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1.
Morita Y Ujike H Tanaka Y Uchida N Nomura A Ohtani K Kishimoto M Morio A Imamura T Sakai A Inada T Harano M Komiyama T Yamada M Sekine Y Iwata N Iyo M Sora I Ozaki N Kuroda S 《Neuroscience letters》2005,376(3):182-187
Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia. 相似文献
2.
Previous studies showed that the Mcg dimer of immunoglobulin light chains bound bis(dinitrophenyl)lysine both in trigonal crystals and in solution. On prolonged storage in ammonium sulfate, mixtures of ligand and protein produced small trigonal cocrystals in low frequency. These crystals were nearly isomorphous with those of the unliganded dimer in which the subunits were covalently linked by an interchain disulfide bond. By difference Fourier analyses at 3.5 A resolution and subsequent crystallographic refinement, the cocrystals were found to contain molecules with two ligands aligned in tandem along the interface of the variable (V) domains of the protein. One ligand molecule adopted an almost fully extended conformation, with the epsilon-DNP ring situated near the floor, the alpha-carboxyl group directed toward the solvent at the entry, and the alpha-DNP ring outside the rim of the main cavity. As if architecturally designed, the ligand was located symmetrically between the two domains in an orientation that was compatible with both the unaltered structure of the cavity lining and with the known crystal packing interactions of neighboring protein molecules. The second ligand molecule in the cocrystal lodged in the deep pocket immediately under the floor of the main cavity. The ligand adopted a very compact conformation with the two DNP rings roughly antiparallel to each other. This molecule appeared to be semi-permanently sequestered in the pocket since it could not be dislodged by exhaustive perfusion with ammonium sulfate crystallizing media. Relative to its volume in the native dimer, the pocket was expanded to accommodate the oversized ligand. Within a single protein molecule, therefore, two types of binding of a flexible ligand were observed, one with and one without accompanying conformational changes in the protein. The number of cocrystals which could be produced was markedly increased if the interchain disulfide bond between the Mcg monomers was first reduced and alkylated. 相似文献
3.
DNA polymerase mu gene expression in B-cell non-Hodgkin's lymphomas: an analysis utilizing in situ hybridization
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Chiu A Pan L Li Z Ely S Chadburn A Knowles DM 《The American journal of pathology》2002,161(4):1349-1355
DNA polymerase mu (pol mu) is a novel error-prone DNA repair enzyme bearing significant structural homology with terminal deoxynucleotidyltransferase. Whereas other human error-prone DNA polymerases identified thus far show no preferential lymphoid tissue distribution, the highest levels of pol mu mRNA have been detected in peripheral lymphoid tissues, particularly germinal center B cells. Conceivably, up-regulation of the pol mu gene may be biologically significant in lymphomagenesis, especially in the development of B-cell non-Hodgkin's lymphomas (B-NHLs), because of enhanced error-prone DNA repair activities. To explore this possibility, we generated a digoxigenin-labeled riboprobe to pol mu mRNA and used the probe and in situ hybridization to examine the expression pattern of the pol mu gene in formalin-fixed, paraffin-embedded tissue sections of 37 B-NHLs. This included eight chronic lymphocytic leukemia/small lymphocytic lymphomas, six mantle cell lymphomas, seven follicular lymphomas, nine diffuse large B-cell lymphomas, three splenic marginal zone lymphomas, two Burkitt's lymphomas, and two precursor B-lymphoblastic lymphomas. We also correlated the pol mu mRNA expression levels with the tumor proliferation index, which was assessed in each case by image analysis of Ki-67 immunostained slides. Nineteen of 21 (90%) B-NHLs arising from postgerminal center B cells (follicular lymphomas, diffuse large B-cell lymphomas, splenic marginal zone lymphomas, and Burkitt's lymphomas) exhibited high expression of pol mu mRNA. In contrast, only 2 of 16 (13%) B-NHLs arising from pregerminal center B cells (chronic lymphocytic leukemia/small lymphocytic lymphomas, mantle cell lymphomas, and precursor B-lymphoblastic lymphomas) expressed significant levels of pol mu mRNA. Pol mu gene expression did not seem to correlate with the proliferation index, especially because a significant level of pol mu mRNA was not detected in either case of precursor B-lymphoblastic lymphomas. In conclusion, pol mu gene expression is highly associated with B-NHLs of postgerminal center B-cell derivation. Furthermore, the expression level is independent of the proliferation rate and thus is unrelated to the biological aggressiveness of the tumors. These findings, along with the error-prone nature of the enzyme, suggest that up-regulation of pol mu gene expression may be a contributing factor to the pathogenesis of a subset of B-NHLs through DNA repair-associated genomic instability. 相似文献
4.
Deborah Elstein Judith Guedalia Glen M Doniger Ely S Simon Vered Antebi Yael Arnon Ari Zimran 《Genetics in medicine》2005,7(2):124-130
PURPOSE: Because of concern for drug-induced cognitive dysfunction during clinical trials using substrate reduction therapy (miglustat) in type 1 Gaucher disease and because it has been suggested that some patients with type 1 Gaucher disease may develop neurocognitive impairment as part of the natural history, two different batteries of neuropsychological tests were devised to examine these issues. Using these tests, cognitive function was assessed in patients treated with miglustat, in patients receiving enzyme replacement (standard care for symptomatic patients), and in untreated (milder) patients. METHODS: For this study, 55/60 patients exposed to miglustat in Israel participated in psychologist-administered testing; 36/55 participated in computerized testing. Of these, 31 enzyme-treated patients and 22 untreated patients participated in the psychologist-administered testing, and 15 enzyme-treated patients and 18 untreated patients participated in computerized testing. The psychologist-administered battery consisted of 18 standard neuropsychological subtests specific to executive and visuospatial functioning. The computerized battery (Mindstreams, NeuroTrax Corp., New York, NY) consisted of 10 subtests tapping multiple cognitive domains. Between-group analyses for each modality compared cognitive performance. RESULTS: In the psychologist-administered testing, patients exposed to miglustat performed significantly less well than the other groups in 5/18 subtests. On the computerized tests, all patients performed comparably to normal controls. Scores in patients exposed to miglustat were higher than in untreated patients, particularly in visuospatial function, whereas enzyme-treated patients performed less well. However, with the exception of visuospatial function, these results were not statistically significant. CONCLUSIONS: It is unclear why different testing methods yielded discordant results. Any dysfunction suggested by the current study is apparently subtle and of doubtful clinical relevance given that cognitive status did not interfere with patients' daily intellectual function. The computerized battery has methodological advantages (e.g., language options, objectivity, brevity, and ease of use) that make it well-suited for longitudinal studies, for long-term surveillance of substrate reduction therapy as well as for comparisons with other lysosomal storage disorders and other chronic diseases. These preliminary findings should allay fears of cognitive dysfunction due to short-term miglustat therapy. 相似文献
5.
Suligoi B Massi M Galli C Sciandra M Di Sora F Pezzotti P Recchia O Montella F Sinicco A Rezza G 《Journal of acquired immune deficiency syndromes (1999)》2003,32(4):424-428
We evaluated a procedure for identifying recent HIV infections, using sequential serum samples from 47 HIV-positive persons for whom the seroconversion date could be accurately estimated. Each serum sample was divided into two aliquots: one diluted with phosphate-buffered saline and the other diluted with 1 M guanidine. We assayed the aliquots with the automated AxSYM HIV1/2gO test (Abbott Diagnostics Division), without modifying the manufacturer's protocol. We then calculated the avidity index (AI): the ratio of the sample/cutoff value for the guanidine aliquot to that of the phosphate-buffered saline aliquot. We analyzed 216 serum samples: 34 samples were collected within 6 months of seroconversion (recent seroconversions), and 182 were collected after 6 months. The mean AIs, by time from seroconversion, were 0.68 +/- 0.16 (within 6 months) and 0.98 +/- 0.10 (after 6 months) (P < 0.0001). AI of <0.90 correctly identified 88.2% of recent infections but misclassified as recent infections 13.2% of serum samples collected afterward. The probability of an infection being classified as recent and having AI of > or = 0.90 would be 0.7% in a population with 5% recent infections. AI can identify with a certain degree of accuracy recent HIV infections, and being a quantitative index, it provides different levels of sensitivity and specificity, depending on the selected cutoff value. The standard assay procedure is not modified. This test is simple and inexpensive and could be used for surveillance, decision-making in treatment, and prevention. 相似文献
6.
Efficacy and safety of recombinant human activated protein C for severe sepsis 总被引:168,自引:0,他引:168
Bernard GR Vincent JL Laterre PF LaRosa SP Dhainaut JF Lopez-Rodriguez A Steingrub JS Garber GE Helterbrand JD Ely EW Fisher CJ;Recombinant human protein C Worldwide Evaluation in Severe Sepsis 《The New England journal of medicine》2001,344(10):699-709
BACKGROUND: Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS: A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS: Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding. 相似文献
7.
Rabin E Gordon AM 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2004,155(3):362-369
Touch typing movements are typically too brief to use on-line feedback. Yet, previous studies have shown that blocking tactile feedback of the fingertip of typists leads to an increase in typing errors. To determine the contribution of tactile information to rapid fine motor skills, we analyzed kinematics of the right index finger during typing with and without tactile feedback. Twelve expert touch typists copy-typed sentences on a computer keyboard without vision of their hands or the computer screen. Following control trials, their right index fingertip was anesthetized, and sentences were typed again. The movements of the finger were recorded with an instrumented glove and electromagnetic position sensor. During anesthesia, typing errors of that finger increased sevenfold. While the inter-keypress timing and average kinematics were unaffected, there was an increase in variability of all measures. Regression analysis showed that endpoint variability was largely accounted for by start location variability. The results suggest that tactile cues provide information about the start location of the finger, which is necessary to perform typing movements accurately. 相似文献
8.
Takahiro Yamanaka Kenyu Nakayama-Iwatsuki Sora Fujimoto Naoki Hirono Jun Negishi Yasushi Tamada Masumi Hirabayashi Shinichi Hochi 《Transplantation proceedings》2021,53(5):1744-1750
Islet transplantation is a promising option for the clinical treatment of insulin-dependent diabetes, but a reliable islet cryopreservation/transplantation protocol should be established to overcome the donor shortage. The current study reports that a silk fibroin (SF) sponge disk can be used as a cryodevice for vitrification of large quantity pancreatic islets and the scaffold for subsequent subrenal transplantation in a rat model. The marginal islet mass (550 islet equivalents [IEQs]) on an SF sponge disk was vitrified-warmed and transplanted beneath the kidney capsule of a streptozotocin-induced diabetic rat with or without vascular endothelial growth factor (VEGF). Subrenal transplantation (no scaffold) of 550 IEQ fresh islets and post-warm islets vitrified on a nylon mesh device resulted in achieving euglycemia of recipient rats at 60% and 0%, respectively. Transplantation of 550 IEQ islets vitrified-warmed on an SF sponge disk failed to achieve euglycemia of recipient rats (0%), but the VEGF inclusion in the SF sponge disk contributed to acquiring the euglycemic recipients (33%). All cured recipient rats regained hyperglycemia after nephrectomy, and the histopathologic analysis exhibited a well-developing blood vessel network into the islet engrafts. Thus, an SF sponge disc was successively available as the cryodevice for islet vitrification, the transporter of the angiogenic VEGF, and the scaffold for subrenal transplantation in the rat model. 相似文献
9.
C.P. Garcia D.F.V. Avila V.R. de A. Ferreira F.C. da Silva M.M. de S. Fortkamp R.S. Gomes J.B. Ely 《Journal of plastic, reconstructive & aesthetic surgery》2021,74(2):364-369
IntroductionWith the emergence of blunt-tipped microcannulas, there is a hypothesis that these could cause less damage and reduce pain as compared to conventional sharp needles in eyelid surgery. The purpose is to determine whether an 18G blunt-tipped cannula can be better than a 26G needle.MethodsThis prospective, observer-blinded, randomized clinical trial was conducted from June 2017 to December 2018. Sixty-eight patients were randomized to receive local anesthesia injections for upper blepharoplasty. Infiltration was performed by using a 26-gauge sharp needle on one side and on the other side, infiltration was performed by using an 18-gauge stainless-steel blunt-tipped microcannula. A numeric rating scale (NRS) from 0 to 10 was used to blindly assess pain in patients receiving anesthesia injections with both needle types. Photographs of the eyelids of each patient were taken in five different periods and used by three blinded observers to identify bruise or ecchymoses.ResultsA total of 136 eyelid operations were performed. There was no statistically significant difference when both groups were compared; however, the average score of pain was higher in patients taking the infiltration through the needle (2.85 versus 2.50). Regarding the evaluation of bruising and ecchymoses, the results showed that, in the five periods evaluated, there was no statistical difference in bruising and ecchymosis in the eyelids when taking the infiltration through a sharp needle when compared with that of the eyelids taking infiltration through a (blunt-tipped) microcannula.ConclusionThe evaluation of the blunt-tipped microcannula showed a lower pain score mean than that obtained for the sharp needle (2.5 versus 2.85) (p > 0.05). There was no statistically significant difference in the bruising and ecchymosis courses. 相似文献
10.
Total hip replacement has become one of the most successful surgical operations over the past 25 years. The duration of a total hip prosthesis depends on primary stability, and many studies have tried precisely to evaluate hip joint morphology to obtain excellent contact between bone and prosthetic component. This study performed a morphometric analysis of the human hip joint using, for the first time, the P40 plastination procedure. We cut 42 hip joint compounds into slices 3 mm thick; for exact distance measuring the sections were scanned into the computer. The following mean measurements for hip geometry were obtained: vertical diameter of acetabulum 4.894±0.274 cm, depth of acetabulum 1.643±0.245 cm, femoral head radius 2.268±0.149 cm, femoral neck length 4.3670±0.528 cm, acetabular perimeter 6.711±0.434 cm, vertical diameter of labrum acetabulare 4.759±0.476 cm, depth of labrum acetabulare 2.599±0.395 cm, sum of femoral head and neck lengths 6.759±0.550 cm, hip axis length 11.859±1.007 cm, femoral neck axis length 10.12±0.555 cm, and femoral neck diameter 3.349±0.276 cm. All of these data reveal a significant gender difference. Our aim was to indicate an unconventional and new method of gaining morphometric hip data by using plastination. 相似文献