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ABSTRACT: Proteolipid protein (Plp) gene mutation in rodents causes severe CNS dysmyelination, early death, and lethal hypoxic ventilatory depression (Miller et al., 2004). To determine if Plp mutation alters neuronal function critical for control of breathing, the nucleus tractus solitarii (nTS) of four rodent strains were studied: myelin deficient rats (MD), myelin synthesis deficient (Plp(msd)), and Plp(null) mice, as well as shiverer (Mbp(shi)) mice, a myelin basic protein mutant. Current-voltage relationships were analyzed using whole-cell patch-clamp in 300 microm brainstem slices. Voltage steps were applied, and inward and outward currents quantified. MD, Plp(msd), and Plp(null), but not Mbp(shi) neurons exhibited reduced outward current in nTS at P21. Apamin blockade of SK calcium-dependent currents and iberiotoxin blockade of BK calcium-dependent currents in the P21 MD rat demonstrated reduced outward current due to dysfunction of these channels. These results provide evidence that Plp mutation specifically alters neuronal excitability through calcium-dependent potassium channels in nTS.
Respiratory Physiology & Neurobiology 10/2009; 169(3):303-14. · 2.24 Impact Factor
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ABSTRACT: The proteolipid protein (PLP) gene (Plp) encodes the major myelin proteins, PLP and DM20. Expression of Plp occurs predominantly in oligodendrocytes, but evidence is accumulating that this gene is also expressed in neurons. In earlier studies, we demonstrated that myelin-deficient (MD) rats, which carry a mutation in the Plp gene, exhibit lethal hypoxic ventilatory depression. Furthermore, we found that, in the MD rat, PLP accumulated in neuronal cell bodies in the medulla oblongata. In the current study, we sought to determine which neurons expressed the Plp gene in the medulla oblongata and whether Plp gene expression changed in neurons with maturation. A transgenic mouse expressing the Plp promoter driving expression of enhanced green fluorescent protein (Plp-EGFP) was used to identify neurons expressing this gene. Plp expression in neurons was confirmed by immunostaining EGFP-positive cells for NeuN and by in situ hybridization for PLP mRNA. The numbers of neurons expressing Plp-EGFP and their distribution increased between P5 and P10 in the medulla. Immunostaining for surface receptors and classes of neurons expressing Plp-EGFP revealed that Plp gene expression in brainstem neurons was restricted to neurons expressing specific ligand-gated channels and biosynthetic enzymes, including glutamatergic NMDA receptors, GABA(A) receptors, and ChAT in defined areas of the medulla. Plp gene expression was rarely found in interneurons expressing GABA and was never found in AMPA receptor- or tyrosine hydroxylase-expressing neurons. Thus, Plp expression in the mouse caudal medulla was found to be developmentally regulated and restricted to specific groups of neurons.
Journal of Neuroscience Research 06/2009; 87(13):2842-53. · 2.74 Impact Factor
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ABSTRACT: We used a rat pup model to delineate whether mechanical ventilation of <or=4 h duration in the absence of supplemental oxygen contributes to the development of airway hyperreactivity. Eight-day-old rat pups were assigned to unventilated normoxic controls, ventilated under normoxic conditions, ventilated under hyperoxic conditions (100% O2), or unventilated hyperoxic groups (>95% O2). After each intervention, they were returned to their mothers. On d 10 of life, all animals were anesthetized, paralyzed, and ventilated to measure pulmonary function. Total lung resistance (RL) and dynamic lung compliance (Cdyn) were measured in response to increasing intravenous doses of methacholine (0.03-1 microg/g) by head-out body plethysmography. Injection of methacholine caused a dose-dependent increase in RL and decrease in Cdyn. The response of both RL and Cdyn to methacholine was significantly potentiated by prior exposure to mechanical ventilation when compared with unventilated normoxic controls. The addition of hyperoxia to mechanical ventilation did not further potentiate responses to methacholine. Mechanical ventilation did not alter lung myosin or the number of inflammatory cells in airways of room air ventilated versus unventilated control animals. We conclude that a brief period of mechanical ventilation in rat pups increases airway reactivity 48 h after such exposure in the presence as well as absence of hyperoxic exposure. This represents a potentially important model to investigate the mechanisms involved in airway hyperreactivity induced by neonatal lung injury.
Pediatric Research 09/2006; 60(2):136-40. · 2.70 Impact Factor
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ABSTRACT: Treatment of air pollutants in a biofilter requires that the compound be effectively transported from the gas phase to the organisms that reside in a biofilm that forms upon a packing material. Models of biofiltration generally treat the biofilm like water by using a Henry's law constant to predict mass transfer rates into the biofilm where degradation occurs and, hence, predict low rates for hydrophobic compounds. However, some compounds that are virtually insoluble in water are also treated unusually well. The objective of this study was to develop a fundamental understanding of the apparent enhanced degradation of hydrophobic pollutants in biofilms. Specifically, the goals of this study were to experimentally determine transport and reaction rates of hydrophobic pollutants in artificial biofilms. We studied the transport and reaction rates of alpha-pinene (as a model hydrophobic pollutant) in a headspace in contact with a well-defined biofilm made up of biomass immobilized in low melting point agarose and found that reaction rates were similar in order of magnitude to biofilter rates. The transport rates through these films once deactivated were found to be the same as through agar (diffusion coefficient between 2.6 and 3.4 x 10(-6) cm2/s). The degradation rates through model biofilms ranged from 2 to 4 x 10(-7) (g/(cm2 min)). A new explanation of high degradation rates was put forth whereby a biologically mediated transformation is taking place in which alpha-pinene is oxidized into a more soluble, less volatile compound that can then penetrate deeper into the biofilm. The formation of this more soluble byproduct was confirmed with batch kinetics experiments using filtered samples, and its proposed identity is cis-2,8-p-menthadien-1-ol, a menthadienol, a novel metabolite of alpha-pinene degradation. A simple conceptual model based on these results is also presented.
Environmental Science and Technology 09/2005; 39(15):5856-63. · 5.23 Impact Factor
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ABSTRACT: Simultaneous breathing and nursing from a bottle or breast requires intricate coordination of the muscles that serve both respiration and feeding. During the buccopharyngeal phase of feeding reflex input to the brainstem from the oropharynx and larynx, as well as suprabulbar and chemoreceptor areas controls the sequential activity of the muscles of deglutition. Coordinated development of buccopharyngeal functions generally occurs by 35 weeks post-conceptional age in infants, but can be disrupted by respiratory disease or neuropathology. During the oesophageal phase of feeding, the bolus of food traverses the oesophagus and lower oesophageal sphincter, whose tone is also regulated by nuclei in the brainstem and modulated by respiratory drive. Control of the lower oesophageal sphincter gradually develops postnatally in premature infants. Although symptomatic gastro-oesophageal reflux can be problematic for the term or preterm infant, it does not appear that reflux is a common stimulus for apnoea of prematurity.
Seminars in Neonatology 07/2004; 9(3):221-7.
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Advances in experimental medicine and biology 02/2004; 551:85-91. · 1.09 Impact Factor
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ABSTRACT: Pelizaeus Merzbacher disease is an X-linked dysmyelinating disorder of the CNS, resulting from mutations in the proteolipid protein (PLP) gene. An animal model for this disorder, the myelin-deficient (MD) rat, carries a point mutation in the PLP gene and exhibits a phenotype similar to the fatal, connatal disease, including extensive dysmyelination, tremors, ataxia, and death at approximately postnatal day 21 (P21). We postulated that early death might result from disruption of myelinated neural pathways in the caudal brainstem and altered ventilatory response to oxygen deprivation or hypercapnic stimulus. Using barometric plethysmography to measure respiratory function, we found that the MD rat develops lethal hypoxic depression of breathing at P21, but hypercapnic ventilatory response is normal. Histologic examination of the caudal brainstem in the MD rat at this age showed extensive dysmyelination and downregulation of NMDA and to a lesser extent GABA(A) receptors on neurons in the nucleus tractus solitarius, hypoglossal nucleus, and dorsal motor nucleus of the vagus. Unexpectedly, immunoreactive PLP/DM20 was detected in neurons in the caudal brainstem. Not all biosynthetic functions and structural elements were altered in these neurons, because phosphorylated and nonphosphorylated neurofilament and choline acetyltransferase expression were comparable between MD and wild-type rats. These findings suggest that PLP is expressed in neurons in the developing brainstem and that PLP gene mutation can selectively disrupt central processing of afferent neural input from peripheral chemoreceptors, leaving the central chemosensory system for hypercapnia intact.
Journal of Neuroscience 04/2003; 23(6):2265-73. · 7.11 Impact Factor
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ABSTRACT: To determine whether hypoxemic episodes in ventilated extremely-low-birth-weight infants correlate with specific behavioral states. Study design: Three-hour video-electroencephalography-polysomnography was performed on 13 ventilated extremely-low-birth-weight infants with mean postconceptional age of 28.3 weeks. The electroencephalogram was scored for discontinuity. Rapid eye movements, body, head, and limb movements were scored from synchronized video. Sleep states were defined from electroencephalography, rapid eye movements, and movement criteria. Nonparametric statistics were used to test for differences in the proportion of time hypoxemic (oxygen saturation </=85%) between behavioral states.
The proportions of time hypoxemic were 0.6% during quiet sleep, 4.4% during active sleep, 10.7% during indeterminate sleep, and 16.7% during arousal. There was a significant overall difference between the states (P =.004) and a significant difference between active sleep and indeterminate sleep in a pairwise comparison (P =.001).
Higher proportions of hypoxemia were found during indeterminate sleep and arousal compared with active sleep and quiet sleep. We speculate that motor activity during sleep disruption could prevent effective mechanical delivery of ventilator breaths and contribute to episodes of hypoxemia. Our results suggest that strategies promoting uninterrupted sleep cycling analogous to the intrauterine state could improve ventilatory stability.
Journal of Pediatrics 10/2002; 141(3):363-8. · 4.11 Impact Factor
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ABSTRACT: In recent years cases of often fatal pulmonary hemorrhage in infants have been associated with water damaged homes and the toxigenic fungus Stachybotrys chartarum. The fungal spores contain mycotoxins which could be injurious to the rapidly developing lung. In order to understand the developmental pathophysiology of this disease we developed an infant rat model of stachybotrytoxicosis describing the effects of fungal spores on survival, growth, histopathology of the lung and respiration. Conidia of S. chartarum were instilled intratracheally (1.0-8.0 x 10(5)/gm wt.) in 4-d old Sprague-Dawley rat pups. Two control groups received either sterile PBS or a suspension of spores extensively extracted with ethanol to remove toxins. Lethal dose response was determined (LD50 = 2.7 x 10(5) spores/gm wt.). All dead pups had extensively hemorrhagic lungs. Growth of surviving animals was impaired in a dose-dependent manner. Changes of pulmonary function parameters in rats treated with 1.1 x 10(5) spores/g were consistent with an increased respiratory resistance. Histology of lungs revealed fresh hemorrhage, sparse hemosiderin-laden macrophages, and evidence of inflammation including thickened alveolar septa infiltrated by lymphocytes and mononuclear cells and intra-alveolar macrophages. Significant increases (p = 0.001) in numbers of macrophages (2-fold), lymphocytes (5-fold) and neutrophils (7-fold) were found in BAL fluid. Hemoglobin was elevated 2-fold (p = 0.004). Proinflammatory mediator IL-1beta increased more than 6-fold and TNF-alpha 30-fold (p = 0.001). Extracted spores had a minimal effect on all examined parameters in BAL fluid indicating that mycotoxins are primarily responsible for the hemorrhagic and inflammatory response.
Mycopathologia 02/2002; 154(3):139-52. · 1.65 Impact Factor
