Gene mutation is one of the etiologies of early-onset epileptic encephalopathy (EOEE), an age-dependent seizure in infants, which leads to brain defects. Previous studies have shown that several genes namely, aristalessrelated homeobox (ARX), cyclindependent kinaselike 5 (CDKL5) and syntaxinbinding protein 1 (STXBP1) are responsible for the pathophysiology of the syndrome. Thestudy involved 20 EOEE patients and 60 control subjects, which aimed toinvestigatethe clinical association of Malaysian EOEE subjects with 13 known pathogenic mutations in the genes of interest. In addition, the entire ARX exonic region was also sequenced for known and novel mutations. PCR specificity and efficiency were optimized using conventional PCR and High Resolution Melting Analysis (HRMA). All cases and approximately 10% of control amplicon samples were purified and subjected to DNA sequencing. All known mutations reported previously were not found in control subjects and Malaysian EOEE patients with 100% confirmation by sequencing results. Sequencing of ARX exonic regionsof patient samplesdid not find any mutation in all exons. The preliminary study indicates that selected known pathogenic mutations of ARX, CDKL5and STXBP1are not associated with EOEE in Malaysian paediatric patients.
The human brain is made up of billions of neurons and glial cells which are interconnected and organized into specific patternsof neural circuitry, and hence is arguably the most sophisticated organ in human, both structurally and functionally.Studying the underlying mechanisms responsible for neurologicalor neurodegenerativedisorders and the developmental basis of complex brain diseases such as autism, schizophrenia, bipolar disorder, Alzheimer’s and Parkinson’s disease has proven challenging due to practical and ethical limitations on experiments with human material and the limitationsof existing biological/animal models. Recently,cerebral organoids havebeen proposed as apromisingand revolutionary model for understanding complex brain disorders and preclinical drug screening.
The use of in vitromodel for screening pharmacological compounds or natural products has gained global interest. The choice of cells to be manipulated plays a vital role in coming up with the best-suitedmodel for specific diseases, including neurodegenerativediseases (ND). A good in vitro ND model should provide appropriate morphological and molecular features that mimic ND conditions where it can be used to screen potential properties of natural products in addition to unravelling the molecular mechanisms of ND. In this mini review, we intend to demonstrate two prospective stem cell lines as the potential cell source for in vitroND model and compare them to the commonly used cells. The common source of cells that have been usedas the in vitroND models is discussedbefore going into details talking about the two prospective stem cell lines.
Epilepsy is a common neurological disorder affecting approximately 50 million people worldwide. Antiepileptic drugs (AEDs) are commonly used to treat the disease depending, mainlyon the type of seizure. However, the useof AEDs mayalso lead to cutaneous adverse drug reactions (cADR) such as toxic epidermal necrolysis (TEN), Stevens-Johnsonsyndrome (SJS), exfoliative dermatitis (ED) and drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), which are unwanted comorbidities in epilepsy. It was first discoveredthat the HLA-B*15:02 allele was strongly associatedwith carbamazepine(CBZ)-induced SJS/TEN amongHan Chinese and this ledto the discovery of other HLAallelesand cytochrome P450 (CYP) genes that were significantly associatedwith various AED-inducedcADRsacross variouspopulations. This mini-reviewis an update on the latest findings ofthe involvement of various HLA alleles and CYP alleles in cADRs caused by CBZ, phenytoin (PHT), oxcarbazepine (OXC) and lamotrigine(LTG) in different case-control studies around the world. From our review, we found that CBZ-and PHT-induced cADRsweremore commonly reportedthan the other AEDs.Therefore,there were morerobust pharmacogenetics studies related to these AEDs. OXC-and LTG-induced cADRswereless commonly reported,and somore studies are needed to validate the reported association of the newer reported HLA alleles with theseAEDs. It is also importantto considerthe allelic frequency within a given population before concludingthe use of thesealleles as genetic markers to prevent AED-induced cADR. Overall, the current body of research pointto a combination of alleles as a better pharmacogenetic marker comparedto the use of a single gene as a genetic marker for AED-induced cADR.
Epilepsy is a chronic neurological disorder characterized by the rapid occurrence of epileptic seizures affecting approximately 70 million people worldwide[1,2]. The quality of life of people with epilepsy (PWE) is challenged by a series of comorbidities that might include neurologic and neuropsychiatric disorders (cognitive decline, depression, anxiety, schizophrenia, and autism) as well as metabolic, cardiovascular and respiratory diseases[3]. Neurobehavioral and other comorbidities might share a reciprocal and complex relationship with epileptogenesis and ictogenesis thus biomarkers of the former might be useful for the prediction of the latter and vice versa[4].
Epileptic seizures result from excessive brain activity and may affect sensory, motor and autonomic function; as well as, emotional state, memory, cognition or behaviour. Effective anti-epileptic drugs (AEDs) are available but have tolerability issues due to their side effects. Medicinal plants are potential candidates for novel AEDs, as many are traditional epilepsy remedies. Malaysia is a megadiverse country, with many endemic plants serving as a large pool of potential candidates for the development of local herbal products. The large variety of flora makesMalaysia a prime location for the discovery of medicinal plants with anti-convulsive potential. This review lists 23 Malaysian medicinal plants, of which four are used traditionally to treat epilepsy, without any scientific evidence. A further eight plants have no known traditional anti-epileptic usebut have scientific evidence of its anti-epileptic activity. The remaining 11 plants possess both traditional use and scientific evidence. Thus, this review identified several potential candidates for the development of novel AEDs or enhancing current ones; as well as identified an imbalance between traditional use and scientific evidence. In addition, this review also identified several limitations in the reviewed studies and provided additional information to facilitate the design of future studies.
Abstract: Meningitis after spinal anaesthesia is a rare yet devastating complication of spinal anaesthesia. The exact incidence is unknown. Our patient developed signs and symptoms of meningitis 48 hours after spinal anaesthesia and required intensive care unit admission. Her cerebrospinal fluid was sterile. Computed tomography of brain showed left subdural collection. She recovered well after 6 weeks of intravenous antibiotics. No neurological sequela noted from subsequent follow-upexaminations. Our case provides an important insight of meningitis with subdural collection after spinal anaesthesia for emergency caesarean section.
The conjoint 17thAsian and Oceanian Myology Centre (AOMC) and 28thMalaysian Society of Neurosciences (MSN) Annual Scientific Meeting, held in Hotel Istana, Kuala Lumpur, Malaysia from 27 to 29 July 2018, was a great success to gather all neurosciences professionals locally and in the Asian-Oceanian region to share the latest updates in Neurology and specifically Myology. This congress attracted 516 local participants and 167 international delegates from 14 countries
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small cerebral arteries. This case series aims to describe the mutations in NOTCH3and their phenotypes in Malaysia. We includedpatients who were genetically confirmed to have CADASIL, diagnosed at the University of Malaya Medical Centre, Malaysia. Family members who fulfilled clinical or imaging criteria, and patients from two previous published Malaysian families were also included. Six families (eleven cases) were included in this series. Genetic testing revealed NOTCH3 mutations in c.328C>T (p.Arg110Cys, R110C), c.553T>G (p.Cys185Gly, C185G), c.1630C>T (p.Arg544Cys, R544C) and c.160C>T (p.Arg54Cys, R54C). Two out of four Chinese families had R544C mutation in exon 11, with a later age of onset, absence of migraine and lack of anterior temporal pole involvement on MRI. One family with mixed Indian and Chinese ancestry had a mutation in exon 3 with R110C and another Indian family exon 4 with C185G mutation. This case series highlights the genotypic and phenotypic variability of CADASIL in a multi-ethniccountry. The finding of p.Arg544Cys mutation among the older Chinese families, similar to those reported in Jeju Island and Taiwan, suggest the need to screen the older Chinese stroke patients with typical MRI changes.
Major depressive disorder (MDD) compromises the individual’s capacity for self-care and productivity. Single nucleotide polymorphisms (SNP) of a number of genes have been associated with MDD. The zinc transporter-3 protein, encoded by the ZnT3 (SLC30A3) gene, maintains zinc-glutamate homeostasis at the glutamatergic synapse, a disruption of which increases risk of MDD. We hypothesise that variation in SLC30A3 (rs11126936)SNP increases risk of MDD. We recruited 300 MDD cases and 300 controls, matched in theratio of 1:1 by age, gender and ethnicity. PCR-restriction fragment length polymorphism analysis was used in DNA genotyping, validated by sequencing 10%of samples. Deviation from the Hardy-Weinberg equilibrium was tested using the chi-square test. Conditional logistic regression was used to estimate adjusted odds ratios, controlling for age, gender, ethnicity, occupation and family monthly income.Genotypes G/G and G/T showed two times greater odds of developing MDD compared to variant genotype T/T (OR=1.983, 95% CI=1.031-3.815; p=0.040 and OR=2.232, 95% CI=1.100-4.533; p=0.026 respectively). Carriers of genotypes G/G and G/T of the SNP rs11126936 in SLC30A3are associated with increased risk of MDD.
Major depressive disorder (MDD) is a serious mental illness with a multifactorial aetiology that was shown to influence behaviour and affect cognition. Previous research has favoured the involvement of dopamine in the aetiology of the disorder, and since one of the critical regulators of the dopamine levels and activity in the brain is DAT1, the present study investigated the association of a single nucleotide polymorphism in the DAT1gene (rs40184) and MDD in the Malaysian population. A total of 300cases and 300 matched controls were recruited from four Klang valley hospitals and were screened for DAT1rs40184 using high resolution melting assays. The allele and genotype frequencies were analysed by using Chi-square. Hardy Weinberg equilibrium for the distribution of alleles and genotypes was tested by using Chi-square. Determination of the association between rs40184 and MDD was achieved by conditional logistic regression using SPSS. In the present study, no significant association was obtained between DAT1and MDD in the Malaysianpopulation.
Neuromarketing has become a central marketing issue in the new global economy. The term neuromarketing is a combination of neuroscience and marketing. This new concept provides new insights and powerful techniques in marketing research, especially on consumer analysis. The central concept of neuromarketing is strongly related to brain activities, understanding the consumers’ subconscious mind, explaining consumers’ preferences, motivations, and expectations, and predicting consumers’ behavior. Neuromarketing is not to replace traditional marketing methods, but rather to provide unique and complementary insights. This paper focuses on the growing field of neuromarketing and aims to explain the fundamental concepts of neuromarketing to ensure that its unexplored practical usefulness can positively contribute to the field of marketing. Therefore, this review will help researchers to develop effective approaches further, to provide better and more efficient services to consumers through the use of scientific methods to understand how consumers respond to marketing campaigns.
Vascular dementia (VaD) is one of the most common types of dementia in Alzheimer’s disease (AD). Two-vessel occlusion (2VO), also known as permanent bilateral occlusion of the common carotid arteries, induces chronic cerebral hypoperfusion (CCH) in rats, resulting in neuronal loss and inflammation (particularly in the cortex and hippocampus). The 2VO rat model has been widely used to represent VaDconditions similar to those seen in humans. Synaptic plasticity or long-term potentiation (LTP) is one of the most important neurochemical foundations in learning and memory, deficits of which occur as a result of VaD. The aim of this study is to evaluatethe role of cholinergic transmission in LTP impairment of CCH rat model. There is a significant impairment of LTP following the induction of 2VO surgery (p< .05). Treatment with oxotremorine and tacrine cause significant enhancement of LTP and potentiation levels (p < .05). There are also significant effects of paired-pulse facilitations when treated with cholinergic agonists and baseline synaptic transmission with increasing stimulation intensity (p < .0001). AChE activity was only found to increase significantly in the hippocampal region (p< .05).The role of cholinergic neurotransmission has been clearly demonstrated in LTP impairment of the CCH rat model. Augmentation of synaptic transmission was clearly observed in this model via changes of basal synaptic transmission and neurotransmitter release presynaptically.
Genetic hereditary has been implicated in bipolar disorder pathogenesis. The PDLIM5 and HTR2A genes have been investigated for its association with bipolar disorder in various populations, however, the results have been conflicting. In this study, we investigate the association between bipolar disorder and the two genes of interest, PDLIM5 and HTR2A genes. We recruited 253 bipolar disorder patients (75 Malays, 104 Chinese, and 74 Indians) and 505 control individuals (198 Malays, 155 Chinese, and 152 Indians) from three ethnic groups within Malaysian population. We genotyped for 3 SNPs of the PDLIM5 (rs2433320, rs2433322 and rs2438146) and 3 SNPs of the HTR2A (rs6313, rs2070040 and rs6311). Significant associations between bipolar disorder and each of the 3 SNPs of PDLIM5 in Malays, Indians and pooled samples. However, only rs2438146 remains significant in the Malays as co-dominant (T/T vs. C/C, p=0.004, OR=0.128, 95%CI=0.031-0.524) and recessive genetic models (T/T vs. C/T+C/C, p=0.003, OR=0.122, 95%CI=0.030-0.494) after applying conservative Bonferroni correction. Haplotype analysis of 3 SNPs of PDLIM5 also showed a significant association with bipolar disorder. No association was observed between bipolar disorder and each of the 3 SNPs of HTR2A in any of the ethnicities. We conclude that PDLIM5 polymorphisms are associated with bipolar disorder in the pooled analysis. After stratification to different ethnic groups, the association remains significant in the Malay and Indian groups. The association is also supported by the significant association in haplotype analysis of PDLIM5. We also conclude there is no association between the HTR2A polymorphisms in the Malaysian population.
Ts1Cje is a mouse model of Down syndrome (DS) with partial triplication of chromosome 16, which encompasses a high number of human chromosome 21 (HSA21) orthologous genes. The mouse model exhibits muscle weakness resembling hypotonia in DS individuals. The effect of extra gene dosages on muscle weakness or hypotonia in Ts1Cje and DS individuals remains unknown. To identify molecular dysregulation of the skeletal muscle, we compared the transcriptomic signatures of soleus and extensor digitorum longus (EDL) muscles between the adult Ts1Cje and disomic littermates. A total of 166 and 262 differentially expressed protein-coding genes (DEGs) were identified in the soleus and EDL muscles, respectively. The partial trisomy of MMU16 in Ts1Cje mice has a greater effect on gene expression in EDL. Top-down clustering analysis of all DEGs for represented functional ontologies revealed 5 functional clusters in soleus associated with signal transduction, development of reproductive system, nucleic acid biosynthesis, protein modification and metabolism as well as regulation of gene expression. On the other hand, only 3 functional clusters were observed for EDL namely neuron and cell development, protein modification and metabolic processes as well as ion transport. A total of 11 selected DEGs were validated using qPCR (disomic DEGs: Mansc1; trisomic DEGs: Itsn1, Rcan1, Synj1, Donson, Dyrk1a, Ifnar1, Ifnar2, Runx1, Sod1 and Tmem50b). The validated DEGs were implicated in neuromuscular junction signalling (Itsn1, Syn1), oxidative stress (Sod1, Runx1) and chronic inflammation processes (Runx1, Rcan1, Ifnar1, Ifnar2). Other validated DEGs have not been well-documented as involved in the skeletal muscle development or function, thus serve as interesting novel candidates for future investigations. To our knowledge, the study was the first attempt to determine the transcriptomic profiles of both soleus and EDL muscles in Ts1Cje mice. It provides new insights on the possible disrupted molecular pathways associated with hypotonia in DS individuals.
Down syndrome (DS) is a genetic condition resulting from triplication of human chromosome (HSA)21. Besides intellectual disability, DS is frequently associated with hypotonia. Satellite cells are the resident cells that provides robust and remarkable regenerative capacity to the skeletal muscles, and its population size has been reported to be disease-associated. However, little is known about the population size of satellite cells in DS and the association of its intrinsic cellular functionality and hypotonia seen in DS. Here, we studied the Ts1Cje mouse, a DS murine model displays the muscle weakness characteristic. Satellite cell populations were immunostained with Pax7 and myonuclei numbers in the Ts1Cje extensor digitorum longus muscle were assessed. Their cellular function was further determined via in vitro assay in high-serum conditioned medium. Subsequently, the in vitro self-renewal, proliferative, and differentiation activities of these myogenic precursor cells were assessed after 24, 48, and 72h using Pax7, MyoD, and Ki67 immunomarkers. Our results showed that the population and functionality of Ts1Cje satellite cell did not differ significantly when compared to the wildtype cells isolated from disomic littermates. In conclusion, our findings indicated that intrinsic cellular functionality of the satellite cells, do not contribute to muscle weakness in Ts1Cje mouse.