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PubMed1999

beta1 to beta3 switch in control of cyclic adenosine monophosphate during brown adipocyte development explains distinct beta-adrenoceptor subtype mediation of proliferation and differentiation.

To explain the distinctive pharmacological profiles observed for adrenergic stimulation of cell proliferation (beta1) and cell differentiation (beta3), the adrenergic control of cAMP accumulation was investigated during brown adipocyte development. In preadipocytes, norepinephrine (NE) increased cAMP levels but the beta3-agonists BRL-37344 and CGP-12177 did not; in contrast, when the cells had differentiated into mature brown adipocytes, a large cAMP response to the beta3-agonists had emerged and was now double that to NE (although the affinity of NE had increased 10-fold). Beta1-messenger RNA (mRNA) levels were high in both pre- and mature brown adipocytes; beta3-mRNA did not appear until maturation but then abruptly. Although beta1-receptors remained detectable by [3H]CGP-12177 binding in the mature brown adipocytes, the cAMP response to NE (based on propranolol inhibitory potency) switched from beta1 to beta3. Even the established beta1-agonist dobutamine acted through beta3-receptors in the mature brown adipocytes. The increases in cAMP levels could adequately explain the increased cell proliferation in NE-stimulated preadipocytes and the NE-induced UCP1 gene expression in mature brown adipocytes. The distinctive adrenergic profiles for stimulation of proliferation and of differentiation were thus not due to the existence of additional pathways but to a switch in the type of beta-receptor mediating the NE response, coordinated with an alteration in the nuclear response to increased cAMP levels. The study implies that full recruitment of brown adipose tissue cannot be induced by exclusive beta3-stimulation.

Adipocytes↗

PubMed1995

Analysis of structure and expression of the Xenopus thyroid hormone receptor-beta gene to explain its autoinduction.

Transcription of both Xenopus thyroid hormone receptor (TR) genes, xTR alpha and -beta, is strongly up-regulated by their own ligand T3 during natural or T3-induced metamorphosis of tadpoles and in some Xenopus cell lines. To explain this autoinduction, we analyzed the sequence of 1.6 kilobases of xTR beta promoter for putative T3-responsive elements. Two direct repeat +4 AGGTCA hexamer motifs (DR+4), an imperfect distal (-793/-778) and a perfect proximal (-5/11) site, a DR+1 site, and some possible half-sites were located in the 1.6-kilobase promoter. Transfection of Xenopus XTC-2 cells (which express xTR alpha and -beta) and XL-2 cells (which predominantly express TR alpha) with chloramphenicol acetyltransferase reporter constructs of deletion mutants and promoter fragments showed that the distal and proximal DR+4 sites responded to T3, although other flanking sequences may also play a role. The thyroid hormone-responsive element half-site present as DR+1 in the up-stream sequence at -1260/-950, when cloned in front of a heterologous promoter, functions independently. T3 enhanced transcription from the two DR+4-containing fragments when present together by only 2- to 3-fold due to a high basal activity. Overexpression of unliganded xTR alpha and xTR beta in XTC-2 cells repressed basal activity, which was then enhanced 7- to 4-fold by T3, respectively; with XL-2 cells cotransfected with xTR beta, T3 inducibility increased to 16-fold. Electrophoretic mobility shift assays with recombinant Xenopus TR alpha, TR beta, retinoid-X receptor-alpha (RXR alpha) and RXR gamma proteins showed that TR-RXR heterodimers, but not TR or RXR monomers or homodimers, strongly bound the natural and synthetic distal and proximal DR+4 elements in a ligand-independent manner. TR/RXR heterodimers exhibited the highest binding affinity for a 28-mer oligonucleotide probe for the -5/11 proximal DR+4 site, with only slight binding to DR+1 (retinoid-X-responsive element-like) site. The xTR beta promoter binding to XTC-2 cell nuclear extract suggested the in vivo relevance of the findings with recombinant TR/RXR heterodimers. It is concluded that xTR alpha and -beta proteins are capable of regulating the expression of xTR beta gene, which can explain its autoinduction seen during T3-induced metamorphosis.

Animals↗

PubMed2006

The environmental "riskscape" and social inequality: implications for explaining maternal and child health disparities.

BACKGROUND: Research indicates that the double jeopardy of exposure to environmental hazards combined with place-based stressors is associated with maternal and child health (MCH) disparities. OBJECTIVE AND DISCUSSION: Our aim is to present evidence that individual-level and place-based psychosocial stressors may compromise host resistance such that environmental pollutants would have adverse health effects at relatively lower doses, thus partially explaining MCH disparities, particularly poor birth outcomes. Allostatic load may be a physiologic mechanism behind the moderation of the toxic effect of environmental pollutants by social stressors. We propose a conceptual framework for holistic approaches to future MCH research that elucidates the interplay of psychosocial stressors and environmental hazards in order to better explain drivers of MCH disparities. CONCLUSION: Given the complexity of the link between environmental factors and MCH disparities, a holistic approach to future MCH research that seeks to untangle the double jeopardy of chronic stressors and environmental hazard exposures could help elucidate how the interplay of these factors shapes persistent racial and economic disparities in MCH.

Child↗

PubMed1991

Hypotheses to explain the higher symptom rates observed around hazardous waste sites.

Five studies were carried out around hazardous waste sites in California in which the main route of exposure was to low-level parts per billion concentrations of either gaseous emissions or airborne dust particles. Although there was no evidence suggesting excesses in cancer or birth defects, the total number and the prevalence of many of subjective symptoms were higher in areas near the site than in control neighborhoods. We discuss a number of causal processes that could explain these results. We conclude that a classical toxicological response and mass psychogenic illness are not valid explanations. Recall bias may explain part of the pattern. We present data from situations where stress alone from environmental anxiety has produced a similar magnitude of excess symptoms in populations. The fact that excess symptoms in waste site neighbors is found primarily in those who complain of odors or who are worried about environmental chemicals suggests the possibility that autonomic, stress-mediated mechanisms or behavioral sensitization are active in the genesis of these symptoms. A variety of confounders were controlled for. The hypothesis that chemically "acquired immune deficiency" can cause subtle symptomatology as a prodrome to subsequent serious disease has been raised in testimony at several toxic tort trials about waste sites. Although this hypothesis seems unlikely, particularly at sites such as the ones we studied with low airborne exposures, if true it would have profound regulatory implications.

Anxiety↗

PubMed2006

Explaining family caregiver role strain following autologous blood and marrow transplantation.

This research project explores family caregiving processes during the first 100 days following autologous blood and marrow transplantation (ABMT). In this paper, we (1) explore patterns in caregiving, and ABMT recipient function early recovery from ABMT; (2) examine the relationships among caregiver demographics, relationship quality, preparedness, ABMT recipient function, predictability of caregiving, caregiver role strain and rewards of caregiving; and (3) examine the relative contribution of caregiver age, preparedness, relationship quality, and ABMT recipient function on caregiver role strain, and rewards of caregiving. Fifty-two family caregivers of ABMT recipients completed questionnaires about caregiving at hospital discharge, and again 2, 6, and 12 weeks following discharge. The amount of caregiving activities performed, and caregiver role strain, declined steadily from 2 weeks to 12 weeks of recovery. The caregiving situation was relatively predictable during recovery, and caregivers reported that caregiving was consistently rewarding. The caregiving activities rated as most difficult were those related to supporting recipients' emotional well-being. Strain from caregiving, although low, was explained by disruption in recipients' emotional and physical functioning, while caregiving rewards were explained by caregivers' preparedness for caregiving. Relationship quality, a significant predictor of strain in other samples, did not influence caregiving strain or rewards in this population. Caregiving processes delineated in studies of caregivers of persons with chronic illness are quite different from those described in this study. The acuity of the recipients' illness, the life threatening nature of the treatment, and the younger age of caregivers, and recipients, may underlie these differences.

Adaptation, Psychological↗

PubMed2005

Explaining race differences in mortality among the Tennessee Medicare elderly: the role of physician services.

We investigated the impact of socioeconomic conditions, patterns of morbidity, and physician service utilization on race differences in rates of mortality, and mortality associated with specific diagnoses. Longitudinal data from the Center for Medicare and Medicaid Services (CMS) Physician Billing File data and the Medicare Enrollment Database (EDB) were analyzed to assess physician-diagnosed morbidity, health service use, and mortality, among the population of Medicare beneficiaries in Tennessee (N=665,887). Proportional hazards models were used to examine the effects of race, socioeconomic status, morbidity, and physician service utilization on mortality. Race differences in physician visits explain the largest portion of mortality differentials between African Americans and Whites. Race disparities in mortality associated with particular forms of morbidity are also mostly a function of differences in physician service use. Our examination suggested that race differences in patterns of physician service use principally explain race disparities in mortality. Further, race differences in the use of physician services were substantially responsible for race disparities in mortality associated with particular forms of morbidity.

Black or African American↗

PubMed2006

Modeling of oxygen transport and cellular energetics explains observations on in vivo cardiac energy metabolism.

Observations on the relationship between cardiac work rate and the levels of energy metabolites adenosine triphosphate (ATP), adenosine diphosphate (ADP), and phosphocreatine (CrP) have not been satisfactorily explained by theoretical models of cardiac energy metabolism. Specifically, the in vivo stability of ATP, ADP, and CrP levels in response to changes in work and respiratory rate has eluded explanation. Here a previously developed model of mitochondrial oxidative phosphorylation, which was developed based on data obtained from isolated cardiac mitochondria, is integrated with a spatially distributed model of oxygen transport in the myocardium to analyze data obtained from several laboratories over the past two decades. The model includes the components of the respiratory chain, the F0F1-ATPase, adenine nucleotide translocase, and the mitochondrial phosphate transporter at the mitochondrial level; adenylate kinase, creatine kinase, and ATP consumption in the cytoplasm; and oxygen transport between capillaries, interstitial fluid, and cardiomyocytes. The integrated model is able to reproduce experimental observations on ATP, ADP, CrP, and inorganic phosphate levels in canine hearts over a range of workload and during coronary hypoperfusion and predicts that cytoplasmic inorganic phosphate level is a key regulator of the rate of mitochondrial respiration at workloads for which the rate of cardiac oxygen consumption is less than or equal to approximately 12 mumol per minute per gram of tissue. At work rates corresponding to oxygen consumption higher than 12 mumol min(-1) g(-1), model predictions deviate from the experimental data, indicating that at high work rates, additional regulatory mechanisms that are not currently incorporated into the model may be important. Nevertheless, the integrated model explains metabolite levels observed at low to moderate workloads and the changes in metabolite levels and tissue oxygenation observed during graded hypoperfusion. These findings suggest that the observed stability of energy metabolites emerges as a property of a properly constructed model of cardiac substrate transport and mitochondrial metabolism. In addition, the validated model provides quantitative predictions of changes in phosphate metabolites during cardiac ischemia.

Adenosine Triphosphate↗

PubMed2006

Computational model explains high activity and rapid cycling of Rho GTPases within protein complexes.

Formation of multiprotein complexes on cellular membranes is critically dependent on the cyclic activation of small GTPases. FRAP-based analyses demonstrate that within protein complexes, some small GTPases cycle nearly three orders of magnitude faster than they would spontaneously cycle in vitro. At the same time, experiments report concomitant excess of the activated, GTP-bound form of GTPases over their inactive form. Intuitively, high activity and rapid turnover are contradictory requirements. How the cells manage to maximize both remains poorly understood. Here, using GTPases of the Rab and Rho families as a prototype, we introduce a computational model of the GTPase cycle. We quantitatively investigate several plausible layouts of the cycling control module that consist of GEFs, GAPs, and GTPase effectors. We explain the existing experimental data and predict how the cycling of GTPases is controlled by the regulatory proteins in vivo. Our model explains distinct and separable roles that the activating GEFs and deactivating GAPs play in the GTPase cycling control. While the activity of GTPase is mainly defined by GEF, the turnover rate is a sole function of GAP. Maximization of the GTPase activity and turnover rate places conflicting requirements on the concentration of GAP. Therefore, to achieve a high activity and turnover rate at once, cells must carefully maintain concentrations of GEFs and GAPs within the optimal range. The values of these optimal concentrations indicate that efficient cycling can be achieved only within dense protein complexes typically assembled on the membrane surfaces. We show that the concentration requirement for GEF can be dramatically reduced by a GEF-activating GTPase effector that can also significantly boost the cycling efficiency. Interestingly, we find that the cycling regimes are only weakly dependent on the concentration of GTPase itself.

Amino Acid Sequence↗

PubMed2002

A model explaining declining rate in hydrolysis of lignocellulose substrates with cellobiohydrolase I (cel7A) and endoglucanase I (cel7B) of Trichoderma reesei.

It is commonly observed that the rate of enzymatic hydrolysis of solid cellulose substrates declines markedly with time. In this work the mechanism behind the rate reduction was investigated using two dominant cellulases of Trichoderma reesei: exoglucanase Cel7A (formerly known as CBHI) and endoglucanase Cel7B (formerly EGI). Hydrolysis of steam-pretreated spruce (SPS) was performed with Cel7A and Cel7B alone, and in reconstituted mixtures. Throughout the 48-h hydrolysis, soluble products, hydrolysis rates, and enzyme adsorption to the substrate were measured. The hydrolysis rate for both enzymes decreases rapidly with hydrolysis time. Both enzymes adsorbed rapidly to the substrate during hydrolysis. Cel7A and Cel7B cooperate synergistically, and synergism was approximately constant during the SPS hydrolysis. Thermal instability of the enzymes and product inhibition was not the main cause of reduced hydrolysis rates. Adding fresh substrate to substrate previously hydrolyzed for 24 h with Cel7A slightly increased the hydrolysis of SPS; however, the rate increased even more by adding fresh Cel7A. This suggests that enzymes become inactivated while adsorbed to the substrate and that unproductive binding is the main cause of hydrolysis rate reduction. The strongest increase in hydrolysis rate was achieved by adding Cel7B. An improved model is proposed that extends the standard endo-exo synergy model and explains the rapid decrease in hydrolysis rate. It appears that the processive action of Cel7A becomes hindered by obstacles in the lignocellulose substrate. Obstacles created by disordered cellulose chains can be removed by the endo activity of Cel7B, which explains some of the observed synergism between Cel7A and Cel7B. The improved model is supported by adsorption studies during hydrolysis.

Adsorption↗

PubMed2006

A single mechanism can explain the speed tuning properties of MT and V1 complex neurons.

A recent study by Priebe et al., (2006) has shown that a small proportion (27%) of primate directionally selective, complex V1 neurons are tuned for the speed of image motion. In this study, I show that the weighted intersection mechanism (WIM) model, which was previously proposed to explain speed tuning in middle temporal neurons, can also explain the tuning found in complex V1 neurons. With the addition of a contrast gain mechanism, this model is able to replicate the effects of contrast on V1 speed tuning, a phenomenon that was recently discovered by Priebe et al., (2006). The WIM model simulations also indicate that V1 neuron spatiotemporal frequency response maps may be asymmetrical in shape and hence poorly characterized by the symmetrical two-dimensional Gaussian fitting function used by Priebe et al., (2006) to classify their cells. Therefore, the actual proportion of speed tuning among directional complex V1 cells may be higher than the 27% estimate suggested by these authors.

Action Potentials↗

PubMed2002

Explaining higher levels of alcohol use among working adolescents: an analysis of potential explanatory variables.

OBJECTIVE: The purpose ofthis study was to explain higher rates of alcohol use observed among working adolescents relative to nonworking adolescents. METHOD: In-home survey data were collected from a representative sample of 4,497 (50% male) 14-17 year olds who participated in the 1998 National Household Survey on Drug Abuse (NHSDA). Multivariate logistic regression analyses were conducted to determine whether relationships between work status and past-month alcohol use and heavy drinking would persist after adjusting for demographic characteristics and selected risk and protective factors in the community, family, school and peer-individual domains. RESULTS: As anticipated, significantly higher rates of past-month alcohol use and heavy drinking were reported by working than nonworking adolescents. Multivariate analyses indicated that the higher rates of past-month alcohol use and heavy drinking among working adolescents were largely explained by demographic characteristics (e.g., age, race/ethnicity), together with perceived drinking norms among adults, other students and friends. CONCLUSIONS: Findings of this study suggest that the relationship between employment and alcohol use among adolescents is largely spurious, due to demographic differences between working and nonworking adolescents. Our findings also suggest, however, that working adolescents are more likely to be exposed to adults and peers who drink, which may be attributed in part to their work setting.

Adolescent↗

PubMed2006

pK(a) values for side-chain carboxyl groups of a PGB1 variant explain salt and pH-dependent stability.

Determination of pK(a) values of titrating residues in proteins provides a direct means of studying electrostatic coupling as well as pH-dependent stability. The B1 domain of protein G provides an excellent model system for such investigations. In this work, we analyze the observed pK(a) values of all carboxyl groups in a variant of PGB1 (T2Q, N8D, N37D) at low and high ionic strength as determined using (1)H-(13)C heteronuclear NMR in a structural context. The pK(a) values are used to calculate the pH-dependent stability in low and high salt and to investigate electrostatic coupling in the system. The observed pK(a) values can explain the pH dependence of protein stability but require pK(a) shifts relative to model values in the unfolded state, consistent with persistent residual structure in the denatured state. In particular, we find that most of the deviations from the expected random coil values can be explained by a significantly upshifted pK(a) value. We show also that (13)C backbone carbonyl data can be used to study electrostatic coupling in proteins and provide specific information on hydrogen bonding and electrostatic potential at nontitrating sites.

Bacterial Proteins↗

PubMed2000

Do clinical markers of barotrauma and oxygen toxicity explain interhospital variation in rates of chronic lung disease? The Neonatology Committee for the Developmental Network.

OBJECTIVE: To explore the hypothesis that variation in respiratory management among newborn intensive care units (NICUs) explains differences in chronic lung disease (CLD) rates. DESIGN: Case-cohort study. SETTING: NICUs at 1 medical center in New York (Babies' and Children's Hospital [Babies']) and 2 in Boston (Beth Israel Hospital and Brigham and Women's Hospital [Boston]). STUDY POPULATION: Four hundred fifty-two infants born at 500 to 1500 g birth weight between January 1991 and December 1993, who were enrolled in an epidemiologic study of neonatal intracranial white matter disorders. CASE DEFINITION: Supplemental oxygen required at 36 weeks' postmenstrual age. RESULTS: The prevalence rates of CLD differed substantially between the centers: 4% at Babies' and 22% at the 2 Boston hospitals, despite similar mortality rates. Initial respiratory management at Boston was more likely than at Babies' to include mechanical ventilation (75% vs 29%) and surfactant treatment (45% vs 10%). Case and control infants at Babies' were more likely than were those at Boston to have higher partial pressure of carbon dioxide and lower pH values on arterial blood gases. However, measures of oxygenation and ventilator settings among case and control infants were similar at the 2 medical centers in time-oriented logistic regression analyses. In multivariate logistic regression analyses, the initiation of mechanical ventilation was associated with increased risk of CLD: after adjusting for other potential confounding factors, the odds ratios for mechanical ventilation were 13.4 on day of birth, 9.6 on days 1 to 3, and 6.3 on days 4 to 7. Among ventilated infants, CLD risk was elevated for maximum peak inspiratory pressure >25 and maximum fraction of inspired oxygen = 1.0 on the day of birth, lowest peak inspiratory pressure >20 and maximum partial pressure of carbon dioxide >50 on days 1 to 3, and lowest white blood count <8 K on days 4 to 7. Even after adjusting for white blood count <8 K and the 4 respiratory care variables, infants in Boston continued to be at increased risk of CLD, compared with premature infants at Babies' Hospital. CONCLUSION: In multivariate analyses, a number of specific measures of respiratory care practice during the first postnatal week were associated with the risk of a very low birth weight infant developing CLD. However, after adjusting for baseline risk, most of the increased risk of CLD among very low birth weight infants hospitalized at 2 Boston NICUs, compared with those at Babies' Hospital, was explained simply by the initiation of mechanical ventilation.

Barotrauma↗

PubMed2000

Different beta-casein fractions in Icelandic versus Scandinavian cow's milk may influence diabetogenicity of cow's milk in infancy and explain low incidence of insulin-dependent diabetes mellitus in Iceland.

OBJECTIVES: To compare children with insulin-dependent diabetes mellitus (IDDM) with controls in Iceland regarding their consumption of cow's milk in infancy, and to investigate the beta-casein fractions in Scandinavian and Icelandic cow's milk. The A1 variant of beta-casein has been shown to be diabetogenic in animal studies, and suggestions have been made that the B variant of beta-casein acts similarly. Differences in the relative proportions of beta-casein fractions might explain the lower incidence of IDDM in Iceland than in Scandinavia. METHODS: A retrospective case-control study on IDDM patients and matching controls was performed in Iceland to compare their diets in infancy. Fifty-five children with IDDM born in Iceland over a 16-year period and randomly collected controls (n = 165) were recruited to the study. Mothers of the children answered questions on breastfeeding habits and on when cow's milk products were introduced. Samples of cow's milk from randomly selected milk batches from the largest consumption areas in Iceland and Scandinavia were collected. The milk samples were freeze-dried and their beta-casein fractions were analyzed using capillary electrophoresis. RESULTS: No significant difference was found between IDDM patients and controls in the frequency and duration of breastfeeding or the first introduction of cow's milk products. The analyses of milk samples showed that the percentage of the A1 and B variants of beta-casein in Icelandic milk was significantly lower than in the milk from the Scandinavian countries. CONCLUSIONS: Cow's milk consumption in infancy is not related to IDDM in Iceland. The lower fraction of A1 and B beta-caseins in Icelandic cow's milk may explain why there is a lower incidence of IDDM in Iceland than in Scandinavia.

Adolescent↗

PubMed2006

To what extent is the protective effect of breastfeeding on future overweight explained by decreased maternal feeding restriction?

OBJECTIVE: Previous studies have found that breastfeeding may protect infants against future overweight. One proposed mechanism is that breastfeeding, as opposed to bottle feeding, promotes maternal feeding styles that are less controlling and more responsive to infant cues of hunger and satiety, thereby allowing infants greater self-regulation of energy intake. The objective of this study was to determine the extent to which the protective effect of breastfeeding on future overweight is explained by decreased maternal feeding restriction. PATIENTS AND METHODS: We studied 1012 mother-infant pairs in Project Viva, an ongoing prospective cohort study of pregnant mothers and their children. The main exposure was breastfeeding duration, assessed at 1 year postpartum. At 3 years of age, the main outcomes were age- and gender-specific BMI z score and the sum of subscapular and triceps skinfold thicknesses, with overweight defined as a BMI > or = 95th percentile. We defined maternal restriction of infant's access to food as strongly agreeing or agreeing, with the following question from the Child Feeding Questionnaire: "I have to be careful not to feed my child too much." To examine the association between breastfeeding duration and our outcomes, we used multivariate linear and logistic models, adjusting for several potential confounders. In subsequent models, we also adjusted for maternal restriction of infant's access to food. RESULTS: The mean duration of breastfeeding was 6.5 months, and 12% of women strongly agreed or agreed with the restriction question. At age 3, mean for BMI z score was 0.47. Each 3-month increment in breastfeeding duration was associated with a reduction of 0.045 BMI z score. After adjusting for maternal restriction, the estimate was -0.039, a 13% attenuation. CONCLUSION: The protective effect of breastfeeding on future overweight seems to be explained only partially by decreased maternal feeding restriction.

Adult↗

PubMed2001

Trying to predict and explain the presence of African trypanosomes in tsetse flies.

Trypanosome infections identified by polymerase chain reaction on field-caught tsetse flies from various locations were analyzed with respect to factors intrinsic and extrinsic to the trypanosome-tsetse association. These factors were then simultaneously analyzed using artificial neural networks (ANNs) and the important factors were identified to predict and explain the presence of trypanosomes in tsetse. Among 4 trypanosome subgroups (Trypanosoma brucei s.l., T. congolense of the 'savannah' and of the 'riverine-forest' types, and T. simiae), the presence of the 2 types of T. congolense was predictable in more than 80% of cases, suggesting that the model incorporated some of the key variables. These 2 types of T. congolense were significantly associated in tsetse. Among all the examined factors, it was the presence of T. congolense savannah type that best explained the presence of T. congolense riverine forest type. One possible biological mechanism would be 'hitchhiking,' as previously suspected for other parasites. The model could be improved by adding other important variables to the trypanosome tsetse associations.

Africa, Western↗

PubMed2006

Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients.

Large between- and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P<0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

Adult↗

PubMed2001

Ten-year changes in smoking among young adults: are racial differences explained by socioeconomic factors in the CARDIA study?

OBJECTIVES: This study investigated whether socioeconomic factors explain racial/ethnic differences in regular smoking initiation and cessation. METHODS: Data were derived from the CARDIA study, a cohort of 5115 healthy adults aged 18 to 30 years at baseline (1985-1986) and recruited from the populations of 4 US cities. Respondents were followed over 10 years. RESULTS: Among 3950 respondents reexamined in 1995-1996, 20% of Whites and 33% of African Americans were smokers, as compared with 25% and 32%, respectively, in 1985-1986. On average, African Americans were of lower socioeconomic status. Ten-year regular smoking initiation rates for African American women, White women, African American men, and White men were 7.1%, 3.5%, 13.2%, and 5.1%, respectively, and the corresponding cessation rates were 25%, 35.1%, 19.2%, and 31.3%. After adjustment for socioeconomic factors, most 95% confidence intervals of the odds ratios for regular smoking initiation and cessation in African Americans vs Whites included 1. CONCLUSIONS: Less beneficial 10-year changes in smoking were observed in African Americans, but socioeconomic factors explained most of the racial disparity.

Adolescent↗