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Fulltext AarF Domain Containing Kinase 3 (ADCK3) Mutant Cells Display Signs of Oxidative Stress, Defects in Mitochondrial Homeostasis and Lysosomal Accumulation

Cullen JK, Abdul Murad N, Yeo A, McKenzie M, Ward M, Chong KL, et al.

PLoS One, 2016;11(2):e0148213.
PMID: 26866375 DOI: 10.1371/journal.pone.0148213

Autosomal recessive ataxias are a clinically diverse group of syndromes that in some cases are caused by mutations in genes with roles in the DNA damage response, transcriptional regulation or mitochondrial function. One of these ataxias, known as Autosomal Recessive Cerebellar Ataxia Type-2 (ARCA-2, also known as SCAR9/COQ10D4; OMIM: #612016), arises due to mutations in the ADCK3 gene. The product of this gene (ADCK3) is an atypical kinase that is thought to play a regulatory role in coenzyme Q10 (CoQ10) biosynthesis. Although much work has been performed on the S. cerevisiae orthologue of ADCK3, the cellular and biochemical role of its mammalian counterpart, and why mutations in this gene lead to human disease is poorly understood. Here, we demonstrate that ADCK3 localises to mitochondrial cristae and is targeted to this organelle via the presence of an N-terminal localisation signal. Consistent with a role in CoQ10 biosynthesis, ADCK3 deficiency decreased cellular CoQ10 content. In addition, endogenous ADCK3 was found to associate in vitro with recombinant Coq3, Coq5, Coq7 and Coq9, components of the CoQ10 biosynthetic machinery. Furthermore, cell lines derived from ARCA-2 patients display signs of oxidative stress, defects in mitochondrial homeostasis and increases in lysosomal content. Together, these data shed light on the possible molecular role of ADCK3 and provide insight into the cellular pathways affected in ARCA-2 patients.
Fulltext Concerns, perceived impact, practices, preventive measures, and stress among healthcare workers during COVID-19 pandemic in Malaysia

Pahrol MA, Ismail R, Mohamad N, Lim YC, Muhamad Robat R, Rajendiran S, et al.

Front Public Health, 2023;11:1028443.
PMID: 36935685 DOI: 10.3389/fpubh.2023.1028443

INTRODUCTION: Healthcare workers (HCWs) have been continually exposed to patients with COVID-19 and are at higher risk of contracting the disease. Their psychological health is important for overall wellbeing and productivity, which could lead to a reduction in human errors during the pandemic crisis. This study aimed to measure the level of concerns, work practices, adequacy of preventive measures among HCWs, and the impacts on their life and work, including mental health status during the second wave of the COVID-19 pandemic in Malaysia.
METHODS: An online questionnaire was distributed randomly to 1,050 HCWs from the Ministry of Health facilities in the Klang Valley who were involved directly in managing or screening COVID-19 cases from May to August 2020. The questionnaire was divided into five domains, which were concerns, impact on life and work, practice, perceived adequacy of preventive measures, and Revised Impact of Event Scale (IES-R). Logistic regression was used to identify sociodemographic predictors of the five domains.
RESULTS: A total of 907 respondents (86.4%) participated in this survey. Approximately half of the respondents had a low concern (50.5%), most of them had a good practice (85.1%), with 67.5% perceiving there were adequate preventive measures, and they perceived the outbreak had a low impact (92%) on their life and work. From the IES-R domain, 18.6% of respondents potentially suffered from post-traumatic stress disorder (PTSD).
CONCLUSION: During the second wave of the COVID-19 outbreak in Malaysia, HCWs practiced high levels of precautions and preventive measures because they were aware of the risk of infection as an occupational hazard. With the adequate implementation of policy and control measures, the psychological wellbeing of the majority HCWs remained well and adequately supported.
Fulltext Cytotoxicity and Toxicity Evaluation of Xanthone Crude Extract on Hypoxic Human Hepatocellular Carcinoma and Zebrafish (Danio rerio) Embryos

Fazry S, Noordin MAM, Sanusi S, Noor MM, Aizat WM, Lazim AM, et al.

Toxics, 2018 Oct 09;6(4).
PMID: 30304811 DOI: 10.3390/toxics6040060

Xanthone is an organic compound mostly found in mangosteen pericarp and widely known for its anti-proliferating effect on cancer cells. In this study, we evaluated the effects of xanthone crude extract (XCE) and α-mangostin (α-MG) on normoxic and hypoxic human hepatocellular carcinoma (HepG2) cells and their toxicity towards zebrafish embryos. XCE was isolated using a mixture of acetone and water (80:20) and verified via high performance liquid chromatography (HPLC). Both XCE and α-MG showed higher anti-proliferation effects on normoxic HepG2 cells compared to the control drug, 5-fluorouracil (IC50 = 50.23 ± 1.38, 8.39 ± 0.14, and 143.75 ± 15.31 μg/mL, respectively). In hypoxic conditions, HepG2 cells were two times less sensitive towards XCE compared to normoxic HepG2 cells (IC50 = 109.38 ± 1.80 μg/mL) and three times less sensitive when treated with >500 μg/mL 5-fluorouracil (5-FU). A similar trend was seen with the α-MG treatment on hypoxic HepG2 cells (IC50 = 10.11 ± 0.05 μg/mL) compared to normoxic HepG2 cells. However, at a concentration of 12.5 μg/mL, the α-MG treatment caused tail-bend deformities in surviving zebrafish embryos, while no malformation was observed when embryos were exposed to XCE and 5-FU treatments. Our study suggests that both XCE and α-MG are capable of inhibiting HepG2 cell proliferation during normoxic and hypoxic conditions, more effectively than 5-FU. However, XCE is the preferred option as no malformation was observed in surviving zebrafish embryos and it is more cost efficient than α-MG.
Non-Fellowship regional anesthesia training and assessment: an international Delphi study on a consensus curriculum

Chuan A, Jeyaratnam B, Fathil S, Ferraro LH, Kessow A, Lim YC, et al.

Reg Anesth Pain Med, 2021 10;46(10):867-873.
PMID: 34285116 DOI: 10.1136/rapm-2021-102934

BACKGROUND AND OBJECTIVES: While there are several published recommendations and guidelines for trainees undertaking subspecialty Fellowships in regional anesthesia, a similar document describing a core regional anesthesia curriculum for non-fellowship trainees is less well defined. We aimed to produce an international consensus for the training and teaching of regional anesthesia that is applicable for the majority of worldwide anesthesiologists.
METHODS: This anonymous, electronic Delphi study was conducted over two rounds and distributed to current and immediate past (within 5 years) directors of regional anesthesia training worldwide. The steering committee formulated an initial list of items covering nerve block techniques, learning objectives and skills assessment and volume of practice, relevant to a non-fellowship regional anesthesia curriculum. Participants scored these items in order of importance using a 10-point Likert scale, with free-text feedback. Strong consensus items were defined as highest importance (score ≥8) by ≥70% of all participants.
RESULTS: 469 participants/586 invitations (80.0% response) scored in round 1, and 402/469 participants (85.7% response) scored in round 2. Participants represented 66 countries. Strong consensus was reached for 8 core peripheral and neuraxial blocks and 17 items describing learning objectives and skills assessment. Volume of practice for peripheral blocks was uniformly 16-20 blocks per anatomical region, while ≥50 neuraxial blocks were considered minimum.
CONCLUSIONS: This international consensus study provides specific information for designing a non-fellowship regional anesthesia curriculum. Implementation of a standardized curriculum has benefits for patient care through improving quality of training and quality of nerve blocks.