Paraoxonases (PONs) are involved in the detoxification of organophosphate pesticides and chemical nerve agents. Due to a reported possible twofold increased risk of ALS in Gulf War veterans and the associations of PON1 polymorphisms with the neurologic symptom complex of the Gulf War syndrome, the authors investigated the association between sporadic ALS (SALS) and PON gene cluster variants in a large North American Caucasian family-based and case-control cohort (N = 1,891).Clinically definite and probable ALS was diagnosed according to the revised El Escorial criteria, exclusion of family history of ALS, and SOD1 mutation analysis. Single nucleotide polymorphism (SNP) genotyping was done using TaqMan assays on ABI7900HT. Data were analyzed using SPSS, Haploview, FBAT, and THESIAS.A haploblock of high linkage disequilibrium (LD) spanning PON2 and PON3 was associated with SALS. The SNPs rs10487132 and rs11981433 were in strong LD and associated with SALS in the trio (parents-affected child triad) model. The association of rs10487132 was replicated in 450 nuclear pedigrees comprising trios and discordant sibpairs. No association was found in case-control models, and their haplostructure was different from that of the trios with overall reduced LD. Resequencing identified an intronic variant (rs17876088) that differentiated between detrimental and protective SALS haplotypes.This study demonstrates evidence of significant association of variants in the Paraoxonase gene cluster with sporadic ALS and is compatible with the hypothesis that environmental toxicity in a susceptible host may precipitate ALS.
This cross-sectional analytical study was conducted in the department of Paediatrics, Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh from March 2017 to August 2018 to assess the pattern of serum iron profile and red cell indices in children with severe acute malnutrition. Seventy children having severe acute malnutrition were compared with 70 age matched children those had normal growth. Age range of the studied children was 6 months to 59 completed months. Male was found predominant (54.3%) in both study group and comparison group. Mean serum iron, serum ferritin, serum total iron binding capacity and transferrin saturation in severely malnourished children were 45.3±19.3μg/dl, 26.5±20.0ng/ml, 246.3±47.5μg/dl and 16.4±2.0% respectively which were significantly lower than that of healthy children (p<0.05). Mean Hb level in children with severe acute malnutrition was found 8.3±1.6gm/dl which was also found significantly lower than that of normal children (p<0.05). Anaemia was found in all (100%) severely malnourished children compared to 25.7% of children in comparison group. Mean MCV, MCH and MCHC in children with severe acute malnutrition was found 71.7±13.5fl, 24.0±5.8pg and 31.4±4.0gm/dl respectively which were significantly lower than that of comparison group (p<0.05). Serum iron profile and red cell indices should be routinely done in severely malnourished children for early intervention and management of iron deficiency anaemia.
Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10−8; OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10−9; OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10−9; OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.
Media Discourse explores the interactions occurring on broadcast platforms and is pivotal in global news dissemination. It also can propagate divergent viewpoints aligned with prevailing power structures. A comprehensive approach involving qualitative and quantitative methods addressed these aspects. Fairclough's Sociocultural Approach of Critical Discourse Analysis was applied for a critical qualitative examination, while a questionnaire was developed for quantitative analysis. The qualitative analysis involved three stages: characterization, understanding the relationship between message and communication, and elucidating the connection between communication and social context. Specifically, "USA Today" and "Dawn" were selected as representatives of American and Pakistani newspapers, respectively. For the quantitative phase, a random sample of 50 respondents completed the questionnaire, and the data were analyzed using SPSS software. The findings revealed discernible differences in the writing tone between the two newspapers, both contributing to the propagation of Islamophobia. Respondents exhibited a mix of positive and negative reactions to the questionnaire, reflecting varied perspectives on the media discourse under scrutiny.
Objective: Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE). Methods: All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561–726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations. Results: We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations. Conclusions:FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and ∼4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.
The construction of gender and imaging gender as a reason for inequality is a well- established field of linguistic research. This study seeks to investigate the representation of gender in English textbooks for grade IX published by the Punjab Textbook Board (PTB), Pakistan. In order to assess the textbook from a gender perspective, the qualitative research method was employed. The text is examined using content analysis from a gender viewpoint. In this study, secondary data watches the main subject. According to the data, the grade IX English textbook from the Punjab textbook board has more phrases that are specifically slang for men. Additionally, there is a representation of female gender-specific terminology in the ninth-grade English textbook. Despite the Constitution of Pakistan of 1973's stated intention to reduce gender imbalances, male supremacy permeates all of the themes and sub-themes. It is observed that the government, textbook boards, and curriculum directorate should ensure an equal distribution of information for both sexes to boost women’s visibility in Pakistan.
The authors tested the association of three vascular endothelial growth factor (VEGF) promoter polymorphisms with sporadic ALS (SALS) to verify the results of a previous study and to investigate their modifier effects on the subphenotypes of SALS in a large family-based and case-control cohort of North American white subjects (N = 1,603). They did not find any association of the VEGF promoter polymorphisms with SALS or its subphenotypes, suggesting that they do not have a direct causal role in ALS.
Objective: To identify the genetic defect causing dominant X-linked ALS and ALS/dementia, and characterize the functional and pathological determinants. Background Most cases of ALS are sporadic but about 5-10% are familial. Mutations in SOD1, TDP43 and FUS account for approximately 30% of classic familial ALS. The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. More than a decade ago, we had linked a large ALS family to the pericentric region of the X chromosome. Design/Methods: Detailed mapping was done with dense microsatellite markers and Illumina Sentrix HumanHap300 Genotyping BeadChip. Candidate genes were sequenced using Beckman Coulter CEQ 8000 DNA analysis system. Immunohistochemistry and light and confocal microscopy were performed according to standard protocols. Neuro2a and SHSY-5Y cells were transiently co-transfected with a ubiquitin-proteasome system (UPS) reporter plasmid (Ub-G76V-GFP) and pIRES2-DsRed2 dual expression vectors containing either wildtype or mutant UBQLN2 and analyzed using a MoFlo cell sorter and Summit software. Results: We show mutations of ubiquilin2, a ubiquitin-like protein, in five families with ALS and ALS/dementia. We also show that inclusions containing ubiquilin2 are a common pathological feature in a wide spectrum of ALS and ALS/dementia. Functional studies indicate an impairment of ubiquitin-mediated proteasomal degradation in cells expressing mutant ubiquilin2. Conclusions: These data provide evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia. Further elucidation of these processes may be central to the understanding of pathogenic pathways. These pathways should provide novel molecular targets for the design of rational therapies for these disorders. Supported by: The National Institute of Neurological Disorders and Stroke (NS050641), the Les Turner ALS Foundation, the Vena E. Schaff ALS Research Fund, the Harold Post Research Professorship, the Herbert and Florence C. Wenske Foundation, the David C. Asselin MD Memorial Fund, the Help America Foundation and the Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship. F.F. has support from NIH (T32 AG20506). K.A. is a postdoctoral fellow of the Blazeman Foundation for ALS. G.H.G. received travel funds from MND Scotland. Disclosure: Dr. Fecto has nothing to disclose. Dr. Deng has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Hong has nothing to disclose. Dr. Boycott has nothing to disclose. Dr. Gorrie has nothing to disclose. Dr. Siddique has nothing to disclose. Dr. Yang has nothing to disclose. Dr. Shi has nothing to disclose. Dr. Zhai has nothing to disclose. Dr. Jiang has nothing to disclose. Dr. Hirano has nothing to disclose. Dr. Rampersaud has nothing to disclose. Dr. Jansen has nothing to disclose. Dr. Donkervoort has nothing to disclose. Dr. Bigio has nothing to disclose. Dr. Brooks has received personal compensation for activities with Avanir Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Biogen Idec, Genentech, Inc., and Teva Neuroscience. Dr. Brooks has received research support from Avanir Pharmaceuticals, Biogen Idec, NINDS, Novartis, and Teva Neuroscience. Dr. Ajroud has nothing to disclose. Dr. Sufit has nothing to disclose. Dr. Haines has nothing to disclose. Dr. Mugnaini has nothing to disclose. Dr. Pericak-Vance has nothing to disclose. Dr. Siddique has nothing to disclose.
The alanine to valine mutation at codon 4 (A4V) of SOD1 causes a rapidly progressive dominant form of amyotrophic lateral sclerosis (ALS) with exclusively lower motor neuron disease and is responsible for 50% of SOD1 mutations associated with familial ALS in North America. This mutation is rare in Europe. The authors investigated the origin (geographic and time) of the A4V mutation.Several cohorts were genotyped: North American patients with confirmed A4V mutation (n = 54), Swedish (n = 3) and Italian (n = 6) A4V patients, patients with ALS with SOD1 non-A4V mutations (n = 66) and patients with sporadic ALS (n = 96), healthy white (n = 96), African American (n = 17), Chinese (n = 53), Amerindian (n = 11), and Hispanic (n = 12) subjects. High-throughput SNP genotyping was performed using Taqman assay in 384-well format. A novel biallelic CA repeat in exon 5 of SOD1, tightly linked to A4V, was genotyped on sequencing gels. Association statistics were estimated using Haploview. p Values less than 0.05 were considered significant. Age of A4V was estimated using a novel method based on r(2) degeneration with genetic distance and a Bayesian method incorporated in DMLE+.A single haplotype of 10 polymorphisms across a 5.86-cM region was associated with A4V (p = 3.0e-11) when white controls were used, suggesting a founder effect. The strength of association of this haplotype progressively decreased when African American, Chinese, Hispanic, and Amerindian subjects were used as controls. The associated European haplotype was different from the North American haplotype, indicating two founder effects for A4V (Amerindian and European). The estimated age of A4V with the r(2) degeneration method was 458 +/- 59 years (range 398-569) and in agreement with the Bayesian method (554-734 years with 80-90% posterior probability).North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400-500 years ago.
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