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PubMed1983

Calcium sensitivity and cardiac performance in genetic and renal models of hypertension.

We have compared cardiac performance, hypertrophy and sensitivity to calcium and verapamil of hearts of six to nine-month-old spontaneously hypertensive rats (SHR), two-kidney, one clip renal hypertensive rats (RHR) and age-matched controls. Cardiac output and heart rate were measured using an isolated perfused heart preparation. Mean blood pressure (BP) and heart weight were equally increased in SHR and RHR as was optimal left atrial filling pressure. Cardiac output was increased in both SHR and RHR at any given work load; this improvement was seen especially in SHR and at high aortic pressure (160 cm H2O) was significant in SHR but not RHR. In low [Ca2+], 0.6 mM, cardiac output of RHR and controls fell markedly, but changed little in SHR, whereas in high [Ca2+], 5.1 mM, cardiac performance deteriorated in SHR but was improved in RHR and controls. Verapamil 2 X 10(-7) M reduced Ca2+ responsiveness of RHR and controls threefold but had no effect in SHR. The results suggest there may be an abnormality of cardiac calcium utilization in inherited but not in acquired hypertension.

Animals↗
PubMed2001

Caudal ropivacaine in infants: population pharmacokinetics and plasma concentrations.

BACKGROUND: Ropivacaine is a new long-acting amino-amide local anesthetic. However, there are no data on its use in infants. In the current study, the authors investigated the pharmacokinetics of caudal ropivacaine in 30 infants younger than 12 months. METHODS: Two groups of infants (group 1 [n = 15], aged 0-3 months; group 2 [n = 15], aged 3-12 months) were given a caudal bolus dose of 0.2% ropivacaine (2 mg/kg) and a standardized general anesthetic technique. Serial blood samples taken for up to 12 h were analyzed for total and free ropivacaine using high-performance liquid chromatography. Population pharmacokinetic modeling was performed to yield estimates of clearance, volume of distribution, and absorption rate constant. An analysis of covariates on the kinetic parameters also was made. RESULTS: Median maximum free ropivacaine concentration was significantly higher in group 1 (99 micog/l) than in group 2 (38 microg/l) (P = 0.0002), as was the median free fraction of ropivacaine (10% vs. 5%; P = 0.01). Pharmacokinetic variables of the total population were best described by a one-compartment model with first-order absorption. Mean clearance was 0.31 l.h(-1).kg(-1) (coefficient of variation [CV], 51%), volume of distribution was 2.12 l/kg (CV, 34%), and absorption rate constant was 1.61 h(-1) (CV, 46%). Mean absorption and elimination half-lives were 0.43 and 5.1 h, respectively. Age and percentage of free ropivacaine were significant covariates for clearance. Posterior Bayesian estimates of clearance were significantly higher (38%) in older children. CONCLUSION: Total and free plasma ropivacaine concentrations after caudal ropivacaine (0.2%, 2 mg/kg) in infants were within the range of concentrations previously reported in adults and older children. Age and percentage of free ropivacaine were significant covariates of clearance.

Age Factors↗
PubMed2000

A criterion-referenced multidimensional job-related model prediction capability to perform occupations among persons with chronic pain.

OBJECTIVE: The purpose of this prospective study was an exploration of the construct of the criterion-referenced multidimensional job-related model (CMVA) aimed for predicting patients' with chronic pain capability to perform occupations. METHODS: The study samples were 1) participants (n=84) who at present were not performing employed work (median sick-listing period 12 months) because of chronic pain and 2) participants (n = 104) who at present were performing employed work at least 20 hours of a workweek. The participants had experiences of 40 different occupations classified into five of the occupational categories of Jist's Enhanced Dictionary of Occupational Titles. Data were collected through ten assessment instruments and a structured interview, comprising 54 variables and 465 items. Data were analyzed using multiple regression with forward entering of variables. RESULTS: The CMVA model (Adjusted R^2 0.777, F (4, 183) = 164.067; p<0.001) was able to explain 78% of the variance. CMVA contained the aspects; "the work demands-variable, the person-variable of work life values, the environment-variable of social support and the two occupational performances-variables; self-perceived capability to perform work tasks/the simulated work tasks". CONCLUSIONS: The construct of CMVA was robust suggesting that among persons with chronic pain, the predictors focusing on their capability to perform occupations are of great importance.

Journal Article↗
PubMed2002

Bayesian model adequacy and choice in phylogenetics.

Bayesian inference is becoming a common statistical approach to phylogenetic estimation because, among other reasons, it allows for rapid analysis of large data sets with complex evolutionary models. Conveniently, Bayesian phylogenetic methods use currently available stochastic models of sequence evolution. However, as with other model-based approaches, the results of Bayesian inference are conditional on the assumed model of evolution: inadequate models (models that poorly fit the data) may result in erroneous inferences. In this article, I present a Bayesian phylogenetic method that evaluates the adequacy of evolutionary models using posterior predictive distributions. By evaluating a model's posterior predictive performance, an adequate model can be selected for a Bayesian phylogenetic study. Although I present a single test statistic that assesses the overall (global) performance of a phylogenetic model, a variety of test statistics can be tailored to evaluate specific features (local performance) of evolutionary models to identify sources failure. The method presented here, unlike the likelihood-ratio test and parametric bootstrap, accounts for uncertainty in the phylogeny and model parameters.

Animals↗
PubMed2006

Effects of single-site versus biventricular epicardial pacing on myocardial performance in an immature animal model of atrioventricular block.

INTRODUCTION: Single-site ventricular pacing results in dyssynchronous ventricular activation and may contribute to ventricular dysfunction. We evaluated epicardial biventricular (BiV) pacing as a means of maintaining synchronous ventricular activation in an acute piglet model of AV block with normal ventricular anatomy and function. METHODS AND RESULTS: We used left ventricular (LV) impedance catheters and tissue Doppler imaging to assess the cardiodynamics of immature piglets (n = 6, 33-78 days, 9.35 +/- 0.85 kg). Following catheter ablation of the AV node, a pacemaker was programmed 20 beats per minute above the intrinsic atrial rate. The animals were paced at 5-minute intervals via the following AV sequential configurations: Right atrial appendage (RA)-RV apex (RVA), RA-LV apex (LVA), and RA-biventricular (RVA/LVA). RA-RVA was the experimental control. LV systolic mechanics, measured by the slope of the end-systolic pressure-volume relationship (E(es)), increased with BiV pacing (12.8 +/- 3.4 mmHg/mL, P < 0.02) or single-site LVA pacing (10.6 +/- 3.4 mmHg/mL, P < 0.05) compared with single-site RVA pacing (8.3 +/- 1.4 mmHg/mL). QRS duration lengthened compared with sinus rhythm (42 +/- 8 msec) with either RVA (56 +/- 9 msec, P < 0.02) or LVA (54 +/- 7 msec, P < 0.03), but not with BiV (48 +/- 7 msec, P = 0.08) pacing. Tissue Doppler imaging showed LV dyssynchrony with RVA (septal-to-lateral delay 46.0 +/- 51.7 msec), with return toward normal with LVA (-9.6 +/- 33.6 msec, P < 0.04) or BiV (-4.1 +/- 33.8 msec, P < 0.04) pacing. CONCLUSIONS: In this acute immature piglet model of AV block, LV performance improved with single-site pacing from the LVA and BiV pacing (RVA/LVA), as compared with single-site pacing from the RVA. These changes correlated with tissue Doppler indices of mechanical synchrony, though not necessarily with QRS duration.

Animals↗
PubMed2005

Separating multiple processes in implicit social cognition: the quad model of implicit task performance.

The authors argue that implicit measures of social cognition do not reflect only automatic processes but rather the joint contributions of multiple, qualitatively different processes. The quadruple process model proposed and tested in the present article quantitatively disentangles the influences of 4 distinct processes on implicit task performance: the likelihood that automatic bias is activated by a stimulus; that a correct response can be determined; that automatic bias is overcome; and that, in the absence of other information, a guessing bias drives responses. The stochastic and construct validity of the model is confirmed in 5 studies. The model is shown to provide a more nuanced and detailed understanding of the interplay of multiple processes in implicit task performance, including implicit measures of attitudes, prejudice, and stereotyping.

Automatism↗
PubMed2005

MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability.

BACKGROUND: Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier. METHODS: We set out to construct a model for estimating CDKN2A mutation carrier probability using a cohort of 116 consecutive familial cutaneous melanoma patients evaluated at Massachusetts General Hospital Pigmented Lesion Center between April 2001 and September 2004. Germline CDKN2A and CDK4 status on the familial melanoma cases and clinical features associated with mutational status were then used to build a multiple logistic regression model to predict carrier probability and performance of model on external validation. RESULTS: From the 116 kindreds prone to melanoma in the Boston area, 13 CDKN2A mutation carriers were identified and 12 were subsequently used in the modeling. Proband age at diagnosis, number of proband primaries, and number of additional family primaries were most closely associated with germline mutations. The estimated probability of the proband being a mutation carrier based on the logistic regression model (MELPREDICT) is given by e(L)/(1 + e(L) where L = 1.99+[0.92x(no. of proband primaries)]+[0.74x(no. of additional family primaries)]-[2.11xln(age)]. The mean estimated probabilities for subjects in the Boston dataset were 55.4% and 5.1% for the mutation carriers and non-carriers respectively. In a receiver operator characteristic analysis, the area under the curve was 0.881 (95% confidence interval 0.739 to 1.000) for the Boston model set (n = 116) and 0.803 (0.729 to 0.877) for an external Toronto hereditary melanoma cohort (n = 143). CONCLUSIONS: These results represent the first-iteration logistic regression model to approximate CDKN2A carrier probability. Validation of this model with an external dataset revealed relatively robust performance.

Adolescent↗
PubMed2001

The role of Glu39 in MnII binding and oxidation by manganese peroxidase from Phanerochaete chrysoporium.

Manganese peroxidase (MnP) is a heme-containing enzyme produced by white-rot fungi and is part of the extracellular lignin degrading system in these organisms. MnP is unique among Mn binding enzymes in its ability to bind and oxidize Mn(II) and efficiently release Mn(III). Initial site-directed mutagenesis studies identified the residues E35, E39, and D179 as the Mn binding ligands. However, an E39D variant was recently reported to display wild-type Mn binding and rate of oxidation, calling into question the role of E39 as an Mn ligand. To investigate this hypothesis, we performed computer modeling studies which indicated metal-ligand bond distances in the E39D variant and in an E35D--E39D--D179E triple variant which might allow Mn binding and oxidation. To test the model, we reconstructed the E35D and E39D variants used in the previous study, as well as an E39A single variant and the E35D--E39D--D179E triple variant of MnP isozyme 1 from Phanerochaete chrysosporium. We find that all of the variant proteins are impaired for Mn(II) binding (K(m) increases 20--30-fold) and Mn(II) oxidation (k(cat) decreases 50--400-fold) in both the steady state and the transient state. In particular, mutation of the E39 residue in MnP decreases both Mn binding and oxidation. The catalytic efficiency of the E39A variants decreased approximately 10(4)-fold, while that of the E39D variant decreased approximately 10(3)-fold. Contrary to initial modeling results, the triple variant performed only as well as any of the single Mn ligand variants. Interestingly, the catalytic efficiency of the triple variant decreased only 10(4)-fold, which is approximately 10(2)-fold better than that reported for the E35Q--D179N double variant. These combined studies indicate that precise geometry of the Mn ligands within the Mn binding site of MnP is essential for the efficient binding, oxidation, and release of Mn by this enzyme. The results clearly indicate that E39 is a Mn ligand and that mutation of this ligand decreases both Mn binding and the rate of Mn oxidation.

Amino Acid Substitution↗
PubMed2003

[Evaluation of an animal model in endoscopic surgery of the cerebello-pontine angle].

In the last few years one can observe a dynamic evolution of the minimal invasive surgery, particularly in the field of the skull base surgery. We are now in a front of a big problem with human specimen for dissection. They become rare. Those circumstances force us to look for an animal model to perform dissections. The swine is a very well known model for general and thoracic surgery but we can hear also some attempt of using it in the field of the skull base surgery. Authors tried to deal with the endoscopic anatomy of the cerebello-pontine angle through the retrosigmoid approach. During this study they found that we could find structures which are analogical to human's one. Animal models will not take place of human specimens in surgical training but they can considerably reduce their number. Difficult technique and unusual tools demands a lot of hours of training, and a big part of it can be easily performed on animal models. Authors present their own experience.

Animals↗
PubMed2005

A new mathematical function for describing electrophoretic peaks.

A new model is proposed for characterizing skewed electrophoretic peaks, which is a combination of leading and trailing edge functions, empirically modified to get a rapid recovery of the baseline. The peak model is a sum of square roots and is called thereby "combined square roots (CSR) model". The flexibility of the model was checked on theoretical and experimental peaks with asymmetries in the range of 0-10 (expressed as the ratio of the distance between the center and the trailing edge, and the center and the leading edge of the chromatographic peak, measured at 10% of peak height). Excellent fits were found in all cases. The new model was compared with other three models that have shown good performance in modelling chromatographic peaks: the empirically transformed Gaussian, the parabolic Lorentzian-modified Gaussian, and the Haarhoff-van der Linde function. The latter model was proposed recently to describe electrophoretic peaks. The CSR model offered the highest flexibility to describe electrophoretic peak profiles, even those extremely asymmetrical with long tails. The new function has the advantage of using measurable parameters that allow the direct estimation of peak areas, which is useful for quantitative purposes.

Electrophoresis↗
PubMedDate not supplied

Non-linear renal and biliary clearances of antiviral polyoxometalates in rats.

The polyoxometalates, JM 1591 (K12H2[P2W12O48].24 H2O), JM 1596 (K10[P2W18Zn4(H2O)2O68].20 H2O), and JM 2820 ([Me3NH]8[Si2W18Nb6O77]) have been shown to have potent activity against HIV-1 and HIV-2. The pharmacokinetics of JM 1591, JM 1596 and JM 2820 after intravenous administration of 50 mg/kg were investigated in rats. Renal and biliary clearances of the three compounds were found to be dependent on unbound plasma polyoxometalate concentration. Computer modeling was performed by fitting nonlinear pharmacokinetic models simultaneously to unbound plasma concentration, urinary excretion rate and biliary excretion rate versus time data. The renal clearances of JM 1591 and JM 2820 were described by glomerular filtration, saturated active tubular secretion at all plasma concentrations observed and saturable active tubular reabsorption. The urinary excretion of JM 1596 was characterized by glomerular filtration, saturable active tubular secretion and apparent linear reabsorption. Biliary clearances of all three polyoxometalates were described by a Michaelis-Menten function.

Animals↗
PubMed1991

Modeling plant response to tropospheric ozone: a critical review.

The advantages and disadvantages, benefits and limitations, of a number of published mathematical models representing the effects of ozone on crops and native vegetation are described. Several levels of modeling are addressed: word models, graphic models, mathematical models, and computer simulation implementation. Special attention is given to evaluating: (1) how the interaction between ozone exposure and vegetation effects is quantified, (2) the status of field testing of the model, and (3) the adequacy of information for enabling other investigators to replicate the model for further testing. Original contributions, not previously published, are made in this evaluation in the form of: (1) graphic model flow charts for published models, (2) clarification of mathematical equations for existing models, (3) graphic forms of functional relations comprising portions of models, and (4) graphic displays of model output performance versus observed data. The models that are evaluated cover acute exposure-response models, statistical and mechanistic-process models, including a partial model of ambient exposure versus ozone flux, and uptake. They also cover chronic exposure statistical approaches, including time-series modeling, mechanistic-process models, 'disintegrated' models of forest system simulations, chronic flux density-uptake-response, and models for regional effects assessment in forests and agricultural lands.

Journal Article↗
PubMed2004

Experimental parameters affecting the Morris water maze performance of a mouse model of Down syndrome.

The Ts65Dn mouse is the most studied and genetically the most complete animal model of Down syndrome (DS) available. These mice display many DS-like features, including performance deficits in different behavioral tasks, motor dysfunction, and age-dependent loss of cholinergic markers in the basal forebrain. At present, the only robust data demonstrating a behavioral deficit potentially associated with learning and memory in Ts65Dn mice less than 6 months old have come from studies that used some variation of the Morris water maze task. However, the specific features of the water maze deficits seen in these animals are still poorly defined. This study is an initial attempt to bridge this knowledge gap. We investigated three major factors potentially influencing the performance of Ts65Dn mice in the water maze: (1) order in which the test is executed; (2) age of the animals; and (3) levels of aversiveness associated with the test. Measurements of plasma corticosterone levels and core body temperature after swimming were also carried out in additional subsets of mice. Overall, we found that the behavioral phenotype of Ts65Dn mice was milder than previously described in the literature. Additionally, Ts65Dn mice were significantly more responsive to potential stressors and more prone to swim-induced hypothermia than euploid control animals. More studies are needed to tease out further the potential effects of confounding factors on the performance of Ts65Dn mice.

Age Factors↗
PubMed2006

Bla g 6: a troponin C allergen from Blattella germanica with IgE binding calcium dependence.

BACKGROUND: The known cockroach allergens do not appear to account for the full repertoire of IgE responses. OBJECTIVE: To identify and investigate the importance of other Blattella germanica allergens contributing to cockroach allergy. METHODS: A B germanica cDNA library was screened with pooled sera from patients with cockroach allergy. Three isoallergens of troponin C (Bla g 6) were cloned and expressed in Pichia pastoris. Homology modeling was performed by using Swiss-Model. IgE responses to purified allergens were simultaneously measured in 104 sera by using a fluorescent multiplex array system. The effect of calcium on IgE binding was investigated by ELISA. RESULTS: Three isoallergens, Bla g 6.0101, Bla g 6.0201, and Bla g 6.0301, were identified which share homology with insect troponin Cs and vertebrate calmodulins (61% to 78% and 42% to 44% amino acid identity, respectively) and have 2 EF-hand calcium binding domains. Molecular models of Bla g 6 showed 2 structurally homologous lobes connected by a linker that confers flexibility to the allergen. The prevalence of IgE binding to recombinant Bla g 6 was 14%. Calcium depletion by 10 mmol/L ethyleneglycol-bis-(beta-aminoethylether)-N,N,N',N'-tetraacetic acid did not significantly affect IgE binding in most cases. Interestingly, addition of 10 mmol/L CaCl2 after calcium depletion increased IgE binding by approximately 2-fold, a finding not previously reported for calcium binding allergens. CONCLUSION: Bla g 6 is a troponin allergen with a calcium dependent IgE reactivity that may be involved in muscle contraction. CLINICAL IMPLICATIONS: Bla g 6 homologous allergens may occur among other insects and cause cosensitization or allergenic cross-reactivity.

Allergens↗
PubMed2005

Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain.

The saphenous partial ligation (SPL) model is a new, easily performed, rodent model of neuropathic pain that consists of a unilateral partial injury to the saphenous nerve. The present study describes behavioral, pharmacological and molecular properties of this model. Starting between 3 and 5 days after surgery, depending on the modality tested, animals developed clear behaviors indicative of neuropathic pain such as cold and mechanical allodynia, and thermal and mechanical hyperalgesia compared with naive and sham animals. These pain behaviors were still present at 1 month. Signs of allodynia also extended to the sciatic nerve territory. No evidence of autotomy or bodyweight loss was observed. Cold and mechanical allodynia but not thermal and mechanical hyperalgesia was reversed by morphine (4 mg/kg i.p.). The cannabinoid receptor agonist WIN 55,212-2 (5 mg/kg i.p.) improved signs of allodynia and hyperalgesia tested except for mechanical hyperalgesia. Gabapentin (50 mg/kg i.p.) was effective against cold and mechanical allodynia but not hyperalgesia. Finally, amitriptyline (10 mg/kg i.p.) failed to reverse allodynia and hyperalgesia and its administration even led to hyperesthesia. Neurobiological studies looking at the expression of mu opioid receptor (MOR), cannabinoid CB(1) and CB(2) receptors showed a significant increase for all three receptors in ipsilateral paw skin, L3-L4 dorsal root ganglia and spinal cord of neuropathic rats compared with naive and sham animals. These changes in MOR, CB(1) and CB(2) receptor expression are compatible with what is observed in other neuropathic pain models and may explain the analgesia produced by morphine and WIN 55,212-2 administrations. In conclusion, we have shown that the SPL is an adequate model that will provide a new tool for clarifying peripheral mechanisms of neuropathic pain in an exclusive sensory nerve.

Amines↗
PubMed2000

A frequency domain inversion method applied to propagation models in unconsolidated granular materials

The measurement setup consists of a water filled tank within which a smaller Plexiglas tank containing a known sediment is placed. This provides a Plexiglas-sediment-Plexiglas configuration, which is then used in conjunction with transducers and a pulser-receiver for a transmission and reflection experiment. The aim of this work is to find some physical parameters of the sediment from these measurements. A general viscoelastic model that considers losses due to absorption and dispersion along the propagation of the wave through the sediments is proposed. A rational transfer function is used to model the viscoelastic modulus of the bulk sediments, and comparisons with constant Q viscoelastic modelling and Biot modelling are performed. The estimation of the model parameters is elaborated using a maximum likelihood estimator in the frequency domain.

Journal Article↗
PubMed2000

Radiation pneumonitis after breast cancer irradiation: analysis of the complication probability using the relative seriality model.

BACKGROUND: Toxicity of the respiratory system is quite common after radiotherapy of thoracic tumors; breast cancer patients represent one of the groups for which there is also a long expected survival. The quantification of lung tissue response to irradiation is important in designing treatments associated with a minimum of complications and maximum tumor control. METHODS: The study population consisted of 68 patients who received irradiation for breast cancer at Stage II. Radiation pneumonitis was retrospectively assessed on the basis of clinical symptoms and radiological findings. For each patient, a measure of the exposure (i.e., the lung dose-volume histogram [DVH]) and a measure of the outcome was available. Based on these data, a maximum likelihood fitting to the relative seriality model was performed. The uncertainties of the model parameters were calculated and their impact on the dose-response curve was studied. The optimum parameter set was then applied to 5 other patient groups treated for breast cancer, and the normal tissue complication probability (NTCP) was calculated. Each group was individuated by the radiotherapy treatment technique used; the dose distribution in the lung was described by a mean DVH and the incidence of radiation pneumonitis in each group was known. Lung radiosensitivity was assumed to be homogeneous through all of the calculations. RESULTS: The relative seriality model could describe the dataset. The volume effect was found to be relevant in the description of radiation pneumonitis. Age was found to be associated with increased risk of radiation pneumonitis. Two distinct dose-response curves were obtained by splitting the group according to age. The impact of the parameter uncertainties on the dose-response curve was quite large. The parameter set determined could be used predictively on 3 of the 5 patient groups. CONCLUSION: The complication data could be modeled with the relative seriality model. However, further independent datasets, classified according to the same endpoint, must be analyzed before introducing NTCP modeling in clinical practice.

Age Factors↗