Bark extract of Chaetocarpus castanocarpus (Roxb.) exhibits potent sedative, anxiolytic, and antidepressant effects through an in vivo approach in Swiss albino mice.

OBJECTIVE: Standard phytochemical investigations were performed to identify the secondary metabolites in the methanol extract of Chaetocarpus castanocarpus bark (MECC) and investigate the neuropharmacological potential of MECC in Swiss albino mice. MATERIALS AND METHODS: Swiss albino mice were used in the forced swimming test (FST) and tail suspension test (TST) to evaluate the antidepressant effect of MECC. Also, the hole board test (HBT) and elevated plus maze (EPM) were conducted to examine anxiolytic activities. In contrast, the open field test (OFT) and hole cross test (HCT) were employed to evaluate sleeping disorders. RESULTS: Alkaloids, glycosides, flavonoids, terpenoids, coumarins, and tannins are only a few secondary metabolites identified in MECC by qualitative and quantitative phytochemical investigations. The oral administration of MECC considerably shortened the immobility duration during FST and TST. Encouraging dose-dependent anxiolytic effects were also observed in all relevant experiments compared to the control. Additionally, during the OFT and HCT assessment, a noteworthy decline in the locomotor activities of the experimental animals was observed. CONCLUSIONS: The results of this investigation suggest that the Chaetocarpus castanocarpus bark is a possible source of therapeutic candidates for treating neurological disorders.

Foliar application of triacontanol ameliorates heat stress through regulation of the antioxidant defense system and improves yield of eggplant

Abstract Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.

Resumo O tempo de transplante e o genótipo contribuem para melhorar a produtividade e a qualidade da cultura da berinjela (Solanum melongena L.). Um experimento de campo foi conduzido para investigar o impacto da aplicação foliar de triacontanol (TRIA) e genótipos de berinjela 25919, Nirala, 28389 e Pak-10927, transplantados em 1 de março, 15 de março e 1 de abril de exposição a condições de alta temperatura do ar. O experimento foi realizado de acordo com o Randomized Complete Block Design e os dados foram analisados pelo teste de Tuckey. O TRIA foi aplicado a 10 µM na fase de floração; água destilada foi utilizada como controle. Taxa de fotossíntese e transpiração, condutância estomática, eficiência do uso da água e efeitos sobre as enzimas antioxidantes (superóxido dismutase, catalase e peroxidase) foram avaliados. O TRIA 10 µM aumentou a taxa de fotossíntese e a eficiência do uso da água e o rendimento foi melhorado em todos os genótipos transplantados nas diferentes datas. A aplicação foliar de TRIA 10µM aumentou as atividades das enzimas antioxidantes (SOD, POD e CAT) e melhorou os atributos fisiológicos e bioquímicos de genótipos de berinjela expostos a condições de alto calor. A atividade mais elevada da enzima dismutase 5,41mg / 1g FW foi registrada no genótipo Nirala no segundo transplante. Considerando que o mais baixo foi observado em PAK-10927 (2,30 mg / g FW). A produtividade máxima de frutos foi encontrada no acesso 25919 (1,725 kg por planta) no 1º transplante com Triacontanol, enquanto o acesso PAK-10927 deu a menor produção (0,285 kg por planta) no tratamento de controle no 3º transplante. Genótipo, data de transplante e aplicação de TRIA, melhoramento do crescimento, rendimento e atributos de qualidade sob estresse térmico em berinjela.

Foliar application of triacontanol ameliorates heat stress through regulation of the antioxidant defense system and improves yield of eggplant / Title in the second language of the article: Amelioration of heat stress in egg plant through application of tricontanol

Abstract Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.

Resumo O tempo de transplante e o genótipo contribuem para melhorar a produtividade e a qualidade da cultura da berinjela (Solanum melongena L.). Um experimento de campo foi conduzido para investigar o impacto da aplicação foliar de triacontanol (TRIA) e genótipos de berinjela 25919, Nirala, 28389 e Pak-10927, transplantados em 1 de março, 15 de março e 1 de abril de exposição a condições de alta temperatura do ar. O experimento foi realizado de acordo com o Randomized Complete Block Design e os dados foram analisados pelo teste de Tuckey. O TRIA foi aplicado a 10 µM na fase de floração; água destilada foi utilizada como controle. Taxa de fotossíntese e transpiração, condutância estomática, eficiência do uso da água e efeitos sobre as enzimas antioxidantes (superóxido dismutase, catalase e peroxidase) foram avaliados. O TRIA 10 µM aumentou a taxa de fotossíntese e a eficiência do uso da água e o rendimento foi melhorado em todos os genótipos transplantados nas diferentes datas. A aplicação foliar de TRIA 10µM aumentou as atividades das enzimas antioxidantes (SOD, POD e CAT) e melhorou os atributos fisiológicos e bioquímicos de genótipos de berinjela expostos a condições de alto calor. A atividade mais elevada da enzima dismutase 5,41mg / 1g FW foi registrada no genótipo Nirala no segundo transplante. Considerando que o mais baixo foi observado em PAK-10927 (2,30 mg / g FW). A produtividade máxima de frutos foi encontrada no acesso 25919 (1,725 ​​kg por planta) no 1º transplante com Triacontanol, enquanto o acesso PAK-10927 deu a menor produção (0,285 kg por planta) no tratamento de controle no 3º transplante. Genótipo, data de transplante e aplicação de TRIA, melhoramento do crescimento, rendimento e atributos de qualidade sob estresse térmico em berinjela.

Foliar application of triacontanol ameliorates heat stress through regulation of the antioxidant defense system and improves yield of eggplant.

Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.

Sleep disruption in nonalcoholic fatty liver disease: What is the role of lifestyle and diet?

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) have sleep disruption. The aim of this study is to understand how underlying factors such as diet, degree of liver disease and morningness-eveningness tendencies contribute to this sleep disruption. METHODS: Patients with NAFLD were recruited from liver clinics at a University and Veterans Affairs practice. Patients with decompensated cirrhosis were excluded. Patients completed self-reported surveys to evaluate sleep disturbance using the Epworth Sleepiness Scale (ESS) and chronotype (circadian preference) using the morningness-eveningness questionnaire (MEQ). Information on occupation, physical activity and dietary intake were collected at clinic intake. Dietary intake was evaluated via food-frequency questionnaire and analyzed as individual categories or grouped on the basis of dietary composition. RESULTS: A 54 patients completed the survey; 37% were female. Median ESS was 8 ± 4.2 and 37% of NAFLD patients were found to have sleep disturbance as defined by ESS >10. Sleep disturbance was common in NAFLD regardless of the liver disease stage. Dietary factors, including higher added sugar (P = 0.01), candy intake (P = 0.01), elevated Ferritin level (P = 0.04) and elevated platelet count (P = 0.05), were significantly associated with sleep disturbance. Chronotype, time to sleep, and duration of sleep were not associated with sleep disruption. CONCLUSIONS: Sleep disruption is present in NAFLD regardless of underlying cirrhosis. Interventions aimed at improving dietary and lifestyle practices such as reduced sugar intake may help mitigate the risk for sleep disruption in NAFLD. Further longitudinal studies are needed to further delineate these links.

Nanofiltration for Arsenic Removal: Challenges, Recent Developments, and Perspectives.

Arsenic (As) removal is of major significance because inorganic arsenic is highly toxic to all life forms, is a confirmed carcinogen, and is of significant environmental concern. As contamination in drinking water alone threatens more than 150 million people all over the world. Therefore, several conventional methods such as oxidation, coagulation, adsorption, etc., have been implemented for As removal, but due to their cost-maintenance limitations; there is a drive for advanced, low cost nanofiltration membrane-based technology. Thus, in order to address the increasing demand of fresh and drinking water, this review focuses on advanced nanofiltration (NF) strategy for As removal to safeguard water security. The review concentrates on different types of NF membranes, membrane fabrication processes, and their mechanism and efficiency of performance for removing As from contaminated water. The article provides an overview of the current status of polymer-, polymer composite-, and polymer nanocomposite-based NF membranes, to assess the status of nanomaterial-facilitated NF membranes and to incite progress in this area. Finally, future perspectives and future trends are highlighted.

A Study of the Association between Diabetes Mellitus and Chronic Hepatitis B Virus Infection / Un Estudio de la Asociación entre la Diabetes Mellitus y la Infección Crónica por el Virus de la Hepatitis B

ABSTRACT Background: Hepatitis B virus (HBV) infection and diabetes mellitus are major health problems associated with significant morbidity and mortality. The published literature suggests an association of diabetes mellitus with liver disease. However, the role of HBV infection in diabetes aetiology is still controversial. The present study was conducted to explore the veracity of this enigmatic association among Pakistani subjects. Methodology: The blood samples and clinical information were collected from chronic HBV-positive patients Group 1 (n = 120), and their age and gender were matched with those of the healthy control subjects Group 2 (n = 120). Hepatitis B virus-positive patients were also subdivided into two groups; (Group 1a and Group 1b) with and without liver cirrhosis for evaluation of the prevalence of diabetes. Results: The study revealed that there were statistically significant differences in the biochemical parameters in the HBV-positive and control groups. There was no correlation between diabetes and HBV with the prevalence of diabetes mellitus being similar in subjects with and without HBsAg (11.7% in the positive group and 10% in the controls). Since there were a relatively large number (32.5%) of HBV-positive patients with liver cirrhosis, a comparison of biochemical parameters was also carried out to evaluate the extent of the liver damage and its association with diabetes. During the comparison of HBV patients with and without cirrhosis for the prevalence of diabetes, no aetiologic association was found with diabetes. Conclusion: Study revealed that there was no correlation between HBV infection and diaabetes despite the significantly different biochemical parameters in the HBV-infected group and control subjects.

RESUMEN Antecedentes: La infección por el virus de la hepatitis B (VHB) y la diabetes mellitus son problemas de salud importantes asociados con morbilidad y mortalidad significativas. La literatura publicada sugiere una asociación de la diabetes mellitus con las enfermedades hepáticas. Sin embargo, el papel de la infección por VHB en la etiología de diabetes sigue siendo contro-versial. El presente estudio fue conducido con el propósito de explorar la veracidad de esta enigmática asociación entre sujetos paquistaníes. Metodología: Se recogieron muestras de sangre e información clínica de pacientes crónicos VHB positivos Grupo 1 (n = 120), y su edad y género fueron comparados con los de los sujetos sanos del control Grupo 2 (n = 120). Los pacientes positivos al virus de la hepatitis B también se subdividieron en dos grupos, a saber, (Grupo 1a y Grupo 1b) con y sin cirrosis hepática en relación con la prevalencia de la diabetes. Resultados: El estudio reveló que hubo diferencias significativas en estos dos grupos en los parámetros bioquímicos entre el grupo de control y el grupo VHB positivo. En estos dos grupos no hubo correlación entre la diabetes y el VHB. Puesto que hubo un número relativamente grande (32.5%) de pacientes VHB positivos con cirrosis hepática, se realizó también una comparación de los parámetros bioquímicos a fin de comprender el grado del daño hepático y su asociación con la diabetes. Durante la comparación de los pacientes con VHB con y sin cirrosis en relación con la prevalencia de diabetes, no se halló asociación etiológica con la diabetes. Conclusión: Este estudio reveló que no hubo correlación entre la infección por VHB y la diabetes, a pesar de los parámetros bioquímicos significativamente diferentes entre el grupo infectado por el VHB y los sujetos del control.

Evaluation of functional properties of Zein extracted from various maize varieties.

Zein is the major storage protein of maize and was identified initially on the basis of solubility in aqueous alcohol solution. It is comprised of 45-50% grain portion and has a wide range of application as a functional ingredient in the food industry. In the current study, five different maize varieties were analyzed and compared for the physicochemical, mineral and functional characteristics. Zein protein was extracted at different concentrations of ethanol and was further characterized for its antioxidant and functional properties. Significant variations in the characteristics were observed in different varieties related to their mineral and chemical composition. Likewise, antioxidant properties of zein extracted from Agaiti-2002 variety were 32.61% and minimum value (30%) was observed in the Pearl variety. Zein protein has the potential to be used as encapsulating material for controlled release of different bioactive compounds.

Effect of fluoxetine on disease progression in a mouse model of ALS.

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.

Effect of prolonged riluzole exposure on cultured motoneurons in a mouse model of ALS.

Riluzole is the only FDA-approved drug to treat amyotrophic lateral sclerosis, but its long-term effects on motoneurons are unknown. Therefore, we treated primary mouse spinal cord cultures with 2 µM riluzole for 4-9 days and then used whole cell patch clamp to record the passive and active properties of both wild-type and SOD1(G93A) motoneurons. At this concentration, riluzole blocks >50% of the sodium component of a persistent inward current that plays a major role in determining motoneuron excitability. Prolonged riluzole treatment significantly decreased the amplitude of the persistent inward current. This effect was specific for SOD1(G93A) motoneurons, where the amplitude decreased by 55.4%. In addition, prolonged treatment hyperpolarized the resting membrane potential as well as the voltage onset and voltage maximum of the persistent inward current (∼2-3 mV in each case). These effects appeared to offset one another and resulted in no change in the firing properties. In a subset of cells, acute reapplication of 2 µM riluzole during the recording decreased repetitive firing and the persistent inward current, which is consistent with the normal effects of riluzole. The downregulation of the persistent inward current in response to prolonged riluzole administration is in contrast to the strong upregulation of this same current after descending neuromodulatory drive to the cord is lost following spinal injury. This dichotomy suggests that decreased activation of G protein-coupled pathways can induce upregulation in the persistent inward current but that direct channel block is ineffective.

Familial amyotrophic lateral sclerosis, a historical perspective.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease of the upper and lower motor neuron of unknown etiology. Although a familial cause for this disease has been suspected early one, it is only in the past two decades that advances in modern genetics led to the identification of more than 10 genes linked to familial ALS and helped us understand some of the complex genetic and environmental interactions that may contribute to sporadic ALS. In this article, we chronologically summarize the genetic breakthroughs in familial and sporadic ALS and depict how it shaped our understanding of disease pathogenesis and our quest for rational therapies.

Altered postnatal maturation of electrical properties in spinal motoneurons in a mouse model of amyotrophic lateral sclerosis.

Spinal motoneurons are highly vulnerable in amyotrophic lateral sclerosis (ALS).Previous research using a standard animal model, the mutant superoxide dismutase-1 (SOD1)mouse, has revealed deficits in many cellular properties throughout its lifespan. The electrical properties underlying motoneuron excitability are some of the earliest to change; starting at 1 week postnatal, persistent inward currents (PICs) mediated by Na+ are upregulated and electrical conductance, a measure of cell size, increases. However, during this period these properties and many others undergo large developmental changes which have not been fully analysed.Therefore, we undertook a systematic analysis of electrical properties in more than 100 normal and mutant SOD1 motoneurons from 0 to 12 days postnatal, the neonatal to juvenile period.We compared normal mice with the most severe SOD1 model, the G93A high-expressor line. We found that the Na+ PIC and the conductance increased during development. However, mutant SOD1 motoneurons showed much greater increases than normal motoneurons; the mean Na+PIC in SOD1 motoneurons was double that of wild-type motoneurons. Additionally, in mutant SOD1 motoneurons the PIC mediated by Ca2+ increased, spike width decreased and the time course of the after-spike after-hyperpolarization shortened. These changes were advances of the normal effects of maturation. Thus, our results show that the development of normal and mutant SOD1 motoneurons follows generally similar patterns, but that the rate of development is accelerated in the mutant SOD1 motoneurons. Statistical analysis of all measured properties indicates that approximately 55% of changes attributed to the G93A SOD1 mutation can be attributed to an increased rate of maturation.

TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.

OBJECTIVE: To improve understanding of TRPV4-associated axonal Charcot-Marie-Tooth (CMT) neuropathy phenotypes and their debated pathologic mechanism. METHODS: A total of 17 CMT2C phenotypic families with vocal cord and diaphragmatic involvement and 36 clinically undifferentiated CMT2 subjects underwent sequencing analysis of the coding region of TRPV4. Functional studies of mutant proteins were performed using transiently transfected cells for TRPV4 subcellular localization, basal and stimulated Ca(2+) channel analysis, and cell viability assay with or without channel blockade. RESULTS: Two TRPV4 mutations R232C and R316H from 17 CMT2C families were identified in the ankyrin repeat domains. The R316H is a novel de novo mutation found in a patient with CMT2C phenotype. The family with R232C mutation had individuals with and without vocal cord and diaphragm involvement. Both mutant TRPV4 proteins had normal subcellular localization in HEK293 and HeLa cells. Cells transfected with R232C and R316H displayed increased intracellular Ca(2+) levels and reversible cell death by the TRPV channel antagonist, ruthenium red. CONCLUSION: TRPV4 ankyrin domain alterations including a novel de novo mutation cause axonal CMT2. Individuals with the same mutation may have nondistinct CMT2 or have phenotypic CMT2C with vocal cord paresis. Reversible hypercalcemic gain-of-function of mutant TRPV4 instead of loss-of-function appears to be pathologically important. The reversibility of cell death by channel blockade provides an attractive area of investigation in consideration of treatable axonal degeneration.

Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.

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 approximately 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.

Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.

Age and founder effect of SOD1 A4V mutation causing ALS.

BACKGROUND: 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. METHODS: 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+. RESULTS: 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). CONCLUSIONS: North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400-500 years ago.

Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.

BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. METHODS AND FINDINGS: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

Lack of association of VEGF promoter polymorphisms with sporadic ALS.

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.

Paraoxonase cluster polymorphisms are associated with sporadic ALS.

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.