Prevalence of renal artery stenosis in high-risk veterans referred to cardiac catheterization

OBJECTIVE: The prevalence of atherosclerotic renal artery stenosis (RAS) varies depending on patient selection with no specific guidelines on indications for selective renal angiography in patients referred for coronary angiography. The goal of this study is to determine the prevalence and predictors of renal artery stenosis in hypertensive veterans referred for coronary angiography. DESIGN: Prospective study. SETTING: Tertiary care veterans' administration facility in the USA. PATIENTS, PARTICIPANTS: A total of 90 veterans referred for coronary angiography with an initial ascending aortic pressure > 135 mmHg. INTERVENTIONS: Selective renal angiography was performed following coronary angiography. RESULTS: We found that 28% of the patients had single RAS (> or = 50% stenosis), while 16% had single RAS > or = 70% stenosis, 10% had bilateral RAS >or = 50% and 6% had bilateral RAS > or = 70%. Significant positive univariate predictors of RAS (> or = 50%) were age, peripheral vascular disease (PVD), creatinine level (Cr) and myocardial infarction. Significant multivariate predictors of RAS (> or = 50%) were age > 65 years [relative risk (RR), 3.6; 95% confidence interval (CI), (1.2-10.6)], PVD [RR 3.2, 95% CI (1.1-9.1)] and Cr > 1 mg/dl [RR 4.9, 95% CI (1.53-15.9)]. No complications related to renal angiography were noted. CONCLUSIONS: Selective renal angiography during routine coronary angiography in hypertensive veterans with coronary artery disease is safe and uncovers RAS in many older patients with PVD and renal insufficiency.     

Progression of cardiovascular disease in acromegalic patients treated by external pituitary irradiation

Cardiovascular complications are a major cause of morbidity and mortality in acromegaly and seem to be related to the long duration of the disorder. Conventional external pituitary irradiation for acromegaly produces a consistent, but slow, fall in elevated serum growth hormone (GH) levels. It has not been established whether such treatment is effective in preventing the development of cardiovascular complications. The evolution of cardiovascular disease has therefore been studied in 11 acromegalic patients followed up for a mean 10 years (range 3-17) after external pituitary irradiation. At the final follow-up fasting serum GH were significantly (P less than 0.01) lower than pre-irradiation levels, but cardiovascular events (myocardial infarction, dysrhythmias, hypertension, major arterial disease, heart failure) increased significantly in prevalence (P less than 0.01) during this period. Electrocardiographic abnormalities also increased in prevalence. At the final follow-up 6 patients had cardiomegaly on chest X-ray and echocardiographs (10 patients) were abnormal in every case. All 11 patients had evidence of complete or partial anterior hypopituitarism. We confirm that external pituitary irradiation is effective in reducing elevated serum GH levels in acromegaly, but suggest that such a slow reduction in serum GH levels does not retard the development of cardiovascular complications.     

Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III

Single gene mutations in beta integrins can account for functional defects of individual cells of the hematopoietic system. In humans, mutations in beta(2) integrin lead to leukocyte adhesion deficiency (LAD) syndrome and mutations in beta(3) integrin cause the bleeding disorder Glanzmann thrombasthenia. However, multiple defects in blood cells involving various beta integrins (beta(1), beta(2), and beta(3)) occur simultaneously in patients with the recently described LAD type III (LAD-III). Here we show that the product of a single gene, Ca(2+) and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), controlled the activation of all 3 integrins in the hematopoietic system. Neutrophils from CalDAG-GEFI(-/-) mice exhibited strong defects in Rap1 and beta(1) and beta(2) integrin activation while maintaining normal calcium flux, degranulation, and ROS generation. Neutrophils from CalDAG-GEFI-deficient mice failed to adhere firmly to stimulated venules and to migrate into sites of inflammation. Furthermore, CalDAG-GEFI regulated the activation of beta(1) and beta(3) integrins in platelets, and CalDAG-GEFI deficiency caused complete inhibition of arterial thrombus formation in mice. Thus, mice engineered to lack CalDAG-GEFI have a combination of defects in leukocyte and platelet functions similar to that of LAD-III patients.     

非亲缘异基因外周血干细胞移植重建白血病幼儿造血功能：1例报告

目的:分析非亲缘异基因外周血干细胞移植治疗幼儿急性非淋巴性白血病的可行性。方法:患儿,男,3岁,于2005-07-18为行造血干细胞移植入本院血液科骨髓移植病房,入院诊断为急性非淋巴细胞性白血病-M5b。经抗肿瘤药物治疗病情获得完全缓解。患儿首先接受清髓性预处理,然后接受同性别非亲缘异基因外周血造血干细胞移植。①移植预处理包括马利兰、阿糖胞苷和环磷酰胺。移植前依次用药为马利兰3.2mg/(kg·d)×4d,口服,于移植前6,7,8,9d给药;阿糖胞苷3.2g/(m2·d)×2d,于移植前4,5d给药;环磷酰胺54mg/(kg·d),于移植前2,3d给药。②急性移植物抗宿主病的预防用药包括环孢菌素A和氨甲蝶呤、抗胸腺细胞球蛋白及吗替麦考酚酯。供者接受粒细胞集落刺激因子动员4d后采集外周血造血干细胞,供、受者间HLA全相合,患者血型A,供者血型B,主次要均不合。结果:①患儿移植后早期获得造血重建,中性粒细胞>0.5×109L-1和血小板>50×109L-1的天数分别是12d和11d。②移植后1个月经DNA短串联重复序列多态性分析证明为供者型完全植入,移植后3个月查骨髓象正常。③移植后3,6个月定期行淋巴细胞亚群检查表明除CD19 ,CD4 细胞未恢复外,自然杀伤细胞在移植后3个月恢复正常,T淋巴细胞CD3 与CD8 、体液免疫球蛋白在移植后6个月中均获得重建。④整个移植过程顺利,未出现明显感染和重度急性移植物抗宿主病。移植后96d时出现Ⅰ度皮肤移植物抗宿主病,经加用激素治疗,皮疹消失。移植术后已随访观察12个月,患儿正常生活。结论:如果患儿有HLA完全相合的供者,非亲缘异基因外周血干细胞移植治疗儿童高危白血病是一种有效和安全的方法,对国内独生子女家庭拓宽供者来源有重要的实用价值。     

Myeloid‐derived suppressor cells increase and inhibit donor‐reactive T cell responses to graft intestinal epithelium in intestinal transplant patients

Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid‐derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33⁺CD11b⁺ lineage(CD3/CD56/CD19)^?HLA‐DR^?/low cells with 3 subsets, CD14^?CD15^? (e‐MDSCs), CD14⁺CD15^? (M‐MDSCs), and CD14^?CD15⁺ (PMN‐MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa. Total MDSC numbers increased in PBMCs after ITx; among MDSC subsets, M‐MDSC numbers were maintained at a high level after 2 months post ITx. The MDSC numbers decreased in ITx recipients with ACR. MDSC numbers were positively correlated with serum interleukin (IL)‐6 levels and the glucocorticoid administration index. IL‐6 and methylprednisolone enhanced the differentiation of bone marrow cells to MDSCs in vitro. M‐MDSCs and e‐MDSCs expressed CCR1, ‐2, and ‐3; e‐MDSCs and PMN‐MDSCs expressed CXCR2; and intestinal grafts expressed the corresponding chemokine ligands after ITx. Of note, the percentage of MDSCs among intestinal mucosal CD45⁺ cells increased after ITx. A novel in vitro assay demonstrated that MDSCs suppressed donor‐reactive T cell–mediated destruction of donor intestinal epithelial organoids. Taken together, our results suggest that MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa in ITx, and may regulate ACR.     

Control of growth of benzo(a)pyrene-transformed 3T3 cells.

The growth controls observed in benzo[a]pyrene-transformed 3T3 cells (BP3T3) are compared with those of virus-transformed and normal 3T3 cells. Superficially, the chemically transformed BP3T3 cells have the same behavior as virus-transformed SV3T3 cells. Both grow to high cell density in culture medium with 10% serum, both form colonies in Methocel, and both are tumorigenic. Closer examination, however, has disclosed that BP3T3 cells exhibit "normal" growth controls at low serum concentrations. In contrast to the behavior of SV3T3 cells, the initiation of DNA synthesis in BP3T3 cells is still dependent on a serum factor. If BP3T3 cells are grown in medium with 0.2% serum, the cells become quiescent, with growth arrested in the Gu or G0 phase of the cell cycle. The addition of serum or the fibroblast growth factor (FGF) to such quiescent cells leads to the initiation of DNA synthesis and the resumption of growth. As with normal 3T3 cells, if the growth rate of BP3T3 cells is limited by a suboptimal concentration of serum, the growth rate of the cells is increased by the addition of FGF. Also, BP3T3 cells show density-dependent regulation of growth, if the medium contains a low concentration of serum. BP3T3 cells, therefore, have the behavior of "transformed" cells when cultured in medium with 10% serum, but behave as "normal" cells in medium with low serum. In comparison with normal 3T3 cells, the difference in growth behavior of BP3T3 cells appears to be due to a substantial decrease in the cells' requirement for a serum growth factor of the FGF type. Exploration of possible causes of this substantial decrease indicates that the primary cause is a lower rate of depletion of the serum growth factor from the culture medium by BP3T3 cells. The decrease in rate of depletion is sufficient to account for the uncontrolled growth of BP3T3 cells in medium with 10% serum. It is suggested that a decreased rate of depletion of a growth factor may contribute to tumorigenicity of cells in vivo.     

Alanine is helix-stabilizing in both template-nucleated and standard peptide helices

Alanine-based peptides of defined sequence and length show measurable helix contents, allowing them to be used as a model system both for analyzing the mechanism of helix formation and for investigating the contributions of side-chain interactions to protein stability. Extensive characterization of many peptide sequences with varying amino acid contents indicates that the favorable helicity of alanine-based peptides can be attributed to the large helix-stabilizing propensity of alanine. Based on their analysis of alanine-rich sequences N-terminally linked to a synthetic helix-inducing template, Kemp and coworkers [Kemp, D. S., Boyd, J. G. & Muendel, C. C. (1991) Nature (London) 352, 451-454; Kemp, D. S., Oslick, S. L. & Allen, T. J. (1996) J. Am. Chem. Soc. 118, 4249-4255] argue that alanine is helix-indifferent, however, and that the favorable helix contents of alanine-based peptides must have some other explanation. Here, we show that the helix contents of template-nucleated sequences are influenced strongly by properties of the template-helix junction. A model in which the helix propensities of residues at the template-peptide junction are treated separately brings the results from alanine-based peptides and template-nucleated helices into agreement. The resulting model provides a physically plausible resolution of the discrepancies between the two systems and allows the helix contents of both template-nucleated and standard peptide helices to be predicted by using a single set of helix propensities. Helix formation in both standard peptides and template-peptide conjugates can be attributed to the large intrinsic helix-forming tendency of alanine.