RESUMO
BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Assuntos
Miopatias Distais/genética , Proteínas de Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/genética , Linhagem , FenótipoRESUMO
OBJECTIVES: The aim of the study was to compare prospectively indicator-condition (IC)-guided testing versus testing of those with non-indicator conditions (NICs) in four primary care centres (PCCs) in Barcelona, Spain. METHODS: From October 2009 to February 2011, patients aged from 18 to 65 years old who attended a PCC for a new herpes zoster infection, seborrhoeic eczema, mononucleosis syndrome or leucopenia/thrombopenia were included in the IC group, and one in every 10 randomly selected patients consulting for other reasons were included in the NIC group. A proportion of patients in each group were offered an HIV test; those who agreed to be tested were given a rapid finger-stick HIV test (6 per test). Epidemiological and clinical data were collected and analysed. RESULTS: During the study period, 775 patients attended with one of the four selected ICs, while 66,043 patients presented with an NIC. HIV screening was offered to 89 patients with ICs (offer rate 11.5%), of whom 85 agreed to and completed testing (94.4 and 100% acceptance and completion rates, respectively). In the NIC group, an HIV test was offered to 344 persons (offer rate 5.2%), of whom 313 accepted (90.9%) and 304 completed (97.1%) testing. HIV tests were positive in four persons [prevalence 4.7%; 95% confidence interval (CI) 1.3-11.6%] in the IC group and in one person in the NIC group (prevalence 0.3%; 95% CI 0.01-1.82%; P < 0.009). If every eligible person had taken an HIV test, we would have spent 4650 in the IC group and 396,258 in the NIC group, and an estimated 36 (95% CI 25-49) and 198 persons (95% CI 171-227), respectively, would have been diagnosed with HIV infection. The estimated cost per new HIV diagnosis would have been 129 (95% CI 107-153) in the IC group and 2001 (95% CI 1913-2088) in the NIC group. CONCLUSIONS: Although the number of patients included in the study was small and the results should be treated with caution, IC-guided HIV testing, based on four selected ICs, in PCCs seems to be a more feasible and less expensive strategy to improve diagnosis of HIV infection in Spain than a nontargeted HIV testing strategy.
Assuntos
Infecções por HIV/diagnóstico , Programas de Rastreamento/economia , Programas de Rastreamento/métodos , Adolescente , Adulto , Idoso , Feminino , Infecções por HIV/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Estudos Prospectivos , Espanha/epidemiologia , Adulto JovemRESUMO
Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.
Assuntos
Coreia/genética , Mutação , Proteínas/genética , Proteínas de Saccharomyces cerevisiae , Processamento Alternativo , Animais , Caenorhabditis elegans/genética , Linhagem Celular , Cromossomos Humanos Par 6 , Eritrócitos/fisiologia , Éxons , Proteínas Fúngicas/genética , Regulação da Expressão Gênica , Haplótipos , Humanos , Linhagem , Transporte Proteico , Proteínas/metabolismo , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Proteínas de Transporte VesicularRESUMO
Autosomal recessive Charcot-Marie-Tooth disease (AR-CMT) is often characterized by onset in early childhood and severe phenotype compared to the dominant forms. CMT disease associated with periaxin gene (PRX) is rare and characterized by demyelination limited to the major peripheral nerves. Following the discovery of a high frequency of a specific periaxin gene mutation (E1085fsX4 homozygote) in the Reunion Island, we examined all French patients known as carriers of the periaxin gene mutation. There were 24 patients. Eighteen were from the Reunion Island (6 families and 10 sporadic cases). The six remaining patients were in two families, each with two affected individuals, and two sporadic cases. The series included 17 female and seven male patients. Walking was acquired late, on average at 3.4±1.6 years. One patient never learned to walk. The Charcot Marie Tooth Neuropathy Score (CMTNS) averaged 24.5±8.1. Seven patients had been wheelchair-bound since the age of 24±22. Other symptoms were: scoliosis most often observed after the age of 12 years and sometimes complicated by a restrictive respiratory syndrome; foot deformity in 24 patients; strabismus; glaucoma; myopia. When conduction recordings are available, median nerve motor conduction was slow (<10m/s), associated with a major lengthening of distal latencies. Study of the periaxin gene should be considered in patients with severe demyelinating neuropathy associated with early infantile scoliosis. This disease leads to major disability (29% of patients in this series were wheelchair-bound) and to respiratory insufficiency. Genetic counselling is highly recommended for consanguineous families.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Proteínas de Membrana/genética , Mutação , Adulto , Doença de Charcot-Marie-Tooth/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Eletrofisiologia , Família , Feminino , França , Humanos , Lactente , Masculino , Reunião , Adulto JovemRESUMO
BACKGROUND: Multiple mitochondrial DNA (mtDNA) deletions usually have a mendelian inheritance secondary to mutation in nuclear genes. One of these is the Twinkle gene whose mutation is responsible for autosomal dominant progressive external ophthalmoplegia (PEO). The number of reported cases with mainly myopathic symptoms and possible nervous system involvement related to Twinkle gene mutation is limited. We present a new French family of whom two members displayed myopathy and neuropathy associated with PEO, and we perform a clinical review in light of other observations reported in the literature. METHODS: The proband, one son and the daughter have been investigated. Southern blot analysis and long-range PCR assay have been performed from muscle biopsy specimens. Coding exons and flanking intron regions of polymerase gamma (POLG) and DNA helicase (Twinkle) genes were sequenced. RESULTS: Multiple mitochondrial DNA deletions have been found and sequencing of the Twinkle gene showed the change p.R374Q. CONCLUSION: Two other families from the literature also had the R374Q mutation. Symptoms reported in association with this mutation were myopathy, peripheral neuropathy, dysarthria and/or dysphagia, respiratory insufficiency and parkinsonism. Respiratory insufficiency caused by chest wall weakness was reported in other families with different Twinkle gene mutations, and one might provide exercise intolerance, dysarthria and/or dysphagia as symptoms in favor of the diagnosis. Occurrence of impressive emaciation was a peculiarity in our family.
Assuntos
DNA Helicases/genética , Mutação , Oftalmoplegia Externa Progressiva Crônica/genética , Biópsia , Southern Blotting , DNA Mitocondrial/genética , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais , Músculo Esquelético/patologia , Oftalmoplegia Externa Progressiva Crônica/patologia , Oftalmoplegia Externa Progressiva Crônica/fisiopatologia , Linhagem , Reação em Cadeia da Polimerase , Adulto JovemAssuntos
Atrofia Óptica Hereditária de Leber/complicações , Transtornos Parkinsonianos/etiologia , Adulto , Biópsia , DNA Mitocondrial/genética , Distúrbios Distônicos/etiologia , Distúrbios Distônicos/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Transtornos Parkinsonianos/genética , Nervo Fibular/patologia , Mutação PuntualRESUMO
BACKGROUND: Limb girdle muscular dystrophies are rare genetic diseases. Despite constant progress in genetics and biochemistry, the pathogenic mechanisms are not completely understood. Calpainopathy (LGMD2A) has been reported to be the most frequent autosomal recessive form of muscular dystrophy in several populations. Point mutations in CAPN3 are difficult to identify and the analysis is long and costly. The use of western blot does not seem to provide the expected sensitivity and specificity. PATIENTS AND METHOD: We studied all the patients diagnosed in the neuromuscular center of Bordeaux (France) with confirmed calpainopathy in order to establish the appropriate diagnostic approach (inclusion criteria: muscular biopsy with calpain 3 western blot study, two mutations in CAPN3). Patients with highly suspected calpainopathy (same criteria with only one mutation) were also analyzed. RESULTS: Our 13 patients belonged to 10 different families. Four patients had a normal western blot for calpain (WBn). We found high phenotypic variability with frequent atypical signs. The WBn group had less severe disease (a statistically significant later age of onset, a tendency toward lower CK levels and a slower disease course). We extended this comparison to the single mutation patients and we found the same results. CONCLUSION: Considering the lack of sensitivity of western blot protein analysis in LGMD2A, a normal western blot for calpain should not halt the genetic analysis. The western blot result seems to have prognostic value. A normal western blot may help genetic testing by highlighting some mutational hot spots in the CAPN3 gene.
Assuntos
Calpaína/fisiologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Adolescente , Adulto , Idade de Início , Western Blotting , Calpaína/genética , Criança , Estudos de Coortes , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Doenças Neuromusculares/diagnóstico , Fenótipo , Mutação Puntual , Prognóstico , Adulto JovemRESUMO
Limb-girdle muscular dystrophy type 2A (LGMD2A) is an autosomal recessive disorder caused by mutations in the CAPN3 gene. Its definitive diagnosis is laborious, since the clinical phenotype is often similar to other types of muscular dystrophy and since the CAPN3 gene encompasses a large genomic region with more than 300 pathogenic mutations described to date. In fact, it is estimated that nearly 25% of the cases with a phenotype suggestive of LGMD2A do not have mutations in the CAPN3 gene and that, in up to 22% of the cases, only one mutation is identified. In the present work, we have characterised CAPN3 messenger RNA (mRNA) expression in peripheral blood, and we have performed a retrospective diagnostic study with 26 LGMD2A patients, sequencing a transcript of CAPN3 present in white blood cells (WBCs). The 25% of the mutations presented in this paper (7/28) act modifying pre-mRNA splicing of the CAPN3 transcript, including the first deep-intronic mutation described to date in the CAPN3 gene. Our results determine that the sequencing of CAPN3 transcripts present in WBCs could be applied as a new approach for LGMD2A diagnosis. This method improves and simplifies diagnosis, since it combines the advantages of mRNA analysis in a more accessible and rapidly regenerated tissue. However, the lack of exon 15 in the CAPN3 isoforms present in blood, and the presence of mRNA degradation make it necessary to combine mRNA and DNA analyses in some specific cases.
Assuntos
Calpaína/sangue , Calpaína/genética , Leucócitos/enzimologia , Proteínas Musculares/sangue , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/enzimologia , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Processamento Alternativo , Sequência de Bases , Estudos de Casos e Controles , Criança , Análise Mutacional de DNA , DNA Complementar/genética , Feminino , Humanos , Isoenzimas/sangue , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Músculos/enzimologia , Distrofia Muscular do Cíngulo dos Membros/classificação , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Mutação , RNA Mensageiro/sangue , RNA Mensageiro/genética , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto JovemRESUMO
There are several reviews devoted to neurosarcoidosis and a few reports restricted to sarcoid neuropathy. Since 1989, we have investigated 4 new cases of sarcoid neuropathy, 1 with chronic sensory motor neuropathy (CSMN), another with painful neuropathy and 2 with atypical chronic inflammatory demyelinating polyneuropathy (CIDP). In each case, biopsy specimens from the superficial peroneal nerve and peroneus brevis muscle were taken by the same cutaneous incision and studied on paraffin sections, semi-thin sections and under electron microscope. We compared neuropathological findings from our 4 cases with those from 34 well-studied nerve biopsies previously reported in the literature, and which concerned 16 cases of CSMN, 13 cases ofmononeuropathy multiplex, 2 cases of painful neuropathy and three cases of CIDP. In all of these 38 cases of sarcoid neuropathy, the characteristic noncaseiting granulomas (NCG) were observed on the nerve in 11 cases, on the muscle alone in 5, on both muscle and nerve in 10, and in the nerve and another parenchyma in 4. In the 8 remaining cases, NCG were observed in another parenchyma, mainly lung or lymph nodes. Moreover, necrotizing vasculitis was present in nerve biopsies from 8 cases and microvasculitis without obvious necrosis in 2 others. Nerve fiber lesions, which are mainly axonal, are probably related to mechanical compression by NCG and/or to an ischemic process due to vasculitis. Cytokines and immune factors may also play a role, especially in certain cases with a clinical presentation of CIDP.
Assuntos
Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Sarcoidose/patologia , Sarcoidose/fisiopatologia , Idoso , Feminino , Granuloma/patologia , Humanos , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Doenças do Sistema Nervoso Periférico/etiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/etiologia , Sarcoidose/complicaçõesRESUMO
We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing approximately 50% (238 out of 484) of the suspected calpainopathy cases referred for the molecular study of the calpain 3 (CAPN3) gene. The mean age at onset of LGMD2A patients was approximately 14 years, and the first symptoms occurred between 6 and 18 years of age in 71% of patients. The mean age at which the patients became wheelchair bound was 32.2 years, with 84% requiring the use of a wheelchair between the age of 21 and 40 years. There was no correlation between the age at onset and the time at which the patient became wheelchair bound, nor between the sex of the patient and the risk of becoming wheelchair bound. Of the cases where the CAPN3 gene was not affected, approximately 20% were diagnosed as LGMD2I muscular dystrophy, while facioscapulohumeral muscular dystrophy (FSHD) was uncommon in this sample. We identified 105 different mutations in the CAPN3 gene of which 50 have not been described previously. These were distributed throughout the coding region of the gene, although some exons remained free of mutations. The most frequent mutation was 2362AG-->TCATCT (exon 22), which was present in 30.7% of the chromosomes analysed (146 chromosomes). Other recurrent mutations described were N50S, 550DeltaA, G222R, IVS6-1G-->A, A483D, IVS17+1G-->T, 2069-2070DeltaAC, R748Q and R748X, each of which was found in >5 chromosomes. The type of mutation in the CAPN3 gene does not appear to be a risk factor for becoming dependent on a wheelchair at a determined age. However, in the cases with two null mutations, there were significantly fewer patients that were able to walk than in the group of patients with at least one missense mutation. Despite the fact that the results of phenotyping and western blot might be biased due to multiple referral centres, producing a diagnosis on the basis of the classical phenotype is neither sufficiently sensitive (86.7%) nor specific (69.3%), although western blot proved to be even less sensitive (52.5%) yet more specific (87.8%). In this case LGMD2I was a relevant cause of false-positive diagnoses. Considering both the clinical phenotype and the biochemical information together, the probability of correctly diagnosing a calpainopathy is very high (90.8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%.
Assuntos
Calpaína/genética , Isoenzimas/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Idade de Início , Teorema de Bayes , Western Blotting , Criança , Análise Mutacional de DNA/métodos , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Mutação de Sentido Incorreto , Fenótipo , Estudos RetrospectivosRESUMO
INTRODUCTION: Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B. PATIENTS AND METHODS: We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation. CONCLUSION: This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.
Assuntos
Laminas/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Condução Nervosa/fisiologia , Adolescente , Adulto , Idoso , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Biomarcadores , Creatina Quinase/sangue , Ecocardiografia , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias/diagnóstico por imagem , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Lamina Tipo A , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Mutação/genética , Mutação/fisiologia , Linhagem , Fenótipo , Tomografia Computadorizada por Raios XRESUMO
We report a father and son with striopallidodentate calcifications. Metabolic studies excluded calcium/phosphorus metabolism disturbances and no specific etiology was found. The structure of the calcified areas differed, on magnetic resonance imaging, depending on location and, probably, age. There are nine families with similar clinical and radiologic backgrounds and no evident etiology in the literature. Transmission is most often autosomal dominant, and in contrast with physiologic senescent basal ganglia calcification, the prognosis appears to be poor.
Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Corpo Estriado , Doenças dos Gânglios da Base/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Globo Pálido/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
A chronic demyelinating neuropathy with "benign" IgM gammopathy was followed for 6 years in a 63-year-old man. The clinical, biologic, and EMG aspects were similar to those already reported, but a lymphoplasmocytic infiltrate in the nerve connective tissue of this patient has only rarely been observed in benign IgM gammopathy. The paraprotein was not evident in the serum until 5 years after symptoms of the neuropathy started.
Assuntos
Doenças Desmielinizantes/patologia , Hipergamaglobulinemia/patologia , Linfócitos/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças Desmielinizantes/sangue , Doenças Desmielinizantes/imunologia , Humanos , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/imunologiaRESUMO
Three members of a Basque family carrying a novel six R2 octapeptide repeat 144-bp insertion in the prion protein gene (PRNP) showed a slowly progressive dementia associated with cerebellar signs, myoclonic jerks, and seizures. Although postmortem examination revealed only focal and minimal spongiform degeneration in one subject with a 4-year course, significant astrogliosis and neuronal loss were associated with pronounced spongiform degeneration in the patient with a duration of symptoms of 10 years. Prion protein (PrP)-immunoreactive patches with a unique morphology were present in the molecular layer of the cerebellum in both subjects. Western blot analysis demonstrated the presence of protease-resistant prion protein (PrPres) with the same characteristics (size and ratio of the three differently glycosylated isoforms) of that found in typical sporadic Creutzfeldt-Jakob disease (CJD129M/M, PrPres type 1). The amount of PrPres correlated with presence and severity of spongiform degeneration in the cerebral cortex. The findings suggest that a relatively low rate of PrPres deposition is the cause of the lack of spongiform degeneration in subjects carrying a 144-bp insertion in PRNP. The presence of PrP-immunoreactive patches with unique morphology in the molecular layer of the cerebellum is a hallmark of certain prion encephalopathies with insertional mutations and is useful in the diagnosis of this subtype of human prion disease.
Assuntos
Doenças Priônicas/genética , Príons/genética , Adulto , Western Blotting , Cerebelo/patologia , Humanos , Imuno-Histoquímica , Masculino , Linhagem , Reação em Cadeia da Polimerase , Doenças Priônicas/patologia , Sequências Repetitivas de Ácido Nucleico , EspanhaRESUMO
Autopsy findings are reported from a patient with chorea-acanthocytosis treated for 2 years by deep brain stimulation (DBS) of the motor thalamus. Postoperative testing showed a progressive improvement in axial truncal spasms. Although relatively high currents were used for 2 years in this patient, postmortem analysis showed minimal tissue damage in the vicinity of the electrode tip. It is concluded that DBS has little impact on the surrounding tissues.
Assuntos
Coreia/patologia , Coreia/terapia , Terapia por Estimulação Elétrica/efeitos adversos , Tálamo/patologia , Tálamo/fisiologia , Adulto , Autopsia , Coreia/complicações , Eletrodos Implantados/efeitos adversos , Humanos , Masculino , Radiografia , Espasmo/etiologia , Espasmo/terapia , Tálamo/diagnóstico por imagemRESUMO
Morphological modifications were investigated in the peripheral nerve of three unrelated patients with CMT1B. In two patients, molecular genetic analysis showed an Arg98His mutation in the extracellular domain of MPZ, associated with irregularly uncompacted lamellae. This observation confirms previous studies of a well-defined correlation between mutations and morphological phenotypes. In the third patient, a de novo Asp109Asn mutation was associated with abnormally thick myelin sheaths. This adds to the known list of MPZ gene mutations associated with this morphological phenotype.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Proteína P0 da Mielina/genética , Bainha de Mielina/patologia , Mutação Puntual , Adulto , Substituição de Aminoácidos , Mapeamento Cromossômico , Cromossomos Humanos Par 17 , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Fibras Nervosas/patologia , Linhagem , Nervos Periféricos/patologia , Polimorfismo Conformacional de Fita Simples , Mapeamento por RestriçãoRESUMO
OBJECTIVE: The proportion of tuberculin reactors in a population and the intensity of tuberculin reactions have been shown to increase with increasing exposure to mycobacterial infection, eg, repeated BCG immunization. These observations suggested that tuberculin reactivity would become uniformly high in individuals with a high mycobacterial load who did not have a known cause of anergy. Since tuberculin reactivity has been measured to evaluate the possible genetic regulation of responses to mycobacteria in humans, it is important to study its behavior under conditions of ongoing, maximal exposure to mycobacteria. In the present study, we determined the mean size of tuberculin reactivity in BCG-immunized and unimmunized patients with pulmonary tuberculosis of recent onset, and the stability of tuberculin reactions during and after treatment of pulmonary tuberculosis. METHOD: Serial tuberculin testing was performed on patients with newly diagnosed active pulmonary tuberculosis diagnosed over a period of 2 years at the National Institute for Respiratory Diseases in Santiago, Chile. The first tuberculin test was performed at the time of diagnosis in 58 patients. Repeated tuberculin testing was performed 2 weeks later in 15 patients with initial reaction sizes < 15 mm. Four additional tuberculin tests were performed, one each at 3-months intervals in 42 patients regardless of the size of the initial tuberculin reaction. RESULTS: Tuberculin reactions at entry had a unimodal distribution in patients both with and without BCG scars (14.8 +/- 5.0 mm and 16.5 +/- 5.2 mm, respectively). A second tuberculin test in patients with initial reaction sizes < 15 mm showed a moderate, statistically significant increase in the mean reaction size (PPD1: 10.1 +/- 3.2 mm; PPD2: 11.9 +/- 4.8 mm). Repeated tuberculin testing over 1 year revealed no significant changes in reaction size. The mean reaction sizes were 15.8 +/- 5.0 mm at entry, 15.5 +/- 5.4 mm at 3 months, 17.2 +/- 5.2 mm at 6 months, 17.0 +/- 5.1 mm at 9 months, and 16.7 +/- 54 mm at 12 months. The standard deviation of a random observation within patients was 5.3 mm. The largest variations due to increased reactivity after 6 months of treatment were observed in patients with reaction < 15 mm at entry compared with hyperergic patients, and in BCG-immunized patients compared to unimmunized patients. CONCLUSIONS: In the presence of an ongoing mycobacterial infection, patients without anergizing conditions express a tuberculin reactivity that is relatively constant during and after treatment of pulmonary tuberculosis. The size and stability of the reactions seem to be determined by individual conditions that include the tuberculin reactivity at the time of diagnosis and the BCG immunization status.
Assuntos
Teste Tuberculínico , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Idoso , Vacina BCG , Humanos , Pessoa de Meia-Idade , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/prevenção & controleRESUMO
In order to determine whether tuberculin testing caused a booster effect in children vaccinated with Bacillus Calmette-Guérin (BCG) at birth, we studied forty 6-year-olds by repeat tuberculin testing 2 weeks later on the contralateral forearm. All children were healthy and had no known exposure to tuberculosis. None of the children had a history of mycobacteriosis other than tuberculosis. The mean induration was 2.3 +/- 1.8 mm for the first tuberculin reaction and 7.6 +/- 3.3 mm for the second tuberculin reaction (P less than 0.005). Four children had positive reactions (greater than or equal to 10 mm) to the first purified protein derivative test; 18 children were positive upon retesting. Eleven of these latter children had increases of at least 6 mm from reactions less than 10 mm to greater than or equal to 10 mm. The size of the BCG scar was significantly correlated to the size of both the first and second purified protein derivative reactions (P less than 0.01), suggesting that the increased reactivity upon retesting was a consequence of sensitization induced by BCG vaccination 6 years earlier. All children remained healthy after this study was completed. Retesting of tuberculin reactivity within 2 weeks in BCG-vaccinated children with reactions less than 10 mm will produce reactions greater than 10 mm in some healthy children who may not require antituberculosis treatment.
Assuntos
Anticorpos Antibacterianos/análise , Vacina BCG/imunologia , Imunização Secundária , Mycobacterium tuberculosis/imunologia , Teste Tuberculínico , Tuberculose Pulmonar/prevenção & controle , Vacina BCG/administração & dosagem , Criança , Feminino , Humanos , Hipersensibilidade Tardia/imunologia , Masculino , Tuberculose Pulmonar/imunologiaRESUMO
Many studies indicate that the S-enantiomers of arylpropionic (APA) nonsteroidal antiinflammatory drugs (NSAIDs) are the pharmacologically active enantiomers. S(+)-ketoprofen (dexketoprofen) stereoselectively inhibits cyclooxygenase (COX) in vitro but very little is known about the differential activity of ketoprofen enantiomers in vivo. We examined the analgesic, antiinflammatory, and antipyretic activities of S(+)-ketoprofen in rats and mice. First, we measured the antinociceptive action of S(+)-ketoprofen in abdominal pain models. After intravenous administration. 0.5 mg/kg S(+)-ketoprofen inhibited 92.1+/-2.2% of writhing in mice. Stereoselectivity in the activity was detected; intravenous administration of the R(-)-enantiomer resulted in no statistically significant activity in a dose range of 0.15-1 mg/kg. Similar results were obtained after oral administration in mice. In the rat, S(+)-ketoprofen was a more potent analgesic than diclofenac by both intravenous and oral administration. There was no significant difference between the analgesic effect of S(+)-ketoprofen treatment and the twofold dose of the racemic form in both the mouse and rat models. Second, we measured the antiinflammatory activity of S(+)-ketoprofen using a carrageenan-induced paw edema model in the rat. Intravenous administration of 5 mg/kg of S(+)-ketoprofen almost completely inhibited edema formation. After oral administration, S(+)-ketoprofen is both more potent and effective than diclofenac. Third, we measured antipyretic activity. S(+)-ketoprofen showed a marked antipyretic action (ED50 = 1.6 mg/kg) and was the most potent of the NSAIDs tested. S(+)-ketoprofen is a potent antiinflammatory, analgesic, and antipyretic agent in vivo, consistent with its potent anti-COX activity.