The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior

Recently, we defined a new syndromic form of X-linked mental retardation in a 4-generation family with a unique clinical phenotype characterized by mild mental retardation, choreoathetosis, and abnormal behavior (MRXS10). Linkage analysis in this family revealed a candidate region of 13.4 Mb between markers DXS1201 and DXS991 on Xp11; therefore, mutation analysis was performed by direct sequencing in most of the 135 annotated genes located in the region. The gene (HADH2) encoding L-3-hydroxyacyl-CoA dehydrogenase II displayed a sequence alteration (c.574 C-->A; p.R192R) in all patients and carrier females that was absent in unaffected male family members and could not be found in 2,500 control X chromosomes, including in those of 500 healthy males. The silent C-->A substitution is located in exon 5 and was shown by western blot to reduce the amount of HADH2 protein by 60%-70% in the patient. Quantitative in vivo and in vitro expression studies revealed a ratio of splicing transcript amounts different from those normally seen in controls. Apparently, the reduced expression of the wild-type fragment, which results in the decreased protein expression, rather than the increased amount of aberrant splicing fragments of the HADH2 gene, is pathogenic. Our data therefore strongly suggest that reduced expression of the HADH2 protein causes MRXS10, a phenotype different from that caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, which is a neurodegenerative disorder caused by missense mutations in this multifunctional protein.

Disaster resilience in tertiary hospitals : a cross-sectional survey in Shandong Province, China

Background: Hospital disaster resilience can be defined as a hospital’s ability to resist, absorb, and respond to the shock of disasters while maintaining critical functions, and then to recover to its original state or adapt to a new one. This study aims to explore the status of resilience among tertiary hospitals in Shandong Province, China. Methods: A stratified random sample (n = 50) was derived from tertiary A, tertiary B, and tertiary C hospitals in Shandong Province, and was surveyed by questionnaire. Data on hospital characteristics and 8 key domains of hospital resilience were collected and analysed. Variables were binary, and analysed using descriptive statistics such as frequencies. Results: A response rate of 82% (n = 41) was attained. Factor analysis identified four key factors from eight domains which appear to reflect the overall level of disaster resilience. These were hospital safety, disaster management mechanisms, disaster resources and disaster medical care capability. The survey demonstrated that in regard to hospital safety, 93% had syndromic surveillance systems for infectious diseases and 68% had evaluated their safety standards. In regard to disaster management mechanisms, all had general plans, while only 20% had specific plans for individual hazards. 49% had a public communication protocol and 43.9% attended the local coordination meetings. In regard to disaster resources, 75.6% and 87.5% stockpiled emergency drugs and materials respectively, while less than a third (30%) had a signed Memorandum of Understanding with other hospitals to share these resources. Finally in regard to medical care, 66% could dispatch an on-site medical rescue team, but only 5% had a ‘portable hospital’ function and 36.6% and 12% of the hospitals could surge their beds and staff capacity respectively. The average beds surge capacity within 1 day was 13%. Conclusions: This study validated the broad utility of a framework for understanding and measuring the level of hospital resilience. The survey demonstrated considerable variability in disaster resilience arrangements of tertiary hospitals in Shandong province, and the difference between tertiary A hospitals and tertiary B hospitals was also identified in essential areas.

H2AX phosphorylation screen of cells from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype

BACKGROUND: About 1-5% of cancer patients suffer from significant normal tissue reactions as a result of radiotherapy (RT). It is not possible at this time to predict how most patients' normal tissues will respond to RT. DNA repair dysfunction is implicated in sensitivity to RT particularly in genes that mediate the repair of DNA double-strand breaks (DSBs). Phosphorylation of histone H2AX (phosphorylated molecules are known as gammaH2AX) occurs rapidly in response to DNA DSBs, and, among its other roles, contributes to repair protein recruitment to these damaged sites. Mammalian cell lines have also been crucial in facilitating the successful cloning of many DNA DSB repair genes; yet, very few mutant cell lines exist for non-syndromic clinical radiosensitivity (RS). METHODS: Here, we survey DNA DSB induction and repair in whole cells from RS patients, as revealed by gammaH2AX foci assays, as potential predictive markers of clinical radiation response. RESULTS: With one exception, both DNA focus induction and repair in cell lines from RS patients were comparable with controls. Using gammaH2AX foci assays, we identified a RS cancer patient cell line with a novel ionising radiation-induced DNA DSB repair defect; these data were confirmed by an independent DNA DSB repair assay. CONCLUSION: gammaH2AX focus measurement has limited scope as a pre-RT predictive assay in lymphoblast cell lines from RT patients; however, the assay can successfully identify novel DNA DSB repair-defective patient cell lines, thus potentially facilitating the discovery of novel constitutional contributions to clinical RS.

The shared genetics of migraine and anxious depression

OBJECTIVES To investigate: - (1) whether shared genetic factors influence migraine and anxious depression; - (2) whether the genetic architecture of migraine depends on anxious depression; - (3) whether the association between migraine and anxious depression is causal. BACKGROUND Migraine and anxious depression frequently occur together, but little is known about the mechanisms causing this association. METHODS A twin study was conducted to model the genetic architecture of migraine and anxious depression and the covariance between them. Anxious depression was also added to the model as a moderator variable to examine whether anxious depression affects the genetic architecture of migraine. Causal models were explored with the co-twin control method. RESULTS Modest but significant phenotypic (rP=0.28), genetic (rG=0.30), and nonshared environmental (rE=0.26) correlations were found between the 2 traits. Interestingly, the heritability of migraine depended on the level of anxious depression: the higher the anxious depression score, the lower the relative contribution of genetic factors to the individual differences in migraine susceptibility. The observed risk patterns in discordant twins are most consistent with a bidirectional causal relationship. CONCLUSIONS These findings confirm the genetic association between migraine and anxious depression and are consistent with a syndromic association between the 2 traits. This highlights the importance of taking comorbidity into account in genetic studies of migraine, especially in the context of selection for large-scale genotyping efforts. Genetic studies may be most effective when migraine with and without comorbid anxious depression are treated as separate phenotypes.