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81.
X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox 总被引:3,自引:0,他引:3
Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of patients have defects in an X- linked gene (X-CGD) encoding gp91-phox, the large subunit of the membrane cytochrome b-245 component of NADPH oxidase. Epstein-Barr virus-transformed B-cell lines from patients with CGD provide a model system for the disease. We have used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from three unrelated patients with X-CGD. The protein is glycosylated and membrane associated, and the reconstituted oxidase is appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells is similar to that of normal B-cell lines. These data show the potential of gene therapy for this disease. 相似文献
82.
O'Day SJ; Rabinowe SN; Neuberg D; Freedman AS; Soiffer RJ; Spector NA; Robertson MJ; Anderson K; Whelan M; Pesek K 《Blood》1994,83(9):2707-2714
Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity. 相似文献
83.
A Randomized Controlled Trial of Intensive Care Management for Disabled Medicaid Beneficiaries with High Health Care Costs 下载免费PDF全文
Janice F Bell Antoinette Krupski Jutta M Joesch Imara I West David C Atkins Beverly Court David Mancuso Peter Roy-Byrne 《Health services research》2015,50(3):663-689
ObjectiveTo evaluate outcomes of a registered nurse–led care management intervention for disabled Medicaid beneficiaries with high health care costs.ConclusionsWe found no health care cost savings for disabled Medicaid beneficiaries randomized to intensive care management. Among participants, care management may have the potential to increase access to needed care, slow growth in the number and therefore cost of unplanned hospitalizations, and prevent homelessness. These findings apply to start-up care management programs targeted at high-cost, high-risk Medicaid populations. 相似文献
84.
Perrillo RP Lai CL Liaw YF Dienstag JL Schiff ER Schalm SW Heathcote EJ Brown NA Atkins M Woessner M Gardner SD 《Hepatology (Baltimore, Md.)》2002,36(1):186-194
Elevated alanine transaminase (ALT) levels and low serum hepatitis B virus (HBV) DNA predict a higher likelihood of hepatitis B e antigen (HBeAg) loss in patients with chronic hepatitis B treated with interferon. Predictors of HBeAg loss in patients treated with lamivudine are not known. The objective of this analysis of 4 lamivudine-controlled Phase III trials was to determine patient-dependent or laboratory variables that predict HBeAg loss. Predictors of HBeAg loss in patients treated with interferon, lamivudine plus interferon, or placebo are also described. A total of 805 adults with chronic hepatitis B were treated either with lamivudine (n = 406), matching placebo (n = 196), interferon (n = 68), or the combination of lamivudine plus interferon (n = 135). Demographic and baseline disease characteristics were used in stepwise multivariate analyses to identify features that were predictive of lamivudine-induced HBeAg loss. HBeAg loss correlated with increased pretreatment ALT levels in all groups. The rate of HBeAg loss was highest among patients with pretreatment ALT levels greater than 5 times the upper limit of normal (ULN) and was most pronounced in the lamivudine group (56%). Multivariate modeling indicated that elevated baseline ALT levels (P <.001) and histologic activity index (HAI) score (P <.001) were important predictors of HBeAg loss in response to lamivudine. The effect of pretreatment ALT levels on HBeAg loss was similar for Asians and Caucasians. In conclusion, elevated pretreatment ALT levels and/or active histologic disease were the most important predictors of lamivudine-induced HBeAg loss. Asians and Caucasians had similar rates of response to lamivudine at comparable ALT levels. 相似文献
85.
Distribution and properties of Ca2+-ATPase, phytase, and alkaline phosphatase in isolated enterocytes from normal and vitamin D-deficient rats. 下载免费PDF全文
The effects of vitamin D-deficiency and repletion on the distribution and activities of Ca2+-ATPase, phytase, and alkaline phosphatase in intact epithelial cells isolated from different regions of the villi and the crypts of the rat jejunum were studied. Similar distribution patterns of activities were found for the three enzymes. In all cases, the enzyme levels were the highest at the villus tip and gradually declined to low activities in the crypt. The Kms were very different between cells in the crypt base and those at the villus tip, the highest Kms being found in the crypt. The activities of these enzymes were reduced in the entire length of the villus in vitamin D-deficient rats. Recovery of the enzymatic levels was observed on vitamin D repletion, but at different rates. Total recovery of activity of Ca2+-ATPase, phytase, and alkaline phosphatase was observed after 18, 24, and 36 hours, respectively, after a single dose of 6.5 nmol (2.5 micrograms) vitamin D3. Enzymatic activities in the crypt cells were not affected by vitamin D3 treatment. These data suggest that Ca2+-ATPase, phytase, and alkaline phosphatase may be distinct entities, and that their activities in the crypt cells may not be vitamin D-dependent. 相似文献
86.
The grey zone (GZ; 45–54 CGG repeats in the FMR1 gene) is considered a normal allele; however, several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of fragile X‐associated tremor/ataxia syndrome (FXTAS) in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55–200 CGG repeats). Both patients had family members who had premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated fragile X mental retardation 1 mRNA (FMR1‐mRNA) combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may require revision. 相似文献
87.
Makin OS Atkins E Sikorski P Johansson J Serpell LC 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(2):315-320
The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 A) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel beta-sheets in a cross-beta arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel beta-sheets are zipped together by means of pi-bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid-lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils. 相似文献
88.
The dosage of (131)I for the treatment of metastatic well-differentiated thyroid cancer is typically selected empirically. Benua and Leeper implemented a method to estimate the maximum dosages of (131)I that could be administered to a patient so as not to exceed a maximum tolerated radiation absorbed dose (MTD), which was defined as 200 rads (cGy) to the blood. The objective of this study was to determine the frequency of (131)I treatments in which the patient (1) would have exceeded the MTD (i.e., overtreatment) or (2) would have been able to receive higher dosages of (131)I thereby delivering a potentially higher radiation absorbed dose to their metastases (i.e., undertreatment) had the patient been administered various assumed empiric dosages of (131)I. The dosimetrically- determined maximum tolerated radioactivities (MTA) to deliver 200 rads to the blood (MTD) were tabulated at our facility. Data were then grouped to determine the percentage of patients who would have received less than or more than the MTD for various assumed empiric dosages of (131)I. A total of 127 dosimetries were performed. For assumed empiric dosages of (131)I (100 mCi, 150 mCi, 200 mCi, 250 mCi, and 300 mCi), the percentage of treatments for which patients would have exceeded the MTD were less than 1%, 5%, 11%, 17%, and 22%, respectively, and could have received a higher dosage of (131)I were more than 99%, 95%, 89%, 83%, and 78%, respectively. A significant number of patients receiving various empiric dosages of (131)I may exceed 200 rads (cGy) to the blood (potential overtreating). Likewise, the majority of patients may be able to receive much higher dosages of (131)I relative to empiric dosages thereby delivering potentially higher radiation absorbed doses to the metastases without exceeding 200 rads (cGy) to the blood (potential undertreating). 相似文献
89.
Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease 总被引:7,自引:2,他引:7
Gruss HJ; Hirschstein D; Wright B; Ulrich D; Caligiuri MA; Barcos M; Strockbine L; Armitage RJ; Dower SK 《Blood》1994,84(7):2305-2314
CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7-1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD. 相似文献
90.
Kameoka J; Sato T; Torimoto Y; Sugita K; Soiffer RJ; Schlossman SF; Ritz J; Morimoto C 《Blood》1995,85(4):1132-1137
Patients who have undergone allogeneic bone marrow transplantation (allo-BMT) are susceptible to a variety of opportunistic infectious complications in the months to years after engraftment. Impaired in vitro T-cell functions have been documented in these patients, and these T-cell dysfunctions contribute to the prolonged immune deficiency after allo-BMT. In the present study, we examined the expression of CD26 as well as the reconstitution of CD26-mediated T-cell costimulation via the CD3 and CD2 pathways at various times in patients aged greater than 18 years after CD6-positive, T-cell depleted allo- BMT. We found that the percentage of CD26- and CD3-positive cells, as well as the levels of expression of both antigens, was lower than in normal controls during the first 4 months after CD6-depleted allo-BMT. Subsequently, the amount of lymphocytes expressing CD3 and CD26 and the quantitative surface expression of CD3 and CD26 were not significantly different in patients and normal controls. Functional studies showed that CD26-mediated T-cell proliferation via the CD3 pathway was considerably improved and almost reached normal levels by 1 year, whereas recovery of CD26-mediated T-cell proliferation via the CD2 pathway was delayed for at least 2 years after CD6-depleted allo-BMT. As CD26 involvement in the regulation of human thymocyte activation is restricted preferentially to the CD3 pathway--unlike its involvement with both CD3 and CD2 pathways of peripheral T cells--our results suggest that the different effects of CD26-mediated costimulation via the CD3 and CD2 pathways after CD6-depleted allo-BMT may be a reflection of peripheral T-cell immaturity in those individuals, similar to that seen in mature medullary thymocytes or cord T lymphocytes. 相似文献