Fatal non-accidental pediatric cranial fracture risk and three-layered cranial architecture development.

This study examines the influence of three-layered cranial architecture development upon blunt force trauma (BFT) cranial outcomes associated with pediatric non-accidental injury (NAI). Macroscopic and microscopic metric and morphological comparisons of subadult crania ranging from perinatal to 17 years of age chronicle the ontogenetic development and spatial and temporal variability in the emergence of a mature cranial architecture. Cranial vault thickness increases with subadult age, accelerating in the first 2 years of life due to rapid brain growth during this period. Three-layer differentiation of the cranial tables and diploë initiates by 3-6 months but is not consistently observed until 18 months to 2 years; diploë formation is not well developed until after age 4 and does not manifest a mature appearance until after age 8. These results allow topographic documentation of cortical and diploic development and temporal and spatial variability across the growing cranium. The lateral cranial vault is identified as expressing delayed development and reduced expression of the three-layer architecture, a pattern that continues into adulthood. Comparison of fracture locations from known BFT pediatric cases with identified cranial fracture high-risk impact regions shows a concordance and suggests the presence of a higher fracture risk associated with non-accidental BFT in the lateral vault region in subadults below the age of 2. The absence or lesser development of a three-layered architecture in subadults leaves their cranial bones, particularly in the lateral vault, thin and vulnerable to the effects of BFT.

Validation of the use of zebrafish larvae in visual safety assessment.

INTRODUCTION: The use of zebrafish (Danio rerio) larvae was investigated to predict adverse visual effects and to establish the potential application of this organism in early drug safety assessment. METHODS: Following a comparison of the effects of 4 compounds in TL and WIK strains of zebrafish larvae, a blinded validation set of 27 compounds was tested on WIK strain of larval zebrafish in the optomotor response (OMR) assay. Selected compounds were also tested in the optokinetic response (OKR) and locomotor assays. Larvae were exposed from 3-8 days post-fertilisation (d.p.f.) by immersion in embryo culture media (E3) containing the compound in 1% DMSO (v/v). At 8 d.p.f. toxicity was assessed and the OMR or OKR assays were undertaken at non-toxic treatment levels. Compounds were then rated as 'red', 'amber' or 'green' according to their effects on visual function prior to unblinding of the identities of the test compounds. RESULTS: Overall, the OMR assay revealed a good concordance between the effects of compounds in WIK strain zebrafish with the data available from other in vivo and in vitro models or the clinic: thirteen out of nineteen positive compounds produced the expected effect while six of the eight negative compounds were correctly predicted. This gave an overall predictivity of 70% with a sensitivity of 68% and a specificity of 75%. The two false positive compounds were further tested in locomotor and optokinetic response assays and it was shown that a motility defect, rather than an effect on vision, had given rise to the positive result in the OMR assays. Therefore, the OMR assay would best be employed with other techniques to identify false positives. Further studies on two of the false negatives at higher concentrations suggested that the initial concentrations tested were too low. Therefore, it should be ensured that the maximum tolerated concentration is tested in the OMR assay. A comparison of four standard compounds in the OMR assay in WIK and TL zebrafish wild type strains revealed no difference in sensitivity between the strains. DISCUSSION: Overall, these results suggest that the OMR assay in zebrafish could be useful in predicting the adverse effects of drugs on visual function in man and would support its potential as a screen for 'frontloading' safety pharmacology assessment of this endpoint in vivo.

Repetitive DNA variation and pivotal-differential evolution of wild wheats.

Several polyploid species in the genus Triticum contain a U genome derived from the diploid T. umbellulatum. In these species, the U genome is considered to be unmodified from the diploid based on chromosome pairing analysis, and it is referred to as pivotal. The additional genome(s) are considered to be modified, and they are thus referred to as differential genomes. The M genome derived from the diploid T. comosum is found in many U genome polyploids. In this study, we cloned three repetitive DNA sequences found primarily in the U genome and two repetitive DNA sequences found primarily in the M genome. We used these to monitor variation for these sequences in a large set of species containing U and M genomes. Investigation of sympatric and allopatric accessions of polyploid species did not show repetitive DNA similarities among sympatric species. This result does not support the idea that the polyploid species are continually exchanging genetic information through introgression. However, it is also possible that repetitive DNA is not a suitable means of addressing the question of introgression. The U genomes of both diploid and polyploid U genome species were similar regarding hybridization patterns observed with U genome probes. Much more variation was found both among diploid T. comosum accessions and polyploids containing M genomes. The observed variation supports the cytogenetic evidence that the M genome is more variable than the U genome. It also raises the possibility that the differential nature of the M genome may be due to variation within the diploid T. comosum, as well as among polyploid M genome species and accessions.

Developments in the meiotic analysis of hybrids. II. Amended models for tetraploids.

Amended models of meiotic behaviour in tetraploid species' hybrids have been constructed which better reflect the theory and assumptions about chromosome pairing necessary to conduct such analyses. In particular they correct problems concerning the distribution of chiasmata among and within chromosome configurations inherent in the earlier models of Kimber & Alonso (1981). In general these analyses give similar interpretations to the earlier models but in some cases call the previous conclusions into question.

Developments in the meiotic analysis of hybrids. I. Review of theory and optimization in triploids.

The theory, construction and optimization of a model of chromosome pairing in triploid hybrids are re-examined and the model reconstructed. A new approach to optimization is described that removes a bias in the estimation of x, the measure of relative affinity, by weighting the observed and calculated meiotic figure frequencies by the number of chromosomes in each figure type. The amended analysis is compared with its antecedent and with other models.

Genomic analysis of diploid plants.

The numerical analysis of meiosis in the triploid hybrid between an induced autotetraploid and a related diploid provides the basis for investigations of the genomic relationships of diploid species based on chromosome pairing. It is also possible to make legitimate comparisons between different triploid hybrids of this type so that the genomic relationships can be converted into measures of phylogenetic distance for taxa where only diploids are known.

Production and meiotic analysis of autotriploid Triticum speltoides and T. bicorne.

Autotriploid Triticum speltoides and T. bicorne (2n=3x=21) were produced by pollinating autotetraploids with pollen from their respective diploids. The autotriploid plants were vigorous, male sterile, and morphologically resembled their diploid parents. At meiosis, T. speltoides (3x) averaged 2.52 univalents, 0.42 rod bivalents, 2.03 ring bivalents, 4.48 trivalents, and 0.03 chain quadrivalents per cell, and T. bicorne (3x) had 2.30 univalents, 0.20 rod bivalents, 2.10 ring bivalents, and 4.70 trivalents. Panhandle trivalents made up 27% of the total trivalents, and involved 18% of the total number of chromosomes observed in T. bicorne (3x), and 26% and 17% in T. speltoides (3x), respectively. The observed chromosome pairing in both triploids was predicted well from the expressions developed by Alonso and Kimber.

Headache and blood pressure: evidence of a close relationship.

Although headache is sometimes regarded as a symptom of severe hypertension, its relationship to blood pressure is not clear. In 11,710 patients with mild to moderate essential hypertension we have found that headache was common and may be reduced by treatment. We found a clear relationship between the frequency of reports of headache and both systolic and diastolic blood pressure irrespective of treatment or the type of drug used to treat hypertension. Calcium antagonists appeared most likely to be a cause of headache in hypertensive patients.

Analysis of pivotal-differential evolutionary patterns.

The numerical analysis of meiosis in hybrids between a wild allotetraploid and an autotetraploid of one of its putative diploid progenitors allows the identification of which genomes are pairing and also the verification of pivotal-differential evolution. This type of analysis should be applicable to all genera in which allopolyploid series exist.

Post-marketing surveillance of enalapril: experience in 11,710 hypertensive patients in general practice.

Post-marketing surveillance in general practice represents an important part of the monitoring of adverse events associated with newly introduced drugs. Such a study of the angiotensin-converting enzyme inhibitor enalapril maleate has been undertaken in 11 710 patients with essential hypertension. Serious adverse events occurred in 1.7% of patients, though most of these were not thought to be related to the treatment. The incidence rates of death (0.09%), stroke (0.11%) and myocardial infarction (0.15%) were compatible with rates predicted from age, sex and blood pressure considerations. Other events reported were hypotension (0.3%), angioneurotic oedema (0.03%), rash (0.5%), taste disturbance (0.2%) and cough (1.0%). The degree of blood pressure reduction attained was similar to that previously reported from pre-marketing development studies, as was the overall nature and frequency of both serious and non-serious adverse events. The most frequently reported event during enalapril therapy was of an improvement in well-being (19.8%).

Influence of age on blood pressure response to enalapril.

Based on prevailing hypotheses about the role of renin in essential hypertension, both Laragh and Buhler independently predicted that angiotensin-converting enzyme (ACE) inhibitors would become less effective with increasing age, as elderly hypertensive patients tend to have low plasma renin activity. We have investigated this situation in a large postmarketing surveillance study with enalapril. Following a 2-week no-treatment period, a total of 11,710 patients with essential hypertension received 10-20 mg of enalapril once daily for 6 weeks. BP was measured on two occasions prior to enalapril treatment, and on two occasions during enalapril treatment (after 2 and 6 weeks). Enquiry for symptom events was also made on each of these four occasions. Systolic BP (SBP) prior to enalapril treatment rose steeply with increasing age, whereas diastolic BP (DBP) rose only very slightly with age and reached a plateau by the 5th decade. The fall in SBP in response to enalapril increased with increasing age, but DBP was relatively uninfluenced by age. However, when corrected for initial BP, the percentage changes in both SBP (13%) and DBP (14%) were not different across the age range studied. Prior to receiving enalapril, 67.8% of patients were reporting symptoms, and this showed a positive correlation with age. During enalapril therapy, the overall level of symptom events reported fell significantly in all age groups (35.0%) but more so in the elderly, such that at the end of the study no significant age-related difference was detected. In all age groups, more than half of the events reported during enalapril therapy were of an improvement in general well-being.(ABSTRACT TRUNCATED AT 250 WORDS)

The theory of the pairing of telocentric chromosomes in triploids and trisomics.

The possible pairing patterns of telocentric chromosomes in triploids and trisomics are considered and expressions are derived allowing the prediction of expected meiotic, chromosomal, and cellular pairing patterns. The calculation of the relative affinity of the homoeologous chromosomes involved in the pairing patterns with the telocentrics is discussed.

New hybrids with d genome wheat relatives.

The cytology of nine new D genome hybrids involving Triticum syriacum, Triticum ventricosum, Triticum cyclindricum, Triticum juvenale, Triticum crassum, Triticum tauschii and Triticum aestivum is described. The calculation of numerical values of the relative affinity and the patterns of chromosome pairing indicate that the D genome in T. syriacum and T. juvenale may have been substantially modified and that of T. crassum somewhat modified from that of the diploid progenitor, T. tauschii.

A comparative bioavailability study of Molipaxin capsules and a trazodone liquid formulation in normal volunteers.

The pharmacokinetic parameters of Molipaxin capsules and a trazodone liquid formulation have been compared in healthy volunteers. The mean area under the plasma concentration/time curve was 10.07 micrograms h ml-1 and 10.44 micrograms h ml-1, for Molipaxin capsules and trazodone liquid, respectively. The difference was not statistically significant. There was considerable individual variation between the observed maximum plasma concentration of Molipaxin capsules and trazodone liquid but the mean values of 1.61 micrograms/ml and 1.66 micrograms/ml, respectively, were very similar. The time to observed maximum plasma concentrations varied from 15 min to 4 h, but there was no statistical difference between the two formulations. The terminal phase half-life was 7.16 h for Molipaxin capsules and 6.73 h for trazodone liquid. The difference was not statistically significant. Molipaxin capsules and trazodone liquid have similar kinetic profiles and they are considered to have comparable bioavailability. Tolerance to the two formulations was similar.

A computer simulation of the behavior of reciprocal translocations in autotetraploids.

Reciprocal translocations in autotetraploids create extremely complex cytological and genetic situations. Along with three types of heterozygotes with one, two or three pairs of translocated chromosomes, a large array of aneuploid and unbalanced genotypes can be expected in the F2 and advanced generations. These types arise from gametes formed by adjacent and anomalous disjunctions of multivalents and by numerical non-disjunction of non-cooriented multivalents.To determine the expected patterns of meiotic chromosome pairing configurations in all of these genotypes without the use of a computer program that constructs all possible pairing configurations, and recognizes and sums both the individual meiotic figures (univalents, rod and ring bivalents etc.) and combinations of meiotic figures, would be a very difficult task. The program has been used to construct all the possible meiotic configurations for a large array of normal and translocated genotypes with five, six, seven, eight, nine or ten chromosomes. Several inferences about the behavior of translocated chromosomes in autotetraploid populations have been drawn.

Mathematics of chromosome pairing.

Analysis of frequencies of chromosome configurations in wheat-related species hybrids is extended to include cases involving homoeologous groups of size six. Further, the expected frequencies of the various configurations emanating from homologous and homoeologous pairing events have been determined for groups consisting of two and three homoeologous pairs of homologous chromosomes. Analysis of configuration frequencies of nullisomic 5B of wheat, in which both homologous and homoeologous pairing occurs, led to estimation of the relative frequencies of homologous and homoeologous pairing events as 17.9:1. In the samples analyzed, slightly less than one homoeologous exchange occurred per gamete.

Comparison of the metabolic response to a glucose tolerance test and a standardized test meal and the response to serial test meals in normal healthy subjects.

The plasma glucose and insulin response to a standardized meal test breakfast was compared with the time-honored glucose tolerance test in the same normal healthy subjects. The amplitude of glycemic excursion and between-subject variation was less with the more physiologic standardized test meal than with that seen with the glucose tolerance test. The glucose tolerance test's prime function is to amplify any glucose intolerance, thus aiding diagnosis, whereas a standardized meal gives a more clinically relevant metabolic status. The administration of serial test meals during the same day in a smaller group of normal subjects indicated, as seen previously with repeated glucose tolerance tests, a diminishing carbohydrate tolerance during the day.

Uses of wheat aneuploids.

There is available in wheat a unique series of aneuploids ranging from all 21 possible monosomics to complex types that are simultaneously deficient for one chromosome and duplicate for another. Furthermore, lines with chromosomes from related alien species either added to or substituted for wheat chromosomes are in common cytological use. This contribution condiders the use of this range of material in studies designed to elucidate the evolutionary relationships of the species, in investigations of the genetics of a polyploid with cytological diploidization, and in potential breeding manipulations.