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21.
GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies 总被引:11,自引:0,他引:11
Dibbens LM Feng HJ Richards MC Harkin LA Hodgson BL Scott D Jenkins M Petrou S Sutherland GR Scheffer IE Berkovic SF Macdonald RL Mulley JC 《Human molecular genetics》2004,13(13):1315-1319
A major challenge in understanding complex idiopathic generalized epilepsies has been the characterization of their underlying molecular genetic basis. Here, we report that genetic variation within the GABRD gene, which encodes the GABAA receptor delta subunit, affects GABA current amplitude consistent with a model of polygenic susceptibility to epilepsy in humans. We have found a GABRD Glu177Ala variant which is heterozygously associated with generalized epilepsy with febrile seizures plus. We also report an Arg220His allele in GABRD which is present in the general population. Compared with wild-type receptors, alpha1beta2Sdelta GABAA receptors containing delta Glu177Ala or Arg220His have decreased GABAA receptor current amplitudes. As GABAA receptors mediate neuronal inhibition, the reduced receptor current associated with both variants is likely to be associated with increased neuronal excitability. Since delta subunit-containing receptors localize to extra- or peri-synaptic membranes and are thought to be involved in tonic inhibition, our results suggest that alteration of this process may contribute to the common generalized epilepsies. 相似文献
22.
Leanne Tamm Jeffery N. Epstein Richard E.A. Loren Stephen P. Becker Sarah B. Brenner Morgan E. Bamberger 《Journal of clinical child and adolescent psychology》2019,48(2):S131-S145
This goal of this study was to assess the initial feasibility and efficacy of a play-based intervention targeting executive functions (EF) and parent–child relationships in preschoolers compared with an active control group. Preschoolers with EF deficits (M age = 3.7 ± 0.47, predominantly White boys) and their parents were randomized to intervention (n = 36) or active control (n = 32) conditions. Child performance on EF tasks, parent and masked teacher ratings of EF and behavior, and masked clinician ratings of severity were collected at baseline and at 3 and 6 months postbaseline. Partial eta-squared effect sizes at .02 or higher comparing performance across the two groups was considered evidence of meaningful, albeit small, intervention effects. Intervention effects were observed for parent ratings of inattention, hyperactivity/impulsivity, and number/severity of problems experienced in various home situations, teacher ratings of severity of problems in various school situations, parent and teacher ratings of overall impairment, and clinician ratings of impairment. Intervention effects for functional improvements were maintained at the 6-month follow-up. No effect of the intervention was observed on the objective EF measures, although parent ratings of emotional control were improved for children in the intervention group. An intervention utilizing play-based activities targeting EF, when administered in a structured way by parents, is a promising approach for improving behavior in preschoolers with self-regulation deficits. More work is needed to investigate potential impact on EF and to disentangle mechanisms of action. It may be that the intervention’s focus on the structure and quality of parent–child interactions is a mediator of outcomes, rather than improved EFs. 相似文献
23.
Xun Shen J Michael Collier Myint Hlaing Leanne Zhang Elizabeth H Delshad James Bristow Harold S Bernstein 《Developmental dynamics》2003,226(1):128-138
Skeletal and cardiac myocytes cease division within weeks of birth. Although skeletal muscle retains limited capacity for regeneration through recruitment of satellite cells, resident populations of adult myocardial stem cells have not been identified. Because cell cycle withdrawal accompanies myocyte differentiation, we hypothesized that C2C12 cells, a mouse myoblast cell line previously used to characterize myocyte differentiation, also would provide a model for studying cell cycle withdrawal during differentiation. C2C12 cells were differentiated in culture medium containing horse serum and harvested at various time points to characterize the expression profiles of known cell cycle and myogenic regulatory factors by immunoblot analysis. BrdU incorporation decreased dramatically in confluent cultures 48 hr after addition of horse serum, as cells started to form myotubes. This finding was preceded by up-regulation of MyoD, followed by myogenin, and activation of Bcl-2. Cyclin D1 was expressed in proliferating cultures and became undetectable in cultures containing 40% fused myotubes, as levels of p21(WAF1/Cip1) increased and alpha-actin became detectable. Because C2C12 myoblasts withdraw from the cell cycle during myocyte differentiation following a course that recapitulates this process in vivo, we performed a genome-wide screen to identify other gene products involved in this process. Using microarrays containing approximately 10,000 minimally redundant mouse sequences that map to the UniGene database of the National Center for Biotechnology Information, we compared gene expression profiles between proliferating, differentiating, and differentiated C2C12 cells and verified candidate genes demonstrating differential expression by RT-PCR. Cluster analysis of differentially expressed genes revealed groups of gene products involved in cell cycle withdrawal, muscle differentiation, and apoptosis. In addition, we identified several genes, including DDAH2 and Ly-6A, whose expression specifically was up-regulated during cell cycle withdrawal coincident with early myoblast differentiation. 相似文献
24.
Peiser L De Winther MP Makepeace K Hollinshead M Coull P Plested J Kodama T Moxon ER Gordon S 《Infection and immunity》2002,70(10):5346-5354
Macrophages (Mphi) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the Mphi scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mphi (BMMphi). Surprisingly, a comparison of BMMphi from wild-type and SR-A knockout (SR-A(-/-)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate Mphi activation, we examined TLR-4-deficient Mphi from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mphi-dependent cytokine response. Thus, we show that Mphi SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the Mphi secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans. 相似文献
25.
Jinhui Ma Kerry Siminoski Peiyao Wang Jacob L Jaremko Khaldoun Koujok Mary Ann Matzinger Nazih Shenouda Brian Lentle Nathalie Alos Elizabeth A Cummings Josephine Ho Kristin Houghton Paivi M Miettunen Rosie Scuccimarri Frank Rauch Leanne M Ward the Canadian STOPP Consortium 《Journal of bone and mineral research》2021,36(7):1255-1268
Vertebral fractures are clinically important sequelae of a wide array of pediatric diseases. In this study, we examined the accuracy of case-finding strategies for detecting incident vertebral fractures (IVF) over 2 years in glucocorticoid-treated children (n = 343) with leukemia, rheumatic disorders, or nephrotic syndrome. Two clinical situations were addressed: the prevalent vertebral fracture (PVF) scenario (when baseline PVF status was known), which assessed the utility of PVF and low lumbar spine bone mineral density (LS BMD; Z-score <−1.4), and the non-PVF scenario (when PVF status was unknown), which evaluated low LS BMD and back pain. LS BMD was measured by dual-energy X-ray absorptiometry, vertebral fractures were quantified on spine radiographs using the modified Genant semiquantitative method, and back pain was assessed by patient report. Forty-four patients (12.8%) had IVF. In the PVF scenario, both low LS BMD and PVF were significant predictors of IVF. Using PVF to determine which patients should have radiographs, 11% would undergo radiography (95% confidence interval [CI] 8–15) with 46% of IVF (95% CI 30–61) detected. Sensitivity would be higher with a strategy of PVF or low LS BMD at baseline (73%; 95% CI 57–85) but would require radiographs in 37% of children (95% CI 32–42). In the non-PVF scenario, the strategy of low LS BMD and back pain produced the highest specificity of any non-PVF model at 87% (95% CI 83–91), the greatest overall accuracy at 82% (95% CI 78–86), and the lowest radiography rate at 17% (95% CI 14–22). Low LS BMD or back pain in the non-PVF scenario produced the highest sensitivity at 82% (95% CI 67–92), but required radiographs in 65% (95% CI 60–70). These results provide guidance for targeting spine radiography in children at risk for IVF. © 2021 American Society for Bone and Mineral Research (ASBMR). 相似文献
26.
Hernia - Patients who present with symptomatic, clinically occult, radiologically evident (SCORE) inguinal hernia represent diagnostic and therapeutic challenge with a wide differential diagnosis... 相似文献
27.
BACKGROUND: In studies of adult humans and in animal models, dietary intakes of the macronutrients, particularly fat, are related to body composition; however, data on children are more scarce. OBJECTIVE: We sought to determine whether diet composition is related to percentage body fat in children aged 1.5-4.5 y. DESIGN: In 77 preschool children, a 4-d weighed-food record was used to determine intakes of total energy and energy from each macronutrient. An oxygen-18 dilution method was used to calculate percentage body fat. Habitual physical activity level was determined by calculating the ratio of total energy expenditure (from stable isotope analyses) to predicted basal metabolic rate. Dietary intake and body-composition data were analyzed to evaluate whether diet composition was related to body fat. Further analyses incorporating physical activity level were performed. RESULTS: Percentage body fat was not significantly correlated with dietary intake variables (total energy or percentage of energy from fat, carbohydrate, or protein) and did not differ significantly among 3 increasing levels of each dietary intake variable by analysis of variance. In multiple regression analysis, physical activity level was related to body fat whereas diet composition was not. CONCLUSIONS: We found no relations between dietary intakes of total energy, fat, carbohydrate, or protein and percentage body fat in children. The relation between fat intake and body fat may develop over time and may not be evident in preschool children. Energy expenditure, in particular physical activity level, may have a greater influence on body composition in early childhood. 相似文献
28.
Alexandra E. Butler Jenan Obaid Pearl Wasif Jean V. Varghese Rawan Abdulrahman Dalal Alromaihi Stephen L. Atkin Naji Alamuddin 《Nutrients》2022,14(17)
Objective. Date fruit has been reported to have benefits in type 2 diabetes (T2D), though there is a concern, given the high sugar content, about its effects on glycemic control. Design and Setting. Prospective, interventional, randomized, parallel study. Participants. In total, 79 patients with T2D (39 male and 40 female). Intervention. Participants were randomly allocated to either 60 g date fruit or 60 g raisins daily of the equivalent glycemic index (amount split, given as midmorning and midafternoon snack) for 12 weeks. Main Outcome Measures. The primary outcome was to investigate the effect of date fruit on HbA1c and fasting blood glucose, and their variability, in patients with T2D in comparison to the same glycemic load of raisins. The secondary outcomes were to determine whether date fruit affected cardiovascular risk by measuring fasting lipids, C-reactive protein (CRP), blood pressure, and insulin resistance (IR) as measured by Homeostatic Model Assessment (HOMA-IR). Results. In total, 61 (27 female and 34 male) of 79 patients completed the study. There was no difference between or within groups for HbA1c or HbA1c variability, fasting glucose or glucose variability, insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S), beta cell function (HOMA-B), the disposition index, lipids, systolic (SBP) or diastolic blood pressure (DBP), or C-reactive protein (CRP) (p > 0.05). Conclusion. No improvement in glycemic indices was seen following supplementation of 60 g daily date fruit or raisins, though neither had a deleterious effect on glycemic control over a 12-week period, indicating their safety when consumed in T2D. Additionally, no beneficial therapeutic effects of date fruit on other cardiovascular indices in T2D were seen. 相似文献
29.
Introduction. Chronic low-grade inflammation is a characteristic of women with polycystic ovary syndrome (PCOS), although this may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, vitamin D deficiency, another common feature of PCOS, is reported to have an association with increased inflammation. Therefore, circulating inflammatory protein levels and circulating levels of vitamin D may be linked in PCOS, though it is unclear which vitamin D metabolites may be important. Methods. We measured plasma levels of 24 inflammatory proteins and 12 matrix metalloproteinases (proteins modulated by the inflammatory process) by slow off-rate modified aptamer (SOMA)-scan plasma protein measurement in weight and aged-matched non-obese non-insulin resistant PCOS (n = 24) and control (n = 24) women. Inflammatory proteins and matrix metalloproteinases were correlated to 25-hydroxy vitamin D3 (25(OH)D3), its epimer 25-hydroxy-3epi-vitamin D (3epi25(OH)D) and the active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) as measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. Results. PCOS women had both an elevated free androgen index and circulating anti-mullerian hormone, though insulin resistance was comparable to controls. C-reactive protein, as a standard circulatory marker of inflammation, was comparable between cohorts. Levels of circulating inflammatory proteins and matrix metalloproteinases were not different between the PCOS and control women, with no correlation of 25(OH)D3, 1,25(OH)2D3 or 3epi25(OH)D with any of the inflammatory proteins. Conclusion. In a non-obese PCOS population matched for age and insulin resistance, circulating inflammatory proteins and matrix metalloproteinases were not elevated and did not correlate with 25(OH)D3, its epimer 3epi25(OH)D or 1,25(OH)2D3 in either control or PCOS women, indicating that the inflammatory response is absent and the vitamin D-metabolite independent in non-obese women with PCOS. 相似文献
30.