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Biomedical subjects

M Paiva

Publications and source records attributed to M Paiva.

At least 19 recordsLinked to original sources
PubMed2000

Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum.

Transgenic mice overexpressing NGF in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter were exposed to ethanol via vapor inhalation on postnatal days 4 and 5 (P4-5), the period of maximal cerebellar Purkinje cell sensitivity to ethanol. Wild-type controls were exposed in a similar manner. There were no differences in body weight or size following these procedures, but the transgenic brain weights at this age were significantly greater than wild-type controls. In the wild-type animals, a significant 33.3% ethanol-mediated loss of Purkinje cells in lobule I was detected via unbiased three-dimensional stereological counting on P5. In the GFAP-NGF transgenic animals, however, the 17.6% difference in Purkinje cell number in control and ethanol-exposed animals was not significant. There was a similar difference in Purkinje cell density in both groups, which did reach statistical significance (-32.7% in wild-type ethanol-treated animals, -17% in transgenic ethanol-exposed animals). These results suggest that endogenous overexpression of neurotrophic factors, which have previously been shown to protect against ethanol neurotoxicity in culture, can serve a similar protective function in the intact animal.

Alcohol-Induced Disorders, Nervous System↗
PubMed2000

Neurotrophic factor protection against ethanol toxicity in rat cerebellar granule cell cultures requires phosphatidylinositol 3-kinase activation.

Neonatal rat cerebellar granule cells were used to assess the possible role of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway in the neuroprotective effects of neurotrophic factors against ethanol toxicity. Culture conditions included medium with ethanol (400 and 600 mg/dl), nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF), ethanol+NGF or BDNF, the PI3-K inhibitor wortmannin (10 or 100 microM), and wortmannin+ethanol+NGF or BDNF. Neuronal survival was determined via the MTT assay. The results indicated that both NGF and BDNF ameliorate ethanol neurotoxicity, and wortmannin abolished this effect, except at the higher ethanol concentration combined with the lower wortmannin level. These data strongly implicate the PI3-K pathway in growth factor protection against ethanol neurotoxicity.

Androstadienes↗
PubMed2000

Ethanol-induced alterations in the expression of neurotrophic factors in the developing rat central nervous system.

Neonatal rats were exposed to ethanol throughout gestation, or during the early postnatal period (postnatal days 4-10 (P4-10)), and enzyme-linked immunoabsorbent assays were subsequently conducted in order to assess nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein content in hippocampus, septum, cortex/striatum and cerebellum. These determinations revealed that following prenatal ethanol treatment, there were significant ethanol-induced increases in NGF in P1 cortex/striatum, but no changes in any of the three neurotrophic factors (NTFs) in the other brain regions. Cortex/striatal NGF protein returned to control levels by P10. Following early postnatal exposure, BDNF was elevated in hippocampus and cortex/striatum (assessed on P10), and NGF was also enhanced in cortex/striatum at this age. Hippocampal and cortex/striatal BDNF returned to control levels by P21, but cortex/striatal NGF levels remained enhanced at this age. This NTF did not differ in ethanol and control animals by P60, however. The possible significance of elevated levels of NTFs as a function of ethanol exposure is discussed, and it is speculated that while such alterations could play a protective role, increases in these substances during critical developmental periods could also prove to be deleterious, and could even contribute to certain of the neuropathologies which have been observed following developmental ethanol exposure.

Animals↗
PubMed2000

Effect of neonatal ethanol exposure on parvalbumin-expressing GABAergic neurons of the rat medial septum and cingulate cortex.

This study was performed to determine the long-term effects of ethanol exposure during the brain growth spurt (postnatal days 4-10) on the number of parvalbumin-immunoreactive (PA+) GABAergic neurons in the adult (P60) rat medial septum and anterior cingulate cortex. Significant loss of neurons within each of these populations has previously been demonstrated following prenatal ethanol exposure. In the present study, no significant differences in the number of PA+ neurons were found in either the medial septum or the cingulate cortex when control and ethanol-exposed animals were compared. The cellular densities and volumetric measures in both brain regions were also similar in the two groups. We speculate that compensatory up-regulative mechanisms may have accounted for the protection of the PA neuronal populations in these two areas following the early neonatal exposure.

Animals↗
PubMed2000

N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats.

This study investigated the effect of cigarette smoke exposure and the potential protection N-acetylcysteine (NAC) in rat lungs. Forty-eight rats were exposed to cigarette smoke (CS) for 10 weeks, without (CS group) or with (CS+NAC group) oral intake of NAC 200 mg x rat(-1) x day(-1), or to fresh air (Control). All rat lungs were assessed in terms of lung function, ventilation distribution (nitrogen, helium and sulphur hexafluoride phase III slopes), and morphometry (airway wall thickening of small, medium and large bronchi). The small bronchi, defined as the airways with an internal perimeter <1,000 microm showed significantly thicker airway walls in the CS than in the Control group. By contrast, no airway wall thickening was observed in the CS+NAC group with respect to Control. Except for decreased lung volumes and compliance in CS and CS+NAC groups, which were entirely attributable to smaller body weight gain, lung function was indistinguishable from Control. Phase III slopes were significantly increased only in the CS group. In conclusion, smoke-induced alterations in the rat lungs were reflected in wall thickening of the small bronchi and increased ventilation maldistribution. These smoke-induced morphometric and ventilation distribution alterations were prevented by N-acetylcysteine.

Acetylcysteine↗
PubMed2000

Lung function and ventilation inhomogeneity in rat lungs after allergen challenge.

We studied the early response to ovalbumin challenge in sensitized Brown-Norway rats through its effect on N(2), He, and SF(6) phase III slopes of the single-breath washout and on indexes of lung function. Sensitized rats showed varying degrees of response in terms of pulmonary pressure (PL), with increases ranging between 125 and 225% of baseline. The sensitized rats presented decreased quasistatic compliance, forced vital capacity, and end-expiratory flow, with all three lung function indexes showing a significant negative correlation with corresponding PL values. They also showed significant positive correlations of PL with the N(2), He, and SF(6) phase III slopes, reflecting diffusion-convection-dependent inhomogeneities generated by conformation changes throughout the entire rat lung. In addition, the rats showing the most marked PL increases (>150% baseline PL) also revealed a reversal of the SF(6)-He slope difference because of a more marked SF(6) than He slope increase. This latter finding suggests that the degree of structural heterogeneity during early response is even more marked in the most peripheral rat lung generations.

Allergens↗
PubMed2000

Measurement of thoracoabdominal asynchrony: importance of sensor sensitivity to cross section deformations.

Discrepancies in the assessment of thoracoabdominal asynchrony are observed depending on the choice of respiratory movement sensors. We test the hypothesis that these discrepancies are due to a different dependence of the sensors on cross-sectional perimeter and area variations of the chest wall. First, we study the phase shift between perimeter and area (Phi(PA)) for an elliptical model, which is deformed by sinusoidal changes of its principal axes. We show that perimeter and area vary sinusoidally in the physiological range of deformations, and we discuss how Phi(PA) depends on the ellipticity of the cross section, on the ratio of transverse and dorsoventral movement amplitudes, and on their phase difference. Second, we compute the relationship between perimeter, area, and the output of the inductive sensor, and we proceed by comparing inductive plethysmography with strain gauges for several cross section deformations. We demonstrate that both sensors can provide different phase information for identical cross section deformations and, hence, can estimate thoracoabdominal asynchrony differently. Furthermore, the complex dependence of the inductive sensor on perimeter and area warns against this sensor for the evaluation of thoracoabdominal asynchrony.

Abdomen↗
PubMed2000

Effect of gravity on aerosol dispersion and deposition in the human lung after periods of breath holding.

To determine the extent of the role that gravity plays in dispersion and deposition during breath holds, we performed aerosol bolus inhalations of 1-microm-diameter particles followed by breath holds of various lengths on four subjects on the ground (1G) and during short periods of microgravity (microG). Boluses of approximately 70 ml were inhaled to penetration volumes (V(p)) of 150 and 500 ml, at a constant flow rate of approximately 0.45 l/s. Aerosol concentration and flow rate were continuously measured at the mouth. Aerosol deposition and dispersion were calculated from these data. Deposition was independent of breath-hold time at both V(p) in microG, whereas, in 1G, deposition increased with increasing breath hold time. At V(p) = 150 ml, dispersion was similar at both gravity levels and increased with breath hold time. At V(p) = 500 ml, dispersion in 1G was always significantly higher than in microG. The data provide direct evidence that gravitational sedimentation is the main mechanism of deposition and dispersion during breath holds. The data also suggest that cardiogenic mixing and turbulent mixing contribute to deposition and dispersion at shallow V(p).

Adult↗
PubMed2000

A human acinar structure for simulation of realistic alveolar plateau slopes.

We simulated the intra-acinar contribution to phase III slope (S(acin)) for gases of differing diffusivities (He and SF(6)) by solving equations of diffusive and convective gas transport in multi-branch-point models (MBPM) of the human acinus. We first conducted a sensitivity study of S(acin) to asymmetry and its variability in successive generations. S(acin) increases were greatest when asymmetry and variability of asymmetry were increased at the level of the respiratory bronchioles (generations 17-18) for He and at the level of the alveolar ducts (generations 20-21) for SF(6), corresponding to the location of their respective diffusion fronts. On the basis of this sensitivity study and in keeping with reported acinar morphometry, we built a MBPM that actually reproduced experimental S(acin) values obtained in normal subjects for He, N(2), and SF(6). Ten variants of such a MBPM were constructed to estimate intrinsic S(acin) variability owing to peripheral lung structure. The realistic simulation of S(acin) in the normal lung and the understanding of how asymmetry affects S(acin) for different diffusivity gases make S(acin) a powerful tool to detect structural alterations at different depths in the lung periphery.

Bronchi↗
PubMed2000

Ventilation-perfusion matching in long-term microgravity.

We studied the ventilation-perfusion matching pattern in normal gravity (1 G) and short- and long-duration microgravity (microG) using the cardiogenic oscillations in the sulfur hexaflouride (SF(6)) and CO(2) concentration signals during the phase III portion of vital capacity single-breath washout experiments. The signal power of the cardiogenic concentration variations was assessed by spectral analysis, and the phase angle between the oscillations of the two simultaneously expired gases was obtained through cross-correlation. For CO(2), a significant reduction of cardiogenic power was observed in microG, with respect to 1 G, but the reduction was smaller and more variable in the case of SF(6). A shift from an in-phase condition in 1 G to an out-of-phase condition was found for both short- and long-duration microG. We conclude that, although the distribution of ventilation and perfusion becomes more homogeneous in microG, significant inhomogeneities persist and that areas of high perfusion become associated with areas of relatively lower ventilation. In addition, these modifications seem to remain constant during long-term exposure to microG.

Carbon Dioxide↗
PubMed2000

Amelioration of ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy.

BACKGROUND: The cerebellum of the neonatal rat is highly susceptible to ethanol, with profound loss of Purkinje cells resulting from even brief exposure during the first postnatal week. Developmental ethanol exposure previously has been shown to induce free radicals/oxidative stress processes and/or down-regulate protective antioxidants. In an earlier study, we found antioxidants protected against ethanol neurotoxicity in a tissue culture environment. The present study was designed to determine whether similar protection could be manifested in the intact animal. METHODS: Neonatal rats were administered a liquid diet via intragastric intubation on postnatal days 4 and 5 (P4-P5), the peak period of ethanol sensitivity in the developing cerebellum. The diet consisted of milk formula with 12% ethanol, the isocaloric substitution of maltose-dextrin for ethanol, or ethanol plus the antioxidant vitamin E. Unbiased three-dimensional counting was utilized to analyze Purkinje cell numbers and density within defined volumes from these animals on P5. RESULTS: These determinations revealed a substantial loss of Purkinje cells in the ethanol-treated animals compared to controls (approximately 30-44%), but this loss was prevented by the inclusion of vitamin E (601U/100 ml) in the diet. A lower concentration of the antioxidant (301U/100 ml) was not effective in this regard, however. CONCLUSIONS: These results suggest that ethanol-related cerebellar damage during this early postnatal period may be related to oxidative stress processes or the insufficiency of protective antioxidants. Thus, antioxidant treatment may represent a possible therapy for preventing or ameliorating the central nervous system (CNS) damage seen in the fetal alcohol syndrome.

Animals↗
PubMed1999

Vitamin E and beta-carotene protect against ethanol combined with ischemia in an embryonic rat hippocampal culture model of fetal alcohol syndrome.

Neurodevelopmental damage can occur as a result of in utero exposure to alcohol. Oxidative stress processes are one of many proposed mechanisms thought to contribute to nervous system dysfunction characterized in fetal alcohol syndrome (FAS). Therefore, this study examined neuroprotective effects of antioxidant supplementation during ethanol (EtOH) treatment (0, 200, 400, 800 or 1600 mg/dl) combined with concomitants of EtOH exposure: acute (2-h) ischemia (aISCH) and chronic (16-h) hypoglycemia (cHG). The antioxidants vitamin E and beta-carotene protected embryonic hippocampal cultures against 0-1600 mg/dl EtOH/aISCH/cHG treatments. In addition, neuronal viability, as measured by MTT ((3,4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; 5 mg/ml)), was equal to untreated cultures when supplemented with vitamin E or beta-carotene at 0-800 mg/dl or 0-200 mg/dl EtOH/aISCH/cHG, respectively. These in vitro studies mirror potential in utero ethanol-exposed CNS conditions and may lead to therapeutic strategies targeted at attenuating neurodevelopmental FAS-related deficits.

Animals↗
PubMed1999

Bcl-2 overexpression protects the neonatal cerebellum from ethanol neurotoxicity.

The developing nervous system is extremely sensitive to ethanol, and exposure often produces a condition known as the fetal alcohol syndrome. Although mechanisms underlying developmental ethanol toxicity have long been sought, they remain poorly understood. In this study, we examined the ability of the cell death repressor gene bcl-2 to protect against ethanol neurotoxicity. Transgenic mice overexpressing bcl-2 in neurons were exposed to ethanol vapor on postnatal days 4 and 5, which is the peak period of vulnerability of cerebellar Purkinje cells to ethanol. While exposure of wild-type animals to ethanol resulted in significant loss of Purkinje cells by P5, similar exposure of homozygous and heterozygous transgenics had no effect on the number of these neurons. This study suggests that bcl-2 can protect neurons from ethanol neurotoxicity and that modulation of cell death effector or repressor gene products may play a significant role in developmental ethanol neurotoxicity.

Analysis of Variance↗
PubMed1999

The antioxidants vitamin E and beta-carotene protect against ethanol-induced neurotoxicity in embryonic rat hippocampal cultures.

Fetal alcohol syndrome is characterized by numerous nervous system anomalies with the developing hippocampus being highly vulnerable. Other conditions can result from maternal ethanol consumption including oxidative stress. Critical antioxidants, such as vitamin E, can be decreased and antioxidative defenses altered. Gestational day 18 rat hippocampal cultures were exposed to ethanol ranging from 400 to 2400 mg/dl (16 h). MTT assays assessed neurotoxicity. Viability was decreased dose dependently. Supplementation with vitamin E or beta-carotene afforded neuroprotection against all ethanol concentrations. Vitamin E completely ameliorated neuronal loss following 400 and 800 mg/dl ethanol. Vitamin E increased survival to 95%, 79%, 66%, and 75% during 1600, 1800, and 2000 and 2400 mg/dl ethanol compared to nonethanol treatment. Vitamin E increased viability by 38%, 23%, 12%, and 29% at 1600, 1800, 2000, and 2400 mg/dl compared to non-vitamin E-supplemented, ethanol treatment. beta-Carotene completely ameliorated cell loss from 400 mg/dl ethanol and increased survival by 18% at 1600 mg/dl and 12% at 2000 mg/dl. This study demonstrates in vitro antioxidative neuroprotection against developmental ethanol exposure and suggests that nutritional therapies incorporating antioxidants may help protect against deleterious fetal effects from maternal alcohol abuse.

Animals↗
PubMed1999

A source of experimental underestimation of aerosol bolus deposition.

We examined the measurement error in inhaled and exhaled aerosol concentration resulting from the bolus delivery system when small volumes of monodisperse aerosols are inspired to different lung depths. A laser photometer that illuminated approximately 75% of the breathing path cross section recorded low inhaled bolus half-widths (42 ml) and negative deposition values for shallow bolus inhalation when the inhalation path of a 60-ml aerosol was straight and unobstructed. We attributed these results to incomplete mixing of the inhaled aerosol bolus over the breathing path cross section, on the basis of simultaneous recordings of the photometer with a particle-counter sampling from either the center or the edge of the breathing path. Inserting a 90 degrees bend into the inhaled bolus path increased the photometer measurement of inhaled bolus half-width to 57 ml and yielded positive deposition values. Dispersion, which is predominantly affected by exhaled bolus half-width, was not significantly altered by the 90 degrees bend. We conclude that aerosol bolus-delivery systems should ensure adequate mixing of the inhaled bolus to avoid error in measurement of bolus deposition.

Administration, Inhalation↗
PubMed1999

Helium and sulfur hexafluoride bolus washin in short-term microgravity.

We performed single-breath washout (SBW) tests in which He and sulfur hexafluoride (SF6) were inspired throughout the vital capacity inspirations or were inhaled as discrete boluses at different points in the inspiration. Tests were performed in normal gravity (1 G) and in up to 27 s of microgravity (microG) during parabolic flight. The phase III slope of the SBW could be accurately reconstructed from individual bolus tests when allowance for airways closure was made. Bolus tests showed that most of the SBW phase III slope results from events during inspiration at lung volumes below closing capacity and near total lung capacity, as does the SF6-He phase III slope difference. Similarly, the difference between 1 G and microG in phase III slopes for both gases was entirely accounted for by gravity-dependent events at high and low lung volumes. Phase IV height was always larger for SF6 than for He, suggesting at least some airway closure in close proximity to airways that remain open at residual volume. These results help explain previous studies in microG, which show large changes in gas mixing in vital capacity maneuvers but only small effects in tidal volume breaths.

Adult↗
PubMed1999

BDNF and NGF afford in vitro neuroprotection against ethanol combined with acute ischemia and chronic hypoglycemia.

Consumption of alcohol during pregnancy can result in central nervous system deficits in infants ranging from fetal alcohol effects to fetal alcohol syndrome. Changes in cerebral metabolism causing ischemic in utero conditions can also result from ethanol (EtOH). Growth factors have been shown to ameliorate ischemic damage and EtOH-induced neurotoxicity. However, using an in vitro model system of fetal alcohol effects/fetal alcohol syndrome, this study examines the neuroprotective effects of nerve growth factor, brain-derived neurotrophic factor, or glial cell line derived neurotrophic factor against EtOH treatment (0, 200, 400, 800, or 1, 600 mg/dl) combined with acute ischemia (2-hour hypoxia in EtOH-containing glucose-free media) followed by chronic hypoglycemia (16-hour glucose deprivation in EtOH-containing media). 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays assessed relative neurotoxicity. Glial cell derived neurotrophic factor was not neuroprotective. Nerve growth factor protected against ischemia/hypoglycemia combined with 0-1,600 mg/dl EtOH. Brain-derived neurotrophic factor protected against ischemia/hypoglycemia combined with 0-800 mg/dl EtOH. These studies demonstrate marked growth factor neuroprotection against a myriad of conditions encountered by developing EtOH-exposed fetuses.

Acute Disease↗