Cancer as a Complex Phenotype: Pattern of Cancer Distribution within and beyond the Nuclear Family

BACKGROUND: The contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century. METHODS AND FINDINGS: We have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland. We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not. CONCLUSION: We conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family

Compound heterozygous mutations in UBA5 causing early-onset epileptic encephalopathy in two sisters.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesEpileptic encephalopathies are a group of childhood epilepsies that display high phenotypic and genetic heterogeneity. The recent, extensive use of next-generation sequencing has identified a large number of genes in epileptic encephalopathies, including UBA5 in which biallelic mutations were first described as pathogenic in 2016 (Colin E et al., Am J Hum Genet 99(3):695-703, 2016. Muona M et al., Am J Hum Genet 99(3):683-694, 2016). UBA5 encodes an activating enzyme for a post-translational modification mechanism known as ufmylation, and is the first gene from the ufmylation pathway that is linked to disease.We sequenced the genomes of two sisters with early-onset epileptic encephalopathy along with their unaffected parents in an attempt to find a genetic cause for their condition. The sisters, born in 2004 and 2006, presented with infantile spasms at six months of age, which later progressed to recurrent, treatment-resistant seizures. We detected a compound heterozygous genotype in UBA5 in the sisters, a genotype not seen elsewhere in an Icelandic reference set of 30,067 individuals nor in public databases. One of the mutations, c.684G > A, is a paternally inherited exonic splicing mutation, occuring at the last nucleotide of exon 7 of UBA5. The mutation is predicted to disrupt the splice site, resulting in loss-of-function of one allele of UBA5. The second mutation is a maternally inherited missense mutation, p.Ala371Thr, previously reported as pathogenic when in compound heterozygosity with a loss-of-function mutation in UBA5 and is believed to produce a hypomorphic allele. Supportive of this, we have identified three adult Icelanders homozygous for the p.Ala371Thr mutation who show no signs of neurological disease.We describe compound heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy. To our knowledge, this is the first description of mutations in UBA5 since the initial discovery that pathogenic biallelic variants in the gene cause early-onset epileptic encephalopathy. We further provide confirmatory evidence that p.Ala371Thr is a hypomorphic mutation, by presenting three adult homozygotes who show no signs of neurological disease

James Warner starting the starboard motor of the Southern Cross, Fokker monoplane F.VII/3m, VH-USU, before takeoff to Melbourne from Sydney, 10 June 1928 [picture] /

"Jim Warner does his cranking job before the take-off for Melbourne"--label, on verso.; Part of the collection: Charles Ulm national aviation collection.; Title devised by cataloguer based on accompanying documentation.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3930739

U-EPX levels and wheezing in infants and young children with and without RSV bronchiolitis

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldAn association between severe infant bronchiolitis due to respiratory syncytial virus (RSV) and subsequent wheezing is well documented. High levels of urinary eosinophil protein X (U-EPX) have been related to active disease in asthmatic children. The aim of this study was to analyse whether RSV bronchiolitis leads to an increase in U-EPX levels and whether wheezing is more common in children with high U-EPX values. Seventeen infants requiring in-ward care for verified RSV lower respiratory tract infection were followed and compared with age-matched controls. A reference group without a history of RSV bronchiolitis was also included. At inclusion at mean age 3.3 months and at follow-up at mean age 32.9 months, U-EPX levels were comparable in the RSV group. However, at follow-up at mean age 6.4 months, the RSV group had significantly increased levels of U-EPX compared with inclusion (median 167.8; range 46.2-470.7 vs. 122.8; 43.7-266.0 microg/mmol creatinine; P=0.023) and also significantly increased compared with the 6-month-old controls (167.8 vs. 93.0; 19.0-204.0 microg/mmol creatinine; P=0.0095). RSV infected subjects that experienced wheezing had significantly higher U-EPX values both at inclusion and at age 32.9 months than those who did not. Also, in the reference group (mean age 18.4 months), the children who had wheezed during the preceding year had higher U-EPX levels than those who had not wheezed. In conclusion, RSV bronchiolitis severe enough to require in-ward care produces a significant, but transient increase in U-EPX. Furthermore, a high U-EPX at baseline appears to be associated with an increased risk of future wheezing

Clara cell protein 16 (CC16) serum levels in infants during respiratory syncytial virus infection

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldNo Abstrac

Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local TH2-like response

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldBACKGROUND: Respiratory syncytial virus (RSV) infections during infancy are considered to be a risk factor for developing asthma and possibly allergic sensitization. OBJECTIVE: The aim of this study was to investigate the cytokines, chemokines, and eosinophil cationic protein in the nasopharyngeal secretions of infants < or = 7 months of age with RSV infections or other respiratory viral infections and healthy infants as controls. Groups were also analyzed according to age, < or = 3 months and >3 months, and the levels were compared within and between groups. RESULTS: Thirty-nine infants with RSV, 9 with influenza or parainfluenza virus infections and 50 controls with no history of infections, were enrolled in the study. The RSV-infected infants had significantly higher levels of IL-4; macrophage inflammatory protein 1beta, a chemoattractant for T cells; and eosinophil cationic protein in nasopharyngeal secretions compared with the control group. The levels of the TH2 cytokine IL-4 were significantly higher in RSV-infected infants < or = months of age compared with RSV-infected infants >3 months of age. In infants < or = 3 months of age, infections with influenza or parainfluenza virus caused TH2-like responses similar to those produced by RSV. CONCLUSION: Infections with RSV as well as with influenza and parainfluenza virus during early infancy preferentially promote a TH2-like response in the nose with local production of IL-4, IL-5, and macrophage inflammatory protein 1beta and infiltration and activation of eosinophils

Tairona culture artefacts, Museo del Oro, Bogota, Colombia, 1977, [14] [picture] /

Condition: Good.; Title devised by cataloguer based on inscription on reverse.; Part of Wolfgang Sievers photographic archive.; Sievers number: EK-4560-add88 (devised number).; Inscriptions: "Tairona-20289".; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4195875

Linkage of essential hypertension to chromosome 18q

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldWe performed a genomewide scan with 904 microsatellite markers using 120 extended Icelandic families with 490 hypertensive patients. The families were identified by cross-matching a list of hypertensive patients from the Hypertension Clinic of the University Hospital (Landspitalinn) in Iceland with a genealogy database of the entire Icelandic nation. After adding 5 markers, we found linkage to chromosome 18q with an allele-sharing LOD score of 4.60 (P=2.1x 10(-6)). These results provide evidence for a novel susceptibility gene for essential hypertension on chromosome 18q and show that it is possible to study the genetics of essential hypertension without stratifying by subphenotypes