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PubMed2006

Population pharmacokinetics of oxycodone in children 6 months to 7 years old.

Young children are often undertreated for pain. One barrier to effective pain treatment is understanding the pharmacokinetic behavior of analgesics in this age group. Oxycodone is a commonly prescribed opioid for severe pain, yet little is known about its pharmacokinetics in young children. This article used population pharmacokinetic modeling to synthesize pharmacokinetic data from several studies into a model. A single population model that described the observed pharmacokinetics was developed. The combined data were best described with a 2-compartment linear model with different first-order absorption rates depending on route of administration. Weight was found to significantly influence both clearance (CL) and volume of distribution (Vd). The following model adequately describes the population pharmacokinetic profile of oxycodone where absolute bioavailability (F) is estimated for each administration route: CL/F=55x(body weight/70)0.87; V/F=86x(body weight/70)1.16. The interindividual coefficients of variation in CL and Vd were 20.2 and 19.7%, respectively. This finding confirms that the allometric scaling using the above model explained most of the variability in exposure observed among children. This model confirms using a weight-based dose for oxycodone without adjustment for age between 6 months and 7 years and is valuable for evaluating dosing schedules and dosing routes.

Analgesics, Opioid↗

PubMedDate not supplied

Mapping the SF-12 to the EuroQol EQ-5D Index in a national US sample.

BACKGROUND: Preference scores for the Medical Outcomes Study (MOS) SF-12 would enable its use in cost-effectiveness analyses. Previous mapping studies of MOS instruments top reference-based instruments have not examined performance in national samples. PARTICIPANTS: 15,000 adults in the 2000 Medical Expenditure Panel Survey annual survey including the SF-12 and EQ-5D Index. METHODS: Regression of the EQ-5D Index scores onto the physical and mental component summary scores of the SF-12, testing 2nd-4th degree polynomial and spline models, including and excluding sociodemographics. RESULTS: A 2nd degree polynomial model explained 63% of the variance in EQ-5D scores, with robust internal and external validation. More complex mod-els explained minimally additional variance. Compared with EQ-5D valuations, prediction models overestimated the lowest health states (6% of the population). CONCLUSIONS: The mapped SF-12 yields usable preference-scaled scores, with some caution for the lowest health states.

Adult↗

PubMed2004

A model of perceived risk for colorectal cancer among Japanese Americans.

BACKGROUND: Despite the higher rate of colorectal cancer (CRC) among Japanese Americans, little is known about their risk perceptions. The objective of this study was to test an exploratory model explaining psychosocial pathways to perceived risk of CRC. METHODS: The postulated model was tested using path analysis with data from a random sample of 306 Japanese Americans aged 30 and older. RESULTS: The model fit the data very well: chi(2)(10) = 10.22, P = .42; goodness-of-fit index = .993; comparative fit index = .999; and root mean square are of approximation = .008. Cancer fear exerted the strongest effect on perceived risk followed by family history. CONCLUSIONS: Risk communication for Japanese Americans should be tailored to individual emotional patterns associated with cancer to alleviate fear that may impede accurate risk self-assessment.

Acculturation↗

PubMed2003

The mitotic checkpoint: a signaling pathway that allows a single unattached kinetochore to inhibit mitotic exit.

The mitotic checkpoint is a failsafe mechanism for the cell to ensure accurate chromosome segregation during mitosis. Mutations in genes encoding essential checkpoint proteins lead to chromosome instability and promote carcinogenesis. The BUB and MAD genes are essential components of the mitotic checkpoint pathway. BUB and MAD inhibit the ubiquitin ligase activity of the Anaphase Promoting Complex/Cyclosome (APC/C) during mitosis to ensure cells with unaligned chromosomes do not prematurely enter anaphase. Two models explain how the APC/C is inhibited by the checkpoint. The Sequestration Model postulates that Mad2 and BubR1 bind and sequester Cdc20, an APC/C activator, away from APC/C so substrates whose destruction drives mitotic exit are no longer ubiquitinated. In this model, the unattached kinetochore is postulated to catalytically convert Mad2 to a form that binds Cdc20. In the Direct Inhibition Model, the Mitotic Checkpoint Complex (MCC) consisting of BubR1, Bub3, Mad2 and Cdc20 binds and inhibits the APC/C independently of the kinetochore. However, the "wait anaphase" signal generated by unattached kinetochores sensitizes the APC/C to prolonged inhibition by the MCC. A single unattached kinetochore is proposed to amplify the "wait anaphase" signal through a kinase cascade involving checkpoint kinases such as hBubR1, hBub1 and Mps1.

Anaphase↗

PubMed1991

Determinants of focal and segmental glomerulosclerosis in the rat after renal ablation. Evidence for involvement of macrophages and lipids.

The present study was undertaken to estimate the relative impact of a number of clinicopathologic and glomerular structural changes on severity and composition of focal and segmental glomerular sclerosis (FGS) in rats subjected to renal ablation. Groups of eight 1 1/2-nephrectomized (Nx) and sham-operated (Sh) male Wistar rats were studied at intervals of 2, 4, 8, 12, and 16 weeks. At sacrifice, kidney tissue was embedded in glycolmethacrylate to achieve optimal morphology for light microscopy, immunohistochemistry, and morphometry. FGS lesions were defined by the presence of focal and segmental glomerular scarring and collapse of the glomerular tuft with increased mesangial cellularity (MC), mesangial matrix expansion (MME), and adhesions between the tuft and Bowman's capsule (Adh). The severity of FGS and extent of MC, MME, and Adh was graded seimquantitatively to establish an injury score. The dependence of FGS injury score and of the scores of MC, MME, and Adh on a variety of clinicopathologic and glomerular structural alterations, taking account of possible correlations among them, was estimated with partial correlation and multiple linear regression analysis. The structural parameters included hyalinosis (H, PAS stain), glomerular lipid deposits (GLD, Oil Red O stain), glomerular volume expansion (GVE, morphometry), glomerular cellular proliferation (labeling of S-phase cells by 5 bromo-2'-deoxyuridine, BrdU)--and glomerular influx of macrophages (m phi), T cells, natural killer cells, and granulocytes (immunohistochemistry with mouse monoclonal antibodies). The clinicopathologic variables were urinary protein excretion (UP), fasting serum cholesterol levels (FChol), body weight (BW), total wet kidney weight (KW), heart weight (HW), and systolic blood pressure (SBP). The best fitting linear regression model, explaining 91% of the total variation of the FGS injury score (multiple r2 = 0.91), included UP as the main clinical, and H as the main structural variable. MC was explained best by BrdU incorporation (multiple r2 = 0.77). The optimal regression model describing MME contained the variables H, m phi, and FChol (multiple r2 = 0.84). The extent of Adh formation was optimally described by UP, m phi, and FChol (multiple r2 = .88). In conclusion, although none of these statistically significant associations indicate causal relationships, they identify - in addition to UP, H, and cellular proliferation - FChol as a major clinical determinant and glomerular m phi influx as a major structural alteration associated with FGS in the setting of renal ablation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Limitations of the standard linear solid model of intervertebral discs subject to prolonged loading and low-frequency vibration in axial compression.

The purpose of this study was to answer the following questions: (1) Can the standard linear solid model for viscoelastic material simulate the influence of disc level and degeneration on the ability of a disc to withstand prolonged loading and low-frequency vibration? (2) How well does the SLS model explain the relationship between the ability of a disc to resist prolonged loading and its ability to resist dynamic loads and dissipate energy when subjected to low-frequency vibration? Responses of human thoracic and lumbar discs were measured in axial compression under a constant load, and for cyclic deformations at three frequencies. Parameters of the SLS model for each disc were determined by a least-squares fit to the experimental creep response. The model was subsequently used to predict the disc's response to cyclic deformations. The SLS model was able to qualitatively simulate the effects of disc level and degeneration on the ability of an intervertebral disc to resist both prolonged loading and low-frequency vibration. However, the model underestimated the stress relaxation, dynamic modulus and hysteresis of thoracic and lumbar discs subjected to low-frequency vibration. The SLS model was unable to explain the relationship between the ability of a disc to resist prolonged loading and its ability to resist dynamic loads and dissipate energy when subjected to low-frequency vibration. Although in the lumbar discs the steady-state predictions of the SLS model were significantly correlated to the experimental response, the strength of model predictions decreased with increasing frequency, particularly for hysteresis.

Adult↗

PubMed1992

Ion channel enzyme in an oscillating electric field.

To explain the electrical activation of several membrane ATPases, an electroconformational coupling (ECC) model has previously been proposed. The model explained many features of experimental data but failed to reproduce a window of the field intensity for the stimulated activity. It is shown here that if the affinities of the ion for the two conformational states of the transporter (one with binding site on the left side and the other on the right side of the membrane) are dependent on the electric field, the field-dependent transport can exhibit the observed window. The transporter may be described as a channel enzyme which opens to one side of the membrane at a time. It retains the energy-transducing ability of the earlier ECC models. Analysis of the channel enzyme in terms of the Michaelis-Menten kinetics has been done. The model reproduced the amplitude window for the electric field-induced cation pumping by (Na,K)-ATPase.

Adenosine Triphosphatases↗

PubMed1999

Explaining variations in prescribing costs: results from a comparison of nursing home patients with matched pairs living in the community.

OBJECTIVES: To examine and explain variations in prescribing costs associated with nursing home patients and patients matched by age and sex living in the community. DESIGN: A 12-month case control study. SUBJECTS: All nursing home residents over 65-years-old registered with nine general practices and patients matched with them for age and sex living in the community. METHOD: Multivariate regression analysis of variations in monthly GP prescribing costs. RESULTS: Multivariate regression models explaining cost variations in terms of the GP practice delivering care and patients' age and sex had little explanatory power (R(2)=0.07 for nursing home patients, R(2)=0.03 for matched pairs). A fuller model for nursing home patients only, incorporating the patient's Barthel score and initial diagnosis as additional explanatory variables, added little to the explanatory power of the model (R(2)=0.16). CONCLUSION: The ability of the multivariate models used here to explain variations in prescribing costs among a group of elderly patients is poor. Adjusting weighted capitation formulae with respect to older patients to take account of such information or referring to it in negotiations on prescribing budgets would not appear to be warranted.

Age Factors↗

PubMed2001

Cerebral venous blood outflow: a theoretical model based on laboratory simulation.

OBJECTIVE: The cerebrovascular bed and cerebrospinal fluid circulation have been modeled extensively except for the cerebral venous outflow, which is the object of this study. METHODS: A hydraulic experiment was designed for perfusion of a collapsible tube in a pressurized chamber to simulate the venous outflow from the cranial cavity. CONCEPT: The laboratory measurements demonstrate that the majority of change in venous flow can be attributed to either inflow pressure when the outflow is open, or the upstream transmural pressure when outflow is collapsed. On this basis, we propose a mathematical model for pressure distribution along the venous outflow pathway depending on cerebral blood flow and intracranial pressure. The model explains the physiological strong coupling between intracranial pressure and venous pressure in the bridging veins, and we discuss the limits of applicability of the Starling resistor formula to the venous flow rates. The model provides a complementary explanation for ventricular collapse and origin of subdural hematomas resulting from overshunting in hydrocephalus. The noncontinuous pressure flow characteristic of the venous outflow is pinpointed as a possible source of the spontaneous generation of intracranial slow waves. CONCLUSION: A new conceptual mathematical model can be used to explain the relationship between pressures and flow at the venous outflow from the cranium.

Blood Flow Velocity↗

PubMed2000

Variations in GP nursing home patient workload: results of a multivariate analysis.

The number of old people living in UK nursing homes has increased substantially over the past 15 y. There is evidence that such patients generate larger workloads for primary carers than do those of similar age and sex living in their own homes. Clearly, any extra workload involved in providing primary care services to nursing home patients, needs to be reflected in the resources afforded general practitioners (GPs) who are tasked with its provision. By the same token variations in workloads between patients need to be examined and explained for any insights these might provide on funding issues. To examine and explain variations in GP workload associated with nursing home patients and determine the implications of these for GP funding, a 12 month case control study of all nursing home residents over 65 y old registered with nine general practices was undertaken. A multivariate regression analysis was used to examine variations in GP workload associated with 270 nursing home patients. Multivariate regression models explaining the variation in workload cost per month in terms of the GP practice delivering care and patients age and sex had little explanatory power (R(2)=0.07). A fuller method including the patient's Barthel score and initial diagnosis as additional explanatory variables added little to the explanatory power of the model (R(2)=0.12). The ability of the multivariate models used here to explain the variation in GP workload was poor. GPs may require an allowance to compensate for differences in workload associated with nursing home patients but adjusting these payments for differences in age, sex, initial diagnosis or the other variables included in this analysis would not appear to be supported.

Aged↗

PubMed1999

Historical and biomechanical analysis of integration and dissociation in molluscan feeding, with special emphasis on the true limpets (Patellogastropoda: Gastropoda).

Modifications of the molluscan feeding apparatus have long been recognized as a crucial feature in molluscan diversification, related to the important process of gathering energy from the environment. An ecologically and evolutionarily significant dichotomy in molluscan feeding kinematics is whether radular teeth flex laterally (flexoglossate) or do not (stereoglossate). In this study, we use a combination of phylogenetic inference and biomechanical modeling to understand the transformational and causal basis for flexure or lack thereof. We also determine whether structural subsystems making up the feeding system are structurally, functionally, and evolutionarily integrated or dissociated. Regarding evolutionary dissociation, statistical analysis of state changes revealed by the phylogenetic analysis shows that radular and cartilage subsystems evolved independently. Regarding kinematics, the phylogenetic analysis shows that flexure arose at the base of the Mollusca and lack of flexure is a derived condition in one gastropod clade, the Patellogastropoda. Significantly, radular morphology shows no change at the node where kinematics become stereoglossate. However, acquisition of stereoglossy in the Patellogastropoda is correlated with the structural dissociation of the subradular membrane and underlying cartilages. Correlation is not causality, so we present a biomechanical model explaining the structural conditions necessary for the plesiomorphic kinematic state (flexoglossy). Our model suggests that plesiomorphically the radular teeth must flex laterally as they pass over the bending plane as a result of the mechanical restrictions in the flexible but inelastic subradular membrane and close association between subradular membrane and cartilages. Relating this model to the specific character states of the clades, we conclude that lack of flexure in patellogastropods is caused by the dissociation of the subradular membrane and cartilage supports.

Animals↗

PubMed2004

Predictors of plasma lead among lithographic print shop workers in Mexico City.

BACKGROUND: Plasma lead is considered a biological marker that reflects the fraction of lead in blood that is toxicologically available. We examined the relationship between plasma lead and other biomarkers of lead exposure in 69 lithographic print shop workers. METHODS: Lead was measured in plasma and whole blood (by inductively coupled plasma-magnetic sector mass spectrometry), in bone (by 109Cd X-ray fluorescence), and in hand wipes and occupational air samples. Personal hygiene habits at work were surveyed. RESULTS: Mean age was 47 years and 86% (n=59) were men. Mean lead levels were 0.3 microg/L in plasma, 11.9 microg/dL in blood, 46.7 microg/g in patella, and 27.6 microg/g in tibia. Taken together, two multivariate linear models explained 57% of variability in plasma lead levels. Predictors for the first model were lead in patella (beta = 0.006), blood (beta = 0.008), and hygiene index (beta = -0.11). Predictors for the second model were lead in tibia (beta = 0.008), blood (beta = 0.008), and hygiene index (beta = -0.13). CONCLUSIONS: This study demonstrates that accumulated bone stores and hygiene habits are both significant independent predictors of plasma lead levels in active workers at this print shop.

Air Pollutants, Occupational↗

PubMed1987

In vitro studies of microwave-induced cataract. II. Comparison of damage observed for continuous wave and pulsed microwaves.

Depth of damage caused by pulsed (PU) and continuous wave (CW) microwaves was estimated by scanning electron microscopy in rat lenses fixed immediately, after irradiation in vitro in circulating thermostatically controlled buffered saline. Pulses of 10 microseconds width and 24 kW peak power were delivered to the lens at different repetition rates in order to permit the same total energy to be delivered during 6, 20 or 60 min of irradiation at specific absorption rate (SAR) values of 0, 5.75, 11.5, 23, 69, 231 and 750 mW g-1; total energy [power (pow) x time] deposited in the lens was 0, 0.23, 0.46, 1.38, 4.6, and 15 W min g-1. Damage (granular degeneration of cells at the lens equator) was measured at the apex of penetration of the degeneration. The depth of degeneration (dep) of Pu or CW was compared either: (1) by a one-way analysis of variance (ANOVA) for the CW data alone and the 11 combinations of (pow x time); or (2) by using two alternative models to fit the data, to permit experimental distinguishment between: (a) reciprocal effects of pow x time; and (b) separate effects. Using the ANOVA analysis, the Pu mode of irradiation resulted in more damage at the same average power for every combination tested except one (23 mW g-1, 6 min). Although the separate-effects models explained more of the variation in depth of damage, the reciprocal effects model may provide an adequate fit for practical purposes and has the advantage of greater simplicity. For both models, the pulsed irradiation mode produced 4.7 times the depth of damage caused by CW irradiation. These results are discussed in relation to previous Pu-CW comparisons. It is proposed that this additional damage at the same average power is caused by thermoelastic expansion (TEE).

Animals↗

PubMed2006

Three-dimensional quantitative structure-activity relationships of ATP-sensitive potassium (KATP) channel openers belonging to the 3-alkylamino-4H-1,2,4-benzo- and 3-alkylamino-4H-1,2,4-pyridothiadiazine 1,1-dioxide families.

Recent studies have demonstrated that selective activation of pancreatic ATP-sensitive potassium (KATP) channels could be of clinical value in the treatment of type I and type II diabetes, obesity, and hypersinsulinemia. Taking into account these promising therapeutic opportunities, we have explored the 3-alkylamino-4H-1,2,4-pyrido- and 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide families. Among these series, numerous drugs were identified as highly potent and selective openers of either the pancreatic or the aortic KATP channels. Thanks to comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), quantitative structure-activity relationship approaches using more than 100 compounds, pharmacophoric models explaining the activity and selectivity of the drugs have been elaborated. These models highlighted the importance of several chemical regions for KATP channel activation and could be very helpful for future improvement of drug potency, selectivity, or both. Moreover, an original CoMSIA analysis, using a selectivity index (SI) as a dependent variable, was also performed with the aim of identifying the structural parameters influencing tissue selectivity.

Adenosine Triphosphate↗

PubMed2002

Seeing strangers or announcing "danger": galectin-3 in two models of innate immunity.

Recent investigations on the molecular mechanisms by which our immune system recognizes infections and initiates defense against those infections have led to the proposition of two models explaining the way our innate immunity system functions; the self-nonself model and the Danger model. In this review, the roles of galectin-3 in innate immunity against infections--host-pathogen interactions--will be discussed. We will shed light on the potential contribution of a beta-galactoside binding mammalian lectin, galectin-3 as a molecule implicated in innate immunity from the angle of both the self-nonself model and the Danger model.

Animals↗

PubMed1999

Relations of diabetes intrusiveness and personal control to symptoms of depression among adults with diabetes.

The generalizability of a model linking illness characteristics to psychosocial well-being was tested in a cross-sectional study of 237 adults with type 2 diabetes. It was hypothesized that diabetic complications increase illness intrusiveness, which in turn increases depressive symptomatology either directly or indirectly by reducing personal control over health outcomes. Illness intrusiveness was defined as the result of disruptions of valued activities and interests due to constraints imposed by the illness. An excellent fit of this model to the data was found using structural equation modeling. The model explained 65% of the variance in depressive symptomatology. Assessment of an alternative model excluding personal control suggested that the extent to which diabetes intrudes in life, rather than diabetic complications per se or personal control, is a key factor in relation to depressive symptomatology in individuals with diabetes.

Adult↗

PubMed2002

Physiologic, psychologic, and health predictors of 6-minute walk performance in older people.

OBJECTIVE: To determine the extent to which physiologic, psychologic, and health-related factors predict 6-minute walk distance (6MWD) in older people. DESIGN: Cross-sectional study. SETTING: Retirement villages. PARTICIPANTS: A total of 515 people between the ages of 62 and 95 years (mean +/- standard deviation, 79.5+/-6.4y) residing in retirement villages in Australia. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Quantitative tests of vision, strength, peripheral sensation, reaction time, and balance and short Mini-Mental State Examination, Geriatric Depression Scale, Positive and Negative Affect Schedule (PANAS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and 6MWD. RESULTS: All physiologic, psychologic, and health scores were significantly associated with 6MWD. Multiple regression analysis revealed that 10 factors (visual contrast sensitivity, lower-limb strength, simple reaction time, postural sway, maximal balance range, PANAS positive scale score, SF-36 pain score, number of medications used, SF-36 general health subscale score, age) were significant and independent predictors of 6MWD performance. Of these measures, strength, maximal balance range, medication use, and age explained the largest proportions of the variance in 6MWD. The final regression model explained over half (52.5%) of the variance in 6MWD (multiple r=.72). CONCLUSIONS: In older people, 6MWD depends on multiple physiologic, psychologic, and health factors. Thus, 6MWD appears to provide a measure of overall mobility and physical functioning in this population group rather than a specific measure of cardiovascular fitness.

Age Distribution↗

PubMed1987

Conserved putative signals in 3' intron junctions in rodents.

Several 3' splice signals are known todate. At the 3' splice site an AG doublet is frequently found. Just upstream of the splice site there is a string of 6-11 pyrimidines. More recently it has been found that one of the stages in the splicing process involves formation of a lariat, in which the 5' end of the intron forms a 2'-5' branch with an A residue located 18-37 nucleotides upstream of the 3' splice site. The branching-point consensus is weakly defined and consists of the sequence YNYTRAY, where Y is a pyrimidine, R a purine and N any base. The A in the sixth position is the one with which branching occurs. Here we present the results of extensive searches for additional putative signals around the branching-point consensus and the 3' splice site in rodent nuclear precursor mRNAs. The signals obtained for the over 370 rodent introns are compared with those found in a larger eukaryotic sample containing over 900 nuclear pre-mRNA introns. Of particular interest are GGGA and CCCA. In both analyses GGGA occurs about 60 nucleotides upstream and CCCA is found 3-40 nucleotides downstream from the 3' splice site. A model explaining some of the putative signals discussed here is also proposed. This model involves formation of alternate stem-loop structures around the branching point and 3' splice site. Such signals and structures can possibly aid in protein or nucleoprotein branching point and splice site recognition.

Animals↗