A BPA survey of recently appointed consultants

A postal survey of recently appointed consultant paediatricians was undertaken to determine whether they perceived their training had adequately equipped them for their current job. The response rate was 69% (207/299). After excluding replies from consultants trained outside the UK the analysis was carried out on 167 replies. Trainees held a mean 5.2 posts during general and higher professional training, necessitating a mean 1.8 house moves. Altogether 82% felt moves were beneficial to training but 46% found moves 'very disruptive' to family life. Only 12% of district general hospital and 22% of teaching hospital senior registrars took two research sessions a week. Supervision and training in research was absent or poor for more than 60%; 24% felt major changes and 55% moderate changes were needed to current training. Training in non-clinical skills was particularly in demand and a curriculum for both trainers and trainees with regular appraisals is required. Research at senior registrar level needs review and educational methods improved to achieve better training in a shorter period.     

Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.     

Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B

Protein Tyrosine phosphatase 1B (PTP1B) has been implicated as a key negative regulator of both insulin and leptin signaling pathways. Using an NMR-based screening approach with 15N- and 13C-labeled PTP1B, we have identified 2,3-dimethylphenyloxalylaminobenzoic acid (1) as a general, reversible, and competitive PTPase inhibitor. Structure-based approach guided by X-ray crystallography facilitated the development of 1 into a novel series of potent and selective PTP1B inhibitors occupying both the catalytic site and a portion of the noncatalytic, second phosphotyrosine binding site. Interestingly, oral biovailability has been observed in rats for some compounds. Furthermore, we demonstrated in vivo plasma glucose lowering effects with compound 12d in ob/ob mice.     

Identification of novel inhibitors of urokinase via NMR-based screening

Using an NMR-based screen, a novel class of urokinase inhibitors were identified that contain a 2-aminobenzimidazole moiety. The inhibitory potency of this family of inhibitors is similar to that of inhibitors containing a guanidine or amidine group. However, unlike previously described guanidino- or amidino-based inhibitors which have pK(a) values greater than 9.0, urokinase inhibitors containing a 2-aminobenzimidazole have pK(a) values of 7.5. Thus, 2-aminobenzimidazoles may have improved pharmacokinetic properties which could increase the bioavailability of inhibitors which contain this moiety. A crystal structure of one of the lead inhibitors, 2-amino-5-hydroxybenzimidazole, complexed with urokinase reveals the electrostatic and hydrophobic interactions that stabilize complex formation and suggests nearby subsites that may be accessed to increase the potency of this new series of urokinase inhibitors.     

NMR study of the possible interaction in solution of angiotensin II with a peptide encoded by angiotensin II complementary RNA.

The potential binding of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) (AII) to a peptide encoded by its complementary RNA (Lys-Gly-Val-Asp-Val-Tyr-Ala-Val) (IIA) has been studied by monitoring the 1H NMR spectrum of IIA in aqueous phosphate or Tris.HCl buffer (2H2O) as it is titrated with AII. For molar ratios of AII/IIA ranging from 0.2 to 1.8, the NMR spectra are unchanged as compared to the spectra of the isolated peptides. Based on these findings, the Kd for the putative biomolecular complex of the two peptides under these conditions is calculated to be greater than 10(-4) M. This result does not support the suggestion of Elton et al. [Elton, T. S., Dion, L.D., Bost, K. L., Oparil, S. & Blalock, J. E. (1988) Proc. Natl. Acad. Sci. USA 85, 2518-2522] that AII and IIA engage in high-affinity binding (Kd approximately 5 x 10(-8) M) with each other.     

应用Heath-Carter体型法分析辽西地区城市汉族儿童青少年1263名体型特征

目的:分析辽西地区城市汉族儿童青少年的体型发育规律和特点,为体质人类学补充必要的数据。方法:按整群分层抽样法,抽取2001-07/2003-09辽西地区城市7所中小学7～19岁经学校正常体质检查证明身体健康的汉族学生,按性别分两大组,每大组按年龄分12小组,7～18岁每岁为1个年龄组,18～19岁为1个年龄组,每小组45～86名,共分24组,搜集完整资料1263名(男657名,女606名)。采用Heath-Carter体型法,每项指标测量2次,取平均值,10项指标由专人负责,测试数据按年龄和性别在微机中建立数据库,依次计算出各年龄组的内因子、中因子和外因子,体型图上的X,Y坐标值,身高/体质量1/3,样本中平均体型点到所有体型点空间距离的均数,三维空间中两个体型点间的差异,体脂含量和各类体型分布频数。结果:参加调查1263名,均进入结果分析。①7～17岁儿童青少年身高、体质量随年龄的增加而增长。平均身高、体质量男生大于女生。身高/体质量1/3指数除14,16和17岁外,各年龄组女生>男生,平均值女生>男生。体脂含量11岁以前男生>女生,12岁以后女生>男生。②辽西地区城市汉族男生的平均体型值为3.9-3.5-3.4,属中间型,女生平均体型值为4.3-2.9-3.6,属偏外胚层的内胚层体型。体型频数的变化提示辽西城市汉族男生体型分布较散,女生分布较集中,主要在内胚层体型。③内因子男生在3.18～4.81,女生在3.05～5.33,11岁以前男生>女生,12岁以后女生>男生;中因子男生在3.02～4.23,女生在2.54～3.42,除16岁男女相差不多外,其他年龄组男生>女生,外因子男生在2.64～4.22,女生在2.92～4.14,13岁以前女生>男生,14岁以后男生>女生。因此,男生较女生骨骼粗壮,肌肉发达,随着年龄的增长,女生的皮下脂肪更发达,体态丰满,男生的身体相对瘦高程度增长,身材修长。男女各年龄组间体型比较,7～,8～,9～,10～,11～,12～,13～,14～,15～,16～,17～,18～19岁三维空间中两个体型点间的差异值分别为0.95,0.85,1.10,1.06,1.37,0.43,0.87,1.44,1.42,1.12,1.11,1.33,7～,8～,12～,14～,17～,18～19年龄组男女间体型差异有显著性(t=2.07,4.09,3.12,3.86,3.39,3.99,P<0.05)。④与国内汉族及其他少数民族相比,辽西汉族男生体脂最多,骨骼肌肉不发达,身体相对矮小;辽西地区汉族女生体脂较多,骨骼肌肉不发达,体型修长。结论:辽西地区城市男生较女生骨骼粗壮,肌肉发达,随着年龄的增长,女生的皮下脂肪更发达,体态丰满,男生的身体相对瘦高程度增长,身材修长。与国内汉族及其他少数民族相比,辽西地区城市汉族儿童青少年体脂发育较好,骨骼肌肉欠发达,青春期是形成健壮体型的关键时期,辽西地区城市儿童青少年应注意合理饮食和加强体育锻炼。     

大黄苷元联合溶栓对血栓栓塞性脑缺血大鼠肺胃损伤的保护作用

目的:观察大黄苷元联合溶栓治疗对大鼠脑缺血损伤肺胃组织的保护作用。方法:实验于2005-08/2006-07在河南中医学院老年医学研究所实验室完成。①260只SD大鼠采用随机数字法分为假手术组20只、模型组60只、尿激酶组60只、大黄苷元组60只、大黄苷元 尿激酶组60只;除假手术组外,其余各组根据缺血后动脉用药时间又各分为3,6,9h3个时间点,每个时间点20只。②自体血栓结合线栓阻塞大鼠大脑中动脉制备局灶性脑缺血动物模型。③各组大鼠均于术前4d灌胃用药,大黄苷元组、大黄苷元 尿激酶组用大黄苷元灌胃(灌胃体积为每100g大鼠1mL),假手术组、模型组和尿激酶组用等体积的生理盐水灌胃;动脉用药除假手术组外,其余各组分别于造模后3,6,9h经导管由区域动脉给药,尿激酶组与大黄苷元 尿激酶组用尿激酶(用药体积为20μL),模型组和大黄苷元组区域动脉用同等体积的生理盐水。④动脉给药后24h,观察大鼠脑组织病理损伤、颅内和胃出血率、脑和肺组织含水量、肺和胃病理损伤变化。结果:实验过程中因麻醉、操作等原因死亡及剔除大鼠156只,进入结果分析104只。①颅内和胃出血率:尿激酶组9h大鼠颅内出血率较模型组高(66.67%,28.57%,P<0.05);尿激酶组9h脑和胃出血率较3h高(脑:66.67%,18.75%;胃:41.18%,17.65,P<0.05);大黄苷元 尿激酶组9h颅内出血率较尿激酶组9h低(P<0.05)。②脑和肺及胃组织病理改变:各模型组大鼠脑、胃和肺组织病理损伤均较假手术组明显;各用药组脑和肺组织分别较相应时间模型组减轻;各组脑、胃和肺组织损伤9h均较其3h明显;大黄苷元 尿激酶组9h较相应时间点尿激酶组和大黄苷元组损伤减轻(P<0.05)。③脑和肺组织含水量:各模型组脑和肺组织含水量均较假手术组增高(P<0.01);尿激酶组和大黄苷元 尿激酶组各时间点均较模型组降低(P<0.01);各组9h分别较其3h脑和肺含水量增加(P<0.01,P<0.05);大黄苷元 尿激酶组6h脑组织和9h肺含水量分别较尿激酶组降低(P<0.05)。结论:脑缺血后延迟溶栓治疗可引起大鼠脑和胃出血率增高、脑组织和肺组织水肿加重,脑和肺及胃组织病理损伤明显;大黄苷元联合溶栓可降低脑出血率,改善神经细胞超微结构,降低脑和肺组织含水量,对脑缺血肺和胃组织损伤具有保护作用。