ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Cystic fibrosis (CF), due to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), exhibits a wide range of disease severity, even among &Dgr;F508 homozygous patients, and the mechanisms of this variability have yet to be elucidated. In view of the close structural homology and possible functional overlap between CFTR and Multidrug Resistance-associated Proteins (MRPs), MRPs were investigated as potentially relevant factors in CF pathophysiology.MRP1-5gene expression was analyzed in nasal respiratory epithelial cells from &Dgr;F508 homozygous patients (n= 19) and control subjects (n= 20) using semiquantitative RT-PCR. Significantly lowerMRP1andMRP5transcript levels were found in CF patients than in control subjects.MRP1andMRP5transcript levels were strongly correlated (r= 0.71). In CF patients, lowMRP1transcript levels were associated with more severe disease as assessed by the Shwachman score. A relation was also observed betweenMRP1levels and presence of a cAMP-independent chloride conductive pathway, as determined by a halide-sensitive fluorescent assay. These results suggest that MRPs, especially MRP1, might play a role in CF phenotype and might therefore constitute a target for a novel pharmacotherapy of CF.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ThePOU1F1gene encodes a transcription factor that is important for the development and differentiation of the cells producing GH, prolactin, and TSH in the anterior pituitary gland. Patients withPOU1F1mutations show a combined pituitary hormone deficiency with low or absent levels of GH, prolactin, and TSH. Fourteen mutations have been reported in thePOU1F1gene up to now. These genetic lesions can be inherited either in an autosomal dominant or an autosomal recessive mode. We report on the first Italian patient, a girl, affected by combined pituitary hormone deficiency. The patient was found to be positive for congenital hypothyroidism (with low TSH levels) at neonatal screening. Substitutive therapy was started, but subsequent growth was very poor, although psychomotor development was substantially normal. Hospitalized at 10 mo she showed hypotonic crises, growth retardation, delayed bone age, and facial dysmorphism. In addition to congenital hypothyroidism, GH and prolactin deficiencies were found. Mutation DNA analysis of the patient’sPOU1F1gene identified the novel Q167K amino acid change at the heterozygous level. The highly conserved Q167 residue is located in thePOU-specific domain. No mutation was detected in the other allele. DNA analysis in the proband’s parents did not identify this amino acid substitution, suggesting ade novogenetic lesion. From these data it can be hypothesized that the Q167K mutation has a dominant negative effect.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Neonates with congenital diaphragmatic hernia (CDH) suffer from a diaphragmatic defect, lung hypoplasia, and pulmonary hypertension, with poor lung function forming the major clinical challenge. Despite prenatal diagnosis and advanced postnatal treatment strategies, the mortality rate of CDH is still high. CDH has been subject of extensive research over the past decades, but its etiology remains unknown. A major problem with CDH is the failure to predict the individual response to treatment modalities like high-frequency ventilation, inhaled nitric oxide, and extracorporeal membrane oxygenation. In this study, we tested the possibility that CDH lungs are surfactant protein deficient, which could explain the respiratory failure and difficulties in treating CDH infants. We investigated this hypothesis in the nitrofen-induced CDH rat model and assessed the cellular concentrations of surfactant protein (SP)-A, -B, and -C mRNA with a quantitative radioactivein situhybridization technique. No differences were observed between control and CDH lungs for SP mRNA expression patterns. The cellular concentration (mean OD) of SP-A and SP-B mRNA was similar at all stages whereas the mean OD of SP-C mRNA and the volume fraction of cells (% Area) expressing SP mRNA was higher in CDH lungs at term. Immunohistochemical analysis revealed no differences between control and CDH lungs for SP protein expression. No differences in the mean OD or % Area for the SP mRNAs were found between the ipsi- and contralateral side of CDH lungs. We conclude that there is no primary deficiency of surfactant proteins in the nitrofen-induced CDH rat model.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

In animal CDH models, surfactant deficiency contributes to the pathophysiology of the condition but information on human disease is very limited. The aim of our study was to investigate surfactant kinetics in CDH newborns. We studied surfactant disaturated-phosphatidylcholine (DSPC) half-life, turnover and apparent pool size by stable isotope methodology in CDH newborns with no ExtraCorporeal Membrane Oxygenation (ECMO) support (n= 13, birth weight (BW) 3.2 ± 2.2 kg, gestational age (GA) 39 ± 0.4 wks, postnatal age 43 ± 11 h) and in 8 term infants with no lung disease (CONTROLS, BW 2.7 ± 0 kg, GA 38 ± 0.8 wks, postnatal age 96 ± 26 h). We administered a trace dose of13C-palmitic acid dipalmitoyl-phosphatidylcholine (DPPC) through the endotracheal (ET) tube and we measured DSPC kinetics by gas chromatography-mass spectrometry from DSPC13C-enrichment decay curves obtained from sequential tracheal aspirates. DSPC amount from tracheal aspirates (TA-DSPC) was measured by gas chromatography. In CDH infants DSPC half-life was shorter (24 ± 4 and 53 ± 11 h,p= 0.01), turnover faster (0.6 ± 0.1 and 1.5 ± 0.3 d−1p= 0.01), apparent pool size smaller (34 ± 6 and 57 ± 7 mg/kg body weight,p= 0.02) and tracheal aspirates DSPC amount lower (2.4 ± 0.4 and 4.6 ± 0.5 mg/mL Epithelial Lining Fluid (ELF),p= 0.007) than in CONTROLS. In conclusion surfactant kinetics is grossly abnormal in mechanically ventilated CDH. Whether alterations of DSPC kinetics in CDH infants are caused by a primary surfactant deficiency or are secondary to oxygen therapy and ventilator support has still to be determined.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Hydrocephalus may result in loss of tissue associated with neuronal degeneration, axonal damage, and reactive gliosis. The soluble form of the anti-apoptotic regulator Fas (sFas) and the pro-apoptotic factors soluble FasL (sFasL) and activated caspase 3 were studied in the cerebrospinal fluid of infants with hydrocephalus. Fifteen preterm infants with posthemorrhagic hydrocephalus undergoing serial reservoir puncture and seven term or near-term infants with nonhemorrhagic hydrocephalus and shunt surgery were included in the study. Twenty-four age-matched patients with lumbar puncture for the exclusion of meningitis served as controls. Elevated levels of sFas were observed in infants with posthemorrhagic hydrocephalus [median (range), 131 ng/mL (51–279 ng/mL)] and in nonhemorrhagic hydrocephalus [127 ng/mL (35–165 ng/mL)]. sFas concentrations were highest in a subgroup of eight patients with posthemorrhagic hydrocephalus developing periventricular leukomalacia [164 ng/mL (76–227 ng/mL)]. In contrast, in 24 control infants, sFas was low, in 15 cases below detection limit (0.5 ng/mL) and in nine cases, 24 ng/mL (20–43 ng/mL). sFasL and activated caspase 3 did not differ from control infants in all groups of patients. Increased intrathecal release of sFas in the cerebrospinal fluid of infants with hydrocephalus may serve as an indicator of brain injury from progressive ventricular dilatation.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

This study was undertaken to measure the effects of mild hypothermia on cerebral blood flow and metabolism and cardiovascular responses to hypoxia in the fetal sheep. Near-term fetal sheep were chronically instrumented with laser Doppler flowmetry in the parietal cortex for measurement of relative changes in cerebral blood flow, as well as with arterial and sagittal sinus catheters for measurement of oxygen extraction by the brain and a cooling coil around the fetal thorax. Fetuses were studied during cooling alone, cooling with superimposed maternal hypoxia to achieve a fetal arterial Po2of 1.33 to 1.60 kPa, or hypoxia alone. In response to cooling alone [1.6° ± 0.1°C (mean ± SEM) decrease in brain temperature], fetal blood pressure and heart rate both increased significantly whereas cerebral blood flow decreased 14 ± 4%, commensurate with a 24 ± 8% decline in cerebral metabolic rate. Administration of moderate hypoxia during cooling resulted in a significant increase in cerebral blood flow, decreased heart rate, and no further increase in blood pressure. In response to hypoxia alone, fetal blood pressure was significantly increased, heart rate was decreased, and cerebral blood flow increased by 24 ± 8%, whereas cerebral metabolic rate decreased by 38 ± 13%. Arteriovenous oxygen extraction was unchanged by cooling alone but increased significantly in response to hypoxia administered during cooling. We therefore conclude that oxygen delivery to the fetal sheep brain remains coupled to metabolic rate during hypothermia and that hypothermia does not impair the compensatory cardiovascular responses of the fetus to acute moderate hypoxia.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Preterm birth frequently involves white matter injury and affects long-term neurologic and cognitive outcomes. Diffusion tensor imaging has been used to show that the white matter microstructure of newborn, preterm children is compromised in a regionally specific manner. However, until now it was not clear whether these lesions would persist and be detectible on long-term follow-up. Hence, we collected diffusion tensor imaging data on a 1.5-T scanner, and computed fractional anisotropy and coherence measures to compare the white matter integrity of children born preterm to that of control subjects. The subjects for the preterm group (10.9 ± 0.29 y;n= 9; birth weight ≤ 1500 g; mean gestational age, 28.6 ± 1.05 wk) possessed attention deficits, a common problem in preterms. They were compared with age- and sex-matched control children (10.8 ± 0.33 y;n= 10; birth weight ≥ 2500; gestational age, ≥ 37 wk). We found that the preterm group had lower fractional anisotropy values in the posterior corpus callosum and bilaterally in the internal capsules. In the posterior corpus callosum this difference in fractional anisotropy values may partially be related to a difference in white matter volume between the groups. An analysis of the coherence measure failed to indicate a group difference in the axonal organization. These results are in agreement with previous diffusion tensor imaging findings in newborn preterm children, and indicate that ex-preterm children with attention deficits have white matter disturbances that are not compensated for or repaired before 11 y of age.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Dynamic changes in electrophysiology of brainstem auditory neurons during the first month after birth were studied in 51 term infants after perinatal asphyxia using maximum length sequence brainstem auditory evoked responses. The responses were recorded on d 1, 3, 5, 7, 10, 15, and 30 after birth. On d 1, wave III and V latencies and all interpeak intervals increased significantly at all repetition rates of clicks used (91–910/s), especially the higher rates (ANOVA,p< 0.05–0.0001). On d 3, all these latencies and intervals increased further and differed more significantly from the normal control subjects. Thereafter, the latencies and intervals decreased progressively. On d 7, wave V latency and all intervals still differed significantly from the control subjects. These dynamic changes were more significant at higher rates of clicks than at lower rates. On d 10 and 15, all intervals decreased significantly. On d 30, all wave latencies decreased to the values in the normal control subjects on the same day. The intervals also approached normal values, although the III–V and I–V intervals still increased slightly. These results indicate that hypoxic-ischemic brain damage persists during the first week, with a peak on d 3, and recovers progressively thereafter. By 1 mo, the damage has largely returned to normal. Maximum length sequence brainstem auditory evoked responses results correlated well with the stage of hypoxic-ischemic encephalopathy during the first week. The present study revealed a general time course of brainstem pathophysiology after asphyxia, although there were individual variations. Our findings can be used as a reference to monitor cerebral function and help judge the value of neuroprotective or therapeutic interventions. The first week, particularly the first 3 d, is a critical period of hypoxic-ischemic brain damage, and early intervention may prevent or reduce deterioration of the damage.

ISSN:0031-3998    

出版商:OVID    

年代:2003

数据来源: OVID