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11.
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
12.
The parameters that characterize the intricate water diffusion in tumors may serve to reveal their distinct pathology. Specifically, the application of diffusion magnetic resonance imaging (MRI) can aid in characterizing breast cancer, as well as monitoring response to therapy. We present here a non-invasive, quantitative MRI investigation, at high spatial resolution, of water diffusion in hormonal dependent MCF7 breast tumors implanted orthotopically in immunodeficient mice. Distinctive MRI protocols were designed in this study, utilizing a broad range of diffusion times and diffusion gradient strengths. Application of these protocols allowed water diffusion in the tissue extracellular and intracellular compartments to be distinguished, and the effect of restricted diffusion and water exchange on the water diffusion in these compartments to be evaluated. Pixel-by-pixel analysis yielded parametric maps of the estimated volume fraction and apparent diffusion coefficient of each compartment. The diffusion of the water in the extracellular microenvironment was approximately two fold slower than that of free water, and in the intracellular compartment was about one order of magnitude slower than that of free water and demonstrated restriction of water diffusion at long diffusion times. Mapping of the water fraction in each compartment was further employed to monitor changes during tumor progression and to assess tumor response to hormonal manipulation with a new antiestrogenic drug, tamoxifen methiodide (TMI). It was found that, in parallel to the growth arrest by this drug, the volume fraction of the slowly diffusing water increased, suggesting a TMI-induced cell swelling. This study can serve as a basis for extending diffusion breast MRI in the clinical setting. 相似文献
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Ari Elson Yael Bernstein Hadassa Degani Ditsa Levanon Herzl Ben-Hur Yoram Groner 《Somatic Cell and Molecular Genetics》1992,18(2):143-161
Down's syndrome (DS) is a human genetic disease caused by triplication of the distal third of chromosome 21 and overexpression of an unknown number of genes residing in it. The gene for the liver-type subunit of phosphofructokinase (PFKL), a key glycolytic enzyme, maps to this region and the product is overproduced in DS erythrocytes and fibroblasts. These facts, together with abnormalities which occur in DS glycolysis, make PFKL overexpression a candidate for causing some aspects of the DS phenotype. A cellular model for examining the consequences of PFKL overexpression in DS was constructed by transfecting rat PC12 cells with the human PFKL cDNA. Phosphofructokinase (PFK) isolated from PFKL-overexpressing clones was more inhibited by ATP and citrate and less activated by fructose-6-phosphate than control PFK; similar results were obtained when PFK preparations from DS and control fibroblasts were compared. In vivo NMR measurements determined that cells overexpressing PFKL performed glycolysis 40% faster than controls. These results show that overexpression of PFKL is the cause for altered biochemical regulatory characteristics of PFK in DS fibroblasts and can result in enhancement of glycolysis rates. It is also shown that increased gene dosage can exert its influence not merely by enhancing the amounts of gene products but also by altering their biochemical nature. 相似文献
15.
Transcriptional profiling of target of RNAIII-activating protein, a master regulator of staphylococcal virulence 下载免费PDF全文
Staphylococcus aureus is a gram-positive bacterium that is part of the normal healthy flora but that can become virulent and cause infections by producing biofilms and toxins. The production of virulence factors is regulated by cell-cell communication (quorum sensing) through the histidine phosphorylation of target of RNAIII-activating protein (TRAP), which is a 21-kDa protein that is highly conserved among staphylococci. Using microarray analysis, we show here that the expression and phosphorylation of TRAP upregulate the expression of most, if not all, toxins known to date, as well as their global regulator agr. In addition, we show here that the expression and phosphorylation of TRAP are also necessary for the expression of genes known to be necessary for the survival of the bacteria in a biofilm, like arc, pyr, and ure. TRAP is thus demonstrated to be a master regulator of staphylococcal pathogenesis. 相似文献
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Derek E. Byers Jennifer Alexander-Brett Anand C. Patel Eugene Agapov Geoffrey Dang-Vu Xiaohua Jin Kangyun Wu Yingjian You Yael Alevy Jean-Philippe Girard Thaddeus S. Stappenbeck G. Alexander Patterson Richard A. Pierce Steven L. Brody Michael J. Holtzman 《The Journal of clinical investigation》2013,123(12):5410
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Nobel Yael R. Su Steven H. Anderson Michaela R. Luk Lyndon Small-Saunders Jennifer L. Reyes-Soffer Gissette Gallagher Dympna Freedberg Daniel E. 《Digestive diseases and sciences》2022,67(9):4484-4491
Digestive Diseases and Sciences - Patients with SARS-CoV-2 who present with gastrointestinal symptoms have a milder clinical course than those who do not. Risk factors for severe COVID-19 disease... 相似文献
20.
Effect of Matrix Metalloproteinase Inhibition by Doxycycline on Myocardial Healing and Remodeling after Myocardial Infarction 总被引:2,自引:0,他引:2
Tessone A Feinberg MS Barbash IM Reich R Holbova R Richmann M Mardor Y Leor J 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2005,19(6):383-390
Summary The aim of conducting this study was to assess the clinical relevance of matrix metalloproteinase (MMP) inhibition by doxycycline,
an effective MMP inhibitor, in a rat model of extensive myocardial infarction (MI) and left ventricular (LV) dysfunction.
Rats (n = 22) were subjected to extensive anterior MI. Doxycycline (25 mg SC, daily) or saline (control) injections were started
for nine days thereafter. The effect of doxycycline on MMP activity in the infarcted and remote myocardium was measured by
zymography, in another subgroup (n = 8), nine days after MI. Echocardiography and magnetic resonance imaging (MRI) studies were performed at one and thirty
days after MI to assess LV remodeling and function. After 4 weeks, hearts were fixed, and subjected to morphometric and histological
analysis. Compared with control, doxycycline treatment attenuated MMP-9 and -2 activity in both infarcted and remote myocardium.
Serial echocardiography studies showed that doxycycline failed to attenuate scar thinning, LV dilatation and dysfunction.
MRI study showed that doxycycline impaired LV compensatory hypertrophy. Furthermore, compared with control, doxycycline reduced
vessel density (/mm2 ± SEM) in the infarcted myocardium (84 ± 16 vs. 46 ± 9/mm2, respectively; p < 0.05).
Our work suggest that effective MMPs’ inhibition in the infarcted and remote myocardium by doxycycline does not prevent LV
remodeling and dysfunction but impairs angiogenesis and compensatory LV hypertrophy. Our findings caution against aggressive,
non-selective inhibition of MMPs in the early healing phase after MI. 相似文献