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71.
72.
Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency 总被引:2,自引:0,他引:2
Oezen I Rossmanith W Forss-Petter S Kemp S Voigtländer T Moser-Thier K Wanders RJ Bittner RE Berger J 《Human molecular genetics》2005,14(9):1127-1137
X-linked adrenoleukodystrophy (X-ALD, OMIM 300100) is a severe inherited neurodegenerative disease, associated with the accumulation of very long-chain fatty acids (VLCFA). The recent unexpected observation that the accumulation of VLCFA in tissues of the Abcd1-deficient mouse model for X-ALD is not due to a deficiency in VLCFA degradation, led to the hypothesis that mitochondrial abnormalities might contribute to X-ALD pathology. Here, we report that in spite of substantial accumulation of VLCFA in whole muscle homogenates, normal VLCFA levels were detected in mitochondria obtained by organellar fractionation. Polarographic analyses of the respiratory chain as well as enzymatic assays of isolated muscle mitochondria revealed no differences between X-ALD and control mice. Moreover, analysis by electron microscopy, revealed normal size, structure and localization of mitochondria in muscle of both groups. Similar to the results obtained in skeletal muscle, the mitochondrial enzyme activities in brain homogenates of Abcd1-deficient and wild-type animals also did not differ. Finally, studies on mitochondrial oxidative phosphorylation in permeabilized human skin fibroblasts of X-ALD patients and controls revealed no abnormalities. Thus, we conclude that the accumulation of VLCFA per se does not cause mitochondrial abnormalities and vice versa-mitochondrial abnormalities are not responsible for the accumulation of VLCFA in X-ALD mice. 相似文献
73.
A molecular oscillator that controls the expression of cyclic genes such as lunatic fringe (Lfng) in the presomitic mesoderm has been shown to be coupled with somite formation in vertebrate embryos. To address the functional significance of oscillating Lfng expression, we have generated transgenic mice expressing Lfng constitutively in the presomitic mesoderm in addition to the intrinsic cyclic Lfng activity. These transgenic lines displayed defects of somite patterning and vertebral organization that were very similar to those of Lfng null mutants. Furthermore, constitutive expression of exogenous Lfng did not compensate for the complete loss of cyclic endogenous Lfng activity. Noncyclic exogenous Lfng expression did not abolish cyclic expression of endogenous Lfng in the posterior presomitic mesoderm (psm) but affected its expression pattern in the anterior psm. Similarly, dynamic expression of Hes7 was not abolished but abnormal expression patterns were obtained. Our data are consistent with a model in which alternations of Lfng activity between ON and OFF states in the presomitic mesoderm prior to somite segmentation are critical for proper somite patterning, and suggest that Notch signaling might not be the only determinant of cyclic gene expression in the presomitic mesoderm of mouse embryos. 相似文献
74.
Therapies that neutralize the function of TNF-alpha suppress rheumatoid arthritis (RA) but not osteoarthritis (OA). We show that patients suffering from RA but not OA have significant levels of autoantibodies directed to TNF-alpha. Thus, the immune system can selectively generate autoimmunity to proinflammatory mediators when such a response is beneficial for the host. A well-defined model of RA was used to elaborate the contribution of beneficial autoimmunity to the regulation of disease. We show that during the disease autoantibody production is elicited against few inflammatory, but not regulatory, mediators. Selective amplification of these beneficial antibodies by targeted DNA vaccines provided protective immunity. Epitope mapping revealed that anti-TNF-alpha immunity is highly restricted and excretes no crossreactivity to other known gene products. Its selective exclusion substantially exacerbated the disease. Administration of anti-TNF-alpha antibodies could then override this aggravation. This substantiates the significance of beneficial autoimmunity in restraining self-destructive immunity. 相似文献
75.
Nigg JT Butler KM Huang-Pollock CL Henderson JM 《Journal of consulting and clinical psychology》2002,70(1):153-157
The theory that attention-deficit/hyperactivity disorder (ADHD) stems from a deficit in an executive behavioral inhibition process has been little studied in adults, where the validity of ADHD is in debate. This study examined, in high-functioning young adults with persistent ADHD and a control group, 2 leading measures of inhibitory control: the antisaccad task and the negative priming task. ADHD adults showed weakened ability to effortfully stop a refle ve or anticipated oculomotor response but had normal ability to automatically suppress irrelevant information. Results suggest that an inhibitory deficit in ADHD is confined to effortful inhibition of motor response, that antisaccade and negative priming tasks index distinct inhibition systems, and that persistence of ADHD symptoms into adulthood is associated with persistence of executive motor inhibition deficits. 相似文献
76.
Otto C Gasser M Waaga-Gasser AM Rohde AC Lenhard M Jost S Gassel HJ Ulrichs K Timmermann W 《Human immunology》2002,63(10):880-887
It has been extensively documented the role of the indirect pathway of allorecognition in allograft rejection. However, recent data demonstrate that the manipulation of this pathway could be also sufficient to promote prolongation of allograft survival. In the present study we evaluated the effect of preoperative immunization with the WF-specific MHC class II peptides RT1.D2 and RT1.B2 in combination with low-dose CsA from days 0 to 7 (5 mg/kg/day) and from days 8 to 30 (1 mg/kg/day) after WF small bowel transplantation. Seven days before and on the day of transplantation, LEW recipients were immunized with the two WF MHC class II peptides RT1.B2 and RT1.D2. The CsA monotherapy induced an allograft survival of 49.3 +/- 6.1 days. MHC class II peptide immunization had a limited effect on allograft survival for RT1.D2 (47.1 +/- 3.8 days) and induced prolongation of allograft survival for RT1.B2 (73.6 +/- 34.6 days). This effect seems to be based on the absence or silence of RT1.B2-reactive T cells and rejection seems to be correlated with the presence of RT1.B2-specific T cells in the late phase. Therefore, the combination of RT1.B2 with low-dose CsA shifts the immunological response and protects small bowel allograft rejection. 相似文献
77.
Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer 总被引:3,自引:0,他引:3
Finkelstein SE Heimann DM Klebanoff CA Antony PA Gattinoni L Hinrichs CS Hwang LN Palmer DC Spiess PJ Surman DR Wrzesiniski C Yu Z Rosenberg SA Restifo NP 《Journal of leukocyte biology》2004,76(2):333-337
Immunotherapy using adoptive cell transfer is a promising approach that can result in the regression of bulky, invasive cancer in some patients. However, currently available therapies remain less successful than desired. To study the mechanisms of action and possible improvements in cell-transfer therapies, we use a murine model system with analogous components to the treatment of patients. T cell receptor transgenic CD8+ T cells (pmel-1) specifically recognizing the melanocyte differentiation antigen gp100 are adoptively transferred into lympho-depleted mice bearing large, established, 14-day subcutaneous B16 melanoma (0.5-1 cm in diameter) on the day of treatment. Adoptive cell transfer in combination with interleukin interleukin-2 or interleukin-15 cytokine administration and vaccination using an altered form of the target antigen, gp100, can result in the complete and durable regression of large tumor burdens. Complete responders frequently develop autoimmunity with vitiligo at the former tumor site that often spreads to involve the whole coat. These findings have important implications for the design of immunotherapy trials in humans. 相似文献
78.
79.
80.
Boot CR van der Gulden JW Vercoulen JH van den Borne BH Orbon KH Rooijackers J van Weel C Folgering HT 《Patient education and counseling》2005,59(1):103-109
We sought to investigate associations between knowledge about the disease and sick leave, health complaints, functional limitations, adaptation and perceived control. Patients with asthma (n = 101) and COPD (n = 64) underwent lung function tests and completed questionnaires. In addition, all were asked the question: ‘what is the diagnosis of your disease?’, with the response categories: ‘asthma’ and ‘COPD (chronic bronchitis or emphysema)’. Thirty-five percent of the asthma patients and 30% of the COPD patients did not know their correct diagnosis. Sick leave was not associated with knowledge about the disease in asthma and COPD. In asthma, much knowledge about management of the disease was associated with better adaptation (P = 0.01) and less perceived control over health by external factors (P = 0.02). Knowing the correct diagnosis was associated with less control over health by powerful others (P = 0.02). For COPD, more knowledge about management of the disease was associated with better adaptation (P = 0.02) and less control over health by internal factors (P = 0.01). Knowing the correct diagnosis was associated with less control over dyspnea at work (P = 0.01). 相似文献