Identification of seven novel SMPD1 mutations causing Niemann–Pick disease types A and B

Niemann–Pick disease (NPD) types A and B are autosomal, recessively inherited, lysosomal storage disorders caused by deficient activity of acid sphingomyelinase (E.C. 3.1.4.12) because of mutations in the sphingomyelin phosphodiesterase‐1 (SMPD1) gene. Here, we present the molecular analysis and clinical characteristics of 15 NPD type A and B patients. Sequencing the SMDP1 gene revealed eight previously described mutations and seven novel mutations including four missense [c.682T>C (p.Cys228Arg), c.1159T>C (p.Cys387Arg), c.1474G>A (p.Gly492Ser), and c.1795C>T (p.Leu599Phe)], one frameshift [c.169delG (p.Ala57Leufs*20)] and two splicing (c.316+1G>T and c.1341delG). The most frequent mutations were p.Arg610del (21%) and p.Gly247Ser (12%). Two patients homozygous for p.Arg610del and initially classified as phenotype B showed different clinical manifestations. Patients homozygous for p.Leu599Phe had phenotype B, and those homozygous for c.1341delG or c.316+1G>T presented phenotype A. The present results provide new insight into genotype/phenotype correlations in NPD and emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes.     

Left Ventricular Functional Recovery During Cardiac Resynchronization Therapy:

Cardiac resynchronization therapy (CRT) improves myocardial performance in patients with heart failure (HF) and left bundle-branch block (LBBB). Tissue Doppler echocardiography (TDE) has already been used to guide the selection of candidates for CRT. The objective of this study is to correlate the effects of CRT on left ventricular (LV) systolic function with wall motion synchrony assessed by TDE. High frame TDE data were obtained in 15 patients (mean age = 68.9 years, 11 men) with LBBB (QRS = 163 ± 13 ms) to derive temporal intraventricular horizontal asynchrony indexes, expressed as the time difference at the onset of shortening between the septum and the lateral (S-L) and antero-inferior (A-I) walls, and measure the amount of delayed longitudinal contraction (DLC) within the LV. All measurements were made at baseline, 24 hours after implantation, and at 1 year of follow-up. The results show that LV ejection fraction (EF) increased from 25 ± 6.2% at baseline to 36.9 ± 7.9% at 1 year, and was strongly related to DLC, expressed either by time duration (DLCd, r =−0.51; P < 0.0001) or percent of the basal segments (%DLC, r =−0.50; P < 0.001). New York Heart Association functional class, which decreased from 3.6 ± 0.5 to 2.3 ± 0.8, was correlated with %DLC (r = 0.50) and DLCd (r = 0.48, P < 0.001). Weaker correlations were found between LVEF and S-Li (r =−0.40) and between NYHA and S-Li (r = 0.40). It is concluded that DLC was the best among intraventricular asynchrony indexes in predicting increases in LVEF after CRT. DLC may be useful to identify responders to CRT.     

FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6- month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.     

妇科腹腔镜手术脏器及血管损伤并发症分析

目的分析腹腔镜手术脏器及血管损伤并发症发生的情况,探讨预防和减少其发生的措施。方法对2003年1月~2005年12月在本院妇产科施行的2 684例腹腔镜手术的资料进行回顾性分析,观察脏器及血管损伤并发症的发生情况。结果妇科腹腔镜手术总的并发症发生率为2.53%(68例),脏器及血管损伤并发症发生率为0.37%(10例)。其中与trocar穿刺相关损伤4例(肠系膜血管损伤与后腹膜血管损伤各2例),术中并发症3例(术中大出血1例,膀胱损伤2例),术后并发症3例(输尿管损伤2例,肠瘘1例)。结论随着手术范围的扩大和手术难度的增加,妇科腹腔镜手术并发症有所增加,并发症的发生也与操作者的经验相关。降低手术并发症发生率,应重视适应证的选择,并提高操作者的手术技术。     

化疗药顺铂对Wnt通路抑制因子的表达作用

目的 研究抗肿瘤药顺铂(cisplatin,Pt)对Wnt通路抑制因子FrpHE(frizzled relatd protein)和 DKK-1(dickkopf-1)表达的调节作用.方法 培养人肝癌HepG2、Hep3B、人大肠癌Lovo和人神经胶质瘤U251细胞,并分别加入5 μmol/L Pt作用24 h,以RT PCR技术检测FrpHE和DKK-1mRNA,以流式细胞术检测肿瘤细胞中Wnt通路的关键调节因子β-catenin的表达.结果 顺铂作用24 h后,FrpHE mRNA表达水平在人肝癌细胞较对照组表达水平显著增加(P<0.001).在人大肠癌细胞和人神经胶质瘤细胞中,未见FrpHE mRNA表达.DKK 1mRNA表达水平在加入Pt作用后的人肝癌细胞、人大肠癌细胞和人神经胶质瘤细胞均较对照组表达水平显著增加.β-catenin的阳性细胞百分比和平均荧光强度与对照组相比均降低(P<0.001).结论 化疗药顺铂能够诱导肝癌细胞FrpHE mRNA和人肝癌、肠癌、神经胶质瘤细胞DKK-1 mRNA的表达,抑制Wnt通路.     

头痛宁治疗偏头痛效果及安全性的Meta分析

目的 评价头痛宁胶囊治疗偏头痛的临床效果.方法 计算机检索维普、中国生物医学文献数据库、中国知网、万方数据库进行资料收集,筛选2001年1月1日～2014年6月1日间所有使用头痛宁与西药治疗偏头痛的随机对照试验(RCT),同时手动检测其参考文献.采用Jadad7分评分法评价纳入文献质量,由2名评价者独立进行文献质量评价和资料提取后,采用RevMan 5.0软件进行Meta分析.结果 检出符合标准RCT文献共144篇,筛选出10项研究(中药组602例,西药组566例)进行Meta分析.头痛宁治疗偏头痛效果与西药比较,其总OR=1.19,95％CI为(1.12,1.27);在治愈率方面,OR=1.61,其95％CI为(1.24,2.09);在安全性方面,其不良反应出现OR=1.64,95％CI为(0.29,0.90).结论 头痛宁治疗偏头痛效果确切,比西药单纯治疗效果好,两者合用可能取得更好的效果,但尚需更多高质量的研究以增加证据的强度.     

前置胎盘合并胎盘植入的临床分析

了解前置胎盘合并胎盘植入的危险及对母儿的影响。方法：对在我院１９９５年１月至１９９８年１１月间分娩的５８７７例产妇中８３例前置胎盘和其中１０例并胎盘植入患者的孕周,胎盘位置,产妇年龄、妊娠次数、产后出血量及新生儿Ａｐｇａｒ评分等指标进行统计分析。结果在５８８７例分娩产妇中,前置胎盘发生率为１．４％,合并胎盘植入占前置胎盘的１２％。经统计分析表明,前置胎盘与胎盘植入有关相关关系,相对危险度为２３２．     

Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study

DNA hyperdiploidy is a favorable prognostic factor in childhood acute lymphoblastic leukemia (ALL). The explanation for this prognostic significance is largely unknown. We have studied whether DNA ploidy was related to cellular resistance to 12 drugs, assessed with the methyl- thiazol-tetrazolium assay, in samples of 74 children with common (CD10+ precursor B-cell) ALL. Sixteen patients had hyperdiploid ALL cells and 58 patients had nonhyperdiploid ALL cells. Hyperdiploid ALL cells were more sensitive to mercaptopurine (median, 9.0-fold; P = .000003), to thioguanine (1.4-fold; P = .023), to cytarabine (1.8-fold; P = .016), and to I-asparaginase (19.5-fold; P = .022) than were nonhyperdiploid ALL cells. In contrast, these two ploidy groups did not differ significantly in resistance to prednisolone, dexamethasone, vincristine, vindesine, daunorubicin, doxorubicin, mitoxantrone, and teniposide. The percentage of S-phase cells was higher (P = .05) in the hyperdiploid ALL samples (median, 8.5%) than in the nonhyperdiploid ALL samples (median, 5.7%). However, the percentage of cells in S-phase was not significantly related to in vitro drug resistance. We conclude that the favorable prognosis associated with DNA hyperdiploidy in childhood common ALL may be explained by a relative sensitivity of hyperdiploid common ALL cells to antimetabolites, especially to mercaptopurine and to I-asparaginase.     

Immunologic stimulation of early murine hematopoiesis and its abrogation by cyclosporin A

Mice injected chronically with antiplatelet serum develop an increase in the number of megakaryocytic progenitor cells compared to animals given normal rabbit serum. To examine the specificity of this response, progenitor cells giving rise to megakaryocyte, granulocyte-macrophage, erythroid, and mixed-cell colonies were assayed after injection of various heterosera or saline. All four colony types increased in the serum-treated groups. Since the in vitro proliferation of hematopoietic progenitor cells is promoted by supernatants of mitogen-stimulated spleen cells, we hypothesized that the immune response following antiserum administration resulted in the in vivo activation of T lymphocytes which produced or led to the production of colony stimulating activities. To test this hypothesis, cyclosporin A, a preferential inhibitor of T lymphocyte function, was given to mice concurrently with antiserum and also added to spleen cell cultures in the presence of pokeweed mitogen. Cyclosporin A abrogated the antiserum- related increases in progenitor cell numbers in vivo and the production of colony stimulating activity in vitro. The results suggest that the immune response related to antiserum administration results in the in vivo production of hematopoietic colony stimulating activities that may be identical to those produced in vitro by mitogen-stimulation of spleen cells.     

Biological effects of recombinant human granulocyte colony-stimulating factor in patients with untreated acute myeloid leukemia

Hematopoietic growth factors are being administered to patients with acute myeloid leukemia (AML) both to shorten the duration of chemotherapy-induced neutropenia and in an attempt to increase cytotoxicity of cell cycle-specific agents. However, limited information is available concerning the effects of growth factors in AML patients. To examine the in vivo effects of recombinant human granulocyte colony-stimulating factor (G-CSF) on AML cells, laboratory studies were performed before and after a 72-hour intravenous infusion of G-CSF (10 micrograms/kg/d) administered to 28 untreated AML patients. Twenty-seven patients (96%) showed increases in at least one of the following parameters after G-CSF: blood blasts, bone marrow (BM) blasts, leukemia cells in S phase or interphase cells with leukemia- specific markers shown by fluorescence in situ hybridization. The median paired change in absolute blast count was +2.7 x 10(9)/L (P = .0001) after G-CSF, as compared with 0.0 during the 72 hours before initiation of G-CSF. The median percentage of BM leukemia cells in S phase increased from 6.0% to 10.7% after G-CSF (median change, %5.9%; P = .009). Interphase BM cells with trisomy 8 or monosomy 7 increased in 6 of 6 patients with these abnormalities (P = .02) with a median percent increase of 47%. Blood neutrophil counts also increased during G-CSF (median paired change, +2.8 x 10(9)/L; P < .0001). Trisomy 8 or monosomy 7 was shown by fluorescence in situ hybridization in post-G- CSF blood neutrophils from 4 of 6 patients but was also present in neutrophils before G-CSF. We conclude that the percentage of leukemia cells in S phase increases and that leukemia cell populations undergo expansion during short-term administration of G-CSF in almost all AML patients.