RESUMO
Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.
Assuntos
Esclerose Lateral Amiotrófica , Cafeína , Citocromo P-450 CYP1A2 , Progressão da Doença , Polimorfismo de Nucleotídeo Único , Receptor A2A de Adenosina , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Receptor A2A de Adenosina/genética , Citocromo P-450 CYP1A2/genética , Cognição/fisiologia , Cognição/efeitos dos fármacos , Estudos Prospectivos , Citocromo P-450 CYP1A1/genética , Receptores de Hidrocarboneto Arílico/genética , Adulto , Disfunção Cognitiva/genética , Riluzol/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice BásicosRESUMO
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.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Mutação , Idoso , Análise por Conglomerados , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Feminino , Testes Genéticos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Proteína FUS de Ligação a RNA/genética , Superóxido Dismutase-1/genéticaRESUMO
In dc magnetrons the electrons emitted from the cathode may return there due to the applied magnetic field. When that happens, they can be recaptured or reflected back into the discharge, depending on the value of the reflection coefficient (RC). A 2d3v (two-dimensional in coordinate and three-dimensional in velocity space) particle-in-cell-Monte Carlo model, including an external circuit, is developed to determine the role of the electron recapture in the discharge processes. The detailed discharge structure as a function of RC for two pressures (4 and 25 mtorr) is studied. The importance of electron recapture is clearly manifested, especially at low pressures. The results indicate that the discharge characteristics are dramatically changed with varying RC between 0 and 1. Thus, the electron recapture at the cathode appears to be a significant mechanism in magnetron discharges and RC a very important parameter in their correct quantitative description that should be dealt with cautiously.
RESUMO
Atomic layer deposition (ALD) is a thin film deposition technique that is based on alternating and saturating surface reactions of two or more gaseous precursors. The excellent conformality of ALD thin films can be exploited for sealing defects in coatings made by other techniques. Here the corrosion protection properties of hard CrN and diamond-like carbon (DLC) coatings on low alloy steel were improved by ALD sealing with 50 nm thick layers consisting of Al2O3 and Ta2O5 nanolaminates or mixtures. In cross sectional images the ALD layers were found to follow the surface morphology of the CrN coatings uniformly. Furthermore, ALD growth into the pinholes of the CrN coating was verified. In electrochemical measurements the ALD sealing was found to decrease the current density of the CrN coated steel by over 2 orders of magnitude. The neutral salt spray (NSS) durability was also improved: on the best samples the appearance of corrosion spots was delayed from 2 to 168 h. On DLC coatings the adhesion of the ALD sealing layers was weaker, but still clear improvement in NSS durability was achieved indicating sealing of the pinholes.
RESUMO
Tangier disease (TD) (OMIM#205400) is a rare autosomal recessive disorder resulting from mutations in the ABCA1 gene, leading to decreased levels of plasma high-density lipoproteins (HDL). Peripheral neuropathy is a common finding in this disease, and may present as relapsing/remitting mono/polyneuropathies or as syringomyelia-like neuropathy. We retrospectively analyzed four patients, and report here their clinical, biological, electrophysiological, imaging, and genetic findings. Three patients had a typical pseudosyringomyelic neuropathy including facial diplegia, but asymmetrical onset was observed in one patient who had first been misdiagnosed with Lewis-Sumner syndrome. Electrophysiological pattern was heterogeneous, showing both signs of demyelination and axonal degeneration. Truncating mutations of the ABCA1 gene, including two previously undescribed mutations, were constantly found. Atypical symptom onset and demyelinating features on electrophysiological examination can be misleading in case of pseudosyringomyelic neuropathy. These reports illustrate two different neurological phenotypes in TD, namely the pseudosyringomyelic type and the Lewis-Sumner-like type, and advocate for a systematic assessment of lipid profile including HDL cholesterol in demyelinating neuropathies.
Assuntos
Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Doença de Tangier/diagnóstico , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Fenômenos Eletrofisiológicos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Estudos Retrospectivos , Doença de Tangier/complicações , Doença de Tangier/fisiopatologiaRESUMO
The aetiology of sporadic ALS is still unknown. Links with several environmental factors have been suggested, and some epidemiological studies have shown an increased incidence of ALS in rural populations. This study was designed to investigate risk exposures in a well-delimited rural population and to assess whether rural residency or occupations, such as farming, were associated with an increased risk of developing ALS. A prospective case-control-study of 108 sporadic ALS cases matched by age and sex to 122 controls was performed in Brittany from 2006 to 2008. A strong association was found between agricultural activity and ALS (odds ratio: 2.919; p = 0.01), while rural residence itself did not influence the risk of the disease. Bulbar forms of onset prevailed among agricultural workers as compared with other occupations (55 vs. 26%; p = 0.009). These results suggest a potential role of exposure to agricultural chemicals or contact with animals linked to agricultural work. The prevalence of bulbar forms of onset in agricultural workers has not been reported before. In addition to variable methodological approaches, differences in agricultural practices could explain the discrepancy between these findings and other studies.
Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Exposição Ambiental , População Rural , Adulto , Idoso , Idoso de 80 Anos ou mais , Agricultura , Estudos de Casos e Controles , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Exposição Ocupacional , Prevalência , Fatores de RiscoRESUMO
A 60-year-old woman presented with a 1-week progressive limb weakness and an areflexic tetraparesis. Both neurophysiological and cerebrospinal fluid examinations were consistent with diagnosis of Guillain-Barré syndrome (GBS) and a treatment by intravenous immunoglobulin over a 5-day period was started. At the end of the treatment, the patient suffered from an acute coronary syndrome (ACS) without stenosis at coronary arteriography. Left ventriculography showed segmental wall motion abnormalities with apical akinesis contrasting with hyperkinesis in basal segments, with a depressed left ventricular ejection fraction at 45%. Cardiac magnetic resonance imaging excluded the diagnosis of myocarditis. A diagnosis of "transient left ventricular apical ballooning syndrome" or "Takotsubo" syndrome was then made and a treatment by angiotensin-converting enzyme inhibitor and beta-blocker was introduced. Left ventricular dysfunction and electrocardiogram normalized within two weeks and the patient remained free from cardiovascular events at one year of follow-up. This cardiomyopathy is a recently known and now commonly diagnosed reversible systolic dysfunction mimicking ACS and is secondary to physical or emotional stress affecting mainly post-menopausal women. Electrocardiographic and echocardiographic abnormalities are often regressive in days or weeks, and rarely responsible for complications. This observation supports clinical evidence that electrocardiographic changes in GBS can be linked to Takotsubo syndrome, by means of the stressful trigger of GBS occurrence. This reversible cardiomyopathy needs adequate management and specific therapeutic strategies. Therefore, trans-thoracic echocardiography should be systematically performed when repolarisation abnormalities are present in this disease to rule out a Takotsubo syndrome, even in asymptomatic patients.
Assuntos
Síndrome de Guillain-Barré/diagnóstico , Cardiomiopatia de Takotsubo/diagnóstico , Diagnóstico Diferencial , Eletrocardiografia , Feminino , Seguimentos , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/tratamento farmacológico , Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Miocárdio/patologia , Disautonomias Primárias/diagnóstico , Disautonomias Primárias/patologia , Cardiomiopatia de Takotsubo/complicações , Cardiomiopatia de Takotsubo/tratamento farmacológico , Resultado do TratamentoRESUMO
The paper presents a lidar study of the aerosol structure in the planetary boundary layer in the case of radiation fog and haze. A conceptual model of the dynamics of the depolarization coefficient profile during the mixing layer development, taking into account the presence of a multilayered inversions and radiation fogs, is proposed. Various techniques are employed in the processing of the lidar signal in order to determine the mixing layer height as well as more details of the aerosol structure in the low atmosphere, namely, finding the maximum of the signal returned from the lowest temperature inversion, the crossing point of the S function's first derivative with the x axis, and profiles of the depolarization ratio. After the complete destruction of the stable stratification, a low constant value of the depolarization ratio within the newly formed mixing layer is being observed. The study of stable boundary layer disintegration and convective boundary layer formation in the presence of fogs and/or clouds is of both scientific and practical significance in what concerns the protection of the environment and the aviation meteorology.