Genome sequencing reveals the role of rare genomic variants in Chinese patients with symptomatic intracranial atherosclerotic disease.

OBJECTIVES: The predisposition of intracranial atherosclerotic disease (ICAD) to East Asians over Caucasians infers a genetic basis which, however, remains largely unknown. Higher prevalence of vascular risk factors (VRFs) in Chinese over Caucasian patients who had a stroke, and shared risk factors of ICAD with other stroke subtypes indicate genes related to VRFs and/or other stroke subtypes may also contribute to ICAD. METHODS: Unrelated symptomatic patients with ICAD were recruited for genome sequencing (GS, 60-fold). Rare and potentially deleterious single-nucleotide variants (SNVs) and small insertions/deletions (InDels) were detected in genome-wide and correlated to genes related to VRFs and/or other stroke subtypes. Rare aneuploidies, copy number variants (CNVs) and chromosomal structural rearrangements were also investigated. Lastly, candidate genes were used for pathway and gene ontology enrichment analysis. RESULTS: Among 92 patients (mean age at stroke onset 61.0±9.3 years), GS identified likely ICAD-associated rare genomic variants in 54.3% (50/92) of patients. Forty-eight patients (52.2%, 48/92) had 59 rare SNVs/InDels reported or predicted to be deleterious in genes related to VRFs and/or other stroke subtypes. None of the 59 rare variants were identified in local subjects without ICAD (n=126). 31 SNVs/InDels were related to conventional VRFs, and 28 were discovered in genes related to other stroke subtypes. Our study also showed that rare CNVs (n=7) and structural rearrangement (a balanced translocation) were potentially related to ICAD in 8.7% (8/92) of patients. Lastly, candidate genes were significantly enriched in pathways related to lipoprotein metabolism and cellular lipid catabolic process. CONCLUSIONS: Our GS study suggests a role of rare genomic variants with various variant types contributing to the development of ICAD in Chinese patients.

Egr2 overexpression in Schwann cells increases myelination frequency in vitro.

Schwann cells are key players in peripheral nerve regeneration, and are uniquely capable of remyelinating axons in this context. Schwann cells orchestrate this process via a set of transcription factors. While it has been shown that overexpression of specific genes, e.g. Egr2, upregulates myelin-related transcripts, it remains unknown if such manipulation can functionalize the cells and enhance their myelination frequency. The ability to do so could have implications in the use of human stem cell-derived Schwann cells, where myelination is hard to achieve. After screening four candidate transcription factors (Sox10, Oct6, Brn2 and Egr2), we found that overexpression of Egr2 in rat Schwann cells co-cultured with sensory neurons enhanced myelination frequency and reduced cell proliferation. However, in a mouse model of sciatic nerve repair with cells engrafted within a nerve guide, myelination frequency in the engrafted cells was reduced upon Egr2 overexpression. Our results show that while overexpression of Egr2 can enhance the myelination frequency in vitro, it is context-dependent, potentially influenced by the microenvironment, timing of association with axons, expression level, species differences, or other factors.

Factors associated with mucosal healing in patients with ulcerative colitis in clinical remission.

BACKGROUND: Mucosal healing (MH) has been associated with improved outcomes in ulcerative colitis but factors associated with MH are not well defined. METHODS: Consecutive patients with ulcerative colitis in clinical remission (Mayo symptomatic subscore = 0) who had at least 1 colonoscopy since diagnosis from 6 centers were included. For patients who had at least 2 colonoscopies during follow-up, each colonoscopy was reviewed to define whether they had early MH (Mayo endoscopic subscore reduced to 0 within 3 yr of clinical remission). Factors associated with MH and early MH were determined using logistic regression. RESULTS: Two hundred thirty-seven patients with ulcerative colitis (mean age 50.39 ± 14.10 yr; 56.5% male) were included. Independent factors for MH were clinical remission >3 years (odds ratio [OR] 4.0; 95% confidence interval [CI], 1.2-13.1), mild/moderate mucosal inflammation (OR 3.3; 95% CI, 1.3-8.5), and immunosuppressant use (OR 4.6; 95% CI, 1.5-14.6). Among patients who had ≥2 of above factors, 74% achieved MH, whereas only 39% with <2 factors achieved MH (P < 0.001). Of patients in clinical remission <1 year, 1 to 3 years and >3 years, 30%, 45.9%, and 62.9% achieved MH, respectively. Immunosuppressant therapy was associated with early MH (P = 0.025). In multivariate analysis, patients with previous mild inflammation were more likely to achieve early MH than those with moderate/severe inflammation (OR 2.8; 95% CI, 1.2-6.2). CONCLUSIONS: A longer disease remission, previous less severe mucosal inflammation, and immunosuppressant use are associated with MH. Severity of mucosal inflammation and use of immunosuppressant are also associated with early MH.

Mode of treatment affects quality of life in head and neck cancer survivors: Implications for holistic care.

CONCLUSION: As adverse effects of live-saving treatment are unavoidable surgeons have a duty to address physical changes and quality of life issues that matter to head and neck (H&N) cancer patients. We propose a tailored holistic care package. OBJECTIVES: This study compared the quality of life of H&N cancer survivors managed with different approaches in the follow-up phase after initial treatment and identified factors adversely impacting quality of life parameters. METHODS: H&N cancer patients studied: 1) surgery only, 2) radiotherapy only, 3) surgery and radiotherapy, and 4) any combination of surgery, chemotherapy or radiotherapy. Patients unable to communicate in Cantonese, with thyroid cancer or end-of-life disease were excluded. EORTC QLQ-H&N35 Cantonese version was administered at least 1 year after initial H&N cancer treatment. RESULTS: Quality of life impairment was worse in all of the domains for combination therapy versus monotherapy patients. Scores between surgery or radiotherapy-only patients were not significantly different. Radiotherapy preceding surgery impacted significantly more on speech than surgery before the radiotherapy. Patients with advanced disease had more impairment of quality of life in each domain than patients with early disease. Coughing, eating problems, sticky saliva, and difficulties with social contact were all significant predictors of problems associated with a dry mouth.

The prevalence of Apo E4 genotype and its relationship to bone mineral density in Hong Kong Chinese.

Apolipoprotein E (Apo E) polymorphism has been implicated in many chronic diseases, including Alzheimer disease and osteoporosis. Significant association of the Apo E4 allele to low bone mineral density (BMD) has been repeatedly reported. We here examined the Apo E genotype frequencies in the Chinese population (n = 692) and its relationship to BMD. A significantly lower frequency (a prevalence of 7%) of the E4 alleles was found in our Chinese subjects compared to that reported in Caucasians (14.7%) or in Japanese (11.7%). However, no significant association between the Apo E4 allele and BMD Z score was observed in our test subjects; this may be due to the rarity of the Apo E4 allele frequency in Chinese, which requires a larger sample size for detection of significant association. Significant associations detected between Apo E2 allele and BMD at the femoral neck in elderly women (P = 0.02) and at the spine in elderly men (P = 0.03) were in the opposite direction and thus regarded as false-positive results. It is concluded that the Apo E4 allele is rare in Chinese, and a larger population size is needed to see if Apo E4 is associated with BMD in Chinese.