Identification of a novel idiopathic epilepsy locus in Belgian Shepherd dogs

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10⁻¹⁰, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10⁻⁸, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10⁻¹¹, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.     

Methylenedioxy- and methoxyflavones from Melicope coodeana syn. Euodia simplex

Three new natural products, 3,8-dimethoxy-5,7-dihydroxy-3′,4′-methylenedioxyflavone, 3,6,8-trimethoxy-5,7-dihydroxy-3′,4′-methylenedioxyflavone and 3,6,8,3′,4′-pentamethoxy-5,7-dihydroxyflavone were isolated from Melicope coodeana syn. Euodia simplex (Rutaceae) along with 3,6,3′-trimethoxy-5,7,4′-trihydroxyflavone and 3,3′-dimethoxy-5,7,4′-trihydroxyflavone. The structural assignments are based on ¹H and ¹³C NMR data, including discussion of the chemical shifts of C-2 in 3,5-dihydroxy- and 3-methoxy-5-hydroxyflavones. The presence of highly methoxylated and methylenedioxyflavones is characteristic of the genus Melicope, and the present findings support the recent transfer of Euodia simplex to Melicope.     

10 year follow up study of mortality among users of hostels for homeless people in Copenhagen

Objectives To investigate mortality among users of hostels for homeless people in Copenhagen, and to identify predictors of death such as conditions during upbringing, mental illness, and misuse of alcohol and drugs.Design Register based follow up study.Setting Two hostels for homeless people in Copenhagen, DenmarkParticipants 579 people who stayed in one hostel in Copenhagen in 1991, and a representative sample of 185 people who stayed in the original hostel and one other in Copenhagen.Main outcome measure Cause specific mortality.Results The age and sex standardised mortality ratio for both sexes was 3.8 (95% confidence interval 3.5 to 4.1); 2.8 (2.6 to 3.1) for men and 5.6 (4.3 to 6.9) for women. The age and sex standardised mortality ratio for suicide for both sexes was 6.0 (3.9 to 8.1), for death from natural causes 2.6 (2.3 to 2.9), for unintentional injuries 14.6 (11.4 to 17.8), and for unknown cause of death 62.9 (52.7 to 73.2). Mortality was comparatively higher in the younger age groups. It was also significantly higher among homeless people who had stayed in a hostel more than once and stayed fewer than 11 days, compared with the rest of the study group. Risk factors for early death were premature death of the father and misuse of alcohol and sedatives.Conclusion Homeless people staying in hostels, particularly young women, are more likely to die early than the general population. Other predictors of early death include adverse experiences in childhood, such as death of the father, and misuse of alcohol and sedatives.     

连续近交下家猪微卫生基因组杂合度与经济性状的相关性研究

从已这位于家猪０１、０２、１１、１３、１７、１８号染色体上的遗传标记中选用５６个具有足够覆盖率的微卫生标记,对１个连续５个代近交家系共１９２个头家猪进行了基因组扫描.平均微卫生标记杂合度估计基因组杂合度（ＧＨ）。ＧＨ对于屠宰重（ＳＷＴ）和日均屠宰重（ＡＤＳＧ）为显著正相关效应,对于背膘厚（ＢＦＤＰ）的相关效应不显著且方向也不一致。ＧＨ的相关效应随近交世代递增而呈非线性变化趋势;ＧＨ对于ＳＷＴ和ＡＤＳＧ的相关效应在近交前２世代呈上升趋势。２代分别到达最大值（２２．４３kg和０．１３２kg/d）,此后随近交世代的递增而递减;ＧＨ对于ＢＦＤＰ的相关效应随世代递增而非线性递减。微卫星杂合度的相关效应在不同染色体间存在较大差异,对ＳＷＴ和ＡＳＤＧ均表现为正效应,其中又以１３号染色体标记杂合度的相关效应为最大（６．３０kg和０．０３２kg／d)其次依镒为１号、１７号、１８号、２号和１１号。各染色体微卫星标记杂合度对于ＢＦＤＰ的相关效应估值的标准误差大,且效应方向不一致（１８号染色体来正效应,其余染色体为负效应）,由引得到如下３点启示,第一,对于经济性状重要的基因（e.g.QTL)不同是均衡分布于各杂染色体上,此差异可能反应出生物性状决定在染色体以及分子分上上的差异;第二,由于基因,基因互作和且背景效应的复杂性,基因（组）杂合度与性能间不为简单的相关,学可能由于标记数目不够或是标记选择不适当而误导;第三,由于高度近交（如连续同胞交配）下较高的连锁不平衡所致,有害基因可能以较高的概率民中性标记连锁遗传,由此可能部分或全部抵消杂合优势的表现,甚至出现杂合劣势。     

Hypersensitive site 4 of the human beta globin locus control region.

The Locus Control Region (LCR) of the human beta globin gene domain is defined by four erythroid-specific DNasel hypersensitive sites (HSS) located upstream of this multigene cluster. The LCR confers copy number dependent high levels of erythroid specific expression to a linked transgene, independent of the site of integration. To assess the role of the individual hypersensitive sites of the LCR, we have localized HSS4 to a 280bp fragment that is functional both in murine erythroleukaemia (MEL) cells and in transgenic mice. This fragment coincides with the major area of hypersensitivity 'in vivo' and contains a number of DNasel footprints. Bandshift analysis shows that these footprints correspond to binding sites for the erythroid specific proteins GATA1 and NF-E2 and a number of ubiquitous proteins, including jun/fos, Sp1 and TEF2.