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Biomedical subjects

M Stevens

Publications and source records attributed to M Stevens.

At least 19 recordsLinked to original sources
PubMed2000

Prospective validation of renal function-based carboplatin dosing in children with cancer: A United Kingdom Children's Cancer Study Group Trial.

PURPOSE: Carboplatin dosing in adults with cancer is based on renal function. The purpose of the current study was to validate a previously developed pediatric carboplatin-dosing formula. PATIENTS AND METHODS: Thirty-eight pediatric patients were randomized to receive a carboplatin dose calculated according to surface area or a renal function-based dosing formula. On the next course of therapy, the alternative dosing method was used for each patient. Carboplatin pharmacokinetics (based on free plasma platinum concentrations) were measured after both courses. RESULTS: The mean observed areas under the carboplatin concentration-versus-time curve (AUCs) after renal function- and surface area-based dosing were 98% and 95% of the target AUCs, respectively. The variation in the observed AUC was significantly less after renal function-based dosing (F test, P =.02), such that 74% of courses had an observed AUC within +/- 20% of the target value, versus 49% for courses after dosing according to surface area. Only one of 22 courses at the center with the most experience with renal function-based dosing was associated with an AUC outside +/- 20% of the target value, versus nine of 22 courses after surface area-based dosing in the same center. There was a relationship (r(2) =.71) between carboplatin AUC and thrombocytopenia in 10 neuroblastoma patients treated with a combination of carboplatin, vincristine, etoposide, and cyclophosphamide. CONCLUSION: Renal function-based carboplatin dosing in children results in more consistent drug exposure than surface area-based drug administration.

Adolescent↗
PubMed2000

Role of insulin receptor substrate-2 in interleukin-9-dependent proliferation.

Interleukin-9 (IL-9) stimulation results in JAK, STAT and IRS1/2 phosphorylation. The role of IRS adaptor proteins in IL-9 signaling is not clear. We show that IL-9 induces IRS2 phosphorylation and association with phosphatidylinositol-3 kinase (PI 3-K) p85 subunit in TS1 cells and BaF/9R cells, which proliferate upon IL-9 stimulation. We observed a PI 3-K-dependent phosphorylation of protein kinase B (PKB) in TS1 cells, but not in BaF/9R, nor in other IL-9-dependent cell lines. Finally, 32D cells that were transfected with the IL-9 receptor but lack IRS expression survived in the presence of IL-9. Ectopic IRS1 expression allowed for IL-9-induced proliferation, in the absence of significant PKB phosphorylation.

Animals↗
PubMed2000

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection: selection of thymidine analog regimen therapy (START I).

BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, -0.204 to 0.036; P= 0.213], with 49% and 47% respectively achieving < or = 50 copies/ml at 48 weeks (90% CI, -0.134 to 0.096; P = 0.834). Median change in CD4 cell counts at 48 weeks was +227 x 10(6)/l and +198 x 10(6)/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 x 10(6)/l versus 110 x 10(6)/l; P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Anti-HIV Agents↗
PubMed2000

A comparison of stavudine, didanosine and indinavir with zidovudine, lamivudine and indinavir for the initial treatment of HIV-1 infected individuals: selection of thymidine analog regimen therapy (START II).

OBJECTIVE: Comparison of stavudine (d4T), didanosine (ddI) and indinavir (IDV) with zidovudine (ZDV), lamivudine (3TC) and IDV in HIV-1 infected patients. DESIGN: Randomized, open-label. SETTING: Fourteen HIV Clinical Research Centers. PATIENTS: Two-hundred and five patients with less than 4 weeks antiretroviral treatment, naive to 3TC and protease inhibitors and with CD4 cell counts > or = 200 x 10(6)/l and plasma HIV-1 RNA levels > or = 10,000 copies/ml. INTERVENTIONS: Stavudine 40 mg and ddI 200 mg twice daily plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h or 300 mg twice daily, 3TC 150 mg twice daily plus IDV. MAIN OUTCOME MEASURES: The proportion of patients with plasma HIV-1 RNA levels < 500 copies/ml and < or = 50 copies/ml and changes in CD4 cell counts were compared. RESULTS: In an analysis of the primary endpoint, 61% of patients on d4T + ddI + IDV and 45% of patients on ZDV + 3TC + IDV had all HIV-1 RNA values obtained between weeks 40 and 48 < 500 copies/ml [95% confidence interval (CI) for the difference between proportions, 1.7-30.3%; P = 0.038]. In an intent-to-treat analysis, the percentage of all patients randomized with all HIV-1 RNA levels < 500 copies/ml between 40 and 48 weeks were 53% for the d4T + ddI + IDV arm and 41% for the ZDV + 3TC + IDV arm (95% CI, -1.4% to 25.7%; P = 0.068). At 48 weeks 41% and 35% were < or = 50 copies/ml for the stavudine- and ZDV-containing arms respectively (P > 0.2). The median time-weighted average increases in CD4 cells count over 48 weeks were 150 x 10(6)/l cells for the d4T arm and 106 x 10(6)/l cells for the ZDV arm (P= 0.001). The occurrence of serious adverse events was not significantly different between arms. CONCLUSION: The combination of stavudine, ddl and IDV resulted in potent antiretroviral effects over a 48-week period, comparable or superior to zidovudine, 3TC and IDV supporting the use of stavudine, ddI and a protease inhibitor as an initial antiretroviral treatment.

Adolescent↗
PubMed2000

Association between HIV in pregnancy and antiretroviral therapy, including protease inhibitors and low birth weight infants.

OBJECTIVE: To determine the incidence of low birth weight infants born to HIV seropositive women and to demonstrate any effects of antiretroviral therapy on birth weight. METHODS: Retrospective review of all obstetrical medical records from January 1, 1995 through June 30, 1998 to identify HIV seropositive women. We evaluated their antiretroviral therapy, CD4 counts, and birth weights of their newborns. We conducted detailed review of the clinical and laboratory findings for the HIV-infected untreated patients, women who received ZDV antepartum alone, and those who received PIs as part of antiretroviral treatment. RESULTS: The frequency of low birth weight infants was significantly increased in HIV seropositive compared to HIV seronegative parturients. Low birth weight infants were more frequent among HIV infected women with lower CD4 counts but the association was not statistically significant. Women who received no antepartum treatment, antepartum only ZDV, and those treated with PIs had significantly more low birth weight infants than did comparison groups. HIV seropositive women also had high frequencies of several obstetrical risk factors for low birth weight infants. CONCLUSION: The present study showed a significantly increased frequency of low birth weight infants among HIV infected women and especially the subgroups of infected women who received no antepartum treatment, antepartum ZDV only, and those treated with PIs. This association, however, may be related to the presence of many other preterm obstetrical risk factors noted in this study. Increasing numbers of HIV seropositive women are being treated with PIs according to the Centers for Disease Control (CDC) guidelines. If PIs are a cause of low birth weight infants, women taking these drugs may have incremental risk of low birth weight.

Adolescent↗
PubMed2000

Effect of cigarette promotions on smoking uptake among adolescents.

BACKGROUND: The purpose of this study was to evaluate the association between receptivity to cigarette promotions and smoking uptake in a cohort of adolescents. METHODS AND MEASURES: This was a prospective cohort study of 480 4th- to 11th-grade students conducted in three rural Vermont K-12 schools. Cigarette use was determined by self-report at baseline, 12 months (survey 2), and 21 months (survey 3). Proportional odds models were used to evaluate smoking uptake as a function of baseline measures of cigarette use, receptivity to cigarette promotions, and confounding factors, including grade, parental education, peer smoking, and family smoking. Adolescents were receptive to cigarette promotions if they owned or were willing to use a personal item bearing a cigarette brand logo [cigarette promotional item (CPI)]. Smoking status was measured using a 6-point ordinal index that combined experience and attitudes: 0 = never smoker/not susceptible to smoking, 1 = never smoker/susceptible to smoking, 2 = puffer (1 cigarette or less in lifetime), 3 = non-current experimenter (2-99 cigarettes in lifetime/none in past 30 days), 4 = current experimenter, and 5 = smoker (> or =100 cigarettes in lifetime). RESULTS: The 480 students were equally distributed across grade at baseline. Environmental exposure to smoking was high, and 30% were receptive to cigarette promotions at baseline. Higher levels on the smoking index at baseline were associated with higher grade in school, peer smoking, and receptivity to cigarette promotions. One hundred eighty-five students (38.5%) had moved to a higher category on the smoking index by survey 3, of whom 30 had become smokers. Receptivity to cigarette promotions at baseline was significantly associated with higher smoking uptake, with 48.7% of receptive students moving up one or more categories on the smoking index [adjusted proportional odds 1.9 (95% CI 1.3, 2.9)]. Acquisition of receptivity to cigarette promotions was also associated with increased smoking uptake, with those becoming receptive in surveys 2 or 3 having significantly higher odds of progression [3.6 (1.8, 7.0) and 2.9 (1.5, 5.5), respectively] compared with those who did not change. Conversely, those who were receptive at one point but became non-receptive in surveys 2 or 3 had lower odds of progression [0.4 (0.2, 0.9) and 0.5 (0.3, 1.1), respectively]. CONCLUSIONS: This study supports a close linkage between tobacco promotional activities and uptake of smoking among adolescents beyond baseline descriptions of receptivity to cigarette promotions. Over time, the likelihood of smoking uptake is increased when an adolescent acquires a CPI or becomes willing to use one and is decreased when an adolescent who owns a CPI loses it or becomes unwilling to use it. This provides strong evidence that elimination of cigarette promotional campaigns could reduce adolescent smoking.

Adolescent↗
PubMed2000

Improved detection and differentiation of poleroviruses infecting beet or rape by multiplex RT-PCR.

Three distinct species of virus inducing yellowing of beet, Beet mild yellowing virus (BMYV), Brassica yellows virus (BrYV, synonym BWYV) and Beet chlorosis virus (BChV) have been characterised from the genus Polerovirus. Until recently, no available tools were available to allow accurate and reliable distinction of the three species. Based on previous nucleotide sequence alignments and phylogenetic studies, we show that the use of molecular methods enabled the discrimination of these three beet Polerovirus species, but with differences in efficiency and specificity. Primers CP+ and CP- encompassing ORF-3, which encodes the coat protein, allowed the amplification by RT-PCR of a fragment of 563 bp for all isolates. Molecular methods such as SSCP or RFLP were able to discriminate these fragments by utilizing the differences in sequence. However, SSCP is a highly sensitive technique and was not suitable for the distinction of the Polerovirus species, because all isolates tested displayed a unique pattern. Analysis of the ORF3 RT-PCR products, digested with SmaI, RsaI and AccI restriction enzymes revealed four distinct patterns specific for the three species. However, point mutations can alter the RFLP patterns, making the interpretation of the results difficult. Primers were designed to amplify specifically sequences corresponding to ORF-0 of the three viral species. By using the three new sets of ORF-0 specific primers and CP+/CP- primers in a single multiplex RT-PCR, the detection and discrimination of the three beet Polerovirus species was possible in infected plants. The multiplex RT-PCR method provides a reliable and highly sensitive method to detect and identify viral species and will be of great interest for epidemiological studies of beet poleroviruses.

Brassica↗
PubMed2000

Ineffectiveness of the SUPPORT intervention: review of explanations.

BACKGROUND: The aim of the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments -- SUPPORT -- was to improve the care of seriously ill patients by improving decision-making for patients with life-threatening illnesses. Several theories have been proposed to explain why the SUPPORT intervention was unsuccessful at improving outcomes. OBJECTIVE: To review and discuss explanations offered by others regarding why the SUPPORT intervention failed to have a discernible impact on its prespecified outcome measures. DESIGN: A descriptive review of published articles and book chapters, with synthesis of data-based and conceptual insights. METHODS: The Medline, Bioethicsline, and Ethx databases were searched for citations to SUPPORT articles between 1994 and the end of 1998. This search was supplemented by other published materials that had come to the authors' attention. RESULTS: The critiques and explanations regarding the reasons the SUPPORT intervention did not improve outcomes were catalogued and organized into 11 major categories, the first 10 of which are explored in the present study: (1) the inception cohort was biased against an effect of the intervention, (2) the intervention was not implemented as designed, (3) the intervention failed because nurses were too readily ignored, (4) the intervention was too polite, (5) the intervention presented information ineffectively, (6) the intervention did not focus on primary care physicians, (7) the intervention falsely dichotomized do not resuscitate (DNR) decisions, (8) the intervention needed more years on site or an earlier start with each patient, (9) the intervention required more appropriate outcome measures, (10) the intervention was irrelevant because usual care is not seriously flawed, (11) the conceptual model behind SUPPORT was fundamentally flawed in aiming to improve individual, patient-level decision-making as the way to improve seriously ill, hospitalized patients' experiences. CONCLUSIONS: Although some of the critiques were found to raise important concerns, we conclude in each case that the explanation offered is inadequate to explain the failure of the intervention. We urge further reflection on the fundamental assumptions that informed the design of that intervention and refer the reader to a more comprehensive treatment of that issue in the companion paper in this volume.

Communication↗
PubMed2000

Rethinking fundamental assumptions: SUPPORT's implications for future reform. Study to Understand Prognoses and Preferences and Risks of Treatment.

BACKGROUND: The intervention in SUPPORT, the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments, was ineffective in changing communication, decision-making, and treatment patterns despite evidence that counseling and information were delivered as planned. The previous paper in this volume shows that modest alterations in the intervention design probably did not explain the lack of substantial effects. OBJECTIVE: To explore the possibility that improved individual, patient-level decision-making is not the most effective strategy for improving end-of-life care and that improving routine practices may be more effective. DESIGN: This paper reflects our efforts to synthesize findings from SUPPORT and other sources in order to explore our conceptual models, their consistency with the data, and their leverage for change. RESULTS: Many of the assumptions underlying the model of improved decision-making are problematic. Furthermore, the results of SUPPORT suggest that implementing an effective intervention based on a normative model of shared decision-making can be quite difficult. Practice patterns and social expectations may be strong influences in shaping patients' courses of care. Innovations in system function, such as quality improvement or changing the financing incentives, may offer more powerful avenues for reform. CONCLUSIONS: SUPPORT's intervention may have failed to have an impact because strong psychological and social forces underlie present practices. System-level innovation and quality improvement in routine care may offer more powerful opportunities for improvement.

Decision Making↗
PubMed2000

The Groningen Enjoyment Questionnaire: a measure of enjoyment in leisure-time physical activity.

The purpose of this study was to develop a short and easily used questionnaire to measure enjoyment in leisure-time physical activity. The first part of the study involved the questionnaire's composition. A set of 30 positively formulated potential items was generated and subsequently completed by 59 subjects. We used these results to trim the questionnaire to 10 items. In the second part of the study, the questionnaire was administered to 82 subjects and research was done into reliability and validity. The results indicate that the Groningen Enjoyment Questionnaire can be considered reliable and valid.

Aged↗
PubMed2000

A Dutch version of the Social Support for Exercise Behaviors Scale.

We studied the reliability of a Dutch version of the Social Support for Exercise Behaviors Scale, originally developed by Sallis, Grossman, Pinski, Patterson, and Nader, using a sample of 461 older adults between 55 and 65 years of age. Cronbach alpha for the three subscales was calculated, respectively, as .69, .71, and .26, which are lower than the alphas reported in the original study. This may be due to the cultural differences between The Netherlands and the United States and differences between the samples of the two studies.

Adult↗
PubMed2000

Description of the SUPPORT intervention. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments.

BACKGROUND: The purpose of Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) was to improve outcomes for seriously ill hospitalized adults by improving information and decision-making. The SUPPORT intervention has been characterized only briefly in previous publications. OBJECTIVE: To characterize the intervention in SUPPORT and its implementation. DESIGN: Reports derived from training and administrative materials, quantitative descriptions of implementation activities, and qualitative analysis of narrative reports and focus group participation by the intervention nurses. SETTING AND PATIENTS: SUPPORT enrolled 2652 patients in the intervention arm and 2152 in the control arm of a block-randomized trial of enhanced information, counseling, and support. The patients were hospitalized with one of nine serious illnesses in one of five US teaching hospitals between 1992 and 1994. MEASUREMENTS: (1) Reports on training and supervisory materials; (2) Rates of intervention component completion from contact logs and reports completed by the intervention nurses; and (3) grounded theory analysis of patient narratives, overview questionnaires, and focus group transcripts from the intervention nurses. RESULTS: Prognostic reports were delivered on time to the caregiving team in 83% of cases on Day 3. Reports of surrogate interviews of patient preferences and understanding were delivered on time to the caregiving team in 72% of first week cases. Patients' own reports of preferences were unavailable for 56% of cases in the first week. Overall, 39% of the rest of the patients had their interview information delivered on time to the caregiving team. The SUPPORT intervention nurses averaged 8.5 contacts with patients, 7.6 with surrogates, 3.5 with physicians, and 11.7 with other staff. The intervention nurses felt that they were fully involved in 81% of cases and had a limited role in another 14%. The major issues for patients were: understanding their situation, communication and decision-making, advance planning, do not resuscitate orders, and general support, including support for loss and grieving. The narrative sources showed that the nurses were enthusiastic, dedicated, and strong in their support of the study objectives. They identified various barriers to effectiveness and voiced doubt that the analytic targets would show an effect from the intervention. CONCLUSIONS: The SUPPORT intervention was implemented vigorously and completely.

Adult↗
PubMed1999

Distinct roles for STAT1, STAT3, and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9.

Interleukin-9 (IL-9) activates three distinct STAT proteins: STAT1, STAT3, and STAT5. This process depends on one tyrosine of the IL-9 receptor, which is necessary for proliferation, gene induction, and inhibition of apoptosis induced by glucocorticoids. By introduction of point mutations in amino acids surrounding this tyrosine, we obtained receptors that activated either STAT5 alone or both STAT1 and STAT3, thus providing us with the possibility to study the respective roles of these factors in the biological activities of IL-9. Both mutant receptors were able to prevent apoptosis, but only the mutant that activated STAT1 and STAT3 was able to support induction of granzyme A and L-selectin. In line with these results, constitutively activated STAT5 blocked glucocorticoid-induced apoptosis. In Ba/F3 cells, significant proliferation and pim-1 induction were observed with both STAT-restricted mutants, though proliferation was lower than with the wild-type receptor. These results suggest that survival and cell growth are redundantly controlled by multiple STAT factors, whereas differentiation gene induction is more specifically correlated with individual STAT activation by IL-9.

Animals↗
PubMed1999

Phenotypic variation in hereditary frontotemporal dementia with tau mutations.

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP-17 with mutations in the tau gene (deltaK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 +/- 5.5 years) and longer duration of illness (12.7 +/- 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and deltaK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.

Adult↗
PubMed1999

Groningen Active Living Model (GALM): stimulating physical activity in sedentary older adults.

BACKGROUND: A significant number of Dutch older adults can be considered sedentary when it comes to regular participation in leisure-time physical activity. Sedentariness is considered a potential public health burden-all the more reason to develop a strategy for stimulating older adults toward becoming more involved in leisure-time physical activity. The Groningen Active Living Model (GALM) is a behavioral change strategy for stimulating participation in leisure-time physical activity. METHODS: The GALM strategy is based on a process model of behavioral change in which behavioral change is seen as a multidimensional and dynamic process. The strategy has three phases: recruitment, introduction, and follow-up, and lasts 18 months. RESULTS: Preliminary results indicate that, up until the summer of 1998, about 4000 older adults were participating in 76 local GALM projects. Further research will be done to assess the validity of the model and its effects on the leisure-time physical activity pattern, ADL performance, and health in newly active older adults. CONCLUSIONS: The GALM strategy is a feasible strategy for stimulating leisure-time physical activity participation on a large-scale basis. The strategy is being implemented in The Netherlands on a nationwide basis.

Activities of Daily Living↗
PubMed1999

Positive and negative outcome expectations of smoking: implications for prevention.

BACKGROUND: To inform the development of messages for tobacco prevention programs, we examined seven positive and five negative outcome expectations of smoking as risk factors for smoking uptake. METHODS: A cross-sectional, self-administered survey of 471 students in grades 6-12 who were never or experimental smokers was performed. Logistic regression was used to examine the relationship between outcome expectations and susceptibility to becoming a smoker in the future, a measure of intent and resistance to peer smoking. RESULTS: A total of 36.1% of the sample was susceptible to smoking. All positive outcome expectations showed a strong and significant association with susceptibility. Students were most likely to be susceptible if they believed they would enjoy smoking (OR = 29.4). Three of the five negative outcome expectations were significantly associated with susceptibility, but the strength of these associations was much lower than that observed for the positive expectations (OR = 0.5 to 0.6). A strong belief in the negative outcomes of smoking did not alter the association between susceptibility and positive outcome expectations. CONCLUSIONS: These findings suggest that teaching adolescents and teens about the negative consequences of smoking is unlikely to change their intent to smoke. Preventive efforts should identify ways to address the positive expectations adolescents have about smoking, possibly by offering alternative means for achieving these outcomes.

Adolescent↗
PubMed1999

CYP 3A proteins are expressed in human neutrophils and lymphocytes but are not induced by rifampicin.

Cytochrome P-450 3A (CYP 3A) enzymes, the prominent subfamily in the cytochrome system, are expressed in various extrahepatic tissues. Until now, their expression has been demonstrated in human polymorphic neutrophils (PMNs) but not in lymphocytes using immunohistochemistry and immunoblot analysis. Moreover, their potential modulation has not been determined yet. To study such an expression in different peripheral blood cell populations, rifampicin (600 mg/day during 6 days) was given to 8 healthy subjects. PMNs and lymphocytes were isolated by centrifugation of whole white blood cell fractions using Ficoll gradients before drug administration, immediately after, and 3 days after drug withdrawal. PMN and lymphocyte smears and homogenates were subjected to immunostaining and immunoblotting, respectively, with a mouse monoclonal antibody recognizing all CYP 3A proteins. These proteins were quantified by densitometric analysis. Before and after rifampicin administration, a positive cytoplasmic staining was observed in all PMNs and in about 50% of lymphocytes. CYP 3A expression in lymphocytes was further confirmed by positive immunoblots for lymphocyte homogenates. Neither in PMNs nor in lymphocytes, induction of CYP 3A protein expression was observed after rifampicin treatment despite overall induction of CYP 3A activity assessed by the urinary excretion of 6beta-hydroxycortisol. These results demonstrate that CYP 3A proteins are constitutively expressed not only in PMNs but also in lymphocytes. However, in both cell lineages CYP 3A protein expression was not induced by rifampicin.

Adult↗