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PubMed2000

Juxtaposed microsatellite systems as diagnostic markers for admixture: an empirical evaluation with brown trout (Salmo trutta) as model organism.

A juxtaposed microsatellite system (JMS) is composed of two microsatellite repeat arrays separated by a sequence of less than 200 bp and more than 20 bp. This paper presents the first empirical evaluation of JMSs for the study of genetic admixture induced by man, with brown trout (Salmo trutta) as model organism. Two distinct admixture situations were studied: native populations from streams of the Atlantic basin and of the Mediterranean basin, respectively, all stocked with domestic strains originating from the Atlantic basin. For these two situations, we first evaluated by simulation the ability of JMSs to differentiate between alien alleles and naturally shared homoplasious or ancestral alleles, and thus to behave as diagnostic markers for admixture. Simulations indicated that JMSs are expected to be reliable diagnostic markers in most divergent (i.e. Mediterranean) populations and nonreliable diagnostic markers in most closely related (i.e. Atlantic) populations. Three JMSs were genotyped in domestic strains as well as in nonstocked and stocked populations of brown trout sampled in different rivers of the Mediterranean and Atlantic basins. The observed distributions of JMS haplotypes were consistent with simulation predictions confirming that JMSs were reliable diagnostic markers only over a given proportion of the species range, i.e. in substantially divergent populations. JMSs also reinforced the diagnostic character of three microsatellite sites for the studied Mediterranean populations. This last result is consistent with our simulation results which showed that, although much less frequently than at JMSs, diagnostic markers are likely to be found at single site microsatellites provided that the native Mediterranean population has a sufficiently small effective population size. For each population of the Mediterranean basin admixture coefficients did not differ significantly across JMSs and mean admixture coefficients sometimes differ among populations. The interpretation of the origin of JMS haplotypes based on the allele length variants was supported by nucleotide sequence analysis.

Animals↗
PubMed2004

Statistical tests for admixture mapping with case-control and cases-only data.

Admixture mapping is a promising new tool for discovering genes that contribute to complex traits. This mapping approach uses samples from recently admixed populations to detect susceptibility loci at which the risk alleles have different frequencies in the original contributing populations. Although the idea for admixture mapping has been around for more than a decade, the genomic tools are only now becoming available to make this a feasible and attractive option for complex-trait mapping. In this article, we describe new statistical methods for analyzing multipoint data from admixture-mapping studies to detect "ancestry association." The new test statistics do not assume a particular disease model; instead, they are based simply on the extent to which the sample's ancestry proportions at a locus deviate from the genome average. Our power calculations show that, for loci at which the underlying risk-allele frequencies are substantially different in the ancestral populations, the power of admixture mapping can be comparable to that of association mapping but with a far smaller number of markers. We also show that, although "ancestry informative markers" (AIMs) are superior to random single-nucleotide polymorphisms (SNPs), random SNPs can perform quite well when AIMs are not available. Hence, researchers who study admixed populations in which AIMs are not available can perform admixture mapping with the use of modestly higher densities of random markers. Software to perform the gene-mapping calculations, "MALDsoft," is freely available on the Pritchard Lab Web site.

Chromosome Mapping↗
PubMed1995

Dependence of pulmonary venous admixture on inspired oxygen fraction and time during regional hypoxia in the rabbit.

In order to examine the value of assuming constant pulmonary venous admixture with respect to changes in inspired oxygen fraction (FIO2) and time during sustained unilateral hypoxia, we studied venous admixture for 6 h in 27 anaesthetized rabbits in which the left lung was filled with liquid, isosmotic with plasma. In one group of 10 rabbits the right lung was ventilated for 6 h with FIO2 = 1; in a second group of 10 the right lung was ventilated with FIO2 = 1 for 2.5 h and then with FIO2 = 0.3 for 3.5 h. A third group was similarly studied by changing from FIO2 = 1 to FIO2 = 0.5. We found that hypoxic pulmonary vasoconstriction continued to intensify over 3 h. At 3-6 h, with FIO2 = 0.3, venous admixture (0.32 (SEM 0.03)) was higher than baseline (0.13 (0.01), t = 0 min during bilateral oxygenation) by twice the elevation above baseline of the venous admixture (0.22 (0.01)) in the group with FIO2 = 1. The finding of a marked increase in venous admixture with decreasing FIO2 is discussed in relation to current models of hypoxic pulmonary vasoconstriction.

Animals↗
PubMed2000

Inspired oxygen fraction after cardiopulmonary bypass: effects on pulmonary function with regard to endothelin-1 concentrations and venous admixture.

Twenty consecutive patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were allocated at random to group 1 (n = 10, high inspired oxygen fraction (FIO2) after CPB), or group 2 (n = 10, moderate FIO2 after CPB). The effects of each FIO2 on arterial and mixed venous concentrations of endothelin-1 (ET-1) and its precursor, Big ET-1, were measured. Venous admixture was calculated to assess the efficiency of pulmonary gas exchange. Patients whose lungs had been ventilated with a FIO2 of 1.0 (exposure time 70 min) after weaning from the CPB machine had significantly greater arterial and mixed venous Big ET-1 concentrations and venous admixture than patients whose lungs were ventilated with a FIO2 of 0.35. In contrast, ET-1 concentrations in the two groups were not significantly different. A reduction of FIO2 from 1.0 to 0.6 reduced venous admixture without lowering endothelial peptide concentrations. On the first postoperative day all peptide concentrations were similar in the two groups, whereas venous admixture remained non-significantly higher in group 1. A short period of high FIO2 immediately after CPB increases endothelin concentrations and pulmonary venous admixture.

Aged↗
PubMed2003

Maximum-likelihood estimation of admixture proportions from genetic data.

For an admixed population, an important question is how much genetic contribution comes from each parental population. Several methods have been developed to estimate such admixture proportions, using data on genetic markers sampled from parental and admixed populations. In this study, I propose a likelihood method to estimate jointly the admixture proportions, the genetic drift that occurred to the admixed population and each parental population during the period between the hybridization and sampling events, and the genetic drift in each ancestral population within the interval between their split and hybridization. The results from extensive simulations using various combinations of relevant parameter values show that in general much more accurate and precise estimates of admixture proportions are obtained from the likelihood method than from previous methods. The likelihood method also yields reasonable estimates of genetic drift that occurred to each population, which translate into relative effective sizes (N(e)) or absolute average N(e)'s if the times when the relevant events (such as population split, admixture, and sampling) occurred are known. The proposed likelihood method also has features such as relatively low computational requirement compared with previous ones, flexibility for admixture models, and marker types. In particular, it allows for missing data from a contributing parental population. The method is applied to a human data set and a wolflike canids data set, and the results obtained are discussed in comparison with those from other estimators and from previous studies.

Animals↗
PubMed2003

Nonneutral admixture of immigrant genotypes in African Drosophila melanogaster populations from Zimbabwe.

Drosophila melanogaster originated in Africa and colonized the rest of the world only recently (approximately 10,000 to 15,000 years ago). Using 151 microsatellite loci, we investigated patterns of gene flow between African D. melanogaster populations representing presumptive ancestral variation and recently colonized European populations. Although we detected almost no evidence for alleles of non-African ancestry in a rural D. melanogaster population from Zimbabwe, an urban population from Zimbabwe showed evidence for admixture. Interestingly, the degree of admixture differed among chromosomes. X chromosomes of both rural and urban populations showed almost no non-African ancestry, but the third chromosome in the urban population showed up to 70% of non-African alleles. When chromosomes were broken into contingent microsatellite blocks, even higher estimates of admixture and significant heterogeneity in admixture was observed among these blocks. The discrepancy between the X chromosome and the third chromosome is not consistent with a neutral admixture hypothesis. The higher number of European alleles on the third chromosome could be due to stronger selection against foreign alleles on the X chromosome or to more introgression of (beneficial) alleles on the third chromosome.

Africa↗
PubMed2006

Analytical correction for multiple testing in admixture mapping.

Admixture mapping, using unrelated individuals from the admixture populations that result from recent mating between members of each parental population, is an efficient approach to localize disease-causing variants that differ in frequency between two or more historically separated populations. Recently, several methods have been proposed to test linkage between a susceptibility gene and a disease locus by using admixture-generated linkage disequilibrium (LD) for each of the genotyped markers. In a genome scan, admixture mapping usually tests 2,000 to 3,000 markers across the genome. Currently, either a very conservative Sidak (or Bonferroni) correction or a very time consuming simulation-based method is used to correct for the multiple tests and evaluate the overall p value. In this report, we propose a computationally efficient analytical approach for correction of the multiple tests and for calculating the overall p value for an admixture genome scan. Except for the Sidak (or Bonferroni) correction, our proposed method is the first analytical approach for correction of the multiple tests and for calculating the overall p value for a genome scan. Our simulation studies show that the proposed method gives correct overall type I error rates for genome scans in all cases, and is much more computationally efficient than simulation-based methods.

Computational Biology↗
PubMedDate not supplied

Lipid peroxidation of intravenous lipid emulsions and all-in-one admixtures in total parenteral nutrition bags: the influence of trace elements.

An iodometric titration was used to assess the influence of a daily portion of trace elements on lipid peroxidation of pure lipid emulsions and lipid-containing all-in-one (AIO) admixtures by measuring the peroxide value (PV; mmol peroxides/L). A pure lipid emulsion (Intralipid 20%; Pharmacia & Upjohn, Dubendorf, Switzerland) was stored in ethylvinylacetate bags under light protection (LP) at 40 degrees C with and without trace elements. In absence of trace elements the PV of Intralipid 20% was significantly lower (day 14: 2.77 vs 18.04; p < .001). After the same time period with the same storage conditions the drop in pH was two times higher in presence of trace elements (1.54 vs 0.77). In an AIO admixture with LP stored at 2 degrees C to 8 degrees C, trace elements increased the PV from 0.04 to 0.19 mmol/L (day 29; p < .01). The drop in pH was 0.01 and 0.02 units, respectively. When stored at 20 degrees C to 30 degrees C and exposed to daylight, the PV of the AIO admixture containing trace elements reached 1.92 compared with 0.52 in their absence (day 19; p < .001) with a pH drop of 0.03 and 0.11, respectively (day 29). Although trace elements led to a much higher drop in pH in pure lipid emulsions, no obvious influence on the pH of AIO admixtures was demonstrated. To minimize lipid peroxidation, AIO admixtures should be stored light-protected and refrigerated without trace elements. The latter should be added immediately before administration or should be given separately.

Fat Emulsions, Intravenous↗
PubMedDate not supplied

Compounding TPN admixtures: then and now.

Compounding TPN admixtures has significantly developed since the first clinical reports by Dr. Dudrick and colleagues from the University of Pennsylvania approximately 35 years ago. Today, the responsibility for the compounding of sage parenteral nutrition admixtures for patients incapable of oral or enteral nutrition primarily rests with the pharmacy department. Although others may influence the desirable components to be contained therin, no one is more qualified to deal with the physicochemical issues and aseptic technique compounding requirements than a registered pharmacist. In fact, the United States Pharmacopeia (USP) , the official drug compendium in the US since 1906, has published Chapter 797 entitled "Pharmaceutical Compounding--Sterile Preparations", enforceable by the FDA, and makes clear the role of the pharmacist in the compounding of safe parenteral admixtures. Ultimately, after careful pharmaceutical review of the final formulation, the composition of the final admixture for infusion will be determined based on the ability to safely compound the prescribed additives in the desired quantities of a specified volume of sterile fluid. There will always be instances, where, for example the patient's needs cannot be safely met through the TPN admixture, primarily because of stability, compatibility and/or sterility issues. When this occurs, suitable alternative methods of delivering the additives in question must be sought so as not to compromise the safety issues of the final TPN infusion. Although there have been many advances in the development of nutritional additives, compounding devices, and containers, significant safety issues continue to arise necessitating further modification of paretneral nutrition protocols. ASPEN, through periodic reviews of tis published guidelines, such as the 1998 Safe Practices for Parenteral Nutrition Formulations, is in a key position to keep nutrition support clinicians abreast of the central issues affecting the safety of TPN therapy.(Journal of Parenteral and Enteral Nutrition

Drug Compounding↗
PubMed1980

The application of a freeze-microwave thaw technique to central admixture services.

The establishment of a centralized, intravenous solution/admixture drug program in a hospital enhances the quality of patient care. Costs for personnel, equipment, and space have constrained the growth of such a service in the past. A method of preparation for admixture units, which capitalizes on the economics of volume and employs personnel at levels of training consistent with need, is proposed. This technique, utilizing freezing, long-term storage at -20 degrees C, and thawing by exposure in a microwave oven minutes before intended use, surmounts the real and perceived difficulties in many planned or existing admixture programs. A strong element of prospective quality control can be introduced. Where demand is insufficient to justify a separate activity, cooperative arrangements among hospitals will bring all the advantages of central admixture to each. It appears that reductions can be made in the pharmacy hours devoted to admixture. Waste of any unused, reconstituted drugs or prepared units that were not administered may be diminished. Thus, there may be substantial savings for existing admixture programs, if the technique described is adopted. The ultimate form of implementation in each institution, as always, is dependent upon the special "personality" of the hospital.

Anti-Bacterial Agents↗
PubMed1990

Time-motion study of intravenous ranitidine admixtures.

This study determined the total preparation time, cost, and contamination rate associated with preparing 50-mL admixtures of ranitidine 50 mg from each of the following commercial source vials: 50 mg/2 mL unit-dose vial (treatment A), 50 mg/2 mL 10 mL multidose vial (treatment B), and 50 mg/2 mL 40 mL multidose vial (treatment C). The study consisted of two separate phases: phase I extemporaneous compounding and phase II batch manufacturing. Twelve technicians prepared ten admixtures from each source vial during each phase. All admixtures were tested for sterility; bacterial contamination was not observed. Multidose vials saved approximately $197 per 200 admixtures. Drug and personnel costs were reduced when batch manufacturing with 40-mL multidose vials was compared with extemporaneous compounding with unit-dose vials. Our study showed that multidose vials decreased the total preparation time and cost for making ranitidine admixtures during both extemporaneous compounding and batch manufacturing by reducing setup time, preparation time, and drug procurement cost.

Drug Compounding↗
PubMed1991

Parenteral nutrient admixtures as drug vehicles: theory and practice in the critical care setting.

Parenteral nutrient (PN) admixtures are the most complex, extemporaneously compounded formulations routinely prepared for hospitalized and home-based patients. In addition, drugs are added with increasing frequency to PN admixtures, thus presenting even greater physicochemical challenges to this highly complex pharmaceutical product. The continuous infusion of selected drugs may provide pharmacokinetic and therapeutic advantages over conventional, intermittent, bolus methods of administration. Fluid conservation, cost savings, and a possible decrease in the risk of infection through reduced catheter manipulation and simplification of therapy provide additional incentives to consider the use of PN admixtures. The many advantages of PN admixtures make them an attractive approach to cost-effective care, with special clinical benefits achieved in the critical care setting. This article reviews our clinical experience using PN admixtures as drug vehicles for selected drugs and presents some theoretical as well as actual benefits associated with this practice.

Aminophylline↗
PubMed2006

Regional admixture mapping and structured association testing: conceptual unification and an extensible general linear model.

Individual genetic admixture estimates, determined both across the genome and at specific genomic regions, have been proposed for use in identifying specific genomic regions harboring loci influencing phenotypes in regional admixture mapping (RAM). Estimates of individual ancestry can be used in structured association tests (SAT) to reduce confounding induced by various forms of population substructure. Although presented as two distinct approaches, we provide a conceptual framework in which both RAM and SAT are special cases of a more general linear model. We clarify which variables are sufficient to condition upon in order to prevent spurious associations and also provide a simple closed form "semiparametric" method of evaluating the reliability of individual admixture estimates. An estimate of the reliability of individual admixture estimates is required to make an inherent errors-in-variables problem tractable. Casting RAM and SAT methods as a general linear model offers enormous flexibility enabling application to a rich set of phenotypes, populations, covariates, and situations, including interaction terms and multilocus models. This approach should allow far wider use of RAM and SAT, often using standard software, in addressing admixture as either a confounder of association studies or a tool for finding loci influencing complex phenotypes in species as diverse as plants, humans, and nonhuman animals.

Computer Simulation↗
PubMedDate not supplied

Computer simulations of the electric interactions between the phospholipid head-groups and ionic admixtures in the membrane surface.

Some phospholipids (e.g. lecithin) form a system of electric dipoles on the membrane surface layer. In the case of lecithin the positive dipole charge is located on the choline and the negative one on the phosphoric molecule group. These dipoles are arranged almost parallel to the membrane surface. Taking the dipole membrane structure as a base for further investigations, a computer model of the electrostatic interaction between the dipole system and the ionic admixture was investigated. The model presumes hexagonal centered or a rectangular flat geometry of the 121 dipoles distribution. The dipoles may rotate freely around round the motionless symmetry axis perpendicular to the system surface. The initial state is given by fixing the geometry of the dipole matrix and ionic admixture distribution. Subsequently this system underwent a computer simulation which consisted of a calculation of resultant force moments acting on each dipole caused by other dipoles and ions. These force moments lead the system to the equilibrium state (minimum of the binding energy). The minimum energy value of the dipoles system depends on concentration and charge of the admixtured ions. The results of repeated simulations indicate that the system achieve the least of all binding energy (the most stable equilibrium state) at 1.5% concentration of admixtured ions in case of ion charge equal to 1Q (where Q denotes arbitrary unit of ion charge) and at 2.5% concentration of admixtured ions in case of ion charge equal to 2Q. The calculated results are in a good agreement with the experimental.

Computer Simulation↗
PubMed2006

Assessing the relative ages of admixture in the bovine hybrid zones of Africa and the Near East using X chromosome haplotype mosaicism.

Historical hybridization events between the two subspecies of cattle, Bos taurus and B. indicus, have occurred in several regions of the world, while other populations have remained nonadmixed. We typed closely linked X chromosome microsatellites in cattle populations with differing histories of admixture from Africa, Europe, the Near East, and India. Haplotype breakdown will occur as admixed populations age, and longer ancestral haplotypes will remain intact in more recently admixed populations compared to older ones. We genotyped male animals from these populations, obtaining unambiguous haplotypes, and measured levels of linkage disequilibrium (LD) and ancestral mosaicism. Extensive LD, likely to be the result of ongoing admixture, was discovered in hybrid cattle populations from the perimeter of the tsetse zone in West Africa. A Bayesian method to assign microsatellite allele ancestry was used to designate the likely origin of each chromosomal segment and assess the relative ages of admixture in the populations. A gradient of the age of admixture in the African continent emerged, where older admixture has produced more fragmented haplotypes in the south, and longer intact haplotypes, indicating more recent hybridization, feature in the northwest.

Africa↗
PubMed2006

Establishing a stability window for medium- and long-chain-triglyceride lipid-based total nutrient admixtures using USP standards.

PURPOSE: The stability window of medium-chain triglyceride (MCT) and long-chain-triglyceride (LCT) lipid-based total nutrient admixtures (TNAs) was studied. METHODS: Sixteen different admixtures were selected for study. Of these, eight base macronutrient concentrations representing low and high concentrations were selected, along with low and high concentrations of electrolytes. All TNAs studied contained 2 mg of elemental iron as part of the trace-element formulation, an amount previously shown to produce unstable TNAs with pure LCT-based lipid injectable emulsions. All admixtures were prepared in triplicate and analyzed over five time intervals: time 1 (immediately after preparation), time 2 (after four days of storage at 6 +/- 2 degrees C), and times 3, 4, and 5, corresponding to 6, 24, and 30 hours of storage at 25 +/- 2 degrees C, respectively, after time 2. Stability was measured by comparing results with USP standards for fat globule size in lipid injectable emulsions. RESULTS: A total of 48 admixtures were studied. Samples at each time interval showed an inconsistent but general increase in the number of globules with a diameter of >1.8 microm over time. All admixtures met both the proposed pharmacopoeial criteria for stability with respect to mean droplet size and volume-weighted proportion of fat globules with a diameter of >5 microm. CONCLUSION: A wide range of macronutrients and micronutrients were tested in a series of MCT-LCT-based TNAs and found to be stable. The use of MCTs and LCTs in lipid injectable emulsions confers greater stability to TNAs than has been achieved with pure LCT-based formulations.

Drug Compounding↗
PubMed1984

Stability of cephapirin sodium admixtures after freezing and conventional or microwave thaw techniques.

The freeze-microwave thaw technique has important advantages compared with conventional piggyback delivery systems. A requirement for the implementation of this technique, however, is the documentation of antibiotic stability following freezing and microwave thawing. The purpose of this study was to assess the stability of a commonly used cephalosporin, cephapirin sodium, following freezing and conventional or microwave thawing. This data was not previously available. Cephapirin sodium was admixed with either 5% dextrose injection or 0.9% sodium chloride injection in polyvinylchloride minibags at concentrations of 10 and 40 mg/ml and then frozen for 14 days. Admixtures were then thawed conventionally or by microwave heating. Cephapirin concentrations were determined spectrophotometrically after reconstitution, immediately after thawing, and 6, 12, and 24 hours after thawing. No significant differences in admixture potency after reconstitution, immediately after thawing, or at 6, 12, and 24 hours after thawing were observed when thaw techniques were compared. All admixtures retained at least 90% of labeled content regardless of thaw technique, type of diluent, or initial concentration. In addition, all admixtures retained at least 90% potency 24 hours after thawing when compared with the actual concentration determined immediately after reconstitution. The rate of cephapirin degradation was not influenced by thaw technique, type of diluent, or initial admixture concentration. The results of this study suggest that cephapirin sodium may be added to the list of drugs capable of withstanding freeze-microwave thaw treatment.

Cephalosporins↗
PubMed1984

Determining staffing for pharmacy chemotherapy admixture program.

This study was designed to assist the hospital pharmacy administrator in assessing personnel and staffing requirements for a pharmacy chemotherapy admixture service. Time study data was collected on 250 consecutive new and refill chemotherapy admixtures. Both pharmacists and technicians admixed during the 32-day study period. Protective clothing and a vertical hood were utilized. The admixtures were divided into three categories depending on the drug's original packaging (ampul or vial) and the delivery system used for the final solution (syringe or IV bag). Total processing time (compounding time plus auxiliary time plus allowance and absentee time) for all admixtures was determined. The average total processing time for new orders was determined to be 16.75 minutes with refill orders requiring 14.61 minutes. From the results of this study, it was found that an average of eight chemotherapeutic admixtures per day would require approximately 0.4 FTEs.

Drug Compounding↗