Placebos, placebo effect, and the response to the healing situation: the evolution of a concept

In spite of its impressive progress, medicine has been strongly criticized for relying on its modern biomedical tradition to the neglect of the psychosocial aspects of health. This neglect may account for patients' dissatisfaction and eventual use of alternative health approaches. The concept of placebo has sustained dramatic "protean" metamorphoses through the ages. For centuries, placebos have been regarded as powerful deceptive therapies. From the middle of the twentieth century, however, conventional medicine has used placebos as methodologic tools to distinguish the specific from the nonspecific ingredients in treatments. In modern medical research, the double-blind, placebo-controlled, randomized clinical trial has been established as the gold standard for the assessment of any new treatment. Recently a new trend regarding placebos seems to have emerged. The placebo and other nonspecific effects elicited by the "healing situation" have been independently subjected to scientific study. Progress in this area may promote useful clinical applications, enabling physicians to broaden their perspectives on the healing process. We present the historical changes of the concept of placebo and the ethical issues raised by their use.     

Potential role of monkey inferior parietal neurons coding action semantic equivalences as precursors of parts of speech

Abstract

The anterior portion of the inferior parietal cortex possesses comprehensive representations of actions embedded in behavioural contexts. Mirror neurons, which respond to both self-executed and observed actions, exist in this brain region in addition to those originally found in the premotor cortex. We found that parietal mirror neurons responded differentially to identical actions embedded in different contexts. Another type of parietal mirror neuron represents an inverse and complementary property of responding equally to dissimilar actions made by itself and others for an identical purpose. Here, we propose a hypothesis that these sets of inferior parietal neurons constitute a neural basis for encoding the semantic equivalence of various actions across different agents and contexts. The neurons have mirror neuron properties, and they encoded generalization of agents, differentiation of outcomes, and categorization of actions that led to common functions. By integrating the activities of these mirror neurons with various codings, we further suggest that in the ancestral primates’ brains, these various representations of meaningful action led to the gradual establishment of equivalence relations among the different types of actions, by sharing common action semantics. Such differential codings of the components of actions might represent precursors to the parts of protolanguage, such as gestural communication, which are shared among various members of a society. Finally, we suggest that the inferior parietal cortex serves as an interface between this action semantics system and other higher semantic systems, through common structures of action representation that mimic language syntax.     

Analytical and biological inequivalence of two commercial formulations of the antitumor agent bleomycin

Bleomycin is an antitumor agent which is a mixture of glycopeptides containing at least 55–75% bleomycin A₂ and 25–32% bleomycin B₂ fractional composition. Two bleomycin formulations, bleomycin sulfate, USP (Blenoxane, Bristol-Myers Squibb Oncology, Princeton, N.J.) and bleomycin HCl (Tianjin Hebei Pharmaceutical, Tianjin, China) were compared analytically and biologically. Reverse-phase high-performance liquid chromatography (HPLC) analyses using the USP methodology showed that Blenoxane contained primarily (69%) bleomycin A₂ and 29.3% bleomycin B₂. In contrast, Tianjin-supplied bleomycin HCl contained 97% bleomycin A₅ fraction. In vitro tumor cell growth inhibition assays showed equivalent activity in human OVCAR-3 ovarian cancer cells and slightly greater potency in murine L-1210 leukemia cells for the Tianjin formulation. In C57/Bl mice bearing B-16 melanoma tumors, Tianjin-supplied bleomycin produced slightly greater tumor growth inhibition at the expense of greater drug-induced lethality at higher dose levels. These studies show there are significant differences in two international bleomycin formulations. These compositional differences lead to altered biologic effects. Received: 16 July 1996 / Accepted: 6 November 1997     

How to establish equivalence between treatments: a one-sided clinical trial in paediatric oncology

The design of clinical trial to establish the equivalence of two treatments differs from that of an efficacy trial. The conventional null hypothesis of equivalent treatment efficacy is replaced by a null hypothesis of inequivalence which must be tested by appropriate statistics. In addition, the maximum allowable value of the true difference between the efficacy of two equivalent treatments must be specified. In oncology, such a trial is necessary when a standard treatment is replaced by a new less toxic one of equivalent efficacy. The statistical formulation is one-sided. A trial comparing two pre-operative treatments in childhood nephroblastoma is presented here and analysed according to this methodology.     

A proposal for interpreting and reporting negative studies

An issue of continuing interest is the interpretation and reporting of 'negative' studies, namely studies that do not find statistically significant differences. The most common approach is the design-power method which determines, irrespective of the observed difference, what differences the study could have been expected to detect. We propose an alternative approach, the application of equivalence testing methods, where we define equivalence to mean that the actual difference lies within some specified limits. This approach, in contrast to the design-power approach, provides a way of quantifying (with p-values) what was actually determined from the study instead of saying what the study may or may not have accomplished with some degree of certainty (power). For example, a possible outcome of the equivalence testing approach is the conclusion at the 5 per cent level that two means (or proportions) do not differ by more than some specified amount. The equivalence testing approach applies to any study design. We illustrate the method with a cancer clinical trial and an epidemiologic case-control study. In addition, for those studies in which one cannot specify limits a priori, we propose the use of equivalence curves to summarize and present the study results.     

DYSBOT: A single-blind,randomized parallel study to determine whether any differences can be detected in the efficacy and tolerability of two formulations of botulinum toxin type A—Dysport and Botox—assuming a ratio of 4:1

Background: Elston and Russell discovered a difference in the biological potency of the English formulation of botulinum toxin type A or BTX-A (Dysport) and the American formulation (Botox). Potency of both is expressed in LD50 mouse units, but because of assay differences, these units are not equivalent. Since the first warning by Quinn and Hallet on the clinical importance of this issue, it has been impossible to reach a consensus on the conversion factor for the potency of these formulations. Objective: To test the hypothesis that the conversion factor for the clinical potency of Dysport to Botox is approximately 4.1. DYSBOT is an acronym that results from adding “DYS” from Dysport with “BOT” from Botox. Patients and Methods: Design: A single-blind, randomized, parallel comparison. A total of 91 patients with blepharospasm or hemifacial spasm were randomized to treatment with Dysport or Botox using a fixed potency ratio of 4:1. Clinical evaluations: The patients were evaluated at baseline (day of the treatment), 1 month after treatment, and whenever the effect was judged to be fading. Objective and functional rating scales were used as quantitative measures of the change in clinical status. Adverse reactions were collected using a systematic questionnaire. Results: Using this ratio between products, both Dysport and Botox groups produced similar clinical efficacy and tolerability. For patients showing a positive response without the need of a booster, the duration of effect was 13.3 ± 5.9 weeks for the Dysport group and 11.2 ± 5.8 weeks for the Botox group. Of 48 patients, 11 (23%) needed booster treatment in the Dysport group compared with five (12%) of 43 in Botox group. Adverse events were noted in 24 (50%) of 48 patients in the Dysport group and 20 (47%) of 43 of the Botox-treated group. Conclusions: Using a 4:1 conversion ratio for Dysport and Botox, similar results were obtained for the two treatments in an appropriately powered study, suggesting that this conversion factor is a good estimate of their comparative clinical potencies.     

刘国辉《伤寒论》英译本的翻译特点与问题研究

中医经典著作《伤寒论》的英译问题一直备受关注,但学界较少对刘国辉译本进行系统研究。本文以刘国辉《伤寒论》英译本为研究对象,并探讨其翻译特色与存在的问题。研究发现,虽然该译本尚有不足之处,但总体来看该译本通过综合运用多种翻译策略,如借助西医术语进行归化翻译,使用汉语拼音进行异化翻译,增加副文本进行深度翻译,统一修辞手段与增补词语以实现对等翻译,达到了介绍《伤寒论》医学理论、传播中国文化的效果,这正是译者重视读者的接受度与译文忠实度翻译思想的集中体现。     

PASS软件实现临床试验中非劣效、等效和优效性检验的样本量估算

用PASS 11软件对非劣效、等效和优效性设计的临床试验进行样本量估算,并与SAS软件运行结果进行比较,探讨PASS 11软件在临床科研中计算样本量的实用性和准确性,为科研工作者在临床试验设计阶段进行科学的样本量估算提供帮助。     

Conceptual and statistical issues in the validation of analytic dilution assays for pharmaceutical applications

The discovery research, and development of a pharmaceutical product relies on the availability of validated assays for assessing product characteristics and drug effects in vivo and in vitro. Development of a validated assay is a multifaceted activity that provides many interesting challenges for bioanalytical chemists and statisticians. In paper this the similarity condition for fundamental validity of an analytic dilution assay is reviewed as a basic concept underlying the validation of assays for pharmaceutical applications. The distinction between the validity and the acceptability of an assay is considered in terms of the characteristics evaluated during four stages of validation. Recent guidelines on the validation of analytical procedures published by the U.S. Food and Drug Administration (1,2) are appraised from a statistical perspective and statistical issues in the validation process are discussed.     

A Bootstrap-Based Test for Establishing Noninferiority in Clinical Trials

A randomized, active-control clinical trial setting with the objective of testing noninferiority for a continuous response variable is considered. Noninferiority margin is based on the concept of preserving a certain fraction of the active control effect. Noninferiority is established if the ratio of the lower (upper) limit of the two-sided 95% confidence interval for the treatment difference to the estimated mean of the active control is greater (less) than a certain fraction. The nominal significance level is not maintained by the above confidence interval-based noninferiority test. We use bootstrapping to derive an accurate lower (upper) limit of the same confidence interval, which approximates the nominal significance level better and improves the power.