Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy.

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2 ) pregnancy ± melatonin (M) treatment (5 µg·ml-1 .day-1 ) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15-20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia-induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair-fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in-vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair-fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch-up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia-induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair-fed pregnancies. Whilst maternal treatment of normoxic or pair-fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.

Acute hypoxia-reoxygenation and vascular oxygen sensing in the chicken embryo.

Fetal/perinatal hypoxia is one of the most common causes of perinatal morbidity and mortality and is frequently accompannied by vascular dysfunction. However, the mechanisms involved have not been fully delineated. We hypothesized that exposure to acute hypoxia-reoxygenation induces alterations in vascular O2 sensing/signaling as well as in endothelial function in the chicken embryo pulmonary artery (PA), mesenteric artery (MA), femoral artery (FA), and ductus arteriosus (DA). Noninternally pipped 19-day embryos were exposed to 10% O2 for 30 min followed by reoxygenation with 21% O2 or 80% O2 Another group was constantly maintained at 21% O2 or at 21% O2 for 30 min and then exposed to 80% O2 Following treatment, responses of isolated blood vessels to hypoxia as well as endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside and forskolin) relaxation were investigated in a wire myograph. Hypoxia increased venous blood lactate from 2.03 ± 0.18 to 15.98 ± 0.73 mmol/L (P < 0.001) and reduced hatchability to 0%. However, ex vivo hypoxic contraction of PA and MA, hypoxic relaxation of FA, and normoxic contraction of DA were not significantly different in any of the experimental groups. Relaxations induced by acetylcholine, sodium nitroprusside, and forskolin in PA, MA, FA, and DA rings were also similar in the four groups. In conclusion, exposure to acute hypoxia-reoxygenation did not affect vascular oxygen sensing or reactivity in the chicken embryo. This suggests that direct effects of acute hypoxia-reoxygenation on vascular function does not play a role in the pathophysiology of hypoxic cardiovascular injury in the perinatal period.

Causas y sobrevida en pacientes quemados en el centro de referencia del nororiente de Colombia / Agent and survival in burn patients on the referral center of northeastern Colombia

Introducción y Objetivo. En el mundo, las quemaduras son causa importante de morbilidad y responsables del fallecimiento de más de 300.000 personas al año. Más del 90% de estas muertes ocurren en países con ingresos bajos o medios. El objetivo de este estudio es caracterizar los pacientes quemados hospitalizados en el centro de referencia para el nororiente de Colombia, el Hospital Universitario de Santander, en Bucaramanga. Material y Método. Realizamos un estudio observacional, descriptivo y longitudinal, con información tomada de historias clínicas de pacientes quemados hospitalizados en el Hospital Universitario de Santander en un periodo de 12 meses. Obtuvimos información sociodemográfica y médica. Llevamos a cabo un análisis estadístico con medidas de tendencia central, proporciones, incidencia global y específica, además de densidad de incidencia global y especifica. Resultados. Durante el 2014 se hospitalizaron en el centro de estudio 402 pacientes quemados provenientes de 12 departamentos del país, 234 (58.2%) hombres y 168 (41.8%) mujeres, con edades de entre 6 días y 83 años. Las quemaduras comprometían entre el 1 - 80% de superficie corporal; el 95.5% de los pacientes tenían vinculación con el Sistema General de Seguridad Social Nacional. Los agentes causales incluyeron líquidos calientes (52.5%), fuego (10.0%), gasolina (9.2%), electricidad (7.5%) y químicos (3.7%), entre otros, y produjeron quemaduras de segundo y/o tercer grado. La mediana de la estancia hospitalaria fue de 14 días, con mortalidad acumulada del 1.5% que se relacionó con la profundidad y extensión de la quemadura. Consideramos que el tipo de agente compromete con mayor frecuencia a un grupo etario determinado por las actividades propias de la edad; que la profundidad de la quemadura puede tener relación con el agente causal debido a la temperatura que alcanza; y que la extensión de la quemadura es el único predictor de mortalidad y se relaciona con el tiempo de vida postquemadura. Conclusiones. En el nororiente de Colombia, la población masculina y pediátrica presenta mayor número de quemaduras. Existe una relación entre el agente causal y su grupo etario, donde los líquidos calientes y las quemaduras por contacto comprometen principalmente a la población joven. Los pacientes con mayor superficie corporal quemada presentan mayor riesgo de muerte. Creemos que esta información facilita a los centros de quemados preparar sus instalaciones y dirigir sus recursos teniendo en cuenta la población que esperan atender. Las autoridades civiles podrían usar también esta información para diseñar campañas de prevención dirigidas a esta población (AU)

Background and Objective. Burns are an important cause of morbidity and responsible for more than 300.000 deaths per year worldwide. Over 90% of these deaths occur in countries with low or medium income. The aim of this study is to characterize burned patients admitted to the referral center for northeastern Colombia, at the University Hospital of Santander, Bucaramanga. Methods. This was an observational, descriptive and longitudinal study, in a 12 month period. Sociodemographic and medical data was collected from the medical records of burn patients hospitalized at the referred hospital. Statistical analysis was performed with measures of central tendency, proportions, overall incidence and specific density in addition to overall and specific incidence density. Results. During 2014, 402 burn patients were hospitalized proceeding from 12 states, 234 (58.2%) men and 168 (41.8%) women, ages between 6 days and 83 years. Burns affected 1-80% of body surface; 95.5% of patients had some sort of insurance. Causative agents include hot liquids (52.5%), fire (10.0%), fuel (9.2%), electricity (7.5%) and chemical substances (3.7%) among others; these agents produce second and / or third grade burns, 14 days median hospital stay and cumulative mortality of 1.5% which is related to the depth and extent of the burn. We considerer that agents are related to certain age group because of the activities of the corresponding age; the depth may be related to the causative agent because of the temperature it can reach; and the extent of the burn is the only predictor of mortality and is associated with postburn survival time. Conclusions. In northeastern Colombia, male and pediatric population have a greater number of burn victims. There is a relationship between burning agent and patients age, were scalds and contact burns mainly involve the younger population. Patients with greater burned surface area have increased risk of death. This information facilitates burn centers to prepare their facilities and organize resources according to the patients they expect to treat. Civil authorities could use this information to design prevention campaigns targeting this population (AU)

High-fat diet exacerbates pain-like behaviors and periarticular bone loss in mice with CFA-induced knee arthritis.

OBJECTIVE: Our aim was to quantify nociceptive spontaneous behaviors, knee edema, proinflammatory cytokines, bone density, and microarchitecture in high-fat diet (HFD)-fed mice with unilateral knee arthritis. METHODS: ICR male mice were fed either standard diet (SD) or HFD starting at 3 weeks old. At 17 weeks, HFD and SD mice received intra-articular injections either with Complete Freund's Adjuvant (CFA) or saline into the right knee joint every 7 days for 4 weeks. Spontaneous pain-like behaviors and knee edema were assessed for 26 days. At day 26 post-first CFA injection, serum levels of IL-1ß, IL-6, and RANKL were measured by ELISA, and microcomputed tomography analysis of knee joints was performed. RESULTS: HFD-fed mice injected with CFA showed greater spontaneous pain-like behaviors of the affected extremity as well as a decrease in the weight-bearing index compared to SD-fed mice injected with CFA. Knee edema was not significantly different between diets. HFD significantly exacerbated arthritis-induced bone loss at the distal femoral metaphysis but had no effect on femoral diaphyseal cortical bone. HFD did not modify serum levels of proinflammatory cytokines. CONCLUSIONS: HFD exacerbates pain-like behaviors and significantly increases the magnitude of periarticular trabecular bone loss in a murine model of unilateral arthritis.

Growth and endothelial function in the first 2 years of life.

OBJECTIVE: To test the hypothesis that the inverse association between infant growth and endothelial function at 6 months would persist to 24 months and that accelerated growth would lead to an increased percent body fat, which would, in turn, impact negatively on endothelial function. STUDY DESIGN: In a prospective observational study, 104 healthy term newborns underwent anthropometry and measurements of vascular vasodilation at 0, 6, 12, and 24 months. We recorded maximum vasodilation in response to acetylcholine (endothelium-dependent) and nitroprusside (endothelium-independent) by use of laser-Doppler vascular perfusion monitoring of the forearm skin vasculature. Additional anthropometry at 1 and 3 months was collected from child welfare centers. The data were analyzed by multilevel linear regression. RESULTS: Weight gain from 0-1 month was associated inversely with maximum perfusion in response to acetylcholine at the age of 2 years (b = -8.28 perfusion units [PU] per Δ z-score, P = .03). Weight gain from 0-1 month was related positively to maximum perfusion in response to nitroprusside (b = 10.12 PU per Δ z-score, P = .04), as was birth weight (b = 8.02 PU per z-score, P = .02). Body fat percentage did not have a significant effect in any of the perfusion models and was not related to maximum perfusion at 2 years. CONCLUSION: Infant weight gain from 0-1 month is inversely related to endothelial function in healthy term infants, at least to the age of 2 years. This relationship was not explained by an increased percentage body fat.

High-altitude hypoxia and echocardiographic indices of pulmonary hypertension in male and female chickens at adulthood.

BACKGROUND: By combining the chick embryo model with incubation at high altitude (HA), the effects of chronic hypoxia on fetal growth, fetal cardiac and aortic wall remodeling and systemic arterial blood pressure at adulthood were reported. Using non-invasive functional echocardiography, here we investigated the in vivo effects of HA hypoxia on the pulmonary circulation at adulthood in male and female chickens. METHODS AND RESULTS: Chick embryos were incubated, hatched and raised at sea level (SL) or at HA. At 6 months of age, functional echocardiography was performed and the body and heart weights were taken. Heart weight was heavier in males but not in female HA chickens compared to their same sex SL counterparts. Similarly, male but not female HA chickens had greater in vivo right ventricular wall thickness compared to their same sex SL counterparts. The tricuspid pressure gradient was greatly enhanced in HA male and HA female chickens. However, the increment in the tricuspid pressure gradient was greater in HA males than in HA females. The pulmonary artery diameter was also enhanced in HA males than in SL males. In contrast, HA did not affect this variable in female chickens. CONCLUSIONS: The data show that chronic hypoxia during development at HA is associated with echocardiocraphic indices of pulmonary hypertension at adulthood in a highly sex-dependent manner.

Influence of growth during infancy on endothelium-dependent vasodilatation at the age of 6 months.

Low birth weight and accelerated infant growth are associated with cardiovascular disease in adulthood. Endothelial dysfunction is regarded as a precursor of atherosclerosis and is also related to infant growth. We aimed to examine whether an association between infant growth and endothelial function is already present during discrete periods of growth during the first 6 months of life in healthy term infants. A cohort of 104 newborns was studied in the first week after birth and reexamined at the age of 6 months. Maximum vasodilatation in response to acetylcholine (endothelium dependent) and nitroprusside (endothelium independent) was measured in the vasculature of the forearm skin, using laser Doppler flowmetry and iontophoresis. Growth was calculated as difference in Z scores for weight, length, weight-for-length, and head circumference. Multivariable multilevel linear regression was used for the analysis. Growth from 0 to 1 month (calculated as difference in weight) was the only window in the first 6 months of life that was significantly and inversely associated with endothelium-dependent vasodilatation at 6 months (b=-11.72 perfusion units per Z score, P=0.01 in multivariable analysis). Birth size was not important when considered simultaneously with infant growth. Maximum endothelium-independent vasodilatation was not associated with birth size or growth parameters. We conclude that growth in the first month of life is inversely associated with endothelium-dependent vasodilatation at the age of 6 months in healthy term infants, regardless of birth size.

Developmental programming of cardiovascular dysfunction by prenatal hypoxia and oxidative stress.

Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O(2)) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.

Endothelial vasodilatation in newborns is related to body size and maternal hypertension.

OBJECTIVE: The fetal response to an adverse intrauterine environment - reflected in low birth weight - is thought to cause an increased risk for adult hypertension. A possible mechanism by which fetal adaptive responses contribute to hypertension is an adverse effect on endothelial function. Identifying individuals with endothelial dysfunction as early as possible may assist in understanding the inverse association between birth weight and hypertension. The present study aimed to identify determinants of endothelial vasodilatation in the first week of life. METHODS: One hundred and four term newborns were studied in the first week after birth with regard to maximum vasodilatation in response to acetylcholine (endothelium-dependent) and nitroprusside (endothelium-independent) in the vasculature of the forearm skin, by use of a laser-Doppler device and iontophoresis. Bivariable and multivariable linear regression with various familial, gestational and neonatal potential covariates were used for the analysis. RESULTS: In the bivariable analysis, maximum perfusion after administration of acetylcholine was positively associated with birth weight, length, head circumference and maternal education level, but negatively associated with maternal hypertension during pregnancy. In the multivariable analysis, head circumference [b = 11.9 perfusion units/z-score, P = 0.02] and hypertension during pregnancy (b = -25.3 perfusion units from nonhypertensive to hypertensive, P = 0.02) remained significantly associated. Maximum perfusion after administration of nitroprusside was not related to any of the anthropometric measures; it was, however, related to gestational age (b = -11.1 perfusion units/week, P = 0.009). CONCLUSION: This study showed that body size, head circumference in particular, is positively associated with endothelial vasodilatation in newborns, whereas hypertension during pregnancy is inversely associated with endothelial vasodilatation.

Adrenocortical suppression in highland chick embryos is restored during incubation at sea level.

By combining the chick embryo model with incubation at high altitude, this study tested the hypothesis that development at high altitude is related to a fetal origin of adrenocortical but not adrenomedullary suppression and that hypoxia is the mechanism underlying the relationship. Fertilized eggs from sea-level or high altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at altitude with oxygen supplementation. At day 20 of incubation, embryonic blood was taken for measurement of plasma corticotropin, corticosterone, and Po(2). Following biometry, the adrenal glands were collected and frozen for measurement of catecholamine content. Development of chick embryos at high altitude led to pronounced adrenocortical blunting, but an increase in adrenal catecholamine content. These effects were similar whether the fertilized eggs were laid by sea-level or high altitude hens. The effects of high altitude on the stress axes were completely prevented by incubation at high altitude with oxygen supplementation. When chick embryos from high altitude hens were incubated at sea level, plasma hormones and adrenal catecholamine content were partially restored toward levels measured in sea-level chick embryos. There was a significant correlation between adrenocortical blunting and elevated adrenal catecholamine content with both asymmetric growth restriction and fetal hypoxia. The data support the hypothesis tested and provide evidence to isolate the direct contribution of developmental hypoxia to alterations in the stress system.

Fisiopatología del paciente quemado / Burn patient physiopathology

Las quemaduras extensas son uno de los traumas más severos al cual puede verse expuesto un individuo, este tipo de trauma tiene efectos locales y sistémicos bien establecidos pero no muy bien comprendidos por la mayoría del personal de salud. Pueden comprometer directa o indirectamente a casi todos los sistemas del organismo. El objetivo de éste artículo es ofrecer una explicación sencilla y sistemática, que permita al lector entender mejor como responde el cuerpo humano ante un trauma extenso por quemadura, se espera que esta lectura mejore la comprensión de la fsiopatología de este tipo de trauma y por lo tanto se manifeste en el actuar diario del personal de salud.

An extensive burn wound is among the most severe trauma a patient can be exposed to, it has well defned local and systemic effects; however, these effects are little understood by most of the health care personal. This injury can compromise directly or indirectly every system in the body. The objective of this article is to offer a simple and systematic review that allows the reader a better understanding of the response of the human body after an extensive burn injury, it is expected that this paper contributes to the better understanding of the physiology of this type of trauma and therefore be expressed in the daily work of the health care personal.

Hypoxia sensing in the fetal chicken femoral artery is mediated by the mitochondrial electron transport chain.

Vascular hypoxia sensing is transduced into vasoconstriction in the pulmonary circulation, whereas systemic arteries dilate. Mitochondrial electron transport chain (mETC), reactive O(2) species (ROS), and K(+) channels have been implicated in the sensing/signaling mechanisms of hypoxic relaxation in mammalian systemic arteries. We aimed to investigate their putative roles in hypoxia-induced relaxation in fetal chicken (19 days of incubation) femoral arteries mounted in a wire myograph. Acute hypoxia (Po(2) approximately 2.5 kPa) relaxed the contraction induced by norepinephrine (1 microM). Hypoxia-induced relaxation was abolished or significantly reduced by the mETC inhibitors rotenone (complex I), myxothiazol and antimycin A (complex III), and NaN(3) (complex IV). The complex II inhibitor 3-nitroproprionic acid enhanced the hypoxic relaxation. In contrast, the relaxations mediated by acetylcholine, sodium nitroprusside, or forskolin were not affected by the mETC blockers. Hypoxia induced a slight increase in ROS production (as measured by 2,7-dichlorofluorescein-fluorescence), but hypoxia-induced relaxation was not affected by scavenging of superoxide (polyethylene glycol-superoxide dismutase) or H(2)O(2) (polyethylene glycol-catalase) or by NADPH-oxidase inhibition (apocynin). Also, the K(+) channel inhibitors tetraethylammonium (nonselective), diphenyl phosphine oxide-1 (voltage-gated K(+) channel 1.5), glibenclamide (ATP-sensitive K(+) channel), iberiotoxin (large-conductance Ca(2+)-activated K(+) channel), and BaCl(2) (inward-rectifying K(+) channel), as well as ouabain (Na(+)-K(+)-ATPase inhibitor) did not affect hypoxia-induced relaxation. The relaxation was enhanced in the presence of the voltage-gated K(+) channel blocker 4-aminopyridine. In conclusion, our experiments suggest that the mETC plays a critical role in O(2) sensing in fetal chicken femoral arteries. In contrast, hypoxia-induced relaxation appears not to be mediated by ROS or K(+) channels.

Fetal asphyctic preconditioning protects against perinatal asphyxia-induced behavioral consequences in adulthood.

Perinatal asphyxia is one of the major causes of neuronal injury and impaired development in infants. We recently have shown that a brief episode of experimental fetal asphyxia (FA) can provoke an endogenous neuroprotection against subsequent severe perinatal asphyxia (SPA). The long-lasting functional consequences of FA preconditioning are not clear yet. The aim of the study was to determine if FA preconditioning can provide a long-lasting behavioral protection against SPA. FA was induced, as a preconditioning stimulus, by clamping the uterine vasculature for 30 min on E17. At birth, SPA was induced by placing the uterine horns in a water bath for 19 min. At 6 months of age, functional outcome was assessed using different behavioral tests: the open field for locomotor activity, the elevated zero maze for anxiety-related behavior, the forced swim test for depression-related behavior and the object recognition task for cognition. Data showed that FA preconditioning improved postnatal mortality after SPA. At the age of 6 months, the total distance moved in the open field and elevated zero maze was significantly less in the SPA group compared to the control groups. In addition, cognitive performance in the object recognition task was impaired in the SPA offspring compared to the control groups. Most importantly, FA preconditioning was able to preserve both locomotor activity and cognition function. In conclusion, FA preconditioning induces a long-lasting, functional protection against SPA. Therefore, this model seems to offer good opportunities for the identification and characterization of the underlying mechanisms of preconditioning.

Role of Rho-kinase in mediating contraction of chicken embryo femoral arteries.

Rho-kinase-dependent Ca2+ sensitization is an essential process for contraction of mammalian vascular smooth muscle but the information about its effects in non-mammalian vessels is scarce. We aimed to investigate, using the Rho-kinase inhibitor hydroxyfasudil, the potential role of the Rho-kinase pathway of Ca2+ sensitization in depolarization- and agonist-mediated contraction of chicken embryo (at day 19 of the 21 days of incubation) femoral arteries. Contraction elicited by KCl (125 mM) comprised two phases (phasic and tonic contraction), both of which were abolished in the absence of extracellular Ca2+. Hydroxyfasudil (10 microM) left the initial phasic component nearly intact but abolished the tonic component. Hydroxyfasudil also induced a marked impairment of the contractions elicited by phenylephrine (PE), the thromboxane A2 mimetic U46619, and endothelin-1. In contrast, inhibition of protein kinase C (PKC) by chelerythrine did not affect KCl- or PE-induced contractions, indicating lack of participation of PKC-mediated Ca2+ sensitization. Incubation under chronic hypoxia (15% O2 from day 0) impaired embryonic growth but did not significantly affect hydroxyfasudil-mediated relaxation. In summary, our findings are indicative of a role for Rho-kinase activity in depolarization- and agonist-induced force generation in chicken embryo femoral arteries.

Maternal stress-induced reduction in birth weight as a marker for adult affective state.

It is known that adverse events experienced by a pregnant woman may be reflected upon the developing fetus and adversely affect its mental wellbeing in later life. In a recent study by our group, prenatal stress was associated with a clear increase in anxiety- and depression-related behavior in male, but not female Sprague-Dawley offspring. Since birth weight data were recorded we were able to determine whether birth weight, as an important outcome measure of fetal distress, may be used as a predictive indicator for adult performance. For this purpose, a correlation analysis was performed, aimed at studying the possible link between stress-induced fetal growth restriction and adult affective state. Male birth weight correlated positively to depression-related behavior in the forced swim test. Furthermore, it weight was correlated negatively to basal, and positively to stress-induced, plasma corticosterone levels in adulthood. Female birth weight did not correlate to any of the studied outcome measures. These data suggest that male birth weight may represent a valuable indicative marker for variations in adult affective state with a developmental origin.

Age-related changes in isoprostane-mediated relaxation of piglet blood vessels.

We studied the putative relaxant effects of several isoprostanes (8-iso-PGE1, and 8-iso-PGE2, 8-iso-PGF1alpha, 8-iso-PGF1beta, 8-iso-PGF2alpha, and 8-iso-PGF2beta) on pulmonary (PA), mesenteric (MA), coronary (CA) arteries and pulmonary veins (PV), from newborn and 2-week-old piglets. Isoprostanes were compared with agonists of the EP (PGE1, PGE2, and misoprostol), DP (PGD2), and IP (iloprost) receptors. Isoprostane-induced relaxation was only observed when TP receptors were occupied (by U46619) or blocked (by SQ 29,548). Under these conditions, 8-iso-PGE2 induced a relaxation of PA (but not PV or MA) that increased with postnatal age. 8-iso-PGE1, 8-iso-PGE2, and 8-iso-PGF2alpha evoked modest relaxations in CA. 8-iso-PGE2-induced relaxation of PA was impaired by endothelium removal and by the presence of blockers of NO synthase (L-NAME), guanylate cyclase (ODQ), or EP receptor (AH6809). PGE1, PGE2, and misoprostol (but not PGD2 or iloprost) induced a relaxation of PA that increased with age. In conclusion, occupancy or blockade of TP receptors unmasked a relaxant effect of 8-iso-PGE2 in piglet PA. This relaxation increased with postnatal age, was endothelium-dependent and involved EP receptors and NO.

Morphological and functional alterations of the ductus arteriosus in a chicken model of hypoxia-induced fetal growth retardation.

The hypoxic conditions in which children with intrauterine growth retardation (IUGR) develop are hypothesized to alter the development of the ductus arteriosus (DA). We aimed to evaluate the effects of in ovo hypoxia on chicken DA morphometry and reactivity. Hypoxia (15% O2 from day 6 to 19 of the 21-d incubation period) produced a reduction in the body mass of the 19-d fetuses and a shortening of right and left DAs. However, ductal lumen and media cross-sectional areas were not affected by hypoxia. The ductal contractions induced by oxygen, KCl, H2O2, 4-aminopyridine, and endothelin-1 were similar in control and hypoxic fetuses. In contrast, the DAs from the hypoxic fetuses showed increased contractile responses to norepinephrine and phenylephrine and impaired relaxations to acetylcholine, sodium nitroprusside, and isoproterenol. The relaxations induced by 8-Br-cGMP, forskolin, Y-27632, and hydroxyfasudil were not altered by chronic hypoxia. In conclusion, chronic in ovo hypoxia-induced growth retardation in fetal chickens and altered the response of the DA to adrenergic agonists and to endothelium-dependent and -independent relaxing agents. Our observations support the concept that prolonged patency of the DA in infants with IUGR may be partially related with hypoxia-induced changes in local vascular mechanisms.

Developmental changes in the effects of prostaglandin E2 in the chicken ductus arteriosus.

Prostaglandin E(2) (PGE(2)) is the major vasodilator prostanoid of the mammalian ductus arteriosus (DA). In the present study we analyzed the response of isolated DA rings from 15-, 19- and 21-day-old chicken embryos to PGE(2) and other vascular smooth muscle relaxing agents acting through the cyclic AMP signaling pathway. PGE(2) exhibited a relaxant response in the 15-day DA, but not in the 19- and 21-day DA. Moreover, high concentrations of PGE(2) (>or= 3 microM in 15-day and >or= 1 microM in 19-day and 21-day DA) induced contraction of the chicken DA. The presence of the TP receptor antagonist SQ29,548, unmasked a relaxant effect of PGE(2) in the 19- and 21-day DA and increased the relaxation induced by PGE(2) in the 15-day DA. The presence of the EP receptor antagonist AH6809 abolished PGE(2)-mediated relaxation. The relaxant responses induced by PGE(2) and the beta-adrenoceptor agonist isoproterenol, but not those elicited by the adenylate cyclase activator forskolin or the phosphodiesterase 3 inhibitor milrinone, decreased with maturation. High oxygen concentrations (95%) decreased the relaxation to PGE(2). The relaxing potency and efficacy of isoproterenol and milrinone were higher in the pulmonary than in the aortic side of the DA, whereas no regional differences were found in the response to PGE(2). We conclude that, in contrast to the mammalian situation, PGE(2) is a weak relaxant agent of the chicken DA and, with advancing incubation, it even stimulates TP vasoconstrictive receptors.

Fetal asphyxia leads to a decrease in dorsal raphe serotonergic neurons.

The aim of the present study was to determine the effects of fetal asphyxia (FA) on anxiety and serotonergic neurons in young adult and middle-aged rats. FA was induced at embryonic day 17 by clamping the uterine circulation for 75 min. Anxiety-related behavior was tested in an open field, and design-based stereology was used for counting serotonergic (5-hydroxytryptamine/serotonin, 5-HT) neurons in the dorsal raphe nucleus (DRN). The open field revealed increased anxiety in the 19-month-old FA rats in comparison to control animals. No significant differences were found in DRN 5-HT neuron numbers at 6 months. At 19 months, however, FA significantly lowered the mean density and volume of 5-HT neurons in the DRN as compared to controls. Further, an age-related reduction was found in the total number, the mean density and the mean volume of 5-HT neurons within the FA group. In conclusion, FA is associated with increased anxiety and age-related changes in 5-HT immunohistochemistry within the DRN. These results support the notion that insults caused by asphyxiation during critical periods of brain development could create a predisposition to serotonergic abnormalities and anxiety deficits in adulthood.

Feasibility of noninvasive continuous finger arterial blood pressure measurements in very young children, aged 0-4 years.

Our goal was to study the feasibility of continuous noninvasive finger blood pressure (BP) monitoring in very young children, aged 0-4 y. To achieve this, we designed a set of small-sized finger cuffs based on the assessment of finger circumference. Finger arterial BP measured by a volume clamp device (Finapres technology) was compared with simultaneously measured intra-arterial BP in 15 very young children (median age, 5 mo; range, 0-48), admitted to the intensive care unit for vital monitoring. The finger cuff-derived BP waveforms showed good resemblance with the invasive arterial waveforms (mean root-mean-square error, 3 mm Hg). The correlation coefficient between both methods was 0.79 +/- 0.19 systolic and 0.74 +/- 0.24 diastolic. The correlation coefficient of beat-to-beat changes between both methods was 0.82 +/- 0.18 and 0.75 +/- 0.21, respectively. Three measurements were related to measurement errors (loose cuff application; wrong set-point). Excluding these erroneous measurements resulted in clinically acceptable measurement bias (-3.8 mm Hg) and 95% limits of agreement (-10.4 to + 2.8 mm Hg) of mean BP values. We conclude that continuous finger BP measurement is feasible in very young children. However, cuff application is critical, and the current set-point algorithm needs to be revised in very young children.