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Biomedical subjects

Augusto Sola

Publications and source records attributed to Augusto Sola.

At least 19 recordsLinked to original sources
PubMed2007

Low doses of ethanol and hypoxia administered together act synergistically to promote the death of cortical neurons.

The majority of clinically relevant injuries to the developing brain are increasingly being recognized as the result of a combination of least two insults. Evidence from epidemiologic and clinical studies suggests that many of these insults do not cause injury in and of themselves. Rather, they act as predisposing factors (pre-conditioning cytotoxic factors, such as chronic ethanol consumption), increasing the susceptibility to a second, injury-producing (precipitating), unfavorable event (such as hypoxia-ischemia). In this study we make use of primary neuronal cultures to test, in a reproducible system, this two-hit hypothesis. We show that, when administered in combination, low levels of two clinically important environmental insults, hypoxia and ethanol, despite having minimal effects on their own, can act synergistically produce a significant degree of neuronal injury. We further show that one indicator of apoptotic cell death, activated caspase 3, undetectable in neurons subjected to low levels of either insult alone, is detectable when they are administered together.

Animals↗
PubMed2006

Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study.

BACKGROUND: Persistent pulmonary hypertension (PPHN) occurs in as many as 6.8 of 1000 live births. Mortality is approximately 10% to 20% with high-frequency ventilation, surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation but is much higher when these therapies are not available. Sildenafil is a phosphodiesterase inhibitor type 5 that selectively reduces pulmonary vascular resistance. OBJECTIVE: Our goal was to evaluate the feasibility of using oral sildenafil and its effect on oxygenation in PPHN. DESIGN: This study was a proof-of-concept, randomized, masked study in infants >35.5 weeks' gestation and <3 days old with severe PPHN and oxygenation index (OI) >25 admitted to the NICU (Hospital Niño Jesús, Barranquilla, Colombia). The sildenafil solution was prepared from a 50-mg tablet. The first dose (1 mg/kg) or placebo was given by orogastric tube <30 minutes after randomization and every 6 hours. Preductal saturation and blood pressure were monitored continuously. OI was calculated every 6 hours. The main outcome variable was the effect of oral sildenafil on oxygenation. Sildenafil or placebo was discontinued when OI was <20 or if there was no significant change in OI after 36 hours. RESULTS: Six infants with an OI of >25 received placebo, and 7 received oral sildenafil at a median age of 25 hours. All infants were severely ill, on fraction of inspired oxygen 1.0, and with similar ventilatory parameters. Intragastric sildenafil and placebo were well tolerated. In the treatment group, OI improved in all infants within 6 to 30 hours, all showed a steady improvement in pulse oxygen saturation over time, and none had noticeable effect on blood pressure; 6 of 7 survived. In the placebo group, 1 of 6 infants survived. CONCLUSIONS: Oral sildenafil was administered easily and tolerated as well as placebo and improved OI in infants with severe PPHN, which suggests that oral sildenafil may be effective in the treatment of PPHN and underscores the need for a large, controlled trial.

Administration, Oral↗
PubMed2005

Cardiotrophin-1 protects cortical neuronal cells against free radical-induced injuries in vitro.

Cardiotrophin-1 (CT-1) was initially defined as a mediator of cardiomyocyte hypertrophy. Additional studies have showed that CT-1 enhanced survival of differentiated cardiac muscle cells and inhibited cardiac myocyte apoptosis after serum deprivation or cytokine stimulation. Moreover, CT-1 has recently been shown to act as a neuroregulatory cytokine in the peripheral nervous system. However, its effects in the central nervous system have not been determined. In the present study, we evaluated whether CT-1 protects cultured cortical neurons against oxidative injuries caused by the hydroxyl radical-producing agent FeSO4 and by the peroxynitrite-producing agent 3-morpholinosydnonimine (SIN-1). CT-1 reduced neuronal cell death caused by FeSO4 and also attenuated the neurotoxic effect of SIN-1 in a dose-dependent manner. These results indicate that CT-1 is neuroprotective in an in vitro model of cerebral ischemia. This study indicates that further evaluation of CT-1 in acute brain injury should be investigated in vivo.

Animals↗
PubMed2005

Mild intermittent hypoxia does not induce stress responses in the neonatal rat brain.

We previously demonstrated that intermittent hypoxia evokes persistent changes in extracellular striatal dopamine, locomotor activity and executive function, using a rodent model emulating apnea of prematurity in which rat pups are exposed to 20-second bursts of hypoxic gas mix containing 10% oxygen (60 events/h; 6 h/day) from postnatal days 7 to 11. To determine whether subtle repetitive hypoxic insults also induce expression of stress-related genes, we employed real-time RT-PCR to assay gene transcription in neonatal rats subjected to the same paradigm. In addition, we also measured expression of stress-induced transcripts in an age-matched cohort following a more severe oxidative stressor: permanent focal ischemia. Four transcripts were elevated following the ischemic insult: heat shock protein 70 (Hsp70), CL100, nurr77, and heme oxygenase-1. In contrast, these transcripts were not regulated in the majority of neonatal rats exposed to an intermittent hypoxia protocol. Hsp70 was strongly induced, and CL100 and nurr77 were slightly induced in only 2 of 11 post-hypoxic rats compared to controls. These data demonstrate that a single ischemic event elicits expression of specific stress-related genes, whereas 5 days of brief intermittent hypoxic insults typically do not. Thus, it is unlikely that the neurochemical and behavioral morbidity observed in juvenile and adult rodents exposed to intermittent hypoxia during a critical period of brain development are related to stress-induced changes in gene expression.

Animals↗
PubMed2005

Potential for protection and repair following injury to the developing brain: a role for erythropoietin?

Perinatal brain injury is a major contributor to perinatal morbidity and mortality, and a considerable number of these children will develop long term neurodevelopmental disabilities. Despite the severe clinical and socio-economic significance and the advances in neonatal care over the past twenty years, no therapy yet exists that effectively prevents or ameliorates detrimental neurodevelopmental effects in cases of perinatal/neonatal brain injury. Our objective is to review recent evidence in relation to the pervading hypothesis for targeting time-dependent molecular and cellular repair mechanisms in the developing brain. In addition we review several potential neuroprotective strategies specific to the developing nervous system, with a focus on erythropoietin (Epo) because of its potential role in protection as well as repair.

Animals↗
PubMed2005

Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats.

Erythropoietin (Epo) plays a central role in erythropoiesis but also has neuroprotective properties. Recently, Epo-related neuroprotective studies used a hypoxic-ischemic neonatal model, which is different from focal stroke, a frequent cause of neonatal brain injury. We report on the effects of Epo treatment given after focal stroke and its potential neuroprotective mechanisms in postnatal day 7 rats with focal cerebral ischemia (FCI) achieved by occlusion of the middle cerebral artery. The experimental groups included sham operation, FCI plus vehicle, and FCI plus Epo. In the Epo-treated group, pups received a single intraperitoneal injection of 1000 U/kg 15 min after FCI or three injections of 100, 1000, or 5000 U/kg, starting at 15 min and repeated at 1 and 2 d after FCI. Epo treatment produced significant reductions in the mean infarct area and volume at 1 and 3 d after FCI, demonstrated by 2,3,5-triphenyltetrazolium chloride staining. Terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining showed a markedly reduced number of TUNEL-positive cells in the Epo-treated group when compared with the vehicle control 3 d after FCI (p<0.01). The most effective dose after FCI was 1000 U/kg for 3 d. Immunoanalyses showed that Epo induced a significant increase in phosphorylated Janus kinase 2 and signal transducer and activator of transcription-5 expressions at 1 and 3 d and up-regulated Bcl-xL expression by 24 h after FCI but did not affect Epo receptor or NF-kappaB expression. In conclusion, Epo given after FCI in neonatal rats provides significant neuroprotection, mediated possibly by activation of the Janus kinase-signal transducer and activator of transcription-Bcl-xL signaling pathways.

Animals↗
PubMed2005

Different doses of dopamine have heterogeneous effects on cerebral hemodynamics and dopamine receptors in young rabbits as measured with near infrared spectroscopy.

BACKGROUND: Fluctuations in cerebral blood volume and cerebral oxygenation may be important in the pathogenesis of intraventricular hemorrhage and hypoxic-ischemic brain injury in the neonate. The cerebral hemodynamic response to dopamine infusion in premature infants is not well established. The newborn rabbit, a rather immature species at birth, is a suitable model for monitoring the physiological changes of the cerebral circulation. METHODS: The effect of dopamine upon cerebral hemodynamics and basal ganglia dopaminergic receptors were studied using four different dopamine doses. RESULTS: No significant changes in near infrared spectroscopy (NIRS) parameters were observed in the animals that received 0.5 (n = 5) and 1 microg/kg/min (n = 4) of dopamine intravenously. In contrast, in those animals that received dopamine at 5 microg/kg/min (n = 7) and 50 microg/kg/min (n = 7), there was a significant decrease in oxygenated hemoglobin. Moreover, this was accompanied by a significant increase in deoxygenated hemoglobin soon after drug infusion. Cerebral blood volume was increased in the group that received 5 microg/kg/min, but significantly decreased in the group that received 50 microg/kg/min. In both groups NIRS parameters returned to baseline values soon after stopping dopamine infusion. CONCLUSION: Despite evidence of a physiological response, we found no difference in the distribution of dopamine receptors between experimental and control animals. We therefore speculate that dopamine has an effect on the cerebrovasculature that could be mediated by factors other than changes in the basal ganglia dopamine receptors.

Animals↗
PubMed2005

The impact of vaginal delivery in premature infants weighing less than 1,251 grams.

OBJECTIVE: To evaluate whether mode of delivery is a predictor of poor short-term outcome at different birth weight categories in very low birth weight infants. METHODS: This study examined a cohort of infants weighing less than 1,251 g born at 2 perinatal centers from January 1, 2000, to December 31, 2003. Outborn infants or those with major anomalies were excluded from the study. Outcome variables included death, severe intraventricular hemorrhage, periventricular leukomalacia (PVL), and combined poor short-term outcomes (death, severe intraventricular hemorrhage, and PVL). RESULTS: Of the 397 infants who met enrollment criteria, 44% were born vaginally and 56% by cesarean delivery. The proportion of multiparous, breech presentation and prolonged rupture of membranes was significantly different between groups. For infants weighing less than 751 g, the risks of severe intraventricular hemorrhage (41% versus 22%; odds ratio [OR] 2.79, 95% confidence interval [CI] 1.08-7.72) and combined poor short-term outcome (67% versus 41%; OR 2.95, 95% CI 1.25-6.95) were significantly higher if delivered vaginally. Among survivors weighing less than 751 g, the risk of severe intraventricular hemorrhage was higher among those delivered vaginally (24% versus 9%; OR 8.18, 95% CI 1.58-42.20). In infants less 1,251 g who survived, vaginal delivery had a strong association with PVL (5% versus 1%; OR 11.53, 95% CI 1.66-125). CONCLUSION: In infants less than 1,251 g who survived to discharge, vaginal delivery is associated with higher risk for PVL. Furthermore, in infants less than 751 g, vaginal delivery is a predictor for severe intraventricular hemorrhage and combined poor short-term outcome. The negative impact of vaginal delivery mode decreases as birth weight category increases.

Cerebral Hemorrhage↗
PubMed2004

A case of Adams-Oliver syndrome with associated brain and pulmonary involvement: further evidence of vascular pathology?

We report on a case of Adams-Oliver syndrome (AOS) with typical skin and limb defects along with the unique findings of pulmonary hypertension and central nervous system (CNS) involvement. Adams-Oliver syndrome has a wide spectrum of physical anomalies ranging from characteristic aplasia cutis congenita (ACC), transverse limb defects, and cutis marmorata telangiectica to extensive lethal anomalies. While pulmonary hypertension is usually not associated with AOS, the abnormal endothelial regulation of vascular tone seen in the pulmonary vasculature may enhance current pathophysiologic concepts of vascular abnormalities in AOS. There is accumulating evidence of significant CNS defects in AOS. This infant had hypoplastic corpus callosum and focal findings in the periventricular white matter. Evaluation for pulmonary hypertension and CNS anomalies in patients suspected to have AOS, can help identify those who are at risk for acute morbidities and associated developmental delays.

Abnormalities, Multiple↗
PubMed2004

Permanent focal cerebral ischemia activates erythropoietin receptor in the neonatal rat brain.

Erythropoietin (Epo) has been shown to act as a neurotrophic and neuroprotective factor via binding to its receptor (EpoR) which is activated in adult brains following hypoxia and ischemia. However, no evidence suggests that cerebral ischemia can activate EpoR in the neonatal brain. In the present study, the changes in EpoR expression were investigated using a modified model of permanent focal cerebral ischemia (FCI) in 7-day-old rat pups. Western blot analysis with an anti-rabbit EpoR antibody revealed a significant increase in the EpoR protein in the ischemic areas, starting from 6 to 12 h after FCI. Moreover, many EpoR-positive cells were detected in the ischemic areas from 12 h after FCI, and the positive cells were identified as neurons and microglia/macrophage but not astrocytes 24 h after FCI. Additionally, double staining with a red in situ apoptosis detection kit and the EpoR antibody indicated that EpoR-positive cells were in apoptotic cell death in the ischemic area. Therefore, these results suggest that EpoR is activated in the ischemic areas of neonatal rats and plays an important role in brain injury during development.

Animals↗
PubMed2004

A reproducible experimental model of focal cerebral ischemia in the neonatal rat.

Recent data suggest that the incidence of focal cerebral ischemia (FCI) and stroke is higher than previously recognized and could account for a large proportion of brain lesions in the preterm and full term neonate. Therefore, it is critically important to develop an appropriate model of FCI in neonatal animals. We describe here a modified model of permanent FCI in rat pups at postnatal day-7 (P7). To produce permanent FCI, a suture embolus with different diameters (180-220 microm) was inserted into the left common carotid artery (CCA) of the pups with different weight (14-19 g). Then the suture embolus was advanced to the middle cerebral artery (MCA) to produce its occlusion. The success of vascular occlusion was evaluated by imaging the ischemic territory on serial brain sections with carbon black staining immediately after permanent FCI. The consistent cerebral infarction was confirmed by 2,3,5-triphenyltetrazolium chloride (TTC) staining 24 h after permanent FCI. Terminal deoxynucleotidyltransferase-mediated 2'-deoxyuridine 5'-triphospate-biotin nick end labeling (TUNEL) staining showed cell death with TUNEL labeling in the ischemic areas, which is one of the features of apoptosis. The present model opens the way for advanced pathophysiological studies of FCI in neonates.

Animals↗
PubMed2004

Intrauterine growth restriction impacts tolerance to total parenteral nutrition in extremely low birth weight infants.

BACKGROUND: Hepatobiliary dysfunction is well recognized as a complication of long-term total parenteral nutrition (TPN). Because intrauterine growth restriction (IUGR) alters a number of metabolic and physiologic variables in the fetus that probably affect the hepatocyte function and tolerance to feedings in the IUGR extremely low birth weight (ELBW), we hypothesized that this group of babies would have an increased incidence of TPN-associated cholestasis and chronic liver failure. METHODS: We performed a review of all ELBW infants (birth weight <1000 g) that received TPN for >7 days. RESULTS: Among 1768 infants admitted to the neonatal intensive care unit there were 103 ELBW who received TPN >7 days, 38 (37%) of them developed TPN cholestasis. Among 69 appropriate for gestational age (AGA)-ELBW infants, 19 (27%) developed cholestasis compared to 19/34 small for gestational age (SGA)-ELBW infants (56%) (p<0.0009). Maximum direct bilirubin values and days on TPN were similar in both groups. SGA-ELBW infants had an increased incidence and earlier onset of cholestasis when compared to AGA-ELBW patients. Liver biopsies and/or autopsies of infants that developed liver failure (four AGA/four SGA) showed extensive sinusoidal/portal fibrosis compatible with "TPN lesion". In the other 30 cases, liver function eventually returned to normal after TPN discontinuation. CONCLUSIONS: When compared, SGA-ELBW infants who received TPN >7 days, despite being more mature than AGA-ELBW infants, have an increased risk for TPN cholestasis and developed this complication earlier in life. However, the incidence of chronic liver failure was not different in these two groups.

Cholestasis↗
PubMed2003

Fructose-1,6-biphosphate prevents excitotoxic neuronal cell death in the neonatal mouse brain.

The excitotoxic cascade may represent an important pathway leading to brain damage and cerebral palsy. Brain lesions induced in newborn mice by ibotenate (acting on N-methyl-D-aspartate receptors) and by S-bromowillardiine (acting on alpha-3-amino-hydroxy-5-methyl-4-isoxazole propionic acid and kainate receptors) mimic some aspects of white matter cysts and transcortical necrosis observed in human perinatal brain damage. Fructose 1,6-biphosphate (FBP) is a high-energy glycolytic pathway intermediate which, in therapeutic doses, is non-toxic and neuroprotective in hypoxic-ischemic models of brain injury. Mechanisms of action include modulation of intracellular calcium through phospholipase C (PLC) activation. The goal of this study was to determine the neuroprotective effects of FBP in a mouse model of neonatal excitotoxic brain injury. Mice that received intraperitoneal FBP had a significant reduction in size of ibotenate-induced (80% reduction) or S-bromowillardiine-induced (40% reduction) cortical plate lesions when compared with control animals. Studies of fragmented DNA and cleaved caspase 3 confirmed the survival promoting effects of FBP. FBP had no detectable effect on excitotoxic white matter lesions. The effects of FBP were antagonized by co-administration of PLC, protein kinase C or mitogen-associated protein kinase inhibitors but not by protein kinase A inhibitor. A moderate, transient cooling of pups immediately after the insult extended the therapeutic window for FBP, as FBP administered 24 h after ibotenate was still significantly neuroprotective in these pups. This data extends the neuroprotective profile of FBP in neonatal brain injury and identifies gray matter lesions involving N-methyl-D-aspartate receptors as a major target for this promising drug.

Alanine↗
PubMed2003

Cerebrovascular response in small preterm infants during routine nursery gavage feedings.

Although gavage feedings are considered a standard of care, they are often accompanied by hemodynamic changes that may have important effects on the cerebral circulation. In 23 premature infants receiving intermittent bolus gavage feeds, changes in cerebral hemodynamics and oxygenation were studied using near-infrared spectroscopy. Orogastric tube insertion resulted in an increased cerebral blood volume in 73% of the infants and in an increase in reduced hemoglobin and in cytochrome AA(3) oxygenase in approximately 66% of the patients. Within 10 min of initiating a gavage feed, cerebral blood volume, oxygenated hemoglobin, reduced hemoglobin, and cytochrome AA(3) oxygenase decreased from baseline in about 60% of the infants. Towards the end of the study, during the postfeeding period, cytochrome AA(3) oxygenase and oxygenated hemoglobin increased in 60%, while reduced hemoglobin decreased in 78% of the infants.

Blood Volume↗
PubMed2003

Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants?

OBJECTIVE: A wide variability in the incidence of severe retinopathy of prematurity (ROP) is reported by different centers. The altered regulation of vascular endothelial growth factor from repeated episodes of hyperoxia and hypoxia is 1 important factor in the pathogenesis of ROP. Strict management of O(2) delivery and monitoring to minimize these episodes may be associated with decreased rates of ROP. The objective of this study was to compare the incidence of and need for surgery for severe ROP (stages >or=3) in infants of 500 to 1500 g birth weight before and after the implementation of a new clinical practice of O(2) management in a large level 3 neonatal intensive care unit (NICU). METHODS: An oxygen management policy that included strict guidelines in the practices of increasing and weaning of fraction of inspired oxygen (FIO(2)) and the monitoring of O(2) saturation parameters in the delivery room, during in-house transport of infants to the NICU, and throughout hospitalization was implemented in April 1998. The main objectives were to monitor oxygenation levels more precisely and to avoid hyperoxia and repeated episodes of hypoxia-hyperoxia in very low birth weight infants. Included in the policy were equipment for monitoring, initiation of monitoring at birth, avoidance of repeated increases and decreases of the FIO(2), minimization of "titration" of FIO(2), modification of previously used alarm limits, and others. After an educational process, each staff member signed an agreement stating understanding of and future compliance with the guidelines. Examinations were performed by experienced ophthalmologists following international classification and American Academy of Pediatrics recommendations. ROP data from January 1997 to December 2002 for infants of 500 to 1500 g were analyzed as usual and also have been reported to Vermont Oxford Network since 1998. RESULTS: The incidence of ROP 3 to 4 at this center decreased consistently in a 5-year period from 12.5% in 1997 to 2.5% in 2001. The need for ROP laser treatment decreased from 4.5% in 1997 to 0% in the last 3 years. CONCLUSION: We observed a significant decrease in the rate of severe ROP in very low birth weight infants in association with an educational program provided to all NICU staff and the implementation and enforcement of clinical practices of O(2) management and monitoring. Although several confounders cannot be excluded, it is likely that differences in these clinical practices may be, at least in part, responsible for the documented intercenter variability in rates of ROP.

Humans↗
PubMed2002

Are tidal volume measurements in neonatal pressure-controlled ventilation accurate?

Bedside pulmonary mechanics monitors (PMM) have become useful in ventilatory management in neonates. These monitors are used more frequently due to recent improvements in data-processing capabilities. PMM devices are often part of the ventilator or are separate units. The accuracy and reliability of these systems have not been carefully evaluated. We compared a single ventilatory parameter, tidal volume (V(t)), as measured by several systems. We looked at two freestanding PMMs: the Ventrak Respiratory Monitoring System (Novametrix, Wallingford, CT) and the Bicore CP-100 Neonatal Pulmonary Monitor (Allied Health Care Products, Riverside, CA), and three ventilators with built-in PMM: the VIP Bird Ventilator (Bird Products Corp., Palm Springs, CA), Siemens Servo 300A (Siemens-Elema AB, Solna, Sweden), and Drager Babylog 8000 (Drager, Inc., Chantilly, VA). A calibrated syringe (Hans Rudolph, Inc., Kansas City, MO) was used to deliver tidal volumes of 4, 10, and 20 mL to each ventilator system coupled with a freestanding PMM. After achieving steady state, six consecutive V(t) readings were taken simultaneously from the freestanding PMM and each ventilator. In a second portion of the bench study, we used pressure-control ventilation and measured exhaled tidal volume (V(te)) while ventilating a Bear Test Lung with the same three ventilators. We adjusted peak inspiratory pressure (PIP) under controlled conditions to achieve the three different targeted tidal volumes on the paired freestanding PMM. Again, six V(te) measurements were recorded for each tidal volume. Means and standard deviations were calculated.The percentage difference in measurement of V(t) delivered by calibrated syringe varied greatly, with the greatest discrepancy seen in the smallest tidal volumes, by up to 28%. In pressure control mode, V(te) as measured by the Siemens was significantly overestimated by 20-95%, with the biggest discrepancy at the smallest V(te), particularly when paired with the Bicore PMM. V(te), as measured by the VIP Bird and Drager paired with the Ventrak PMM, had a tendency to underestimate V(t) by up to 25% at the smallest V(te). However, when paired with the Bicore PMM, these same two ventilators read over target by up to 18%. Under controlled laboratory conditions, we demonstrated that true delivered V(te), as measured by the three ventilators and two freestanding PMM, differed markedly. In general, decreasing dynamic compliance of the tubing was not associated with greater inaccuracy in V(te) measurements.

Calibration↗