Toxic shock syndrome: characterization of human immune responses to TSST-1 and evidence for sensitivity thresholds.

Noninvasive vaginal infections by Staphylococcus aureus strains producing the superantigen TSST-1 can cause menstrual toxic shock syndrome (mTSS). With the objective of exploring the basis for differential susceptibility to mTSS, the relative responsiveness to TSST-1 of healthy women has been investigated. Peripheral blood mononuclear cells from healthy donors were incubated with purified TSST-1 or with the T-cell mitogen phytohemmaglutinin (PHA), and proliferation was measured. The concentrations of TSST-1 and PHA required to elicit a response equivalent to 15% of the maximal achievable response (EC15) were determined. Although with PHA, EC15 values were comparable between donors, subjects could be classified as being of high, medium, or low sensitivity based on responsiveness to TSST-1. Sensitivity to TSST-1-induced proliferation was associated with increased production of the cytokines interleukin-2 and interferon-γ. When the entire T lymphocyte population was considered, there were no differences between sensitivity groups with respect to the frequency of cells known to be responsive to TSST-1 (those bearing CD3(+) Vß2(+)). However, there was an association between sensitivity to TSST-1 and certain HLA-class II haplotypes. Thus, the frequencies of DR7DQ2, DR14DQ5, DR4DQ8, and DR8DQ4 haplotypes were greater among those with high sensitivity, a finding confirmed by analysis of responses to immortalized homozygous B cell lines. Collectively, the results reveal that factors other than neutralizing antibody and the frequency of Vß2(+) T lymphocytes determine immunological responsiveness to TSST-1. Differential responsiveness of lymphocytes to TSST-1 may form the basis of interindividual variations in susceptibility to mTSS.

Sample size determination for alternate periods of use study designs with binary responses.

In this article, we consider several study designs that arise in practice, which are variations of standard crossover designs. Often, they may result from modifications made to a standard crossover design due to practical considerations. Characteristic features of the studies we are concerned with are (a) treatments consist of external use of products with little or no possibility of carry over effects, and (b) the periods of use are dictated by the subjects or by some specific event, such as diaper leakage or menstrual flow. We consider a number of such study designs for estimating the difference in the efficacy of two treatments or test products. We provide brief descriptions of studies to motivate the study design, the underlying data structure, and computations of the variances of the usual unbiased estimators of the difference in efficacy, and the sample size formulas. The situations considered here cover a number of popular crossover designs. The objective of our work is to provide guidance to members of a wide audience on how to answer the sample size question for their own nonstandard situations. We conclude the article with a brief report on a simulation study we conducted to investigate the impact of estimation on the sample size determination and consequently on the actual power realized in an effort to promote the "best practice" of checking whether the recommended sample sizes indeed achieve the desired level of power.

Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome.

BACKGROUND: Probiotic bacteria exhibit a variety of properties, including immunomodulatory activity, which are unique to a particular strain. Thus, not all species will necessarily have the same therapeutic potential in a particular condition. We have preliminary evidence that Bifidobacterium infantis 35624 may have utility in irritable bowel syndrome (IBS). OBJECTIVES: This study was designed to confirm the efficacy of the probiotic bacteria B. infantis 35624 in a large-scale, multicenter, clinical trial of women with IBS. A second objective of the study was to determine the optimal dosage of probiotic for administration in an encapsulated formulation. METHODS: After a 2-wk baseline, 362 primary care IBS patients, with any bowel habit subtype, were randomized to either placebo or freeze-dried, encapsulated B. infantis at a dose of 1 x 10(6), 1 x 10(8), or 1 x 10(10), cfu/mL for 4 wk. IBS symptoms were monitored daily and scored on to a 6-point Likert scale with the primary outcome variable being abdominal pain or discomfort. A composite symptom score, the subject's global assessment of IBS symptom relief, and measures of quality of life (using the IBS-QOL instrument) were also recorded. RESULTS: B. infantis 35624 at a dose of 1 x 10(8) cfu was significantly superior to placebo and all other bifidobacterium doses for the primary efficacy variable of abdominal pain as well as the composite score and scores for bloating, bowel dysfunction, incomplete evacuation, straining, and the passage of gas at the end of the 4-wk study. The improvement in global symptom assessment exceeded placebo by more than 20% (p < 0.02). Two other doses of probiotic (1 x 10(6) and 1 x 10(10)) were not significantly different from placebo; of these, the 1 x 10(10) dose was associated with significant formulation problems. No significant adverse events were recorded. CONCLUSIONS: B. infantis 35624 is a probiotic that specifically relieves many of the symptoms of IBS. At a dosage level of 1 x 10(8) cfu, it can be delivered by a capsule making it stable, convenient to administer, and amenable to widespread use. The lack of benefits observed with the other dosage levels of the probiotic highlight the need for clinical data in the final dosage form and dose of probiotic before these products should be used in practice.