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81.
Clinical depression and other mood disorders are relatively common mental illnesses but therapy for a substantial number of patients is unsatisfactory. For many years clinicians and neuroscientists believed that the evidence pointed toward alterations in brain monoamine function as the underlying cause of depression. This point of view is still valid. Indeed, much of current drug therapy appears to be targeted at central monoamine function. Other results, though, indicate that GABAergic mechanisms also might play a role in depression. Such indications stem from both direct and indirect evidence. Direct evidence has been gathered in the clinic from brain scans or postmortem brain samples, and cerebrospinal fluid (CSF) and serum analysis in depressed patients. Indirect evidence comes from interaction of antidepressant drugs with GABAergic system as assessed by in vivo and in vitro studies in animals. Most of the data from direct and indirect studies are consistent with GABA involvement in depression. 相似文献
82.
Kourie JI Kenna BL Tew D Jobling MF Curtain CC Masters CL Barnham KJ Cappai R 《The Journal of membrane biology》2003,193(1):35-45
We have shown previously that the protease-resistant and neurotoxic prion peptide fragment PrP[106-126] of human PrP incorporates into lipid bilayer membranes to form heterogeneous ion channels, one of which is a Cu(2+)-sensitive fast cation channel. To investigate the role of PrP[106-126]'s hydrophobic core, AGAAAAGA, on its ability to form ion channels and their regulation with Cu(2+), we used the lipid-bilayer technique to examine membrane currents induced as a result of PrP[106-126] (AA/SS) and PrP[106-126] (VVAA/SSSS) interaction with lipid membranes and channel formation. Channel analysis of the mutant (VVAAA/SSS), which has a reduced hydrophobicity due to substitution of hydrophobic residues with the hydrophilic serine residue, showed a significant change in channel activity, which reflects a decrease in the beta-sheet structure, as shown by CD spectroscopy. One of the channels formed by the PrP[106-126] mutant has fast kinetics with three modes: burst, open and spike. The biophysical properties of this channel are similar to those of channels formed with other aggregation-prone amyloids, indicating their ability to form the common beta sheet-based channel structure. The current-voltage (I-V) relationship of the fast cation channel, which had a reversal potential, E(rev), between -40 and -10 mV, close to the equilibrium potential for K(+) ( E(K) = -35 mV), exhibited a sigmoidal shape. The value of the maximal slope conductance (g(max)) was 58 pS at positive potentials between 0 and 140 mV. Cu(2+) shifted the kinetics of the channel from being in the open and "burst" states to the spike mode. Cu(2+) reduced the probability of the channel being open (P(o)) and the mean open time (T(o)) and increased the channel's opening frequency (F(o)) and the mean closed time (T(c)) at a membrane potential ( V(m)) between +20 and + 140 mV. The fact that Cu(2+) induced changes in the kinetics of this channel with no changes in its conductance, indicates that Cu(2+) binds at the mouth of the channel via a fast channel block mechanism. The Cu(2+)-induced changes in the kinetic parameters of this channel suggest that the hydrophobic core is not a ligand Cu(2+) site, and they are in agreement with the suggestion that the Cu(2+)-binding site is located at M(109) and H(111) of this prion fragment. Although the data indicate that the hydrophobic core sequence plays a role in PrP[106-126] channel formation, it is not a binding site for Cu(2+). We suggest that the role of the hydrophobic region in modulating PrP toxicity is to influence PrP assembly into neurotoxic channel conformations. Such conformations may underlie toxicity observed in prion diseases. We further suggest that the conversions of the normal cellular isoform of prion protein (PrP(c)) to abnormal scrapie isoform (PrP(Sc)) and intermediates represent conversions to protease-resistant neurotoxic channel conformations. 相似文献
83.
Orvisky E Stubblefield B Long RT Martin BM Sidransky E Krasnewich D 《Analytical biochemistry》2003,317(1):12-18
Congenital disorders of glycosylation (CDG) are a group of multisystemic disorders resulting from defects in the synthesis and processing of N-linked oligosaccharides. The most common form, CDG type Ia (CDG-Ia), results from a deficiency of the enzyme phosphomannomutase (PMM). PMM converts mannose 6-phosphate (man-6-P) to mannose-1-phosphate (man-1-P), which is required for the synthesis of GDP-mannose, a substrate for dolichol-linked oligosaccharide synthesis. The traditional assay for PMM, a coupled enzyme system based on the reduction of NADP(+) to NADPH using man-1-P as a substrate, has limitations in accuracy and reproducibility. Therefore, a more sensitive, direct test for PMM activity, based on the detection of the conversion of man-1-P to man-6-P by high-pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD), was developed. Using this assay, the activity of PMM was markedly deficient in fibroblasts and lymphoblasts from 23 patients with CDG-Ia (range 0-15.3% of control, average 4.9+/-4.7%) and also decreased in seven obligate heterozygotes (range 33.0-72.0% of control, average 52.2+/-14.7%). Unlike the spectrophotometric method, there was no overlap in PMM activity among patients, obligate heterozygotes, or controls. Thus, the PMM assay based on HPAEC-PAD has increased utility in the clinical setting, and can be used, together with transferrin isoelectric focusing, to diagnose patients with CDG-Ia and to identify heterozygotes when clinically indicated. 相似文献
84.
Proteomics: Current technologies and applications in neurological disorders and toxicology 总被引:5,自引:0,他引:5
Fountoulakis M 《Amino acids》2001,21(4):363-381
Summary. Proteomics is the science that studies the proteins in general and in particular their changes, resulting from various disorders
or the effect of external factors, such as toxic agents. It has as goal the detection of novel drug targets, diagnostic markers
and the investigation of biological events. Proteomics has emerged the last few years and its major difference from the previously
existing protein analytical techniques is that it does not analyze the proteins one by one, but in a possibly automated, large-scale
mode. In this article, the state of the art of proteomics in our laboratory is presented, as well as selected applications
of proteomics in the study of disorders of the central nervous system and of toxic events.
Received March 5, 2001 Accepted September 13, 2001 相似文献
85.
A patient with Gilles de la Tourette syndrome treated with haloperidol, ingested once daily after awakening from sleep, exhibited an irregular sleep-wake pattern with a free-running component of approximately 48 h. Transfer to risperidone, ingested once daily after awakening from sleep, was beneficial resulting in a sleep-wake cycle more synchronized at the appropriate phase to the external zeitgebers, and fewer nocturnal disturbances. The circadian sleep-wake schedule was fully synchronized when the patient had been subsequently treated with melatonin at 21:00h, before intended nocturnal sleep, in addition to risperidone in the morning. Restoration of the sleep-wake circadian pattern was accompanied by the patient's subjective report of significant improvement in his quality of life, social interactions, and occupational status. This observation suggests that circadian rhythm sleep disorders can be related to the typical neuroleptic haloperidol and restored by the atypical neuroleptic risperidone. Similar findings reported in patients suffering from other disorders support the hypothesis that the described disruption of the sleep-wake schedule is medication rather than illness-related. Therefore, it is very important to realize that circadian rhythm sleep disorders may be a side effect of neuroleptics. 相似文献
86.
Hot topics in behavioral and neural genetics 总被引:1,自引:0,他引:1
87.
Effect of electrical stimulation on musculoskeletal systems; a meta-analysis of controlled clinical trials 总被引:2,自引:0,他引:2
This study was a meta-analysis to examine whether electrical stimulation has specific effects in the healing of musculoskeletal repair process and in the diminution of symptoms with bone and joint disorders. Using MEDLINE (1966-1999) and EMBASE (1985-1999) a search for articles was carried out with four medical subject headings. Data were extracted from all the accessed articles and additionally collected from appropriate journal lists. A total of 20 randomized controlled trials on bones was identified which assessed healing of fractures, bone graft, and other conditions; and 29 randomized controlled trials on soft tissues and joints were also found, dealing with healing of skin wounds or dermal ulcers, soft tissue injury, and other conditions. Using criteria through which the quality of studies was assessed, the content of the articles was reorganized into a tabular form. The majority of the identified articles reported positive findings, but all the trials showed methodological flaws to some extent. Because of heterogeneity of the studies and the various outcome measurements, pooling of only part of the data was performed. The combined results of 12 trials on bones and 16 trials on soft tissues, the cases in which major endpoints were mainly union or healing rate, revealed statistically significant effects. The studies in this review had some methodological limitations, and the selected pooled trials do not constitute acceptable proof that electrical stimulation has specific effects on health. However, one cannot ignore the statistically significant positive findings reported in the trials, from which extracted data were able to be combined. 相似文献
88.
An update of the human obesity gene map incorporating published results up to October 1997 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature; single-gene mutation rodent models; quantitative trait loci uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, and pig models; association and case-control studies with candidate genes; and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all of these loci reveals that all but chromosome Y of the 24 human chromosomes are represented. Some chromosomes show at least three putative loci related to obesity on both arms (1, 2, 6, 8, 11, and 20) and several on one chromosome arm only (3p, 4q, 5q, 7q, 12q, 13q, 15q, 15p, 22q, and Xq). Studies reporting negative association and linkage results are also listed, with the exception of the unlinked markers from genome-wide scans. 相似文献
89.
SIRO PASSI MAURO GRANDINETTI FRANCESCO MAGGIO ANDREA STANCATO CHIARA DE LUCA 《Pigment cell & melanoma research》1998,11(2):81-85
Epidermal levels of enzymatic and non-enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), vitamin E (Vit E), ubiquinol (CoQ10H2), and reduced glutathione (GSH), as well as polyunsaturated fatty acids of phospholipids (PL-PUFA), were evaluated in the affected epidermis of 15 patients with active vitiligo (AVP) and in the corresponding epidermis of 15 healthy phototype matched controls. The epidermal levels of CoQ10H2, Vit E, GSH, and CAT activity were significantly reduced in AVP and were associated with a marked increase of oxidized glutathione, whereas SODs and GSH-Px activities and ubiquinone concentration remained similar to control values. Antioxidant deficiency, in particular the decline of lipophilic antioxidants, i. e., CoQ10H2 and Vit E, accounts well for PL-PUFA reduction observed in vitiligo epidermis, mainly affecting C18: 3 n-3, C20: 3 n-6, C20: 4 n-6, and C22: 6 n-3 fatty acids and suggesting the occurrence of a lipoperoxidative process. In conclusion, both an imbalance of the intracellular redox status and a significant depletion of enzymatic and non-enzymatic antioxidants feature the epidermis of AVP, and represent a fingerprint of an abnormal oxidative stress leading to epidermal cell injury. 相似文献
90.
目的:观察MMP-1、MMP-3 和MMP-13 在慢性睡眠剥夺所致颞下颌关节损伤中表达的变化,探讨慢性睡眠剥夺所致颞下颌
关节损伤的可能机制。方法:采用改良多平台(MMPM)建立大鼠慢性睡眠剥夺模型,将90 只成年雄性Wastar 大鼠随机分为小平
台组、网格组和对照组。小平台组和网格组大鼠接受每天18 h的睡眠剥夺和6 h间歇期(10:00-16:00),间歇期大鼠正常笼养。实验
第7、14 和21 d时分别观察动物的行为学观察、检测动物血浆皮质醇(CORT)和促肾上腺皮质激素(ACTH)水平检测,通过免疫印
迹法和实时定量聚合酶链反应(PRC)检测颞下颌关节软骨中MMP-1、MMP-3 和MMP-13 的蛋白和mRNA表达,并通过HE 染色
法观察颞下颌关节结构的变化。结果:与对照组和网格组大鼠相比,小平台组大鼠第14 d和21 d 时髁突软骨中间部位表面纤维
在出现明显的炎症、松解及脱落现象;第21天时的血浆ACTH 和CORT 水平均显著高于网格组和对照组,差异有统计学意义
(P<0.05);第7、14、21 d时关节软骨MMP-1 和MMP-13 蛋白和mRNA 的表达水平均显著上调(P<0.05)。结论:慢性睡眠剥夺所致
的颞下颌关节损伤可能与关节软骨中MMP-1、MMP-3 和MMP-13 的表达上调有关。 相似文献