Molecular Biomarkers Predictive of Sertraline Treatment Response in Young Children With Autism Spectrum Disorder.

Sertraline is one among several selective serotonin reuptake inhibitors (SSRIs) that exhibited improvement of language development in Autism Spectrum Disorder (ASD); however, the molecular mechanism has not been elucidated. A double blind, randomized, 6-month, placebo-controlled, clinical trial of low-dose sertraline in children ages (3-6 years) with ASD was conducted at the UC Davis MIND Institute. It aimed at evaluating the efficacy and benefit with respect to early expressive language development and global clinical improvement. This study aimed to identify molecular biomarkers that might be key players in the serotonin pathway and might be predictive of a clinical response to sertraline. Fifty eight subjects with the diagnosis of ASD were randomized to sertraline or placebo. Eight subjects from the sertraline arm and five from the placebo arm discontinued from the study. Furthermore, four subjects did not have a successful blood draw. Hence, genotypes for 41 subjects (20 on placebo and 21 on sertraline) were determined for several genes involved in the serotonin pathway including the serotonin transporter-linked polymorphic region (5-HTTLPR), the tryptophan hydroxylase 2 (TPH2), and the Brain-Derived Neurotrophic Factor (BDNF). In addition, plasma levels of BDNF, Matrix metallopeptidase 9 (MMP-9) and a selected panel of cytokines were determined at baseline and post-treatment. Intent-to-treat analysis revealed several primary significant correlations between molecular changes and the Mullen Scales of Early Learning (MSEL) and Clinical Global Impression Scale - Improvement (CGI-I) of treatment and control groups but they were not significant after adjustment for multiple testing. Thus, sertraline showed no benefit for treatment of young children with ASD in language development or changes in molecular markers in this study. These results indicate that sertraline may not be beneficial for the treatment of children with ASD; however, further investigation of larger groups as well as longer term follow-up studies are warranted

Rapidly Progressing Neurocognitive Disorder in a Male with FXTAS and Alzheimer's Disease.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that usually begins in the early 60s and affects carriers of premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Additional disorders can co-occur with FXTAS including Alzheimer's disease (AD). Here we discuss a case report of a male with 67 CGG repeats in FMR1 who had mild late-onset FXTAS symptoms followed by neurocognitive disorder symptoms consistent with AD. The patient has developed tremor and ataxia that are the two characteristic symptoms of FXTAS. In addition, he shows rapid cognitive decline, brain atrophy most substantial in the medial temporal lobe, and decreased metabolism in the brain regions that are the characteristic findings of AD. The purpose of this study is to describe a patient profile with both diseases and review the details of an overlap between these two diseases

Clinical and molecular correlates in fragile X premutation females.

The prevalence of the fragile X premutation (55-200 CGG repeats) among the general population is relatively high, but there remains a lack of clear understanding of the links between molecular biomarkers and clinical outcomes. In this study we investigated the correlations between molecular measures (CGG repeat size, FMR1 mRNA, FMRP expression levels, and methylation status at the promoter region and in FREE2 site) and clinical phenotypes (anxiety, obsessive compulsive symptoms, depression and executive function deficits) in 36 adult premutation female carriers and compared to 24 normal control subjects. Premutation carriers reported higher levels of obsessive compulsive symptoms, depression, and anxiety, but demonstrated no significant deficits in global cognitive functions or executive function compared to the control group. Increased age in carriers was significantly associated with increased anxiety levels. As expected, FMR1 mRNA expression was significantly correlated with CGG repeat number. However, no significant correlations were observed between molecular (including epigenetic) measures and clinical phenotypes in this sample. Our study, albeit limited by the sample size, establishes the complexity of the mechanisms that link the FMR1 locus to the clinical phenotypes commonly observed in female carriers suggesting that other factors, including environment or additional genetic changes, may have an impact on the clinical phenotypes. However, it continues to emphasize the need for assessment and treatment of psychiatric problems in female premutation carriers

Clinical and molecular implications of mosaicism in FMR1 full mutations

Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ (FSIQ) scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation, methylation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS.These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome

精神病及癌症照顧者的社會支持及需要研究報告

本研究旨在探討非正式照顧者在照顧60歲或以上受精神病或癌症困擾的家庭成員時遇到的困難、長時間照顧工作帶來的問題和他們的非正式社會支持。同時亦針對他們的需要提出相關建議。受精神問題及癌症困擾的年長患者數字持續上升，這兩類患者的非正式照顧者(下文統稱為照顧者)多面對因患者的情緒起伏和病情轉變化而帶來的巨大壓力。為深入了解他們的現況和為制定相關政策及服務提供參考，研究團隊以半結構性訪談的方法搜集了15位精神病及癌症患者的照顧者和17位服務提供者的意見。 研究結果發現，精神病患者照顧者常遇到的困難包括：缺乏私人空間、經濟壓力大、對相關疾病資訊不了解和因社會的負面標籤不願向外界求助。同時，他們因要長時間照顧患者，人際關係、身體狀況和就業狀況均受到負面影響。對於照顧癌症家屬的照顧者，他們多不了解現有的支援服務，而且需要面對沉重的經濟壓力。由於需要長時間照顧患者，照顧者的日常生活和心理狀況皆受到影響，他們與患者的關係轉差。這兩類照顧者的非正式社會支援網絡主要為家人、朋友及教會會友。 針對照顧者的需要，研究團隊提出了五個建議。一、加強公眾教育以去除社會對精神病患者的負面標籤，減低患者家人及照顧者對尋求外界協助的顧慮。二、增加暫託服務的資源和人手以縮短輪候時間，並推行以地區為本的照顧者「社區保姆」計劃，提供空間予照顧者暫時離開患者，以處理突發或私人事務。三、設立地區性照顧者服務中心，提供輔導服務，推行照顧者技巧培訓、經濟諮詢、喘息活動和「社區保姆」計劃，令到照顧者可以在同一個服務單位獲得所需的服務。四、政府可透過線上資源整合平台為照顧者提供相關照顧資訊，讓照顧者及其家庭更易知悉社會支援服務。對於年長的照顧者，建議政府可以在他們常出現或較容易接觸到的地方擺設攤位街站，派發相關小冊子。五、增加照顧者的經濟支援，提供「喘息及活動津貼」，並且將「照顧元素」融入經濟援助項目，使到綜援申請人和長者生活津貼領取人可獲得一定比率的照顧者津貼金額

Assessment of Molecular Measures in Non-FXTAS Male Premutation Carriers

Approximately 30–40% of male and 8–16% of female carriers of the Fragile X premutation will develop a neurodegenerative movement disorder characterized by intentional tremor, gait ataxia, autonomic dysfunction, cognitive decline, and Parkinsonism during their lifetime. At the molecular level, premutation carriers have increased expression levels of the FMR1 and the antisense FMR1 (ASFMR1) mRNAs. Both genes undergo alternative splicing giving rise to a number of different transcripts. Alteration in the alternative splicing process might be associated with FXTAS. In this study, we have investigated the correlation between objective measures of movement (balance and tremor using the CATSYS battery) and the expression of both the FMR1 and the ASFMR1 genes. In addition, we investigated whether their expression level and that of the ASFMR1 131 bp splice isoform could distinguish between premutation carriers with FXTAS and non-FXTAS premutation carriers. Confirming previous findings, the expression levels of transcripts at the FMR1 locus positively correlated with the CGG repeat number and significantly differentiated the premutation carriers from the control groups. Furthermore, premutation carriers with and without FXTAS, showed a significant difference in the expression level of the ASFMR1 131 bp splice isoform when compared to age and gender matched controls. However, there was no significant difference in the ASFMR1 131 bp splice isoform expression level when comparing premutation carriers with and without FXTAS. Finally, our results indicate significant group differences in CATSYS dominant hand reaction time and postural sway with eyes closed in premutation carriers without FXTAS compared to controls. In addition, a significant inverse association between the tremor intensity and the expression level of ASFMR1 131 bp splice isoform in premutation carriers compared to controls, was observed, suggesting a potential role in the pathogenesis of FXTAS

「回首．動情．傳承」長者生命故事計劃

嶺南大學亞太老年學研究中心獲華人永遠墳場管理委員會（「華永會」）資助為期一年的「回首．動情．傳承」長者生命故事計劃(「計劃」)。此計劃旨在讓青年人認識長者生命經驗，學習克服困難與挫折以提升抗逆力，建立正向人生觀。 近年，主流媒體經常批評年輕人的負面人生觀，例如：「躺平主義」、「享樂主義」、「犬儒心態」等，亦不時看到青年人輕生的新聞。我們曾在大學內處理過不少受情緒困擾及企圖自殺的個案，與學生深入交流後，發現他們面對着沉重的學業壓力、財政困難或複雜的家庭關係，內心充滿掙扎不安。 此計劃讓嶺大學生與長者導師進行深度的對談，透過了解長者走過的路、他們經歷過的挫折和教訓，給予年輕人生命的啟示。如果我們以旅遊比喻人生，長者就像環遊世界的資深背包客，即使大家遊覽不同的地點、觀賞過不同的風景，他們總能夠分享一些旅遊的心得，讓新手遊客走少一點冤枉路，或領悟到旅遊的樂趣和意義。長者亦可以藉由敍述人生片段回顧他們生命中的故事，學習接納過去，增加自我認同感。青年人創作生命教育書冊，將長者積極的人生觀傳給年輕一代，並藉此鼓勵其他長者豁達地度過餘年。 我們於2022年初招募嶺南大學學生接受「生命故事敍述」培訓，內容包括：本港的人口老化現象、敍述治療理論、與長者溝通的技巧及模擬實踐練習等，以裝備同學的知識和技巧。本中心再向屯門、元朗區的長者機構發邀請信，誠邀長者擔任生命導師接受訪問。 嶺大安排同學以兩人一組的小隊形式，於2022年6至7月期間前往長者中心、日間護理中心、嶺南大學或長者家中，與十二位長者進行深入訪談。訪談結束後，同學根據訪談的內容，為長者書寫他們獨特的生命故事。例如在人離鄉賤的異國環境下，努力打拼事業的Alfred；堅持不懈持續進修的淑芹和馮春林；即使沒機會求學，仍憑一雙巧手闖出一片天的譚惠；在文化大革命的漩渦中，憑着熱忱而改變命運的蘭英；還有為家人無私奉獻的鳳群、歐婆婆、雅芳及細女；離鄉別井勇闖異地的阿美和阿水；即使被家人賣去做「妹仔」，仍能以「阿Q精神」面對的諒餘。 為保障長者的私隱權益，本書內所有刊登之故事皆經過受訪者或社工審閱，部份受訪者選擇以化名的形式來分享自己的故事，我們亦移除了部份敏感的個人資料。https://commons.ln.edu.hk/apias_guide/1008/thumbnail.jp

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations