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101.
Systematic interindividual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability 总被引:17,自引:6,他引:17
OBJECTIVES: To investigate interindividual differences in neurobehavioral deficits during sleep deprivation, and to establish to what extent the neurobehavioral responses to sleep loss are a function of sleep history versus trait-like differential vulnerability. DESIGN: Individuals were exposed to sleep deprivation on 3 separate occasions in order to determine the stability of interindividual differences in neurobehavioral impairment. SETTING: The sleep-deprivation experiments were conducted under standardized laboratory conditions with continuous monitoring of wakefulness. Each subject underwent a laboratory-adaptation session before entering the sleep-deprivation phase of the study. PARTICIPANTS: A total of 21 healthy adults (aged 21-38 years) completed the experiment. INTERVENTIONS: Subjects came to the laboratory 3 times at intervals of at least 2 weeks. During each laboratory session, they underwent neurobehavioral testing every 2 hours during 36 hours of total sleep deprivation, which was preceded by baseline sleep and followed by recovery sleep. In the week prior to each sleep-deprivation session and on the baseline night in the laboratory, subjects were required to either restrict their sleep to 6 hours per day (prior sleep restriction condition) or to extend their time in bed to 12 hours per day (prior sleep extension condition), so as to experimentally manipulate sleep history (in randomized counterbalanced order). RESULTS: There was strong evidence that interindividual differences in neurobehavioral deficits during sleep deprivation were systematic and trait-like. The magnitude of interindividual variability was substantial relative to the magnitude of the effect of prior sleep restriction (which on average involved a reduction of 4.1 hours sleep per day, compared to prior sleep extension, for 7 days). Overall, interindividual differences were not explained by subjects' baseline functioning or a variety of other potential predictors. Interindividual variability clustered on 3 distinct neurobehavioral dimensions: self-evaluation of sleepiness, fatigue, and mood; cognitive processing capability; and behavioral alertness as measured by sustained attention performance. CONCLUSIONS: Neurobehavioral deficits from sleep loss varied significantly among individuals and were stable within individuals. Interindividual differences in neurobehavioral responses to sleep deprivation were not merely a consequence of variations in sleep history. Rather, they involved trait-like differential vulnerability to impairment from sleep loss, for which neurobiologic correlates have yet to be discovered. 相似文献
102.
Clara cell secretory protein deficiency alters clara cell secretory apparatus and the protein composition of airway lining fluid 总被引:2,自引:0,他引:2
Stripp BR Reynolds SD Boe IM Lund J Power JH Coppens JT Wong V Reynolds PR Plopper CG 《American journal of respiratory cell and molecular biology》2002,27(2):170-178
Clara cells represent the predominant secretory cell within distal conducting airways of mammals and exhibit functional alterations with chronic lung disease. We previously demonstrated that Clara cell secretory protein (CCSP) deficiency results in enhanced susceptibility to environmental agents. The present study was undertaken to define changes in Clara cell secretory function associated with CCSP deficiency in knockout mice. Comparative morphometry of Clara cell ultrastructure revealed dramatic alterations in secretory apparatus between wild-type (WT) and CCSP knockout (CCSP-/-) mice. Secretory granules, which occupy greater than 2% of Clara cell cytoplasmic volume in WT mice, were completely absent among Clara cells of CCSP-/- mice. Moreover, Clara cells of CCSP-/- mice exhibited a > 95% reduction in rough endoplasmic reticulum and alterations to Golgi apparatus, relative to WT controls. Ultrastructural perturbations to Clara cells were associated with altered protein composition of airway lining fluid as revealed by two-dimensional gel analysis of bronchoalveolar lavage proteins, but were not associated with altered abundance or secretion of CC26, another Clara cell secretory protein. We conclude that CCSP is required for the appearance of Clara cell secretory granules and that functional changes to Clara cells that result from CCSP deficiency lead to alterations in the composition of epithelial lining fluid. 相似文献
103.
Biotinidase deficiency is inherited as an antosomal recessive trait that, unless treated with pharmacologic doses of biotin, can result in neurologic and cutaneous symptoms. We have identified two new mutations in exon D of the biotinidase gene of children with profound biotinidase deficiency ascertained by newborn screening. Transition 511G->A near the 5' end of exon D results in a substitution of threonine for alanine 171 (A171T) and transversion 1330G->C occurs close to the 3' end of exon D causing a substitution of histidine for aspartic acid 444 (D444H). The D444H mutation was detected in four individuals from our normal population whose mean serum biotinidase activity is 5.25 nmol/min/ml, which is significantly lower than the mean normal activity (7.1 nmol/min/ml). We calculated that this mutation causes a 52% loss of activity in the aberrant enzyme. Twenty-three individuals with the D444H mutation were found by allele specific oligonucleotide analysis of DNA from 296 randomly-selected, anonymous dried-blood spots. We estimate the frequency of this allele in the general population to be 0.039. In contrast, no individuals in 376 have the A171T mutation. Fourteen children (eleven probands and three siblings) out of the 31 enzyme-deficient children have both the A171T and D444H mutations. Both mutations are inherited from a single parent as a double mutation allele. The nine families in which this allele was identified are of mostly European ancestry, although the mutation cannot be attributed to a specific nationality or ethnic group. The serum of a child who is homozygous for the double mutation allele has very little CRM and the aberrant enzyme has very low biotinylhydrolase activity and no botinyl-transferase activity. This double mutation allele (A171T and D444H) is a common cause of profound biotinidase deficience in children ascertained by newborn screening in the United States. 相似文献
104.
Calorie restriction (CR) extends life span in a wide variety of species. Previously, we showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase. Here we test whether CR activates Sir2 by increasing the NAD/NADH ratio or by regulating the level of nicotinamide, a known inhibitor of Sir2. We show that CR decreases NADH levels, and that NADH is a competitive inhibitor of Sir2. A genetic intervention that specifically decreases NADH levels increases life span, validating the model that NADH regulates yeast longevity in response to CR. 相似文献
105.
Jean-Pierre Fryns Walter Bettens Herman Van Den Berghe James F. Reynolds 《American journal of medical genetics. Part A》1986,24(1):175-178
We report on an8-month-old girl with a de novo 5q/6q autosomal translocation with loss of the distal part of the long arm of chromosome 6 (6q23.3→6qter); clinical manifestations are peculiar craniofacial stigmata, truncal obesity and persisting hypotonia. The similarity with a previously reported patient with 6q interstitial deletion is discussed. 相似文献
106.
Cyclosporin A in the prevention and treatment of experimental autoimmune glomerulonephritis in the brown Norway rat. 总被引:2,自引:1,他引:2
Experimental autoimmune glomerulonephritis (EAG) was induced in brown Norway (BN) rats by a single i.m. injection of collagenase-solubilized homologous glomerular basement membrane (GBM) in Freund's complete adjuvant. This model of anti-GBM disease is characterized by the development, over several weeks, of circulating and deposited anti-GBM antibodies, accompanied by albuminuria. We examined the effects of treatment with oral cyclosporin A (CsA) at different doses, starting at the time of immunization and during the course of the disease. Pretreatment with CsA 5 mg kg daily produced a moderate reduction in circulating anti-GBM antibody levels, reduced deposition of antibody on the GBM and decreased albuminuria. Doses of 10 and 20 mg/kg CsA produced a marked reduction in circulating antibody, absence of detectable deposited antibody and virtual absence of albuminuria. Renal function remained normal in CsA-treated and control animals. When CsA treatment was introduced at 2 or 4 weeks after immunization, there were significant effects on the subsequent autoimmune response and albuminuria at 10 and 20 mg/kg daily. These studies demonstrate that CsA in conventional doses has a therapeutic effect in this model of anti-GBM disease, and suggest a role for T lymphocytes in the pathogenesis of EAG. 相似文献
107.
John M. Opitz Gunnar B. Stickler James F. Reynolds 《American journal of medical genetics. Part A》1987,27(4):971-975
We report on a consanguineous Brazilian couple whose 2 children had tibial aplasia-ectrodactyly. Femoral bifurcation was present in one of the affected children. The relationship of tibial aplasia-ectrodactyly to the Gollop-Wolfgang complex is discussed. Clinical and genetic aspects of the conditions involving tibial aplasia and femoral bifurcation are discussed. 相似文献
108.
Bruce Motyka Hardeep S. Bhogal John D. Reynolds 《European journal of immunology》1995,25(7):1865-1871
The ileal Peyer's patch (PP) in sheep plays a central role in the development and production of B cells. Associated with a tremendous amount of B cell proliferation in this site is the extensive diversification of the Ig repertoire by somatic hypermutation. Very few (<5%) of the B cells produced in the ileal PP differentiate and emigrate; instead, the vast majority of these cells soon die, and we have previously shown that death is associated with apoptosis. When placed in culture, ileal PP B cells die rapidly by apoptosis, such that after 24h, 60 ± 1 % of DNA is fragmented. Here, we show that the extent of this spontaneous B cell apoptosis in culture, as quantitated by DNA fragmentation, was significantly increased in a dose-dependent manner by the glucocorticoids hydrocortisone or dexamethasone. Furthermore, treatment of lambs with 2–2.5 mg/kg of dexamethasone resulted in a marked increase in the number of apoptotic cells in the ileal PP and an increase in ileal PP B cell DNA fragmentation to 20 ± 6%, compared with 2.4 ± 0.1 % in untreated lambs. Anti-immunoglobulin (Ig) antibodies also increased the extent of DNA fragmentation in cultured ileal PP B cells. After 24 or 48 h of culture with anti-Ig (PIg47A), DNA fragmentation was 74 ± 2 % and 75 ± 3 %, respectively. Ileal PP B cells are rescued from apoptosis by agents that activate protein kinase C and increase cytosolic Ca2+, and here we show that this treatment also results in apoptotic rescue in the presence of dexamethasone or anti-Ig. We speculate that the apoptosis of ileal PP B cells in situ may be modulated by glucocorticoids and by the cross-linking of surface Ig. Apoptosis, induced by a signal through surface Ig, may be an important mechanism in the deletion of self-reactive B cells during the expansion of the Ig repertoire in the ileal PP. 相似文献
109.
Evidence for presynaptic 5-hydroxytryptamine3 recognition sites on vagal afferent terminals in the brainstem of the ferret 总被引:1,自引:0,他引:1
R A Leslie D J Reynolds P L Andrews D G Grahame-Smith C J Davis J M Harvey 《Neuroscience》1990,38(3):667-673
Antagonists acting at the 5-hydroxytryptamine3 receptor are potent anti-emetic agents in cases of cytotoxic- and radiation-induced vomiting, and binding sites for these compounds have been described in brainstem areas known to be involved in mediation of nausea and vomiting. We have used autoradiography to examine the distribution of one of these antagonists, [3H]granisetron in the caudal brainstem of the ferret, a commonly used animal model for physiological investigations of emesis. The highest density of binding sites was found to be in the dorsomedial region of the nucleus of the solitary tract, the principal terminus for gastric vagal afferent fibres. Lower levels of binding were observed in the area postrema and the dorsal motor nucleus of the vagus. Following unilateral nodose ganglion excision, displaceable binding of [3H]granisetron in the nucleus of the solitary tract was attenuated on the ipsilateral side by 65%. Bilateral subdiaphragmatic vagotomy abolished binding of [3H]granisetron in the entire dorsal vagal complex. These results provide strong circumstantial evidence that 5-hydroxytryptamine3 receptors are located on vagal afferent terminals in the ferret brainstem. 相似文献
110.
Bernardo Ochoa Robert J. Gorlin John M. Opitz James F. Reynolds 《American journal of medical genetics. Part A》1987,27(3):661-667
Between 1965 and 1986 we saw 36 children with enuresis and urinary tract infection in association with “inversion” of facial expression when laughing. Urologic work-up of these patients disclosed characteristic findings of mild neuropathic bladder in all cases, with severe urinary tract damage in most of them. The clear association of distortion in facial expression and neuropathic bladder with resultant damage to the genitourinary tract should prompt urological evaluation of individuals with “inversion” of facial expression. About two thirds of the patients also had moderate to severe constipation. We suggest the term urofacial syndrome for this disorder. The occurrence of the disorder in multiple sibs, normal parents, increased parental consanguinity, and equal sex ratio indicate autosomal recessive inheritance. 相似文献