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.     

Molecular interactions during pregnancy: Association between mannan binding protein deficiency and recurrent miscarriage

The distribution of mannan binding protein (MBP) in blood donorsera was determined by enzyme-linked immunosorbent assay toestablish normal concentrations. Abnormally low MBP concentrationswere found in 16% (21 out of 135) of female partners and 14%(15 out of 108) of male partners of couples experiencing recurrentmiscarriage, compared with <5% of obstetrically normal controls(P < 0.005). This relationship was even stronger (9.5 versus1.0%) and more significant (P < 0.002) when only subjectspresumed to be homozygous for the mutant allele responsiblefor MBP deficiency were considered. By immunohistochemistry,MBP could be demonstrated in first trimester placenta. We suggestthat low concentrations of MBP within the feto-placental unitincrease susceptibility to fetal loss, possibly via an infection-inducedplacental cytokine imbalance.     

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.     

Will the spectrum of lesions prompting a "B3" breast core biopsy increase the benign biopsy rate?

Aim: To audit the benign surgical biopsies in women screened, assessed, and referred by the Leeds/Wakefield Breast Screening Unit for the year 1999-2000 with a view to determining any association with a preoperative B3 core biopsy categorisation. METHODS: The results of all preoperative diagnostic procedures in all patients who underwent surgical excision for a lesion proving benign in the year 1999-2000 were reviewed. Cases were categorised according to whether the preoperative fine needle aspirate cytology (FNAC) or core biopsy had been equivocal or of uncertain malignant potential (C3/B3), inadequate or unrepresentative (C1/B1), or benign (C2/B2). In those cases with a C3/B3 FNAC or core biopsy result, reasons for the uncertainty were determined by examination of the report and, where necessary, slides. In cases with C1/B1 or C2/B2 investigations and in those without a preoperative procedure, the reasons for surgical referral were determined from the screening records. Case records of all patients with a B3 core biopsy categorisation who subsequently proved to have malignancy were also reviewed. RESULTS: Thirty six women had benign surgical biopsies in the 1999-2000 screening year. In 13 of the 36 patients, referral for diagnostic biopsy rested on radiological and/or pathological suspicion of radial scar. The core biopsy category was B3 in all but one, which was in the B1 category. In a further 10 patients, referral was based primarily on a pathological B3 categorisation. The reasons for this were as follows: papillary lesion (two), fibroepithelial lesion (two), atypical intraductal epithelial proliferation (two), stromal mucin (two), atypical lobular hyperplasia (one), and an unusual vascular lesion (one). Two cases with a C3 on FNAC also derived from papillary lesions. In the remaining nine patients, the radiological features were sufficiently suspicious to prompt referral in the presence of either inadequate/unrepresentative (C1/B1) or benign (B2) preoperative pathological findings. Two women had no preoperative needle biopsy. CONCLUSIONS: In 22 of 36 benign biopsies, the initial core biopsy categorisation was B3. According to the current system of core biopsy categorisation, a diversity of lesions must be designated as of "uncertain malignant potential" (B3) because the technique provides insufficient tissue for full histological assessment. The use of this category may increase the number of benign biopsies if all such cases are referred for surgery. An increase in the benign biopsy rate may be averted if larger amounts of tissue can be obtained using newer vacuum assisted techniques such as the Mammotome.