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11.
Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls. Individuals classified as haplogroup I demonstrated a significant decrease in risk of ALS versus individuals carrying the most common haplogroup, H (odds ratio 0.08, 95% confidence interval 0.04-0.4, p < 0.01). Further stratification of the dataset by sex, age and site of onset of disease and survival failed to reach significance for association. Our study provides evidence of the contribution of mitochondrial variation to the risk of ALS development in Caucasians. Further it may help elucidate the mechanism of the mitochondrial dysfunction detectable in ALS, and may be of relevance in development of strategies for the treatment of this disease.  相似文献   
12.
Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.  相似文献   
13.
Evidence is accumulating that intermediates of oxygen reduction may be associated with the development of alcoholic disease. Free radical-induced perturbation of the oxidant/antioxidant balance in the cell is widely recognized as the main causative factor of age-related disorders. In the present study we investigated the effects of 20 months of ethanol consumption on the antioxidant defense system in different rat organs compared with normal aging in the absence and presence of treatment with L-acetyl carnitine. We demonstrate that aged rats underwent significant perturbation of the antioxidant defense system, as indicated by depletion of reduced glutathione (GSH) content, increased oxidized GSH, free radical-induced luminescence associated with increased hydroxynonenal content and decreased GSH reductase activity. These modifications, observed particularly in brain and liver compared with other organs, were enhanced by long-term alcohol exposure and, interestingly, were significantly reduced with acetyl carnitine supplements. Our results indicate that decreased GSH reductase activity and thiol depletion are important factors in effecting a pathogenic role for oxidative stress in aging and in all situations in which age-correlated and oxidant-induced changes occur, such as in alcoholism. Administration of acetyl carnitine greatly reduces these metabolic abnormalities. Our findings support its pharmacological potential in the management of alcoholic disturbances.  相似文献   
14.
It is generally recognized that activation through membrane effector molecules such as CD40 or the B cell receptor (BCR) is mandatory to allow B cells to proliferate and differentiate into antibody (Ab)-secreting cells in response to cytokines. We show here that purified tonsillar B cells can be stimulated directly by a cytokine combination to proliferate and secrete immunoglobulins when cultures are performed at high cell density. The contact-mediated activation of B cells in this experimental system is strongly inhibited both by anti-very late antigen (VLA)-4 monoclonal Ab and by a peptide containing the LDV sequence specifically recognized by the α4 integrin binding site. These reagents also significantly suppressed the B cell responses elicited by engagement of the BCR or CD40. Our data reveal that memory B cells but not virgin or germinal center B cells are sensitive to the direct stimulatory effect of cytokines in high-density cultures. Finally, we found that the dual expression of the α and β chains of VLA-4 is a distinctive feature of the memory B cell population. Collectively, our findings support the notion that VLA-4-dependent homotypic B cell interactions can mediate a co-stimulatory signal to human memory B cells and might participate in the B cell activation triggered through the BCR and CD40.  相似文献   
15.
In an attempt to recognize early stages of focal segmental glomerulosclerosis (FSGS) in patients with a clinical course suggesting a diagnosis other than minimal change disease (MCD) and normal histology, or minor, nondiagnostic changes on light microscopy (LM), we used a protocol for systematic and extensive electron microscopy (EM) examination of kidney biopsies obtained from such patients. By this method ultrastructural pathology was found in 8 patients. These changes were localized, involving only portions of single glomerular segments. The findings included mild to moderate increase of the mesangial matrix, focal wrinkling of the capillary basement membrane, and early obliteration of the normal architecture of individual capillary loops, as well as electron-dense deposits in a mesangial and subendothelial distribution. Of these 8 patients, 2 are at present in remission without therapy (in 1, following therapy with cyclophosphamide); 3 are in remission on steroid therapy; 1 developed massive proteinuria during pregnancy, after a spontaneous remission lasting almost 2 years; 1 patient advanced to terminal renal failure 3 1/2 years after biopsy; and 1 died of sepsis 1 month after biopsy. We believe that the ultrastructural changes found may represent early or mild FSGS and that the protocol described can add valuable information in clinically worrisome patients in whom renal histology appears normal.  相似文献   
16.
BackgroundIn rectal cancer, extramural vascular invasion (EMVI) is the presence of tumour cells in blood vessels outside the muscular layer, which is associated with poor prognosis. Regression of EMVI on MRI following neoadjuvant chemoradiotherapy or its persistence may have prognostic implications.MethodsThis retrospective study included 52 patients with rectal cancer who underwent total mesorectal excision following long-course neoadjuvant chemoradiotherapy (CRT). EMVI assessments were done on previous pelvic MRIs obtained before neoadjuvant CRT and eight weeks after the completion of neoadjuvant chemoradiotherapy in initially EMVI positive cases.ResultsPersistently EMVI positive patients had worse overall survival and disease-free survival compared to initially EMVI negative patients and patients who returned to negative (p < 0.001 for both). Multivariate analysis identified persistent EMVI positivity after neoadjuvant treatment (HR, 102.9; p = 0.003) as significant independent predictor of worse overall survival; and persistent EMVI positivity (HR, 17.0; p = 0.002), mesorectal fascia involvement after neoadjuvant treatment (HR, 8.0; p = 0.017), and poor differentiation (HR, 10.3, p = 0.012) as significant independent predictors of worse disease-free survival.ConclusionPersistent EMVI positivity after neoadjuvant therapy appears to be an independent factor for poor overall survival; and persistent EMVI positivity as well as mesorectal fascia involvement on post neoadjuvant therapy MRI and poor differentiation appears to be important predictors of poor disease-free survival in rectal cancer patients.  相似文献   
17.
Objective: Intravesical Bacillus Calmette-Guèrin (BCG) is an effective treatment in non––muscle-invasive bladder cancer, however, extravesical BCG infection may occur in remote organs as a potentially serious complication. Researchers aimed to assess whether a different timing of BCG infection after intravesical administration of BCG could be identified and estimated for each single involved organ. Methods: We performed a systematic literature review over systemic and genitourinary BCG infection case reports, including 271 published case reports for a total of 307 patients. Demographic data, clinical features, and timing of BCG infection development were collected and analyzed for each patient. Results: BCG infection developed with a different timing from last instillation, depending on the involved organ. Among the genitourinary complications, penile lesions occurred as early as 1 (1;3) weeks, while orchiepididymitis occurred as late as 56 (6.25;156) weeks. At the same time, granulomatous hepatitis and lungs involvement such as miliary pulmonary BCG infection occurred earlier, with a median time of 1 (1;4) and 1 (1;6) weeks respectively, whereas vascular, osteoarticular, and muscular complications developed with a median timing from last instillation of 52 (20;104), 68 (14;156), and 93 (29;156) weeks, respectively. The analysis detected a cluster between lungs, liver, and bone marrow complications on one side and muscular and osteoarticular or vascular complications on the other side was also observed. Conclusions: BCG infection after intravesical BCG for bladder cancer may develop even several months or years after the last instillation, depending on the involved organs. When BCG infection interests one or more organ, 2 main associative patterns are common: one involving lungs, liver, and bone marrow, with earlier occurrence but lower rates of microbiological diagnosis achievement, and one involving muscular and osteoarticular or vascular districts, with later occurrence but higher rates of microbiological evidence.  相似文献   
18.
19.
A genetic contribution to the pathogenesis of panic disorder has been demonstrated by clinical genetic studies. Molecular genetic studies have focused on candidate genes suggested by the molecular mechanisms implied in the action of drugs utilized for therapy or in challenge tests. One class of drugs effective in the treatment of panic disorder is represented by monoamine oxidase A inhibitors. Therefore, the monoamine oxidase A gene on chromosome X is a prime candidate gene. In the present study we investigated a novel repeat polymorphism in the promoter of the monoamine oxidase A gene for association with panic disorder in two independent samples (German sample, n = 80; Italian sample, n = 129). Two alleles (3 and 4 repeats) were most common and constituted >97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3a, 4 and 5) were more active than allele 3. Among females of both the German and the Italian samples of panic disorder patients (combined, n = 209) the longer alleles (3a, 4 and 5) were significantly more frequent than among females of the corresponding control samples (combined, n = 190, chi2 = 10.27, df = 1, P = 0.001). Together with the observation that inhibition of monoamine oxidase A is clinically effective in the treatment of panic disorder these findings suggest that increased monoamine oxidase A activity is a risk factor for panic disorder in female patients.  相似文献   
20.
The Sudanese village midwife can be defined as "an illiterate (or sometimes literate) woman, usually a mother, community chose, trained in a district midwifery school for about 9 months, after which she receives a certificate, is registered and becomes responsible for antenatal; intrapartum; and postnatal care of the mother and child in her village. She is a part-time worker, not salaried and she is supervised by the community." The difference between the village midwife and the TBA (traditional birth attendant) as defined by WHO is that the village midwife receives formal training from the beginning, and ends by being registered and being legally recognized. The activities and standard of performance of the village midwife are of high standard, even approximating English standards. The community employs the midwife and fees are paid on an optional basis, as midwives who demand fees are generally looked upon with disapproval. The midwives are not only trained to conduct deliveries at home, but also to be "missionaries in the homes of people in the cause of cleanliness and hygiene" and to spread a "health sense" among mothers and thus promote the health of the next generation. Over all, the midwifery training program shows that utilization of part-time health workers can be a valid and feasible concept.  相似文献   
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