Biomedical subjects

Paul W Stewart

Publications and source records attributed to Paul W Stewart.

15 recordsLinked to original sources

PubMed2006

Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.

CONTEXT: During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed. OBJECTIVE: To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo. DESIGN, SETTING, AND PARTICIPANTS: A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units. INTERVENTION: Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter. RESULTS: None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. CONCLUSIONS: Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.

Acetaminophen↗

PubMed2006

A method for fitting regression splines with varying polynomial order in the linear mixed model.

The linear mixed model has become a widely used tool for longitudinal analysis of continuous variables. The use of regression splines in these models offers the analyst additional flexibility in the formulation of descriptive analyses, exploratory analyses and hypothesis-driven confirmatory analyses. We propose a method for fitting piecewise polynomial regression splines with varying polynomial order in the fixed effects and/or random effects of the linear mixed model. The polynomial segments are explicitly constrained by side conditions for continuity and some smoothness at the points where they join. By using a reparameterization of this explicitly constrained linear mixed model, an implicitly constrained linear mixed model is constructed that simplifies implementation of fixed-knot regression splines. The proposed approach is relatively simple, handles splines in one variable or multiple variables, and can be easily programmed using existing commercial software such as SAS or S-plus. The method is illustrated using two examples: an analysis of longitudinal viral load data from a study of subjects with acute HIV-1 infection and an analysis of 24-hour ambulatory blood pressure profiles.

Blood Pressure Monitoring, Ambulatory↗

PubMed2006

Response inhibition during Differential Reinforcement of Low Rates (DRL) schedules may be sensitive to low-level polychlorinated biphenyl, methylmercury, and lead exposure in children.

BACKGROUND: Animal studies have shown that exposure to common, low-level environmental contaminants [e.g., polychlorinated biphenyls (PCBs), lead] causes excessive and inappropriate responding on intermittent reinforcement schedules. The Differential Reinforcement of Low Rates task (DRL) has been shown to be especially sensitive to low-level PCB exposure in monkeys. OBJECTIVES: We investigated the relationships between prenatal PCB and postnatal Pb exposure performance on a DRL schedule in children. We predicted that a) prenatal PCB exposure would reduce interresponse times (IRTs) and reinforcements earned, and b) postnatal Pb exposure would reduce IRTs and reinforcements earned. METHODS: We tested 167 children on a DRL20 (20 sec) reinforcement schedule, and recorded IRTs and the number of reinforced responses across the session. We measured prenatal PCB exposure (cord blood), methylmercury (MeHg) (maternal hair), and postnatal Pb exposure (venous blood), and > 50 potentially confounding variables. RESULTS: Results indicated impaired performance in children exposed to PCBs, MeHg, and Pb. Children prenatally exposed to PCBs responded excessively, with significantly lower IRTs and fewer reinforcers earned across the session. In addition, exposure to either MeHg or Pb predicted statistically significant impairments of a similar magnitude to those for PCBs, and the associated impairments of all three contaminants (PCB, MeHg, and Pb) were statistically independent of one another. CONCLUSIONS: These results, taken with animal literature, argue the high sensitivity of DRL performance to low-level PCB, MeHg, and Pb exposure. Future research should employ behavioral tasks in children, such as DRL, that have been demonstrably sensitive to low-level PCB, MeHg, and Pb exposure in animals.

Analysis of Variance↗

PubMed2005

Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5.

OBJECTIVE: Saquinavir, a widely prescribed human immunodeficiency virus 1 protease inhibitor, has a low and variable oral bioavailability that has been attributed to extensive first-pass extraction mediated by hepatic or intestinal cytochrome P450 (CYP) 3A4 and intestinal P-glycoprotein (P-gp). The polymorphic CYP3A5 has also been shown to influence the saquinavir metabolite/parent urinary ratio, suggesting a role for CYP3A5. METHODS: Twenty healthy subjects received a single oral dose of saquinavir (600 mg) with water (control) and, on a separate occasion, with Seville orange juice (a selective intestinal CYP3A4/5 inhibitor). Hepatic CYP3A4 activity was evaluated by use of the erythromycin breath test. Duodenal biopsy specimens were used to assess relative intestinal CYP3A4 and CYP3A5 protein contents. Relative P-gp content was also assessed in the biopsy specimens and in lymphocytes. Genetic polymorphisms in MDR1 (in exon 21 and 26), CYP3A5 (*1 and *3), and CYP3A4*1B were identified by direct sequencing. Saquinavir plasma concentrations were measured by tandem liquid chromatography-mass spectrometry. Pharmacokinetic parameter estimates (maximum concentration, time to reach maximum concentration, area under the concentration-time curve, apparent oral clearance [CL/F]) were computed by standard noncompartmental methods. Stepwise multiple regression analysis was used to identify the hepatic or intestinal variables that predicted variation in saquinavir pharmacokinetic measures. RESULTS: Baseline saquinavir CL/F was not correlated with liver CYP3A4 activity (the erythromycin breath test result), intestinal CYP3A4 content, or intestinal P-gp content (r(2) = 0.08, 0.08, and 0.007, respectively; P > .2). MDR1 genotype and lymphocyte P-gp content were also not predictive. Among the 6 subjects expressing intestinal CYP3A5, the mean saquinavir CL/F was almost twice as high as for the 14 nonexpressors (36.7 L/h [95% confidence interval (CI), 18.7-54.6 L/h] and 19.3 L/h [95% CI, 11.2-27.4 L/h], respectively; P = .03). However, among the 6 CYP3A5 expressors, there was an unexpected negative correlation between CL/F and intestinal CYP3A5 content (r(2) = 0.58, P = .05). Seville orange juice decreased the mean CL/F in all 20 subjects from 24.5 L/h (95% CI, 16.7-32.3 L/h) to 14.7 L/h (95% CI, 8.4-20.6 L/h) (P = .05). The effect size did not appear to be influenced by CYP3A5 expression. CONCLUSIONS: The CYP3A5*1 genotype is associated with increased saquinavir CL/F. This does not appear to reflect intestinal CYP3A5 expression and presumably reflects the contribution of hepatic CYP3A5. The interaction with Seville orange juice in subjects not expressing CYP3A5 supports a role for intestinal CYP3A4. However, the modest nature of the interaction, combined with the inability to detect a correlation between CL/F and CYP3A4 enterocyte content, supports our recent in vitro work suggesting a smaller contribution of intestinal CYP3A4 than has been assumed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Cigarette smoking, stress-induced analgesia and pain perception in men and women.

This study examined gender differences in smoking-related analgesia and stress-induced analgesia (SIA), as a function of pain modality. Forty men (20 smokers, 20 nonsmokers) and 37 women (17 smokers) were tested twice for pain sensitivity to tourniquet ischemia, thermal heat, and cold pressor tests; once following mental stress and once following rest control, counterbalancing order. Cardiovascular and neuroendocrine responses to mental stress were also examined. While expected gender differences in pain sensitivity were observed, women smokers had greater threshold and tolerance times to ischemic pain than women nonsmokers (P<0.05) when pain testing followed rest. Male smokers had greater threshold and tolerance to cold pressor pain than male nonsmokers (P<0.05) after both rest and stress. Only women showed evidence for SIA, since women nonsmokers demonstrated greater ischemic pain threshold and tolerance following mental stress versus rest (P<0.05), and all women reported lower thermal heat pain unpleasantness after stress versus rest (P=0.05). Only nonsmokers showed expected inverse relationships between sympathetic and hypothalamic-pituitary-adrenal (HPA) axis reactivity measures and sensitivity to pain. Smokers showed evidence for blunted HPA-axis function at rest and stress. These results indicate that analgesia related to both being a smoker and stress is influenced by gender and pain modality. The reduced pain perception in smokers and absence of relationships between endogenous pain regulatory mechanisms and pain sensitivity may reflect a maladaptive response to chronic smoking.

Adrenocorticotropic Hormone↗

PubMed2004

Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression?

The higher systemic clearance of some CYP3A4 [whether also P-glycoprotein (P-gp)] drug substrates in women versus men is attributed in part to a higher hepatic CYP3A4 content in women. This, combined with the general paucity of reported sex differences in the apparent oral clearance of CYP3A4 substrates, suggested a sex-dependent expression of CYP3A4 in the intestine, but in a pattern opposite to that in the liver. Accordingly, duodenal biopsies obtained from healthy men (n = 46) and women (n = 45) were analyzed, by Western blot, for relative CYP3A4, as well as for CYP3A5 and P-gp, expression levels. Among all subjects, CYP3A4 and P-gp varied 8- and 10-fold, respectively. CYP3A5, which was readily detected in 27% of these predominantly white individuals, varied 7-fold. For all three proteins, a sex difference was not detected (p >/= 0.55). The lack of a difference remained for CYP3A4 and P-gp when the analysis was restricted to white individuals (n = 74) or to individuals with undetectable CYP3A5. Comparing the 21 premenopausal women (all were aged <45 years) with the 43 men aged <45 years, again no sex differences were detected in CYP3A4 and P-gp. Comparing the pre- with postmenopausal women, mean CYP3A4 content was 20% lower in the postmenopausal individuals (p = 0.01). The lack of a sex-dependent difference in proximal intestinal CYP3A4 could account, in part, for the lack of reported sex differences in the oral, relative to systemic, clearance of some CYP3A4 substrates. Ramifications of lower intestinal CYP3A4 content in post- versus premenopausal women require further investigation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Brief but efficient: acute HIV infection and the sexual transmission of HIV.

BACKGROUND: We examined whether viral dynamics in the genital tract during the natural history of acute human immunodeficiency virus type 1 (HIV-1) infection could explain efficient heterosexual transmission of HIV. METHODS: We measured HIV-1 concentration in blood and semen samples from patients with acute and long-term HIV-1 infection. We explored the effect of changes in viral dynamics in semen on the probability of transmission per coital act, using a probabilistic model published elsewhere. RESULTS: Considered over time from infection, semen HIV-1 concentrations, in men with acute infection, increase and decrease in approximate parallel with changes occurring in blood. Modeling suggests that these acute dynamics alone are sufficient to increase probability of heterosexual transmission by 8-10-fold between peak (day 20 after infection, based on the model) and virologic set points (day 54 and later after infection). Depending on the frequency of coitus, men with average semen HIV-1 loads and without sexually transmitted diseases (STDs) would be expected to infect 7%-24% of susceptible female sex partners during the first 2 months of infection. The predicted infection rate would be much higher when either partner has an STD. CONCLUSIONS: Empirical biological data strongly support the hypothesis that sexual transmission by acutely infected individuals has a disproportionate effect on the spread of HIV-1 infection. Acute hyperinfectiousness may, in part, explain the current pandemic in heterosexual individuals.

Cohort Studies↗

PubMed2004

6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect.

OBJECTIVE: Our objective was to assess the contribution of 6',7'-dihydroxybergamottin (DHB) to the inhibitory effect of grapefruit juice toward intestinal cytochrome P450 (CYP) 3A4. METHODS: An aqueous extract was prepared from grapefruit juice by centrifugation, filtration, and repeated washing of the particulate with water. The concentrations of various furanocoumarins in this grapefruit juice "serum" and in whole grapefruit juice were measured by HPLC and their identities confirmed by liquid chromatography-tandem mass spectrometry. Five healthy volunteers were given a single tablet of felodipine (10 mg) with whole grapefruit juice, orange juice-containing serum, or plain orange juice (control). The pharmacokinetic outcomes of felodipine were evaluated by noncompartmental methods. The effects of serum and purified DHB (at the same concentrations as those measured in the orange juice-containing serum used in the clinical study) were compared, in vitro, with regard to (1) the reversible and mechanism-based inhibition of the catalytic activity of complementary deoxyribonucleic acid-expressed CYP3A4 and (2) the time-dependent loss of immunoreactive CYP3A4 protein in modified Caco-2 cells. RESULTS: The concentration of DHB in serum was comparable to that measured in whole grapefruit juice (38 micromol/L versus 43 micromol/L), and the concentrations of other known furanocoumarins were well below the lowest published concentration required to inhibit catalytic activity by 50%. Relative to plain orange juice, orange juice-containing serum significantly increased the median felodipine area under the plasma concentration-time curve by 1.9-fold (P =.04) and increased the maximum concentration by 1.7-fold (P =.01). In vitro, serum and purified DHB had similar inhibitory effects toward CYP3A4 activity with respect to both reversible inhibition (95% confidence interval, 85% +/- 5.7% and 75% +/- 4.5%, respectively) and mechanism-based inhibition after a 15-minute preincubation (95% confidence interval, 79% +/- 6.8% and 78% +/- 5.7%, respectively). In Caco-2 cells the time-averaged extents of CYP3A4 protein loss caused by serum and purified DHB were identical (43%). CONCLUSION: The interaction between grapefruit juice serum and felodipine can be attributed largely to DHB. This establishes DHB as an important contributor to the grapefruit juice effect.

Adult↗

PubMed2004

Making inferences about projected completors in longitudinal studies.

In this article, we present methodology for making inferences about projected completors in the presence of attrition. The approach is motivated by a clinical trial that investigates a treatment for disability among individuals who sustain severe head injuries. Although most studies attempt to make inferences about the entire study population, our application poses important scientific questions targeting individuals who are likely to complete the study or to remain on protocol for a specified time period. We propose using measures of each individual's dropout inclination to identify projected completors and then building a stratified response model based on projected completion status. We present several prediction measures along with procedures for evaluating accuracy with respect to observed dropout. Estimation of model parameters proceeds using maximum likelihood and restricted maximum likelihood methods. We illustrate the utility of our proposed analysis by using the motivating disability data example.

Algorithms↗

PubMed2003

Human immunodeficiency virus type 1 RNA in breast-milk components.

We conducted the present study to determine which of the 4 components of breast milk (whole milk, skim milk, lipid layer, and breast-milk cells) had the highest sensitivity and concentration of human immunodeficiency virus (HIV) type 1 RNA burden and to determine biological correlates to these factors. The probability of detection of HIV (sensitivity) and the concentration of HIV-1 RNA were both associated with the choice of milk component, CD4(+) cell count, concentration of blood serum HIV-1 RNA, and the presence of breast inflammation. Whole milk demonstrated higher sensitivity and mean concentration than any other single component. Sensitivity was enhanced by analyzing all 4 components of breast milk.

Adult↗

PubMed2003

CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults.

A single-nucleotide polymorphism (A6986G) in the cytochrome p-450 3A5 (CYP3A5) gene distinguishes an expressor (*1) and a reduced-expressor (*3) allele and largely predicts CYP3A5 content in liver and intestine. CYP3A5 is the prevailing CYP3A isoform in kidney. We report that, among renal microsomes from 21 organ donors, those from *1/*3 individuals had at least eightfold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from *3/*3 individuals (P = 0.0001 and P = 0.0137, respectively). We also report significant associations between the A6986G polymorphism and systolic blood pressure (P = 0.0007), mean arterial pressure (P = 0.0075), and creatinine clearance (P = 0.0035) among 25 healthy African-American adults. These associations remained significant when sex, age, and body mass index were taken into account. The mean systolic blood pressure of homozygous CYP3A5 expressors (*1/*1) exceeded that of homozygous nonexpressors (*3/*3) by 19.3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population.

Adolescent↗

PubMed2003

A new method for choosing sample size for confidence interval-based inferences.

Scientists often need to test hypotheses and construct corresponding confidence intervals. In designing a study to test a particular null hypothesis, traditional methods lead to a sample size large enough to provide sufficient statistical power. In contrast, traditional methods based on constructing a confidence interval lead to a sample size likely to control the width of the interval. With either approach, a sample size so large as to waste resources or introduce ethical concerns is undesirable. This work was motivated by the concern that existing sample size methods often make it difficult for scientists to achieve their actual goals. We focus on situations which involve a fixed, unknown scalar parameter representing the true state of nature. The width of the confidence interval is defined as the difference between the (random) upper and lower bounds. An event width is said to occur if the observed confidence interval width is less than a fixed constant chosen a priori. An event validity is said to occur if the parameter of interest is contained between the observed upper and lower confidence interval bounds. An event rejection is said to occur if the confidence interval excludes the null value of the parameter. In our opinion, scientists often implicitly seek to have all three occur: width, validity, and rejection. New results illustrate that neglecting rejection or width (and less so validity) often provides a sample size with a low probability of the simultaneous occurrence of all three events. We recommend considering all three events simultaneously when choosing a criterion for determining a sample size. We provide new theoretical results for any scalar (mean) parameter in a general linear model with Gaussian errors and fixed predictors. Convenient computational forms are included, as well as numerical examples to illustrate our methods.

Biometry↗

PubMed2002

Elevated virus loads of Kaposi's sarcoma-associated human herpesvirus 8 predict Kaposi's sarcoma disease progression, but elevated levels of human immunodeficiency virus type 1 do not.

Kaposi's sarcoma-associated herpesvirus (KSHV) is found in Kaposi's sarcoma (KS), multicentric Castleman's disease, and primary effusion lymphomas. To prospectively evaluate KSHV load as a biomarker for KS clinical status and prognosis in a cohort of men with AIDS-related KS, 2 quantitative polymerase chain reaction (PCR) assays were developed and tested to determine KSHV peripheral blood mononuclear cell (PBMC) virus loads. Most patients (13/15) with good-prognosis KS had < or =1.5 log KSHV copies/10(5) PBMC by both quantitative competitive (QC) and real-time Applied Biosystems (ABI) PCR. Both assays provided 94% specificity for identifying the 16 patients without KS progression during 20 months of follow-up. QC-PCR and ABI-PCR exhibited 100% and 80% levels of diagnostic sensitivity, respectively, for identifying the 5 patients whose KS progressed. Neither dichotomized human immunodeficiency virus loads nor dichotomized CD4 counts predicted either KS progression or KS clinical stage (all positive predictive values < 30%). These results are evidence that the quantity of circulating KSHV in KS patients is biologically meaningful and is measurable with sufficient accuracy to provide clinically useful information.

Adult↗

PubMed2002

Growth failure in early life: an important manifestation of Turner syndrome.

The goals of this study were to test the hypothesis that girls with Turner syndrome (TS) experience growth failure early in life and to establish model-based normative growth charts for 0- to 8-year-old American girls with TS. Full-term girls with TS who had 5 or more measurements of height obtained during their first 10 years of life prior to initiation of growth hormone, estrogen and/or androgen therapy were eligible for this study. A nonlinear mixed-effects model comprising the first two components of the infancy-childhood-puberty (ICP) model of growth was fitted to the longitudinal height measurements and compared with those of healthy American girls. Height measurements (n = 1,146) from 112 girls with TS (45,X: 57.1%; 45,X/46,XX: 12.5%; 46,X, iso(X): 4.5%, and other: 25.9%) were analyzed. Mean height SDS fell from -0.68 at birth to -1.60 at 1 year, -1.80 at 2 years and -1.95 at 3 years. When compared to controls (676 girls, 4,537 measurements), girls with TS grew more slowly due to three principal factors: a slow growth rate of the infancy component, a slow growth rate at the onset of the childhood component, and delayed onset of the childhood component. Traditional concepts of growth failure in TS should be revised. Physicians should consider the diagnosis of TS in any girl with unexplained failure to thrive or short stature, even in the first 3 years of life.

Aging↗

PubMedDate not supplied

Cognitive development in preschool children prenatally exposed to PCBs and MeHg.

A number of epidemiological studies have shown predictive relationships between prenatal exposure to polychlorinated biphenyls (PCBs) and subtle deficits in cognitive development in infancy through the preschool years [Child Dev. 56 (1985) 853; J. Pediatr. 116 (1990) 38; J. Pediatr. 134 (1999) 33; Toxicol. Lett. 102-103 (1998) 423; Neurotox. 21 (6) (2000) 1029-1038]. However, since not all studies have demonstrated these relationships (J. Pediatr. 119 (1991) 58-63), debate regarding the role of prenatal PCB exposure in cognitive development continues. The current study was designed to provide additional data to assist in resolving this question. Two hundred twelve children enrolled in the Oswego Newborn and Infant Development Project were assessed using the McCarthy Scales of Children's Abilities at 38 months of age, followed by a reassessment at 54 months of age. The relationship between prenatal exposure to PCBs (cord blood PCBs) and McCarthy performance was assessed at both ages after first controlling for a wide range of important predictors of cognitive development, including socioeconomic status (SES), maternal IQ, maternal education, home environment, cigarette smoking, and many others. Cord blood PCBs were statistically significant predictors of small but measurable deficits in McCarthy performance at 38 months of age. Moreover, a significant interaction between cord blood PCBs and maternal hair mercury (MeHg) was found, such that negative associations between prenatal MeHg exposure and McCarthy performance were found in subjects with higher levels of prenatal PCB exposure. No relationship between PCBs and/or MeHg and McCarthy performance was observed when the children were reassessed almost 1.5 years later (54 months of age). Inspection of the age-related trajectory of McCarthy performance revealed that the more highly exposed children caught up with the least exposed children by 54 months. Although the current data partially replicate the findings of Jacobson et al., Patandin et al., and Walkowiak et al. [J. Pediatr. 116 (1990) 38; J. Pediatr. 134 (1999) 33; Lancet 358 (2001) 1602], results reported here suggest that functional recovery may occur. Moreover, the interaction between PCB and MeHg cannot be considered conclusive until it has been replicated in subsequent investigations.

Age Factors↗