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Development and testing of a revised dynamic model of radiocaesium transfer to sheep tissues.

The model of radiocaesium transfer to sheep presented by Galer et al. provides reliable predictions only for sheep of a similar body weight to those used in the development of the model (approximately 30 kg). To extend the applicability of the model, it was necessary to re-parameterise it in terms of activity concentrations in tissues rather than total activities within them (although for gut compartments the use of activity has been retained). The rate coefficients for the new model have been estimated by fitting the model to the data used by Galer et al. which was derived from a single "calibration" experiment. The new model was found to account for 94% of the observed variation in the data (n = 42), a result similar to that obtained by Galer et al. The model has also been tested against data not used in its development but obtained from four separate experiments undertaken by three different laboratories. Good agreement between the predictions of the new model and observations was found for most circumstances and for several breeds of sheep with different body weights. It is concluded that the new model provides a useful dynamic description of radiocaesium transfers to the tissues of sheep of different breeds and under different contamination scenarios.

Administration, Oral↗

Use of coronary angiography and revascularization procedures following acute myocardial infarction. A European perspective.

AIMS: There is little evidence to inform routine practice in the use of coronary angiography and revascularization procedures after acute myocardial infarction. Large differences in the uptake of these procedures have been reported but representative data are scarce. Outcome studies have produced opposing conclusions concerning the impact of the high rate of these cardiac procedures. METHODS AND RESULTS: A population-based patient sampling approach was utilized to identify routine practice in representative samples from 11 European countries. Data were collected retrospectively on treatment in the 6 months following acute myocardial infarction (n=2807). There was wide variation in utilization of coronary angiography and revascularization procedures. Even after restricting the analysis to patients <65 years (n=1262), there remained a 6 13 fold variation in the use of these procedures. A decreased likelihood of undergoing these procedures was associated with older age. In addition, there was an independent and negative association between female sex and utilization of coronary angiography and coronary artery bypass grafting (CABG). CONCLUSION: The effect on patient outcome of the observed variation in use of these procedures is not known but has important cost and resource implications for the health services. Outcome research is needed to define patient selection criteria and to measure the cost-utility of different angiography and revascularization rates.

Adult↗

Laboratory testing, diagnosis, and management of von Willebrand disease. Current practice in Australasia. RCPA Quality Assurance Program in Haematology Scientific Haemostasis Advisory Panel.

We report an evaluation of current laboratory and clinical practice for the diagnosis and management of von Willebrand disease (VWD) for a wide geographic area including Australia, New Zealand, and parts of Southeast Asia. This assessment has been undertaken in conjunction with the RCPA Quality Assurance Program (QAP) in Haematology. This external QAP currently comprises around 550 participating laboratories, of which some 450 perform coagulation testing, and from which 32 laboratories were identified to be actively involved in testing for VWD. These laboratories were targeted and their current laboratory and clinical practice evaluated by using various questionnaires. Our overall findings indicate a wide variation in laboratory test practice for VWD-based investigations. There was considerable variation among laboratories in the tests and test methods used, the control and calibration material used, the reported test reference intervals and units used, and the composite test panels used to diagnose VWD. However, substantial consensus in the clinical evaluation process, as undertaken by hematologists, also was identified. Despite the observed variations, most laboratory professionals seemed to understand the complexities involved in the diagnosis and subclassification of VWD, and the laboratories can provide an effective diagnostic service.

Asia, Southeastern↗

Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice.

Genetic heterogeneity underlies many phenotypic variations observed in circadian rhythmicity. Continuous distributions in measures of circadian behavior observed among multiple inbred strains of mice suggest that the inherent contributions to variability are polygenic in nature. To identify genetic loci that underlie this complex behavior, we have carried out a genome-wide complex trait analysis in 196 (C57BL/6J X BALB/cJ)F(2) hybrid mice. We have characterized variation in this panel of F(2) mice among five circadian phenotypes: free-running circadian period, phase angle of entrainment, amplitude of the circadian rhythm, circadian activity level, and dissociation of rhythmicity. Our genetic analyses of these phenotypes have led to the identification of 14 loci having significant effects on this behavior, including significant main effect loci that contribute to three of these phenotypic measures: period, phase, and amplitude. We describe an additional locus detection method, genome-wide genetic interaction analysis, developed to identify locus pairs that may interact epistatically to significantly affect phenotype. Using this analysis, we identified two additional pairs of loci that have significant effects on dissociation and activity level; we also detected interaction effects in loci contributing to differences of period, phase, and amplitude. Although single gene mutations can affect circadian rhythms, the analysis of interstrain variants demonstrates that significant genetic complexity underlies this behavior. Importantly, most of the loci that we have detected by these methods map to locations that differ from the nine known clock genes, indicating the presence of additional clock-relevant genes in the mammalian circadian system. These data demonstrate the analytical value of both genome-wide complex trait and epistatic interaction analyses in further understanding complex phenotypes, and point to promising approaches for genetic analysis of such phenotypes in other mammals, including humans.

Animals↗

Proton magnetic resonance spectroscopic imaging of pediatric low-grade astrocytomas.

Despite their uniform histologic appearance, pediatric low-grade astrocytomas (LGA) often exhibit a rather unpredictable clinical course. It is presently unclear whether certain specific genetic, immunologic and/or metabolic features underlie these observed variations. In order to address this question we examined the tumor distribution of choline compounds (Cho), creatine (Cr) and N-acetyl aspartate (NAA) in seven children with midline LGA by means of proton magnetic resonance spectroscopy imaging (H-MRSI). Studies were performed with a 1.5 T GE Signa Scanner equipped with the standard head coil; nominal voxel size was 7.5 x 7.5 x 15 mm. This spatial resolution allowed us to select and independently evaluate multiple regions of interest (ROI) in the tumor as well as in areas of normal brain from the same individual. Normalized values of the observed signal intensities demonstrated a lower NAA and Cr content in the tumors than in the surrounding normal brain. Intratumoral Cho signals were also below normal values in all but one patient. The average Cho:NAA ratio was consistently higher in the tumor than in the normal brain. However, there was a wide variation (up to fourfold) in the Cho:NAA ratios of different ROIs, even within the same tumor. Our results clearly indicate that pediatric LGAs are metabolically heterogeneous, a feature that may be relevant to the understanding of their variable biologic behavior. Inasmuch as unique metabolic patterns were observed in some LGAs, we believe that systematic HMRSI studies of these patients may help define subsets within the group with specific therapeutic requirements.

Astrocytoma↗

Following the LINEs: an analysis of primate genomic variation at human-specific LINE-1 insertion sites.

The L1 Ta subfamily of long interspersed elements (LINEs) consists exclusively of human-specific L1 elements. Polymerase chain reaction-based screening in nonhuman primate genomes of the orthologous sites for 249 human L1 Ta elements resulted in the recovery of various types of sequence variants for approximately 12% of these loci. Sequence analysis was employed to capture the nature of the observed variation and to determine the levels of gene conversion and insertion site homoplasy associated with LINE elements. Half of the orthologous loci differed from the predicted sizes due to localized sequence variants that occurred as a result of common mutational processes in ancestral sequences, often including regions containing simple sequence repeats. Additional sequence variation included genomic deletions that occurred upon L1 insertion, as well as successive mobile element insertions that accumulated within a single locus over evolutionary time. Parallel independent mobile element insertions at orthologous loci in distinct species may introduce homoplasy into retroelement-based phylogenetic and population genetic data. We estimate the overall frequency of parallel independent insertion events at L1 insertion sites in seven different primate species to be very low (0.52%). In addition, no cases of insertion site homoplasy involved the integration of a second L1 element at any of the loci, but rather largely involved secondary insertions of Alu elements. No independent mobile element insertion events were found at orthologous loci in the human and chimpanzee genomes. Therefore, L1 insertion polymorphisms appear to be essentially homoplasy free characters well suited for the study of population genetics and phylogenetic relationships within closely related species.

Animals↗

Distribution of insulin-like growth factor 1 (IGF-1) and 2 (IGF-2) receptors in the hippocampal formation of rats and mice.

This study demonstrated species differences in IGF-1 and IGF-2 receptor binding and localization in the hippocampus of the rat and mouse. Competition binding studies indicated that there were no differences in the relative binding affinities for the type 1 or type 2 receptors between the brains of these animals. These results suggested that the observed species differences were not attributable to alterations in IGF receptor kinetics. Receptor autoradiographic analyses demonstrated that IGF-1 binding differed in both the localization and overall receptor densities observed, with the rat demonstrating more specific localization and greater receptor density in the hippocampus than the mouse. The rat also exhibited a greater density of IGF-2 receptors in the hippocampus than the mouse. Despite differences in IGF receptor populations, both species exhibit similar hippocampal structure and lamination. Therefore, these results demonstrate a disparity in the localization of IGF receptor binding in the rat and mouse, suggesting that IGFs in these species are differentially regulated, with distinct neuromodulatory, neurotrophic, and/or developmental roles in this region of the brain. Previous comparative anatomical studies of the hippocampal formation of rats and mice fail to offer an explanation for the absence or reduction of binding of IGF-1 in the mouse. Although the mouse has a greater cell density in the s. granulosum than the rat, and both species exhibit similar glia and synaptic contact densities in the s. moleculare of the dentate gyrus, the mouse exhibits a complete absence of IGF-1 binding in this region. The lack of anatomical differences in the hippocampal formation of these species suggests that the patterns observed in IGF binding result from alterations in either neurochemical modulation of these neurons or specific neurotrophic requirements of the cells in this region. Differences have been reported on the concentrations and binding of various neurotransmitters in the hippocampus of these species, however these differences do not easily account for the variations observed in IGF binding in this study. IGFs are known to influence acetylcholine neurotransmission in the hippocampus as well as other brain areas in the rat. Recently, a truncated form of IGF-1, in which a tripeptide is cleaved from the N-terminus of the peptide, has been reported in brain. The cleaved tripeptide has been shown to activate glutamate receptors, which may dramatically influence excitatory neurotransmission in this region. Therefore, in addition to the possible neurotrophic actions of the peptide itself, subsequent processing of IGF-1 may be an important aspect of IGF-1 activity in the brain.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

Utility of esophageal Doppler as a minimally invasive hemodynamic monitor: a review.

PURPOSE: The current bedside "gold standard" for cardiac output (CO) monitoring is thermodilution using a pulmonary artery catheter (PAC) but there is a number of risks associated with its use. The primary objective of this review was to evaluate the utility of esophageal Doppler (ED) as a minimally invasive monitor of CO. SOURCE: Medline literature search from 1966 to 2001 with citation review for studies comparing ED to PAC thermodilution for CO in perioperative and critically ill patients. PRINCIPAL FINDINGS: Twenty-five publications were identified comparing ED and PAC measurement of CO in a broad range of patients. There was a good overall correlation between CO determined by ED and thermodilution (n = 18 studies, median R = 0.89, range 0.52 to 0.98) and minimal bias (n = 13, median -0.01, range 1.38 to 2 L x min(-1)). The precision of ED was only fair overall as assessed by limits of agreement. The ED technique was found to be responsive in detecting changes in thermodilution CO and was reliable demonstrating both low intra- and inter-observer variation. ED was reportedly easy to insert after minimal training and was safe, with no significant complications identified. CONCLUSION: ED is a practical, reliable, and valid device for measuring CO in perioperative and critically ill patients. Further studies with larger numbers of patients are needed to determine if the limited precision observed is inherent to the technique, the diagnoses of patients studied, or the small sample sizes.

Catheterization, Swan-Ganz↗

Phase-I study of a new schedule based on increasing days of topotecan administration associated with dose individualisation.

BACKGROUND: The most commonly prescribed schedule of topotecan administration is daily for five days, every 21 days. Both pre-clinical and clinical studies suggest that a more protracted schedule may increase its therapeutic index. The current study was undertaken to determine the maximum tolerated number of days with 30-minute i.v. infusion of topotecan daily at fixed area under the plasma concentration-time curve (AUC) (i.e., 35 microg/Lxh). PATIENTS AND METHODS: Topotecan was administered i.v. over 30 min. The planned levels of number of days of administration were: 7, 10, 13, 15 and 17. The dose was individualized according to the patient's individual topotecan clearance observed after the first infusion of each cycle. RESULTS: Twenty-three patients were enrolled and received 71 cycles of therapy. The 13-day level was defined as the maximum number of days of administration. The main side effects were thrombocytopenia and anaemia, whereas neutropenia was infrequent. The mean (coefficient of variation) observed AUC was 34.6 (21%), and 33.4 (19%) microg/Lxh, for the last day of cycle 1, and of cycle 2, respectively. Confirmed partial responses were observed in one patient with metastatic desmoplastic tumour and in two patients with small round metastatic endocrine carcinoma. CONCLUSION: The recommended number of topotecan administration is 10 days. Beyond the potential clinical interest of topotecan administered for a 10-day period, this is the first trial showing the feasibility of a phase-I study exploring a number of administrations of daily AUC rather than a total dose in mg/m(2).

Adult↗

Sex-biased DNA methylation in small hive beetles (Aethina tumida).

DNA methylation is an important epigenomic modification that significantly influences various cellular and organismal functions. In this study, we investigate the methylome of the small hive beetle, Aethina tumida. Our analysis reveals an average of 58,306 CpG methylation marks per beetle, representing approximately 0.99% of the genome's total CpGs. Notably, 85.4% of these methylation marks are located within genic regions on autosomes, with similar rates observed in both male and female beetles. However, male beetles exhibit a lower number of methylation marks and upregulated genes on Chromosome X when compared to female beetles. To evaluate the impact of epialleles on methylation, we identified 5828 associations between SNPs and methylation, with genotypes accounting for 39.2% of the variation observed at highly methylated sites. Interestingly, unfertilised eggs display slightly higher levels of DNA methylation compared to adult beetles, whereas embryos show methylation levels that are only about half of those in adults. This suggests that DNA methylation is dynamic during early development.

Animals↗

What Mendel did not discover: exceptions in Mendelian genetics and their role in inherited human disease.

It has been one hundred and thirty-eight years after the initial publication of Mendel's laws of inheritance. Following a couple of decades of unprecedented progress in deciphering the molecular basis of human genetic disease, we have the luxury of hindsight to revisit Mendel's original discoveries in order to recognize variations in the themes that have otherwise endured the test of time. In this article we focus on diseases inherited in a Mendelian (or near Mendelian) fashion and describe deviations from the laws of Mendelian inheritance. We discuss relevant examples of inherited human disease and the underlying molecular mechanisms for the observed variations in Mendelian laws of inheritance.

Female↗

Variation in the sequence and modification state of the human insulin gene flanking regions.

The nucleotide sequence of a highly repetitive sequence region upstream from the human insulin gene is reported. The length of this region varies between alleles in the population, and appears to be stably transmitted to the next generation in a Mendelian fashion. There is no significant correlation between the length of this sequence and two types of diabetes mellitus. We observe variation in the cleavability of a BglI recognition site downstream from the human insulin gene, which is probably due to variable nucleotide modification. This presumed modification state appears not to be inherited, and varies between tissues within an individual and between individuals for a given tissue. Both alleles in a given tissue DNA sample are modified to the same extent.

Alleles↗

Variability of polymorphic cellular enzymes in medical students with different serum lipid levels: a preliminary survey.

Groups of male Caucasian medical students who had, relative to their classmates, eitherhigh or low lipid levels were screened for electrophoretic variants of haptoglobin, transferrin, and 10 polymorphic erythrocyte enzymes. Members of both the "high" and "low" lipid groups were found to be polymorphic at 7 genetic loci, 6 of which were enzymatic. Consistently, at most polymorphic loci the high lipid groups had somewhat higher frequencies of nonpredominant phenotypes (patterns other than the phenotype reported to occur most frequently in U.S.A. Caucasian populations). A higher frequency of the less common nonpredominant phenotypes (reported Caucasian population frequency less than 0.200) in the high lipid groups was primarily responsible for the observed variations in the phenotypic distributions. Gene frequency distributions were correspondingly skewed. In 14 comparisons between the high and low lipid groups the least common allele of the 7 polymorphic series had a higher frequency in the high lipid group 9 times and in the low lipid group only once. Collectively, our preliminary observations suggest quantitative and qualitative genetic trends related to serum lipid levels that warrant more extensive investigation.

Alleles↗

Variations in cerebellar morphology of the Atlantic stingray, Dasyatis sabina.

The cerebellar corpus of the Atlantic stingray consists of an anterior lobe which is divided into rostral and caudal lobules, and a posterior lobe. The long axis of the posterior lobe and rostral lobule of the anterior lobe both lie along the midline, whereas the orientation of the caudal lobule varies. We examined this variation in 127 animals. In 52% the long axis of the caudal lobule lay on the right of the midline, in 21% it was on the left, and in 27% across the midline. While this distribution is not random, it is not related to size or sex. It is proposed that the observed variation is the reflection of variation in the cerebellar developmental program.

Animals↗

Intraspecific nucleotide variation at the pheromone binding protein locus in the turnip moth, Agrotis segetum.

Inter- and intraspecific amino acid variability in the pheromone binding proteins (PBPs) of the Lepidoptera is believed to contribute to a molecular mechanism of pheromone blend discrimination. Messenger RNA coding for PBP sequence in Agrotis segetum (Noctuidae) was cloned, and nucleotide and inferred amino acid variation across a 769-bp region of a PBP locus was studied in two populations. A single gene copy was fully sequenced, revealing an intron/exon structure conserved with distant saturniids. While several nucleotide substitutions are predicted to result in amino acid replacement, tests for the presence of natural selection suggest that the observed variation is neutral. A phylogenetic analysis provides evidence that the two populations are in the process of genetic isolation.

Amino Acid Sequence↗

Familial resemblance in energy intake: contribution of genetic and environmental factors.

Total energy intake and intakes of carbohydrate, fat, and protein as well as the percentage of energy derived from these nutrients were calculated from a 3-d dietary record in 1597 subjects living in 375 families of French descent. Familial correlations were computed in pairs of biological relatives and relatives by adoption and used in the path-analysis BETA model to determine the contribution of genetic and nongenetic factors in the familial resemblance observed in energy intake. No significant genetic effect was found for intake of any nutrient tested (h2 less than or equal to 11%) and cultural inheritance was found to be more important than genetic inheritance. Nontransmitted environmental factors, including home environmental effects, were found to account for more than 50% of the variation observed in the energy-intake components. These results suggest that the average genetic influence on nutrient intake is negligible and that nongenetic effects associated mainly with home environmental effects are the major affecters of energy intake.

Adolescent↗

Natural abundance carbon isotope composition of isoprene reflects incomplete coupling between isoprene synthesis and photosynthetic carbon flow.

Isoprene emission from leaves is dynamically coupled to photosynthesis through the use of primary and recent photosynthate in the chloroplast. However, natural abundance carbon isotope composition (delta(13)C) measurements in myrtle (Myrtus communis), buckthorn (Rhamnus alaternus), and velvet bean (Mucuna pruriens) showed that only 72% to 91% of the variations in the delta(13)C values of fixed carbon were reflected in the delta(13)C values of concurrently emitted isoprene. The results indicated that 9% to 28% carbon was contributed from alternative, slow turnover, carbon source(s). This contribution increased when photosynthesis was inhibited by CO(2)-free air. The observed variations in the delta(13)C of isoprene under ambient and CO(2)-free air were consistent with contributions to isoprene synthesis in the chloroplast from pyruvate associated with cytosolic Glc metabolism. Irrespective of alternative carbon source(s), isoprene was depleted in (13)C relative to mean photosynthetically fixed carbon by 4 per thousand to 11 per thousand. Variable (13)C discrimination, its increase by partially inhibiting isoprene synthesis with fosmidomicin, and the associated accumulation of pyruvate suggested that the main isotopic discrimination step was the deoxyxylulose-5-phosphate synthase reaction.

Atmosphere↗

Comparison of ytterbium chloride and chromium sesquioxide as fecal indicators.

To assess the potential of ytterbium chloride (Yb) as an indicator of fecal output, we dosed 13 mature beef cows with Yb and chromic oxide (Cr2O3) either once (0800) or twice (0800 and 1600 hr) daily. Fecal output and digestible dry matter were estimated from fecal marker concentration determined in grab samples collected at 0800, 1600 or 0800 and 1600 hr, and compared with values obtained by total fecal collection. With single daily dosings, fecal outputs estimated from Yb at all collection times did not differ from values obtained by total collection, whereas Cr2O3 underestimated (P greater than .05) fecal production at 0800 hr and in the composited (0800 and 1600 hr) collections. With twice-daily dosing, fecal outputs estimated from Yb differed to a greater extent from the total collection values for the 1600 hr collection; however, the Cr2O3 values more closely approximated those estimated by total fecal collection at 0800 hours. Relative marker concentration in the feces collected from grab samples at 4.hr intervals indicated that twice-daily dosing appeared to reduce diurnal variation. Diurnal fecal excretion patterns of Yb and Cr2O3 differed (P greater than .05); however, the variation observed for both markers within dosing schedule appeared to be as great for Yb as it was for Cr2O3. Although fecal output was accurately estimated from Yb with one simultaneous collection and dosing period, the response appeared to be due to time of collection rather than to an actual reduction in diurnal variation.

Animals↗