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The occurrence of overweight and obesity among individuals with Autism Spectrum Disorder (ASD) has become a worldwide epidemic. However, there is limited research on this topic in the Lebanese population. Therefore, this study aimed to assess the differences in anthropometric measurements and body composition variables among Lebanese children, pre-adolescents, and adolescents diagnosed with ASD in contrast to typically developing peers across various developmental stages. Additionally, it aimed to investigate the prevalence of overweight and obesity within this population. A total of 86 participants with ASD and 86 controls were involved in this case-control study, conducted between June 2022 and June 2023. Anthropometric measurements and body composition variables were assessed, followed by statistical analyses to examine the differences between these two groups. The results revealed a significantly higher prevalence of overweight and obesity among individuals with ASD, particularly evident during childhood and pre-adolescence. Additionally, this group exhibited a higher body fat mass and total body fat percentage compared to controls. However, there were no significant differences observed between the two groups during adolescence. These findings emphasize the significance of monitoring and addressing weight status in individuals with ASD to improve their overall health outcomes. Future research directions could focus on investigating the underlying mechanisms contributing to the heightened prevalence of overweight and obesity in this population, ultimately enhancing their quality of life and well-being.
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Transtorno do Espectro Autista , Criança , Humanos , Adolescente , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/diagnóstico , Sobrepeso/epidemiologia , Estudos de Casos e Controles , Líbano/epidemiologia , Qualidade de Vida , Obesidade/epidemiologia , Composição CorporalRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative motor neuron disease and remains misunderstood with a difficult diagnosis and prognosis. The implication of the immune system is recognized in ALS pathophysiology, hence the interest in leucocyte count as lymphocytes and neutrophils. The neutrophil-to-lymphocyte ratio (NLR) has recently been used as a prognosis factor to assess the progression of ALS. Thus, the aim of this study was to analyze the evolution of the NLR during disease evolution in a French cohort of ALS patients and its relation with survival. In this monocentric retrospective study, clinical parameters and NLR were collected in ALS patients followed at the University Hospital of Tours (France). ALS patients were subdivided into three groups regarding their NLR value at inclusion: group 1 (NLR < 2); group 2 (NLR: 2-3); group 3 (NLR > 3). A comparison of qualitative and quantitative clinical and biological variables between NLR groups was performed. Then, Cox regressions were carried out to determine the association of NLR with survival. We observed a significant correlation of NLR with ALSFRS-r score (p < 0.0001) and with vital forced capacity (p = 0.0004) at inclusion. We observed that increased NLR at diagnosis is associated with decreased ALS patients' survival.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Neutrófilos , Estudos Retrospectivos , Prognóstico , Progressão da Doença , LinfócitosRESUMO
Current evidence increasingly supports CYP2C19 genotype-guided P2Y12 inhibitor selection. Clopidogrel remains the most prescribed P2Y12 inhibitor despite higher readmission rates than those of more efficacious third-generation P2Y12 inhibitors. It remains unclear whether pharmacogenetically (PGx)-guided antiplatelet therapy directly reduces readmissions after percutaneous coronary intervention (PCI). A single-center retrospective observational cohort study at a tertiary academic medical center was conducted. Patients receiving CYP2C19 genotyping after PCI were included and stratified into 2 groups (PGx-optimal vs PGx-suboptimal P2Y12 inhibitor prescribed) on the basis of CPIC (Clinical Pharmacogenetics Implementation Consortium) recommendations. Primary outcomes included 30-day and 90-day readmissions after index PCI. Most patients (78%) were of non-European ancestry. Among patients receiving PGx-optimal therapy, 50% had acute coronary syndromes whereas 61% receiving PGx-suboptimal therapy had stable coronary artery disease. Comparable 30-day (12% vs 10%, p = 0.481) and 90-day readmission rates (24% vs 28%, p = 0.323) were observed between patients receiving PGx-optimal or PGx-suboptimal therapies. PGx-optimal therapy was associated with fewer emergency department visits (3.4% vs 4.0%, p = 0.021) within 30 days, and patients initially prescribed PGx-suboptimal therapy were switched more often to PGx-optimal therapy during a readmission than were patients prescribed PGx-suboptimal antiplatelet therapy (p <0.001). In conclusion, CYP2C19 genotype-guided P2Y12 inhibitor therapy did not improve 30- and 90-day all-cause readmission rates in a predominantly non-European population. However, P2Y12 inhibitor therapy became concordant with CYP2C19 genotype in approximately half of patients during the first readmission after PCI, which may present further opportunities to revisit and optimize dual antiplatelet therapy in patients who undergo PCI.
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Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/uso terapêutico , Readmissão do Paciente , Intervenção Coronária Percutânea/efeitos adversos , Estudos Retrospectivos , Genótipo , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/cirurgiaRESUMO
Central nervous system (CNS) barrier impairment has been reported in amyotrophic lateral sclerosis (ALS), highlighting its potential significance in the disease. In this context, we aim to shed light on its involvement in the disease, by determining albumin quotient (QAlb) at the time of diagnosis of ALS in a large cohort of patients. Patients from the university hospital of Tours (n = 307) were included in this monocentric, retrospective study. In total, 92 patients (30%) had elevated QAlb levels. This percentage was higher in males (43%) than in females (15%). Interestingly, QAlb was not associated with age of onset, age at sampling or diagnostic delay. However, we found an association with ALS functional rating scale-revised (ALSFRS-r) at diagnosis but this was significant only in males. The QAlb levels were not linked to the presence of a pathogenic mutation. Finally, we performed a multivariate survival analysis and found that QAlb was significantly associated with survival in male patients (HR = 2.3, 95% CI = 1.2-4.3, p = 0.009). A longitudinal evaluation of markers of barrier impairment, in combination with inflammatory biomarkers, could give insight into the involvement of CNS barrier impairment in the pathogenesis of the disease. The gender difference might guide the development of new drugs and help personalise the treatment of ALS.
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Esclerose Lateral Amiotrófica , Feminino , Humanos , Masculino , Esclerose Lateral Amiotrófica/genética , Estudos Retrospectivos , Fatores Sexuais , Diagnóstico Tardio , Sistema Nervoso CentralRESUMO
BACKGROUND: Forced vital capacity (FVC) remains difficult to determine for some patients suffering from amyotrophic lateral sclerosis (ALS) due to the rapid progression of the disease. Arterial blood gas (ABG) parameters could represent a valuable alternative. The aim of this study was therefore to evaluate the correlation between ABG parameters and FVC, along with the prognostic ability of ABG parameters, in a large cohort of ALS patients. METHODS: ALS patients (n=302) with FVC and ABG parameters available at diagnosis were included. Correlations between ABG parameters and FVC were evaluated. Cox regression was then carried out to determine the association of each parameter (ABG and clinical data) with survival. Finally, receiver operating characteristic (ROC) curves were built to predict the survival of ALS. RESULTS: Bicarbonates (HCO3 - ), oxygen partial pressure (pO2 ), carbon dioxide partial pressure (pCO2 ), base excess (BE), oxygen saturation and oxyhemoglobin were significantly correlated with FVC both in patients with spinal or bulbar onset. Univariate Cox regression showed that HCO3 - and BE were associated with survival but only in spinal forms. ABG parameters predicted the survival of ALS with a similar performance to FVC, HCO3 - being the parameter with the highest area under the curve. CONCLUSIONS: Our results suggest that there is an interest in conducting a longitudinal evaluation throughout disease progression to confirm the equal performances of FVC and ABG. This study highlights the benefits of performing ABG analysis that could be used as an interesting alternative to FVC when spirometry cannot be performed.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/complicações , Prognóstico , Gasometria , Progressão da DoençaRESUMO
The daily functioning and overall well-being of people with ASD depends largely on understanding how the wider public views ASD. Indeed, an increased level of ASD knowledge in the general population may result in earlier diagnosis, earlier intervention, and better overall outcomes. The present study aimed to examine the current state of ASD knowledge, beliefs, and sources of information in a Lebanese general population sample, to identify the factors that could influence this knowledge. A total of 500 participants were involved in this cross-sectional study, which was conducted in Lebanon between May 2022 and August 2022 using the Autism Spectrum Knowledge scale, General Population version (ASKSG). Overall, the participants' understanding of autism spectrum disorder was low, with a mean score of 13.8 (6.69) out of 32, or 43.1%. The highest knowledge score was found for items related to knowledge of the symptoms and associated behaviors (52%). However, the level of knowledge regarding the etiology and prevalence, assessment and diagnosis, treatment, outcomes, and prognosis of the disease was low (29%, 39.2%, 46%, and 43.4%, respectively). Moreover, age, gender, place of residence, sources of information, and ASD case were all statistically significant predictors of ASD knowledge (p < 0.001, p < 0.001, and p = 0.012, p < 0.001, p < 0.001, respectively). The general public in Lebanon perceive a lack of awareness and insufficient knowledge regarding ASD. This results in delayed identification and intervention, leading to unsatisfactory outcomes in patients. Raising awareness about autism among parents, teachers, and healthcare professionals should be a top priority.
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Transtorno do Espectro Autista , Transtorno Autístico , Pessoal de Educação , Humanos , Adulto , Transtorno do Espectro Autista/epidemiologia , Estudos Transversais , PrevalênciaRESUMO
Autism Spectrum Disorder (ASD) has become a major public health concern due to its rapidly rising incidence over the past few years. Disturbances in folate or methionine metabolism have been identified in many individuals with ASD, suggesting that the folate-methionine cycle may play an essential role in the pathogenesis of autism. Thus, changes in metabolite concentrations associated with this cycle could be used as potential biomarkers and therapeutic targets for ASD. The aim of this systematic review is to elucidate the perturbations of this cycle and the possible interventions that may be proposed in this context. Several studies have shown that high levels of homocysteine and low levels of vitamins B12 and folate are associated with ASD. These changes in serum metabolites are influenced by poor diet. In fact, children with ASD tend to eat selectively, which could compromise the quality of their diet and result in nutrient deficiencies. Moreover, these disturbances may also be caused by genetic predispositions such as polymorphisms of the MTHFR gene. Few studies have demonstrated the beneficial effects of the use of nutritional supplements in treating ASD children. Therefore, larger, well-structured studies are recommended to examine the impact of vitamin B12 and folate supplementation on homocysteine levels.
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Transtorno do Espectro Autista , Ácido Fólico , Criança , Humanos , Ácido Fólico/uso terapêutico , Metionina , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/genética , Vitamina B 12/uso terapêutico , Suplementos Nutricionais , RacemetioninaRESUMO
The ubiquitin pathway, one of the main actors regulating cell signaling processes and cellular protein homeostasis, is directly involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). We first analyzed, by a next-generation sequencing (NGS) strategy, a series of genes of the ubiquitin pathway in two cohorts of familial and sporadic ALS patients comprising 176 ALS patients. We identified several pathogenic variants in different genes of this ubiquitin pathway already described in ALS, such as FUS, CCNF and UBQLN2. Other variants of interest were discovered in new genes studied in this disease, in particular in the HECW1 gene. We have shown that the HECT E3 ligase called NEDL1, encoded by the HECW1 gene, is expressed in neurons, mainly in their somas. Its overexpression is associated with increased cell death in vitro and, very interestingly, with the cytoplasmic mislocalization of TDP-43, a major protein involved in ALS. These results give new support for the role of the ubiquitin pathway in ALS, and suggest further studies of the HECW1 gene and its protein NEDL1 in the pathophysiology of ALS.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismo , Neurônios/metabolismo , Transdução de Sinais/genética , Proteínas Relacionadas à Autofagia/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
There is currently no diagnostic or prognostic biomarker available in clinical practice for Amyotrophic Lateral Sclerosis (ALS). The objective of this study was to monitor a combination of various inflammatory markers, lipids, and apolipoproteins alterations in ALS patients at the time of diagnosis, to assess their role as early diagnostic or prognostic biomarker candidates. C-reactive protein, orosomucoid, prealbumin, calprotectin, lipids and apoliproteins were determined in the blood of all subjects (25 ALS patients, 23 controls) as routinely performed in our laboratory. Inflammatory mediators were evaluated by a bead-based multiplex assay. A two-step approach was used for each analytical strategy: univariate analysis followed by multivariate analysis. Eight features were significantly different between ALS patients and controls, sometimes with important fold changes. The supervised Partial least Squares Discriminant Analysis separated ALS and controls with great accuracy (94 %) and the permutation test was significant (p < 0.01), ensuring the robustness of the model. The prediction model leads to a mean sensitivity and specificity of 90 (+/- 10) and 78 (+/- 10) %, respectively, with a mean predictive positive value and negative predictive value of 80 (+/- 8.9) and 89 (+/- 11.8) %, respectively. However, the models did not discriminate subgroups of ALS patients based on ALS characteristics. This study highlights the usefulness of evaluating a combination of multiple pathways rather than focusing on a single target. These promising results suggest the need for the longitudinal monitoring of these candidates to determine their role in disease evolution.
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Esclerose Lateral Amiotrófica , Esclerose Lateral Amiotrófica/diagnóstico , Apolipoproteínas , Biomarcadores , Proteína C-Reativa , Diagnóstico Precoce , Humanos , Mediadores da Inflamação , Complexo Antígeno L1 Leucocitário , Lipídeos , Lipoproteínas , Orosomucoide , Pré-AlbuminaRESUMO
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that still lacks an efficient therapy. The barriers between the central nervous system (CNS) and the blood represent a major limiting factor to the development of drugs for CNS diseases, including ALS. Alterations of the blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB) have been reported in this disease but still require further investigations. Interestingly, these alterations might be involved in the complex etiology and pathogenesis of ALS. Moreover, they can have potential consequences on the diffusion of candidate drugs across the brain. The development of techniques to bypass these barriers is continuously evolving and might open the door for personalized medical approaches. Therefore, identifying robust and non-invasive markers of BBB and BSCB alterations can help distinguish different subgroups of patients, such as those in whom barrier disruption can negatively affect the delivery of drugs to their CNS targets. The restoration of CNS barriers using innovative therapies could consequently present the advantage of both alleviating the disease progression and optimizing the safety and efficiency of ALS-specific therapies.
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Diverse biomarkers and pathological alterations have been found in muscle of patients with Amyotrophic lateral sclerosis (ALS), but the relation between such alterations and dysfunction in energetic metabolism remains to be investigated. We established the metabolome of muscle and serum of ALS patients and correlated these findings with the clinical status and pathological alterations observed in the muscle. We obtained data from 20 controls and 17 ALS patients (disease duration: 9.4 ± 6.8 months). Multivariate metabolomics analysis identified a distinct serum metabolome for ALS compared to controls (p-CV-ANOVA < 0.035) and revealed an excellent discriminant profile for muscle metabolome (p-CV-ANOVA < 0.0012). Citramalate was discriminant for both muscle and serum. High lauroylcarnitine levels in muscle were associated with low Forced Vital Capacity. Transcriptomics analysis of key antioxidant enzymes showed an upregulation of SOD3 (p = 0.0017) and GLRX2(1) (p = 0.0022) in ALS muscle. Analysis of mitochondrial enzymatic activity in muscle revealed higher complex II/CS (p = 0.04) and lower LDH (p = 0.03) activity in ALS than in controls. Our study showed, for the first time, a global dysfunction in the muscle of early-stage ALS patients. Furthermore, we identified novel metabolites to be employed as biomarkers for diagnosis and prognosis of ALS patients.
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The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons in the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them.
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Doença de Parkinson , Ubiquitina-Proteína Ligases , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
Iron metabolism is tightly linked to infectious and inflammatory signals through hepcidin synthesis. To date, iron homeostasis during SARS-CoV-2 infection has not yet been described. The aim of this study is to characterize the hepcidin and erythroid regulators (growth differentiation factor 15 (GDF-15) and erythroferrone (ERFE)) by measuring concentrations in plasma in context of COVID-19 disease.We performed a single-center observational study of patients with COVID-19 to evaluate concentrations of main regulatory proteins involved in iron homeostasis, namely: hepcidin, ERFE and GDF-15. SARS-CoV-2 infection (COVID-19+) was defined by a positive RT-PCR. Sixteen patients with COVID-19+ were gender-matched and age-matched to 16 patients with a sepsis unrelated to SARS-CoV-2 (COVID-19-) and were compared with non-parametric statistic test.Clinical and hematological parameters, plasma iron, transferrin, transferrin saturation, ferritin, soluble transferrin receptor and C reactive protein were not statistically different between both groups. Median plasma hepcidin concentrations were higher in the COVID-19+ group (44.1 (IQR 16.55-70.48) vs 14.2 (IQR 5.95-18.98) nmol/L, p=0.003), while median ERFE and GDF-15 concentrations were lower in the COVID-19+ group (0.16 (IQR 0.01-0.73) vs 0.89 (IQR 0.19-3.82) ng/mL, p=0.035; 2003 (IQR 1355-2447) vs 4713 (IQR 2082-7774) pg/mL, p=0015), respectively) compared with the COVID-19- group.This is the first study reporting lower ERFE and GDF-15 median concentrations in patients with COVID-19+ compared with patients with COVID-19-, associated with an increased median concentration of hepcidin in the COVID-19+ group compared with COVID19- group.
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COVID-19 , Hepcidinas , COVID-19/metabolismo , Fator 15 de Diferenciação de Crescimento , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , SARS-CoV-2 , Transferrina/metabolismoRESUMO
In our previous study, in which array CGH was used on 19 Lebanese ASD subjects and their parents, we identified rare copy number variants (CNVs) in 14 subjects. The five remaining subjects did not show any CNVs related to autism spectrum disorders (ASD). In the present complementary study, we applied whole-exome sequencing (WES), which allows the identification of rare genetic variations such as single nucleotide variations and small insertions/deletions, to the five negative CNV subjects. After stringent filtering of initial data on the five families, three novel genes potentially related to neurodevelopment were identified, including a de novo mutation in the MIS18BP1 gene. In addition, genes already known to be related to ASD contained sequence variations. Our findings outline the potential involvement of the novel de novo mutation in the MIS18BP1 gene in the genetic etiology and pathophysiology of ASD and highlights the genetic complexity of these disorders. Further studies with larger cohorts of subjects are needed to confirm these observations, and functional analyses need to be performed to understand the precise pathophysiology in these cases.
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Transtorno do Espectro Autista , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Exoma/genética , Humanos , Sequenciamento do ExomaRESUMO
Research in global change ecology relies heavily on global climatic grids derived from estimates of air temperature in open areas at around 2 m above the ground. These climatic grids do not reflect conditions below vegetation canopies and near the ground surface, where critical ecosystem functions occur and most terrestrial species reside. Here, we provide global maps of soil temperature and bioclimatic variables at a 1-km2 resolution for 0-5 and 5-15 cm soil depth. These maps were created by calculating the difference (i.e. offset) between in situ soil temperature measurements, based on time series from over 1200 1-km2 pixels (summarized from 8519 unique temperature sensors) across all the world's major terrestrial biomes, and coarse-grained air temperature estimates from ERA5-Land (an atmospheric reanalysis by the European Centre for Medium-Range Weather Forecasts). We show that mean annual soil temperature differs markedly from the corresponding gridded air temperature, by up to 10°C (mean = 3.0 ± 2.1°C), with substantial variation across biomes and seasons. Over the year, soils in cold and/or dry biomes are substantially warmer (+3.6 ± 2.3°C) than gridded air temperature, whereas soils in warm and humid environments are on average slightly cooler (-0.7 ± 2.3°C). The observed substantial and biome-specific offsets emphasize that the projected impacts of climate and climate change on near-surface biodiversity and ecosystem functioning are inaccurately assessed when air rather than soil temperature is used, especially in cold environments. The global soil-related bioclimatic variables provided here are an important step forward for any application in ecology and related disciplines. Nevertheless, we highlight the need to fill remaining geographic gaps by collecting more in situ measurements of microclimate conditions to further enhance the spatiotemporal resolution of global soil temperature products for ecological applications.
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Ecossistema , Solo , Mudança Climática , Microclima , TemperaturaRESUMO
OBJECTIVES: Trimethylaminuria, also known as Fish Odor Syndrome (FOS), is a condition characterized by the presence of high concentrations of trimethylamine (TMA) in urine, sweat and expired air of affected patients. Diagnosis of this benign but unpleasant disease is mainly based on clinical presentation and assessment of TMA and its metabolite, TMAO (trimethylamine-N-oxide), concentrations in urine of patients. MATERIAL AND METHODS: We here described the validation of an analytical method for measurement of TMA and TMAO in urine using nuclear magnetic resonance (NMR) according to the specifications of the ISO 15189 norm. We used a fast validation protocol, based exactitude profile method, enabling to determine accuracy, intra and inter-day precision from a limited number of samples. RESULTS: The linearity was established from 2.5 to 100 mg/L for TMA measurement and from 10 to 1000 mg/L for TMAO measurement, with good analytical performances i.e. accuracy, intra and inter-day precision. We also report a case diagnose for FOS from this method. CONCLUSIONS: This method validation ensures the robustness of NMR in routine use for diagnosis of trimethylaminuria, as part of the reference center for inherited metabolic diseases at the Tours hospital.
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Erros Inatos do Metabolismo/urina , Metilaminas/urina , Calibragem , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Erros Inatos do Metabolismo/diagnóstico , Pessoa de Meia-Idade , Controle de QualidadeRESUMO
The aim of this study was to evaluate the kynurenine pathway (KP) and amino acids profile, using mass spectrometry, in the cerebrospinal fluid (CSF) of 42 amyotrophic lateral sclerosis (ALS) patients at the diagnosis and 40 controls to detect early disorders of these pathways. Diagnostic and predictive ability (based on weight loss, forced vital capacity, ALS Functional Rating Scale-Revised evolution over 12 months, and survival time) of these metabolites were evaluated using univariate followed by supervised multivariate analysis. The multivariate model between ALS and controls was not significant but highlighted some KP metabolites (kynurenine (KYN), kynurenic acid (KYNA), 3-Hydroxynurenine (3-HK)/KYNA ratio), and amino acids (Lysine, asparagine) as involved in the discrimination between groups (accuracy 62%). It revealed a probable KP impairment toward neurotoxicity in ALS patients and in bulbar forms. Regarding the prognostic effect of metabolites, 12 were commonly discriminant for at least 3 of 4 disease evolution criteria. This investigation was crucial as it did not show significant changes in CSF concentrations of amino acids and KP intermediates in early ALS evolution. However, trends of KP modifications suggest further exploration. The unclear kinetics of neuroinflammation linked to KP support the interest in exploring these pathways during disease evolution through a longitudinal strategy.
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Aminoácidos/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/fisiopatologia , Biomarcadores/líquido cefalorraquidiano , Cinurenina/líquido cefalorraquidiano , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Esclerose Lateral Amiotrófica/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais , Capacidade VitalRESUMO
Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.
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Esclerose Lateral Amiotrófica/metabolismo , Regulação da Expressão Gênica , Modelos Neurológicos , Neurônios Motores/metabolismo , Estresse Oxidativo , Proteína SUMO-1/biossíntese , Superóxido Dismutase-1/metabolismo , Ubiquitina/biossíntese , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Linhagem Celular , Humanos , Neurônios Motores/patologia , Mutação , Proteína SUMO-1/genética , Superóxido Dismutase-1/genética , Ubiquitina/genéticaRESUMO
OBJECTIVES: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. METHODS: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. RESULTS: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. CONCLUSION: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.