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BACKGROUND: Exergaming is a fun, engaging, and interactive form of exercising that may help overcome some of the traditional exercise barriers and help improve adherence on the part of older adults, providing therapeutic applications for balance recovery and functional mobility. The purpose of this systematic review is to summarize the effects of exergames on mobility and balance in older adults. METHODS: The PRISMA guidelines for systematic reviews were followed. The following databases were searched from inception to August 2019: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PEDro, CINAHL, and INSPEC. We selected randomized controlled trials that assessed the effects of exergames on balance or mobility of older adults without neurological conditions, in comparison to no intervention or health education. Two review authors independently screened the trials' titles and abstracts and identified trials for inclusion according to the eligibility criteria. An almost perfect agreement between the authors was observed with respect to interrater reliability of trial selection (kappa = 0.84; P < 0.001). We performed descriptive analysis of the quantitative data to summarize the evidence. Meta-analysis was carried out using RevMan. A random effects model was used to compute the pooled prevalence with 95% confidence intervals. RESULTS: After screening 822 records, 12 trials comparing exergames with no intervention were included. A total of 1520 older adults participated in the studies, with a mean age of 76 ± 6 years for the experimental group and 76 ± 5 years for the control group. Quantitative synthesis showed significant improvements in balance and mobility based on the center of pressure sway (SMD = - 0.89; 95%CI = - 1.26 to - 0.51; P = 0.0001; I2 = 58%), Berg Balance Scale (MD = 2.15; 95%CI = 1.77 to 2.56; P = 0.0001; I2 = 96%), and on Timed Up and Go test (MD = - 2.48; 95%CI = - 3.83 to - 1.12; P = 0.0003; I2 = 0). CONCLUSIONS: Exergames improved balance and mobility in older adults without neurological disorders and motivate patients to keep performing balance exercises. High quality studies with standardized assessment protocols are necessary to improve the strength of the evidence.
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Terapia por Ejercicio , Equilibrio Postural , Anciano , Anciano de 80 o más Años , Ejercicio Físico , Humanos , Reproducibilidad de los Resultados , Estudios de Tiempo y MovimientoRESUMEN
Anastrepha fraterculus (Wied.) is the main insect pest of table grapes (Vitis vinifera) in the Southern Region of Brazil. In this study, we aimed to investigate the effect of fruit puncturing by adult females and larval infestation by A. fraterculus on the occurrence of bunch rot disease in the grape (cultivar "Itália") by evaluating grapes (a) punctured for oviposition by females of A. fraterculus, sterilized in laboratory with novaluron (40 mg L(-1)) and further spray-inoculated separately with Botrytis cinerea (1 × 10(6) conidia mL(-1)), Glomerella cingulata (1 × 10(6) conidia mL(-1)), and bacteria and yeast that cause sour rot (1 × 10(5) cells mL(-1)), (b) grapes punctured for oviposition by non-sterilized females with pathogen spraying, (c) grapes with mechanical wounds and pathogen spraying, (d) grapes with no wounds and with pathogen spraying, (e) grapes punctured for oviposition by A. fraterculus chemically sterilized in laboratory with novaluron, (f) grapes punctured for oviposition by A. fraterculus non-sterilized in laboratory with novaluron, (g) grapes with mechanical wounds, and (h) grapes with no sterilization or pathogen spraying. Our data indicated that the mechanical and oviposition wounds caused by A. fraterculus increased the percentage of grapes infected by B. cinerea, G. cingulata, and microorganisms of acid rot. The grape puncturing by A. fraterculus and the mechanical wound allows the penetration of B. cinerea and microorganisms leading to acid rot. We conclude that the fruit fly A. fraterculus may facilitate phytopathogens penetration leading to bunch rots in the table grape Itália.
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Enfermedades de las Plantas/etiología , Tephritidae , Vitis , Animales , Brasil , Femenino , Frutas , IncidenciaRESUMEN
OBJECTIVE: The objective of this paper is to examine the role of place of residency in the expression and outcomes of systemic lupus erythematosus (SLE) in a multi-ethnic Latin American cohort. PATIENTS AND METHODS: SLE patients (< two years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses. RESULTS: Of 1426 patients, 122 (8.6%) were rural residents. Their median ages (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) were African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in rural and urban patients. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06-2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00-3.11). CONCLUSIONS: Rural residency associates with Mestizo ethnicity, lower socioeconomic status and renal disease occurrence. It also plays a role in disease activity at diagnosis and kidney involvement but not on the other end-points examined.
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Lupus Eritematoso Sistémico/etnología , Grupos Raciales/estadística & datos numéricos , Características de la Residencia/estadística & datos numéricos , Salud Rural/estadística & datos numéricos , Salud Urbana/estadística & datos numéricos , Adulto , Factores de Edad , Indio Americano o Nativo de Alaska/estadística & datos numéricos , Población Negra/estadística & datos numéricos , Distribución de Chi-Cuadrado , Comorbilidad , Ciclofosfamida/uso terapéutico , Progresión de la Enfermedad , Escolaridad , Femenino , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/etnología , Humanos , Hipertensión/etnología , Inmunosupresores/uso terapéutico , América Latina/epidemiología , Modelos Logísticos , Estudios Longitudinales , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/terapia , Nefritis Lúpica/etnología , Masculino , Pacientes no Asegurados/etnología , Metotrexato/uso terapéutico , Análisis Multivariante , Oportunidad Relativa , Pronóstico , Diálisis Renal , Factores de Riesgo , Factores Socioeconómicos , Factores de Tiempo , Población Blanca , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: The p38 kinase regulates the release of proinflammatory cytokines including tumour-necrosis factor-alpha (TNFalpha) and is regarded as a potential therapeutic target in rheumatoid arthritis (RA). Using the novel p38 inhibitor Org 48762-0, we investigated the therapeutic potential of p38 inhibition and compared this to anti-mouse (m)TNFalpha antibody treatment in murine collagen-induced arthritis (CIA). EXPERIMENTAL APPROACH: Pharmacological profiles of Org 48762-0 were characterized in kinase assays, cellular assays and in lipopolysaccharide (LPS)-induced inflammation in mice. The effects of Org 48762-0 and of mTNFalpha-neutralization on established arthritis were examined in murine CIA. KEY RESULTS: Org 48762-0 potently inhibited p38alpha kinase with a high degree of kinase selectivity. In cellular assays, Org 48762-0 reduced LPS-induced TNFalpha release. Oral administration of Org 48762-0 in mice showed drug-like pharmacokinetic properties and inhibited LPS-induced cytokine production. These pharmacological characteristics of Org 48762-0 prompted a comparison of therapeutic efficacy with mTNFalpha-neutralization in CIA. Org 48762-0 and anti-mTNFalpha antibody treatment equally inhibited development of arthritis when evaluated macroscopically. Radiological analyses revealed protection against bone damage for both treatments, although statistical difference was reached with Org 48762-0 treatment only. Further, micro-computed tomographical and histopathological analyses confirmed the protective effects of Org 48762-0 on joint damage. CONCLUSIONS AND IMPLICATIONS: Pharmacological targeting of p38 kinase provided good protection against joint tissue damage in CIA. In our experiments, neutralization of mTNFalpha produced less prominent suppression of bone damage. Our data suggest a therapeutic potential for selective and potent p38 inhibitors in RA.
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Anticuerpos Bloqueadores/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Piridinas/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Antiinflamatorios/uso terapéutico , Artritis Experimental/patología , Western Blotting , Cartílago/patología , Endotoxemia/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Femenino , Inflamación/inducido químicamente , Lipopolisacáridos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Prednisolona/uso terapéutico , Especificidad por Sustrato , Tomografía Computarizada por Rayos XRESUMEN
A farinha da casca de maracujá é rica em uma fibra solúvel chamada pectina. Para avaliar o efeito dessa farinha na redução do colesterol foi realizado um estudo clínico piloto com dezenove mulheres, com idade entre 30 e 60 anos e apresentando hipercolesterolemia (colesterol > 200 mg/dL). Elas foram tratadas diariamente com 30 g da farinha da casca de maracujá por 60 dias. Após esse tempo foi observada uma redução estatisticamente significante (p < 0,05) nos níveis colesterol total (p = 0,00000) e colesterol LDL (p = 0,01193). Os resultados sugerem que a farinha da casca de maracujá seja utilizada na alimentação humana, juntamente com os alimentos, ou como matéria prima na produção de outros produtos, com o objetivo de reduzir o colesterol.
The flour of the passion fruit peel is rich in a soluble fiber called pectin. In order to evaluate the effect of this flour on cholesterol reduction, a pilot clinical study, was carried out with nineteen women, aged between 30 and 60 years, all of whom presented high cholesterol level (cholesterol > 200 mg/dL). The treatment consisted of daily doses of 30 g of the flour during 60 days. At the end of the 60 days it was observed a statistical reduction (p < 0.05) of the total cholesterol (p = 0,00000) and LDL-cholesterol (p = 0,01193) levels. The results suggested that the passion fruit peel flour, rich in pectin, can be used in human diet, with a large variety of foods, or as a raw material for other products intending to reduce cholesterol levels.
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Humanos , Femenino , Colesterol , Passiflora , Passifloraceae , Pectinas/farmacologíaAsunto(s)
Humanos , Anciano , Analgésicos , Antiinflamatorios , Ejercicio Físico , Terapia por Ejercicio , Osteoartritis , Enfermedades ReumáticasRESUMEN
The synthesis and pharmacological activity of a series of bicyclic pyrazolo[1,5-a]pyrimidines as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema and air-pouch model). Modification of the pyrimidine substituents showed that 6,7-disubstitution provided the best activity and led to the identification of 3-(4-fluorophenyl)-6,7-dimethyl-2-(4-methylsulfonylphenyl)pyrazolo[1,5-a]pyrimidine (10f) as one of the most potent and selective COX-2 inhibitor in this series.
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Antiinflamatorios no Esteroideos/síntesis química , Inhibidores Enzimáticos/síntesis química , Isoenzimas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Carragenina , Línea Celular , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Edema/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Exudados y Transudados/enzimología , Humanos , Masculino , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Estómago/enzimología , Relación Estructura-ActividadRESUMEN
The accuracy of the diagnostic criteria for Friedreich's ataxia proposed by Harding and by the Quebec Cooperative Study on Friedreich's Ataxia was studied in 142 patients with progressive unremitting ataxia of autosomal recessive inheritance or sporadic occurrence. Eighty-eight patients received the molecular diagnosis of Friedreich's ataxia. Traditional diagnostic criteria are characterized by high specificity, but they yield a high number of false-negative diagnoses. We suggest three levels of diagnostic certainty: (1) possible Friedreich's ataxia, defined as sporadic or recessive progressive ataxia with (a) lower limb areflexia and dysarthria, Babinski sign, or electrocardiographic repolarization abnormalities, or (b) with lower limb retained reflexes and electrocardiographic repolarization abnormalities (95% sensitivity and 88% positive predictive value); (2) probable Friedreich's ataxia as defined by Harding's criteria (63% sensitivity and 96% positive predictive value) or by Quebec Cooperative Study on Friedreich's Ataxia criteria (63% sensitivity and 98% positive predictive value); (3) definite diagnosis, molecularly confirmed.
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Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/genética , Mutación Puntual , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Análisis Mutacional de ADN/métodos , Diagnóstico Diferencial , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estándares de Referencia , Sensibilidad y Especificidad , Expansión de Repetición de TrinucleótidoRESUMEN
El factor de transcripción nuclear NF-kB controla la expresión de diversos genes implicados en la patogénesis de la ateroclerosis. El triflusal (ácido 2-acetoxi-4-trifluorometilbenzoico) es un fármaco antiagregante que, aunque relacionado estructuralmente con la aspirina y otros salicilatos, muestra un perfil farmacológico y farmacocinético característico. Dado que recientemente se ha demostrado que los salicilatos pueden inhibir el NF-kB, el objetivo del presente estudio ha sido probar la actividad inhibitoria tanto del triflusal como de su metabolito desacetilado, el HTB, sobre la activación de NF-kB. Los resultados aquí descritos muestran que ambos compuestos, trifulsal y HTB, son inhibidores de la activación de NF-kB más potentes que la aspirina o el salicilato, y como consecuencia de ello, pueden bloquear la inducción de la síntesis de citocinas (TNF-a), quimiocinas (MCP-1), moléculas de adhesión (VCAM-1) y enzimas proinflamatorios (COX-2, NOS 2).Además, a diferencia de la aspirina, estos efectos antiinflamatorios del trifulsal se alcanzan a concentraciones similares a las obtenidas en su uso terapeútico como fármaco antiagregante plaquetario. El trifulsal puede ejercer efectos antiinflamatorios en trastornos cardiovasculares en los que se ha observado que genes controlados por el NF-kB están sobrexpresados (AU)
No disponible
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Humanos , Aspirina/farmacología , FN-kappa B/antagonistas & inhibidores , Aterosclerosis/etiología , Aspirina/farmacocinética , Aspirina/química , Salicilatos/farmacología , Quimiocinas/antagonistas & inhibidores , Moléculas de Adhesión Celular , Linfotoxina-alfa/antagonistas & inhibidoresRESUMEN
We describe two sisters with early onset gait ataxia, rapid disease progression, absent or very mild dysarthria and upper limb dysmetria, retained knee jerks in one, slight to moderate peripheral nerve involvement, and diabetes. Molecular analysis showed that they are compound heterozygotes for GAA expansion and a novel exon 5a missense mutation (R165P). This mutation appears to be associated with an atypical but not milder Friedreich ataxia phenotype.
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Ataxia de Friedreich/genética , Proteínas de Unión a Hierro , Mutación Missense , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Adulto , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Humanos , Datos de Secuencia Molecular , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Repeticiones de Trinucleótidos , FrataxinaRESUMEN
We report on 2 brothers (aged 19 and 12 years) with Marinesco-Sjögren syndrome who also had very low serum vitamin E concentrations with an absence of postprandial chylomicrons. The molecular study ruled out ataxia with isolated vitamin E deficiency, abetalipoproteinemia, and hypobetalipoproteinemia. The electron microscopy of the intestinal mucosa was consistent with a chylomicron retention disease. We speculate that both chylomicron retention disease and Marinesco-Sjögren syndrome are related to defects in a gene crucial for the assembly or secretion of the chylomicron particles, leading to very low serum levels of vitamin E.
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Quilomicrones/metabolismo , Degeneraciones Espinocerebelosas/complicaciones , Degeneraciones Espinocerebelosas/metabolismo , Deficiencia de Vitamina E/etiología , Adulto , Niño , Quilomicrones/ultraestructura , Humanos , Mucosa Intestinal/ultraestructura , Imagen por Resonancia Magnética , Masculino , Microscopía Electrónica , Degeneraciones Espinocerebelosas/sangre , Degeneraciones Espinocerebelosas/diagnóstico , Degeneraciones Espinocerebelosas/genética , Vitamina E/sangre , Deficiencia de Vitamina E/sangreRESUMEN
Among 101 patients homozygous for GAA expansion within the X25 gene, 11 from 8 families had Friedreich's ataxia with retained reflexes in the lower limbs (FARR). These patients had a lower occurrence of decreased vibration sense, pes cavus, and echocardiographic signs of left ventricular hypertrophy than the 90 FA patients with areflexia. The mean age at onset was significantly later (26.6+/-11.4 vs. 14.2+/-6.9 years), and the mean size of the smaller allele was significantly less (408+/-252 vs. 719+/-184 GAA triplets) in FARR patients. The neurophysiological findings were consistent with milder peripheral neuropathy and milder impairment of the somatosensory pathways in FARR patients.
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Ataxia de Friedreich/genética , Ataxia de Friedreich/fisiopatología , Reflejo de Estiramiento/fisiología , Adulto , Electrofisiología , Femenino , Humanos , Masculino , Sistema Nervioso/fisiopatología , Conducción Nerviosa/fisiología , Secuencias Repetitivas de Ácidos Nucleicos/genética , Sensación/fisiologíaRESUMEN
The therapeutic potential of drugs that block the induction of cyclooxygenase-2 has been emphasized. When two 4-trifluoromethyl salicylate derivatives [2-acetoxy-4-trifluoromethyl-benzoic acid (triflusal) and its deacetylated metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB)] were compared with aspirin and sodium salicylate as cyclooxygenase-2 (COX-2) inhibitors, we observed that in bacterial lipopolysaccharide-activated human blood, triflusal, aspirin, and HTB, but not sodium salicylate, inhibited COX-2-mediated prostaglandin E2 (PGE2) production (IC50 = 0.16, 0.18, 0.39, and >10 mM, respectively). However, only triflusal and aspirin inhibited purified COX-2 enzyme. To test this apparent discrepancy, we realized that HTB and triflusal (but neither aspirin nor salicylate) produced a concentration-dependent inhibition of COX-2 protein expression in peripheral human mononuclear cells. This observation was further confirmed in a rat air pouch model in vivo, in which both aspirin and triflusal inhibited PGE2 production (ID50 = 18.9 and 11.4 mg/kg p.o., respectively) but only triflusal-treated animals showed a decrease in COX-2 expression. This different behavior may be, at least in part, due to the ability of HTB and triflusal to block the activation of the transcription factor nuclear factor-kappaB to a higher extent than aspirin and sodium salicylate. Thus, in addition to inhibiting the COX-2 activity at therapeutic concentrations, triflusal is able to block through its metabolite HTB the expression of new enzyme, and hence the resumption of PGE2 synthesis. Triflusal and HTB may exert beneficial effects in processes in which de novo COX-2 expression is involved and, in a broader sense, in pathological situations in which genes under nuclear factor-kappaB control are up-regulated.
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Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/biosíntesis , Inhibidores de Agregación Plaquetaria/farmacología , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Salicilatos/farmacología , Animales , Antiinflamatorios no Esteroideos/química , Aspirina/farmacología , Células Cultivadas , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/química , Dinoprostona/biosíntesis , Dinoprostona/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Isoenzimas/genética , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Masculino , Proteínas de la Membrana , FN-kappa B/metabolismo , Prostaglandina-Endoperóxido Sintasas/genética , Ratas , Ratas Endogámicas LewRESUMEN
Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.
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Ataxia de Friedreich/genética , Heterocigoto , Mutación Puntual/genética , Adolescente , Adulto , Niño , Preescolar , Mapeo Cromosómico , Análisis Mutacional de ADN , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVE: To verify if GAA expansion size in Friedreich's ataxia could account for the severity of sensory neuropathy. METHODS: Retrospective study of 56 patients with Friedreich's ataxia selected according to homozygosity for GAA expansion and availability of electrophysiological findings. Orthodromic sensory conduction velocity in the median nerve was available in all patients and that of the tibial nerve in 46 of them. Data of sural nerve biopsy and of a morphometric analysis were available in 12 of the selected patients. The sensory action potential amplitude at the wrist (wSAP) and at the medial malleolus (m mal SAP) and the percentage of myelinated fibres with diameter larger than 7, 9, and 11 microm in the sural nerve were correlated with disease duration and GAA expansion size on the shorter (GAA1) and larger (GAA2) expanded allele in each pair. Pearson's correlation test and stepwise multiple regression were used for statistical analysis. RESULTS: A significant inverse correlation between GAA1 size and wSAP, m mal SAP, and percentage of myelinated fibres was found. Stepwise multiple regression showed that GAA1 size significantly affects electrophysiological and morphometric data, whereas duration of disease has no effect. CONCLUSION: The data suggest that the severity of the sensory neuropathy is probably genetically determined and that it is not progressive.
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Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/genética , Expansión de Repetición de Trinucleótido/genética , Adolescente , Adulto , Alelos , Biopsia , Potenciales Evocados , Humanos , Pierna/inervación , Nervio Mediano/fisiología , Conducción Nerviosa/fisiología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Nervio Sural/patología , Nervio Tibial/fisiologíaRESUMEN
Friedreich's ataxia is the first known autosomal recessive disease caused by an unstable trinucleotide expansion mutation. The most frequent mutation is expansion of a GAA repeat in the first intron of gene X25. We studied transmission of the expanded GAA repeat in 37 Friedreich's ataxia pedigrees and analysed blood and sperm alleles in eight patients. We showed intergenerational instability in 84% of the alleles with an overall excess of contractions. Both contractions and expansions of the GAA repeat occurred in maternal transmission with a stronger tendency to expand for smaller repeats and to contract for longer repeats. Paternally transmitted alleles contracted only. Parental age and the intergenerational change in expansion size were directly correlated in maternal transmission and inversely in paternal transmission. The size of the GAA expansion was slightly lower in patients than heterozygous carriers. Sperm analysis confirmed the tendency to contract of paternal alleles, which was more marked with ageing. The degree of contraction of the GAA repeat in sperm was much higher than that found in intergenerational transmission and was directly related to the repeat size. A blood expanded allele reverted to normal size in the sperm of one patient. This study suggests the existence of different mutational mechanisms in Friedreich's ataxia alleles, which occur both pre- and post-zygotically.
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Genes/genética , Proteínas de Unión a Hierro , Edad Materna , Padres , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Repeticiones de Trinucleótidos/genética , Adulto , Alelos , ADN/sangre , ADN/genética , Familia , Femenino , Ataxia de Friedreich/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Factores Sexuales , Espermatozoides/metabolismo , FrataxinaRESUMEN
Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.
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Cromosomas Humanos Par 16/genética , Ligamiento Genético/genética , Paraplejía/genética , Adulto , Edad de Inicio , Mapeo Cromosómico , Genes Recesivos/genética , Enfermedades Genéticas Congénitas/genética , Marcadores Genéticos/genética , Humanos , Escala de Lod , Persona de Mediana Edad , LinajeRESUMEN
We studied the factors that might influence onset age in Friedreich's ataxia in 41 cases (20 male, 21 female) homozygous for GAA expansion on the first intron of X25 gene. Patients came from 18 multiplex families (13 couples, 5 triplets). Mean age (SD) was 18.1 (8.9) years and did not differ by gender. Onset age and the sizes of the smaller (GAA1) and the larger (GAA2) allele in each pair showed high intrafamily correlation. We found an inverse correlation between age at onset and GAA1 size, but not between age at onset and GAA2 size. Stepwise multiple regression of onset age on GAA1 size, sibling onset age, and GAA2 size showed that GAA1 accounts for 73% of onset age variance, and sibling onset age for an additional 13%. The study demonstrates that, in addition to GAA expansion size, other environmental or genetic familial factors influence disease expression.
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Ataxia de Friedreich/epidemiología , Adolescente , Adulto , Edad de Inicio , Alelos , Niño , Femenino , Ataxia de Friedreich/genética , Humanos , Italia , Masculino , Factores de Riesgo , Repeticiones de Trinucleótidos/genéticaRESUMEN
We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreich's ataxia.