Modelling and costing the consequences of using an ACE inhibitor to slow the progression of renal failure in type I diabetic patients

Antihypertensive drugs slow the progressive decline in renal function seen in patients with insulin-dependent diabetes and nephropathy. In a recent study, the ACE inhibitor captopril protected against this deterioration in renal function. We developed an economic model to analyse the cost impact of ACE inhibitor treatment on progression to endstage renal failure (ESRF) in diabetic patients over 4 years. Two scenarios were compared: one describing the progression of a cohort of 1000 patients receiving 25 mg captopril three times daily, and the other for an equivalent cohort without such prophylactic treatment. Previously published data were used to estimate the transition rates for each stage from the onset of renal failure until death. All direct costs were discounted by an annual rate of 6%, and were subjected to sensitivity analysis. The discounted cost saving of ACE inhibitor treatment for a cohort of 1000 patients was estimated as 0.95 million pounds over 4 years. Under sensitivity analysis, these results were very robust to variations in the costs of ESRF treatment. Prophylactic treatment with ACE inhibitors was predicted to provide substantial increases in life expectancy and reduction in the incidence of ESRF, while also providing significant economic savings.      

电针对单纯性肥胖大鼠下丘脑组织中瘦素和神经肽Y表达的影响

目的:观察电针对单纯性肥胖大鼠下丘脑瘦素和神经肽Y表达的影响,探索电针减肥的机制。方法:实验于2005-12/2006-06在中南大学湘雅医院中西医结合研究所实验室完成。①取1月龄刚断乳SD雄性大鼠,随机取6只饲以普通饲料为正常对照组,其他大鼠饲以高脂饲料,喂养3个月后,选择体质量超过正常对照组20%的单纯性肥胖大鼠12只,随机分为模型组和电针组2组,每组6只。②电针组大鼠电针双侧足三里、天枢、三阴交穴,采用疏密波,电流强度0.3～0.6mA,留针20min,1次/d,共20次;其他2组不电针。实验期间均饲以普通饲料。③观察实验大鼠体质量、体长、Lee's指数及体脂,采用Western-blot技术检测下丘脑组织中瘦素、神经肽Y表达的变化。结果:18只大鼠进入结果分析。①模型组大鼠体质量和Lee’s指数高于正常对照组[(451.8±14.8),(323.6±6.8)g;324.25±1.4,305.14±1.5;P均<0.01];电针组电针后体质量和Lee’s指数低于电针前[(372.2±20.4),(454.7±19.7)g;307.71±1.5,323.56±1.6;P均<0.01]。②模型组大鼠心包、肾周和附睾脂肪量均高于正常对照组(P<0.01);电针组电针后心包、肾周和附睾脂肪量低于电针前(P<0.01)。③模型组下丘脑组织中瘦素蛋白表达低于正常对照组(0.62±0.11,0.88±0.15,P<0.01),电针组高于模型组(0.85±0.13,P<0.01);模型组下丘脑组织中神经肽蛋白表达高于正常对照组(2.42±0.27,1.75±0.24,P<0.01),电针组高于模型组(1.87±0.21,P<0.01)。结论:电针有良好的减肥效果,其作用可能与电针增强下丘脑组织瘦素蛋白的表达、同时抑制下丘脑组织中的神经肽Y蛋白表达有关。     

Autologous transplantation of bone marrow purged in vitro with anti-CD7- (WT1-) ricin A immunotoxin in T-cell lymphoblastic leukemia and lymphoma

Seven patients with high-risk acute T-cell lymphoblastic leukemia (T- ALL) and six with T cell lymphoma (T-LL) were treated with autologous bone marrow transplantation (ABMT) after in vitro purging of their bone marrow with WT1 (CD7)-ricin A-chain immunotoxin. CD7 expression on the tumor cells showed large variations between the individual patients and was highly related to the specific cytotoxicity of WT1-ricin A. Incubation of bone marrow with up to 10(-8)mol/L WT1-ricin A in the presence of 6 mmol/L NH4Cl did not compromise the growth potential of the hematopoietic progenitors CFU-GM, CFU-GEMM, and BFU-E. Hematologic engraftment (greater than 10(9) leukocytes/L) occurred within a normal time period (median, 17 days). Seven patients are alive and in complete remission (CR) at 48+, 44+, 40+, 26+, 11+, 7+, and 6+ months after ABMT. Four patients relapsed within 6 months after ABMT. Two of them had the lowest CD7 expression on their tumor cells, the other two were transplanted in CR2 and CR3. Two patients died from transplantation related infections. The immunologic reconstitution was delayed, although the numbers of T cells reached normal levels within 1 month. The number of CD7+ cells remained low up to 1 year after transplantation. The T4/T8-ratio was decreased for at least 6 months. The T-cell response to mitogens recovered to normal levels after 1 year. This study shows that ABMT with WT1-ricin A purged bone marrow in high-risk T-cell malignancies results in a complete hematopoietic and a delayed immunologic reconstitution. The actuarial relapse free survival is 61% at 3 years.     

The localization of a platelet GpIIb-IIIa-related protein in endothelial cell adhesion structures

Previous studies have shown that human endothelial cells (ECs) adhere to fibrinogen (fg) and fibronectin (fn) and organize their cytoskeleton on these substrata. However, the mechanism governing this chain of events is poorly known. In ECs glycoproteins immunologically and biochemically similar to the platelet membrane GpIIb-IIIa complex have been described. The functional role of this complex in ECs remains to be established. In this study we show that the antigens recognized by polyclonal antibodies raised against human platelet GpIIb-IIIa and crossreacting with the EC form have a discrete and well-organized distribution at cell adhesion structures. Indeed these antigens are located at vinculin-rich focal contacts found at the membrane insertion of microfilament bundles of the stress fiber type. They are also found at cell-to-cell contacts and, with a diffuse pattern, at the dorsal surface of ECs. GpIIb-IIIa antibodies, added to EC suspensions prior to plating, inhibit EC spreading on fg and vitronectin (vn) substrata in a concentration-dependent way. In contrast, the antibodies are very poorly active when the cells are seeded on fn-coated glass. The same antibodies, added to adherent cells, disrupt cell-to-cell contacts and cause their rounding and detachment. Overall these results indicate that EC GpIIb-IIIa complex is involved in controlling the adhesion mechanism of these cells to extracellular matrix proteins.     

Clonal evolution in atypical chronic granulocytic leukemia: a non- Philadelphia translocation

Hemopoietic cells in chronic granulocytic leukemia (CGL) frequently contain a chromosome translocation involving chromosome 22 and another autosome, usually number 9. The translocated chromosome 22 is known as the Philadelphia (Ph) chromosome. The appearance of a second Ph chromosome is the most common cytogenetic abnormality in CGL signaling the blastic phase. For 6 yr we serially studied a man with atypical CGL whose marrow cells were marked by a translocation from chromosome 18 to chromosome 11 [46XY,t(11;18)(q23;q12)]. Three months prior to blast transformation there appeared an extra copy of the marker chromosome 18: 47XY,t(11;18)(q23;q12),+(18p11 leads to 18q12). This man presents a new cytogenetic pattern of clonal evolution in CGL. The pattern is analogous to that of the Ph chromosome and is characterized by a balanced chromosomal rearrangement and the subsequent acquisition of an extra copy of the small translocation chromosome immediately prior to blast transformation.     

A gene for a myosin peptide is disrupted by the inv(16)(p13q22) in acute nonlymphocytic leukemia M4Eo

Chromosome 16 aberrations are well known in acute nonlymphocytic leukemia (ANLL). The most frequent chromosome 16 aberration in ANLL subtype M4Eo is the inv(16)(p13q22). Recently, we showed that in 5 inv(16) patients with ANLL M4Eo the short arm breakpoints are clustered within a 14-kb genomic EcoRI fragment. We report here the identification of a gene situated in the 14-kb fragment. The gene, which codes for a myosin peptide, is disrupted by the inversion of chromosome 16 in the 5 patients. To the best of our knowledge, this is the first report of a myosin gene disrupted in leukemia.     

Granulocyte macrophage colony-stimulating activity production by cultured human thymic nonlymphoid cells is regulated by endogenous interleukin-1

Supernatants of cultured human thymic nonlymphoid cells were assayed for granulopoietic factors using cultures of low density bone marrow mononuclear cells (LD-BMMC). Thymic nonlymphoid cell-conditioned medium (TNLC-CM) supported vigorous myeloid colony growth of LD-BMMC, and of LD-BMMC depleted of T lymphocytes and/or monocytes. Colony stimulating activity (CSA) in TNLC-CM was abrogated by a highly specific neutralizing antiserum against recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). TNLC-CM also enhanced colony growth in LD-BMMC stimulated by colony stimulating activity from a giant cell tumor culture (GCT). The enhancing activity of TNLC-CM, unlike its CSA activity, required the presence of adherent cells in the marrow cell culture. The addition of anti-interleukin-1 (anti-IL-1) antibody to TNLC-CM inhibited the GCT-enhancing activity, but not the CSA. When the anti-IL-1 immunoglobulin was added directly to cultures of thymic nonlymphoid cells, GM-CSF production was completely inhibited, and the GCT enhancing activity was neutralized. We conclude that an intercellular regulatory network exists in cultured thymic explants in which GM-CSF expression is induced by IL-1. In this system, the granulopoietic effect of IL-1 derives not from a direct effect on myeloid progenitors, but from its ability to recruit CSA production by other cells.     

Allogeneic bone marrow transplantation with a fixed low number of T cells in the marrow graft [see comments]

Despite prophylaxis with immunosuppressive drugs, severe acute graft- versus-host disease (GVHD) remains a major cause of morbidity and mortality in patients transplanted with unmodified bone marrow (BM) grafts from HLA-identical siblings. Although T-cell depletion of the BM graft has evolved as the most effective method to prevent severe acute GVHD, this beneficial effect is counterbalanced by an increased rate of graft failure and relapse of the disease. To find an approach to T-cell depletion that may avoid these extreme risks, we gave BM recipients a fixed low number of 1 x 10(5) donor T cells per kilogram of recipient's body weight in the graft. This corresponds with 99% T-cell depletion and is achieved by the addition of T cells to the graft that was previously depleted of T cells. A total of 70 patients with hematologic malignancies or aplastic anemia, including 40 patients with standard- risk leukemias, received BM grafts, depleted of T cells according to this approach, from HLA-identical siblings. The preparative regimen consisted of cyclophosphamide and total body irradiation. The patients also received a short course of cyclosporine posttransplant. Graft failure did not occur. Acute GVHD, only grade I or II, was seen in 70% of the patients and was limited to the skin in all patients. Chronic GVHD occurred in 31% of the patients and, with the exception of 1 patient, was limited to the skin as well. Relapse occurred in 3 of 40 (8%) patients with standard-risk leukemias, resulting in a projected survival at 5 years of 80%. Patients with standard-risk diseases had a procedure-related mortality of 11%. Quality of life, determined 1 year after BM transplant, was good in almost all patients with standard-risk diseases. Thus, this approach of T-cell depletion may be an approach that avoids the development of severe acute and chronic GVHD without damaging the function or antileukemic effect of the graft and that has a low transplant-related morbidity and mortality.     

BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents

A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.