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Study Question: What is the likelihood of identifying genetic or endocrine abnormalities in a group of boys with 46, XY who present to a specialist clinic with a suspected disorder of sex development (DSD)?Summary Answer: An endocrine abnormality of the gonadal axis may be present in a quarter of cases and copy number variants (CNVs) or single gene variants may be present in about half of the cases.What Is Known Already: Evaluation of 46, XY DSD requires a combination of endocrine and genetic tests but the prevalence of these abnormalities in a sufficiently large group of boys presenting to one specialist multidisciplinary service is unclear.Study, Design, Size, Duration: This study was a retrospective review of investigations performed on 122 boys.Participants/materials, Setting, Methods: All boys who attended the Glasgow DSD clinic, between 2010 and 2015 were included in the study. The median external masculinization score (EMS) of this group was 9 (range 1-11). Details of phenotype, endocrine and genetic investigations were obtained from case records.Main Results and the Role Of Chance: An endocrine abnormality of gonadal function was present in 28 (23%) with a median EMS of 8.3 (1-10.5) whilst the median EMS of boys with normal endocrine investigations was 9 (1.5-11) (P = 0.03). Endocrine abnormalities included a disorder of gonadal development in 19 (16%), LH deficiency in 5 (4%) and a disorder of androgen synthesis in 4 (3%) boys. Of 43 cases who had array-comparative genomic hybridization (array-CGH), CNVs were reported in 13 (30%) with a median EMS of 8.5 (1.5-11). Candidate gene analysis using a limited seven-gene panel in 64 boys identified variants in 9 (14%) with a median EMS of 8 (1-9). Of the 21 boys with a genetic abnormality, 11 (52%) had normal endocrine investigations.Limitations, Reasons For Caution: A selection bias for performing array-CGH in cases with multiple congenital malformations may have led to a high yield of CNVs. It is also possible that the yield of single gene variants may have been higher than reported if the investigators had used a more extended gene panel.Wider Implications Of the Findings: The lack of a clear association between the extent of under-masculinization and presence of endocrine and genetic abnormalities suggests a role for parallel endocrine and genetic investigations in cases of suspected XY DSD.Study Funding/competing Interest(s): RN was supported by the James Paterson Bursary and the Glasgow Children's Hospital Charity Summer Scholarship. SFA, RM and EST are supported by a Scottish Executive Health Department grant 74250/1 for the Scottish Genomes Partnership. EST is also supported by MRC/EPSRC Molecular Pathology Node and Wellcome Trust ISSF funding. There are no conflicts of interest.Trial Registration Number: None. [ABSTRACT FROM AUTHOR]

In wheat, semidwarfism resulting from reduced height ( Rht)- B1b and Rht-D1b was integral to the 'green revolution'. The principal donors of these alleles are ' Norin 10', ' Seu Seun 27' and ' Suwon 92' that, according to historical records, inherited semidwarfism from the Japanese landrace ' Daruma'. The objective of this study was to examine the origins of Rht- B1b and Rht- D1b by growing multiple seed bank sources of cultivars comprising the historical pedigrees of the principal donor lines and scoring Rht-1 genotype and plant height. This revealed that ' Norin 10' and ' Suwon 92' sources contained Rht- B1b and Rht- D1b, but the ' Seu Seun 27' source did not contain a semidwarf allele. Neither Rht- B1b nor Rht- D1b could be definitively traced back to ' Daruma', and both ' Daruma' sources contained only Rht- B1b. However, ' Daruma' remains the most likely donor of Rht- B1b and Rht- D1b. We suggest that the disparity between historical pedigrees and Rht-1 genotypes occurs because the genetic make-up of seed bank sources differs from that of the cultivars actually used in the pedigrees. Some evidence also suggests that an alternative Rht- D1b donor may exist. [ABSTRACT FROM AUTHOR]

The gene ST7 has been proposed as the multi-tissue tumor-suppressor gene (TSG) at chromosome 7q31.1. However, we have sought and failed to detect the truncating mutations reported to exist in this gene.

Glucagon elicited a profound increase in the intracellular cAMP concentration of COS-7 cells which had been transiently transfected with a cDNA encoding the rat glucagon receptor and under conditions where cAMP phosphodiesterase activity was fully inhibited. This was achieved in a dose-dependent fashion with an EC50 of 1.8+/-0.4 nM glucagon. In contrast with previous observations made using hepatocytes [Heyworth, Whetton, Kinsella and Houslay (1984) FEBS Lett. 170, 38-42], treatment of transfected COS-7 cells with PMA did not inhibit the ability of glucagon to increase intracellular cAMP levels. PMA-mediated inhibition was not conferred by treatment with okadaic acid, nor by co-transfecting cells with cDNAs encoding various protein kinase C isoforms (PKC-alpha, PKC-betaII and PKC-epsilon) or with the PMA-activated G-protein-receptor kinases GRK2 and GRK3. In contrast, PMA induced the marked inhibition of glucagon-stimulated cAMP production in COS-7 cells that had been co-transfected with a cDNA encoding protein kinase D (PKD). Such inhibition was not due to an action on the catalytic unit of adenylate cyclase, as forskolin-stimulated cAMP production was unchanged by PMA treatment of COS cells that had been co-transfected with both the glucagon receptor and PKD. PKD transcripts were detected in RNA isolated from hepatocytes but not from COS-7 cells. Transcripts for GRK2 were present in hepatocytes but not in COS cells, whereas transcripts for GRK3 were not found in either cell type. It is suggested that PKD may play a role in the regulation of glucagon-stimulated adenylate cyclase.

The clinical details, specialist investigation, pharmacological treatment and outcome in 1000 consecutive patients referred to the epilepsy clinic at the Western Infirmary in Glasgow were reviewed. Data were collected by detailed proforma at initial referral and from the clinical notes at audit. 524 (52%) of the patients were 30 years of age or younger. 527 (53%) were sent to the clinic by their general practitioner with the majority of the remainder being referred by another hospital consultant. 240 (24%) came from outwith greater Glasgow. In 253 (25%) patients a possible predisposing factor was identified, usually a major head injury or alcohol abuse. Sixty (6%) patients suffered from additional mental handicap. Focal spike and wave activity was identified in 26% of electroencephalograms. One or more abnormality was found in 33% of the 356 patients who underwent computerized tomographic brain scanning. In 13 (11%) of these, a tumour was demonstrated. On referral, 65% of patients were being treated with antiepileptic drugs; 58% were on monotherapy and 42% took more than one anticonvulsant. The figure at audit was 77% treated, with a higher proportion (68%) than at referral receiving monotherapy (P < 0.005). Sedative anticonvulsants, such as phenobarbitone and primidone, were withdrawn in 29% of cases. 50% of the 519 patients, for whom seizure frequency data were available for the years before referral and audit, were seizure-free and seizure numbers had been reduced by 50% or more in a further 23%. A poorer response to treatment was associated with mental handicap (P < 0.05), birth injury (P < 0.01), and partial or secondary generalized seizures (P < 0.005).