Integrative analysis of multiple cancer genomic datasets under the heterogeneity model

In the analysis of cancer studies with high‐dimensional genomic measurements, integrative analysis provides an effective way of pooling information across multiple heterogeneous datasets. The genomic basis of multiple independent datasets, which can be characterized by the sets of genomic markers, can be described using the homogeneity model or heterogeneity model. Under the homogeneity model, all datasets share the same set of markers associated with responses. In contrast, under the heterogeneity model, different studies have overlapping but possibly different sets of markers. The heterogeneity model contains the homogeneity model as a special case and can be much more flexible. Marker selection under the heterogeneity model calls for bi‐level selection to determine whether a covariate is associated with response in any study at all as well as in which studies it is associated with responses. In this study, we consider two minimax concave penalty‐based penalization approaches for marker selection under the heterogeneity model. For each approach, we describe its rationale and an effective computational algorithm. We conduct simulations to investigate their performance and compare with the existing alternatives. We also apply the proposed approaches to the analysis of gene expression data on multiple cancers. Copyright © 2013 John Wiley & Sons, Ltd.     

Aortic Valve Replacement Using Local Myocardial Hypothermia

This material comprises 100 cases of aortic valve replacement. Ninety-one of the valves were replaced with the Björk—Shiley tilting disc valve prosthesis and 9 with the Smeloff—Cutter ball valve. No coronary perfusion was used during surgery. The myocardium was protected by local myocardial hypothermia, achieved by an intracoronary infusion of Bretschneider's solution (+4°C) prior to surgery. A weak and flaccid heart without coronary perfusion cannulas facilitated the surgical procedure. Myocardial function was very good and the course of the patients excellent postoperatively. Seven percent of the patients were lost within one month after operation and late mortality was 13%. A comparison between clinical and haemodynamic findings obtained 2–3 months before and one year after surgery was made in 55 patients. A marked subjective improvement was seen in all but five patients. There was a significant increase of average physical working capacity and regression of ECG-signs of left ventricular hypertrophy and strain as well as of roentgenological heart size. Angina pectoris was present in only three patients postoperatively as compared with 23 before surgery. The improvement of physical working capacity was paralleled by a significant increase of cardiac output during exercise, caused by a rise of stroke volume, heart rate on maximal load tolerated remaining unchanged. Blood pressure reactions during work were normalized in patients with both pre-operative aortic stenosis and aortic insufficiency. A significant postoperative paravalvular leakage was rare in the present material.     

胰腺损伤并发症的治疗进展

胰腺损伤发生率较低,但是病死率很高。并发症是其致死的主要原因,对于并发症的正确处理是提高胰腺损伤抢救成功率的关键。胰腺损伤的常见并发症包括胰瘘、大出血、感染、腹腔间隙综合征、胰腺假性囊肿。应该根据胰腺损伤的程度,针对不同的并发症采取不同的治疗措施。治疗应遵循损害控制的原则,抢救生命是第一位。胰周充分引流,抑制胰液分泌,控制腹腔感染,综合运用介入和内镜等技术,酌情应用腹腔开放减压术。     

丹参饮合温胆汤加减对稳定型心绞痛患者心肌缺血的保护机制

目的:观察丹参饮合温胆汤加减治疗痰瘀阻滞型稳定型心绞痛(SAP)的疗效及对心肌缺血的保护机制研究。方法:将132例患者随机按数字表法分为对照组和观察组各66例。除去脱落、失访和剔除病例,两组最后分别完成63例。所有患者进行抗心绞痛药物和控制风险因素药物治疗。对照组口服丹蒌片,5片/次,3次/d;观察组给予丹参饮合温胆汤加减,1剂/d;两组疗程均为治疗3个月。每周进行心绞痛发作情况评分;冠心病心肌缺血情况采用心电图平板运动试验评价,中医症状和生活质量分别进行痰瘀阻滞证、西雅图心绞痛量表(SAQ)评分,血液流变学指标、白细胞介素-6(IL-6),肿瘤坏死因子-α(TNF-α),细胞间黏附分子-1(ICAM-1),胱抑素C(CysC),同型半胱氨酸(Hcy),缺血修饰白蛋白(IMA)和巨噬细胞移动抑制因子(MIF)水平,均治疗前后各评价1次;并进行安全性评价。结果:观察组心绞痛发作次数、持续时间、疼痛程度和硝酸甘油用量评分均低于对照组(P<0.01);观察组Duke评分、总运动时间、出现ST段压低1.0 mm的时间、心绞痛出现时间和代谢当量均多于对照组(P<0.01);观察组SAQ评分高于对照组(P<0.01),痰瘀阻滞证积分低于对照组(P<0.01);观察组心绞痛疗效优于对照组(Z=2.091,P<0.05);观察组ICAM-1,CysC,IL-6,TNF-α水平均低于对照组(P<0.01);观察组全血黏度(低切、高切)、全血还原黏度、血浆黏度、血小板聚集率、纤维蛋白原(FIB)均低于对照组(P<0.01);观察组IMA,Hcy和MIF水平均低于对照组(P<0.01)。没有发现服用丹参饮合温胆汤相关不良反应。结论:在西医常规治疗的基础上,丹参饮合温胆汤加减治疗SAP,可控制心绞痛发作,减轻痰瘀阻滞证症状,提高生活质量,有着较好临床疗效,且安全,并能改善患者血液流变性,抑制炎症反应,减轻管腔狭窄或阻塞,从而改善心肌缺血程度。     

Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories

Inhalation is the main pathway of ZnO exposure in the occupational environment but only few studies have addressed toxic effects after pulmonary exposure to ZnO nanoparticles (NP). Here we present results from three studies of pulmonary exposure and toxicity of ZnO NP in mice. The studies were prematurely terminated because interim results unexpectedly showed severe pulmonary toxicity. High bolus doses of ZnO NP (25 up to 100 μg; ≥1.4 mg/kg) were clearly associated with a dose dependent mortality in the mice. Lower doses (≥6 μg; ≥0.3 mg/kg) elicited acute toxicity in terms of reduced weight gain, desquamation of epithelial cells with concomitantly increased barrier permeability of the alveolar/blood as well as DNA damage. Oxidative stress was shown via a strong increase in lipid peroxidation and reduced glutathione in the pulmonary tissue. Two months post-exposure revealed no obvious toxicity for 12.5 and 25 μg on a range of parameters. However, mice that survived a high dose (50 μg; 2.7 mg/kg) had an increased pulmonary collagen accumulation (fibrosis) at a similar level as a high bolus dose of crystalline silica. The recovery from these toxicological effects appeared dose-dependent. The results indicate that alveolar deposition of ZnO NP may cause significant adverse health effects.     

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle (MP) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US‐FDA‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.