RESUMO
PURPOSE: Microtia describes a spectrum of auricular malformations ranging from mild dysplasia to anotia. A vast majority of microtia patients demonstrate congenital aural atresia (CAA). Isolated microtia has a right ear predominance (58-61%) and is more common in the male sex. Isolated microtia is a multifactorial condition involving genetic and environmental causes. The aim of this study is to describe the phenotype of children with unilateral isolated microtia and CAA, and to search for a common genetic cause trough DNA analysis. METHODS: Phenotyping included a complete clinical examination. Description on the degree of auricular malformation (Weerda classification-Weerda 1988), assessment for hemifacial microsomia and age-appropriate audiometric testing were documented. Computerized tomography of the temporal bone with 3-D rendering provided a histopathological classification (HEAR classification-Declau et al. 1999). Genetic testing was carried out by single nucleotide polymorphism (SNP) microarray. RESULTS: Complete data are available for 44 children (50% was younger than 33 days at presentation; 59.1% boys; 72.7% right ear). Type III microtia was present in 28 patients. Type 2b CAA existed in 32 patients. All patients had a normal hearing at the non-affected side. Genome wide deletion duplication analysis using microarray did not reveal any pathological copy number variant (CNV) that could explain the phenotype. CONCLUSIONS: Type III microtia (peanut-shell type) in combination with a type 2b CAA was the most common phenotype, present in 23 of 44 (52.3%) patients with isolated unilateral microtia. No abnormalities could be found by copy number variant (CNV) analysis. Whole exome sequencing in a larger sample with a similar phenotype may represent a future diagnostic approach.
Assuntos
Anormalidades Congênitas , Microtia Congênita , Masculino , Feminino , Humanos , Microtia Congênita/genética , Microtia Congênita/cirurgia , Estudos Retrospectivos , Orelha/anormalidades , Testes Auditivos , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genéticaAssuntos
Fibrose Pulmonar Idiopática , Humanos , Indóis , Piridonas , Sistema de Registros , Estados UnidosRESUMO
BACKGROUND: Nintedanib (Ofev®) and pirfenidone (Esbriet®) are recommended by international guidelines as treatment options for idiopathic pulmonary fibrosis (IPF). OBJECTIVES: To compare the cost-effectiveness of nintedanib with that of pirfenidone for the treatment of IPF from a Belgian healthcare payer perspective. METHODS: The economic analysis used a Markov model that calculated outcomes over patient lifetime. Overall survival was assumed to be the same for the two comparators. Data from a network meta-analysis were used for loss of lung function, acute exacerbation events, safety and treatment discontinuation (for any reason). The health-state utility estimates in the model were calculated from EQ-5D scores collected in nintedanib studies. The assumed resource use for background care was also based on patient-level data that were categorised to fit the health states in the model and synthesised with costs and tariffs from Belgian national databases. RESULTS: Treatment with nintedanib resulted in an estimated total cost of 102,315, which was less than the total cost of treatment with pirfenidone (113,313). Given the similarities in the survival and progression outcomes obtained with nintedanib and pirfenidone, the model predicted near equivalence in total QALYs (3.353 QALYs for the nintedanib arm and 3.318 for the pirfenidone arm). Results were largely driven by model assumptions underlying mortality, acute exacerbations and treatment discontinuation. CONCLUSIONS: After performing a synthesis of the most recently published evidence for IPF patients and assuming a Belgian healthcare payer perspective, we found nintedanib to be more cost-saving than pirfenidone.
Assuntos
Transplante de Órgãos , Sarcoidose Pulmonar/cirurgia , Sarcoidose/cirurgia , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/cirurgia , Humanos , Falência Hepática/etiologia , Falência Hepática/cirurgia , Insuficiência Renal/etiologia , Insuficiência Renal/cirurgia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/cirurgia , Sarcoidose/complicações , Sarcoidose Pulmonar/complicações , Taxa de SobrevidaAssuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Proteínas de Ligação ao Cálcio/genética , Quinase de Cadeia Leve de Miosina/genética , Idoso , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/fisiopatologia , Códon sem Sentido/genética , Feminino , Haploinsuficiência/genética , Humanos , Masculino , Anamnese , Pessoa de Meia-Idade , LinhagemRESUMO
Pulmonary alveolar (phospholipo)proteinosis (PAP) is a rare lung disease, predominantly autoimmune in nature. This case report describes a patient with insidious dyspnoea since 5 years and a milky appearance of her bronchoalveolar fluid, leading to the diagnosis of PAP. The onset of symptoms coincided with an exchange of her silicone breast implants. Giant cell reaction in axillary adenopathies pointed towards silicone leakage. Adjuvants, such as silicone, might boost pre-existing antigen reactions of the immune system, potentially leading to autoimmune phenomena.
Assuntos
Doenças Autoimunes/diagnóstico , Implantes de Mama/efeitos adversos , Proteinose Alveolar Pulmonar/diagnóstico , Géis de Silicone/efeitos adversos , Doenças Autoimunes/etiologia , Feminino , Granuloma de Células Gigantes/patologia , Humanos , Pessoa de Meia-Idade , Proteinose Alveolar Pulmonar/etiologiaRESUMO
Interstitial lung disease (ILD) is one of the most critical complications associated with idiopathic inflammatory myopathies (IIM). If medical treatment fails, the only option is lung transplantation (LTx), however, this is still controversial mainly because the outcome is unknown. This case series compared patients with IIM who underwent transplantation in the University Hospitals of Leuven among a total of 90 LTxs for ILD between January 2004 and August 2013. From the 5 IIM patients with associated ILD there were 4 males and 1 female. The mean age at transplantation was 54.4 ± 4.3 years. Three patients underwent sequential single lung (SSLTx) and 2 underwent single lung transplantation (SLTx). Their mean pre-LTx % predicted forced expiratory volume in the first second (FEV1) was 42.8 ± 7.5%, forced vital capacity (FVC) was 49.8 ± 9.6%, total lung capacity (TLC) was 60.8 ± 8.1%, and transfer coefficient for carbon monoxide (DLCO) was 35.1 ± 9.3%. Mean 6-minute walking test (SMWT) before LTx was 316.0 ± 146 meters. In one patient there was an acute rejection (AR) after 20 days. No lymphocytic bronchiolitis (LB) nor chronic rejection was observed. The 1-year survival rate was 100%, and the 2- and 5-year survival rates were 75% (follow-up period of 32.6 ± 4.4 months) compared with 86%, 67%, and 58%, respectively, for patients undergoing LTx for idiopathic pulmonary fibrosis (IPF) (follow-up period of 35.2 ± 3.9) and 86%, 63%, and 57%, respectively, for patients undergoing LTx for non-IPF non-IIM ILD (follow-up period of 40.6 ± 20.5 months). LTx could be a valid option in well-selected patients with ILD related to IIM, yielding a good postoperative course and acceptable 1-, 2-, and 5-year survival rates, compared with patients undergoing LTx for IPF and non-IPF non-IIM-related ILD.
Assuntos
Pneumopatias/mortalidade , Transplante de Pulmão , Polimiosite/cirurgia , Adulto , Bélgica , Feminino , Volume Expiratório Forçado , Rejeição de Enxerto , Humanos , Fibrose Pulmonar Idiopática/cirurgia , Pneumopatias/fisiopatologia , Transplante de Pulmão/mortalidade , Masculino , Pessoa de Meia-Idade , Polimiosite/fisiopatologia , Taxa de SobrevidaRESUMO
We describe the case of a man with known dermatomyositis who presented with a dry cough and who early after admission rapidly evolved to respiratory insufficiency. Based on pathological and radiological findings, the diagnosis of diffuse alveolar damage was made. Postmortem examination also revealed infection with yeast, Torulopsis glabrata. Polymyositis (PM) and dermatomyositis (DM) are both auto-immune diseases, which are characterised by the presence of auto-antibodies and tissue-inflammation, mainly involving the muscles. Patients with PM/DM may have pulmonary complications, often responsible for higher morbidity and mortality. Interstitial lung disease can present itself in different shapes and forms (bronchiolitis obliterans organising pneumonia, non-specific organising pneumonia, usual interstitial pneumonia, acute interstitial pneumonia) and the diagnosis is made based on the combination of pathological examination and radiological findings.
Assuntos
Dermatomiosite/complicações , Doenças Pulmonares Intersticiais/etiologia , Dermatomiosite/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Sarcoidosis is a multisystem disorder of unknown cause with a highly variable course. Corticosteroids are considered the standard agent for treatment, however there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. There seems to be a limited benefit on chest radiographic findings, forced vital capacity and diffusing capacity. The evidence supporting the disease-modulating effect is limited. Cytotoxic agents are often used as steroid-sparing in patients requiring chronic therapy, however there are only little randomized controlled trials to support their use and side effects are common. Tumour necrosis factor-a is thought to be crucial in the development of the typical granulomas in sarcoidosis. Many case reports and case series suggest that specific therapy targeted against this cytokine is very effective. Despite these promising results, only limited evidence is found in multicenter randomized controlled trials.
Assuntos
Sarcoidose/terapia , Adalimumab , Anticorpos Monoclonais Humanizados/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Sarcoidose Pulmonar/terapia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Pulmonary artery intima sarcoma is an uncommon but fatal tumor, which often masquerades chronic thromboembolic pulmonary hypertension (CTEPH) and in the present case Takayasu arteritis. Pulmonary arterial pressure is mildly elevated in the presence of extensive proximal lesions. A parenchyma thin-walled cavitary lesion may be a sign of pulmonary extravasation of the tumor.
RESUMO
BACKGROUND: The development of targeted therapies has created a pressing clinical need for molecular characterisation of cancers. In this retrospective study, high-resolution melting analysis (HRMA) was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect KRAS hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS: After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of KRAS mutations in CRC was evaluated using survival analysis. RESULTS: HRMA revealed abnormal melting patterns in 34.1% CRC samples. Kaplan-Meier survival curves revealed a significantly shorter overall (OS) and disease-free survival (DFS) for CRC patients harbouring a KRAS mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, KRAS mutation was a negative predictor for OS in patients with rectal cancer and DFS in those with stage II colon cancer. CONCLUSIONS: HRMA was found to be a valid screening method for KRAS mutation detection. The KRAS mutation came forward as a negative predictive factor for OS in patients with rectal cancer and for DFS in stage II colon cancer patients.
Assuntos
Neoplasias Colorretais/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Primers do DNA , DNA de Neoplasias/genética , Variação Genética , Humanos , Programas de Rastreamento/métodos , Mutação , Desnaturação de Ácido Nucleico , Reação em Cadeia da Polimerase , Prognóstico , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Retais/genética , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Análise de Regressão , Análise de SobrevidaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a devastating disease without proper treatment. Despite intensive research, the exact underlying pathogenesis remains elusive. It is regarded as a continuous injury, resulting in inflammation, infiltration, and proliferation of fibroblasts and extracellular matrix deposition, leading to an irreversible restrictive lung function deterioration and death. In this study the effect of azithromycin, a macrolide antibiotic on bleomycin-induced pulmonary fibrosis was investigated. C57BL/6 mice were intratracheally instilled with bleomycin (0.5 mg/kg) or saline. In the bleomycin group, half of the animals received azithromycin every other day from day 1 on. Bronchoalveolar lavage and histology were performed at days 7 and 35, and pulmonary function tests on day 35. At day 35, fibrotic lesions (spindle cell proliferation/collagen I deposition) were paralleled by a restrictive lung function pattern. Alterations were found in neutrophils and macrophages (innate immunity) and in T(H)2, T(H)17, and Treg cytokines (adaptive immunity). Azithromycin significantly reduced both fibrosis and the restrictive lung function pattern. This study demonstrated a beneficial effect of azithromycin on bleomycin-induced pulmonary fibrosis. A possible mechanism could be a modulation of both innate immunity and adaptive immunity. These findings might suggest a potential role for azithromycin in the treatment of IPF.
Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Linfócitos T CD4-Positivos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Imunidade Inata/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Azitromicina/farmacologia , Biomarcadores/análise , Bleomicina , Peso Corporal , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/análise , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Contagem de Leucócitos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Função RespiratóriaRESUMO
Eleven affected members of a large German-American family segregating recessively inherited, congenital, non-syndromic sensorineural hearing loss (SNHL) were found to be homozygous for the common 35delG mutation of GJB2, the gene encoding the gap junction protein Connexin 26. Surprisingly, four additional family members with bilateral profound SNHL carried only a single 35delG mutation. Previously, we demonstrated reduced expression of both GJB2 and GJB6 mRNA from the allele carried in trans with that bearing the 35delG mutation in these four persons. Using array comparative genome hybridization (array CGH), we have now identified on this allele a deletion of 131.4 kb whose proximal breakpoint lies more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6. This deletion, del(chr13:19,837,344-19,968,698), segregates as a completely penetrant DFNB1 allele in this family. It is not present in 528 persons with SNHL and monoallelic mutation of GJB2 or GJB6, and we have not identified any other candidate pathogenic copy number variation by arrayCGH in a subset of 10 such persons. Characterization of distant GJB2/GJB6 cis-regulatory regions evidenced by this allele may be required to find the 'missing' DFNB1 mutations that are believed to exist.
Assuntos
Conexinas/genética , Regulação da Expressão Gênica , Sequências Reguladoras de Ácido Nucleico/genética , Deleção de Sequência , Alelos , Sequência de Bases , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Hibridização Genômica Comparativa , Conexina 26 , Conexina 30 , Saúde da Família , Feminino , Testes Genéticos , Genótipo , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Penetrância , Homologia de Sequência do Ácido NucleicoRESUMO
A 51-year-old woman with eosinophilic pneumonia due to minocycline is described and a review of available literature is added. Until now, only 49 cases have been described, mainly in the Japanese population. Minocycline induced eosinophilic pneumonia is probably underreported and even underdiagnosed. This case highlights the importance of careful history taking, especially the use of drugs. Relatively safe drugs (like minocycline) can cause serious adverse events. On presentation, the disease mimics an infectious pneumonia. Peripheral eosinophilia can occur but isn't obligatory. A bronchoalveolar lavage may provide the first (and sometimes only) sign of eosinophilic lung disease. Withdrawal of minocycline is often enough although sometimes corticosteroids are needed. In general, prognosis is good when the diagnosis is made on time.
Assuntos
Antibacterianos/efeitos adversos , Minociclina/efeitos adversos , Eosinofilia Pulmonar/complicações , Acne Vulgar/tratamento farmacológico , Antibacterianos/uso terapêutico , Lavagem Broncoalveolar , Broncoscopia , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Minociclina/uso terapêutico , Eosinofilia Pulmonar/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
Bronchiolitis obliterans syndrome (BOS) is the leading cause of death after lung transplantation. Treatment is challenging, as the precise pathophysiology remains unclear. We hypothesize that T(H)17 lineage plays a key role in the pathophysiology of BOS by linking T-cell activation to neutrophil influx and chronic inflammation. In a cross-sectional study, bronchoalveolar lavage (BAL) samples of 132 lung transplant recipients were analyzed. Patients were divided in four groups: stable or suffering from infection (INF), acute rejection (AR) or BOS. The upstream T(H)17 skewing (TGF-beta/IL1beta/IL6/IL23), T(H)17 counteracting (IL2), T(H)17 effector cytokine (IL17) and the principal neutrophil-attracting chemokine (IL8), were quantified at the mRNA or protein level in combination with the cell profiles. The BOS group (n = 36) showed an increase in IL1beta protein (x1.5), IL6 protein (x3), transforming growth factor-beta (TGF-beta) mRNA (x3), IL17 mRNA (x20), IL23 mRNA (x10), IL8 protein (x2), IL8 mRNA (x3) and a decrease in IL2 protein (x0.8). The infection group (n = 11) demonstrated an increase in IL1beta protein (x5), IL6 protein (x20), TGF-beta mRNA (x10), IL17 mRNA (x300), IL23 mRNA (x200) and IL8 protein (x6). The acute rejection group (n = 43) only revealed an increase in IL6 protein (x6) and IL8 protein (x2) and a decrease in IL2 protein (x0.7). Lymphocytes and neutrophils were increased in all groups compared to the stable (n = 42). Our findings demonstrate the IL23/IL17 axis to be involved in the pathophysiology of BOS potentially triggering the IL8-mediated neutrophilia. IL6, IL1beta and IL23 seem to be skewing cytokines and IL2 a counteracting cytokine for T(H)17 alignment. The involvement of TGF-beta could not be confirmed, either as T(H)17 steering or as counteracting cytokine.
Assuntos
Bronquiolite Obliterante/fisiopatologia , Interleucina-17/fisiologia , Interleucina-23/fisiologia , Transplante de Pulmão/efeitos adversos , Adulto , Bronquiolite Obliterante/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutrófilos/metabolismo , RNA Mensageiro/análise , SíndromeRESUMO
The proximal chromosome 11p contiguous gene deletion syndrome (P11pDS), also known as Potocki-Shaffer syndrome (PSS) or DEFECT 11 (OMIM 601224), is a disorder associated with foramina parietalia permagna and multiple osteochondroma (exostoses). Additional features include mental retardation, craniofacial anomalies, seizures and genitourinary abnormalities. Here, clinico-pathological findings of a unique patient with all of these features and, additionally, enlarged ventricles, hypertrophic obstructive cardiomyopathy and adipositas are described. The brain showed malformative lesions with hallmarks of disturbed bulk growth including micrencephaly, periventricular nodular heterotopias and focal cortical dysplasia in the nodulus of the cerebellar vermis. In addition, symmetric foci with vacuolation of the underlying neuropil, intermingled macrophages and large bizarre, partially vacuolated, reactive astrocytes were found. The proximal short arm of chromosome 11 harbors several candidate genes that could explain the patient's signs and symptoms including ALX4 and EXT2, which are always present in the interstitial deletion of the short arm of chromosome 11 in PSS. In addition, MYBPC3 would be a good candidate for the hypertrophic cardiomyopathy. Furthermore, adipositas might be related to the MAPK8IP1 gene. To the best of our knowledge, the present patient is the oldest one so far described with PSS phenotype and the only case that has undergone detailed neuropathological investigation.