摘要:

Neural activity is critical for sculpting the intricate circuits of the nervous system from initially imprecise neuronal connections. Disrupting the formation of these precise circuits may underlie many common neurodevelopmental disorders, ranging from subtle learning disorders to pervasive developmental delay. The necessity for sensory-driven activity has been widely recognized as crucial for infant brain development. Recent experiments in neurobiology now point to a similar requirement for endogenous neural activity generated by the nervous system itself before sensory input is available. Here we use the formation of precise neural circuits in the visual system to illustrate the principles of activity-dependent development. Competition between the projections from lateral geniculate nucleus neurons that receive sensory input from the two eyes shapes eye-specific connections from an initially diffuse projection into ocular dominance columns. When the competition is altered during a critical period for these changes, by depriving one eye of vision, the normal ocular dominance column pattern is disrupted. Before ocular dominance column formation, the highly ordered projection from retina to lateral geniculate nucleus develops. These connections form before the retina can respond to light, but at a time when retinal ganglion cells spontaneously generate highly correlated bursts of action potentials. Blockade of this endogenous activity, or biasing the competition in favor of one eye, results in a severe disruption of the pattern of retinogeniculate connections. Similar spontaneous, correlated activity has been identified in many locations in the developing central nervous system and is likely to be used during the formation of precise connections in many other neural systems. Understanding the processes of activity-dependent development could revolutionize our ability to identify, prevent, and treat developmental disorders resulting from disruptions of neural activity that interfere with the formation of precise neural circuits.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Inhalation is the principal mode of entry forMycobacterium tuberculosisin humans. Primary infection is usually restricted to the lungs and contiguous lymph nodes. In a subset of infected individuals, predominantly children, the infection is spread hematogenously to the meninges. The host factors that influence the development of tuberculous meningitis have not been well elucidated. The mannose-binding protein (MBP), a serum protein, is considered as an "ante-antibody." MBP has been shown to bind mycobacteria and acts as an opsoninin vitro. Although MBP plays a role in first-line host defense, it may under certain circumstances be deleterious to the host. In tuberculosis (TB), MBP may assist the spread of this intracellular pathogen. Therefore, we hypothesized that MBP genotypes that result in a phenotype of low MBP levels might be protective. We studied a well-defined South African population in which TB has reached epidemic levels. We found that the MBP B allele (G54D), which disrupts the collagen region of the protein and results in low MBP levels, was found in 22 of 79 (28%) of the TB-negative controls from the same community, compared with 12 of 91 (13%) of the patients with pulmonary TB (p< 0.017), and 5 of 64 (8%) of patients with tuberculous meningitis (p< 0.002). In addition, we found significantly lower serum MBP concentrations in TB-negative controls compared with postacute phase, fully recovered TB patients (p< 0.004). These findings suggest that the MBP B allele affords protection against tuberculous meningitis.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) in the liver. Patients with PKU show increased L-phenylalanine in blood, which leads to mental retardation and hypopigmentation of skin and hair. As a step toward gene therapy for PKU, we constructed a replication-defective, E1/E3-deleted recombinant adenovirus harboring human PAH cDNA under the control of a potent CAG promoter. When a solution containing 1.2 × 109plaque-forming units of the recombinant adenovirus was infused into tail veins of PKU model mice (Pahenu2), predominant expression of PAH activity was observed in the liver. The gene transfer normalized the serum phenylalanine level within 24 h. However, it also provoked a profound host immune response against the recombinant virus; as a consequence, the biochemical changes lasted for only 10 d and rechallenge with the virus failed to reduce the serum phenylalanine concentration. Administration of an immunosuppresant, FK506, to mice successfully blocked the host immune response, prolonged the duration of gene expression to more than 35 d, and allowed repeated gene delivery. We noted a change in coat pigmentation from grayish to black after gene delivery. The current study is the first to demonstrate the reversal of hypopigmentation, one of the major clinical phenotypes of PKU in mice as well as in humans, by adenovirus-mediated gene transfer, suggesting the feasibility of gene therapy for PKU.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Previous studies have shown that genotype correlates with biochemical phenotype in treated phenylketonuria. If there is a strong correlation between genotype and intellectual phenotype of untreated patients, it would be possible to determine which individuals would have normal intelligence without treatment. In this study, 42 families with untreated phenylketonuria were analyzed to examine whether there was an association between genotype and untreated intellectual phenotype. Previously 12 of the 42 families were genotyped; now the genotyping of these patients is almost complete (40/42), a more thorough investigation was possible. Although the predicted phenylalanine hydroxylase (PAH) enzyme activity, based on genotype, showed an association with the patients' intellectual phenotype, the extensive overlap between the groups means the association is of little clinical value. Unrelated individuals with the same genotype and also siblings were found to have very different intellectual phenotypes. These phenotypic differences could not be explained by a difference in diet; therefore, we propose that another gene or genes may be modifying the intellectual phenotype of untreated patients. A preliminary search for possible modifying genes was performed. The possibility that a modifying gene was linked to the PAH gene on chromosome 12 was investigated using markers closely linked to the gene; however, no evidence for a modifying gene close to the PAH gene was found. Tyrosine hydroxylase was chosen as a candidate gene, because it can perform the same reaction as PAH. Using a common polymorphism within the gene, we found that this gene did not cause the discordant results and thus, did not modify the PAH phenotype.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We evaluated pancreatic enzyme secretory response to secretagogues (cAMP- and Ca2+-mediating) involved in exocytosis and in chloride channel activation in an exon 10 knockout cystic fibrosis (CF) mouse model. Experiments were performed in isolated pancreatic acini from liquid-fedCftr-/-mice (5∼6 wk of age) and age-matchedCftr+/+controls fed a solid or liquid diet. BrcAMP and forskolin alone induced higher amylase secretion (% initial amylase content) in theCftr+/+acini than carbachol (p< 0.05). Carbachol and BrcAMP or BrcAMP and forskolin, given in combination, produced additive effects on enzyme secretion in theCftr+/+acini. Ca2+- and cAMP-mediated amylase secretion in isolated pancreatic acini from theCftr-/-mice was no different to that observed in the age- and diet-matchedCftr+/+animals. However,Cftr-/-pancreatic acini showed a significantly greater amylase response to the combination of BrcAMP and carbachol than the sum of the individual responses in separate experiments (p< 0.05). The amylase response was not different in acini from solid-fed or liquid-fedCftr+/+controls. In summary, this study suggests that cystic fibrosis transmembrane conductance regulator is not essential for enzyme secretion as evidenced by no reduction in cAMP-mediated amylase secretion inCftr-/-mice. The results inCftr+/+acini suggest pancreatic enzyme secretion is mediated via multiple intracellular pathways acting in parallel and probably converge at a distal step in the secretory process. However,Cftr-/-pancreatic acini exhibited a synergistic secretory response following stimulation by BrcAMP plus carbachol. The enhanced secretory response may partially contribute to the development of pancreatic dysfunction in CF patients by facilitating occlusion of digestive enzymes in the secretory canaliculus of the pancreatic acini.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

During pregnancy, 17β-estradiol (E2) and progesterone (P) plasma concentrations increase up to 100-fold. The fetus is exposed to these increasing amounts of E2 and P. Within 1 d after delivery, E2 and P concentrations fall to nonpregnancy concentrations in the mother and the infant. Extremely premature infants are cut off from the placental supply of E2 and P at a very early developmental stage, and therefore they suffer from this deprivation for a longer period than infants born at term. Nothing is known about the consequences of this deprivation. The purpose of this study was to investigate how intrauterine concentrations of E2 and P could be maintained after birth. In 13 infants with a median gestational age of 26.4 wk (24.1-28.7), a phospholipid-stabilized soybean oil emulsion available for parenteral nutrition that contains different amounts of E2 and P was continuously administered, starting within the first postnatal hours. The supplementation was continued as long as venous access was indicated but not longer than 6 wk (median 20 d, 12-44). To maintain intrauterine plasma concentrations of 2000-6000 pg/mL E2 and 300-600 ng/mL P, 2.30 mg·kg-1·d-1E2 (1.13-3.42 mg·kg-1·d-1) and 21.20 mg·kg-1·d-1P (11.23-27.36 mg·kg-1·d-1) were needed. We conclude that supplementation of E2 and P to maintain intrauterine concentrations in extremely premature infants is possible intravenously. The infants in this study are enrolled in a randomized, controlled pilot study to evaluate the potential benefits of E2 and P supplementation.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Fetal and maternal plasma noradrenaline responses to invasive procedures were determined in pregnancies of 18 to 37 wk gestation. Fetal umbilical venous blood sampling was performed either from the placental cord insertion, which is not innervated, or the intrahepatic vein, which is innervated, and thus may be more stressful for the fetus. Samples from diagnostic procedures, as well as from transfusion procedures, were compared between the two sites. Fetal plasma levels were significantly elevated in blood samples obtained from the intrahepatic vein compared with those from the placental cord insertion during diagnostic procedures [p< 0.05, geometric means and 95% confidence intervals (CI) were 0.67 nmol/L (0.43-1.04) and 0.36 nmol/L (0.25-0.54), respectively]. Plasma levels in samples taken before transfusion from the intrahepatic vein were also significantly higher than those from the placental cord insertion. After transfusion, there was a significant rise in fetal plasma noradrenaline levels at both sites; however, after transfusion through the intrahepatic vein, the rise was substantially greater than after transfusion through the placental cord insertion (p< 0.05, change, mean ΔNA, and 95% CI were 0.67 (0.37-1.22), and 0.20 (0.12-0.33), respectively). The ΔNAwas significantly associated with the duration of the stimulus (the time the needle remainedin situ) (p= 0.05, adjusted R2= 0.48) and with gestational age. Maternal levels rose substantially and equally after transfusions at either site (mean ΔNAand 95% CI, 6.46 nmol/L, 1.74 to 11.18 and 9.49 nmol/L, 6.24 to 12.75 for the intrahepatic vein and placental cord insertion groups, respectively). There was no significant correlation between baseline fetal and maternal levels (r= 0.08,n= 41) or between ΔNApre- and posttransfusion maternal and fetal values in either group. These results indicate that the fetus is capable of mounting an independent noradrenaline stress response to a needle transgressing its trunk from 18 wk gestation. The effect was observable in samples taken at a mean of 5.6 min after needling. The lack of correlation between maternal and fetal levels suggests that virtually no noradrenaline crosses the placenta directly, and that the observed fetal responses are not due to direct transport from the mother.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Hypoxia-ischemia induces an inflammatory response in the immature central nervous system that may be important for development of brain injury. Recent data implicate that chemoattractant cytokines, chemokines, are involved in the recruitment of immune cells. The aim was to study α- and β-chemokines in relation to the temporal activation of inflammatory cells after hypoxia-ischemia in immature rats. Hypoxia-ischemia was induced in 7-day-old rats (left carotid artery occlusion + 7.7% oxygen). The pups were decapitated at different times after the insult. Immunohistochemistry was used for evaluation of the inflammatory cell response and RT-PCR to analyze the cytokine mRNA and chemokine mRNA expression. A distinct interleukin-1β and tumor necrosis factor-α cytokine expression was found 0-24 h after hypoxia-ischemia that was accompanied by induction of α-chemokines (growth related gene and macrophage inflammatory protein-2). In the next phase, the β2-integrin expression was increased (12 h and onward) and neutrophils transiently invaded the vessels and tissue in the infarct region. The mRNA induction for the β-chemokines macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, and RANTES preceded the expression of markers for lymphocytes [cluster of differentiation (CD)4, CD8], microglia/macrophages (MHC I), and natural killer cells in the infarct area. The activation of microglia/macrophages, CD4 lymphocytes, and astroglia persisted up to at least 42 d of postnatal age implicating a chronic component of immunoinflammatory activation. The expression of mRNA for α- and β-chemokines preceded the appearance of immune cells suggesting that these molecules may have a role in the inflammatory response to insults in the immature central nervous system.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The purpose of this research was to study the changes in the molecular weight of hyaluronic acid in Wharton's jelly altered by necrotizing funisitis. Umbilical cords were collected at delivery from 20 newborns without funisitis, 6 newborns with acute funisitis, and 4 newborns with necrotizing funistis. Agarose gel electrophoresis of Wharton's jelly was performed to analyze the molecular weight of hyaluronic acid (HA). We also investigated the effects of low or high molecular weight HA on the production of interleukin-8 in human umbilical fibroblasts. In Wharton's jelly without funisitis, HA was 1150 ± 280 kD in preterm newborns, regardless of gestational week at birth, and that in full-term newborns was 1100 ± 200 kD. When acute funisitis was present, HA was 700 ± 250 kD, and when necrotizing funisitis was present, HA was 520 ± kD. The molecular weight of HA was significantly below normal in newborns with necrotizing funisitis. Low molecular weight HA was associated with increased levels of IL-8 in the supernatant of cultured human umbilical fibroblasts in a time- and dose-dependent manner. High molecular weight HA did not induce the production of IL-8 in the same cells. Low molecular weight HA has a potent inflammatory action. The conversion from high to low molecular weight HA in Wharton's jelly may be important in the pathophysiology of necrotizing funisitis.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Heart rate (HR) acceleration is an essential mechanism for adaptation to changes in hemodynamic and energetic needs resulting from body movements. To evaluate age-related development of coupling between spontaneous movement and HR changes, we performed polysomnographic recordings in 20 clinically and neurologically normal newborns including 10 premature (31- to 36-wk gestational age, wGA) and 10 full-term (38- to 41-wk gestational age) infants. Recordings were sampled at 286 Hz and processed using a signal-to-noise ratio algorithm for QRS complex detection. Movements were automatically detected and the logical signal obtained was sampled at QRS fiducial points and written in the attributes of each QRS. The study included the 402 movements that were less than 30 s in duration and were neither preceded nor followed by another movement or by a respiratory event (pause, sigh). The amplitude of movement-induced HR acceleration was significantly lower in premature compared with full-term newborns (p < 0.01). This difference persisted when the other factors influencing the HR response (basal HR, movement duration, and amplitude) were taken into consideration. Our data identify HR acceleration induced by spontaneous body movements as a fundamental reflex response that develops with gestational age from premature to full-term newborns.

ISSN:0031-3998    

出版商:OVID    

年代:1999

数据来源: OVID