High-dose continuous venous infusion of interleukin-2: Influence of dose and infusion rate on tumoricidal function and lymphocyte subsets

Previous clinical studies have demonstrated a dose-response relationship between enhancement of certain immune parameters and interleukin-2 (IL-2) dose in trials with low dosages of the cytokine. This has not been demonstrated for high-dose (greater than 18×10⁶ IU/m² per day) IL-2. We completed phase II trials of sustained administration of indomethacin and ranitidine with IL-2 given as a continuous infusion over 5 days for three courses. Peripheral blood mononuclear cells, both fresh and cultured in vitro with IL-2 or IL-2 and indomethacin, were tested for tumoricidal function against K562 and Daudi targets; these results were then correlated with actual delivered dose and mean infusion rate per course. Similar correlations were calculated between delivered dose or infusion rate and absolute and proportional counts of lymphocyte subsets as determined by flow cytometry. No enhancement of in vitro tumoricidal function with either increasing delivered dose or increasing infusion rate was seen. No consistent pattern of correlation was found between the absolute counts of lymphocyte subsets after each course of IL-2 with delivered dose or infusion rate. The percent rise in absolute counts of selected T- and NK-cell subsets at the end of course 1 compared with baseline values correlated positively with infusion rate; however, a similar correlation between the infusion rate and an increase in lymphocyte tumoricidal function was lacking. Little evidence was found for improved tumoricidal function of mononuclear cells or consistent enhancement of lymphocyte subset counts in patients able to tolerate doses of IL-2 beyond 18×10⁶ IU/m² per day in a 5-day continuous infusion schedule.Presented in part at the Twenty-eighth Annual Meeting of the American Society of Clinical Oncology, May 17–19, 1992, San Diego, Calif.     

Size and Power of Test Statistics for Gene Correlation in 2 × 2 Contingency Tables

Monte Carlo simulation of size and power of two proposed tests for linkage disequilibrium between two genes each with two alleles were investigated. Results were compared with two commonly used statistics, the correlation coefficient r and the log-odds ratio tests. Depending on the sign of the linkage disequilibrium, the new tests were found to be more powerful than either of the correlation or log-odds ratio tests. However, on average (positive and negative linkage disequilibrium) the Chi-square test using the correlation coefficient was to a small extent more powerful than the other tests.     

The Relative Power of Two Asymptotic Multivariate Tests for Homogeneity in a Contingency Table

In a three way contingency table two multivariate tests for homogeneity have been proposed by the author (1983) a the “catanova” test, which is a trace “metric” test and b the “multinova” test which is determinant based. Both tests are asymptotically distributed as chi-square. In this paper, the power values of the tests are compared and conditions are given for preference of each test.     

One Degree of Freedom for Non-Additivity in a Contingency Table and Its Multivariate Extension

The paper develops a chi-square test with one degree of freedom for row-column interaction in a contingency table. Use is made of the JOHNSON-GRAYBILL [1972] model which is herein generalized to a twoway multiple response situation. Some of the merits of the new test over the better-known tests for the same hypothesis are discussed.     

A Coefficient of Agreement Adjusted for Bias in Paired Ordered Categorical Data

The quality of ordered categorical recordings is determined from repeated measurements on the same subject in order to assess the level of agreement between raters, scales or occasions. The presented rating-invariant method for ordered categorical data provides means of analysing the quality of single-item rating scales, irrespective of the number of possible response values and the marginal distributions. Marginal heterogeneity implies systematic disagreement, so-called bias. An augmented ranking approach is the basis for the separation of inter-rater disagreement into systematic and random components. Correlation between pairs of augmented rank values provides a measure of agreement to the best common ordering of paired classifications, given inter-rater bias. The essential differences in interpretation and applicability of the proposed coefficient of agreement and the Spearman rank-order correlation for ordered categorical data are discussed.     

A randomized, placebo-controlled, double-blind trial of supplemental docosahexaenoic acid on cognitive processing speed and executive function in females of reproductive age with phenylketonuria: A pilot study

Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12–47 years. Participants were randomly assigned to receive DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).     

A Nonparametric Test for Ordered Alternatives in Two-Way Layouts with Censored Data

A nonparametric test is presented to test for ordered alternatives of the treatment effects when the data follow a two-way layout. The observations are subject to arbitrary right censorship. The test is similar to the one developed by Hettmansperger and Norton (1987) for uncensored observations.     

A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin

Clinical investigation of melatonin agonists has been hampered by side effects such as hypothermia, hypotension and bradycardia. The availability of a melatonin agonist devoid of these side effects would improve our understanding of the mechanisms by which melatonin agonists affect sleep. This study investigated the pharmacokinetics, pharmacodynamics and safety of the melatonin agonist beta-methyl-6-chloromelatonin at doses up to 100 mg in healthy volunteers. The design was a single blind, across subjects, placebo controlled, group wise dose escalation using doses of 20, 35, 50 and 100 mg beta-methyl-6-chloromelatonin. Eight subjects received one dose of study drug or placebo. Pharmacokinetic analysis showed a consistent Tmax across all doses with a mean of 1.12 +/- 0.11 hr for all groups (mean +/- SD). The half-life was also consistent across dose, with a mean of 1.04 +/- 0.04 hr. Maximum plasma concentrations increased with increasing dose with values of 44.83 +/- 29.79, 100.3 +/- 41.08, 79.84 +/- 26.36 and 410.3 +/- 129.4 ng/ml at doses of 20, 35, 50 and 100 mg, respectively. Area under the curve showed similar increases. No consistent changes in vital signs occurred as a function of dose or time after study drug. The incidence of all adverse events, the severity of the event or the event's relationship to treatment did not increase with higher doses of beta-methyl-6-chloromelatonin. Sleepiness was reported after all doses of beta-methyl-6-chloromelatonin. beta-methyl-6-chloromelatonin appears safe and well tolerated at doses up to 100 mg. These doses are not associated with hypothermia, bradycardia or hypotension. A melatonin agonist lacking these side effects should allow investigation of the direct soporific effects of melatonin agonists.     

Applications of an efficient method for comparing immunogold labelling patterns in the same sets of compartments in different groups of cells

Quantitative immunoelectron microscopy often involves determining the distributions of gold label in different intracellular compartments and then drawing comparisons between compartments in the same sample of cells or between experimental groups of cells. In the case of within-group comparisons, recent developments in the estimation of relative labelling index and labelling density make it possible to test whether or not particular compartments are preferentially labelled. These methods are ideally suited to analysing gold label restricted to volume (organelle) or surface (membrane) compartments but may be modified to analyse label localised in mixtures of both. Here, a simple and efficient approach to drawing between-group comparisons for label associated with organelles and/or membranes is presented. The method relies on multistage random sampling of specimens (via blocks and microscopic fields) followed by simply counting gold particles associated with different compartments. The distributions of raw gold counts in different groups are then compared by contingency table analysis with statistical degrees of freedom for chi-squared values being determined by the number of compartments and the number of experimental groups of cells. Compartmental chi-squared values making substantial contributions to the total chi-squared values then identify where the main between-group differences reside. The method requires no information about compartment size (for example, organelle profile area or membrane trace length) and does not even depend critically on standardising between-group magnification. Its application is illustrated using datasets from immunolabelling studies designed to localise the KDEL receptor, phosphatidyl-inositol 4,5-bisphosphate, GLUT4 and rab4 at the electron microscopic level.     

Excel在药学数据分析工作中的应用

目的：采用常用的电子表格处理系统Microsoft Excel解决药学实验过程中遇到的数据分析问题。方法：应用工作表函数中内置的统计函数,以线性回归为例说明源数据的输入与结果返回的具体操作过程;对数据分析工具中的＂描述统计＂工具、t检验与方差分析,结合具体实例对药学实践中遇到的药学统计实际问题进行综合探讨。结果：用Excel表中内置的统计函数工具进行线性回归分析,方法简单、结果可靠;Excel表中的数据分析工具适用于日常药学实验数据分析过程中遇到的描述统计分析、t检验与方差分析。Excel与其它数据处理软件相比具有操作快捷、使用方便、计算精确、易于学习与掌握等优点。结论：Excel友好的界面,清晰的统计分析结果,使医药工作者在使用Excel的数据分析软件时会感到非常的方便快捷,灵活实用,值得在药学实践中应用推广。     

Developments in cell biology for quantitative immunoelectron microscopy based on thin sections: a review

Quantitative immunoelectron microscopy uses ultrathin sections and gold particle labelling to determine distributions of molecules across cell compartments. Here, we review a portfolio of new methods for comparing labelling distributions between different compartments in one study group (method 1) and between the same compartments in two or more groups (method 2). Specimen samples are selected unbiasedly and then observed and expected distributions of gold particles are estimated and compared by appropriate statistical procedures. The methods can be used to analyse gold label distributed between volume-occupying (organelle) and surface-occupying (membrane) compartments, but in method 1, membranes must be treated as organelles. With method 1, gold counts are combined with stereological estimators of compartment size to determine labelling density (LD). For volume-occupiers, LD can be expressed simply as golds per test point and, for surface-occupiers, as golds per test line intersection. Expected distributions are generated by randomly assigning gold particles to compartments and expressing observed/expected counts as a relative labelling index (RLI). Preferentially-labelled compartments are identified from their RLI values and by Chi-squared analysis of observed and expected distributions. For method 2, the raw gold particle counts distributed between compartments are simply compared across groups by contingency table and Chi-squared analysis. This identifies the main compartments responsible for the differences between group distributions. Finally, we discuss labelling efficiency (the number of gold particles per target molecule) and describe how it can be estimated for volume- or surface-occupiers by combining stereological data with biochemical determinations.     

The Probability Density Functions of the Contingency Coefficients,defined by KRAMER and PEARSON,in a 2-Dimensional Frequency Distribution of Grouped Bivariate Normal Variables. I

Two general measures for the degree of association in a contingency table are the contingency coefficients defined by PEARSON and KRAMER. In the case of a standardized bivariate normal distribution with correlation coefficient of the variables, whose realizations constitute the rows and columns of the table, the density functions of the two listed association measures are derived.     

A Novel Approach for Measuring the Burden of Uncomplicated Plasmodium falciparum Malaria: Application to Data from Zambia

Measurement of malaria burden is fraught with complexity, due to the natural history of the disease, delays in seeking treatment or failure of case management. Attempts to establish an appropriate case definition for a malaria episode has often resulted in ambiguities and challenges because of poor information about treatment seeking, patterns of infection, recurrence of fever and asymptomatic infection. While the primary reason for treating malaria is to reduce disease burden, the effects of treatment are generally ignored in estimates of the burden of malaria morbidity, which are usually presented in terms of numbers of clinical cases or episodes, with the main data sources being reports from health facilities and parasite prevalence surveys. The use of burden estimates that do not consider effects of treatment, leads to under-estimation of the impact of improvements in case management. Official estimates of burden very likely massively underestimate the impact of the roll-out of ACT as first-line therapy across Africa. This paper proposes a novel approach for estimating burden of disease based on the point prevalence of malaria attributable disease, or equivalently, the days with malaria fever in unit time. The technique makes use of data available from standard community surveys, analyses of fever patterns in malaria therapy patients, and data on recall bias. Application of this approach to data from Zambia for 2009–2010 gave an estimate of 2.6 (95% credible interval: 1.5–3.7) malaria attributable fever days per child-year. The estimates of recall bias, and of the numbers of days with illness contributing to single illness recalls, could be applied more generally. To obtain valid estimates of the overall malaria burden using these methods, there remains a need for surveys to include the whole range of ages of hosts in the population and for data on seasonality patterns in confirmed case series.