Hypescheme: an operational criteria checklist and minimum data set for molecular genetic studies of attention deficit and hyperactivity disorders

Investigators engaged in mapping the genetic basis of attention deficit hyperactivity disorder (ADHD) currently use a number of measures for the collection of clinical information. This gives rise to difficulties in comparing datasets and research communications between independent groups. This paper describes the development of Hypescheme, which is an operational criteria checklist for ADHD, oppositional defiant disorder (ODD), and conduct disorder (CD), and is proposed as a minimum dataset for those engaged in molecular genetic studies of ADHD. Hypescheme consists of a computerised data checklist system that includes all the operational criteria required for both DSM-IV and ICD-10 diagnostic criteria and a systematic record of information about comorbid psychiatric, developmental, and neurological disorders. Using this data, an algorithm applies both DSM-IV and ICD-10 criteria to generate operational diagnostics under both these systems. Hypescheme is not designed to replace current assessment protocols but to be a final common checklist that can be completed by experienced researchers using all available data.     

The mutational spectrum of brachydactyly type C

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.     

The relationship of childhood sexual abuse and depression with somatic symptoms and medical utilization

BACKGROUND: Previous research suggests that childhood sexual abuse is associated with high rates of retrospectively reported medical utilization and medical problems as an adult. The goal of this study was to determine if abused females have higher rates of medical utilization using self-report and objective measures, compared with non-abused females. A further goal was to determine whether findings of prior research would be replicated when childhood physical abuse level was controlled. This study also examined the moderating impact of depressed mood on current health measures in this population. METHODS: Six hundred and eight women recruited from a health maintenance organization completed self-report measures of health symptoms for the previous month and doctor visits for the previous year. Objective doctor records over a 2 year period were examined for a subset of 136 of these women. RESULTS: Results showed significantly more self-reported health symptoms and more self-reported doctor visits in abused participants compared with those who reported no childhood history of sexual abuse. Objective doctor visits demonstrated the same pattern with abused participants exhibiting more visits related to out-patient surgery and out-patient internal medicine. In addition, persons who were both sexually abused and depressed tended to visit the emergency room more frequently and to have more in-patient internal medicine and ophthalmology visits than sexually abused participants who reported low depressed mood and non-abused controls. CONCLUSIONS: These results replicate prior studies and suggest that current depression may moderate the relationship between sexual abuse and medical problems in adulthood.     

Phorbol ester-induced inhibition of the beta-adrenergic system in pulmonary endothelium: role of a pertussis toxin-sensitive protein

To investigate possible cellular mechanisms for how activation of protein kinase C inhibits the relaxation caused by isoproterenol, we studied the effect of the protein kinase C activator 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) on the increase in cyclic AMP (cAMP) production and adenylate cyclase activity caused by isoproterenol in bovine pulmonary artery endothelial cells. Treatment of intact cells with PMA prevented in a time- and dose-dependent manner the increase in cAMP production caused by isoproterenol, whereas 4 alpha-phorbol-12 beta-myristate-13 alpha-acetate (4 alpha-PMA), which does not activate protein kinase C, did not affect isoproterenol-induced cAMP production. PMA also reduced the increase in adenylate cyclase activity caused by isoproterenol, forskolin, and Gpp(NH)p. To test the hypothesis that the inhibitory effect of PMA is mediated via a pertussis toxin-sensitive G protein, we determined whether pretreatment of the cells with pertussis toxin would prevent the inhibitory effects of PMA. In pulmonary endothelial cells, pertussis toxin ADP-ribosylated an Mr 40,000 peptide that comigrated with the pertussis toxin substrate of human erythrocytes. Pertussis toxin treatment eliminated the inhibitory effect of PMA on isoproterenol-stimulated cAMP production and adenylate cyclase activity. Thus, the protein kinase C activator PMA inhibits the increase in cAMP production and adenylate cyclase caused by isoproterenol. This inhibitory effect in endothelial cells appears to be mediated via a pertussis toxin-sensitive protein.     

COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia

The skeletal dysplasias are a clinically and genetically heterogeneous group of conditions affecting the development of the osseous skeleton and fall into the category of rare genetic diseases in which the diagnosis can be difficult for the nonexpert. Two such diseases are pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), which result in varying degrees of short stature, joint pain and stiffness and often resulting in early onset osteoarthritis. PSACH and some forms of MED result from mutations in the cartilage oligomeric matrix protein (COMP) gene and to aid the clinical diagnosis and counselling of patients with a suspected diagnosis of PSACH or MED, we developed an efficient and accurate molecular diagnostic service for the COMP gene. In a 36-month period, 100 families were screened for a mutation in COMP and we identified disease-causing mutations in 78% of PSACH families and 36% of MED families. Furthermore, in several of these families, the identification of a disease-causing mutation provided information that was immediately used to direct reproductive decision-making.     

Herpesvirus saimiri has a gene specifying a homologue of the cellular membrane glycoprotein CD59.

Herpesvirus saimiri (HSV) is a T-lymphotropic tumor virus that causes fulminant lymphomas and leukemias in various New World primates other than its natural host, the squirrel monkey (Saimiri sciureus). In the course of completing the nucleotide sequence of its genome, we identified an open reading frame of 363 nucleotides, designated HVS-15, that has no detectable homology to any other viral sequences to date. HVS-15 encodes a 121-amino-acid protein which shows significant similarities to human CD59, a phosphatidyl-inositol-glycan-anchored glycoprotein involved in T-cell activation and restriction of complement-mediated lysis. The predicted HVS-15 gene product is more similar to human CD59 than to the related murine Ly-6 antigens. A nucleotide sequence identity of 64% was found between HVS-15 and the CD59 reading frame, and a 48% identity exists between the corresponding protein sequences. The comparison of the amino acid sequences revealed a number of conserved structural features such as a similar pattern of hydrophobic termini and an identical cysteine skeleton.     

Idiopathic hydronephrosis. Light microscopic features and pathogenesis

A histological study of surgical specimens of idiopathic hydronephrosis demonstrated an abnormal muscle arrangement at the ureteropelvic junction in 18 of 26 cases. We believe this abnormality to be the cause in these cases. At this junction, the muscle bundles, instead of displaying the normal interwoven (braided) pattern, are arranged into an outer circular and an inner longitudinal layer. This abnormal muscle arrangement can be attributed to local failure of the physiological uncoiling during growth and development.