Altered morphine glucuronide and bile acid disposition in patients with nonalcoholic steatohepatitis.

The functional impact of altered drug transport protein expression on the systemic pharmacokinetics of morphine, hepatically derived morphine glucuronide (morphine-3- and morphine-6-glucuronide), and fasting bile acids was evaluated in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) compared to healthy subjects. The maximum concentration (Cmax ) and area under the concentration-time curve (AUC0-last ) of morphine glucuronide in serum were increased in NASH patients (343 vs. 225 nM and 58.8 vs. 37.2 µM*min, respectively; P ≤ 0.005); morphine pharmacokinetics did not differ between groups. Linear regression analyses detected an association of NASH severity with increased morphine glucuronide Cmax and AUC0-last (P < 0.001). Fasting serum glycocholate, taurocholate, and total bile acid concentrations were associated with NASH severity (P < 0.006). Increased hepatic basolateral efflux of morphine glucuronide and bile acids is consistent with altered hepatic transport protein expression in patients with NASH and may partially explain differences in efficacy and/or toxicity of some highly transported anionic drugs/metabolites in this patient population.

Virological outcomes and treatment algorithms utilisation in observational study of patients with chronic hepatitis C treated with boceprevir or telaprevir.

BACKGROUND: HCV-TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct-acting anti-viral agents (DAAs) in a US consortium of 90 academic and community medical centres. AIM: To assess utilisation of response-guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients. METHODS: Patients received peginterferon (PEG-IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow-up. RGT and treatment futility stopping rules was assessed at key time points. RESULTS: Of 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24-40) and 50% (95% CI: 44-56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42-50) and 60% (95% CI: 57-64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients. CONCLUSIONS: In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811.

Plasma HIV burden in Malawian children co-infected with rotavirus.

Fifty-eight HIV-infected children with acute rotavirus diarrhea were tested for plasma HIV RNA. There was no difference between acute and convalescent mean viral loads, and little change in CD4 cell counts. Compared with the 16 children who died within 4 weeks, 31 survivors had slightly lower viral loads at presentation and significantly higher CD4 cell counts. Low CD4 cell counts, but not HIV-1-RNA concentrations, were predictive of Death. Local, enteric rotavirus infection did not appear to affect blood HIV viral load or CD4 cell counts in this small group of children.

Variation of lipids and lipoproteins in premenopausal women compared with men and postmenopausal women. DELTA (Dietary Effects on Lipoproteins and Thrombogenic Activity) Investigators.

Numerous studies have reported cyclic fluctuations in lipids and lipoproteins as a function of the phase of the menstrual cycle. However, the reported patterns are quite variable and have led to an unclear picture of the influence of the menstrual cycle on the variability of lipids, and hence of the role of the menstrual cycle phase in the interpretation of serum lipids for premenopausal women. As part of the DELTA Study (Dietary Effects on Lipoproteins and Thrombogenic Activity), we evaluated the cyclic variation of circulating lipids and lipoproteins in 39 premenopausal women and compared intraindividual variances in these women, 18 postmenopausal women, and 46 men under conditions of tight dietary control. Cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, apolipoproteins A-1 (apo A-1) and B-100 (apo B-100), and lipoprotein (a) [Lp(a)] all demonstrated cycling in the premenopausal women. However, the observed cycling accounts for only a small fraction of the total biologic variability of lipids in premenopausal women. The magnitude of total intraindividual variability based on coefficient of variation (CV) for these lipids in premenopausal women (CV, 4% to 8.1%) was similar to that found for men (CV, 4.3% to 9.1%) and for postmenopausal women (CV, 3.7% to 6.7%). These results suggest that protocols for screening and monitoring of serum lipids in premenopausal women need not differ from those used for men or postmenopausal women.

Classification tree prediction models for dental caries from clinical, microbiological, and interview data.

Caries prediction by Classification And Regression Tree (CART) analysis is an appropriate and powerful alternative or complement to the commonly used classification methods of logistic regression and discriminant analysis, both parametric and nonparametric. The binary classification tree method discussed in this article is designed for complex data and does not require assumptions about the predictor variables or about the presence or absence of interactions among the predictor variables. Furthermore, the results give insight into the structures and interactions in the data and are easy to interpret and apply. In preliminary applications of the CART algorithms to data from The University of North Carolina Caries Risk Assessment Study, the method produced prediction rules having sensitivities and specificities that were similar to or slightly better than those associated with logistic and discriminant analyses. The classification trees constructed tended to involve far fewer predictor variables than required for adequate logistic and discriminant models. For example, for first-grade children in Aiken, South Carolina, nine variables were used to define a prediction rule having 64% sensitivity and 86% specificity. Ten-fold cross-validation estimates for future data were 58% and 79%, respectively. For first-grade children in Portland, Maine, two variables were used to define a prediction rule having 62% sensitivity and 77% specificity. The cross-validation estimates for future data were 58% and 78%, respectively. A brief, and previously unavailable, explanation of the CART method is given for the special case of a dichotomous outcome variable.

Cross generation lead ingestion: behavioral and physiological effects in mice.

We examined some developmental and behavioral sequelae of exposing Binghamton Heterogeneous Stock (HET) mice to a 0.5% aqueous lead acetate solution (as the only available fluid source) for either none, one, two, or three generations. Lead exposure, regardless of generation, resulted in decreased body weight and a delay in age of first eye opening relative to controls, but did not delay home nest return latencies. Drinking the lead solution, across two and three successive generations, resulted in a marked and apparently cumulative decrease in pup viability, as well as an increase in dam fatality rates. However, no such cumulative or residual effects were observed on the behavioral activity of those mice who managed to survive. Perhaps a selection effect for lead-tolerant mice occurred in the present study; such an effect could account for the apparent lack of cumulative and residual behavioral effects.

DMSA chelation during co-exposure to lead: increased locomotor activity in lead-exposed mice but not controls.

We investigated the effect of chelating agent meso-2,3 dimercaptosuccinic acid (DMSA) on indices of "hyperactive" behavior in lead-exposed and control Binghamton Heterogeneous Stock (Het) mice. As expected, 6 weeks of ingestion of 0.5% lead acetate in drinking water reduced immobility in a forced water swim relative to controls. DMSA did not attenuate this behavioral change. In fact, DMSA interacted with lead exposure to increase locomotor activity in the forced water swim. DMSA also apparently excacerbated lead's tendency to reduce immobility. While any generalizations to human populations should be cautioned, these results and others suggest the need for further research.

Acute and longer term effects of meso-2,3 dimercaptosuccinic acid (DMSA) on the behavior of lead-exposed and control mice.

We investigated the effect of chelating agent meso-2,3 dimercaptosuccinic acid (DMSA) on spatial learning and forced-swim immobility in Binghamton Heterogeneous Stock (HET) mice. Forced-swim immobility (characterized by increasingly frequent bouts of complete motionlessness in a forced-swim test, i.e., behavioral despair) is reduced by exposure to lead. In Experiment 1, male and female HETs (n = 81) were assigned to lead-exposed (0.5% lead acetate ad lib in drinking fluid), pair-fed (PF), or water control groups. Six weeks after the termination of lead exposure, half of each group was injected intraperitoneally (IP) with 50 mg/kg DMSA or vehicle once per day for 5 days. Following treatment, all animals were tested for acquisition and extinction in the Morris Water maze, followed by immobility testing in an inescapable forced-swim task. Neither Pb nor DMSA affected Morris maze performance. However, consistent with previously published work, Pb reduced immobility in the forced-water swim relative to both PF and water controls. Additionally, lead-exposed males, but not females, showed sustained improvement following DMSA treatment on immobility measures. Experiment 2 was designed to demonstrate the effect of the above DMSA protocol on blood-Pb, and also examined the immediate effects of DMSA on immobility during treatment. Thus, in Experiment 2, animals were exposed to an identical Pb and DMSA treatment protocol, but the effects of DMSA on immobility during the course of DMSA treatment were measured, and animals were sacrificed immediately after treatment so that blood-Pb measures could be taken. Under these circumstances, DMSA markedly reversed the lead-induced reduction in immobility immediately during the treatment phase. Although DMSA clearly reduced blood-lead in males, its influence on female blood levels was far less. Taken together, the data from these experiments suggest that DMSA ameliorates lead-induced immobility changes in mice, but that gender may modulate DMSA's effect on blood-lead and longer-term behavioral effects. However, further work is needed to clarify the role of gender in response to DMSA.

Subacute Pb exposure during development and unbaited tunnel maze performance in mice.

Although research has linked chronic, low-level Pb exposure to behavioral and cognitive changes in humans and animals, far less is known about the effects of transient, subchronic Pb exposure during early postnatal development. The need to understand such effects is underscored by the possibility that subchronic Pb exposure may not produce chronically elevated blood-Pb levels, but may produce long-term behavioral changes. To test this hypothesis, we investigated the effect of low-level Pb exposure on unbaited tunnel maze performance in Binghamton Heterogeneous Stock mice. Mice were either nontreated or given subchronic sodium acetate, 5, 10, or 25 mg/kg Pb acetate intragastrically on postnatal (PN) days 6, 9, 12, 15, and 18. No further Pb exposures were given after postnatal day 18. Blood-Pb measurements were taken from selected mice on PN 18, 19, 23, 28, and 38. On PN 38-42, all mice were individually tested in an unbaited tunnel maze under nondeprived conditions. Locomotor activity, exploration, and experience-dependent changes in cul-de-sac entries were recorded. Although Pb did not affect bodyweight and blood-Pb levels were below 10 microg/dl at the time of behavioral testing, a history of low-level preweaning Pb exposure caused a dose-dependent increase in cul-de-sac entries. This behavioral change was dissociable from changes in bodyweight, degree of exploration or an a priori bias to enter cul-de-sacs. The current results support the hypothesis that brief, subchronic Pb exposure during development produces behavioral changes that last well beyond the exposure period, even when blood Pb declines to within "acceptable" levels (l0 microg/dl).

Black Americans' perceptions of cancer. A study utilizing the Health Belief Model.

The purpose of this study was to determine black adults' knowledge and perceptions of cancer by utilizing the Health Belief Model. The subjects were obtained by randomly selecting 11 churches from a list of 33. There were 769 black adults who responded to the survey (64 percent response rate). Mean age of respondents was 44.3 years, SD = 14.7. Only 29 percent were able to correctly identify all seven of the American Cancer Society warning signs; 13 percent were unable to identify any warning signs. One in four believed it was likely they would develop cancer sometime in their life, and 42 percent believed blacks were more susceptible to cancer than whites. Forty-one percent believed most people who get cancer will die from it. Perceived barriers to treatment included cost and pain. A large number of significant differences (P < .01) were found when responses were examined in relation to the sex, educational level, and age of the subjects.

Risk of child abuse or neglect in a cohort of low-income children.

The purposes of this research were to identify risk factors for reported child abuse or neglect and to examine the roles of stress and social support in the etiology of child maltreatment. Mothers of newborn infants with biomedical and sociodemographic risk factors were recruited from community and regional hospitals and local health departments in 42 counties of North and South Carolina selected for geographic distribution and for large numbers of such newborns. For every four such mothers, the next mother to deliver an otherwise normal newborn was sought. Mothers were interviewed shortly after giving birth, and state Central Registries of Child Abuse and Neglect were reviewed when each infant was 1 year of age. Eight hundred forty-two of 1,111 recruited mothers were successfully interviewed in their homes between March 1986 and June 1987. Seven hundred forty-nine North Carolina births who resided in the state more than 6 months were eligible for inclusion in the analysis. Logistic regression with backward elimination procedures was used in the analysis. Maternal education (p < .01), number of other dependent children in the home (p < .01), receipt of Medicaid (p < .01), maternal depression (p < .05), and whether the maternal subject lived with her own mother at age 14 years (p < .05) were the best predictors of a maltreatment report. Further examination revealed an interaction effect between stressful life events, as measured by life event scores, and social well-being (p < .01). For children born at risk for social and/or medical problems, extreme low income (participation in public income support programs), low maternal education, maternal depression, the presence of any other young children in the home, and a mother's separation at age 14 years from her own mother significantly predict child maltreatment reports in the first year of life. In addition, stressful life events, even if perceived positively, may increase or decrease the risk of maltreatment reports, depending upon the presence of social support.

Stress, social support, and substantiated maltreatment in the second and third years of life.

OBJECTIVE: The purpose of this research was to determine whether risk factors for a maltreatment report in the first year of life, especially the interaction of life event stress and social support, persist into the second and third years of life. METHOD: Predominantly low income mothers who had been interviewed shortly after the birth of infants in a longitudinal cohort were re-interviewed around the infants' first birthdays, and reports to North Carolina's Central Registry of Child Abuse and Neglect were tracked for substantiated maltreatment reports. RESULTS: Variables significantly associated with a substantiated maltreatment report in the second or third year of life (p < .01) were first year maltreatment reports and participation in Medicaid. Three interactions between a stressful life event indicator variable and a social support indicator variable were significant predictors of substantiated second or third year reports (p < .05). CONCLUSIONS: Even in the presence of significant risk factors from the first year of life, life event stress can increase the risk of a substantiated maltreatment report in the second or third years of life, but social support may moderate the effect of life events.

Urban black and white adolescents' physical fitness status and perceptions of exercise.

The modified Harvard Step Test and a 70-item questionnaire based on the Health Belief Model (HBM) were given to 257 high school students, 154 blacks, and 93 whites. Mean age of students was 16.0 years (SD = 1.1) for whites and 15.8 years (SD = 1.1) for blacks. Though more blacks than whites were in poor physical condition (51% females and 27% males vs. 35% females and 16% males, respectively), the difference was not statistically significant. A high level of concurrence existed between individuals in good physical condition and those who stated they regularly exercised, but this agreement was more pronounced among white students (73% vs. 62% for black students). White students were significantly more knowledgeable than black students on the exercise knowledge subscale. No significant differences existed between black and white students on any other HBM subscales. When subscale scores for those in good versus poor physical condition were compared, significant differences were found on all subscales except the perceived benefits subscale. Analysis of individual questionnaire items which best predicted whether one was in poor or good physical condition found four items accounted for 38% of variance in black students, and seven items accounted for 52% of variance in white students.

Turner syndrome: a pattern of early growth failure.

The purpose of this study was to determine the pattern of early growth in girls with Turner syndrome. Analysis was performed on a total of 464 longitudinal measurements of height, obtained from birth to 8 years of age from 37 girls with Turner syndrome who did not have significant cardiac disease or autosomal abnormalities. All data were obtained prior to the initiation of any hormonal therapy. Mean height SDS fell from -0.5 at birth to -1.5 at age 1 year and -1.8 at age 1.5 years. Growth curves fitted using the first two components of the infancy-childhood-puberty model of growth revealed that growth failure was due to (a) mild growth retardation in utero, (b) slow growth during infancy, (c) delayed onset of the childhood component of growth and (d) slow growth during childhood. Physicians should consider the diagnosis of Turner syndrome in any girl with an unexplained failure to thrive or with short stature, even during the first 2 years of life.

Distribution of primary tooth caries in first-grade children from two nonfluoridated US communities.

In a prospective longitudinal study, 1099 first grade children from Aiken, South Carolina, and 1086 children from Portland, Maine, were examined annually for 3 years. Caries prevalence and dmfs incidence were determined. The mean dmfs in Portland children was 2.9. In Aiken, white children had a mean dmfs of 8.4, and black children had a mean dmfs of 10.2. The mean 3-year primary tooth caries increment was 1.5 surfaces in the Portland cohort 3.3 surfaces in the Aiken white cohort and 2.8 surfaces in the Aiken black cohort. These increments were divided evenly between interproximal and fissure surfaces. Twenty percent of the children in Portland had 75% of the caries; in Aiken, 20% of the children had 60% of the caries. This distribution suggests a high-risk group that could be targeted for aggressive caries prevention efforts if risk factors can be identified.

Cognitive-neural effects of brush writing of chinese characters: cortical excitation of theta rhythm.

Chinese calligraphy has been scientifically investigated within the contexts and principles of psychology, cognitive science, and the cognitive neuroscience. On the basis of vast amount of research in the last 30 years, we have developed a cybernetic theory of handwriting and calligraphy to account for the intricate interactions of several psychological dimensions involved in the dynamic act of graphic production. Central to this system of writing are the role of sensory, bio-, cognitive, and neurofeedback mechanisms for the initiation, guidance, and regulation of the writing motions vis-a-vis visual-geometric variations of Chinese characters. This experiment provided the first evidence of cortical excitation in EEG theta wave as a neural hub that integrates information coming from changes in the practitioner's body, emotions, and cognition. In addition, it has also confirmed neurofeedback as an essential component of the cybernetic theory of handwriting and calligraphy.

Study of tuberculosis and AIDS stigma as barriers to tuberculosis treatment adherence using validated stigma scales.

BACKGROUND: Adherence to tuberculosis (TB) treatment is important for TB control. The effect of stigma on adherence has not been well quantified. OBJECTIVE: To identify the effects of TB and acquired immune-deficiency syndrome (AIDS) stigma on missed doses during TB treatment. DESIGN: Validated TB and AIDS stigma scales assessing perceived and experienced/felt stigma were administered in a prospective cohort of 459 TB patients at TB treatment initiation and after 2 months. Repeated measures and multivariable models estimated the effects of stigma on the rate of missed doses. RESULTS: Fifty-six per cent of patients missed no doses, and associations between stigma and missed doses were minimal. Heterogeneity of effects was observed, how- ever, with higher experienced and felt TB stigma increasing missed doses among women (adjusted RR 1.22, 95%CI 1.10-1.34) and human immunodeficiency virus (HIV) co-infected patients (aRR 1.39, 95%CI 1.13-1.72). Experienced and felt AIDS stigma also increased missed doses among HIV co-infected patients (aRR 1.43, 95%CI 1.31-1.56). CONCLUSION: Stigma has a minimal effect in this population with good adherence. Among women and HIV co-infected patients, however, experienced and felt stigma, and not perceived stigma, increased the rate of missed doses. Further research is needed to determine if stigma or coping interventions among these subgroups would improve adherence.

Tuberculosis and AIDS stigma among patients who delay seeking care for tuberculosis symptoms.

BACKGROUND: Delay in presentation to a health facility is an important concern for tuberculosis (TB) control. The effect of stigma on delay in seeking care for TB symptoms is not well studied, especially in the context of the human immunodeficiency virus (HIV) co-epidemic. OBJECTIVE: To estimate the association of TB and acquired immune-deficiency syndrome (AIDS) stigma on delay in seeking care for TB symptoms. METHODS: For 480 newly diagnosed patients with TB, time from first TB symptom to the first visit to a qualified provider was calculated. Stigma scales were administered to each patient to obtain a stigma score. RESULTS: Among men, those with higher TB stigma had a small increase in delay times, while women had a small decrease in delay. Among patients presenting with hemoptysis, higher TB stigma was associated with a small increase in delay, while among patients presenting with fever or extra-pulmonary symptoms only, higher TB and AIDS stigma resulted in shorter delay times. CONCLUSION: In a population with a relatively short median delay (26 days), the impact of TB and AIDS stigma translates into a minimal change in delay time. This suggests that stigma does not have a clinically relevant effect on TB patient delay in southern Thailand.

Line-segment confidence bands for repeated measures.

For the case of repeated measures on Y with mean values linear in a concomitant variable Z in [a, b], a straight-line confidence band over [a, b] is given with width linear in Z. Graphical presentation of such line-segment confidence bands can help emphasize that appropriate inferences are limited to the range of the data. Because the line-segment bands are designed to cover a finite interval, they are usually more efficient than the widely used hyperbolic bands. Conditions for favorable relative efficiency of area bounded are given. This easily computed trapezoidal confidence region is formulated in terms of a growth-curve model.