RESUMO
OBJECTIVE: Mitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G. DESIGN: Retrospective case-comparison study. POPULATION/SETTING: Sixty-seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated. METHODS: Participants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group. MAIN OUTCOME MEASURES: Pregnancy-related complications, mode of delivery, gestational age and birthweight of newborns. RESULTS: Of 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the 'all other mutations' group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3-50.1), breathing difficulties (OR = 7.8, 95% CI 1.0-59.1) and hypertension (OR = 8.2, 95% CI 3.1-21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission. CONCLUSION: Women who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease. TWEETABLE ABSTRACT: Pregnant women with mitochondrial disease - m.3243A>G mutation - are at greatly increased risk of complications and preterm delivery.
Assuntos
Doenças Mitocondriais/genética , Mutação Puntual/genética , Complicações na Gravidez/genética , Adolescente , Adulto , Estudos de Casos e Controles , DNA Mitocondrial/genética , Feminino , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Doenças Mitocondriais/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Estudos Retrospectivos , Reino Unido/epidemiologia , Adulto JovemRESUMO
The 'International Workshop on Alternatives to the Murine Histamine Sensitization Test for Acellular Pertussis Vaccines: In Search of Acceptable Alternatives to the Murine Histamine Sensitization Test (HIST): What is Possible and Practical?' was held on 4 and 5 March 2015 in London, United Kingdom. Participants discussed the results of the data generated from an international collaborative study (BSP114 Phase 2) sponsored by the European Directorate for the Quality of Medicines & Health Care (EDQM) to determine if a modified Chinese hamster ovary (CHO) cell-based clustering assay is a suitable alternative to replace HIST. Workshop participants agreed that protocol transferability demonstrated in the collaborative study indicates that a standardised CHO cell assay is adequate for measuring pure PTx in reference preparations. However, vaccine manufacturers would still need to demonstrate that the method is valid to detect or measure residual PTx in their specific adjuvanted products. The 2 modified CHO cell protocols included in the study (the Direct and the Indirect Methods) deserve further consideration as alternatives to HIST. Using the CHO cell assay, an in vitro alternative, for acellular pertussis (aP) vaccine batch release testing would reduce the number of animals used for aP vaccine safety testing. A strategic, stepwise adoption plan was proposed, in which the alternative test would be used for release purposes first, and then, once sufficient confidence in its suitable performance has been gained, its use would be extended to stability testing.
Assuntos
Alternativas aos Testes com Animais/normas , Química Farmacêutica/normas , Histamina/análise , Toxina Pertussis/análise , Alternativas aos Testes com Animais/métodos , Animais , Células CHO , Química Farmacêutica/métodos , Cricetinae , Cricetulus , Educação , Londres , Camundongos , Toxina Pertussis/uso terapêutico , Vacina contra Coqueluche/normas , Vacina contra Coqueluche/uso terapêutico , Coqueluche/prevenção & controleRESUMO
Mitochondrial diseases are a clinically diverse group of genetic disorders that often present to neurologists. Health related quality of life (HRQOL) is increasingly recognised as a fundamental patient based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess HRQOL across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop disease specific HRQOL measures that centre on symptoms characteristic of a specific disease or condition and their impact. This study presents the initial conceptualisation, development and preliminary psychometric assessment (validity and reliability) of a mitochondrial disease specific HRQOL measure (Newcastle Mitochondrial Quality of life measure (NMQ)). NMQ is a valuable assessment tool and consists of 63 items within 16 unidimensional domains, each demonstrating good internal reliability (Cronbach's α≥0.83) and construct validity.
Assuntos
Doenças Mitocondriais/psicologia , Qualidade de Vida , Adulto , Análise Fatorial , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria/instrumentação , Reprodutibilidade dos Testes , Inquéritos e Questionários , Adulto JovemRESUMO
Veterinary vaccines contribute to improved animal and human health and welfare by preventing infectious diseases. However, testing necessary to ensure vaccine effectiveness and safety can involve large numbers of animals and significant pain and distress. NICEATM and ICCVAM recently convened an international workshop to review the state of the science of human and veterinary vaccine potency and safety testing, and to identify priority activities to advance new and improved methods that can further reduce, refine and replace animal use. Rabies, Clostridium sp., and Leptospira sp. vaccines were identified as the highest priorities, while tests requiring live viruses and bacteria hazardous to laboratory workers, livestock, pets, and wildlife were also considered high priorities. Priority research, development and validation activities to address critical knowledge and data gaps were identified, including opportunities to apply new science and technology. Enhanced international harmonization and cooperation and closer collaborations between human and veterinary researchers were recommended to expedite progress. Implementation of the workshop recommendations is expected to advance new methods for vaccine testing that will benefit animal welfare and ensure continued and improved protection of human and animal health.
Assuntos
Vacinação/veterinária , Vacinas/normas , Drogas Veterinárias/normas , Alternativas aos Testes com Animais/métodos , Alternativas aos Testes com Animais/normas , Alternativas aos Testes com Animais/tendências , Bem-Estar do Animal/normas , Animais , Cooperação Internacional , Medicina Veterinária/métodos , Medicina Veterinária/normas , Medicina Veterinária/tendênciasRESUMO
Mitochondrial diseases are heterogeneous in clinical presentation and genotype. The incidence of known pathogenic mitochondrial DNA mutations in the general population is 1 in 500. Little is known about the implications of pregnancy for women with mitochondrial disease. We undertook a systematic review of the literature on mitochondrial disease in pregnancy. Ten case reports were identified. The most common complications were threatened preterm labour (5 women) and preeclampsia (4 women). Two women experienced magnesium sulphate toxicity. Pregnancy had a varied effect on mitochondrial disease with some women being asymptomatic; others developing mild symptoms such as exercise intolerance or muscle weakness which resolved postnatally; and others developed more serious, persistent symptoms such as symptomatic Wolff-Parkinson-White syndrome, persistent paraesthesia and focal segmental glomerulosclerosis. Women with mitochondrial disease appear to be at increased risk of complications during pregnancy and labour but further prospective cohort studies are needed.
RESUMO
A higher incidence of depression has been described in adults with primary oxidative phosphorylation disease. We evaluated the psychological characteristics of eighteen non-retarded pediatric patients diagnosed with a disorder of the oxidative phosphorylation. We found significantly higher rate of withdrawn, depressive behaviour compared to population norm scores, to children with other types of inborn errors of metabolism and also in comparison to patients with Sotos syndrome. The occurrence of depressive behaviour showed no correlation with the degree of mitochondrial dysfunction. These findings support the hypothesis that mood disorders could be associated to abnormal cerebral energy metabolism.
Assuntos
Depressão/epidemiologia , Doenças Mitocondriais/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Entrevista Psicológica , Masculino , Fosforilação OxidativaRESUMO
The spatial organization of the mouse cerebellum into transverse zones and parasagittal stripes is reflected during the temporal progression of Purkinje cell death in the Lurcher mutant mouse (+/Lc). Neurodegeneration in the +/Lc mutant is apparent by the second postnatal week and is initially seen in all four transverse zones: the anterior (lobules I-V), central (lobules VI, VII), posterior (lobules VIII, dorsal IX), and nodular (ventral lobule IX and lobule X) zone. However, from postnatal day (P)25-P36, Purkinje cell loss proceeds more rapidly in the anterior zone, followed by the posterior and central zones, and is significantly delayed in the nodular zone. Coronal sections through the +/Lc cerebellum reveal that surviving Purkinje cells are restricted to the paraflocculus/flocculus and the nodular zone and could be detected as late as P146 (approximately 5 months). Within this region, the pattern of preferentially surviving calbindin-immunoreactive Purkinje cells reflects the expression of the constitutively expressed small heat shock protein HSP25 in the wild-type cerebellum. Although the role of constitutively expressed HSP25 in the wild-type cerebellum is not clear, it appears to play a neuroprotective role in the flocculonodular region of the +/Lc mutant cerebellum as the percentage of surviving Purkinje cells that are HSP25-immunopositive significantly increases over time.
Assuntos
Sobrevivência Celular , Proteínas de Choque Térmico/metabolismo , Proteínas de Neoplasias/metabolismo , Degeneração Neural/metabolismo , Células de Purkinje/patologia , Células de Purkinje/fisiologia , Animais , Calbindinas , Cerebelo/patologia , Proteínas de Choque Térmico/genética , Camundongos , Camundongos Mutantes Neurológicos , Chaperonas Moleculares , Proteínas de Neoplasias/genética , Degeneração Neural/genética , Degeneração Neural/patologia , Células de Purkinje/citologia , Proteína G de Ligação ao Cálcio S100/metabolismoRESUMO
Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal 'dominant optic atrophy plus' variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44-6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08-4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
Assuntos
Doenças do Sistema Nervoso Central/complicações , GTP Fosfo-Hidrolases/genética , Atrofia Óptica Autossômica Dominante/complicações , Adolescente , Adulto , Idoso , Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Criança , Estudos de Coortes , DNA Mitocondrial/análise , DNA Mitocondrial/genética , Família , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Autossômica Dominante/metabolismo , Atrofia Óptica Autossômica Dominante/patologia , Fenótipo , Adulto JovemAssuntos
Doenças dos Gânglios da Base/fisiopatologia , Predisposição Genética para Doença/genética , Doenças Mitocondriais/diagnóstico , Síndrome das Pernas Inquietas/diagnóstico , Baixa Visão/diagnóstico , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/genética , Blefaroptose/etiologia , Blefaroptose/metabolismo , Blefaroptose/fisiopatologia , Análise Mutacional de DNA , DNA Polimerase gama , DNA Polimerase Dirigida por DNA/genética , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/metabolismo , Transtornos de Deglutição/fisiopatologia , Diagnóstico Diferencial , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/deficiência , Feminino , Humanos , Padrões de Herança/genética , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/metabolismo , Debilidade Muscular/etiologia , Debilidade Muscular/metabolismo , Debilidade Muscular/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mutação/genética , Transtornos da Motilidade Ocular/etiologia , Transtornos da Motilidade Ocular/metabolismo , Transtornos da Motilidade Ocular/fisiopatologia , Putamen/diagnóstico por imagem , Putamen/metabolismo , Putamen/fisiopatologia , Cintilografia , Síndrome das Pernas Inquietas/etiologia , Síndrome das Pernas Inquietas/metabolismo , Baixa Visão/etiologia , Baixa Visão/metabolismoRESUMO
BACKGROUND: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease. METHODS AND RESULTS: We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids. CONCLUSION: The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Doenças Mitocondriais/genética , Adolescente , Adulto , Criança , Deficiência de Citocromo-c Oxidase/genética , Deficiência de Citocromo-c Oxidase/patologia , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/genética , Esclerose Cerebral Difusa de Schilder/patologia , Feminino , Humanos , Lactente , Fígado/ultraestrutura , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/patologia , Músculo Esquelético/ultraestrutura , Mutação de Sentido Incorreto , Oftalmoplegia Externa Progressiva Crônica/genética , Oftalmoplegia Externa Progressiva Crônica/patologia , Alinhamento de SequênciaRESUMO
In 1998, Wallace et al. (Science 1988; 242: 1427-30) published evidence that the mutation m.11778G>A was responsible for causing Leber's hereditary optic neuropathy. This was the first account of a mitochondrial DNA mutation being irrefutably linked with a human disease and was swiftly followed by a report from Holt et al. (Nature 1988; 331: 717-9) identifying deletions in mitochondrial DNA as a cause for myopathy. During the subsequent 20 years there has been an exponential growth in 'mitochondrial medicine', with clinical, biochemical and genetic characterizations of a wide range of mitochondrial diseases and evidence implicating mitochondria in a host of many other clinical conditions including ageing, neurodegenerative illness and cancer. In this review we shall focus on the diagnosis and management of mitochondrial diseases that lead directly or indirectly to disruption of the process of oxidative phosphorylation.
Assuntos
Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/terapia , Fosforilação Oxidativa , DNA Mitocondrial/genética , Deleção de Genes , Humanos , Doenças Mitocondriais/etiologia , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição/genéticaAssuntos
DNA Mitocondrial/genética , DNA Mitocondrial/urina , Testes Genéticos/métodos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Avaliação de Resultados em Cuidados de Saúde/métodos , Precursores de RNA/genética , RNA de Transferência de Leucina/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/urina , Mutação , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIM: To review the height and weight of children with mitochondrial disease attending our supra-regional service. METHODS: This was a retrospective audit of cross-sectional data. Height and weight measurements were available in 24 children and adolescents (median 7.86 years; range 1.76-20.5 years) who all had a confirmed diagnosis of mitochondrial disease. Values were converted to SD scores using UK reference data. RESULTS: Patients with mitochondrial disease were short with an overall SD score of -1.97 (95% confidence intervals -2.72 to -1.23 SD). Patients were also thin with a relatively low BMI SDS of -1.07 (95% confidence intervals -1.69 to - 0.07 SD), which fell with advancing years (r =-0.7; p < 0.000). CONCLUSION: Short stature and a progressive reduction in body mass index (BMI) are features of mitochondrial disease in childhood. The mechanisms underlying the abnormal growth in these patients need to be studied in more detail.
Assuntos
Desenvolvimento do Adolescente , Estatura , Peso Corporal , Desenvolvimento Infantil , Doenças Mitocondriais/fisiopatologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Humanos , Lactente , Estudos Retrospectivos , Adulto JovemRESUMO
We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase γ gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease.
Assuntos
DNA Mitocondrial/genética , Síndrome MELAS/genética , Sulfato de Magnésio/efeitos adversos , Pré-Eclâmpsia/diagnóstico , Resultado da Gravidez , Adulto , Cesárea , Feminino , Seguimentos , Testes Genéticos , Idade Gestacional , Heterozigoto , Humanos , Recém-Nascido , Síndrome MELAS/complicações , Síndrome MELAS/diagnóstico , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/sangue , Masculino , Mutação Puntual , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/cirurgia , Gravidez , Terceiro Trimestre da Gravidez , Medição de RiscoRESUMO
BACKGROUND: Mitochondrial DNA (mtDNA) mutations are important causes of human genetic disease, with mutations in tRNA genes particularly prevalent. In many patients, mutations are heteroplasmic, affecting a population of mtDNA molecules. Establishing the pathogenicity of homoplasmic mitochondrial tRNA (mt-tRNA) mutations, in which the mutation is present in every mtDNA molecule, is extremely difficult. These mutations must conform to specific pathogenic criteria, documenting unequivocally a functional defect of the mutant mt-tRNA. AIMS: To investigate the pathogenic nature of two homoplasmic mt-tRNA(Thr) deletions, m.15940delT (previously reported as pathogenic) and m.15937delA, by assessing the steady state levels of the mutant mt-tRNA in tissue and cell-line samples from six unrelated families, in which affected individuals were thoroughly investigated for mitochondrial DNA disease on the basis of clinical presentations. Rates of de novo mitochondrial protein synthesis were also examined in control and m.15937delA mutant fibroblasts. RESULTS: Our data strongly suggest that both single nucleotide deletions are neutral polymorphisms; no obvious defects were apparent in either steady state mt-tRNA(Thr) levels or rates of mitochondrial protein synthesis. CONCLUSIONS: These findings have important implications for the investigation of other families with suspected mtDNA disease, in particular the requirement to fulfil strict and established pathogenic criteria in order to avoid misattribution of pathogenicity to mt-tRNA variants.
Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação , RNA de Transferência de Treonina/genética , RNA/genética , Adulto , Biópsia , Células Cultivadas , Criança , Análise Mutacional de DNA , Feminino , Fibroblastos , Humanos , Lactente , Masculino , Mitocôndrias Cardíacas/genética , Mitocôndrias Musculares/genética , Doenças Mitocondriais/fisiopatologia , Músculo Esquelético , Polimorfismo Genético , RNA Mitocondrial , Pele/citologiaRESUMO
We report the case of a 2-year-old boy with seizures who developed hepatic failure shortly after commencing sodium valproate. Unexpectedly, liver function returned to normal on stopping the drug. Sequencing of the mitochondrial polymerase gamma gene (POLG1) revealed four heterozygous substitutions, two of which have been identified in cases of Alpers-Huttenlocher disease.
Assuntos
DNA Mitocondrial/genética , DNA Polimerase Dirigida por DNA/genética , Falência Hepática Aguda/induzido quimicamente , Mutação , Ácido Valproico/efeitos adversos , Anticonvulsivantes/efeitos adversos , Pré-Escolar , DNA Polimerase gama , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
Vascular injury as a complication of disc surgery was first reported in 1945 by Linton and White. It is a rare but potentially fatal complication. The high mortality rate (40-100%) is attributed to a combination of rapid blood loss and the failure to recognise the cause of the deteriorating patient. Early diagnosis and treatment is essential. Treatment has traditionally been by open vascular surgical repair, however with modern imaging and endovascular techniques, minimally invasive treatment should be considered first line in patients who are stable. We present the case of a 51-year-old woman who sustained common iliac artery injury during lumbar spinal surgery that was treated successfully using a covered stent.
Assuntos
Descompressão Cirúrgica/efeitos adversos , Artéria Ilíaca/lesões , Laminectomia/efeitos adversos , Vértebras Lombares/cirurgia , Hemorragia Pós-Operatória/etiologia , Procedimentos Cirúrgicos Vasculares/métodos , Diagnóstico Precoce , Extravasamento de Materiais Terapêuticos e Diagnósticos/etiologia , Feminino , Hemostáticos/administração & dosagem , Humanos , Hipotensão/etiologia , Hipotensão/fisiopatologia , Doença Iatrogênica/prevenção & controle , Artéria Ilíaca/patologia , Artéria Ilíaca/cirurgia , Deslocamento do Disco Intervertebral/complicações , Deslocamento do Disco Intervertebral/patologia , Deslocamento do Disco Intervertebral/cirurgia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Hemorragia Pós-Operatória/patologia , Hemorragia Pós-Operatória/cirurgia , Radiculopatia/etiologia , Radiculopatia/patologia , Radiculopatia/fisiopatologia , Espaço Retroperitoneal/diagnóstico por imagem , Espaço Retroperitoneal/patologia , Raízes Nervosas Espinhais/patologia , Raízes Nervosas Espinhais/cirurgia , Stents/normas , Trombina/administração & dosagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/instrumentaçãoRESUMO
We report magnetotransport studies of a two-dimensional electron system formed in an inversion layer at the interface between a hydrogen-passivated Si(111) surface and vacuum. Measurements in the integer quantum Hall regime demonstrate that the expected sixfold valley degeneracy for these surfaces is broken, resulting in an unequal occupation of the six valleys and anisotropy in the resistance. We hypothesize the misorientation of Si surface breaks the valley states into three unequally spaced pairs, but the observation of odd filling factors is difficult to reconcile with noninteracting electron theory.
RESUMO
BACKGROUND: In clinical practice, mitochondrial disease is seldom considered until a variable combination of seizures, alteration in tone, muscle weakness, and developmental problems is evident. However, it is not uncommon for one symptom to occur in isolation and dominate the clinical phenotype. We report six patients from two families where dystonia was the principal clinical manifestation. A mitochondrial etiology was considered in each case because of the association of dystonia with other less prominent clinical features such as epilepsy. METHODS: Histochemical and biochemical analyses were undertaken in skeletal muscle biopsies from individuals in both families. Sequencing of skeletal muscle mtDNA was also performed and suspected mutations were quantified by hot last cycle PCR-RFLP or primer extension assay. Functional consequences of one of the mutations were investigated by measurement of steady state levels of mitochondrial tRNA. RESULTS: Two distinct mitochondrial pathologies were identified: a novel, homoplasmic mitochondrial tRNA(Cys) (MTTC) mutation and the primary, m.11778G>A Leber hereditary optic neuropathy (LHON) mutation. The mild nature of both mutations has permitted very high levels of mutated mtDNA to accumulate. Patients with the mutation in the MTTC gene have no wild type mtDNA detectable and although the LHON mutation is heteroplasmic in the patients we report, it is commonly observed to be homoplasmic. CONCLUSIONS: The mitochondrial etiology identified in these patients emphasizes the pathologic potential of homoplasmic mutations and has important implications for the investigation and genetic counseling of families where dystonia is the principal clinical feature. We advocate that mitochondrial disease should be given serious consideration in patients with familial, progressive dystonia, particularly when additional neurologic features such as epilepsy are present.