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771.
In the C57 mouse strain, loss of sensory hair cells (HCs) begins during early adulthood, starting in the base of the cochlea and progressing toward the apex as aging continues. In contrast, the CBA mouse strain exhibits no significant cochlear histopathology until relatively late in life. These strain and age differences may be related to differences in cochlear energy metabolism. To examine this possibility, we used dehydrogenase and glycogen histochemistry to evaluate the metabolic capacities of HCs and stria vascularis (SV) in cochleas of C57 and CBA mice. Reaction product density was quantified and compared as a function of strain (1.5-month-old C57 mice vs. CBA mice) and age (CBA mice, 1.5, 18 and 36 months). Young C57 mice had significantly less HC dehydrogenase activity than CBA mice of any age, lower HC glycogen levels than 18-month-old CBA mice and lower SV glycogen levels than 18- or 36-month-old CBA animals. Within the CBA strain, HC dehydrogenase activity decreased significantly between 1.5 and 18 months of age, while glycogen levels in both HCs and SV increased over the same time period. Between 18 and 36 months, HC dehydrogenase activity and SV glycogen levels remained stable. The results show that there are significant age-related changes in energy metabolism in the inner ear of CBA mice that are correlated with age-related hearing loss. Genetically determined deficits in cochlear metabolic capacity in C57 mice could be linked to the early onset of hearing loss in this strain.  相似文献   
772.
Primary cultures of rat cerebral cortical cells and cerebellar granule cells die by an apoptotic mechanism after more than 2 weeks in cultures in the absence of medium change and glucose supplement, a process termed age-induced apoptosis of cultured neurons. Our preliminary study has shown that age-induced apoptosis of cerebellar granule cells is protected by pretreatment with tetrahydroaminoacridine (THA), an antidementia drug. In this study, we systematically compared the neuroprotective effects of THA with those of (S)-1-[N-(4-chlorobenzyl)succinamoyl]pyrrolidine-2-carbaldehyde (ONO-1603), a novel prolyl endopeptidase inhibitor and potential antidementia drug. Both ONO-1603 and THA effectively delay age-induced apoptosis of cerebral and cerebellar neurons, as demonstrated morphologically with toluidine blue and fluorescein diacetate/propidium iodide staining or biochemically by DNA laddering analysis on agarose gels. ONO-1603 is about 300 times more potent than THA, with a maximal protective effect at 0.03 and 10 microM, respectively. ONO-1603 shows a wide protective range of 0.03 to 1 microM in contrast to a narrow effective range of 3 to 10 microM for THA. Moreover, ONO-1603 is nontoxic to neurons, even at the high concentration of 100 microM, whereas THA elicits severe neurotoxicity at a dose of >/=30 microM. Both ONO-1603 and THA robustly suppress overexpression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12) mRNA and accumulation of GAPDH protein in a particulate fraction of cultured neurons undergoing age-induced apoptosis. Because we documented that GAPDH overexpression participates in neuronal apoptosis induced by various insults, we conclude that the neuroprotective actions of ONO-1603 and THA appear to be mediated by suppression of this protein overexpression.  相似文献   
773.
BACKGROUND: Enrollment in health maintenance organizations (HMOs) has increased rapidly during the past 10 years, reflecting a growing emphasis on health care cost containment. To determine whether there is a difference in the treatment and outcome for female patients with breast cancer enrolled in HMOs versus a fee-for-service setting, we compared the 10-year survival and initial treatment of patients with breast cancer enrolled in both types of plans. METHODS: With the use of tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas, respectively, we obtained information on the treatment and outcome for 13,358 female patients with breast cancer, aged 65 years and older, diagnosed between 1985 and 1992. We linked registry information with Medicare data and data from the two large HMOs included in the study. We compared the survival and treatment differences between HMO and fee-for-service care after adjusting for tumor stage, comorbidity, and sociodemographic characteristics. RESULTS: In San Francisco-Oakland, the 10-year adjusted risk ratio for breast cancer deaths among HMO patients compared with fee-for-service patients was 0.71 (95% confidence interval [CI] = 0.59-0.87) and was comparable for all deaths. In Seattle-Puget Sound, the risk ratio for breast cancer deaths was 1.01 (95% CI = 0.77-1.33) but somewhat lower for all deaths. Women enrolled in HMOs were more likely to receive breast-conserving surgery than women in fee-for-service (odds ratio = 1.55 in San Francisco-Oakland; 3.39 in Seattle). HMO enrollees undergoing breast-conserving surgery were also more likely to receive adjuvant radiotherapy (San Francisco-Oakland odds ratio = 2.49; Seattle odds ratio = 4.62). CONCLUSIONS: Long-term survival outcomes in the two prepaid group practice HMOs in this study were at least equal to, and possibly better than, outcomes in the fee-for-service system. In addition, the use of recommended therapy for early stage breast cancer was more frequent in the two HMOs.  相似文献   
774.
The aim of the study was to investigate the social background of physicians, the reasons that influenced doctors to enter medicine, and the association between those reasons and satisfaction in career choice of young Finnish doctors. An extensive postal questionnaire was mailed to a random sample of 2632 young Finnish doctors in 1988 and to 2332 doctors in 1993. We found out that majority of the respondents reported that interest in people, a wide range of job opportunities, the fact that medicine is a highly-appreciated profession, and success at school had influenced their decision to enter medicine quite a lot or very much. In 1988, 8% and in 1993, 7% of the respondents reported that interest in people had not influenced their career choice at all or only slightly. More women than men were influenced quite a lot or very much by factors like interest in people, success at school and vocation, meaning the lifelong calling to physicians' profession. A total of 22% of respondents would not enter medicine again. Vocation, interest in people and wide range of job opportunities were significantly more rarely mentioned as an important career choice motive by these respondents. It seems that interest in human beings and vocation are important to would-be doctors, and also help them to get along in the physicians' profession. Medical schools should develop their curricula towards more humanistic medicine in order to maintain their students' interest in people.  相似文献   
775.
BACKGROUND: The laparoscopic application of LAP-BAND is gaining widespread acceptance as a gastric restrictive procedure. At the same time the reported morbidities (i.e., gastric perforation, stomach and/or band slippage) are cause for some concern. METHODS: From September 1993 until May 1997, 260 patients underwent LAP-BAND at the Department of Surgery at the University of Padova, Italy. RESULTS: The mortality rate was zero and the morbidity rate requiring reoperation was 3.4% (stomach slippage, gastric perforation, erosion). In order to avoid complications the key points of the technique are reviewed: (1) reference points for dissection (equator of the balloon, left crus); (2) retrogastric tunnel within the layers of the phrenogastric ligament; (3) embedment of the band; (4) proper outlet calibration; and (5) retention sutures. CONCLUSIONS: Attention to technical details is of paramount importance for a safe, standardized and effective operation.  相似文献   
776.
Paired helical filaments (PHFs) are the structural constituents of neurofibrillary tangles in Alzheimer's disease and are composed of hyperphosphorylated forms of the microtubule-associated protein tau (PHF-tau). Pathological hyperphosphorylation of tau is believed to be an important contributor to the destabilisation of microtubules and their subsequent disappearance from tangle-bearing neurons in Alzheimer's disease, making elucidation of the mechanisms that regulate tau phosphorylation an important research goal. Thus, it is essential to identify, preferably by direct sequencing, all of the sites in PHF-tau that are phosphorylated, a task that is incomplete because of the difficulty to date of purifying insoluble PHF-tau to homogeneity and in sufficient quantities for structural analysis. Here we describe the solubilisation of PHF-tau followed by its purification by Mono Q chromatography and reversed-phase HPLC. Phosphopeptides from proteolytically digested PHF-tau were sequenced by nanoelectrospray mass spectrometry. We identified 22 phosphorylation sites in PHF-tau, including five sites not previously identified. The combination of our new data with previous reports shows that PHF-tau can be phosphorylated on at least 25 different sites.  相似文献   
777.
While the presence of a lipoyl-containing protein (protein X) separate from lipoyl transacetylase in the pyruvate dehydrogenase complex (PDC) has been known for some time, until recently only the cDNA for the yeast enzyme has been cloned. We have cloned, sequenced and characterized the cDNA encoding the human protein X and localized the protein X gene to chromosome 11p13. We also report here a new case of protein X deficiency identified immunologically, with decreased activity of PDC and without mutations in the E1alpha subunit or E1beta subunit. We report that the cDNA and gene of this patient for protein X has a homozygous 4 bp deletion, specifically in the putative mitochondrial targeting signal sequence which results in a premature stop codon. This is the first documented case of a molecular defect in pyruvate dehydrogenase protein X.  相似文献   
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