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961.
962.
基因治疗与心力衰竭 总被引:3,自引:0,他引:3
目的:探讨基因治疗方案的有效性和安全性。资料来源:应用计算机检索PUBMED1980-01/2006-10和EMCC 1994-10/2006-10与心力衰竭的基因治疗相关文章,检索词“Gen Therapy,Heart Failure”,并限定文章语言种类为“English”;同时计算机检索CMCC 1994-01/2006-10的相关文章,限定文章语言种类为中文,检索词“基因治疗、心力衰竭”。资料选择:对资料进行初审,选取试验包括上述治疗组和对照组的文献,然后筛除明显不随机临床试验的研究,对剩余的文献开始查找全文,进一步判断是否为RCT。纳入标准为:①试验包含平行对照组,即一般药物治疗。②治疗组为转基因治疗。资料提炼:共收集到49篇相关的随机和未随机试验,31个试验符合纳入标准。其余的排除。资料综合:31个试验包括478例动物模型,分别对应用不同靶点的转基因或基因敲除等方案进行治疗者予以评价。31篇文章中有10篇未达到预期的治疗目标,主要是在目的基因的选择及转染载体的选择方面出现了偏差。结论:虽动物试验取得了一定的成果,但尚无人体基因治疗的文献报道,随着基因技术的进步,基因治疗有望成为治疗心力衰竭的新途径。 相似文献
963.
Histone deacetylase inhibitors reduce polyglutamine toxicity 总被引:1,自引:0,他引:1
Alexander McCampbell Addis A. Taye Leslie Whitty Ellen Penney Joan S. Steffan Kenneth H. Fischbeck 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(26):15179-15184
Polyglutamine diseases include at least nine neurodegenerative disorders, each caused by a CAG repeat expansion in a different gene. Accumulation of mutant polyglutamine-containing proteins occurs in patients, and evidence from cell culture and animal experiments suggests the nucleus as a site of pathogenesis. To understand the consequences of nuclear accumulation, we created a cell culture system with nuclear-targeted polyglutamine. In our system, cell death can be mitigated by overexpression of full-length cAMP response element binding protein (CREB)-binding protein (CBP) or its amino-terminal portion alone. CBP is one of several histone acetyltransferases sequestered by polyglutamine inclusions. We found histone acetylation to be reduced in cells expressing mutant polyglutamine. Reversal of this hypoacetylation, which can be achieved either by overexpression of CBP or its amino terminus or by treatment with deacetylase inhibitors, reduced cell loss. These findings suggest that nuclear accumulation of polyglutamine can lead to altered protein acetylation in neurons and indicate a novel therapeutic strategy for polyglutamine disease. 相似文献
964.
Cathy C. Schubert MD AGSF Anthony J. Perkins MS Laura J. Myers PhD Teresa M. Damush PhD Lauren S. Penney PhD Ying Zhang PhD Ashley L. Schwartzkopf MSW Alaina K. Preddie MS Sam Riley BA Tetla Menen BS Dawn M. Bravata MD 《Journal of the American Geriatrics Society》2022,70(12):3598-3609
Background
As the Department of Veterans Affairs (VA) healthcare system seeks to expand access to comprehensive geriatric assessments, evidence-based models of care are needed to support community-dwelling older persons. We evaluated the VA Geriatric Resources for Assessment and Care of Elders (VA-GRACE) program's effect on mortality and readmissions, as well as patient, caregiver, and staff satisfaction.Methods
This retrospective cohort included patients admitted to the Richard L. Roudebush VA hospital (2010–2019) who received VA-GRACE services post-discharge and usual care controls who were potentially eligible for VA-GRACE but did not receive services. The VA-GRACE program provided home-based comprehensive, multi-disciplinary geriatrics assessment, and ongoing care. Primary outcomes included 90-day and 1-year all-cause readmissions and mortality, and patient, caregiver, and staff satisfaction. We used propensity score modeling with overlapping weighting to adjust for differences in characteristics between groups.Results
VA-GRACE patients (N = 683) were older than controls (N = 4313) (mean age 78.3 ± 8.2 standard deviation vs. 72.2 ± 6.9 years; p < 0.001) and had greater comorbidity (median Charlson Comorbidity Index 3 vs. 0; p < 0.001). VA-GRACE patients had higher 90-day readmissions (adjusted odds ratio [aOR] 1.55 [95%CI 1.01–2.38]) and higher 1-year readmissions (aOR 1.74 [95%CI 1.22–2.48]). However, VA-GRACE patients had lower 90-day mortality (aOR 0.31 [95%CI 0.11–0.92]), but no statistically significant difference in 1-year mortality was observed (aOR 0.88 [95%CI 0.55–1.41]). Patients and caregivers reported that VA-GRACE home visits reduced travel burden and the program linked Veterans and caregivers to needed resources. Primary care providers reported that the VA-GRACE team helped to reduce their workload, improved medication management for their patients, and provided a view into patients' daily living situation.Conclusions
The VA-GRACE program provides comprehensive geriatric assessments and care to high-risk, community-dwelling older persons with high rates of satisfaction from patients, caregivers, and providers. Widespread deployment of programs like VA-GRACE will be required to support Veterans aging in place.965.
Behavioral experiments tested the idea that the substance P (SP) innervation of the midbrain central gray (MCG) may be involved in the hormonal induction of sexual receptivity in female rats. SP, a SP antiserum or a reported SP antagonist were injected bilaterally into the MCG in ovariectomized, estrogen-treated females, and the lordosis response was recorded at repeated intervals. In the first experiment, three doses of SP (50,500 and 1,000 ng/cannula), a single dose of LHRH (50 ng/cannula) or vehicle were given to separate groups of females. All three doses of SP produced a rapid and long-lasting (3 h) increase in lordosis scores in moderately receptive females in tests with either manual stimulation or male rats. This facilitation was similar in latency, magnitude and duration to that produced by LHRH. In the second experiment, the basic findings of experiment 1 were replicated using blind testing. As no dose-response relation was established in experiment 1, a lower dose of SP (10 ng/cannula) was used in addition to doses of 50 and 500 ng/cannula also used in experiment 1. All three doses produced similar long-lasting increases in lordosis scores as in experiment 1. MCG injections of SP also increased lordosis scores in a second series of tests using manual stimulation alone. This demonstrates that the SP-induced facilitation does not depend on an interaction between the injections and stimuli delivered only by the male rat, eg., vaginal stimuli or ultrasonic calls. The question of the importance of endogenous SP for receptivity was examined in experiment 2 using MCG injections of a SP antiserum or the SP analogue, (D-Pro2, D-Trp7,9)-SP, which has been reported to block the excitation of locus coeruleus neurons by SP.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
966.
Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability 总被引:4,自引:0,他引:4 下载免费PDF全文
Agnes Baross-Francis Susan E. Andrew Janice E. Penney Frank R. Jirik 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(15):8739-8743
DNA mismatch repair (MMR) deficiency is associated with an increased mutational burden and predisposition to certain malignancies. Relatively little is known, however, about gene-specific mutation frequencies within MMR-deficient primary tumors. Thymic lymphomas from Msh2−/− mice were thus analyzed by using a lacI-based transgenic shuttle-phage mutation detection system. All tumors exhibited greatly elevated lacI gene mutation frequencies, ranging from 3.2- to 17.4-fold above the ≈15-fold elevations present within normal Msh2−/− thymi. In addition, lacI genes harboring multiple changes, including clusters of mutations, were found in thymic tumor DNA. The results suggest that an additional mutator activity, such as an error-prone DNA polymerase, leads to increased genomic instability in these MMR-deficient tumors. 相似文献
967.
Childhood acute myeloid leukemia (AML) has a poor prognosis with standard chemotherapy. Allogeneic bone marrow transplantation (BMT) in remission improves the outlook only for the one third of patients with sibling donors. Autologous BMT with a lower morbidity and mortality is available to all. In this study, maximum cytoreduction was achieved by intensive early chemotherapy. Final intensification, with autologous BMT was offered to all those remaining in first complete remission (CR). Patients received two induction and two consolidation courses of intensively scheduled chemotherapy. Cytoreduction was assessed on day 14 and remission was assessed after courses 2 and 4. Bone marrow was harvested after recovery from the second consolidation course or after the first maintenance course and separated on a discontinuous percoll gradient before cryopreservation. Twenty-eight of 31 consecutively enrolled patients achieved CR. Three relapsed early and, of the 25 eligible, 24 underwent autologous BMT. Twenty-three patients received high-dose melphalan and 1 received busulphan and cyclophosphamide before autologous BMT at a median of 113 days (range, 86 to 301) after initial CR. Trilineage engraftment occurred in all. Neutrophil recovery to greater than 0.5 x 10(9)/L occurred at a median of 46 days (range, 13 to 92) after autologous BMT. Platelet recovery was delayed, with a median time to achieve greater than 20 x 10(9)/L of 42 days (range, 18 to 215). With a minimum follow up of 25 months following autologous BMT only 3 children have relapsed. The 5-year event-free survival rate (EFS) from diagnosis is 68% (95% confidence interval, 46% to 90%). Five- year EFS following autologous BMT is 87% (95% confidence interval, 67% to 100%). Autologous BMT with high-dose melphalan administration after intensive chemotherapy has produced EFS equivalent to allogeneic BMT and is associated with a strikingly low relapse rate. High-dose melphalan appears to be a valuable agent for conditioning therapy in AML. 相似文献
968.
In both sickle cell (SS) anemia and beta-thalassemia (beta-thal), an increase in fetal hemoglobin (HbF) ameliorates the clinical symptoms of the underlying disease. Several pharmacologic agents have been used to elevate HbF levels in adults; however, concerns regarding adverse effects of the prevailing drugs raise an urgent need for other agents capable of stimulating HbF production. We show here that sodium phenylacetate (NaPA) and its precursor, sodium 4-phenylbutyrate (NaPB), can enhance HbF production in cultured erythroid progenitor derived from normal donors and patients with SS anemia or beta-thal, when used at pharmacologic concentrations. Treatment resulted in (1) reduced cell proliferation, (2) elevated hemoglobin (Hb) content per cell (mean cellular Hb [MCH]), and (3) an increased proportion of HbF produced, associated with elevated levels of gamma-globin mRNA. Moreover, the active phenyl-fatty acids, with NaPA as a prototype, potentiated HbF induction by other drugs of clinical interest, including hydroxyurea (HU), sodium butyrate, and 5-azacytidine (5AzaC). Efficacy could be further enhanced by introducing chlorine substituents at the phenyl ring to increase drug lipophilicity. Our findings indicate that NaPA and NaPB, both already proven safe and effective in treatment of children with urea cycle disorders, might benefit also patients with severe hemoglobinopathies. The two-phase liquid culture procedure used in this study should prove valuable in further studies exploring the mechanisms of HbF induction by these agents, and might provide an assay to predict patient response in the clinical setting. 相似文献
969.
970.