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PubMed2003

Parental selection, number of breeding populations, and size of each population in inbred development.

Some breeders select inbreds from many F(2) or backcross breeding populations, each with relatively few progenies. Other breeders select inbreds from only a few breeding populations, each with many progenies. My objectives were to: (1) determine the relative importance of parental selection, number of breeding populations, and size of each population, and (2) find optimum combinations between number and size of breeding populations. I assumed that a breeder has resources to test a total of 2,000 recombinant inbreds for a quantitative trait that was controlled by 100 additive loci and had a heritability of 0.20, 0.60, or 1.0. The parental inbreds had an inherent pedigree structure due to advanced cycle breeding. The parental inbreds were ranked according to their mean performance, and breeding populations were made among all parents, the top 25% of parents, and the top 10% of parents. I found that the issue of number versus size of breeding populations was only secondary compared with the ability to identify, prior to making the crosses, the breeding populations with the highest mean performance. For a given level of effectiveness of parental selection, the selection response was largest when the maximum number of breeding populations was used. The effect of the number of breeding populations was minor, however, when selection was practiced among the parents or when heritability was less than 1.0. The results suggested that, in practice, large selection responses could be obtained with a wide range of combinations between number and size of breeding populations.

Computer Simulation↗
PubMed1980

An approach to the analysis of health care needs and resources.

A semi-quantitative method of analysing the relationship between health care resources and need is described. It utilises the Donabedian model which expresses needs and resources in equivalent units in order to estimate the ratio of resources to need. The optimum resource/need ratio is regarded as that pertaining to the reference population; deviation from this optimum ratio in the subunits of the reference population is interpreted as a manifestation of inequitable resource distribution. An example is presented of the application of the method to the Greater Glasgow Health Board and its five constituent districts for the years 1974-77. It is argued that this method might, without undermining the principle of geographical equity, meet some of the objections to the more rigid 'formula' approach in the report of the Resource Allocation Working Party (RAWP) and in the Scottish Health Authorities Revenue Equalisation (SHARE) report.

Health Resources↗
PubMed1979

A priori lithium dosage regimen using population characteristics of pharmacokinetic parameters.

The important problem of initiation of long-term lithium treatment is tackled by means of the selection of an a priori dosage regimen based on the presumed efficacy of lithium and absence of toxicity. The pharmacokinetics of Li+ ion is represented by a four-compartment open model including the supposed first-order processes for the release of the active compound from the dosage form and its absorption. Experimental protocols for measurements of serum concentrations and of urinary amounts after single and multiple dosing to healthy volunteers were derived with several oral dosage forms. Estimation of the pharmacokinetic parameters for each subject made it possible to validate the model for the various dosage forms. The interindividual variability of these parameters is taken into account by estimating the characteristics of the statistical distribution for the whole population. A dosage regimen is considered optimum when serum concentration profiles at steady state range from the threshold of efficacy (0.8 mmol/liter) to the threshold of toxicity (2.0 mmol/liter). When the number of daily intakes is fixed, the search for the optimum dose for the whole population is effected by minimizing the expected value of the random variable which characterizes the risks of excursion out of the therapeutic range. By this means universal dosages are shown to be unsatisfactory. However, certain dosage regimens individualized with respect to the renal clearance value of lithium and based on two or three daily intakes can give excellent results even when conventional dosage forms are used.

Adolescent↗
PubMed1985

Induction of natural killer cell activity by inactivated Candida albicans in mice.

Injection of merthiolate-inactivated yeast form cells of Candida albicans into the peritoneal cavities of mice induced the appearance of a cytolytic effector population against YAC-1 tumor cell lines. This induction was maximally manifested in 5- to 8-week-old animals 3 to 4 days after injection of 2 X 10(7)C. albicans cells, and the peritoneal lytic population exerted its optimum cytotoxic effect after 4 h of incubation. No significant natural cytotoxic activity was generated by C. albicans in the bone marrow or thymus, whereas there was a slight, transient, but significant depression of natural splenic cytotoxicity. Experiments performed to characterize the natural cytotoxic population elicited by the inactivated yeast showed that the effectors were nonadherent, nonphagocytic cells. Moreover, the anti-YAC-1 lytic activity was partially sensitive to anti-Thy1.2 serum and was completely abrogated by treatment of peritoneal nonadherent cells with monoclonal anti-asialo GM1 antibodies. Finally, the peritoneal population of cytotoxic cells induced by C. albicans was fully susceptible to Ly5.1 plus anti-immunoglobulin G2a and complement lysis. Although different cell populations could be induced by inactivated C. albicans, all of our data support the view that the anti-YAC-1 activity was entirely attributable to natural killer lymphocytes.

Adhesiveness↗
PubMed1998

Radiobiologically based assessments of the net costs of fractionated focal radiotherapy.

PURPOSE: To assess the potential changes in the net costs of focal radiotherapy techniques at differing doses per fraction and interfraction intervals. METHODS: Linear quadratic radiobiological modeling is used with appropriate variations in the radiosensitivity and tumor cell proliferation parameters. The notional cost of treatment is calculated from the number of fractions, cost per fraction and the cost of treatment failure, which is itself related to (1-TCP) where TCP is the tumor cure probability. Additional Monte Carlo calculations from ranges of radiobiological parameters have been used to simulate the cost of treatment of tumor populations. RESULTS: The optimum dose per fraction (and optimum overall cost) for conventional (nonfocal) radiotherapy is generally at low doses of around 2 Gy per fraction. The use of hyperfractionated and accelerated radiotherapy in addition to focal radiotherapy techniques appear to be indicated for more radioresistant tumors and if tumor proliferation is extremely rapid, but the need for treatment acceleration is much reduced where effective focal techniques are used. CONCLUSIONS: Radiobiological and economic modeling can be used to guide clinical choices of dose fractionation techniques providing the key radiobiological parameters are known or if the ranges of likely parameters in a tumor population are known. Focal radiotherapy, by the introduction of changes in the physical dose distribution, produces an upward shift in the optimum dose per fraction and a reduced dependency on overall treatment time.

Cell Division↗
PubMed2005

Nonrandom larval dispersal can steepen marine clines.

Sharp and stable clinal variation is enigmatic when found in species with high gene flow. Classical population genetic models treat gene flow as a random homogenizing force countering local adaptation across habitat discontinuities. Under this view, dispersal over large spatial scales will lower the effectiveness of adaptation by natural selection at finer spatial scales. Thus, random gene flow will create a shallow phenotypic cline across an ecotone in response to a steep selection gradient. In sedentary marine species that disperse primarily as larvae, nonrandom dispersal patterns are expected due to coastal hydrodynamics. Surprisingly sharp phenotypic and genotypic clines have been documented in marine species with high gene flow. We are interested in the extent to which nonrandom dispersal could accentuate such clines. We model a linear species range in which populations have stable and uniform densities along a selection gradient; in contrast to random dispersal, convergent advection of larvae can amplify phenotypic differentiation if coupled with a semipermeable dispersal barrier in the convergence zone. The migration load caused by directional dispersal pushes the phenotypic mean away from the local trait optimum in downstream populations, that is, near the convergence zone. A dispersal barrier is possible as a result of colliding currents if the water and larvae are mostly displaced offshore, away from suitable settlement habitat. Disjunctions in a quantitative trait were enlarged in the convergence zone by faster current flows or a more complete dispersal barrier. With advection of larvae per generation one-third as far as the average dispersal distance by diffusion, convergence on a dispersal barrier with 40% permeability generated a trait disjunction across the convergence zone of two phenotypic standard deviations. Without directional dispersal, similar clines also developed across a habitat gap, where population density was low, or across dispersal barriers with less than 1% permeability. These findings suggest that the types of hydrographic phenomena often associated with marine transition zones can strongly affect the balance between gene flow and selection and generate surprisingly steep clines given the large-scale gene flow expected from larvae.

Animal Migration↗
PubMed2004

[Experimental population ecology of Carcelia matsukarehae Shima (Diptera: Tachinidae)].

This paper dealt with the developmental zero, effective accumulated temperature, adult longevity, adult fecundity and specific life table parameters of tachinid fly Carcelia matsukarehae at temperature 15 degrees C, 18 degrees C, 22 degrees C, 25 degrees C, 29 degrees C, and 32 degrees C, relative humidity 70%-85%, and photoperiod L:D = 12:12. The results showed that the developmental zero and effective accumulated temperature for generation were 5.23 degrees C and 525.73 day-degree, respectively. The adult longevity was 1.35-8.06 days without supplying nutrient but water, and while fed with 30% honey water, their longevity could prolong to 9.63-36.42 days. The optimum temperature for oviposition was 23.6 degrees C, maximum eggs laid by a female were 86. The optimum temperature for population growth was 22-25 degrees C. The specific life table parameters of experimental population under temperature 22 degrees C and 25 degrees C were calculated. At 22 degrees C, R0, T0, rc and lambda were 24.89, 37.33, 0.086 and 1.089, respectively, and at 25 degrees C, they were 20.01, 32.38, 0.09 and 1.10, respectively. The maximum LxMx occurred from the 33rd day to the 38th day after adult emergence at temperature 22 degrees C, and from the 29th day to the 34th day at 25 degrees C.

Animals↗
PubMed1996

Endogenous fertility and the Henry George Theorem.

"Models of endogenous demographic change deal with population size as an additional object of the welfare analysis. In these models the overlapping-generations (OLG) model serves as the basic framework. In club theory, too, population size is treated as an endogenous variable. In local public goods (LPG) models, the so-called Henry George Theorem, which requires local public expenditures to be financed by a 100% tax on aggregate land rent, is known as a (first-order) condition for club efficiency. The present paper establishes and exploits an isomorphism between steady states of the OLG model and allocations of the LPG model. The paper revisits Samuelson's fallacy concerning his goldenest golden rule and it explores institutional arrangements that sustain the optimum growth of population."

Demography↗
PubMed2006

Hybrid maize breeding with doubled haploids: I. One-stage versus two-stage selection for testcross performance.

Optimum allocation of resources is of fundamental importance for the efficiency of breeding programs. The objectives of our study were to (1) determine the optimum allocation for the number of lines and test locations in hybrid maize breeding with doubled haploids (DHs) regarding two optimization criteria, the selection gain deltaG(k) and the probability P(k) of identifying superior genotypes, (2) compare both optimization criteria including their standard deviations (SDs), and (3) investigate the influence of production costs of DHs on the optimum allocation. For different budgets, number of finally selected lines, ratios of variance components, and production costs of DHs, the optimum allocation of test resources under one- and two-stage selection for testcross performance with a given tester was determined by using Monte Carlo simulations. In one-stage selection, lines are tested in field trials in a single year. In two-stage selection, optimum allocation of resources involves evaluation of (1) a large number of lines in a small number of test locations in the first year and (2) a small number of the selected superior lines in a large number of test locations in the second year, thereby maximizing both optimization criteria. Furthermore, to have a realistic chance of identifying a superior genotype, the probability P(k) of identifying superior genotypes should be greater than 75%. For budgets between 200 and 5,000 field plot equivalents, P(k) > 75% was reached only for genotypes belonging to the best 5% of the population. As the optimum allocation for P(k)(5%) was similar to that for deltaG(k), the choice of the optimization criterion was not crucial. The production costs of DHs had only a minor effect on the optimum number of locations and on values of the optimization criteria.

Breeding↗
PubMed1993

Pharmacokinetics of the new antiasthma and antiallergy drug, azelastine, in pediatric and adult beagle dogs.

The plasma concentrations and relative bioavailability of azelastine hydrochloride (AZ) and its desmethyl metabolite (DAZ) after a single and 10 once-a-day oral doses of 2.5 mg kg-1 AZ were determined in adult male and female and pediatric male and female beagle dogs. The pediatric and adult dogs were 4-6 weeks and 1-2 years of age, respectively. An analysis of variance (ANOVA) was performed on the bioavailability parameters among all groups and between the first and last doses. No statistically significant (p < 0.05) sex-related differences in the bioavailability parameters were observed. The peak concentration (Cmax) of AZ, especially after the first dose, was significantly higher in pediatric dogs than that in adult dogs, whereas following the multiple AZ administrations, the bioavailability parameters for the last dose were similar in the two age groups. The apparent volume of distribution (Vss) of AZ suggested that the drug was extensively distributed into tissue in adult as well as in pediatric dogs. The Vss was considerably smaller in pediatric dogs, which may explain the higher Cmax in this age group. The bioavailability of the metabolite in adult dogs after multiple administration of AZ was higher than that in pediatric dogs. Although some differences in the parameters among the groups are statistically significant, they do not appear to have any biological significance. Therefore, similar AZ dosages may be required in pediatric and in adult populations to achieve optimum therapeutic drug levels.

Animals↗
PubMed2005

ACE inhibitors and angiotensin II receptor antagonists.

The biological actions of angiotensin II (ANG), the most prominent hormone of the renin-angiotensin-aldosterone system (RAAS), may promote the development of atherosclerosis in many ways. ANG aggravates hypertension, metabolic syndrome, and endothelial dysfunction, and thereby constitutes a major risk factor for cardiovascular disease. The formation of atherosclerotic lesions involves local uptake, synthesis and oxidation of lipids, inflammation, as well as cellular migration and proliferation--mechanisms that may all be enhanced by ANG via its AT1 receptor. ANG may also increase the risk of acute thrombosis by destabilizing atherosclerotic plaques and enhancing the activity of thrombocytes and coagulation. After myocardial infarction, ANG promotes myocardial remodeling and fibrosis, and its many pathological mechanisms deteriorate the prognosis of these high-risk patients in particular. Therapeutically, inhibitors of the angiotensin I-converting enzyme (ACEI) and AT1 receptor blockers (ARB) are available to suppress the generation and cellular signaling of ANG, respectively. Despite major differences in the efficacy of ANG suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating numerous pathomechanisms of ANG in vitro, and in diminishing the development of atherosclerotic lesions and restenosis after angioplasty in various animal models. In clinical therapy, ACEI and ACE are well-tolerated antihypertensive drugs that also improve the prognosis of heart failure patients. After myocardial infarction and in stable coronary heart disease, ACEI have been shown to reduce mortality in a manner independent of hemodynamic alterations. However, there is little evidence that inhibitors of the RAAS may be effective against arterial restenosis, and a possible benefit of these substances compared to other antihypertensive drugs in the primary prevention of coronary heart disease in hypertensive patients is still a matter of debate, possibly depending on the specific substance and condition being investigated. As such, the general clinical efficacy of ACEI and ARB may be due to a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neuro-humoral regulation, rather than to a direct attenuation of the atherosclerotic process. Further therapeutic advances may be achieved by identifying optimum drugs, patient populations, and treatment protocols.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Biochemical indices of renal osteodystrophy in dialysis patients on the island of Malta.

OBJECTIVES: Renal osteodystrophy (ROD) has never been studied on the small Mediterranean island of Malta, which has a largely inbred population. The genetic contribution to the pattern of renal osteodystrophy is being increasingly recognized. We were, thus, interested in studying indices of bone turnover in Maltese end stage renal failure patients. MATERIALS AND METHODS: Sixty unselected patients, representing 65% of all patients undergoing dialysis in the island's renal unit, were prospectively investigated over a period of 5 months with respect to symptoms, calcium/phosphate chemistry, intact parathyroid hormone (iPTH) and bone alkaline phosphatase (bAP). Bone histomorphometry, which is the gold standard in the diagnosis of ROD, was not within the reach of our small unit. Biochemical markers may not be as sensitive and specific as bone biopsy for individual patient diagnosis of ROD sub-type but they can give a fairly good indication of the spectrum of bone turnover on a population basis. The optimum combination of biochemical marker cut-offs available from studies in the literature was then employed to estimate bone turnover. RESULTS: The following biochemical picture emerged: 42% had iPTH < 79.7 pg/ml (which cut off has a reported specificity of 93.7% for low turnover bone disease), 45% had iPTH > 100 pg/ml and bAP > 10 ng/ml (which combined cut off has a reported specificity of 100% for high turnover bone disease), while 13% could not be classified (ie had intermediate values). CONCLUSIONS: Based on biochemical data, the pattern of bone turnover seems to be comparable to the European average. Further indepth study using bone histomorphometry is warranted.

Alkaline Phosphatase↗
PubMed1988

Initiating a surveillance system for childhood injuries.

Important considerations in establishing a surveillance system for pediatric injuries are described. At the start of surveillance, issues such as the purpose of the surveillance project, preferred methods for gathering information, optimum sites, appropriate populations, and requirements for data storage and analysis should be addressed. Since the epidemiology of childhood injuries is different from adult patterns, some specific challenges of pediatric injury surveillance are highlighted.

Child↗
PubMed1974

Synergy among responding lymphoid cells in the one-way mixed lymphocyte reaction. Interaction between two types of thymus-dependent cells.

The present studies have shown that two subpopulations of thymus-dependent lymphocytes may act synergistically in the mixed lymphocyte reaction (MLR) in the mouse. One subpopulation was well represented in the young adult thymus and the other in lymph nodes. For optimum synergy, both populations must be allogeneic to the stimulator cells. Pretreatment of either population with mitomycin-C abolished synergy. Anti-theta serum abolished both MLR responding and synergizing activities of lymphoid cells. The two thymus-dependent subpopulations were both present in the spleen, and displayed different migratory patterns when injected into irradiated mice: one population went to spleens of the irradiated mice, the other to lymph nodes. The effects of anti-thymocyte serum on the MLR and upon synergy were assessed. While minor differences exist and are herein described, our overall results strongly suggest that in our experiments with synergy in MLR, we may be dealing with the same T(1)- and T(2)-cell subpopulations described by Cantor and Asofsky and coworkers (1, 2, 4, 5, 14) as displaying synergy in the graft-vs.-host reaction.

Animals↗
PubMed1985

The effectiveness of drug level monitoring and pharmacokinetics in individualizing theophylline therapy.

A pharmacokinetic method for individualizing theophylline dosage is described. The method was shown to be reliable and accurate, and maintained significantly more patients within the optimum therapeutic range when compared with conventional regimens. The study also showed that when conventional dosage regimens are used, a large proportion of patients exhibit theophylline levels well below the optimum therapeutic range. Population pharmacokinetic data for theophylline and the effect of congestive heart failure on its clearance are also presented.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics of felbamate in pediatric and adult beagle dogs.

The relative bioavailability and pharmacokinetics of felbamate (FBM) after a single oral dose and after 10 once-daily oral doses of 60 mg/kg were investigated in adult and pediatric dogs of both sexes. The pediatric and adult dogs were aged 4-6 weeks and 1-2 years, respectively. Analysis of variance (ANOVA) was performed on the bioavailability parameters among all groups and between the first and last doses. No sex-related differences in bioavailability and pharmacokinetic parameters were observed. The bioavailability of FBM in pediatric dogs was significantly less as compared with that in adult dogs. Rapid overall elimination of the drug in pediatric dogs appears to be responsible for the lower bioavailability. The bioavailability of FBM after the last dose was also significantly lower than after the first dose for both age groups. No major differences in the rate constant of FBM absorption (ka) and volume of distribution at steady state (VSS) were observed between the two age groups. As with other clinically useful antiepileptic drugs (AEDs), higher doses of FBM may be required in pediatric populations to achieve optimum drug levels, assuming that age-related changes in FBM disposition will also be confirmed in humans.

Age Factors↗
PubMed2002

Retroviral transduction efficiency of G-CSF+SCF-mobilized peripheral blood CD34+ cells is superior to G-CSF or G-CSF+Flt3-L-mobilized cells in nonhuman primates.

Gene transfer experiments in nonhuman primates have been shown to be predictive of success in human clinical gene therapy trials. In most nonhuman primate studies, hematopoietic stem cells (HSCs) collected from the peripheral blood or bone marrow after administration of granulocyte colony-stimulating factor (G-CSF) + stem cell factor (SCF) have been used as targets, but this cytokine combination is not generally available for clinical use, and the optimum target cell population has not been systematically studied. In our current study we tested the retroviral transduction efficiency of rhesus macaque peripheral blood CD34(+) cells collected after administration of different cytokine mobilization regimens, directly comparing G-CSF+SCF versus G-CSF alone or G-CSF+Flt3-L in competitive repopulation assays. Vector supernatant was added daily for 96 hours in the presence of stimulatory cytokines. The transduction efficiency of HSCs as assessed by in vitro colony-forming assays was equivalent in all 5 animals tested, but the in vivo levels of mononuclear cell and granulocyte marking was higher at all time points derived from target CD34(+) cells collected after G-CSF+SCF mobilization compared with target cells collected after G-CSF (n = 3) or G-CSF+Flt3-L (n = 2) mobilization. In 3 of the animals long-term marking levels of 5% to 25% were achieved, but originating only from the G-CSF+SCF-mobilized target cells. Transduction efficiency of HSCs collected by different mobilization regimens can vary significantly and is superior with G-CSF+SCF administration. The difference in transduction efficiency of HSCs collected from different sources should be considered whenever planning clinical gene therapy trials and should preferably be tested directly in comparative studies.

Animals↗