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51.
1. Specific therapies to cure the muscular dystrophies are not yet available. Therapeutic trials designed on the basis of our understanding of the pathophysiology of these disorders have had only limited success. 2. However, recent investigations in Duchenne muscular dystrophy have identified the abnormal gene and the missing or defective gene product, dystrophin. 3. These discoveries provide information which will lead to more rational and specific therapeutic approaches. 4. The advances in genetic research have led to more effective preventive therapy. Gene mapping has been applied successfully in carrier detection and antenatal diagnosis, and specific gene probes will soon become available for carrier testing for the two most common forms of muscular dystrophy, Duchenne muscular dystrophy and myotonic dystrophy. 5. Supportive therapies for muscular dystrophy patients now include respiratory support for selected patients with chronic respiratory insufficiency. 6. This review will focus on the two most common muscular dystrophies, Duchenne muscular dystrophy and myotonic dystrophy. 相似文献
52.
Carcinoma of the ampulla of Vater 总被引:3,自引:0,他引:3
Experience in treating tumours of the ampulla of Vater in the North West region of the UK is reviewed. The results of local resection, radical resection and palliative bypass in 61 cases have been compared. Local resection in this series offers a better survival than radical procedures at one, two, three, and five years. The operative mortality for radical procedures was 30 per cent. There were no operative deaths in those patients having a local resection. No patient having palliative bypass surgery survived more than 18 months. 相似文献
53.
Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors. 相似文献
54.
Hai Song Kinglun Kingston Mak Lilia Topol Kangsun Yun Jianxin Hu Lisa Garrett Yongbin Chen Ogyi Park Jia Chang R. Mark Simpson Cun-Yu Wang Bin Gao Jin Jiang Yingzi Yang 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(4):1431-1436
Control of organ size by cell proliferation and survival is a fundamental developmental process, and its deregulation leads to cancer. However, the molecular mechanism underlying organ size control remains elusive in vertebrates. In Drosophila, the Hippo (Hpo) signaling pathway controls organ size by both restricting cell growth and proliferation and promoting cell death. Here we investigated whether mammals also require the Hpo pathway to control organ size and adult tissue homeostasis. We found that Mst1 and Mst2, the two mouse homologs of the Drosophila Hpo, control the sizes of some, but not all organs, in mice, and Mst1 and Mst2 act as tumor suppressors by restricting cell proliferation and survival. We show that Mst1 and Mst2 play redundant roles, and removal of both resulted in early lethality in mouse embryos. Importantly, tumors developed in the liver with a substantial increase of the stem/progenitor cells by 6 months after removing Mst1 and Mst2 postnatally. We show that Mst1 and Mst2 were required in vivo to control Yap phosphorylation and activity. Interestingly, apoptosis induced by TNFα was blocked in the Mst1 and Mst2 double-mutant cells both in vivo and in vitro. As TNFα is a pleiotropic inflammatory cytokine affecting most organs by regulating cell proliferation and cell death, resistance to TNFα-induced cell death may also contribute significantly to tumor formation in the absence of Mst1 and Mst2. 相似文献
55.
Natalie J. Kingston Liriye Kurtovic Renae Walsh Carina Joe George Lovrecz Stephen Locarnini James G. Beeson Hans J. Netter 《Vaccine》2019,37(12):1674-1684
The repetitive structure of compact virus-like particles (VLPs) provides high density displays of antigenic sequences, which trigger key parts of the immune system. The hepatitis B virus (HBV) and human papilloma virus (HPV) vaccines exploit the assembly competence of structural proteins, which are the effective immunogenic components of the prophylactic HBV and HPV vaccines, respectively. To optimize vaccine designs and to promote immune responses against protective epitopes, the “Asp-Ala-Asp-Pro” (NANP)-repeat from the Plasmodium falciparum circumsporozoite protein (CSP) was expressed within the exposed, main antigenic site of the small HBV envelope protein (HBsAgS); this differs from the RTS,S vaccine, in which CSP epitopes are fused to the N-terminus of HBsAgS. The chimeric HBsAgS proteins are assembly competent, produce VLPs, and provide a high antigenic density of the NANP repeat sequence. Chimeric VLPs with four or nine NANP-repeats (NANP4 and NANP9, respectively) were expressed in mammalian cells, the HBsAgS- and CSP-specific antigenicity of the VLPs was determined, and the immunogenicity of the VLPs assessed in relation to the induction of anti-HBsAgS and anti-CSP antibody responses. The chimeric VLPs induced high anti-CSP titres in BALB/c mice independent of the number of the NANP repeats. However, the number of NANP repeats influenced the activity of vaccine-induced antibodies measured by complement fixation to CSP, one of the proposed effector mechanisms for Plasmodium neutralization in vivo. Sera from mice immunized with VLPs containing nine NANP repeats performed better in the complement fixation assay than the group with four NANP repeats. The effect of the epitope-specific density on the antibody quality may instruct VLP platform designs to optimize immunological outcomes and vaccine efficacy. 相似文献
56.
57.
Limiting dilution analysis of the human T cell response to mycobacterial antigens from BCG vaccinated individuals and leprosy patients. 总被引:6,自引:1,他引:6
The number of peripheral blood T lymphocytes responding to soluble mycobacterial antigens from Mycobacterium tuberculosis purified protein derivative (PPD) and M. leprae (MLS) was estimated by limiting dilution analysis. Antigen-induced lymphocyte activation was measured by means of [3H]TdR incorporation on day 10 of culture in the presence of suboptimal concentrations of interleukin 2 (IL-2). In the peripheral blood of BCG-vaccinated individuals from the UK, the frequency of T lymphocytes responding to PPD was 1.5 to 4 times greater than to MLS. Frequencies between 1/1970 and 1/13, 982 were observed in response to PPD and between 1/4097 and 1/24, 717 in response to MLS. A proportion of cells in the peripheral blood were also observed to respond to IL-2 only. The frequency of cells observed in limiting dilution analysis for PPD and MLS reflected the relative amounts of proliferation to these two antigens in bulk culture lymphocyte transformation tests. Use of PPD-specific T cell lines suggested that the responsiveness observed to M. leprae antigens in BCG-vaccinated individuals was due to cross-reactivity with antigens shared with M. bovis BCG. In tuberculoid leprosy, the frequency of peripheral blood T lymphocytes responding to M. leprae antigens was either greater than or similar to the frequency of T cells responding to PPD. In contrast, limiting dilution analysis of T lymphocytes from the peripheral blood of lepromatous leprosy patients revealed the complex regulatory heterogeneity of this group. In some patients M. leprae responsive T cells were detected in the presence of exogenous IL-2. 相似文献
58.
Stephen D. Pask Peter H. Plesch Samuel B. Kingston 《Macromolecular chemistry and physics.》1981,182(11):3031-3039
Acenaphthylene was polymerized in nitrobenzene at 25°C by NO2SbF6, C2H5COSbF6, C6H5COPF6, and (C6H5)2CHSbF6. With monomer so rigorously purified that it contained only ca. 0,01 mol-% of inhibiting impurities the reaction pattern indicated propagation by unpaired cations, and a k = 23,3 ± 2 dm3·mol?1·s?1 (the first for this monomer) was obtained. There are at least two chain-breaking reactions of which one is the proton transfer to monomer which has K = 2,3 dm3·mol?1·s?1. The kinetic irregularities and colours which develop at high conversions are probably due to the formation of non-propagating allylic cations from unsaturated end-groups. 相似文献
59.
Slavotinek A Poyser L Wallace A Martin F Gaunt L Kingston H 《American journal of medical genetics. Part A》2003,(3):282-288
We report two unusual patients with trisomy 18 mosaicism presenting with minor anomalies and failure to thrive in the first year of life. Chromosome analysis showed trisomy 18 in 30/30 peripheral blood lymphocytes in both children. Analysis of skin fibroblasts in the first child showed normal female chromosomes in 30/30 cells, and the fibroblast karyotype in the second child showed mosaicism for tetrasomy 18p, trisomy 18, and normal female chromosomes (karyotype 47,XX, +i(18)(p10)[47]/47,XX, +18[9] /46,XX[4]). Trisomy 18 commonly results from nondisjunction at maternal meiosis II (MII). Nondisjunction at maternal MII has also been postulated to be the initial step in the formation of tetrasomy 18p. In our second case, the additional chromosome 18 was the result of maternal nondisjunction at MII, consistent with this hypothesis. In the first case, nondisjunction at maternal meiosis I (MI) was responsible for the extra chromosome 18. 相似文献
60.
Regulation of Polycomb group complexes by the sequence-specific DNA binding proteins Zeste and GAGA 下载免费PDF全文
Repression and activation of the expression of homeotic genes are maintained by proteins encoded by the Polycomb group (PcG) and trithorax group (trxG) genes. Complexes formed by these proteins are targeted by PcG or trxG response elements (PREs/TREs), which share binding sites for several of the same factors. GAGA factor and Zeste bind specifically to PREs/TREs and have been shown to act as both activators and repressors. We have used purified proteins and complexes reconstituted from recombinant subunits to characterize the effects of GAGA and Zeste proteins on PcG function using a defined in vitro system. Zeste directly associates with the PRC1 core complex (PCC) and enhances the inhibitory activity of this complex on all templates, with a preference for templates with Zeste binding sites. GAGA does not stably associate with PCC, but nucleosomal templates bound by GAGA are more efficiently bound and more efficiently inhibited by PCC. Thus Zeste and GAGA factor use distinct means to increase repression mediated by PRC1. 相似文献