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Objectives: Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored. Methods: We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis. Results: We identified an intronic homozygous MFN2 c.600-31T>G variant that disrupts the branch point critical for intron 6 splicing. Full-length long-read isoform complementary DNA (cDNA) sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates 5 distinct altered splicing transcripts. All 5 altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consistent with MFN2 dysfunction. Although correctly spliced full-length MFN2 transcripts are still produced, this branch point variant results in deficient MFN2 levels and autosomal recessive Charcot-Marie-Tooth disease, axonal, type 2A (CMT2A). Discussion: This case highlights the utility of full-length isoform sequencing for characterizing the molecular mechanism of undiagnosed rare diseases and expands our understanding of the genetic basis for CMT2A.
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OBJECTIVE: Conservative management of cervical intraepithelial neoplasia (CIN) grade 2 in women younger than 25 years may reduce overtreatment. However, long-term efficacy remains uncertain. This retrospective cohort study aimed to determine the rate of recurrence of high-grade abnormalities among young women with a history of CIN 2 that spontaneously regressed within 2 years and compare this with the rate of high-grade abnormality in similar women with an initial diagnosis of CIN 1. STUDY DESIGN: We identified all women aged younger than 25 years who were diagnosed with CIN 1 or CIN 2 between January 2005 and August 2009 within 2 colposcopy units. Follow-up data from the National Cervical Screening Programme were obtained to identify those women who developed recurrent high-grade lesions before October 2012. Comparisons were made using Cox proportional hazards regression. RESULTS: A total of 683 women were included: 106 with CIN 2 that spontaneously regressed, 299 with treated CIN 2, and 278 with conservatively managed CIN 1. Median follow-up was 4 years. There was no significant difference in the risk of development of high-grade abnormalities after 2 years between the spontaneously regressing CIN 2 and CIN 1 groups (P = .83). Women with treated CIN 2 had a significantly lower risk of recurrence than women with untreated CIN 2 (P = .01). CONCLUSION: CIN 2 that has spontaneously regressed appears to behave as a low-grade lesion. This study contributes to the growing body of evidence that careful observation of CIN 2 is an efficacious and appropriate initial management option for women aged younger than 25 years at diagnosis.
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Recidiva Local de Neoplasia/epidemiologia , Displasia do Colo do Útero/epidemiologia , Displasia do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/cirurgia , Adolescente , Estudos de Coortes , Feminino , Humanos , Gradação de Tumores , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologia , Adulto Jovem , Displasia do Colo do Útero/patologiaRESUMO
BACKGROUND: Familial Mediterranean fever (FMF) is a disease characterized by recurrent fever, serositis, arthritis and unspecific myalgia. It is prevalent among Mediterranean people and has been shown to be associated with mutations in the Mediterranean fever (MEFV) gene which, encodes pyrin a regulatory protein of the inflammasome. As heterozygous mutations in MEFV can be associated with only mild inflammatory symptoms, such as arthralgia or chronic fibromyalgic pain, FMF may be underdiagnosed in the current diagnostic work-up of musculoskeletal diseases. METHODS: The selection of patients was carried out according to the following criteria: myofacial pain syndrome, seronegative oligoarthralgia, a slight inflammatory constellation and ethnic origin from the Mediterranean area. When these criteria were fulfilled a molecular genetic investigation was carried out RESULTS: This article presents evidence that 9 out of 12 Mediterranean patients with recurrent myofascial pain syndrome and mild inflammation revealed heterozygote mutations in the MEFV gene and 7 of these patients benefitted from treatment with colchicine. DISCUSSION: As colchicine treatment not only improved the myofascial pain but also prevented FMF-associated amyloidosis and nephropathy, differential diagnosis of fibromyalgia in patients of Mediterranean origin should include FMF and a genetic screening of the MEFV locus.
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Colchicina/uso terapêutico , Proteínas do Citoesqueleto/genética , Neuralgia Facial/tratamento farmacológico , Neuralgia Facial/genética , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Adulto , Neuralgia Facial/diagnóstico , Febre Familiar do Mediterrâneo/diagnóstico , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Pirina , Resultado do TratamentoRESUMO
BACKGROUND: Currently, management of antibody deficient patients differs significantly among caregivers. Evidence and consensus based (S3) guidelines for the treatment of primary antibody deficiencies were developed to improve the management of these patients. METHODS: Based on a thorough analysis of current evidence (systematic literature search in PubMed; deadline November 2011) 14 recommendations were finalized during a consensus meeting in Frankfurt in November 2011 using structured consensus methods (nominal group technique). Experts were nominated by their scientific societies/patient initiatives (Tab. 1). RESULTS: The guidelines focus on indication, practical issues and monitoring of immunoglobulin replacement therapy as well as on different routes of administration. Furthermore recommendations regarding supportive measures such as antiinfective therapy, vaccinations and physiotherapy are given. Combining literature evidence and experience of caregivers within this evidence and consensus based guidelines offers the chance to improve the quality of care for anti-body deficient patients.
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Comportamento Cooperativo , Síndromes de Imunodeficiência/terapia , Comunicação Interdisciplinar , Adulto , Anti-Infecciosos/uso terapêutico , Pré-Escolar , Terapia Combinada , Medicina Baseada em Evidências , Humanos , Imunização Passiva , Modalidades de Fisioterapia , Melhoria de Qualidade , Ensaios Clínicos Controlados Aleatórios como Assunto , VacinaçãoRESUMO
OBJECTIVE: The purpose of this study was to review the outcome of conservatively managed cervical intraepithelial neoplasia (CIN) 2 in women <25 years old. STUDY DESIGN: This was a retrospective review that included women who were <25 years old with biopsy proven CIN2 between 2005 and 2009. Analysis was performed that compared women who had immediate treatment with women whose treatment was deferred >4 months. The primary outcome measure was spontaneous regression of CIN2. Secondary outcomes were treatment rates and loss to follow-up evaluation. RESULTS: Of the 452 women who were identified, 256 women (57%) received immediate treatment; 157 women (35%) met the definition for conservative management, and 39 women (9%) had unknown subsequent management. Of the 157 women who were managed conservatively, 98 women (62%) showed spontaneous regression, with a median of 8 months observation. No conservatively managed women progressed to cancer. CONCLUSION: Based on the 62% regression rate in this study, routine treatment may not be necessary for all women with CIN2 who are <25 years old.
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Displasia do Colo do Útero/terapia , Neoplasias do Colo do Útero/terapia , Adulto , Fatores Etários , Colposcopia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Retrospectivos , Displasia do Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Esfregaço Vaginal , Adulto JovemRESUMO
A prospective, open-label, multicenter, single-arm, Phase III study evaluated the efficacy and safety of Hizentra(®), a 20% human IgG for subcutaneous administration, in 51 primary immunodeficiency patients over 40 weeks. Patients previously on intravenous or subcutaneous IgG were switched to weekly subcutaneous infusions of Hizentra(®) at doses equivalent to their previous treatment. IgG levels achieved with Hizentra(®) were similar to pre-study levels with subcutaneous, and higher by 17.7% than pre-study levels with intravenous IgG. No serious bacterial infections were reported in the efficacy period. The rate of all infections was 5.18/year/patient, the rates of days missed from work/school, and days spent in hospital were 8.00/year/patient and 3.48/year/patient, respectively. Local reactions (rate 0.060/infusion) were mostly mild (87.3%). No serious, Hizentra(®)-related adverse events were reported. Individual median infusion durations ranged between 1.14 and 1.27 h. Hizentra(®) maintained or improved serum IgG levels without dose increases and effectively protected patients against infections.
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Imunoglobulina G/administração & dosagem , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/sangue , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/sangue , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Infusões Intravenosas , Infusões Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (IVIG) therapy. METHODS: We evaluated the efficacy and safety of the SCIG Vivaglobin(formerly known as Beriglobin SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with IVIG (including 11 children <14 years) using the Short Form 36 (SF-36) for patients > or = 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children <14 years of age. Treatment preferences were assessed in adults. RESULTS: The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p<0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by > or = 5 points were observed in 5 of 8 SF-36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p< or =0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over IVIG therapy (92%) and home therapy over therapy at the clinic/physician (83%). CONCLUSION: This study confirms that therapy with Vivaglobin at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency.
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Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Nível de Saúde , Humanos , Imunoglobulinas/sangue , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/fisiopatologia , Imunoterapia/métodos , Lactente , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Adulto JovemRESUMO
Chronic periaortitis is a rare fibroinflammatory disorder which affects the abdominal aorta and may spread into the retroperitoneum, often encasing the ureters. An aneurysma of the abdominal aorta and vasculitis of the thoracic aorta and of supra-aortic vessels may also coexist. Chronic periaortitis can be idiopathic or secondary to different triggers such as drugs, tumors and infections. Abdominal and/or low back pain is the hallmark symptom. Laboratory markers of inflammation are usually increased. The diagnosis rests on computerized tomography or magnetic resonance imaging, which typically show a retroperitoneal mass displacing the aorta anteriorly and the ureters medially. Positron-emission tomography may assist in defining disease activity and extension. Chronic periaortitis should be differentiated from other fibrosing disorders of various origins. Histology is required in atypical cases to secure the diagnosis. Treatment is based on high-dose steroids with a tapering scheme combined with immunosuppressive agents in refractory or relapsing disease. In case of ureter obstruction early DJ-catheter placement is required. Operative interventions to relieve ureter obstruction are rarely necessary provided immunosuppressive treatment is timely instituted.
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Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Fibrose Retroperitoneal/diagnóstico , Fibrose Retroperitoneal/tratamento farmacológico , HumanosRESUMO
The posters presented at the 6th International Immunoglobulin Symposium covered a wide range of fields and included both basic science and clinical research. From the abstracts accepted for poster presentation, 12 abstracts were selected for oral presentations in three parallel sessions on immunodeficiencies, autoimmunity and basic research. The immunodeficiency presentations dealt with novel, rare class-switch recombination (CSR) deficiencies, attenuation of adverse events following IVIg treatment, association of immunoglobulin (Ig)G trough levels and protection against acute infection in patients with X-linked agammaglobulinaemia (XLA) and common variable immunodeficiency (CVID), and the reduction of class-switched memory B cells in patients with specific antibody deficiency (SAD). The impact of intravenous immunoglobulin on fetal alloimmune thrombocytopenia, pregnancy and postpartum-related relapses in multiple sclerosis and refractory myositis, as well as experiences with subcutaneous immunoglobulin in patients with multi-focal motor neuropathy, were the topics presented in the autoimmunity session. The interaction of dendritic cell (DC)-SIGN and alpha2,6-sialylated IgG Fc and its impact on human DCs, the enrichment of sialylated IgG in plasma-derived IgG, as wells as prion surveillance and monitoring of anti-measles titres in immunoglobulin products, were covered in the basic science session. In summary, the presentations illustrated the breadth of immunoglobulin therapy usage and highlighted the progress that is being made in diverse areas of basic and clinical research, extending our understanding of the mechanisms of immunoglobulin action and contributing to improved patient care.
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Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Doenças Autoimunes/tratamento farmacológico , Autoimunidade/imunologia , Pesquisa Biomédica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/imunologiaRESUMO
The objective of our study was to investigate the role of musculoskeletal ultrasound (US) in the assessment of hand and foot small joints in psoriatic arthritis (PsA). Thirteen consecutive patients with PsA of hands or feet underwent B-mode US using a 9- to 13-MHz transducer and simultaneous magnetic resonance imaging (MRI), bone scintigraphy and radiography. US findings were compared with radiography, MRI and scintigraphy in 190, 182 and 109 joints, respectively. To assess the sensitivity and specificity of US, radiography was considered as gold standard for the detection of erosions and osteoproliferations and MRI as gold standard for the detection of joint effusion and synovitis. US, MRI and scintigraphy had a higher sensitivity in the detection of overall joint pathology than radiography in painful and/or swollen joints (71%, 72%, 82% vs 32%) and clinically unaffected joints (17%, 21%, 9% vs 2%). US and radiography detected more erosions and osteoproliferations than MRI, with low agreement between the methods in the detection of erosions. Radiography was superior to US in the visualisation of osteoproliferations. Joint effusions and/or synovitis were more frequently detected by MRI than US. Agreement between both imaging methods was better in carpal joints, carpometacarpal joint I, metacarpophalangeal (MCP)/metatarsophalangeal (MTP) joint I, II and V than in MCP/MTP III, IV, PIP and DIP joints. Compared with MRI, radiography and scintigraphy, the specificity of US ranges between 0.84 and 0.94, depending on the joint pathology. In conclusion, the diagnostic sensitivity of US in the detection of PsA-related synovitis of hands and feet is lower than MRI and depends on the joint region. However, the low cost and the acceptable specificity suggest that US is a useful imaging method in addition to radiography in PsA of hands and feet.
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Artrite Psoriásica/diagnóstico por imagem , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Sinovite/diagnóstico por imagem , Adulto , Artrite Psoriásica/diagnóstico , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Radiografia , Cintilografia , Sensibilidade e Especificidade , Sinovite/diagnóstico , UltrassonografiaRESUMO
Giant cell arteritis (GCA) is a granulomatous vasculitis. Early diagnosis is important for the initiation of corticosteroid treatment because the arteritis can result in blindness. In most of the cases, the superficial cranial arteries are affected. However, extracranial involvement of various arteries is known. Here, we report a case of histologically proven GCA with an inflammatory stenosis of the right vertebral artery. For complete evaluation of the extension of the disease, an optimized protocol of high-resolution magnetic resonance imaging at 3 T in combination with contrast-enhanced magnetic resonance angiography was performed. This non-invasive method facilitates the differentiation of inflamed and healthy segments of small cranial arteries, may help to find appropriate sites for biopsy, and allows the assessment of affected extracranial vessels. In this patient case, even the cause of vertebral stenosis--inflammatory versus arteriosclerotic--could be elucidated.
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Arterite de Células Gigantes/patologia , Artéria Vertebral/patologia , Insuficiência Vertebrobasilar/etiologia , Idoso de 80 Anos ou mais , Feminino , Arterite de Células Gigantes/complicações , Humanos , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVES: This study investigated the long-term effects of bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, in patients with pulmonary arterial hypertension (PAH) exclusively related to connective tissue diseases (CTD). METHODS: A total of 53 patients with PAH related to connective tissue diseases (PAH-CTD) in World Health Organization (WHO) functional class III received bosentan 62.5 mg twice a day for 4 weeks and then 125 mg twice a day for 44 weeks in this open non-comparative study. Assessments at weeks 16 and 48 included WHO class, clinical worsening, quality of life (Short-Form Health Survey (SF-36) and health assessment questionnaire (HAQ) modified for scleroderma), and survival (week 48 only). Safety and tolerability were monitored throughout the study. RESULTS: At week 48, WHO class improved in 27% of patients (95% CI 16-42%) and worsened in 16% (95% CI 7-29%). Kaplan-Meier estimates were 68% (95% CI 55-82%) for absence of clinical worsening and 92% (95% CI 85-100%) for survival. Overall changes in quality of life were minimal. There were no unexpected side effects observed during the study. CONCLUSIONS: In most patients, bosentan was associated with improvement or stability of clinical status. The 92% estimate for survival at 48 weeks is a significant achievement in this patient population.
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Anti-Hipertensivos/uso terapêutico , Doenças do Tecido Conjuntivo/complicações , Hipertensão Pulmonar/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Anti-Hipertensivos/efeitos adversos , Bosentana , Esquema de Medicação , Quimioterapia Combinada , Métodos Epidemiológicos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hipertensão Pulmonar/etiologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the effect of corticosteroid treatment on mural inflammatory hyperenhancement in MRI in GCA. METHODS: MRI of the superficial temporal artery with sub-millimetre in-plane spatial resolution (195 x 260 microm) was performed in 17 patients with proven GCA at the initiation of corticosteroid treatment and after 16 months of therapy. Visual MRI scores for mural inflammation were correlated with clinical and laboratory findings. RESULTS: Intensity of inflammatory hyperenhancement decreased significantly under corticosteroid therapy (2.3 +/- 0.6 vs 0.5 +/- 0.6, P < 0.001, with MRI score >2 indicating vasculitis). This finding correlated with the clinical and serological remission in 15/17 patients. Of the two patients with active disease, one had persisting mural inflammation in MRI indicative of relapsing disease. The other patient presenting with signs of polymyalgia rheumatica had no inflammatory changes of the superficial temporal arteries on MRI scan at follow-up. CONCLUSIONS: Mural contrast enhancement in high-resolution MRI is pronounced in active disease and decreases under corticosteroid treatment, correlating well with laboratory remission.
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Artérias Cerebrais/patologia , Arterite de Células Gigantes/diagnóstico , Glucocorticoides/uso terapêutico , Angiografia por Ressonância Magnética/métodos , Prednisolona/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Sedimentação Sanguínea , Proteína C-Reativa/análise , Meios de Contraste/administração & dosagem , Feminino , Gadolínio DTPA/administração & dosagem , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/tratamento farmacológico , Humanos , Aumento da Imagem , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Clinical indications of giant cell arteritis may be unspecific, and noninvasive diagnosis is often difficult. This study investigated the hypothesis that high-resolution MR imaging of the superficial cranial arteries is a noninvasive imaging technique that can detect the occurrence of giant cell arteritis. MATERIALS AND METHODS: Contrast-enhanced, high-resolution MR imaging was performed on 64 consecutive patients with suspected giant cell arteritis. Mural thickness, lumen diameter, and a mural contrast enhancement score were assessed with T1-weighted spin-echo images with submillimeter in-plane spatial resolution. The final rheumatologist's diagnosis according to the clinical criteria of the American College of Rheumatology including laboratory tests and results of temporal artery biopsies from 32 patients was used as a "gold standard" for the evaluation of the MR imaging findings. RESULTS: All of the examinations provided diagnostic image quality. Evaluation of the mural inflammatory MR imaging signs for diagnosing vasculitis resulted in a sensitivity of 80.6% and a specificity of 97.0%. In comparison, histology results alone showed a sensitivity of 77.8% and specificity of 100%. The mean wall thickness increased significantly from 0.39 mm (+/-0.18 mm) to 0.74 mm (+/-0.32 mm; P < .001), and the lumen diameter decreased significantly from 0.84 mm (+/-0.29 mm) to 0.65 mm (+/-0.38 mm; P < .05) for patients with giant cell arteritis. CONCLUSION: Contrast-enhanced, high-resolution MR imaging allows noninvasive assessment of mural inflammation in giant cell arteritis with good diagnostic certainty. Measures of mural thickening and contrast enhancement can be obtained in these small vessels and provide valuable vasculitic MR imaging findings.