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Igoudjil A Magrané J Fischer LR Kim HJ Hervias I Dumont M Cortez C Glass JD Starkov AA Manfredi G 《The Journal of neuroscience》2011,31(44):15826-15837
Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes a complex array of pathological events, through toxic gain of function mechanisms, leading to selective motor neuron degeneration. Mitochondrial dysfunction is among the well established toxic effects of mutant SOD1, but its mechanisms are just starting to be elucidated. A portion of mutant SOD1 is localized in mitochondria, where it accumulates mostly on the outer membrane and inside the intermembrane space (IMS). Evidence in cultured cells suggests that mutant SOD1 in the IMS causes mitochondrial dysfunction and compromises cell viability. Therefore, to test its pathogenic role in vivo we generated transgenic mice expressing G93A mutant or wild-type (WT) human SOD1 targeted selectively to the mitochondrial IMS (mito-SOD1). We show that mito-SOD1 is correctly localized in the IMS, where it oligomerizes and acquires enzymatic activity. Mito-G93ASOD1 mice, but not mito-WTSOD1 mice, develop a progressive disease characterized by body weight loss, muscle weakness, brain atrophy, and motor impairment, which is more severe in females. These symptoms are associated with reduced spinal motor neuron counts and impaired mitochondrial bioenergetics, characterized by decreased cytochrome oxidase activity and defective calcium handling. However, there is no evidence of muscle denervation, a cardinal pathological feature of ALS. Together, our findings indicate that mutant SOD1 in the mitochondrial IMS causes mitochondrial dysfunction and neurodegeneration, but per se it is not sufficient to cause a full-fledged ALS phenotype, which requires the participation of mutant SOD1 localized in other cellular compartments. 相似文献
103.
Khaled A Kharfi M Zaouek A Rameh S Zermani R Fazaa B Kamoun MR 《Pediatric dermatology》2012,29(4):525-527
We report a new case of postvaccination morphea profunda (MP) in a child and discuss its different clinical presentations, prognosis, and therapy and its relationship with "solitary morphea profunda." A 2-year-old healthy girl presented with an induration of the anterior aspect of the left thigh of 9 months duration. The lesion had appeared 3 months after a third dose of diphtheria-tetanus-pertussis vaccine. Cutaneous examination showed an induration of 7 × 7 cm with an "orange peel" texture after pinching the skin. Histologic examination confirmed the diagnosis of MP. Systemic steroids (1 mg/kg/day) led to the stabilization of the lesion. After 4 months of treatment, we began the concomitant use of oral methotrexate (10 mg/wk) for 2 months. Methotrexate was then continued alone for 10 months, leading to a significant regression of the induration with no relapse. 相似文献
104.
Eline M. P. Poels Ragy R. Girgis Judy L. Thompson Mark Slifstein Anissa Abi-Dargham 《Psychopharmacology》2013,228(1):167-174
Rationale
A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction observed in patients with schizophrenia. However, the results from positron emission tomography imaging studies of D1 receptor levels in individuals with schizophrenia are mixed.Objectives
The aim of this investigation was to determine whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [11C]SCH23390 and [11C]NNC112, may have contributed to these discrepancies reported in the literature.Methods
Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [11C]SCH23390 and [11C]NNC112.Results
[11C]SCH23390 and [11C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were observed.Conclusions
The results of this study suggest that differences in the binding of [11C]SCH23390 and [11C]NNC112 observed in previous studies are not due to differences in the in vivo behavior of these tracers. 相似文献105.
Rachel M. Layman Amy S. Ruppert Melinda Lynn Ewa Mrozek Bhuvaneswari Ramaswamy Maryam B. Lustberg Robert Wesolowski Susan Ottman Sarah Carothers Anissa Bingman Raquel Reinbolt Eric H. Kraut Charles L. Shapiro 《Cancer chemotherapy and pharmacology》2013,71(5):1183-1190
Purpose
Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy.Patients and methods
We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5–21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1.Results
Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59–0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11–0.69) of patients.Conclusions
Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment. 相似文献106.
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Kelly-Irving M Delpierre C Schieber AC Lepage B Rolland C Afrité A Pascal J Cases C Lombrail P Lang T 《Social science & medicine (1982)》2011,73(9):1416-1421
This study sought to ascertain whether disagreement between patients and physicians on the patients' health status varies according to patients' education level. INTERMEDE is a cross-sectional multicentre study. Data were collected from both patients and doctors via pre- and post consultation questionnaires at the GP's office over a two-week period in October 2007 in 3 regions of France. The sample consists of 585 eligible patients (61% women) and 27 GPs. A significant association between agreement/disagreement between GP and patient on the patient's health status and patient's education level was observed: 75% of patients with a high education level agreed with their GP compared to 50% of patients with a low level of education. Patients and GPs disagreed where patients with the lowest education level said that their health was worse relative to their doctor's evaluation 37% of the time, versus 16% and 14% for those with a medium or high education level respectively. A multilevel multivariate analysis revealed that patients with a low educational level and medium educational level respectively were at higher risk of being overestimated by GP's in respect of self-reported health even if controlling for confounders. These findings suggest that people with a lower education level who consider themselves to have poor health are less reliably identified as such in the primary care system. This could potentially result in lack of advice and treatment for these patients and ultimately the maintenance of health inequalities. 相似文献
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