Runs of homozygosity and testicular cancer risk.

BACKGROUND: Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. OBJECTIVE: To examine whether RoH are associated with TGCT risk. METHODS: We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. RESULTS: Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. DISCUSSION AND CONCLUSION: Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.

Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.

5-Aminolaevulinic acid methyl ester transport on amino acid carriers in a human colon adenocarcinoma cell line.

The transport mechanisms of 5-aminolevulinic acid methyl ester (5-ALA-ME) have been studied in a human adenocarcinoma cell line (WiDr) by means of 14[C]-labeled 5-ALA-ME. The transport was found to be partly Na+ dependent, while the extracellular Cl- concentration did not affect the uptake. The transport of 5-ALA-ME into WiDr cells was dependent on the incubation temperature and was found to be completely blocked by the inhibitors of energy metabolism, 2-deoxyglucose and sodium azide. WiDr cells were treated with 10 mM of 14 different amino acids and the substrate specificity of the 5-ALA-ME transporter(s) was analyzed by treating the cells with 23 microM or 1 mM 14[C]-labeled 5-ALA-ME. The transport of 5-ALA-ME was found to be inhibited to the highest extent, i.e. about 60%, by the nonpolar amino acids L-alanine, L-methionine, L-tryptophan and glycine. The uptake of 5-ALA-ME followed an exponential decay with increasing concentration of glycine, reaching a maximum inhibition of uptake of 5-ALA-ME of 55%. Sarcosine, a specific inhibitor of system Gly, did not significantly inhibit 5-ALA-ME transport. In contrast to transport of 5-ALA, 5-ALA-ME does not seem to be taken up by system BETA transporters. In conclusion, the cellular uptake of 5-ALA-ME into WiDr cells seems to be due to active transport mechanisms, involving transporters of nonpolar amino acids.

A new chromogenic medium for the isolation of Listeria spp.

A new medium is described for the isolation of Listeria spp. from foods and environmental samples. It is based on a modified Oxford medium in which 3,4-cyclohexenoesculetin-beta-D-glucoside replaces aesculin. Positive colonies are intensely black with the advantage that the pigment does not diffuse into the medium. The medium, when tested alongside the US Department of Agriculture (spiked samples) and Food and Drug Administration (naturally contaminated samples) isolation procedures, performed significantly better than the current formulations (34% more confirmed positives from naturally contaminated samples) with a reduction of 1 d in the assay time for most samples.

A method for demonstrating subclinical inguinal herniae in patients undergoing peritoneal dialysis: the isotope 'peritoneoscrotogram'.

We report six patients who presented with genital oedema associated with continuous ambulatory peritoneal dialysis (CAPD) who had no clinically detectable inguinal hernia at the time of initial presentation. In the absence of conventional clinical signs of an inguinal hernia, isotope imaging of the pelviscrotal region after introducing technetium-labelled tin colloid through the dialysis tube has proved to be an accurate guide to localisation of the hernia, has avoided unnecessary bilateral explorations, and has facilitated early repair of the hernia, thus allowing reinstitution of CAPD.

Is bile reflux at endoscopy a significant finding?

Postprandial duodenogastric reflux (DGR) was assessed scintigraphically in 10 patients with postprandial dyspepsia and endoscopic evidence of bile reflux (EBR) and in two control groups comprising seven patients with similar symptoms but normal endoscopic findings and 10 asymptomatic subjects without gastrointestinal pathology. DGR of iminodiacetic acid (IDA) after a liquid Lundh meal (250 ml) was assessed dynamically with 1 minute scintiscans and DGR expressed as the percentage of IDA secreted by the liver which appeared in the gastric region. DGR varied from 0-5% in asymptomatic controls and from 0-6% in dyspeptics without EBR. DGR in patients with EBR ranged from 0-16% but only two of 10 had values outside the normal range (0-5%).

A single isotope method of post-prandial duodenogastric reflux assessment using 99Tcm-labelled IDA in patients with gallstones.

A technique for the quantitative assessment of post-prandial duodenogastric bile reflux is described using a single isotopes 99Tcm and a single-channel large-field gamma camera with a data processing system. The stomach is localised with pertechnetate prior to IDA administration and duodenogastric reflux is calculated as the percentage of hepatic IDA output reaching the stomach after correction for background activity and hepatic overlap. The technique has been validated, and used to study reflux in 25 patients with gallstones and in 10 control patients. Gall bladder function was assessed with an oral cholecystogram. Marked reflux (greater than 7%) occurred in 5 out 9 patients with a non-functioning gall bladder but in no controls and in none of 16 patients with gallstones in a functioning gall bladder. When patients were studied again after cholecystectomy, 2 patients with normal functioning gall bladders had developed marked reflux while those with preoperative reflux continued to reflux after cholecystectomy. Symptoms of gallstone dyspepsia before operation were more severe in those with marked reflux than those without. Surgery improved these symptoms even in those who continued to reflux after operation.

Mechanism of bile-pigment synthesis in algae. 18O incorporation into phycocyanobilin in the unicellular rhodophyte, Cyanidium caldarium.

The origin of the lactam oxygen atoms of phycocyanobilin from Cyanidium caldarium was studied using 18O labelling. By inhibiting photosynthesis, a high 18O enrichment was maintained in the gas phase and the resulting incorporation of label showed that the lactam oxygen atoms were derived from two oxygen molecules. Slow exchange of these oxygen atoms with water was demonstrated directly by using H218O.

The measurement of arterial perfusion of the liver in man using the radioisotope xenon-133.

The washout from the liver of xenon-133 injected into the thoracic aorta of human subjects undergoing cardiac investigation was monitored externally with a sodium iodide scintillation detector. The washout curve displayed an initial peak of activity, followed by a brief decline, and then a second, slower rise. The initial peak was thought to be due to isotope arriving in the liver via the hepatic artery, and the second rise due to isotope arriving via the portal vein. A method of analysis is presented which uses the height of this arterial peak to calculate arterial perfusion of the liver.

A preliminary study of the dynamics of resolution of experimental haematomas: radioisotope studies in animals.

A preliminary investigation was carried out in order to establish a method for the study of experimental haematomas. For this purpose haematomas were produced in rabbits by subcutaneous injection of rabbits' own blood after labelling the various blood components with appropriate radioisotopes. In addition, radioisotope labelled human serum albumin and fibrinogen were studied. The results show that there is considerable variation in the rate and pattern of dissipation of the various components of the experimentally produced haematoma. The significance of these findings is discussed.