Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer’s Disease

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer''s disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.     

Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

A simulation study of three sequential methods for the comparison of two treatment groups when the response criterion is censored

Three recent sequential methods, group sequential analysis (GSA), the sequential probability ratio test (SPRT) and the triangular test (TT) are well suited to randomized clinical trials with a censored response criterion, as they do not require matched pairs of patients. We undertook a simulation study to investigate their statistical properties and to compare these three methods with the fixed-sample design. Our results suggest that the three methods have the expected statistical properties for size and power; they allow an important reduction of the average number of events before stopping, except with GSA when there is no treatment difference; the triangular test (closed design) appears the optimal design, as the variance of the number of events is smaller than with the sequential probability ratio test (open design) and analysis after every twenty new events does not alter the statistical properties of these sequential methods and enhances their usefulness.     

Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

应重视口腔颌面部恶性肿瘤的综合序列治疗

口腔颌面部恶性肿瘤约占全身恶性肿瘤的3％，虽然所占比例不高，但l大l其解剖部位特殊．涉及美观和重要的生理功能，冈此对患者机体和心理的影响不容忽视。早期（Ⅰ、Ⅱ期）口腔颌面部恶性肿瘤无论采用手术和（或）放射治疗，均能取得良好效果。但遗憾的是，大多数患者就诊时，已属局部一区域晚期（Ⅲ、Ⅳ期）。由于受到局部解剖和维持功能的限制，单纯通过扩大手术切除范围和改进现有手术技术，除能改善患者生存质量外，已无法提高此类患者的生存率，延长其生存时间。     

活体顺序性荧光标记技术在实验性骨折愈合研究中的应用

目的介绍实验性骨折愈合研究中活体顺序性荧光标记的技术与方法。方法以成年兔胫骨骨折外固定为模型，术后分别以Tetracydin(TC，黄色，25mg／kg)、Calcein(CG，绿色，10mg／kg)、Xylenal(XO，桔色，90mg／kg)、Alizarin—complen(AE，红色，30mg／kg)四种荧光染料于兔颈部皮下定期注射；并于术后第3、6、12及24周活杀动物，解剖出胫骨，梯度乙醇脱水、脱脂，甲基丙烯酸甲脂包埋，切片厚度40～100μm，打磨，荧光显微镜下观察、摄像；同时通过组织学观察、X线摄片了解骨愈合速度与质量。结果顺序性荧光标记显示，加压组中钙化的内、外骨痴均于术后第2周出现于截骨处的远、近断端，但尚未形成骨性连接。亦无骨皮质的改建。外骨痴增生停止于术后12周，且骨皮质的改建至12周已渐减少．至术后24周已基本完成；对照组：内骨痴于术后第3周出现于截骨处远、近断端，无钙化的外骨痴形成，亦无骨皮质的改建；外骨痂增生停止于术后12周，骨皮质改建至24周尚未完成，其结果与组织学观察、X线摄片具有一致性。结论活体顺序性荧光标记技术可以从细胞水平判断新骨的开始时间、骨生长速度及生长方向，并能节约实验动物数量，是实验性骨折愈合研究中较为理想的研究手段。     

胎肝细胞输注对癌症病人化疗中外周血白细胞变化干预的序贯试验研究

本文自１９９１年１月以来．进行了静脉输注胎肝细胞悬液干扰化疗药物降白副反应的医学序贯试验。实验组病人静脉输注４～６月胎龄胎肝细胞悬液１６００～４０００ｍｌ（浓度５～７×１０９个／Ｌ），对照组按常规方法升白。通过２８例病人的序贯试验发现化疗期间输注胎肝细胞悬液的病人骨髓抑制发生延迟，持续时间短，程度减轻，从而为化疗正常进行提供基本条件。结论；胎肝细胞悬液输注可干扰化疗药物降白副反应的发生。     

Salivary gland 99mTc-scintigraphy: a grading scale and correlation with major salivary gland flow rates

Sequential salivary gland scintigraphy with 99mTc-technetium pertechnetate (Tc-99) is a safe, minimally invasive test for study of major salivary glands. However, its relationship to salivary function has not been investigated in detail. We have investigated the relationship between major salivary gland flow rates and Tc-99 scans and developed a new rating scale using scans of a control group with normal salivary function. Salivary flow rates and Tc-99 scans were obtained from healthy, non-medicated subjects (n = 33) and from xerostomic patients (n = 22). There were significant differences between the groups for salivary flow rates and Tc-99 ratings. Significant correlations were found between salivary flow rates and Tc-99 ratings in the control and xerostomic groups. The Tc-99 rating scale proved reliable in assessing salivary dysfunction, and showed a high inter-examiner correlation. These results demonstrate the usefulness of salivary gland scintigraphy in assessing major salivary gland flow rates and the utility of a new rating scale.     

连续切片加免疫组化染色法在乳腺癌微灶转移检测中的应用

目的：推荐一种检测恶性肿瘤微灶转移的方法。方法：应用连续切片的免疫组化法回顾研究50例乳腺癌的淋巴结微灶转移情况，将结果与常规病理切片法进行配对资料的卡方检验，并统计微灶转移率。结果：常规病理切片法的转移灶检出率为30％，连续切片的抗细胞角蛋白免疫组化法的转移灶检出率为50％，二者间差异有显著性。连续切片法发现的微灶转移率为28．5％。结论：对于肿瘤的微灶转移的发现，连续切片的的免疫组化法更有优势，它是一种敏感的检测微灶转移的方法。     

荧光光谱法分析煤焦油组分

研究煤焦油组分时,为了防止组分相互之间的干扰,在测定前用几种不同极性的溶剂:石油醚;80%石油醚-20%甲苯;60%石油醚-40%甲苯;40%石滑醚-60%甲苯;20%石油醚-80%甲苯;甲苯;氯仿;50%氟仿-50%甲醇;甲醇进行洗提,从煤焦油中得到9个级分。然后用荧光法从9个级分中鉴定出28个组分:茶、苊、联苯、三甲基酚、菲、异喹啉、芴、对氨基酚、联苯胺、蒽醌、四氢萘、2,5-二甲酚、蒽、咔唑、间苯二酚、二乙基苯胺、喹啉、吲哚醌、1,3,5-三甲苯、1,2,4-三甲苯、萘醌、菲醌、窟、苾、氧芴、1,2-苯并蒽、2,3-苯并蒽、3,4-苯并苾。同时定量了氯仿和甲醇级分中氧芴、(艹屈)、联苯胺、苾、菲、蒽、咔唑、四氢蔡咔、四氢萘、苯醌、喹啉、8-羟基喹啉等12个组分的含量。