Ethanol Consumption Alters the Expression and Reactivity of Adrenomedullin in the Rat Mesenteric Arterial Bed

Aims: Adrenomedullin (AM) is a peptide that displays cardiovascular protective activity. We investigated the effects of chronic ethanol consumption on arterial blood pressure, vascular reactivity to AM and the expression of AM system components in the rat mesenteric arterial bed (MAB). Methods: Male Wistar rats were treated with ethanol (20% vol/vol) for 6 weeks. Systolic, diastolic and mean arterial blood pressure were monitored in conscious rats. Vascular reactivity experiments were performed on isolated rat MAB. Matrix metalloproteinase-2 (MMP-2) levels were determined by gelatin zymography. Nitrite and nitrate generation were measured by chemiluminescence. Protein and mRNA levels of pre-pro-AM, CRLR (calcitonin receptor-like receptor) and RAMP1, 2 and 3 (receptor activity-modifying proteins) were assessed by western blot and quantitative real-time polymerase chain reaction, respectively. Results: Ethanol consumption induced hypertension and decreased the relaxation induced by AM and acetylcholine in endothelium-intact rat MAB. Phenylephrine-induced contraction was increased in endothelium-intact MAB from ethanol-treated rats. Ethanol consumption did not alter basal levels of nitrate and nitrite, nor did it affect the expression of MMP-2 or the net MMP activity in the rat MAB. Ethanol consumption increased mRNA levels of pre-pro-AM and protein levels of AM in the rat MAB. Finally, no differences in protein levels or mRNA of CRLR and RAMP1, 2 and 3 were observed after treatment with ethanol. Conclusion: Our study demonstrates that ethanol consumption increases blood pressure and the expression of AM in the vasculature and reduces the relaxation induced by this peptide in the rat MAB.

Expression of angiogenic factors in placenta of stressed rats

The aim of the present study was to analyse the influence of stress on pregnant rats, particularly in terms of maternal, placental and fetal weight, placental morphology and placental gene expression of the angiogenic factors Vegfa and Pgf and their receptors. The parameters were evaluated on gestation Day 20. Maternal, fetal and placental weights were statistically lower in stressed animals than controls, suggesting abnormalities in gestational physiology. Morphologically the placentas of rats subjected to stress were reduced in size and weight, with few glycogen cells and a significant increase in the number of apoptotic cells. Stress caused an increase in placental gene expression of Vegfa (P < 0.05) and a reduction in Pgf, Flt1 and Kdr expression (P < 0.05). It has been suggested that increased VEGF is associated with vasodilatation and hypotension, but in this model persistent hypertension was present. This study suggests that the limited hypotensive Vegfa response to stress-induced hypertension could result from reduced expression of Flt1/Kdr disrupting specific VEGF pathways. These findings may elucidate one of the multiple possible factors underlying how stress modulates placental physiology, and could aid the understanding of stress-induced gestational disorders.

Effects of glucocorticoids on vascular NADPH oxidases and endothelial NO synthase

Glukokortikoide (GCs) stellen wichtige Hormone in der Regulation der metabolischen Homöostase dar. Synthetische GCs, wie Dexamethasone (DEX), spielen eine essentielle Rolle in der Behandlung inflammatorischer Krankheiten. Jedoch sind unter einer Dexamethason-Therapie zahlreiche Nebenwirkungen bekannt, so z.B. auch die Entwicklung einer Hypertonie, in deren Pathogenese oxidativer Stress eine entscheidende Rolle spielt. Obwohl sich in den vergangenen Jahren zahlreiche Studien zum Ziel setzten die GC-induzierte Hypertonie (GC-HT) aufzuklären, sind die genauen Mechanismen bis heute unklar. Eine erhöhte Expression von NADPH Oxidasen (Nox) und eine Entkopplung der endothelialen NO Synthase (eNOS), die Hauptquellen reaktiver Sauerstoffspezies (ROS) im vaskulären System, tragen maßgeblich zur Pathogenese kardiovaskulärer Erkrankungen bei. Daher ist eine Beteiligung dieser Enzyme in GC-induziertem oxidativen Stress sehr wahrscheinlich. Folglich wurde die Hypothese aufgestellt, dass NADPH Oxidasen und eine entkoppelte eNOS die vielversprechendsten unter den zahlreichen involvierten pro- und anti-oxidativen Enzymen sind. Mit Fokus auf die oben genannten Systeme wurde in der vorliegenden Studie der Effekt von DEX mit Hilfe von in vivo (WKY Ratten) ebenso wie in vitro Experimenten (A7r5 und EA.hy 926 Zellen) untersucht. Dabei zeigte sich, dass Nox1, Nox4 und p22phox durch DEX unterschiedlich reguliert wurden. Nox1 wurde hoch-, Nox4 hingegen herunterreguliert, während p22phox unverändert blieb. Die Modufikation schien hierbei auf transkriptioneller und post-transkriptioneller Ebene stattzufinden. Durch die gegensätzliche Regulation von Nox1 und Nox4 bleibt die Nettowirkung der verschiedenen Nox Isoformen unklar. Immer mehr Studien bringen vaskulären oxidativen Stress mit der Pathogenese einer GC-HT in Zusammenhang, welche letztendlich zu einer verminderten Bioverfügbarkeit von Stickstoffmonoxid (NO) führt. Durch die eNOS produziertes NO stellt einen essentiellen Schutzfaktor der Blutgefäße dar. Eine verminderte NO-Bioverfügbarkeit könnte die Folge einer eNOS-Entkopplung darstellen, ausgelöst durch oxidativen Stress. Da die Verfügbarkeit von Tetrahydrobiopterin (BH4) entscheident ist für die Aktivität und enzymatische Kopplung der eNOS, beschäftigt sich die vorliegende Arbeit mit GC-induzierten Veränderungen in der BH4-Versorgung. Die Behandlung von EA.hy 926 Zellen mit DEX führte zu einer zeit- und konzentrationsabhängigen Herunterregulation von eNOS auf mRNA- und Proteinebene. Gleichzeitig wurde die Phosphorylierung an Serine1177 vermindert. Als maßgeblicher “Kopplungs-Schalter” kann BH4 endogen über zwei verschiedene Signalwege synthetisiert werden, welche durch die Enzyme GCH1 und DHFR reguliert werden. DEX führte zu einer zeit- und konzentrationsabhängigen Herunterregulation von BH4, BH2 und Biopterin, wobei ebenso das BH4 / BH2 -Verhältnis vermindert wurde. Beide Enzyme, GCH1 genauso wie DHFR, wurden auf mRNA- und Proteinebene herunterreguliert, was auf einen Effekt von GCs auf beide rnBH4-produzierenden Signalwege schließen lässt. Nach Behandlung mit DEX wurde die Produktion von NO in Endothelzellen maßgeblich vermindert. In ROS-Messungen zeigte sich eine Tendenz hin zu einer eNOS-Entkopplung, jedoch war es mit unserem experimentellen Aufbau nicht möglich, diese endgültig zu beweisen.rnZusammenfassend lässt sich sagen, dass die Behandlung mit GCs zu Veränderungen in beiden untersuchten Systemen, den NADPH Oxidasen ebenso wie dem eNOS-NO System, führte. DEX erhöhte die Expression von Nox1 in glatten Muskelzellen und reduzierte die Nox4-Expression in Endothelzellen. Gleichzeitig verminderte DEX die Verfügbarkeit von BH4 und inhibierte die Phosphorylierung / Aktivität von eNOS. Mithilfe weiterer Studien muss die endgültige Beteiligung von NADPH Oxidasen und einer eNOS-Entkopplung an oxidativem Stress in GC-HT abschließend aufgeklärt werden.rn

Normotensive blood pressure in pregnancy – the role of salt and aldosterone

A successful pregnancy requires an accommodating environment. Salt and water availability are critical for plasma volume expansion. Any changes in sodium intake would alter aldosterone, a hormone previously described beneficial in pregnancy. To date, it remains ambiguous whether high aldosterone or high salt intake is preferable. We hypothesized that increased aldosterone is a rescue mechanism and appropriate salt availability is equally effective in maintaining a normotensive blood pressure (BP) phenotype in pregnancy. We compared normotensive pregnant women (n=31) throughout pregnancy with young healthy female individuals (n=31–62) and performed salt sensitivity testing within the first trimester. Suppression of urinary tetrahydro-aldosterone levels by salt intake as measured by gas chromatography–mass spectrometry and urinary sodium excretion corrected for creatinine, respectively, was shifted toward a higher salt intake in pregnancy (P<0.0001). In pregnancy, neither high urinary tetrahydro-aldosterone nor sodium excretion was correlated with higher BP. In contrast, in nonpregnant women, systolic BP rose with aldosterone (P<0.05). Testing the impact of salt on BP, we performed salt sensitivity testing in a final cohort of 19 pregnant and 24 nonpregnant women. On salt loading, 24-hour mean arterial pressure rose by 3.6±1.5 and dropped by –2.8±1.5 mm Hg favoring pregnant women (P<0.01; χ2=6.04; P<0.02). Our data suggest first that salt responsiveness of aldosterone is alleviated in conditions of pregnancy without causing aldosterone-induced hypertension. Second, salt seems to aid in BP lowering in pregnancy for reasons incompletely elucidated, yet involving renin suppression and potentially placental sensing mechanisms. Further research should identify susceptible individuals and clarify effector mechanisms.

An examination of the relationship between maternal and neighborhood-level characteristics and intrauterine growth retardation in Harris County, Texas, 1999--2001

The persistence of low birth weight and intrauterine growth retardation (IUGR) in the United States has puzzled researchers for decades. Much of the work that has been conducted on adverse birth outcomes has focused on low birth weight in general and not on IUGR. Studies that have examined IUGR specifically thus far have focused primarily on individual-level maternal risk factors. These risk factors have only been able to explain a small portion of the variance in IUGR. Therefore, recent work has begun to focus on community-level risk factors in addition to the individual-level maternal characteristics. This study uses Social Ecology to examine the relationship of individual and community-level risk factors and IUGR. Logistic regression was used to establish an individual-level model based on 155, 856 births recorded in Harris County, TX during 1999-2001. IUGR was characterized using a fetal growth ratio method with race/ethnic and sex specific mean birth weights calculated from national vital records. The spatial distributions of 114,460 birth records spatially located within the City of Houston were examined using choropleth, probability and density maps. Census tracts with higher than expected rates of IUGR and high levels of neighborhood disadvantage were highlighted. Neighborhood disadvantage was constructed using socioeconomic variables from the 2000 U.S. Census. Factor analysis was used to create a unified single measure. Lastly, a random coefficients model was used to examine the relationship between varying levels of community disadvantage, given the set of individual-level risk factors for 152,997 birth records spatially located within Harris County, TX. Neighborhood disadvantage was measured using three different indices adapted from previous work. The findings show that pregnancy-induced hypertension, previous preterm infant, tobacco use and insufficient weight gain have the highest association with IUGR. Neighborhood disadvantage only slightly further increases the risk of IUGR (OR 1.12 to 1.23). Although community level disadvantage only helped to explain a small proportion of the variance of IUGR, it did have a significant impact. This finding suggests that community level risk factors should be included in future work with IUGR and that more work needs to be conducted. ^

Risk factors for encephalitis and death from West Nile virus infection: An analysis of hospitalized cases in Houston, Texas from 2002--2008

We conducted a nested case-control study to determine the significant risk factors for developing encephalitis from West Nile virus (WNV) infection. The purpose of this research project was to expand the previously published Houston study of 2002–2004 patients to include data on Houston patients from four additional years (2005–2008) to determine if there were any differences in risk factors shown to be associated with developing the more severe outcomes of WNV infection, encephalitis and death, by having this larger sample size. A re-analysis of the risk factors for encephalitis and death was conducted on all of the patients from 2002–2008 and was the focus of this proposed research. This analysis allowed for the determination to be made that there are differences in the outcome in the risk factors for encephalitis and death with an increased sample size. Retrospective medical chart reviews were completed for the 265 confirmed WNV hospitalized patients; 153 patients had encephalitis (WNE), 112 had either viral syndrome with fever (WNF) or meningitis (WNM); a total of 22 patients died. Univariate logistic regression analyses on demographic, comorbidities, and social risk factors was conducted in a similar manner as in the previously conducted study to determine the risk factors for developing encephalitis from WNV. A multivariate model was developed by using model building strategies for the multivariate logistic regression analysis. The hypothesis of this study was that there would be additional risk factors shown to be significant with the increase in sample size of the dataset. This analysis with a greater sample size and increased power supports the hypothesis in that there were additional risk factors shown to be statistically associated with the more severe outcomes of WNV infection (WNE or death). Based on univariate logistic regression results, these data showed that even though age of 20–44 years was statistically significant as a protecting effect for developing WNE in the original study, the expanded sample lacked significance. This study showed a significant WNE risk factor to be chronic alcohol abuse, when it was not significant in the original analysis. Other WNE risk factors identified in this analysis that showed to be significant but were not significant in the original analysis were cancer not in remission > 5 years, history of stroke, and chronic renal disease. When comparing the two analyses with death as an outcome, two risk factors that were shown to be significant in the original analysis but not in the expanded dataset analysis were diabetes mellitus and immunosuppression. Three risk factors shown to be significant in this expanded analysis but were not significant in the original study were illicit drug use, heroin or opiate use, and injection drug use. However, with the multiple logistic regression models, the same independent risk factors for developing encephalitis of age and history of hypertension including drug induced hypertension were consistent in both studies.^

A case-control study of the risk factors for eclampsia

Objective. To study the risk factors for eclampsia, a rare but significant complication of pregnancy.^ Target population. All deliveries at or after the 20th week of gestation that took place between January 1, 1977 and March 1992, and between January 1990 and April 1992 at two hospitals in Houston, Texas, respectively.^ Study population. Sixty-six confirmed cases of eclampsia, and 2 groups of randomly selected controls: Non-preeclamptic and preeclamptic deliveries matched to cases on hospital and month of delivery on a 1:4 ratio.^ Exclusions. Women with chronic hypertension, gestational epilepsy, a previous history of epilepsy, and convulsions attributed to encephalitis, meningitis, cerebral tumor, and intracerebral bleeding, and women without a definite diagnosis of preeclampsia/eclampsia.^ Results. Eclampsia developed in 0.52-0.93/1000 deliveries. Fifty-six percent of seizures occurred in the antepartum period, 2% as early as 20 weeks of gestation and 39% between 37 and 42 weeks. Twenty-nine percent and 15% occurred in the postpartum and late postpartum periods, respectively, 8% as late as one week postpartum. A different set of risk factors was involved in the development of eclampsia in non-preeclamptic women than in the progression from preeclampsia to eclampsia. Factors involved in the development of eclampsia included, in addition to twin pregnancy and family history of pregnancy-induced hypertension, fewer than 3 prenatal care visits, urinary tract infections, primigravidity, obesity, black ethnicity, diabetes mellitus, and age $\le$20 years. Risk factors involved in the progression from preeclampsia to eclampsia included fewer than 3 of prenatal care visits, and age $\le$20 years. Protective factors were magnesium sulfate administration prior to seizure, history of abortions and longer gestational age. Having less than 3 prenatal care visits and being less than or equal to 20 years of age were predictors of eclampsia, whether of its development or progression from preeclampsia. Once preeclampsia is diagnosed, primigravid, diabetic, black, or obese women and those with urinary tract infections did not appear to exhibit any increased risk for the progression to eclampsia. The administration of magnesium sulfate was especially protective, followed by a positive history of abortions, 3 or more prenatal care visits, and longer gestational age. The protective effect of MgSO$\sb4$ was only slightly diminished when cases were restricted to the 65% who had a diagnosis of preeclampsia. The progression from preeclampsia to eclampsia may be largely preventable through adequate prenatal care and presumably the administration of magnesium sulfate. (Abstract shortened by UMI.) ^

Can hydrogen sulfide prevent preeclampsia and fetal growth restriction?

The exact aetiology of preeclampsia is unknown, but there is a good association with an imbalance in angiogenic growth factors and abnormal placentation [1]. Hydrogen sulphide (H2S), a gaseous messenger produced mainly by cystathionine γ-lyase (CSE), is pro-angiogenic vasodilator [2] and [3]. We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H2S were significantly decreased in preeclamptic women (p < 0.01), which was associated with reduced CSE message and protein expression in human placenta as determined by real-time PCR and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine (PAG) in first trimester (8–12 weeks gestation) human placental explants had reduced placenta growth factor (PlGF) production as assessed by ELISA and inhibited trophoblast invasion in vitro. Endothelial CSE knockdown by siRNA transfection increased the endogenous release of soluble fms-Like tyrosine kinase-1 (sFlt-1) and soluble endoglin, (sEng) from human umbilical vein endothelial cells while adenoviral-mediated CSE overexpression inhibited their release. Administration of PAG to pregnant mice induced hypertension, liver damage, and promoted abnormal labyrinth vascularisation in the placenta and decreased fetal growth. Finally, a slow releasing, H2S-generating compound, GYY4137, inhibited circulating sFlt-1 and sEng levels and restored fetal growth that was compromised by PAG-treatment demonstrating that the effect of CSE inhibitor was due to inhibition of H2S production. These results imply that endogenous H2S is required for healthy placental vasculature and a decrease in of CSE/H2S activity may contribute to the pathogenesis of preeclampsia. References [1] S. Ahmad, A. Ahmed, Elevated placental soluble vascular endothelial growth factor receptor-1 inhibits angiogenesis in preeclampsia, Circ Res., 95 (2004), pp. 884–891. [2] G. Yang, et al., H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase, Science, 322 (2008), pp. 587–590. [3] A. Papapetropoulos, et al., Hydrogen sulfide is an endogenous stimulator of angiogenesis, Proc Natl Acad Sci USA, 106 (2009), pp. 21972–21977.

The effects of resilience and social influences on preventing repeat adolescent pregnancies in parenting adolescent mothers

Every year, 16 million women aged 15 to 19 years give birth globally. Adolescent births account for 11% of all births globally and 23% of the overall burden of disability and diseases due to pregnancy and childbirth. In the United States, 750,000 adolescents (15-19 years) become pregnant each year, making the United States the developed country with the highest rates of adolescent pregnancy. The economic burden of adolescent pregnancy in the U. S. is $7-15 billion per year. Adolescent pregnancy brings risks associated with pregnancy induced hypertension, preterm infants, maternal and neonatal mortality. Social factors include poverty, low educational levels, alcohol, and drug use. Between 30-50% of adolescent mothers who have a first birth before age 18 years will have a second child within 12 to 24 months. Subsequent adolescent pregnancies compound fetal and maternal risks. Many vulnerable adolescent mothers succumb to external pressures and have a repeat adolescent pregnancy while others are able to overcome the challenges of an adolescent pregnancy and prevent a repeat adolescent pregnancy. This cross sectional survey designed study investigated the effects of resilience and social influences on contraceptive use or abstinence by Black and Hispanic adolescent parenting mothers to prevent a repeat adolescent pregnancy. 140 adolescent mothers were recruited from three postpartum units of a tertiary hospital system in Miami, Florida. The Wagnild and Young Resilience Scale and the Adolescent Social Influence Scale were used to measure resilience and social influences, respectively. Demographic data, length of labor, plan for contraceptive use or abstinence were measured by an investigator developed instrument. Point biserial correlation showed a significant positive correlation between Black adolescent mothers' resilience and contraceptive use (r =.366, p2(11, N=133) = 27.08, p =.004. (OR = .28). These results indicate a need for interventional strategies to maximize resilience in parenting adolescents to prevent a repeat adolescent pregnancy.

Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis

Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobarichypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 ± 1.4 versus 13.8 ± 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 ± 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B2 excretion increased following hypoxia (44.6 ± 11.1 versus 14.7 ± 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 ± 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin1α excretion following hypoxia was reduced by COX-2 gene disruption (29 ± 3 versus 52 ± 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA2/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA2, and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

Single layer lead iodide: Computational exploration of structural, electronic and optical properties, strain induced band modulation and the role of spin-orbital-coupling

Graphitic like layered materials exhibit intriguing electronic structures and thus the search for new types of two-dimensional (2D) monolayer materials is of great interest for developing novel nano-devices. By using density functional theory (DFT) method, here we for the first time investigate the structure, stability, electronic and optical properties of monolayer lead iodide (PbI2). The stability of PbI2 monolayer is first confirmed by phonon dispersion calculation. Compared to the calculation using generalized gradient approximation, screened hybrid functional and spin–orbit coupling effects can not only predicts an accurate bandgap (2.63 eV), but also the correct position of valence and conduction band edges. The biaxial strain can tune its bandgap size in a wide range from 1 eV to 3 eV, which can be understood by the strain induced uniformly change of electric field between Pb and I atomic layer. The calculated imaginary part of the dielectric function of 2D graphene/PbI2 van der Waals type hetero-structure shows significant red shift of absorption edge compared to that of a pure monolayer PbI2. Our findings highlight a new interesting 2D material with potential applications in nanoelectronics and optoelectronics.

N-ethyl-N-nitrosourea (ENU) induced mutations within the Klotho gene lead to ectopic calcification and reduced lifespan in mouse models

Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established. © 2015 Esapa et al.

High energy oxygen ion induced modifications in lead based perovskite thin films

The lead based ferroelectric PbZr0.53Ti0.47O3 (PZT), (Pb0.90La0.10)TiO3 (PLT10) and (Pb0.80La0.20)TiO3 (PLT20) thin films, prepared by pulsed laser ablation technique, were studied for their response to the 70 MeV oxygen ion irradiation. The dielectric analysis, capacitance-voltage (C- V) and DC leakage current measurements were performed before and after the irradiation to high-energy oxygen ions. The irradiation produced considerable changes in the dielectric, C-V, leakage characteristics and induced some amount of amorphization. The PZT films showed partial recrystallization after a thermal annealing at 400 degrees C for 10 min. The phase transition temperature [T-c] of PLT20 increased from 115 degrees C to 120 degrees C. The DC conductivity measurements showed a shift in the onset of non-linear conduction region. The current density decreased by two orders of magnitude after irradiation. After annealing the irradiated films at a temperature of 400 degrees C for 10 min, the films partially regained the dielectric and electrical properties. The results are discussed in terms of the irradiation-induced amorphization, the pinning of the ferroelectric domains by trapped charges and the thermal annealing of the defects generated during the irradiation. (C) 2007 Elsevier B.V. All rights reserved.

Molecular mechanisms of hypertension-induced heart failure : Experimental studies with special emphasis on local renin-angiotensin system, cardiac metabolism and levosimendan

Hypertension is a major risk factor for stroke, ischaemic heart disease, and the development of heart failure. Hypertension-induced heart failure is usually preceded by the development of left ventricular hypertrophy (LVH), which represents an adaptive and compensatory response to the increased cardiac workload. Biomechanical stress and neurohumoral activation are the most important triggers of pathologic hypertrophy and the transition of cardiac hypertrophy to heart failure. Non-clinical and clinical studies have also revealed derangements of energy metabolism in hypertensive heart failure. The goal of this study was to investigate in experimental models the molecular mechanisms and signalling pathways involved in hypertension-induced heart failure with special emphasis on local renin-angiotensin-aldosterone system (RAAS), cardiac metabolism, and calcium sensitizers, a novel class of inotropic agents used currently in the treatment of acute decompensated heart failure. Two different animal models of hypertensive heart failure were used in the present study, i.e. hypertensive and salt-sensitive Dahl/Rapp rats on a high salt diet (a salt-sensitive model of hypertensive heart failure) and double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes (a transgenic model of hypertensive heart failure with increased local RAAS activity). The influence of angiotensin II (Ang II) on cardiac substrate utilization and cardiac metabolomic profile was investigated by using gas chromatography coupled to time-of-flight mass spectrometry to detect 247 intermediary metabolites. It was found that Ang II could alter cardiac metabolomics both in normotensive and hypertensive rats in an Ang II receptor type 1 (AT1)-dependent manner. A distinct substrate use from fatty acid oxidation towards glycolysis was found in dTGR. Altered cardiac substrate utilization in dTGR was associated with mitochondrial dysfunction. Cardiac expression of the redox-sensitive metabolic sensor sirtuin1 (SIRT1) was increased in dTGR. Resveratrol supplementation prevented cardiovascular mortality and ameliorated Ang II-induced cardiac remodeling in dTGR via blood pressure-dependent pathways and mechanisms linked to increased mitochondrial biogenesis. Resveratrol dose-dependently increased SIRT1 activity in vitro. Oral levosimendan treatment was also found to improve survival and systolic function in dTGR via blood pressure-independent mechanisms, and ameliorate Ang II-induced coronary and cardiomyocyte damage. Finally, using Dahl/Rapp rats it was demonstrated that oral levosimendan as well as the AT1 receptor antagonist valsartan improved survival and prevented cardiac remodeling. The beneficial effects of levosimendan were associated with improved diastolic function without significantly improved systolic changes. These positive effects were potentiated when the drug combination was administered. In conclusion, the present study points to an important role for local RAAS in the pathophysiology of hypertension-induced heart failure as well as its involvement as a regulator of cardiac substrate utilization and mitochondrial function. Our findings suggest a therapeutic role for natural polyphenol resveratrol and calcium sensitizer, levosimendan, and the novel drug combination of valsartan and levosimendan, in prevention of hypertension-induced heart failure. The present study also provides a better understanding of the pathophysiology of hypertension-induced heart failure, and may help identify potential targets for novel therapeutic interventions.