Activity in Newborn Lambs
Authors: Dorrepaal Caroline A. , Shadid Majidah , Steendijk Paul , Van der Velde Enno T. , Van de Bor Margot , Baan Jan , Van Bel Frank
Published: October 2009

Since an excessive production of nitric oxide upon reperfusion/reoxygenation may play an important role in post-hypoxic-ischemic (HI) brain injury, we investigated whether immediate post-HI blockade of nitric oxide synthesis by N-ω-nitro-L-arginine (NLA) may reduce this injury. In 18 newborn lambs, subjected to severe HI, changes from pre-HI values were measured for carotid blood flow (Qcar [ml/min]) as a measure of changes in brain blood flow, (relative) cerebral metabolic rate of oxygen (CMRO2), and electrocortical brain activity (ECBA) at 15, 60, 120 and 180 min after HI. Upon completion of HI, at the onset of reperfusion and reoxygenation, 6 lambs received a placebo (control group), 6 low-dose NLA (10 mg/kg i.v., NLA-10 group), and 6 high-dose NLA (40 mg/kg i.v., NLA-40 group). Histological damage to cerebellar Purkinje cells was assessed after termination of the experiment. Only the control group showed a distinct initial post-HI cerebral hyperperfusion. From 60 min after HI onward Qcar was decreased to about 75% of pre-HI Qcar in all 3 groups, although none of these changes in Qcar reached statistical significance. Despite the decreased Qcar in all 3 groups, only the control group showed a significantly decreased CMRO2 ECBA and its bandwidth decreased in all groups, but only recovered in the NLA-10 group 180 min after HI. The brain to body mass ratio (%) and percentage necrotic Purkinje cells were, respectively: 15.3 ± 0.8 and 56 ± 10 (control group); 12.5 ± 1.2 and 36 ± 9(NLA-10 group), and 11.3 ± 1.0 (p < 0.05 vs. the control group) and 35 ± 14 (NLA-40 group). Since post-HI reperfusion injury of the brain has been characterized by a decreased CMRO2 and electrical brain activity, we conclude that preservation of CMRO2 in both NLA groups, but a recovery of ECBA and its bandwidth only in the NLA-10 group, suggests that NLA, and especially low-dose NLA, may reduce post-HI brain injury.
Nitric Oxide Inhibition after Hypoxia-Ischemia Elevates Pulmonary Arterial Pressure and Increases Oxygen Need
Authors: de Beaufort Arnout Jan , Lopes Cardozo Robbert H. , Dorrepaal Caroline A. , Steendijk Paul , Van Der Velde Enno T. , Van Bel Frank
Published: October 2009

Inhibition of nitric oxide (NO) production may reduce post-hypoxic-ischemic (HI) neonatal brain damage, but may also induce pulmonary hypertension by inhibiting endogenous NO production in the pulmonary vascular bed. The aim of this study was to evaluate the effect of nitric oxide inhibition on pulmonary artery pressure and oxygen need after hypoxic ischemia. Severe HI was produced in 18 newborn lambs. After completion of HI the lambs were divided into three groups of 6 animals receiving either placebo (Cont), low dose Nω-nitro-L-arginine (10mg/kg i.v., NLA-10) or high dose (40mg/kg i.v., NLA-40) to block NO production. Pulmonary artery pressure (Pap), aortic pressure, blood gases, inspiratory oxygen concentration and ventilator settings were recorded before and 15, 60, 120 and 180 min after HI. Mean Pap rose initially significantly as compared to baseline in all groups at 15 min post-HI, decreased to normal in Cont but not in treated animals; 180 min post-HI mean Pap was significantly higher in both treated groups as compared to control (NLA-10: 32 mm Hg, NLA-40: 34 mm Hg, Cont: 25 mm Hg, p < 0.05 for NLA-10 and NLA-40 vs. Cont). Moreover, in both NLA-treated groups the oxygenation index was significantly elevated 120 and 180 min post-HI as compared to those of the Cont group. NO synthase inhibition after HI causes a prolonged increase in pulmonary artery pressure leading to a higher oxygen need.
Effects of Hyperglycemia on Gasping and Autoresuscitation in Newborn Rats
Authors: Yuan Shi-Zeng , Blennow Mats , Runold Michael , Lagercrantz Hugo
Published: October 2009

The aim of this study was to test the effects of glucose on the gasping ability and survival in a rat pup model during acute anoxia. Newborn rat pups of both 1 and 8 days of age were given glucose (30 and 60 mg/animal) or saline intraperitoneally and subsequently subjected to anoxia (100% N2). Glucose supplement induced hyperglycemia. Respiration was recorded by barometric plethysmography. The rat pups responded to acute anoxia with a robust sequence of respiratory pattern: hyperpnea, primary apnea, hypoxic gasping and secondary apnea. During anoxia the 1-day-old rats gasped much longer than the 8-day-old rats (23.4 ± 1.0 vs. 6.1 ± 0.5 min, p < 0.001). No difference was found in gasping duration between the saline control and the glucose-supplemented 1-day-old rat pups. The 8-day-old supplemented rats gasped much longer (9.3 ± 0.5 min) than the control rats (6.1 ± 0.5 min, p < 0.01). The animals autoresuscitated when they received oxygen (100%) during the gasping period. When oxygen was given after the gasping period, the survival rate was 33.3% in control and 0% in supplemented 1-day-old rats, and 100% in control and 50% in glucose-supplemented 8-day-old rats (p < 0.02). Further controlled experiments for a fixed period of anoxia to 13.5 min resulted in survival rates of 50.0% for controls and 28.6% for supplemented animals, respectively. The overall survival rate was then 85.2% in control and 52.9% in supplemented 8-day-old rats (p < 0.05). Lactate concentration in blood rapidly increased in the first 6 min of anoxia and thereafter gradually increased to 22.1 mmol/l around the last gasp in the 1-day-old rats. Hyperglycemia did not cause further accumulation of lactate despite a transient elevation over the control rats at 6 min of anoxia. In the 8-day-old supplemented animals the lactate level was only modestly increased, probably due to the prolonged gasping period. In conclusion, we found that gasping performance was well preserved in the 8-day-old glucose-supplemented rats, whereas the autoresuscitation mechanism after the last gasp might be altered due to hyperglycemia. In addition, the accumulation of lactate in the blood did not affect the gasping performance and the mechanisms of autoresuscitation.
The Pharmacokinetics of Bumetanide in the Newborn Infant
Authors: Lopez-Samblas Ana M. , Adams Jose A. , Goldberg Ronald N. , Modi Marlene W.
Published: October 2009

This study characterizes the pharmacokinetics of bumetanide after an intravenous dose of 0.05 or 0.10 mg/kgto 14neonates (weight range 820-4,000 g; gestational age 26-40 weeks) during the first week of life. Blood samples and urine were collected for up to 12 h after dosing. Estimated serum clearance was 0.2–1.0 ml/min·kg (range), volume of distribution was 0.22 1/kg (range 0.11–0.32 1/kg), and the harmonic mean half-life was 6–7 h (range of 4–19 h). Nonrenal clearance accounted for 58–97% of the serum clearance with the presence of certain oxidative metabolites of bumetanide in the urine. These findings suggest higher dosing requirements and prolonged intervals as compared to adults. Utilizing these pharmacokinetic data, pharmacodynamic and ototoxicity studies should be conducted to establish a safe and effective neonatal dose.
Hematological Features of Fetal Triploidy: A Report of 11 Cases
Authors: Hohlfeld Patrick , Forestier Francois , Vial Yvan , Tissot Jean-Daniel
Published: October 2009

Using fetal blood sampling, the diagnosis of triploidy can be strongly suspected on the basis of the peculiar hematological picture. Triploid fetuses present with anemia, marked anisopoikilocytosis, and grossly increased mean corpuscular volume, associated with thrombocytopenia and significant platelet anisocytosis. These findings are of considerable immediate diagnostic value. They allow physicians to immediately counsel parents about the prognosis of the fetus. In case of fetal or neonatal distress, this information could orientate decisions about obstetrical and pediatric management while waiting for the definitive diagnosis.
Chronic Intermittent in utero Exposure to Morphine: Effects on Respiratory Control in the Neonatal Guinea Pig
Authors: Hunter Margaret A. , Vangelisti Garrett R. , Olsen George D.
Published: October 2009

This study was done to determine if chronic intermittent in utero exposure to morphine (MOR) during the last half of gestation results in hypoventilation and decreased ventilatory sensitivity to CO2 in the neonate. Pregnant guinea pigs were randomly assigned to once-daily treatment with saline and 1.5, 5.0, or 15.0mg/kg MOR. Neonates were studied for 3 weeks. Prenatal exposure to 5.0 and 15.0 mg/kg MOR significantly increased neonatal minute ventilation and central inspiratory drive on day 7 while breathing room air or 5% CO2. The increase in minute ventilation was part of a withdrawal syndrome that included increased locomotor activity, but was not due to an increase in metabolic rate or sensitivity to CO2. We conclude that neonatal guinea pigs exposed once daily to MOR during the last half of gestation hyperventilate during the 1 st week after birth. These changes are neither permanent nor followed by hypoventilation or depressed sensitivity to CO2.
Combined Effects of Fetal Beta Agonist Stimulation and Glucocorticoids on Lung Function of Preterm Lambs
Authors: Jobe Alan H. , Ikegami Machiko , Padbury James , Polk Daniel H. , Korirnilli Annapurna , Gonzales Linda W. , Ballard Philip L.
Published: October 2009

We asked whether a single-dose fetal treatment strategy using betamethasone plus either a long-acting beta2 agonist (formoterol) or betamethasone plus agents that elevate intracellular cyclic adenosine monophosphate (isobutyl methylxanthine and dibutyryl-cyclic adenosine monophosphate) would augment the effects of prenatal betamethasone on postnatal lung function. Preterm lambs were treated with 0.5 mg/kg betamethasone or betamethasone plus the other agents and delivered 48 h after treatment. The postnatal lung function as assessed by compliance, ventilatory efficiency, and lung volumes at 40 min of age was improved by prenatal betamethasone and improved further by combination treatment, although the augmented responses were not significantly greater than with betamethasone alone. Fatty acid synthase protein and enzymatic activity were not increased by betamethasone or combined treatments, in contrast to responses reported for other animal models. There were no effects of glucocorticoids or the combined treatments on surfactant. Stimulation of the beta2 agonist system did not augment postnatal lung function significantly above that noted for betamethasone alone with the agents, doses, and duration of exposures tested.
Estrogen-Regulated Uterine Vascularization Modulates the Guinea Pig Intrauterine Environment
Authors: Garris David R.
Published: October 2009

The effects of experimentally-induced, uterine vascular restriction on uterine blood flow (UBF) and uterine blood volume (UBV) capacity, as well as the dependent intrauterine oxygen tension (IUpO2) measurements used as an indication of luminal nutrient availability, were examined using ovariectomized, estrogen (E)-treated guinea pigs. Following 3 days of E treatment, both UBF and UBV measurements were found to be elevated and associated with a causally-related increase in intraluminal uterine oxygen availability levels. Following the acute clamping of the uterine arteries, both UBF and UBV levels decreased dramatically and induced a rapid fall in associated intrauterine luminal oxygen tension measurements. As a result of chronic (i.e., 6 h) restriction of segmental blood flow to the uterus by vascular cauterization, both UBV and IUpO2 levels were suppressed as compared with sham-operated control levels, whereas UBF rates were not significantly altered. The results of the present studies are the first quantitative demonstration that either acute or chronic reductions in uterine vascular capacity or competency can induce rapid and dramatic changes in the intrauterine nutritional environment recognized to be essential for the initiation, support and maintenance of nidation and subsequent fetal-placental development.
Assessment of Endogenous Nitric Oxide Formation in Newborns: Measurement of Urinary Nitrite and Nitrate Concentrations
Authors: Tsukahara Hirokazu , Takeuchi Motohiro , Hata Ikue , Hiraoka Masahiro , Kotsuji Fumikazu , Sudo Masakatsu , Mayumi Mitsufumi
Published: October 2009

We measured the urinary nitrite and nitrate (NOx––) excretion, an index of endogenous nitric oxide formation, in term and preterm newborns on the 1st and 4th days of age. In the infants of both groups, the urinary NOx–– excretion significantly increased from the 1st to the 4th day. The urinary NOx–– excretion in preterm infants was significantly higher as compared with term babies on both days. Furthermore, the urinary NOx–– excretion was significantly elevated in preterm infants with respiratory distress syndrome as compared with those without cardiopulmonary complications on the 4th day. These changes of urinary NOx––; excretion in newborns strongly suggest the presence of an active physiological role for nitric oxide in the circulatory adaptation to extrauterine life.
Urinary Excretion of Endogenous Ouabain-Like Substance Is Reduced in NaCl Supplemented Premature Infants
Authors: Worgall S. , Rascher W. , Gyódi G. , Nyul Z. , Baranyai Z. , Sulyok E.
Published: October 2009

Ouabain or an isomer has been identified as endogenous ouabain-like substance (EOLS). The role of EOLS in the adaptation of premature infants to alterations of sodium balance was investigated by measuring urinary ouabain excretion serially in 9 low birth weight premature infants with (group S, mean birth weight 1,578 g, mean gestational age 30.4 weeks) and without (group NS, mean birth weight 1,537 g, mean gestational age 30.8 weeks) NaCl supplementation. The study was performed on the 7th day and weekly thereafter until the 5th week of life. NaCl supplementation was given in a dose of 3–5 and 1.5–2.5 mmol/kg/day at the postnatal ages of 8–21 and 22–35 days, respectively. Prior to NaCl supplementation, urinary ouabain excretion was similar in the two groups (146.2 ± 16.8 pg/kg/h in group S versus 180.0 ± 9.6 pg/kg/h in group NS) and remained at about the same level throughout the study when supplemental NaCl was provided. In infants of group NS, urinary ouabain excretion increased significantly by the 3rd week (p < 0.01) and no consistent change occurred later on. As a result, the differences in urinary ouabain excretion between the two groups proved to be significant during weeks 2–5 (p < 0.001). Essentially the same pattern of ouabain excretion was seen when it was expressed in terms of pg/mg creatinine. In infants receiving high sodium diet there was a significant positive correlation between urinary sodium and ouabain excretion. It is concluded that premature infants receiving low sodium intake have elevated EOLS excretion by the 3rd week of life. Although the relationship between ouabain and sodium excretion in supplemented premature infants suggests some physiological significance for sodium excretion, ouabain does not appear to be regulated by extracellular volume.
Urinary Excretion of Endogenous Ouabain-Like Substance in Furosemide-Treated Neonates: Its Relation to Renal Excretory Pattern and Endocrine Factors
Authors: Sulyok E. , Adamovits K. , Worgall S. , Rascher W.
Published: October 2009

The present study was undertaken to define the possible role of endogenous ouabain-like substance (EOLS) in controlling renal excretory pattern, in mediating the renal responses to furosemide and in inducing endocrine reactions in furosemide-treated neonates. Ten newborn infants with mean birthweight of 2,752 g and mean gestational age of 37.1 weeks were given furosemide in a dose of 1 mg/kg. Prior to and following furosemide therapy, urine was collected for a period of 12 h and analyzed for creatinine, osmolality, sodium and potassium, as well as for EOLS, arginine vasopressin (AVP), aldosterone and endothelin-1 (ET-1). In response to furosemide administration, urine flow rate and urinary osmolar, sodium and potassium excretion increased significantly, whereas creatinine excretion remained unchanged. Furthermore, following furosemide therapy, urinary excretion of EOLS (148.7 ± 70.8 vs. 200.1 ± 98.1 pg/kg/h) and AVP (19.5 ± 5.4 vs. 27.8 ± 7.8 pg/kg/h) tended to increase, whereas ET-1 (36.0 ± 5.6 vs. 61.4 ± 8.7fmol/kg/h, p < 0.01) and aldosterone (507 ± 120 vs. 751 ± 203 ng/kg/h, p < 0.05) increased significantly. Prior to furosemide, urinary EOLS excretion was found to correlate positively with diuresis (r = 0.80, p < 0.01), sodium (r = 0.91, p < 0.001), creatinine (r = 0.75, p < 0.001), osmolar (r = 0.96, p < 0.001), ET-1 (r = 0.90, p < 0.001) and AVP (r = 0.92, p < 0.001) excretion. After furosemide, urinary EOLS excretion significantly correlated only with diuresis (r = 0.69, p < 0.05), ET-1 (r = 0.77, p < 0.01) and AVP (r = 0.92, p < 0.001). Urinary EOLS proved to be independent of aldosterone excretion irrespective of furosemide administration. It is concluded that urinary EOLS excretion is closely related to neonatal renal excretory pattern and it may have a role in controlling diuresis and natriuresis. The renal response to furosemide appears to be independent of EOLS, although interdependent endocrine reactions can be induced by furosemide which may modulate the production rate and urinary excretion of EOLS.
Presence of a Bioactive and Immunoreactive Growth-Hormone-Releasing-Factor-Like Substance in Porcine Placenta
Authors: Farmer C. , Gaudreau P.
Published: October 2009

The present study was conducted to establish whether growth hormone (GH) releasing factor (GRF) is present in porcine placenta. Various concentrations of placental extracts from sows at 90 and 110 days of gestation were added to porcine anterior pituitary cells in culture. The extract-induced GH secretion was compared to that of GRF(1–29)NH2. Experiments were also performed in the presence of the GRF receptor antagonist Nα-acetyl(D-Arg2-Ala15) rat GRF(1–29)NH2 (10––7M). Significant effects on GH production were obtained with increasing concentrations of placental extracts (p < 0.001). This response was significantly diminished in the presence of the GRF receptor antagonist (p < 0.001). The effect of gestational age at the time of collection of the placenta was nonsignificant (p > 0.1). In addition, using a placental extract from 110 days of gestation, an immunoreactive GRF content of 52–63 ng/mg dry weight was detected. Altogether, the detection of an immunoreactive GRF-like substance in porcine placental extracts and the ability of these extracts to stimulate GH release in a concentration-dependent manner, likely by triggering a GRF-receptor-mediated mechanism, support the presence of GRF in this tissue.
Intra-Amniotic Interleukin-1α Treatment Alters Postnatal Adaptation in Premature Lambs
Authors: Emerson George A. , Bry Kristina , Hallman Mikko , Jobe Alan H. , Wada Norihisa , Ervin Gore , Ikegami Machiko
Published: October 2009

We measured the physiological and biochemical responses of preterm lambs to intra-amniotic injection of interleukin-1α (IL-1α). Singleton lamb fetuses at 126 days of gestation were randomized to receive 125 μg IL-1α or vehicle control via ultrasound-guided intra-amniotic injection. Each lamb was delivered 48 h later by cesarian section and ventilated for 120 min. Relative to controls, IL-1α-treated lambs had higher dynamic compliance, ventilatory efficiency indices, and saturated phosphatidylcholine levels (all p < 0.05). Umbilical cord plasma cortisol and catecholamine levels, white blood cells and differentials, cardiac output, regional blood flow, and kidney function did not differ between the groups. However, at 120 min after delivery, the cortisol levels for IL-1α-treated animal were higher than for controls. Single intra-amniotic IL-1α treatment increases surfactant pool size and improves dynamic compliance in the absence of an inflammatory response or differences in other indicators of fetal or newborn organ function.
Sonothrombolysis is effective with recombinant tissue-type plasminogen activator, but not with Abciximab
Authors: Ossadnik Stefan , Hütten Heiko , Seidel Günter , Eggers Jürgen
Published: October 2009

Transcranial “diagnostic” ultrasound (US) has been shown to accelerate thrombolysis related to recombinant tissue-type plasminogen activator (rt-PA). In this in vitro study, we evaluated the potential of US to increase clot dissolution mediated by Abciximab (Abc) compared to rt-PA. The effect of 1.8-MHz pulsed wave (PW) Doppler US on dissolution of whole venous blood clots (WBC) and platelet-rich clots (PRC) treated with Abc and rt-PA was investigated in an in vitro model. Clot dissolution was measured by weight loss. Abc-related WBC dissolution was enhanced by additional US, but the effect was not any more detectable when the US was attenuated by a human temporal bone (US-tb). In PRC there was no additional effect of US on the Abc-related clot lysis. Rt-PA-related clot dissolution was increased by US in WBC and PRC as well, however, US-tb was only effective in WBC. The effect of insonation on WBC dissolution treated with the combination of Abc plus rt-PA was lower compared with those treated with rt-PA. In this in vitro experiment, the additional effect of “diagnostic” US in combination with Abc was only present in WBC and less strong than with rt-PA. The results do not support the use of Abc for sonothrombolysis targeting both, fibrin-rich and platelet-rich clots. In contrast, US when combined with rt-PA increases dissolution in both, WBC and PRC as well.
Are glycoprotein inhibitors safe during percutaneous coronary intervention in patients on chronic warfarin treatment?
Authors: Lahtela Heli , Karjalainen Pasi , Niemelä Matti , Vikman Saila , Kervinen Kari , Ylitalo Antti , Puurunen Marja , Porela Pekka , Nyman Kai , Hinkka-Yli-Salomäki Susanna , Airaksinen K. E.
Published: October 2009

The aim of this study was to evaluate the safety of glycoprotein IIb/IIIa inhibitors (GPIs) during percutaneous coronary intervention (PCI) in patients on chronic warfarin therapy due to atrial fibrillation (AF).We analysed all consecutive AF patients (N = 377, mean age 70 years, male 71%) on warfarin therapy referred for PCI in seven centres. Major bleeding, access site complications and major adverse cardiovascular events were recorded during hospitalisation. A total of 111 patients (29%) received periprocedural GPIs with a wide inter-hospital variation in their use (range 3–68%).The use of GPIs increased with the severity of the disease presentation and 49% of patients with ST-elevation myocardial infarction received GPIs. Mean periprocedural international normalised ratio (INR) of patients who received GPIs was 1.89 (range 1.1–3.3). Major bleeding was more common in the patients treated with GPIs (9.0% vs. 1.5%, p = 0.001) than in those without GPIs, but there was no difference in major adverse cardiovascular events between the groups. In multivariable analysis, use of GPIs (odds ratio [OR]???????????5.1, 95% confidence interval [CI]???????????1.3–20.6, p = 0.02) and old age (OR 1.2, 95% CI 1.0–1.3, p = 0.02) remained as the only independent predictors of major bleeding. Also after adjusting for propensity score, GPIs remained as a significant predictor of major bleeding (OR 3.8, 95% CI 1.03–14.1, p = 0.045). In the GPI group, major bleeding was not predicted by INR level or warfarin pause. GPIs increase the risk of major bleeding events irrespective of periprocedural INR levels and should be used with caution in this fragile patient group.
Driving Rho GTPase activity in endothelial cells regulates barrier integrity
Authors: Beckers Cora , van Hinsbergh Victor , van Nieuw Amerongen Geerten
Published: October 2009

In the past decade understanding of the role of the Rho GTPases RhoA, Rac1 and Cdc42 has been developed from regulatory proteins that regulate specific actin cytoskeletal structures – stress fibers, lamellipodia and filopodia – to complex integrators of cytoskeletal structures that can exert multiple functions depending on the cellular context. Fundamental to these functions are three-dimensional complexes between the individual Rho GTPases, their specific activators (GEFs) and inhibitors (GDIs and GAPs), which greatly outnumber the Rho GTPases themselves, and additional regulatory proteins. By this complexity of regulation different vasoactive mediators can induce various cytoskeletal structures that enable the endothelial cell (EC) to respond adequately. In this review we have focused on this complexity and the consequences of Rho GTPase regulation for endothelial barrier function. The permeability inducers thrombin and VEGF are presented as examples of G-protein coupled receptor- and tyrosine kinase receptormediated Rho GTPase activation, respectively. These mediators induce complex but markedly different networks of activators, inhibitors and effectors of Rho GTPases, which alter the endothelial barrier function. An interesting feature in this regulation is that Rho GTPases often have both barrier-protecting and barrier-disturbing functions. While Rac1 enforces the endothelial junctions, it becomes part of a barrier-disturbing mechanism as activator of reactive oxygen species generating NADPH oxidase. Similarly RhoA is protective under basal conditions, but becomes involved in barrier dysfunction after activation of ECs by thrombin. The challenge and promise lies in unfolding this complex regulation, as this will provide leads for new therapeutic opportunities.
Role of HDL, ABCA1, and ABCG1 Transporters in Cholesterol Efflux and Immune Responses
Authors: Yvan-Charvet Laurent , Wang Nan , Tall Alan R.
Published: October 2009

Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in arteries, but the mechanisms linking cholesterol accumulation in macrophage foam cells to inflammation are poorly understood. Macrophage cholesterol efflux occurs at all stages of atherosclerosis and protects cells from free cholesterol and oxysterol-induced toxicity. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of macrophage cholesterol efflux to serum or HDL in macrophage foam cells, but other less efficient pathways such as passive efflux are also involved. Recent studies have shown that the sterol efflux activities of ABCA1 and ABCG1 modulate macrophage expression of inflammatory cytokines and chemokines as well as lymphocyte proliferative responses. In macrophages, transporter deficiency causes increased signaling via various Toll-like receptors including TLR4. These studies have shown that the traditional roles of HDL and ABC transporters in cholesterol efflux and reverse cholesterol transport are mechanistically linked to antiinflammatory and immunosuppressive functions of HDL. The underlying mechanisms may involve modulation of sterol levels and lipid organization in cell membranes.
Hemostasis, Inflammation, and Fatal and Nonfatal Coronary Heart Disease
Authors: Kucharska-Newton Anna M. , Couper David J. , Pankow James S. , Prineas Ronald J. , Rea Thomas D. , Sotoodehnia Nona , Chakravarti Aravinda , Folsom Aaron R. , Siscovick David S. , Rosamond Wayne D.
Published: October 2009

Objective—

This study examines the hypothesis that chronic inflammation is associated with a higher risk of cardiac death compared to the risk of nonfatal myocardial infarction.

Methods and Results—

Cardiac death and nonfatal MI events were identified in the ARIC cohort during follow-up from 1987 through 2001. Markers of inflammation and hemostasis were determined at baseline using standardized procedures. Cox proportional hazard regression and polytomous logistic regression were used to estimate associations. We observed a positive gradient in incidence of sudden cardiac death (SCD), nonsudden cardiac death (NSCD), and nonfatal MI in association with decreasing levels of albumin and increasing levels of white blood cell count and of markers of hemostasis (fibrinogen, von Willebrand factor, factor VIIIc). Associations for von Willebrand factor were stronger for fatal relative to nonfatal events (3rd versus 1st tertile hazard ratios: SCD 3.11 [95% CI 2.10, 4.59], NSCD 2.12 [95% CI 1.28, 3.49], nonfatal MI 1.42 [95% CI 1.19, 1.70]). For factor VIIIc those associations were strongest for sudden cardiac death: SCD 3.16 (95% CI 2.18, 4.58), NSCD 1.44 (95% CI 0.93, 2.24), nonfatal MI 1.54 (95% CI 1.29, 1.84). Gradients of association for fibrinogen and white blood cell count, examined over tertiles of distribution and per one SD increase, were similar for the 3 end points. All associations were independent of smoking status.

Conclusion—

von Willebrand factor and factor VIIIc are associated with an increased risk of cardiac death as compared to the risk of nonfatal MI.
Shear Stress Increases Expression of the Arterial Endothelial Marker EphrinB2 in Murine ES Cells via the VEGF-Notch Signaling Pathways
Authors: Masumura Tomomi , Yamamoto Kimiko , Shimizu Nobutaka , Obi Syotaro , Ando Joji
Published: October 2009

Objective—

Arterial-venous specification in the embryo has been assumed to depend on the influence of fluid mechanical forces, but its cellular and molecular mechanisms are still poorly understood. Our previous in vitro study revealed that fluid shear stress induces endothelial cell (EC) differentiation by murine embryonic stem (ES) cells. In the present study we investigated whether shear stress regulates the arterial-venous specification of ES-cell-derived ECs.

Methods and Results—

When murine ES cell-derived VEGFR2
+
cells were exposed to shear stress, expression of the arterial EC marker protein ephrinB2 increased dose-dependently. The ephrinB2 mRNA levels also increased in response to shear stress, whereas the mRNA levels of the venous EC marker EphB4 decreased. Notch cleavage and translocation of the Notch intracellular domain (NICD) into the nucleus occurred as early as 30 minutes after the start of shear stress and increased with time. Gamma-Secretase inhibitors (DAPT and L685 458) and the recombinant extracellular domain of the Notch ligand DLL4 abolished the shear stress-induced NICD translocation, and that, in turn, blocked the shear stress-induced upregulation of
ephrinB2
expression. In addition, the VEGF receptor kinase inhibitor SU1498 was found to suppress both the shear-stress-induced Notch cleavage and up-regulation of
ephrinB2
expression.

Conclusion—

Exposure to shear stress induces an increase in expression of ephrinB2 in murine ES cells via VEGF-Notch signaling pathways.
Increased PAFAH and Oxidized Lipids Are Associated With Inflammation and Atherosclerosis in Hypercholesterolemic Pigs
Authors: De Keyzer Dieuwke , Karabina Sonia-Athina , Wei Wenhzong , Geeraert Benjamine , Stengel Dominique , Marsillach Judit , Camps Jordi , Holvoet Paul , Ninio Ewa
Published: October 2009

Objective—

To study the association of PAF-acetyl hydrolase (PAFAH) activity with inflammation, oxidative stress, and atherosclerosis in hypercholesterolemic swine.

Methods and Results—

Cholesterol-rich diet feeding of miniature pigs was associated with an increase in PAFAH activity and an increase of the PAFAH to PON1 ratio.
PLA2G7
RNA (coding for PAFAH) expression was increased in blood monocytes and plaque macrophages. Increased PAFAH activity was associated with higher plasma lysophosphatidylcholine and correlated with oxidized LDL. In THP1 monocytes and macrophages and in human blood-derived macrophages, oxidized LDL induced
PLA2G7
RNA expression. Atherogenic diet feeding induced the accumulation of macrophages and oxidized LDL in the arterial wall leading to atherosclerosis. PAFAH activity correlated positively with plaque size and
TNFalpha
expression in plaque macrophages.

Conclusions—

We demonstrated that an increase in PAFAH activity was associated with increased levels of lysophosphatidylcholine, oxidized LDL, and inflammation, resulting in accelerated atherosclerosis in hypercholesterolemic minipigs. The significant correlation between
PLA2G7
RNA expression in plaque macrophages and plasma PAFAH activity suggests that the latter is a consequence, rather than a cause of macrophage accumulation. Our cell experiments suggest that oxidized LDL can induce PAFAH, resulting in accumulation of lysophosphatidylcholine that increases the inflammatory action of oxidized LDL.
Molecular Identification and Functional Characterization of a Mitochondrial Sulfonylurea Receptor 2 Splice Variant Generated by Intraexonic Splicing
Authors: Ye Bin , Kroboth Stacie L. , Pu Jie-Lin , Sims Jason J. , Aggarwal Nitin T. , McNally Elizabeth M. , Makielski Jonathan C. , Shi Nian-Qing
Published: October 2009

Rationale
:

Cardioprotective pathways may involve a mitochondrial ATP-sensitive potassium (mitoK
ATP
) channel but its composition is not fully understood.

Objective
:

We hypothesized that the mitoK
ATP
channel contains a sulfonylurea receptor (SUR)2 regulatory subunit and aimed to identify the molecular structure.

Methods and Results
:

Western blot analysis in cardiac mitochondria detected a 55-kDa mitochondrial SUR2 (mitoSUR2) short form, 2 additional short forms (28 and 68 kDa), and a 130-kDa long form. RACE (Rapid Amplification of cDNA Ends) identified a 1.5-Kb transcript, which was generated by a nonconventional intraexonic splicing (IES) event within the 4th and 29th exons of the
SUR2
mRNA. The translated product matched the predicted size of the 55-kDa short form. In a knockout mouse (SUR2KO), in which the
SUR2
gene was disrupted, the 130-kDa mitoSUR2 was absent, but the short forms remained expressed. Diazoxide failed to induce increased fluorescence of flavoprotein oxidation in SUR2KO cells, indicating that the diazoxide-sensitive mitoK
ATP
channel activity was associated with 130-kDa–based channels. However, SUR2KO mice displayed similar infarct sizes to preconditioned wild type, suggesting a protective role for the remaining short form-based channels. Heterologous coexpression of the SUR2 IES variant and Kir6.2 in a K
+
transport mutant
Escherichia coli
strain permitted improved cell growth under acidic pH conditions. The SUR2 IES variant was localized to mitochondria, and removal of a predicted mitochondrial targeting sequence allowed surface expression and detection of an ATP-sensitive current when coexpressed with Kir6.2.

Conclusions
:

We identify a novel SUR2 IES variant in cardiac mitochondria and provide evidence that the variant-based channel can form an ATP-sensitive conductance and may contribute to cardioprotection.
Gene Therapy With the Angiogenic Cytokine Secretoneurin Induces Therapeutic Angiogenesis by a Nitric Oxide–Dependent Mechanism
Authors: Schgoer Wilfried , Theurl Markus , Jeschke Johannes , Beer Arno G.E. , Albrecht Karin , Gander Roland , Rong Song , Vasiljevic Danijela , Egger Margot , Wolf Anna Maria , Frauscher Silke , Koller Bernhard , Tancevski Ivan , Patsch Josef R. , Schratzberger Peter , Piza-Katzer Hildegunde , Ritsch Andreas , Bahlmann Ferdinand H. , Fischer-Colbrie Reiner , Wolf Dominik , Kirchmair Rudolf
Published: October 2009

Rationale:

The neuropeptide secretoneurin induces angiogenesis and postnatal vasculogenesis and is upregulated by hypoxia in skeletal muscle cells.

Objective:

We sought to investigate the effects of secretoneurin on therapeutic angiogenesis.

Methods and Results:

We generated a secretoneurin gene therapy vector. In the mouse hindlimb ischemia model secretoneurin gene therapy by intramuscular plasmid injection significantly increased secretoneurin content of injected muscles, improved functional parameters, reduced tissue necrosis, and restored blood perfusion. Increased muscular density of capillaries and arterioles/arteries demonstrates the capability of secretoneurin gene therapy to induce therapeutic angiogenesis and arteriogenesis. Furthermore, recruitment of endothelial progenitor cells was enhanced by secretoneurin gene therapy consistent with induction of postnatal vasculogenesis. Additionally, secretoneurin was able to activate nitric oxide synthase in endothelial cells and inhibition of nitric oxide inhibited secretoneurin-induced effects on chemotaxis and capillary tube formation in vitro. In vivo, secretoneurin induced nitric oxide production and inhibition of nitric oxide attenuated secretoneurin-induced effects on blood perfusion, angiogenesis, arteriogenesis, and vasculogenesis. Secretoneurin also induced upregulation of basic fibroblast growth factor and platelet-derived growth factor-B in endothelial cells.

Conclusions:

In summary, our data indicate that gene therapy with secretoneurin induces therapeutic angiogenesis, arteriogenesis, and vasculogenesis in the hindlimb ischemia model by a nitric oxide–dependent mechanism.
Hospital Arrival Time and Intravenous t-PA Use in US Academic Medical Centers, 2001–2004
Authors: Lichtman Judith H. , Watanabe Emi , Allen Norrina B. , Jones Sara B. , Dostal Jackie , Goldstein Larry B.
Published: October 2009

Background and Purpose—

Prompt care-seeking behavior is a focus of US national public stroke educational campaigns. We determined whether the time between symptom onset and hospital arrival and the receipt of intravenous tissue-type plasminogen activator (IV t-PA) changed for ischemic stroke patients evaluated at US academic centers between 2001 and 2004.

Methods—

Medical records were abstracted for consecutive ischemic stroke patients admitted from the Emergency Department within 48 hours of symptom onset at 35 academic medical centers participating in the University HealthSystem Consortium Ischemic Stroke Benchmarking Project between January 1, 2001 and March 31, 2001, and 32 centers between January 1, 2004 and June 30, 2004. Demographic and clinical characteristics of patients who presented within and after 2 hours of symptom onset were compared. Multivariate logistic regression was used to compare time to arrival by year and to identify patient characteristics associated with earlier hospital arrival.

Results—

The study included 428 patients from 2001 and 481 from 2004. Although there was no difference in the percentage of patients who arrived within 2 hours between the 2 periods (37% in 2001 vs 38% in 2004,
P
=0.63), the percentage of these patients treated with IV t-PA increased (14.0% to 37.5%,
P
<0.0001). In risk-adjusted analysis, black patients had a lower odds of arriving within 2 hours (odds ratio=0.55; 95% CI, 0.39 to 0.78), whereas those with severe strokes were more likely to arrive promptly (odds ratio=2.17; 95% CI, 1.49 to 3.15).

Conclusions—

There was no change in the proportion of stroke patients arriving at hospitals within 2 hours of symptom onset between 2001 and 2004; however, the rate of IV t-PA use increased, indicating system-level improvements of in-hospital care.
Diotima's Eudaemonism: Intrinsic Value and Rational Motivation in Plato's Symposium
Authors: Wedgwood Ralph
Published: October 2009

This paper gives a new interpretation of the central section of Plato's Symposium (199d-212a). According to this interpretation, the term "καλóν", as used by Plato here, stands for what many contemporary philosophers call "intrinsic value"; and "love" (ερωζ) is in effect rational motivation, which for Plato consists in the desire to "possess" intrinsically valuable things – that is, according to Plato, to be happy – for as long as possible. An explanation is given of why Plato believes that "possessing" intrinsically valuable things, at least for mortals like us, consists in actively creating instantiations of the intrinsic values, both in oneself and in the external world, and in knowing and loving these intrinsic values and their instantiations. Finally, it is argued that this interpretation reveals that Plato's "eudaemonism" is a different and more defensible doctrine than many commentators believe.
Twixt Ricardo and Rubin: Debating Kincaid Once More
Authors: Saad-Filho Alfredo , Fine Ben
Published: October 2009

Our final instalment in the debate with Jim Kincaid argues that his value-analysis suffers from weaknesses associated with both Ricardian and Rubinesque (mis-)interpretations of Marx. These approaches are methodologically flawed, because value-theory does not draw upon externally imposed theories or standards of logic or evidence to check the conceptual or empirical validity of its approach to the understanding of capitalism. Rather, Marxian value-theory involves reconstructing in thought the class-based production-processes underpinning capitalism through to their more complex and concrete consequences in the broader economic and social structures, agencies and processes, through which they are formed, albeit with definite effects of their own. Examination of the methodological shortcomings in Kincaid's analysis is followed by specific rebuttals of his claims about the (qualitative and quantitative) determination of value and price, the circulation of capital, the role of competition, fixed capital, productive labour and the leverage of value-theory in informing empirical studies.
Governing Technology through Public Participation
Authors: Bora Alfons , Hausendorf Heiko
Published: October 2009

Against the background of a still controversial debate over participatory governance, the intention of this issue is to scrutinise critically central aspects of this controversy. In particular, the papers here explore regular, routine forms of participatory governance in the heart of political power, namely in administrative procedure. By contrast, political sciences and sociology often focus on new, alternative procedures, including citizen juries, consensus conferences, scenario workshops, and public consultation exercises. Normal forms of participatory governance in constitutional democracy are inevitably governed by rule of law such that a legal framework lies behind participants' concrete actions or communications.