Partial activation of naive CD4 T cells and tolerance induction in response to peptide presented by resting B cells

Tolerance is thought to occur when Ag is presented to T cells in the absence of costimulatory interactions from APC accessory molecules. Of the professional APC, the resting B cell may be the main tolerizing cell in vivo. We have analyzed several aspects of activation of naive transgenic CD4 cells stimulated with resting or activated B cells presenting peptide Ag. Similar results were obtained with stimulation from peptide presenting fibroblast APC lacking or expressing B7-1 with intracellular adhesion molecule-1. TCR ligation with little or no accessory molecule coreceptor engagement induced efficient blastogenesis; up-regulation of CD25, CD44, CD69, CD95 and CD71; and down-regulation of CD62L over a 48-h period. Accessory molecule help enhanced the expression of CD25, CD44, CD69, and CD71, but to very modest degrees. Only two molecules, CD40 ligand and IL-2, were found to be extremely dependent on accessory molecule help, with little or no expression evident with peptide presented on resting B cells or class II-positive fibroblasts. T cells induced on resting B cells expanded minimally over 3 days, and this was followed by extensive cell death and hyporesponsiveness of the resulting cells. These studies suggest that under tolerizing conditions, such as Ag presentation by resting B cells, much of the naive CD4 response is induced efficiently. Partial activation, however, may be the overall result due to the lack of CD40 ligand expression, which may regulate costimulatory activity in APC and, in turn, may contribute to limiting the production of IL-2 required for T cell expansion and survival.     

Type-4 pilus-structure: outside to inside and top to bottom--a minireview

We have recently proposed a computational model of the N. gonorrhoeae pilus fiber based on the high resolution X-ray crystal structure of the component protein pilin, combined with available biophysical and genetic data [Parge et al. (1995) Nature 378, 32-38]. In parallel, we have used anti-peptide antibodies to distinguish buried and exposed regions of pilin within the assembled fiber [Forest et al. (1996) Infect. Immun. 64, 644-652]. This mini-review addresses the properties of the current pilus model and the locations of end-exposed epitopes. The fiber forms a three-layered structure of coiled conserved alpha helices surrounded by beta-sheet, with the hypervariable region as the most highly exposed portion. Overall the pilus model developed from diffraction and antibody mapping is expected to be representative of type-4 pili with general implications for type-4 assembly, function, and interactions with other proteins and cell membranes.     

Physical and sexual assault history in women with serious mental illness: prevalence, correlates, treatment, and future research directions

An emerging body of research on the physical and sexual abuse of seriously mentally ill (SMI) women documents a high incidence and prevalence of victimization within this population. While causal links are not well understood, there is convergent evidence that victimization of SMI women is associated with increased symptom levels, HIV-related risk behaviors, and such comorbid conditions as homelessness and substance abuse. These abuse correlates may influence chronicity, service utilization patterns, and treatment alliance. This article reviews the research literature on the prevalence, symptomatic and behavioral correlates, and treatment of abuse among SMI women, particularly women with schizophrenia. Within each topic, we discuss relevant research findings, limitations of available studies, and key questions that remain unanswered. We also discuss mechanisms that may underlie the relationship between trauma and schizophrenia-spectrum disorders. We conclude by outlining directions for future research in this area.     

The effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of buspirone

OBJECTIVE: The effects of fluvoxamine, a selective serotonin (5-HT) reuptake inhibitor antidepressant, on the pharmacokinetics and pharmacodynamics of buspirone, a non-benzodiazepine anxiolytic agent, were investigated. METHODS: In a randomized, placebo-controlled, two-phase cross-over study, ten healthy volunteers took either 100 mg fluvoxamine or matched placebo orally once daily for 5 days. On day 6, 10 mg buspirone was taken orally. Plasma concentrations of buspirone and its active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), were measured up to 18 h and the pharmacodynamic effects of buspirone up to 8 h. RESULTS: The total area under the plasma buspirone concentration-time curve was increased 2.4-fold (P < 0.05) and the peak plasma buspirone concentration 2.0-fold (P < 0.05) by fluvoxamine, compared with placebo. The half-life of buspirone was not affected. The ratio of the total area under the plasma concentration-time curve of 1-PP to that of buspirone was decreased from 7.4 [6.3 (SD)] to 4.4 (3.6) by fluvoxamine (P < 0.05). The results of the six pharmacodynamic tests remained unchanged. CONCLUSION: Fluvoxamine moderately increased plasma buspirone concentrations and decreased the production of the active 1-PP metabolite of buspirone. The mechanism of this interaction is probably inhibition of the CYP3A4-mediated first-pass metabolism of buspirone by fluvoxamine. However, this pharmacokinetic interaction was not associated with impairment of psychomotor performance and it is probably of limited clinical significance.     

Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways

This study provides a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans. By using a series of short-term in vivo studies, in vitro studies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. To make these comparisons, this study assumes that human and rodent olfactory epithelium have similar susceptibility to the cytotoxic effects of organic acids based on similar histological structure and common mode of action considerations. Interspecies differences in susceptibility to the toxic effects of acidic vapors are therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The acute, subchronic, and in vitro studies have demonstrated that the nasal olfactory epithelium is the most sensitive tissue to the effects of inhalation exposure to organic acids and that the sustentacular cells are the most sensitive cell type of this epithelium. A hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. The CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue concentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when the exposure conditions are the same. The magnitude of this difference varies somewhat with the specific exposure scenario that is simulated. The increased olfactory tissue dose in rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50% of the nasal cavity) and its highly susceptible location (particularly, a projection of olfactory epithelium extending anteriorly in the dorsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and it is in a much less accessible dorsal posterior location. In addition, CFD simulations indicate that human olfactory epithelium is poorly ventilated relative to rodent olfactory epithelium. These studies suggest that the human olfactory epithelium is protected from irritating acidic vapors significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy and nasal air flow. Furthermore, the general structure of the hybrid CFD-PBPK model used for this study appears to be useful for target tissue dosimetry and interspecies dose comparisons for a wide range of inhaled vapors.     

Reexamination of tympanic membrane temperature as a core temperature

Controversies surrounding tympanic temperature (Tty) itself and techniques for measuring it have dampened the potential usefulness of Tty in determining core temperature (operationally defined here as the body temperature taken at a deep body site). The present study was designed to address the following questions. 1) Can a tympanic membrane probe be made that is safer and more reliable than its predecessors? 2) Why is the effect of facial cooling and heating on Tty so inconsistent in reports from different laboratories? 3) Is Tty still useful as a measure of core temperature? Data from this study, obtained with a modified thermocouple probe, suggest that the widely reported facial skin cooling effect on Tty is most probably due to thermal contamination from the surrounding ear canal wall and/or suboptimal contact of the probe sensor with the tympanic membrane because 1) Tty that fell during facial cooling was increased to the precooling level by the repositioning of the probe sensor; 2) Tty determined by using a probe with a larger sensor area (the sensor soldered to a steel wire ring)tended to fall in response to facial cooling, whereas Tty determined with a thermally insulated probe ring did not; and 3) Tty obtained under careful positioning of the insulated probe was relatively insensitive to facial cooling or heating. Because Tty was practically identical to esophageal temperature (Tes) in the steady state, i.e., 36.83 +/- 0.20 (SD) degrees C for Tty and 36.87 +/- 0.16 degrees C for Tes at room temperature (n = 11), and because facial cooling had little effect on both Tty and Tes (36.86 +/- 0.17 degrees C for Tty and 36.86 +/- 0.26 degrees C for Tes during facial or scalp skin cooling), we support the postulate that Tty is a good measure of core temperature. The temperature transient in response to foot warming was detected 5 min (n = 2) faster with Tty than with Tes. Thus, with further improvements in the design of the probe. Tty can become a standard for determination of core body temperature.     

A randomized comparison of the efficacy and toxicity of epirubicin and doxorubicin in the treatment of patients with non-Hodgkin's lymphoma

BACKGROUND: Combination chemotherapy consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B) has been frequently used for the treatment of non-Hodgkin's lymphoma. This randomized study was undertaken to assess the efficacy and toxicity of this regimen when either doxorubicin or epirubicin was used as the anthracycline drug. METHODS: Between April 1989 and December 1993, 211 previously untreated patients with intermediate grade and high grade non-Hodgkin's lymphoma were randomized to receive either doxorubicin (n=106) or epirubicin (n=105) with the MACOP-B regimen. These patients were followed through December 1996. Numerous clinical features predictive of response and survival were analyzed. Cardiac and noncardiac toxicity in the two treatment arms were compared. RESULTS: The median age of the patients was 48 years. Complete remission was experienced by 122 patients (58.3%); 62 patients (58.5%) achieved complete remission in the doxorubicin arm and 60 (58.1%) in the epirubicin arm. Response rates, time to treatment failure, relapse data, and overall survival were comparable between the two arms. Morbidity due to mucositis, vomiting, peripheral neuropathy, and cardiotoxicity were also comparable. The overall mortality was 10%. Mortality due to neutropenic sepsis was considerably higher among patients who received epirubicin (10 patients) than among those who received doxorubicin (5 patients). Cardiac evaluation revealed no difference in toxicity between the two arms. CONCLUSIONS: Epirubicin was as effective as doxorubicin in terms of patients' responses to therapy. There was no difference in cardiotoxicity between the two treatment arms. However, in this study, the mortality due to neutropenic sepsis was significantly higher among patients treated with epirubicin.