Linear combinations of biomarkers to improve diagnostic accuracy with three ordinal diagnostic categories

Many researchers have addressed the problem of finding the optimal linear combination of biomarkers to maximize the area under receiver operating characteristic (ROC) curves for scenarios with binary disease status. In practice, many disease processes such as Alzheimer can be naturally classified into three diagnostic categories such as normal, mild cognitive impairment and Alzheimer's disease (AD), and for such diseases the volume under the ROC surface (VUS) is the most commonly used index of diagnostic accuracy. In this article, we propose a few parametric and nonparametric approaches to address the problem of finding the optimal linear combination to maximize the VUS. We carried out simulation studies to investigate the performance of the proposed methods. We apply all of the investigated approaches to a real data set from a cohort study in early stage AD. Copyright © 2012 John Wiley & Sons, Ltd.     

中药创新药物的研发探讨

作者围绕着中药创新药物的研制的相关问题进行了探讨,认为中药创新药物研制的切入点应重点放在中医临床;组分组合和成分组合创新药物的研究是一个重要的研究方向,但组分组合和成分组合不能替代饮片配伍;组分配伍以中医学理论为指导,其目标是能够按照中医理论辨证用药,并且具有较高的安全性,临床适应证明确且针对性好,成分及作用机制相对清楚,质量稳定可控,能够产业化推广。组分配伍模式有从有效方剂的饮片配伍深入到组分配伍,直接组分配伍及单味药的标准组分配伍几类,组分配伍的作用方式仍然是多组分、多靶点、整体综合调节。中药应该制定中药特色的质量标准,不应该一味追求和迎合国际标准;中药创新药物的服务对象应重点放在中国的老百姓。     

Chemical and antimicrobial properties of calcium hydroxide mixed with irrigating solutions

AIM: Chemical and antimicrobial effects of paste-like suspensions of calcium hydroxide (Ca(OH)2) powder with chlorhexidine (CHx), sodium hypochlorite (NaOCl) or iodine potassium iodide (IPI) solutions were tested and compared to conventional Ca(OH)2/saline paste. METHODOLOGY: Equivalent mixtures of Ca(OH)2 with irrigating solutions were compared to conventional Ca(OH)2/saline paste for their ability to raise the pH in root dentine. Ca(OH)2 pastes were compacted into prepared root canals of single-rooted extracted human teeth. Changes in root pH over time were recorded with a microelectrode placed in standardized wells within root surfaces. Antimicrobial efficacy of test solutions and pastes against Enterococcus faecalis and Candida albicans was assayed using an agar diffusion test. RESULTS: The ability of Ca(OH)2 to raise the pH in the root dentine was maintained when using mixtures of Ca(OH)2 with CHx, NaOCl or IPI (Kruskal-Wallis, P > 0.05). Mixtures of Ca(OH)2 with the test solutions had similar antimicrobial properties as equivalent mixtures with saline (anova, P > 0.05). The efficacy of CHx was reduced when mixed with Ca(OH)2. No additive antiseptic effects were recorded between Ca(OH)2 and IPI or Ca(OH)2 and NaOCl. CONCLUSIONS: Ca(OH)2 is a strong alkali, whose pH is not changed when adding weak acids or alkalis in aqueous suspensions. Under the conditions of this study, mixing Ca(OH)2 powder with the test irrigating solutions did not provide an increased antimicrobial effect compared to a conventional Ca(OH)2/saline medication.     

葛根素和白藜芦醇对青年大鼠峰值骨量的影响研究

目的:比较葛根素、白藜芦醇单体与二者的复合药物对大鼠峰值骨量的影响。方法 :选取雌性SPF级Wistar大鼠40只,体重109.45～119.44 g,平均115.87 g,大鼠适应3 d后采用随机数字表法将其分为4组,每组10只,分别为空白对照组(CON组,每日灌胃等体积的蒸馏水),葛根素组(PR组,每日灌胃15.4 mg/kg葛根素),白藜芦醇组(RES组,每日灌胃8.4 mg/kg白藜芦醇),复合药物组(P+R组,每日灌胃8.4 mg/kg白藜芦醇+15.4 mg/kg葛根素复合药)。每7 d监测1次大鼠体重,每月检测1次大鼠全身骨密度。3个月后处死全部大鼠。采用双能X线骨密度仪检测股骨和椎骨离体骨密度;采用万能材料试验机分析骨生物力学;采用VG染色分析骨形态计量学;采用ELISA试剂盒检测血清骨代谢指标及用Micro-CT扫描仪扫描股骨微结构。结果:各组大鼠在实验期间的体重变化无统计学意义;骨密度结果显示:与CON组比较,其余3组股骨和椎骨骨密度均显著升高,且R+P组显著高于PR组和RES组。股骨三点弯曲和椎骨压缩试验结果显示:与CON组相比,其余3组股骨和椎骨最大载荷值均显著升高,且P+R组高于PR组和RES组,而各组间弹性模量值无统计学意义;股骨VG染色结果显示:与CON组相比,其余3组骨小梁数目显著增加,分离度明显减低,且R+P组明显优于PR组和RES组,而各组间骨小梁厚度无显著变化。Micro-CT扫描重建图结果显示:与CON相比,其余3组股骨骨小梁结构紧密,数目较多,分离度小,连续性好,且R+P组显著优于RES和PR组;Micro-CT扫描指标结果显示:与CON组相比,其余3组股骨骨小梁数目(trabecular number,Tb.N)、骨小梁厚度(trabecular thickness,Tb.Th)显著增加,骨小梁分离度(trabecular spacing,Tb.Sp)显著降低,且差异具有统计学意义(P0.05),且R+P组显著优于RES和PR组。血清生化指标结果显示:与CON组相比,其余3组血清中骨钙素(osteocalcin,OC)水平均升高,抗酒石酸酸性磷酸酶5b(TRACP 5b)含量均下降,差异具有显著性,且P+R组显著高于PR组、RES组,而TRACP 5b含量无显著变化。结论:葛根素与白藜芦醇单体按1∶1比例组合而成的复合药在提高青年大鼠峰值骨密度和骨质量,增强骨生物力学性能,促进成骨细胞的矿化成熟,抑制破骨细胞骨吸收方面的药效显著优于葛根素和白藜芦醇单体的作用,表明中药复方或复合药将作为预防和治疗骨质疏松的新途径。     

养胃合剂对环磷酰胺化疗荷瘤

目的:观察养胃合剂对环磷酰胺化疗荷瘤小鼠骨髓抑制的影响。方法:对C₅₇BL小鼠进行肉瘤180(S₁₈₀)接种造模,给予养胃合剂灌胃和环磷酰胺(CTX)腹腔注射,停药24h后,将各组小鼠断颈处死,每只小鼠取左侧股骨干,冲洗股骨骨髓,计数骨髓有核细胞。结果:用高、低剂量养胃合剂的荷瘤化疗小鼠骨髓有核细胞数,均显著高于荷瘤化疗组(P＜0.01)。结论:养胃合剂能减轻环磷酰胺化疗荷瘤小鼠的骨髓抑制。     

Optimal linear combinations of array elements for B1 mapping

Accuracy of B₁ mapping for array coils can be improved by mapping the fields produced by driving linear combinations of the array elements, chosen to produce a more uniform distribution of B₁ amplitude. Quality of the resulting single element B₁ maps is influenced by the transformation used both via the uniformity of the resulting linear combination fields and by the degree to which these linear combinations differ from one another. In this work we investigate the effect of using different transformations on the quality of B₁ maps by simulating the B₁ mapping process for two different techniques, using real data from a 3T 8‐channel body transmit system. Different transformations are generated using a single complex parameter. It is demonstrated that the optimal transformation within this framework is different for different imaging targets (pelvis and brain of healthy volunteers, and water and oil phantoms). For the same target (pelvis) the optimum condition, however, is similar for a number of subjects, suggesting that optimal configurations to be used for calibrating coils in specific anatomical contexts can be determined in advance. Potential gains may be translated into significant reductions in scan time for equivalent signal‐to‐noise ratio coil maps. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1T315I-compound mutations

Ponatinib is a tyrosine kinase inhibitor (TKI) directed against BCR-ABL1 which is successfully used in patients with BCR-ABL1 ^T315I+ chronic myeloid leukemia (CML). However, BCR-ABL1 compound mutations may develop during therapy in these patients and may lead to drug resistance. Asciminib is a novel drug capable of targeting most BCR-ABL1 mutant-forms, including BCR-ABL1^T315I, but remains ineffective against most BCR-ABL1^T315I+ compound mutation-bearing sub-clones. We demonstrate that asciminib synergizes with ponatinib in inducing growth-arrest and apoptosis in patient-derived CML cell lines and murine Ba/F3 cells harboring BCR-ABL1 ^T315I or T315I-including compound mutations. Asciminib and ponatinib also produced cooperative effects on CRKL phosphorylation in BCR-ABL1-transformed cells. The growth-inhibitory effects of the drug combination ‘asciminib+ponatinib’ was further enhanced by hydroxyurea (HU), a drug which has lately been described to suppresses the proliferation of BCR-ABL1 ^T315I+ CML cells. Cooperative drug effects were also observed in patient-derived CML cells. Most importantly, we were able to show that the combinations ‘asciminib+ponatinib’ and ‘asciminib+ponatinib+HU’ produce synergistic apoptosis-inducing effects in CD34⁺/CD38^- CML stem cells obtained from patients with chronic phase CML or BCR-ABL1 ^T315I+ CML blast phase. Together, asciminib, ponatinib and HU synergize in producing anti-leukemic effects in multi-resistant CML cells, including cells harboring T315I+ BCR-ABL1 compound mutations and CML stem cells. The clinical efficacy of this TKI combination needs to be evaluated within the frame of upcoming clinical trials.     

固定剂量复合剂在省结核病防治规划中应用的研究

目的研究固定剂量复合剂在省结核病防治规划中应用的可行性。方法将初治涂阳肺结核病人按登记序号单双分入研究组和对照组。用对照研究方法对两组的完成治疗率、治疗效果、治疗依从性和不良反应等情况进行分析。结果研究组和对照组在性别、年龄、体重、完成治疗率、督导管理方式和治疗依从性等方面差异无显著性(P值均>0.05)。研究组的2、3个月未痰菌阴转率和治愈率分别为87.0%、93.5%和93.5%,对照组的2、3个月未痰菌阴转率和治愈率分别为89.4%、93.5%和87.0%,两组间的疗效差异无显著性(P值均>0.05)。除因链霉素引起的耳鸣(精确概率法P=0.024)外,两组其他不良反应症状出现的比例都无显著性差异(P值均>0.05)。结论在结核病防治规划中推广应用固定剂量复合剂是可行的。     

An open comparative study of two diuretic combinations,frusemide/amiloride (‘Frumil’) and bumetanide/potassium chloride (‘Burinex’ K), in the treatment of congestive cardiac failure in hospital out-patients

Summary

Forty elderly patients, aged 68 to 89 years, with congestive cardiac failure, who were attending a hospital out-patients department, entered an open, parallel group, comparative study of two diuretic combinations, 40 mgfrusemide plus 5?mg amiloride per tablet and 0.5?mg bumetanide plus 573?mg slow-release potassium chloride per tablet. Patients were assigned at random to receive one or other combination for 8 weeks, dosage being determined by the severity of the individual patient's condition (range 1 to 3 tablets frusemide/amiloride; 2 to 6 tablets bumetanide/potassium chloride). Clinical assessments, including visual analogue scores for dyspnoea at rest and on effort, and laboratory measurements of serum potassium and magnesium levels were carried out on entry and after 2, 4 and 8 weeks of treatment. Other variables were monitored before, during and/or after treatment. Although significant decreases were reported in dyspnoea severity scores at rest and on effort only in the bumetanide/potassium chloride group, global assessment of the patients' condition by patient and clinician at the end of the study indicated that both treatments produced improvement, and a greater proportion of patients considered treatment as satisfactory in the frusemide/amiloride group. Both drug combinations were well-tolerated and only a few minor side-effects were reported. Serum potassium levels were maintained in both treatment groups but there was a significant decrease in mean serum magnesium levels in patients on bumetanide/potassium chloride. Hyponatraemia was also detected in 2 patients on this combination. An increase in body weight was recorded in both groups, the increase being significant in patients receiving bumetanide/potassium chloride.