Optimal Selection of Sib Pairs from Random Samples for Linkage Analysis of a QTL Using the EDAC Test

Percentages of extremely concordant and extremely discordant sib pairs are calculated that maximize the power to detect a quantitative trait locus (QTL) under a variety of circumstances using the EDAC test. We assume a large fixed number of randomly sampled sib pairs, such as one would hope to find in the large twin registries, and limited resources to genotype a certain number of selected sib pairs. Our aim is to investigate whether optimal selection can be achieved when prior knowledge concerning the QTL gene action, QTL allele frequency, QTL effect size, and background (residual) sib correlation is limited or absent. To this end we calculate the best selection percentages for a large number of models, which differ in QTL gene action allele frequency, background correlation, and QTL effect size. By averaging these percentages over gene action, over allele frequency, over gene action, and over allele frequencies, we arrive at general recommendations concerning selection percentages. The soundness of these recommendations is subsequently in a number of test cases.     

Histopathology of the teeth in segmental odontomaxillary dysplasia: new findings

Histological examination of the deciduous teeth in two cases of segmental odontomaxillary dysplasia (SOMD) showed fibrous enlargement of the pulps, an irregular pulp/dentine interface displaying many pseudoinclusions and pulp stones. There were tubular defects in the coronal dentine from pulp horn to cusp tip, an irregular tubular structure to the circumpulpal dentine of the apical half, a focally deficient odontoblast layer and widespread external resorption. Together with the clinical features of unilateral maxillary enlargement, upper alveolar expansion in the distal segment, increased spacing and delayed eruption of the deciduous molars and absence of premolar teeth, these histological appearances allow distinction of this condition from fibrous dysplasia (FD), segmental hemifacial hypertrophy (SHH) and regional odontodysplasia (ROD).     

A Comparison of adults with antisocial personality traits with and without childhood conduct disorder.

BACKGROUND: Antisocial personality disorder (ASPD) in DSM-IV is unique among personality disorder diagnoses in requiring the individual to satisfy a number of childhood criteria in addition to relevant traits exhibited in adulthood. We examined the validity of this childhood requirement. METHODS: Personality disordered individuals assessed using the International Personality Disorder Examination and exhibiting a sufficient number of adult antisocial traits to meet criterion A of DSM-IV were subdivided into those who exhibited antisocial traits in both adulthood and childhood and those who had such traits in adulthood only. The two groups were then compared on a number of historical, clinical, and self-report measures. RESULTS: Thirty individuals meeting both childhood and adult criteria (ASPD) were compared with 39 meeting adult antisocial criteria only (ASS). Few differences were found between the two groups on the measures examined, although those in the ASPD group appeared more severe and had higher anger scores on the STAXI-2 psychometric test. CONCLUSIONS: This failure to find clinically important differences between the two groups is in agreement with previous reports and needs to be taken into account in future revisions of ASPD in DSM.     

Simultaneous genetic analysis of longitudinal means and covariance structure in the simplex model using twin data

A longitudinal model based on the simplex model is presented to analyze simultaneously means and covariance structure using univariate longitudinal twin data. The objective of the model is to decompose the mean trend into components which can be attributed to those genetic and environmental factors which give rise to phenotypic individual differences and a component of unknown constitution which does not involve individual differences. Illustrations are given using simulated data and repeatedly measured weight obtained in a sample of 82 female twin pairs on six occasions.     

Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain‐of‐function variant: Initial experience

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain‐of‐function mutations in the regulatory (SUR2) and pore‐forming (Kir6.1) subunits of K_ATP channels, respectively, suggesting that channel‐blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg^–1 kg^–1 day^–1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg^?1 kg^?1day^?1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.     

A season of football injuries

All rugby and soccer players presenting to the Accident & Emergency department during the football season 1992-1993 (a total of 871) were prospectively studied to compare the injuries sustained in the two sports. The nature and site of injury, treatment required, age, fitness, experience and position of the player, situation giving rise to injury, and medical attention at the grounds were all analysed. The results show that rugby and soccer players had the same number of injuries, and while there were some differences in the nature of the injuries, there was no difference in overall severity. Rugby flankers and soccer goalkeepers are particularly at risk. Competitive matches produce more injuries than training sessions. Experience or fitness did not appear to be a factor and 45% of rugby injuries and 15% of soccer injuries were from school matches. Law changes (e.g. the rugby scrum and the use of gum-shields) have reduced some injuries, but other areas (e.g. jumping for the ball in soccer, rucks and mauls in rugby) also warrant consideration. There was one death, but no spinal cord injuries. Medical attention at the grounds was limited. Rugby injuries, therefore, do not appear to be more numerous or severe than soccer injuries. Law changes have been of benefit but they need to be enforced and perhaps more should be considered. Medical attention at sports grounds could be improved and Registers of injuries kept by the sporting bodies would be of benefit.     

Disposition and placental transfer of etidocaine in pregnancy

Summary Following epidural administration of etidocaine hydrochloride to non-pregnant and pregnant patients, a similar rate of absorption was observed and there was no significant difference in total systemic blood clearance (Cl_sb) of etidocaine in the two groups. There were no major differences in the urinary excretion of etidocaine and metabolites in 48 h urine in both groups. The ability of pregnant women to form the N-glucuronide of the metabolite ABX (2-amino-2-butyroxylidide) was similar to that of non-pregnant individuals. In vitro experiments showed that the blood/plasma concentration ratio () of etidocaine was significantly higher in pregnant females than in males, presumably due to the lower haematocrit in females. The fraction unbound in plasma (f_p) of etidocaine was low in control subjects (mean 0.057) and was not significantly different in pregnant women of 35 to 37 weeks gestation. A marked increase in f_p was observed in pregnant women during delivery (mean 0.264). This finding has potentially serious clinical implications because it is the unbound drug in blood which is pharmacologically important. Placental transfer of etidocaine was rapid and the cord/maternal venous blood concentration ratio at delivery (CM_b) was, with one exception, always less than unity (mean 0.342). Following epidural administration of etidocaine to pregnant women in labour, measurable concentrations of mono-dealkylated metabolites of etidocaine, PABX (2-N-propylamino-2-butyroxylidide) and EABX (2-N-ethylamino-2-butyroxylidide) were detectable in maternal blood within 5 min and cord blood within 30 min. The CM_b for PABX and EABX was 0.401 and 0.658 respectively.List of Abbreviations Used ABX 2-Amino-2-butyroxylidide - EABX 2-N-Ethylamino-2-butyroxylidide - PABX 2-N-Propylamino-2-butyroxylidide - Cl_sb Total systemic blood clearance - Cl_sp Total systemic plasma clearance - Blood/plasma concentration ratio - f_p Fraction of unbound drug in plasma - f_pw Fraction of free drug in plasma water in blood - C_mb Cord/maternal venous blood concentration ratio at delivery - C_mp Cord/maternal venous plasma concentration ratio at delivery - t_1/2 Terminal phase half-life - t_p Time of attainment of peak plasma concentration - E Mean hepatic extraction ratio - Q Liver blood flow