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PubMed2005

An in vitro study on spontaneous myometrial contractility in the mare during estrus and diestrus.

Uterine smooth muscle specimens were collected from euthanatized mares in estrus and diestrus. Longitudinal and circular specimens were mounted in organ baths and the signals transcribed to a Grass polygraph. After equilibration time and 2 g preload, their physiologic isometric contractility was recorded for a continuous 2.0 h. Area under the curve, frequency and time occupied by contractions were studied. Differences between cycle phases, between muscle layers, and over the recorded time periods were statistically evaluated using linear mixed-effect models. In the mare, physiologic contractility of the uterus decreased significantly over time for all variables evaluated (time as covariate on a continuous scale). For area under the curve, there was a significant effect of muscle layer (longitudinal > circular). For frequency, higher values were recorded in estrus for circular smooth muscle layer, whereas higher values were seen in longitudinal smooth muscle layers during diestrus. In longitudinal layer and in diestrus, more time was occupied by contractions than in circular layer, and in estrus. This study is describing physiologic myometrial motility in the organ bath depending on cycle phase.

Animals↗

PubMedDate not supplied

Quantification of perfusion modes in terms of surplus hemodynamic energy levels in a simulated pediatric CPB model.

The objective of this investigation was to compare pulsatile versus nonpulsatile perfusion modes in terms of surplus hemodynamic energy (SHE) levels during cardiopulmonary bypass (CPB) in a simulated neonatal model. The extracorporeal circuit consisted of a Jostra HL-20 heart-lung machine (for both pulsatile and nonpulsatile modes of perfusion), a Capiox Baby RX hollow-fiber membrane oxygenator, a Capiox pediatric arterial filter, 5 feet of arterial tubing and 6 feet of venous tubing with a quarter-inch diameter. The circuit was primed with a lactated Ringers solution. The systemic resistance of a pseudo-patient (mean weight, 3 kg) was simulated by placing a clamp at the end of the arterial line. The pseudo-patient was subjected to five pump flow rates in the 400 to 800 ml/min range. During pulsatile perfusion, the pump rate was kept constant at 120 bpm. Pressure waveforms were recorded at the preoxygenator, postoxygenator, and preaortic cannula sites. SHE was calculated by use of the following formula {SHE (ergs/cm) = 1,332 [((integral fpdt) / (integral fdt)) - Mean Arterial Pressure]} (f = pump flow and p = pressure). A total of 60 experiments were performed (n = 6 for nonpulsatile and n = 6 for pulsatile) at each of the five flow rates. A linear mixed-effects model, which accounts for the correlation among repeated measurements, was fit to the data to assess differences in SHE between flows, pumps, and sites. The Tukey multiple comparison procedure was used to adjust p values for post hoc pairwise comparisons. With a pump flow rate of 400 ml/min, pulsatile flow generated significantly higher surplus hemodynamic energy levels at the preoxygenator site (23,421 +/- 2,068 ergs/cm vs. 4,154 +/- 331 ergs/cm, p < 0.0001), the postoxygenator site (18,784 +/- 1,557 ergs/cm vs. 3,383 +/- 317 ergs/cm, p < 0.0001), and the precannula site (6,324 +/- 772 ergs/cm vs. 1,320 +/- 91 ergs/cm, p < 0.0001), compared with the nonpulsatile group. Pulsatile flow produced higher SHE levels at all other pump flow rates. The Jostra HL-20 roller pump generated significantly higher SHE levels in the pulsatile mode when compared with the nonpulsatile mode at all five pump flow rates.

Blood Flow Velocity↗

PubMed1998

Effect of metabolic inhibitors on cyclosporine pharmacokinetics using a population approach.

Drugs known to inhibit the metabolism of cyclosporine are administered concomitantly to those who undergo cardiothoracic transplantation. The aim of this study was to examine in quantitative terms the relationship between cyclosporine oral dose rate and the trough concentration (Css(trough)) at steady state in patients who undergo cardiothoracic transplantation and are administered cyclosporine alone or in combination with drugs known to inhibit its metabolism. Dose and whole blood cyclosporine Css(trough) observations measured using the enzyme-multiplied immunoassay technique (EMIT) (396 observations) or the TDx assay (435 observations) were collected as part of routine blood concentration monitoring from 182 patients who underwent cardiothoracic transplantation. Data were analyzed using a linear mixed-effects modeling approach to examine the effect of metabolic inhibitors on dose-rate-Css(trough) ratio. The mean (and 95% confidence interval) dose-rate-Css(trough) ratio for cyclosporine generated from concentrations measured using EMIT was 94 (82.5-105.5) Lh(-1) for patients administered cyclosporine alone, 66.7 (58.1-75.3) Lh(-1) for patients administered concomitant diltiazem, 47.9 (15.4 -80.4) Lh(-1) for patients administered concomitant itraconazole, 21.7 (14.8-28.5) Lh(-1) for patients administered concomitant ketoconazole, and 14.9 (11.8-18.1) Lh(-1) for patients concomitantly administered diltiazem and ketoconazole. For patients administered concomitant cyclosporine, ketoconazole, and diltiazem, the dosage of cyclosporine, if it is administered alone, should be 20% to achieve the same blood concentrations. This will allow safer drug concentration targeting of cyclosporine after cardiothoracic transplantation.

Administration, Oral↗

PubMed2000

Neuroendocrine reactivity and recovery from work with different physical and mental demands.

OBJECTIVES: The purpose of this study was to examine the extent to which the type or nature (physical, mental or mixed mental and physical) of work and work characteristics is related to the course of neuroendocrine reactivity and recovery from work. METHODS: Neuroendocrine reactivity and recovery were studied by measuring the urinary excretion of adrenaline, noradrenaline, and cortisol during and after 3 workdays, 1 consecutive day off, and a baseline day. The assessment was made in 3 groups of Dutch male workers (N=60) who differed in the nature (mental, physical, and combined mental and physical demands) of their work. Multilevel analyses were performed to fit linear mixed-effects models for each hormone. RESULTS: Main or interaction effects with time of day were found between the workers in combined mental and physical work and the 2 other groups of workers for cortisol, adrenaline, and noradrenaline excretion. In addition, the baseline levels of the 3 hormones were higher in the workers with combined mental and physical work when compared with the other 2 groups. The excretion rates during the workdays were higher than those on the day off, but a trend towards mobilizing less activity was found from the 1st to the 3rd workday. Job demands were negatively related to cortisol excretion. Job control and social demands at work did not affect the excretion rates of the hormones. CONCLUSIONS: Unfavorable effects on cortisol and adrenaline reactivity or recovery was found for workers with combined mental and physical demands when compared with workers doing mainly mental or mainly physical work. The results of the present study are in accordance with the cognitive activation theory and the allostatic load model.

Adult↗

PubMed2005

Pulmonary metastases: effect of CT section thickness on measurement--initial experience.

PURPOSE: To assess the effect of commonly used computed tomographic (CT) section thicknesses on metastatic tumor measurements calculated with unidimensional, bidimensional, area, and volumetric methods. MATERIALS AND METHODS: Analysis and data collection were approved by the Institutional Review Board, with waived informed patient consent. Forty-two pulmonary metastases in 10 patients (three men and seven women; age range, 43-83 years; mean age, 65.4 years) were analyzed on CT scans obtained with 3.75-, 5.0-, and 7.5-mm section thicknesses. The lesions were automatically delineated by using a three-dimensional multicriteria segmentation algorithm. Unidimensional (the largest diameter), bidimensional (the product of the two maximal perpendicular diameters), maximal cross-sectional area, and volumetric measurements were automatically obtained for each pulmonary lesion on each section thickness. Means and variances were calculated, and the differences across the three section thicknesses for each of the four measurements were studied by using linear mixed-effects models. The Levene test was used to study the equality of variances. RESULTS: Differences in the means for unidimensional, bidimensional, and area measurements were significant between a section thickness of 3.75 and 5.0 mm (unidimensional, P=.05; bidimensional, P=.05; area, P=.01) and 3.75 and 7.5 mm (unidimensional, P=.06; bidimensional, P=.03; area, P=.02), but not 5.0 and 7.5 mm. There was a significant difference in volumetric measurement as section thickness decreased from 7.5 to 5.0 mm (P <.001) and from 7.5 to 3.75 mm (P <.001). Although there was a slight trend for differences in the variances across section thickness for each measurement, none of the differences were significant. CONCLUSION: Volumetric tumor measurements change with a reduction in section thickness from 7.5 to 5.0 and 3.75 mm. For unidimensional measurement, no change was found when thickness decreased from 7.5 to 5.0 mm.

Adult↗

PubMed2005

Associations between health effects and particulate matter and black carbon in subjects with respiratory disease.

We measured fractional exhaled nitric oxide (FE(NO)), spirometry, blood pressure, oxygen saturation of the blood (SaO2), and pulse rate in 16 older subjects with asthma or chronic obstructive pulmonary disease (COPD) in Seattle, Washington. Data were collected daily for 12 days. We simultaneously collected PM10 and PM2.5 (particulate matter < or = 10 microm or < or = 2.5 microm, respectively) filter samples at a central outdoor site, as well as outside and inside the subjects' homes. Personal PM10 filter samples were also collected. All filters were analyzed for mass and light absorbance. We analyzed within-subject associations between health outcomes and air pollution metrics using a linear mixed-effects model with random intercept, controlling for age, ambient relative humidity, and ambient temperature. For the 7 subjects with asthma, a 10 microg/m3 increase in 24-hr average outdoor PM10 and PM2.5 was associated with a 5.9 [95% confidence interval (CI), 2.9-8.9] and 4.2 ppb (95% CI, 1.3-7.1) increase in FE(NO), respectively. A 1 microg/m3 increase in outdoor, indoor, and personal black carbon (BC) was associated with increases in FE(NO) of 2.3 ppb (95% CI, 1.1-3.6), 4.0 ppb (95% CI, 2.0-5.9), and 1.2 ppb (95% CI, 0.2-2.2), respectively. No significant association was found between PM or BC measures and changes in spirometry, blood pressure, pulse rate, or SaO2 in these subjects. Results from this study indicate that FE(NO) may be a more sensitive marker of PM exposure than traditional health outcomes and that particle-associated BC is useful for examining associations between primary combustion constituents of PM and health outcomes.

Age Factors↗

PubMed2006

Carbohydrate balance predicts weight and fat gain in adults.

BACKGROUND: The prevention and treatment of obesity is a public health challenge. OBJECTIVE: We investigated the effects of dietary composition, insulin sensitivity (S(I)), and energy balance on predicted changes in body composition. DESIGN: In a randomized crossover design study, 39 normal-weight (n = 23), overweight (n = 8), and obese (n = 8) men and women (aged 25-36 y) each followed a 15-d isocaloric high-fat (HF; 50% fat) and high-carbohydrate [HC; 55% carbohydrate (CHO)] diet with a 4-6-wk washout period during the first year. During each treatment, energy balance was measured while the subjects were inactive by using indirect calorimetry on day 15, and S(I) was measured by using a euglycemic clamp study (40 mU . m(-2) . min(-1)) on day 16. Weight and body composition were then measured annually for 4 y. The outcomes for fat mass, percentage body fat, and weight were measured by using a linear 2-stage mixed model. RESULTS: CHO balance (day 15) and S(I) (day 16) on the HC diet were highly and significantly correlated (r = 0.55, P < 0.001). On the HC diet, the subjects who had a higher positive CHO balance (day 15) gained less fat mass (P < 0.001), percentage body fat (P = 0.006), and weight (P = 0.024) over time. When adjusted for S(I), CHO balance remained a significant predictor of changes in fat mass (P = 0.021) and percentage body fat (P = 0.025). CONCLUSIONS: On a HC diet, the subjects who had a higher positive CHO balance on day 15 while they were inactive gained less fat mass during 4 y, a predictive effect independent of S(I). As suggested in rodents, the capacity to expand the glycogen pool might reduce energy intake and protect against fat and weight gain.

Adipose Tissue↗

PubMed2006

Fluoride exposure and bone status in patients with chronic intestinal failure who are receiving home parenteral nutrition.

BACKGROUND AND OBJECTIVE: Metabolic bone disease is frequent in chronic intestinal failure. Because fluoride has a major effect on bones, the status of both fluoride and bone was studied in long-term home parenteral nutrition (HPN) patients. DESIGN: We studied 31 adults aged (x +/- SD) 56.3 +/- 15.1 y, mainly patients with short-bowel syndrome, who had been receiving HPN for >1 y. Bone mineral density (BMD) was measured by absorptiometry, and serum fluoride was measured by using a fluoride-sensitive electrode. All patients ate and drank ad libitum. HPN (3.4 +/- 1.2 times/wk) complemented oral nutrition. Potential explicative factors were estimated by using a linear regression model (mixed-effects model). RESULTS: Of 120 fluoride dosages (2-6/patient), 102 were above the upper normal limit (1.58 micromol/L) at the laboratory. Mean (+/- SD) daily fluoride supply was 8.03 +/- 7.71 mg (US adequate intake: 3.1 mg/d for women and 3.8 for men; tolerable upper normal limit: 10 mg/d); intravenous fluoride varied from 0.06 to 1.45 mg, and oral fluoride varied from 0.09 to 27.8 mg. Serum fluoride concentrations were correlated with creatinine clearance and fluoride supply. BMD was significantly lower in the femoral neck than in the spinal area. After adjustment for sex and the duration of HPN, only the effect of serum fluoride on spinal BMD was significant. Two patients had symptoms of fluorosis, eg, calcaneum fissures, interosseous calcifications, or femoral neck osteoporosis. CONCLUSIONS: In chronic intestinal failure, high intakes of fluoride are frequent because of the beverages ingested to compensate for stool losses. Hyperfluoremia has an effect on bone metabolism and may increase skeletal fragility. The consumption of fluoride-rich beverages for extended periods is therefore not advisable.

Adult↗

PubMed2005

Spatial and temporal variations in sea lice (Copepoda: Caligidae) infestations of three salmonid species farmed in net pens in southern Chile.

Sea lice infestations have become a major health problem for farmed salmonids throughout the world including Chile. In southern Chile, 6 geographical areas, divided into 22 geographical zones with a total of 127 salmon farming centers and 1519 sea pens, were regularly sampled from December 1999 to April 2002. A linear mixed-effects model (LME) approach was used to describe the infestations of adult forms of sea lice on 3 salmonid species farmed in southern Chile. The variables fish species, water temperature, water salinity, fish weight, juvenile parasite count, pen shape, treatment status in previous month and the interaction of previous and current month treatments were found to be statistically significant fixed effects for the population sampled. The most susceptible species to sea lice infestation was rainbow trout Oncorhynchus mykiss, while the least susceptible species was coho salmon O. kisutch. Fishes in pens treated in the previous month with avermectins were associated with the smallest sea lice count compared to fishes in pens not treated or treated with other products. The variability in sea lice infestations in areas and zones within areas was not statistically significant when controlling for the previously mentioned fixed variables. The variability between centers, the within-pen variability, and the interaction between within-pen effect and the date of measurement were statistically significant and not explained by the fixed effects. Potential sources for this variability are discussed. We conclude that the epidemiology of sea lice infestations in farmed salmonids in southern Chile is complex and in need of further study.

Animals↗

PubMed2007

A prospective analysis of plasma 25-hydroxyvitamin D concentrations in white and black prepubertal females in the southeastern United States.

BACKGROUND: Little is known regarding changes in vitamin D status among children living in the southern United States and whether these changes are race-dependent. OBJECTIVES: The aims were to prospectively assess plasma 25-hydroxyvitamin D [25(OH)D] concentrations in prepubertal black and white girls (n = 83) living in northeast Georgia and to determine whether 25(OH)D concentrations change with increasing age. DESIGN: Plasma samples were obtained annually over a time frame of 1-7 y, and 25(OH)D concentrations were assessed by using radioimmunoassay. Percentage body fat (%BF) and fat-free soft tissue (FFST) mass were measured by using dual-energy X-ray absorptiometry. Linear mixed-effects models were used with height, weight, body mass index percentile, %BF, FFST, pubertal stage, dietary intake, physical activity, and socioeconomic status as covariates. RESULTS: Plasma 25(OH)D values < 80 nmol/L were observed in 75% of the participants. Plasma 25(OH)D values (analyzed on the natural logarithm scale) decreased with increasing age (P = 0.02), independent of race. Plasma 25(OH)D values were higher in whites than in blacks (P < 0.0001), and the amount of this difference depended on season (P < 0.001 for all seasons). A significant negative association between FFST and 25(OH)D, beyond the effects of age, race, and season (P = 0.007), was observed. The effects of age, race, and season on 25(OH)D remained significant when dietary calcium, vitamin D, and physical activity were used as covariates; however, after adjustment for FFST, only the effects of race and season remained. CONCLUSIONS: White girls living in the southeastern United States have higher 25(OH)D concentrations than do black girls, and the magnitude of this difference depends on the season. Decreases in 25(OH)D with age are associated with increases in FFST. Whether FFST requires additional vitamin D during growth remains to be determined.

Absorptiometry, Photon↗

PubMed2006

Longitudinal anthropometric changes in HIV-infected and HIV-uninfected men.

BACKGROUND: Although morphologic abnormalities are common among HIV-infected persons receiving highly active antiretroviral therapy (HAART), longitudinal comparative body shape changes among HAART-treated HIV-infected men versus HIV-seronegative men of similar age remain unclear. METHODS: Since September 1999, men enrolled in the Multicenter AIDS Cohort Study underwent body mass index (BMI) and circumference measurements of the waist, hip, thigh, and arm at each semiannual visit. Changes in these measurements that occurred between 1999 and 2003 among HIV-infected men were compared with measurements of HIV-seronegative men using linear mixed effects regression models. The HIV-infected men were further stratified by treatment group (no antiretroviral therapy [ART], monotherapy or combination [mono/combo] ART, or HAART). Analyses were adjusted for age, nadir CD4 cell count, and BMI (for circumference measurements). RESULTS: Over the 4-year observation period, mean BMI increased significantly among the 392 HIV-seronegative men (0.12 kg/m/y; P < 0.001) but did not change in the 3 HIV-infected groups (combined n = 661). Mean waist and hip circumferences increased significantly in all groups. Hip circumferences increased more slowly in the HIV-positive HAART-treated group (n = 488) than in the HIV-seronegative group (0.18 vs. 0.49 cm/y; P < 0.001), however, yielding a more rapid increase in the waist/hip ratio in the HIV-positive, HAART-treated group over time (0.005 per year; P < 0.001). CONCLUSIONS: The increased rate of change in waist/hip ratio in HIV-infected men receiving HAART compared with HIV-seronegative men is attributable to slower increases in hip circumference rather than an increased rate of change in waist circumference. These findings underscore the importance of body fat composition changes in the peripheral compartment relative to the central compartment among HIV-infected men receiving HAART.

Anthropometry↗

PubMed2006

The extent to which tobacco marketing and tobacco use in films contribute to children's use of tobacco: a meta-analysis.

OBJECTIVE: To quantify the effect of exposure on initiation of tobacco use among adolescents. DATA SOURCES: A systematic literature search of MEDLINE, PsychINFO, ABI/INFORM, and Business Source Premier through October/November 2005 was conducted. Unpublished studies were solicited from researchers. STUDY SELECTION: Of 401 citations initially identified, 51 (n = 141 949 participants) met the inclusion criteria: reporting on exposure and tobacco use outcomes and participants younger than 18 years. Included studies reported 146 effects; 89 were conceptually independent effects. Data were extracted independently by 3 of us using a standardized tool. Weighted averages were calculated using a linear mixed-effects model. Heterogeneity and publication bias were assessed. Main Exposures Exposures (tobacco advertising, promotions, and samples and pro-tobacco depictions in films, television, and videos) were categorized as low or high engagement based on the degree of psychological involvement required. MAIN OUTCOME MEASURES: Outcomes were categorized as cognitive (attitudes or intentions) or behavioral (initiation, tobacco use status, or progression of use). RESULTS: Exposure to pro-tobacco marketing and media increases the odds of youth holding positive attitudes toward tobacco use (odds ratio, 1.51; 95% confidence interval, 1.08-2.13) and more than doubles the odds of initiating tobacco use (odds ratio, 2.23; 95% confidence interval, 1.79-2.77). Highly engaging marketing and media are more effective at promoting use (odds ratio, 2.67; 95% confidence interval, 2.19-3.25). These effects are observed across time, in different countries, with different study designs and measures of exposure and outcome. CONCLUSIONS: Pro-tobacco marketing and media stimulate tobacco use among youth. A ban on all tobacco promotions is warranted to protect children.

Adolescent↗

PubMed2004

Estimates of global prevalence of childhood underweight in 1990 and 2015.

CONTEXT: One key target of the United Nations Millennium Development goals is to reduce the prevalence of underweight among children younger than 5 years by half between 1990 and 2015. OBJECTIVE: To estimate trends in childhood underweight by geographic regions of the world. DESIGN, SETTING, AND PARTICIPANTS: Time series study of prevalence of underweight, defined as weight 2 SDs below the mean weight for age of the National Center for Health Statistics and World Health Organization (WHO) reference population. National prevalence rates derived from the WHO Global Database on Child Growth and Malnutrition, which includes data on approximately 31 million children younger than 5 years who participated in 419 national nutritional surveys in 139 countries from 1965 through 2002. MAIN OUTCOME MEASURES: Linear mixed-effects modeling was used to estimate prevalence rates and numbers of underweight children by region in 1990 and 2015 and to calculate the changes (ie, increase or decrease) to these values between 1990 and 2015. RESULTS: Worldwide, underweight prevalence was projected to decline from 26.5% in 1990 to 17.6% in 2015, a change of -34% (95% confidence interval [CI], -43% to -23%). In developed countries, the prevalence was estimated to decrease from 1.6% to 0.9%, a change of -41% (95% CI, -92% to 343%). In developing regions, the prevalence was forecasted to decline from 30.2% to 19.3%, a change of -36% (95% CI, -45% to -26%). In Africa, the prevalence of underweight was forecasted to increase from 24.0% to 26.8%, a change of 12% (95% CI, 8%-16%). In Asia, the prevalence was estimated to decrease from 35.1% to 18.5%, a change of -47% (95% CI, -58% to -34%). Worldwide, the number of underweight children was projected to decline from 163.8 million in 1990 to 113.4 million in 2015, a change of -31% (95% CI, -40% to -20%). Numbers are projected to decrease in all subregions except the subregions of sub-Saharan, Eastern, Middle, and Western Africa, which are expected to experience substantial increases in the number of underweight children. CONCLUSIONS: An overall improvement in the global situation is anticipated; however, neither the world as a whole, nor the developing regions, are expected to achieve the Millennium Development goals. This is largely due to the deteriorating situation in Africa where all subregions, except Northern Africa, are expected to fail to meet the goal.

Body Weight↗

PubMed2003

Association of expired nitric oxide with urinary metal concentrations in boilermakers exposed to residual oil fly ash.

BACKGROUND: Exposure to metal-containing particulate matter has been associated with adverse pulmonary responses. Metals in particulate matter are soluble, hence are readily recovered in urine of exposed individuals. This study investigated the association between urinary metal concentrations and the fractional concentration of expired nitric oxide (F(E)NO) in boilermakers (N = 32) exposed to residual oil fly ash (ROFA). METHODS: Subjects were monitored at a boiler overhaul site located in the New England area, USA. F(E)NO and urine samples were collected pre- and post-workshift for 5 consecutive workdays. Metals investigated included vanadium (V), chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), and lead (Pb). RESULTS: The median F(E)NO was 7.5 ppb (95% CI: 7.4-8.0), and the median creatinine-adjusted urinary metal concentrations (mug/g creatinine) were: vanadium, 1.37; chromium, 0.48; manganese, 0.30; nickel, 1.52; copper, 3.70; and lead, 2.32. Linear mixed-effects models indicated significant inverse exposure-response relationships between log F(E)NO and the log-transformed urinary concentrations of vanadium, manganese, nickel, copper, and lead at several lag times, after adjusting for smoking status. CONCLUSIONS: Urine samples may be utilized as a biomarker of occupational metal exposure. The inverse association between F(E)NO and urinary metal concentrations suggests that exposure to metals in particulate matter may have an adverse effect on respiratory health.

Adolescent↗

PubMed2006

The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice.

PURPOSE: This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. METHODS: The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. RESULTS: For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. CONCLUSIONS: CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.

Antidepressive Agents↗

PubMed2004

Modelling of cardiac imaging data with spatial correlation.

Cardiac imaging with single photon emission computed tomography (SPECT) is a common approach for quantifying myocardial perfusion. Fusing serial SPECT studies allows detection and quantification of changes in myocardial perfusion such as those resulting from disease progression or successful treatment therapy for patients with coronary artery disease. The abundance of data for each subject along with the inherent intra-subject correlation due to spatial proximity of multiple perfusion measurements present special analytical challenges. We utilize a standard physiological model of the left ventricle (LV) to construct a general statistical model for cardiac perfusion that incorporates spatial correlation. We illustrate the use of mixed effects models and linear models with correlated errors to estimate myocardial perfusion counts and to compare these counts across serial studies. We address different types of spatial correlation among perfusion measurements in the LV, and we consider various parametric structures for these correlations. We apply the model to data from serial SPECT studies conducted while subjects were in both restful and stressful states approximately two days and one year following a myocardial infarction.

Coronary Circulation↗

PubMed2004

Power analyses for longitudinal trials and other clustered designs.

Existing methods for power and sample size estimation for longitudinal and other clustered study designs have limited applications. In this paper, we review and extend existing approaches to improve these limitations. In particular, we focus on power analysis for the two most popular approaches for clustered data analysis, the generalized estimating equations and the linear mixed-effects models. By basing the derivation of the power function on the asymptotic distribution of the model estimates, the proposed approach provides estimates of power that are consistent with the methods of inference for data analysis. The proposed methodology is illustrated with numerous examples that are motivated by real study designs.

Clinical Trials as Topic↗

PubMed2003

Paracetamol and metabolite pharmacokinetics in infants.

BACKGROUND: Data concerning metabolism of paracetamol in infants are scant. Previous studies have examined urinary metabolite recovery rates after a single dose of paracetamol in either neonates (<6 weeks) or children (3-9 years). There are no studies investigating infants. METHODS: Infants ( n=47) undergoing major craniofacial surgery were given paracetamol 19-45 mg/kg 6-, 8-, or 12-hourly as either elixir or suppository formulation for postoperative analgesia, after a loading dose of 33-59 mg/kg rectally during the operation. Serum was assayed for paracetamol concentration in 40 of these infants at 5, 8, 11, 14, 17 and 20 h postoperatively. Urine samples were collected every 3 h for 24 h in 15 of these infants. The clearances of paracetamol to glucuronide and sulphate metabolites as well as the urinary clearance of unmetabolised paracetamol were estimated using non-linear, mixed-effects models. RESULTS: Mean (+/-SD) age and weight of the patients were 11.8+/-2.5 months and 9.1+/-1.9 kg. Clearances of paracetamol to paracetamol-glucuronide (%CV) and to paracetamol-sulphate were 6.6 (11.5) l/h and 7.5 (11.5) l/h respectively, standardised to a 70-kg person using allometric "1/4 power" models. Glucuronide formation clearance, but not sulphate formation, was related to age and increased with age from a predicted value in a neonate of 2.73 l/h/70 kg to a mature value of 6.6 l/h/70 kg with a maturation half-life of 8.09 months. Urine clearance of paracetamol-glucuronide, paracetamol-sulphate and unchanged paracetamol (%CV) were, respectively, 2.65, 3.03 and 0.55 (28) l/h/70 kg. The urine clearance of unchanged paracetamol and metabolites was related to urine volume flow rate. Clearance attributable to pathways other than these measured in urine was not identifiable. The glucuronide/sulphate formation clearance ratio was 0.69 at 12 months of age. Sulphate metabolism contributed 50% towards paracetamol clearance. CONCLUSION: Glucuronide formation clearance increases with age in the infant age range but sulphate formation does not. Renal clearance of paracetamol and its metabolites increases with urine flow rate. This and other studies show that paracetamol metabolism to glucuronide appears to be similar in infants and children, but in adults is increased in comparison with children. Oxidative pathways were undetectable in this infant study and may explain, in part, the reduced incidence of hepatotoxicity in infants.

Acetaminophen↗