Population pharmacokinetics of tacrolimus in children who receive cut-down or full liver transplants

Background. The aim of this study was to investigate the population pharmacokinetics of tacrolimus in pediatric liver transplant recipients and to identify factors that may explain pharmacokinetic variability. Methods. Data were collected retrospectively from 35 children who received oral immunosuppressant therapy with tacrolimus. Maximum likelihood estimates were sought for the typical values of apparent clearance (CL/F) and apparent volume of distribution (V/F) with the program NONMEM. Factors screened for influence on the pharmacokinetic parameters were weight, age, gender, postoperative day, days since commencing tacrolimus therapy, transplant type (whole child liver or cut-down adult liver), liver function tests (bilirubin, alkaline phosphatase [ALP], aspartate aminotransferase [AST], gamma -glutamyl transferase [GGT], alanine aminotransferase [ALT]), creatinine clearance, hematocrit, corticosteroid dose, and concurrent therapy with metabolic inducers and inhibitors of tacrolimus. Results. No clear correlation existed between tacrolimus dosage and blood concentrations (r(2) =0.003). Transplant type, age, and liver function test values were the most important factors (P

Mark-recapture may reveal more about ecology than about population trends: Demography of a threatened ghost bat (Macroderma gigas) population

Since European settlement in Australia, the geographical range of ghost bats (Macroderma gigas) has contracted northwards. Ghost bats are thought to occur in disjunct populations with little interpopulation migration, raising concerns over the current status and future viability of the southernmost colony, which has also been threatened by mining activity. To address these concerns, demographic parameters of the southernmost colony were estimated from a mark-recapture study conducted during 1975-1981. Female bats gave birth to a single young in late spring, but only 40% (22-70%, 95% CI) of females bred in their second year, increasing to 93% (87-97%, 95% CI) for females greater than or equal to 2 years old. Sixty-five percent of juveniles caught were female. Annual adult survival ranged between 0.57-0.77 for females and 0.43-0.66 for males, and was lowest over winter-spring and greatest in autumn-winter. Juvenile survival for the first year ranged between 0.35-0.46 for females and 0.29-0.42 for males. Adult survival varied among seasons, was negatively associated with rainfall, but was not associated with temperature beyond being lower in late winter. Poor survival may result from the inferior daytime roosts that bats must use if water seepage forces them to leave their normal roosts. Although these age-specific rates of fecundity and survival suggested a declining population, mark-recapture estimates of the population trend indicated stability over the study period. Counts at daytime roosts also suggested a population decline, but were considered unreliable because of an increasing tendency of bats to avoid detection. It is therefore likely that some assumptions in estimating survival were violated. These results provide a caution against the uncritical use of population projections derived from mark-recapture estimates of demographic parameters, and the use of untested indices as the basis for conservation decisions.

Inferring population history from microsatellite and enzyme data in serially introduced cane toads, Bufo marinus

Much progress has been made on inferring population history from molecular data. However, complex demographic scenarios have been considered rarely or have proved intractable. The serial introduction of the South-Central American cane Load Bufo marinas in various Caribbean and Pacific islands involves four major phases: a possible genetic admixture during the first introduction, a bottleneck associated with founding, a transitory, population boom, and finally, a demographic stabilization. A large amount of historical and demographic information is available for those introductions and can be combined profitably with molecular data. We used a Bayesian approach to combine this information With microsatellite (10 loci) and enzyme (22 loci) data and used a rejection algorithm to simultaneously estimate the demographic parameters describing the four major phases of the introduction history,. The general historical trends supported by microsatellites and enzymes were similar. However, there was a stronger support for a larger bottleneck at introductions for microsatellites than enzymes and for a more balanced genetic admixture for enzymes than for microsatellites. Verb, little information was obtained from either marker about the transitory population boom observed after each introduction. Possible explanations for differences in resolution of demographic events and discrepancies between results obtained with microsatellites and enzymes were explored. Limits Of Our model and method for the analysis of nonequilibrium populations were discussed.

Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Population pharmacokinetics of tacrolimus in adult kidney transplant recipients

Objectives: The aims of this study were to investigate the population pharmacokinetics of tacrolimus in adult kidney transplant recipients and to identify factors that explain variability. Methods: Population analysis was performed on retrospective data from 70 patients who received oral tacrolimus twice daily. Morning blood trough concentrations were measured by liquid chromatography-tandem mass spectrometry. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F), with the use of NONMEM (GloboMax LLC, Hanover, Md). Factors screened for influence on these parameters were weight, age, gender, postoperative day, days of tacrolimus therapy, liver function tests, creatinine clearance, hematocrit fraction, corticosteroid dose, and potential interacting drugs. Results. CL/F was greater in patients with abnormally low hematocrit fraction (data from 21 patients only), and it decreased with increasing days of therapy and AST concentrations (P

Modelling the activated sludge flocculation process combining laser light diffraction particle sizing and population balance modelling (PBM)

A technique based on laser light diffraction is shown to be successful in collecting on-line experimental data. Time series of floc size distributions (FSD) under different shear rates (G) and calcium additions were collected. The steady state mass mean diameter decreased with increasing shear rate G and increased when calcium additions exceeded 8 mg/l. A so-called population balance model (PBM) was used to describe the experimental data, This kind of model describes both aggregation and breakage through birth and death terms. A discretised PBM was used since analytical solutions of the integro-partial differential equations are non-existing. Despite the complexity of the model, only 2 parameters need to be estimated: the aggregation rate and the breakage rate. The model seems, however, to lack flexibility. Also, the description of the floc size distribution (FSD) in time is not accurate.

Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte, Philippines: I. Assessment of 'resistance' versus 'susceptibility' to S-japonicum infection

This study describes the categorical classification of 155 individuals living in an endemic village in Macanip, Leyte, Philippines as 'resistant' or 'susceptible' to Schistosoma japonicum infection using available exposure, infection and reinfection data collected from a 3-year water contact (WC) study. Epidemiological parameters including age, sex, and infection intensities in relation to observed reinfection patterns are also described. This classification was used in subsequent immunological studies described in two accompanying papers to identify protective immune mechanisms among resistant individuals induced by defined candidate vaccine molecules for S. japonicum. The study suggests that individuals who were most vulnerable to rapid reinfection were children belonging to the 5-14 age group. A drop in incidence at age group 15-19 and decreased intensity of infection starting at this age group and older (15+) suggests development of immunity. Controlling for the effect of the other variables, a multivariate analysis showed significant association for sex, in that females were more likely to be resistant. This implies that other than acquired immunity to infection, some age-dependent host factors may also play an important role in the overall changes of reinfection patterns seen in schistosomiasis japonica in this population. Crown Copyright (C) 2002 Published by Elsevier Science B.V. All rights reserved.

Differences in lung function, growth parameters and frequency of hospital admissions between adolescents with cystic fibrosis-related diabetes and controls

As survival of patients with CF increases,glucose intolerance and cystic fibrosisrelated diabetes (CFRD),ar e increasingly recognised common complications. CFRD may be preceded by a pre-diabetic state. Using markers identified as being associated with CFRD may improve targeted screening. Aim: To identify features consistently predicting CFRD in paediatric patients. Patients diagnosed with CFRD between January 1997–January 2002 were compared with age and sex matched controls. Clinical,micr obiological, and hospitalisation data was collected at time of CFRD diagnosis,and at six monthly intervals for 3 yr prior to diagnosis. Eight patients with CFRD were identified,mean age 13.7 yr (S.D. 3.49) at time of diagnosis. Control patients underwent OGTT to ensure normal glucose tolerance. Patients with CFRD had a lower FEV1 up to 12 months prior to diagnosis however, this was only significant at diagnosis. There was no difference in weight and height z scores between the 2 groups; however,the decrease in weight and height z scores in the CFRD group over 3 yr prior to diagnosis was significant. Mean number of days in hospital and admissions per patient significantly increased in the CFRD group,6 months prior to diagnosis. No other significant differences were observed between the 2 groups. Conclusions: This study has shown a difference in lung function,gr owth parameters and frequency of hospital admissions between patients with CFRD and controls. These differences may be utilised as tools for targeted screening in the paediatricyadolescent population. Further larger scale studies are required to improve guidelines for targeted screening in this population.

Population structure in high shore littorinids: contrast between riprap and rocky shores

World Congress of Malacology, Ponta Delgada, July 22-28, 2013.

Genetic parameters and mapping quantitative trait loci associated with tibia traits in broilers.

Abstract: Selection among broilers for performance traits is resulting in locomotion problems and bone disorders, once skeletal structure is not strong enough to support body weight in broilers with high growth rates. In this study, genetic parameters were estimated for body weight at 42 days of age (BW42), and tibia traits (length, width, and weight) in a population of broiler chickens. Quantitative trait loci (QTL) were identified for tibia traits to expand our knowledge of the genetic architecture of the broiler population. Genetic correlations ranged from 0.56 +/- 0.18 (between tibia length and BW42) to 0.89 +/- 0.06 (between tibia width and weight), suggesting that these traits are either controlled by pleiotropic genes or by genes that are in linkage disequilibrium. For QTL mapping, the genome was scanned with 127 microsatellites, representing a coverage of 2630 cM. Eight QTL were mapped on Gallus gallus chromosomes (GGA): GGA1, GGA4, GGA6, GGA13, and GGA24. The QTL regions for tibia length and weight were mapped on GGA1, between LEI0079 and MCW145 markers. The gene DACH1 is located in this region; this gene acts to form the apical ectodermal ridge, responsible for limb development. Body weight at 42 days of age was included in the model as a covariate for selection effect of bone traits. Two QTL were found for tibia weight on GGA2 and GGA4, and one for tibia width on GGA3. Information originating from these QTL will assist in the search for candidate genes for these bone traits in future studies.

Population Dynamics Modeling of Arapaima gigas

Pirarucu (Arapaima gigas) has been of the most important natural fishing resources of the Amazon region. Due to its economic importance, and the necessity to preserve the species hand, field research concerning the habits and behavior of the pirarucu has been increasing for the last 20 years. The aim of this paper is to present a mathematical model for the pirarucu population dynamics considering the species peculiarities, particularly the male parental care over the offspring. The solution of the dynamical systems indicates three possible equilibrium points for the population. The first corresponds to extinction; the third corresponds to a stable population close to the environmental carrying capacity. The second corresponds to an unstable equilibrium located between extinction and full use of the carrying capacity. It is shown that lack of males’ parental care closes the gap between the point corresponding to the unstable equilibrium and the point of stable non-trivial equilibrium. If guarding failure reaches a critical point the two points coincide and the population tends irreversibly to extinction. If some event tends to destabilize the population equilibrium, as for instance inadequate parental care, the model responds in such a way as to restore the trajectory towards the stable equilibrium point avoiding the route to extinction. The parameters introduced to solve the system of equations are partially derived from limited but reliable field data collected at the Mamirauá Sustainable Development Reserve (MSDR) in the Brazilian Amazonian Region.

Study to determine the cardiovascular risk ofthe population of Guimarães/Vizela, includingthe prevalence of arterial stiffness and early vascular aging syndrome

Tese de Doutoramento em Medicina.

Chagas' heart disease: evolutive evaluation of electrocardiographic and echocardiographic parameters in patients with the indeterminate form

OBJECTIVE: To identify and associate potential electrocardiographic and echocardiographic changes in patients with the indeterminate form of Chagas' disease during long-term follow-up. METHODS: One hundred sixty patients underwent standard electrocardiography and two-dimensional guided M-mode echocardiography for left ventricular ejection fraction determination. Patients were followed up for 98.6±30.4 months, undergoing repeat electrocardiographic studies at 6-month intervals and echocardiographic studies at 12-month intervals. RESULTS: Based on the electrocardiographic findings, the patients were divided into group I, 125 patients (78.6%) with normal electrocardiograms throughout follow-up, and group II, 34 patients (21.3%) who developed electrocardiographic changes. Group II was further divided into group IIA (9 patients, 5.6%) with permanent electrocardiographic changes, group IIB (14 patients, 8.8%) with transitory electrocardiographic changes, and group IIC (11 patients, 6.9%) with changes appearing only on the final electrocardiogram. Left ventricular ejection fractions remained normal in the entire population studied and did not differ among groups. CONCLUSION: The indeterminate form of Chagas' disease clearly represents a benign condition with a favorable long-term prognosis. Although some patients develop electrocardiographic changes, left ventricular systolic function is well preserved.

Population genetic structure of brown crab (Cancer pagurus) in Irish waters

The brown crab (Cancer pagurus) fishery in Ireland is one of the most important financially and socio-economically, with the species worth approximately €15m per year in the first half of the decade. Only mackerel (Scomber scombrus) and Dublin Bay prawn (Nephrops norvegicus) are of greater value. Despite this, very little research has been conducted to describe the stock structure of brown crab on a national scale. In this study a country-wide assessment of genetic population structure was carried out. Sampling was conducted from commercial fishing boats from 11/06 to 04/08 at seven sample sites representing the central Irish brown crab fisheries, with one sample site from the UK also included in the study. Six microsatellite markers, specifically developed for brown crab, were used to assess genetic diversity and estimate population differentiation parameters. Significant genetic structuring was found using F-statistics (Fst = 0.007) and exact tests, but not with Bayesian methods. Samples from the UK and Wexford were found to be genetically distinct from all other populations. Three northern populations from Malm Head and Stanton Bank were genetically similar with Fst estimates suggesting connectivity between them. Also, Stanton Bank, again on the basis of Fst estimates, appeared to be connected to populations down the west coast of Ireland, as far south as Kerry. Two Galway samples, one inside and one outside of Galway Bay, were genetically differentiated despite their close geographic proximity. It is hypothesised that a persistent northerly summer current could transport pelagic larvae from populations along the southwest and west coasts of Ireland towards Stanton Bank in the North, resulting in the apparent connectivity observed in this study.

Age, growth and population dynamics of lemon sole Microstomus kitt (Walbaum 1792) sampled off the West Coast of Ireland

The age, growth, maturity and population dynamics of lemon sole (Microstomus kitt), captured off the west coast of Ireland (ICES division Vllb), were determined for the period November 2000 to February 2002. The maximum age recorded was 14 years. Males of the population were dominated by 4 year olds, while females were dominated by 5 year olds. Females dominated the sex ratio in the overall sample, each month sampled, at each age and from 22cm in total length onwards (when N > 20). Possible reasons for the dominance of females in the sex ratio are discussed. Three models were used to obtain the parameters of the von Bertalanfly growth equation. These were the Ford-Walford plot (Beverton and Holt 1957), the Gulland and Holt plot (1959) and the Rafail (1973) method. Results of the fitted von Bertalanffy growth curves showed that female lemon sole o f f the west coast of Ireland grew faster than males and attained a greater size. Male and female lemon sole mature from 2 years of age onwards. There is evidence in the population o f a smaller asymptotic length (L«, = 34.47cm), faster growth rate (K = 0.1955) and younger age at first maturity, all of which are indicative o f a decrease in population size, when present results are compared to data collected in the same area 22 years earlier. Results of the yield per recruit curve indicate that lemon sole are currently being over-fished o f f the west coast of Ireland. Problems of selectivity within the sampling method, particularly at the discarding stage, may have influenced the outcome of results of the models used in the assessment of this stock. Therefore, additional/future work on this species should include catch data which incorporates discards and not landings data alone.