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1.
Am J Otolaryngol ; 43(1): 103214, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34607277

RESUMO

PURPOSE: Research indicates that most providers give opiates after endoscopic sinonasal surgery. The effectiveness of non-opiate medications after sinonasal surgery is poorly understood and most studies do not assess medication failure. This study compares oral opiate, oral opiate and topical steroid, and oral non-opiate pain control. Patient call-backs are used as a proxy for pain medication failure. MATERIALS AND METHODS: This study compares three medication regiments after sinonasal surgery for 180 adults with chronic rhinosinusitis. Patients were instructed to take acetaminophen for mild pain. For moderate/severe pain, patients used: 1) oxycodone-acetaminophen, 2) oxycodone-acetaminophen + budesonide nasal rinses, or 3) meloxicam + acetaminophen. Patients were instructed to call clinic if pain was not controlled. Descriptive statistics compared cohorts. Chi-square tests compared call-backs between cohorts. Logistic regression adjusted for baseline differences in covariates, comorbidities, and operative sites. RESULTS: Cohorts had similar age, sex distribution, disease features, and extent of surgery. The meloxicam cohort had less subjects with pain disorders. The oxycodone cohort had less subjects with diabetes, septoplasty, and turbinate reduction. After adjusting for baseline differences and using oxycodone as the reference group (n = 50), the odds of calling clinic for poorly controlled pain was 0.18 (95% Confidence Interval (CI): 0.05-0.6) in the meloxicam cohort (n = 45) and 0.19 (95% CI:0.07-0.5) in the oxycodone + budesonide rinses cohort (n = 85). CONCLUSION: In this study, both meloxicam and oxycodone + budesonide rinses were more effective at controlling pain after sinonasal surgery than oxycodone alone.

2.
Viruses ; 13(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34452405

RESUMO

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.


Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Transcriptoma , Adenosina Trifosfatases/antagonistas & inibidores , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Antivirais/farmacologia , Encéfalo/metabolismo , Simulação por Computador , Dengue/sangue , Dengue/genética , Dengue/metabolismo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , NF-kappa B/metabolismo , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Dengue Grave/sangue , Dengue Grave/tratamento farmacológico , Dengue Grave/genética , Dengue Grave/metabolismo , Baço/metabolismo
3.
Open Forum Infect Dis ; 7(10): ofaa407, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33123608

RESUMO

Early recognition of severe forms of coronavirus disease 2019 (COVID-19) is essential for an opportune and effective intervention, reducing life-risking complications. An altered inflammatory immune response seems to be associated with COVID-19's pathogenesis and progression to severity. Here we demonstrate the utility of early nasopharyngeal swab samples for detection of the early expression of immune markers and the potential value of CCL2/MCP-1 in predicting disease outcome.

4.
Nat Rev Immunol ; 20(10): 594-602, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913283

RESUMO

The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Assuntos
COVID-19/epidemiologia , Infecções por Coronavirus/epidemiologia , Cooperação Internacional , Pandemias , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/epidemiologia , Sociedades Científicas/organização & administração , Antivirais/síntese química , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/terapia , Vacinas contra COVID-19 , Relações Comunidade-Instituição , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Saúde Global/tendências , Humanos , Educação de Pacientes como Assunto/organização & administração , Equipamento de Proteção Individual/provisão & distribuição , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , SARS-CoV-2 , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/terapia , Vacinas Virais/biossíntese
5.
Cir Cir ; 88(4): 448-452, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32567591

RESUMO

Objective: To summarize the features of the Merkel cell carcinoma (MCC) and to sistematyze its diagnosis and therapeutic management. Method: We performed a literature review in PubMed, obtaining a total of 3,308 articles, selecting 10 for its complete reading and 22 for the reading of the summary according to the content. Results: In none of our patients, the MCC was the first suspected diagnosis. The treatment consisted in surgical excision with tumor free margins and lymphadenectomy. We offered ad-juvant RT which they rejected. They remain disease-free at the present time. Conclusions: MCC is a rare and aggressive disease which presents as a fast-growing solitary asymptomatic erythematous nodule in those areas of skin which are exposed to sunlight in elderly patients. The main risk factors include radiative ultraviolet, immunosuppression and merkel cell polyomavirus. Surgery is the main loco-regional treatment. Lymph node metastases in the course of the disease is one of the main prognostic factors. If there are no adenopaties, sentinel lymph node biopsy must be done; if there are adenopaties or a positive biopsy, lymphadenectomy is indicated. Radiotherapy is indicated in all stages of disease since it has shown to improve loco-regional control. In distant metastatic disease, immunotherapy and participating in clinical trials are the first choice.


Assuntos
Carcinoma de Célula de Merkel , Neoplasias Faciais , Hallux , Neoplasias Cutâneas , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/cirurgia , Neoplasias Faciais/diagnóstico , Neoplasias Faciais/mortalidade , Neoplasias Faciais/patologia , Neoplasias Faciais/cirurgia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Margens de Excisão , Radioterapia Adjuvante , Fatores de Risco , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia
6.
Sci Rep ; 10(1): 7194, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32346028

RESUMO

The QuantiFERON-CMV (QF) assay measures cell-mediated immunity against cytomegalovirus (CMV-CMI), which is particularly useful in individuals susceptible to CMV infection such as transplant patients. A positive QF result identifies patients that are better protected against CMV infection. However, the significance of a negative QF result in CMV-seropositive individuals needs to be clarified. CMV-CMI was analyzed in healthy subjects using the QF assay, and, in parallel, the Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA). FASCIA assay measures T-cell proliferation using CMV lysate as stimulus whereas QF assay use a mix of peptides. A total of 93 healthy volunteers were enrolled, and 13/71 CMV-seropositive individuals (18.3%) showed humoral/cellular discordance using QF assay (CMV+ QF-). Interestingly, with FASCIA assay CD4+ and CD8+ T-cell proliferations were lower in CMV+ QF- than in CMV+ QF+ individuals. Furthermore, CMV+ QF- volunteers had a lower level of anti-CMV IgG than CMV+ QF+ subjects. Discordant CMV+ QF- volunteers can be defined as low responder individuals since they show lower CMV-specific humoral and cellular immune responses in comparison to CMV+ QF+ individuals. Immune discordance shows the high heterogeneity of immunity to CMV in healthy subjects.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Imunidade Celular , Adulto , Anticorpos Antivirais/imunologia , Feminino , Humanos , Imunoensaio , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade
7.
Am J Med Genet A ; 182(6): 1473-1476, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32196970
8.
Dev Comp Immunol ; 102: 103485, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461636

RESUMO

The Fasciola hepatica/Pseudosuccinea columella interaction in Cuba involves a unique pattern of phenotypes; while most snails are susceptible, some field populations are naturally resistant to infection and parasites are encapsulated by snail hemocytes. Thus, we investigated the hemocytes of resistant (R) and susceptible (S) P. columella, in particular morphology, abundance, proliferation and in vitro encapsulation activity following exposure to F. hepatica. Compared to susceptible P. columella, hemocytes from exposed resistant snails showed increased levels of spreading and aggregation (large adherent cells), proliferation of circulating blast-like cells and encapsulation activity of the hemocytes, along with a higher expression of the cytokine granulin. By contrast, there was evidence of a putative F. hepatica-driven inhibition of host immunity, only in susceptible snails. Additionally, (pre-)incubation of naïve hemocytes from P. columella (R and S) with different monosaccharides was associated with lower encapsulation activity of F. hepatica larvae. This suggests the involvement in this host-parasite interaction of lectins and lectins receptors (particularly related to mannose and fucose sensing) in association with hemocyte activation and/or binding to F. hepatica.


Assuntos
Resistência à Doença , Fasciola hepatica/fisiologia , Hemócitos/imunologia , Interações Hospedeiro-Parasita/imunologia , Larva/fisiologia , Caramujos/imunologia , Animais , Diferenciação Celular , Proliferação de Células , Cuba , Suscetibilidade a Doenças , Expressão Gênica , Granulinas/genética , Granulinas/imunologia , Hemócitos/parasitologia , Imunidade Inata , Monossacarídeos/química , Monossacarídeos/imunologia , Fenótipo , Caramujos/parasitologia
9.
Mol Genet Genomic Med ; 7(10): e00959, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31469246

RESUMO

BACKGROUND: Oculo-auriculo-vertebral spectrum (OAVS) is a craniofacial developmental disorder that affects structures derived from the first and second pharyngeal arches. The clinically heterogeneous phenotype involves mandibular, oral, and ear development anomalies. Etiology is complex and poorly understood. Genetic factors have been associated, evidenced by chromosomal abnormalities affecting different genomic regions and genes. However, known pathogenic single-nucleotide variants (SNVs) have only been identified in MYT1 in a restricted number of patients. Therefore, investigations of SNVs on candidate genes may reveal other pathogenic mechanisms. METHODS: In a cohort of 73 patients, coding and untranslated regions (UTR) of 10 candidate genes (CRKL, YPEL1, MAPK1, NKX3-2, HMX1, MYT1, OTX2, GSC, PUF60, HOXA2) were sequenced. Rare SNVs were selected and in silico predictions were performed to ascertain pathogenicity. Likely pathogenic variants were validated by Sanger sequencing and heritability was assessed when possible. RESULTS: Four likely pathogenic variants in heterozygous state were identified in different patients. Two SNVs were located in the 5'UTR of YPEL1; one in the 3'UTR of CRKL and one in the 3'UTR of OTX2. CONCLUSION: Our work described variants in candidate genes for OAVS and supported the genetic heterogeneity of the spectrum.


Assuntos
Deficiências do Desenvolvimento/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Fatores de Transcrição Otx/genética , Regiões não Traduzidas
10.
Mol Syndromol ; 10(3): 139-146, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31191202

RESUMO

Patients with deletion of chromosome 13 present with variable clinical features, and the correlation between phenotype and genomic aberration is not well established in the literature, mainly due to variable sizes of the deleted segments and inaccuracy of breakpoint mapping. In order to improve the genotype-phenotype correlation, we obtained clinical and cytogenomic data from 5 Brazilian patients with different chromosome 13 deletions characterized by G-banding and array techniques. Breakpoints were nonrecurrent, with deletion sizes ranging from 3.8 to 43.3 Mb. Our patients showed some classic features associated with 13q deletion, independent of the location and size of the deletion: hypotonia, growth delay, psychomotor developmental delay, microcephaly, central nervous system anomalies, and minor facial dysmorphism as well as urogenital and limb abnormalities. Comparisons between the literature and our patients' data allowed us to narrow the critical regions that were previously reported for microphthalmia and urogenital abnormalities, indicating that gene haploinsufficiency of ARHGEF7, PCDH9 and DIAPH3, of MIR17HG and GPC6, and of EFNB2 may contribute to microcephaly, cardiovascular disease, and urogenital abnormalities, respectively. The knowledge about genes involved in the phenotypic features found in 13q deletion patients may help us to understand how the genes interact and contribute to their clinical phenotype, improving the patient's clinical follow-up.

11.
Cytogenet Genome Res ; 156(4): 173-178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566942

RESUMO

Complex small marker chromosomes (sSMCs) consist of chromosomal material derived from more than 1 chromosome. Complex sSMCs derived from chromosomes 4 and 21 are rare, with only 7 cases reported. Here, we describe a patient who presented with a complex sSMC derived from a maternal translocation between chromosomes 4 and 21, which was revealed by G-banding, MLPA, and array techniques. The marker chromosome der(21)t(4;21)(q32.1; q21.2)mat is composed of a 25.6-Mb 21pterq21.2 duplication and a 32.1-Mb 4q32.1q35.2 duplication. In comparison to patients with sSMCs derived from chromosomes 4 and 21, our patient showed a similar phenotype with neuropsychomotor developmental delay and facial dysmorphism as the most important finding, being a composition of the findings found in pure 4q and 21q duplications. The wide range of phenotypes associated with sSMCs emphasizes the importance of detailed cytogenomic analyses for an accurate diagnosis, prognosis, and genetic counseling.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 4/genética , Análise Citogenética/métodos , Adolescente , Bandeamento Cromossômico , Duplicação Cromossômica , Feminino , Humanos , Herança Materna , Polimorfismo de Nucleotídeo Único , Translocação Genética
12.
Sci Rep ; 8(1): 14905, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297726

RESUMO

Hepatitis C virus (HCV) response to direct-acting antivirals (DAAs) may be influenced by the presence of resistance-associated substitutions (RASs). This study aimed to assess if NS5A baseline RAS-guided treatment enhances the rate of sustained viral response (SVR) in naïve HCV-infected patients in clinical practice. All HCV-infected patients who initiated treatment with interferon (IFN)-free DAA-based regimens between March 2016 and May 2017 in 17 Spanish hospitals and who had evaluable SVR 12 weeks (SVR12) after the end of therapy were included. Patients had to be DAA naïve, with the exception of sofosbuvir with/without IFN. In one hospital, participants received therapy guided by the presence of NS5A-RASs (RGT population). Patients enrolled in the remaining hospitals, without baseline RASs testing, constituted the control population. A total of 120 and 512 patients were included in the RGT and control populations, respectively. Nine (7.5%) individuals in the RGT population showed baseline NS5A-RASs. All of them achieved SVR12. The SVR12 rate in the RGT population was 97.2% (three relapses) whereas it was 98.8% (six relapses) in the control population (p = 0.382). Our findings suggest that testing for baseline NS5A-RASs in naïve HCV-infected patients does not enhance the rate of SVR to DAA-based IFN-free therapy in clinical practice.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepatite C/tratamento farmacológico , Interferons/uso terapêutico , Antivirais/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Resposta Viral Sustentada , Proteínas não Estruturais Virais/genética
13.
Mol Syndromol ; 9(3): 159-163, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29928182

RESUMO

Keutel syndrome is caused by mutations in the matrix gamma-carboxyglutamic acid (MGP) gene (OMIM 154870) and is inherited in an autosomal recessive fashion. It is characterized by brachydactyly, pulmonary artery stenosis, a distinctive facial phenotype, and cartilage calcification. To date, only 36 cases have been reported worldwide. We describe clinical and molecular findings of the first Brazilian patient with Keutel syndrome. Keutel syndrome was suspected based on clinical and morphological evaluation, so we sequenced the MGP gene using the TruSight One Sequencing Panel (Illumina). The obtained MGP gene sequence was then validated by Sanger sequencing. We identified a novel pathogenic homozygous variant of the MGP gene (c.2T>C; p.Met1Thr) confirming Keutel syndrome. Proper diagnosis of this syndrome is important for clinical management and is an indication for genetic counseling. Keutel syndrome should be suspected in patients with cartilage calcifications and brachydactyly when associated with a distinctive facial phenotype and pulmonary artery stenosis.

14.
HIV Clin Trials ; 19(1): 23-30, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29447085

RESUMO

Background Data on the efficacy, safety, and concomitant use with other drugs of the combination ritonavir-boosted paritaprevir/ombitasvir plus dasabuvir (PrOD) in HIV/HCV-coinfected patients in real life are limited. The objectives of this study were to analyze these topics in HIV/HCV-coinfected subjects bearing HCV genotype 1 (GT1). Methods One hundred and eighty-two HIV/HCV-coinfected patients with GT1 (87 1a, 71 1b, 23 other) treated with PrOD, plus ribavirin (RBV) in 119 cases, in routine clinical practice were analyzed. The main variable of efficacy was sustained virological response (SVR) 12 weeks after completing therapy in an intention-to-treat (ITT) analysis and that of safety treatment discontinuation because of adverse effects. Factors associated with SVR were analyzed with a modified ITT (mITT) strategy. Results One hundred and seventy-two (94%) patients attained SVR, 3 (2%) experienced a relapse and two (1%) discontinued therapy due to adverse events. The rates of SVR in subjects with GT 1a and 1b by mITT were, respectively, 97% and 98%. Sixty-five (98%) out of 66 patients with cirrhosis and 107 (98%) out of 110 (p = 1) non-cirrhotics achieved SVR. Fifty-five (95%) patients on concomitant darunavir therapy developed SVR vs. 117 (99%) (p = 0.105) of those without DRV. RBV dose was reduced in 13 (11%) patients and permanently discontinued in 2 (2%), with no impact on SVR. Conclusions PrOD is highly effective and well tolerated in HIV/HCV-coinfected patients with GT1 in routine clinical practice. RBV is often required. However, RBV dose reduction or discontinuation is uncommonly needed and do not impair the SVR rate.


Assuntos
Antivirais/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Anilidas/administração & dosagem , Anilidas/uso terapêutico , Antivirais/administração & dosagem , Antivirais/classificação , Carbamatos/administração & dosagem , Carbamatos/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Infecções por HIV/genética , Humanos , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Ribavirina/administração & dosagem , Ribavirina/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Uracila/administração & dosagem , Uracila/análogos & derivados , Uracila/uso terapêutico
15.
J Med Virol ; 90(6): 1094-1098, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29427437

RESUMO

The presence of resistance-associated substitutions (RASs) at NS5A region might compromise the efficacy of Direct Acting Antiviral agents (DAAs). HCV resistance at NS5A region is mainly focused on patients with hepatitis C virus (HCV) genotypes 1a (G1a) and 3 (G3) with other factors of poor treatment response (ie cirrhosis, prior treatment-exposure, or HCV-RNA >800 000 IU/mL). Herein, we evaluated in a cohort of HCV G1a and G3 infected patients the prevalence of RASs at domain I NS5A using population-based sequencing and the impact of RASs on the optimization of current therapeutic strategies. The RASs considered as clinically relevant were: M28A/G/T, Q30D/E/H/G/K/L/R, L31M/V/F, H58D, and Y93C/H/N/S for G1a and Y93H for G3. A total of 232 patients naïve to NS5A inhibitors were included (166 G1a, 66 G3). The overall prevalence of NS5A RASs for G1a and G3 patients was low (5.5%) or null, respectively. A high proportion of patients harbored, at least, one factor of poor response (78.9% for G1a, and 75.8% for G3). Overall, the rates of patients harboring NS5A RASs in combination with any of the other factors were low and the vast majority of patients (G1a> 94% and G3 100%) could be treated with standard treatments of 12 weeks without ribavirin. In conclusion, testing NS5A RASs in specific HCV-infected populations (ie G1a & G3, cirrhosis, prior treatment experienced, HCV-RNA >800 000 IU/mL) might be useful to optimize current NS5A-based therapies avoiding ribavirin-related toxicities, and shortening treatment duration in the majority of patients.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Genótipo , Hepacivirus/genética , Hepatite C Crônica/virologia , Mutação de Sentido Incorreto , Proteínas não Estruturais Virais/genética , Adulto , Substituição de Aminoácidos , Antivirais/farmacologia , Seguimentos , Hepacivirus/classificação , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/genética , Prevalência , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Análise de Sequência de DNA
16.
Am J Med Genet A ; 176(3): 638-648, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29368383

RESUMO

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.


Assuntos
Aberrações Cromossômicas , Estudos de Associação Genética , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Análise Citogenética , Variações do Número de Cópias de DNA , Feminino , Síndrome de Goldenhar/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
17.
Cytogenet Genome Res ; 152(1): 29-32, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28738335

RESUMO

Miller-Dieker syndrome (MDS) is a contiguous gene deletion syndrome in which almost all patients present de novo 17p13.3 deletions. We report on a male infant with MDS and an unusual unbalanced translocation involving chromosomes Y and 17 that resulted in a large 5.5-Mb 17pterp13.2 deletion and a karyotype with 45 chromosomes. Apart from the deletion of the MDS critical region, the deletion of additional distal genes seemed to have no major influence on the patient's phenotype, since he did not show any unusual clinical findings that are not commonly described in MDS patients.


Assuntos
Pareamento de Bases/genética , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Y/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Translocação Genética , Análise Citogenética , Humanos , Lactente , Masculino
18.
Eur J Hum Genet ; 25(9): 1083-1086, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28612832

RESUMO

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by hemifacial microsomia associated with ear, eyes and vertebrae malformations showing highly variable expressivity. Recently, MYT1, encoding the myelin transcription factor 1, was reported as the first gene involved in OAVS, within the retinoic acid (RA) pathway. Fifty-seven OAVS patients originating from Brazil were screened for MYT1 variants. A novel de novo missense variant affecting function, c.323C>T (p.(Ser108Leu)), was identified in MYT1, in a patient presenting with a severe form of OAVS. Functional studies showed that MYT1 overexpression downregulated all RA receptors genes (RARA, RARB, RARG), involved in RA-mediated transcription, whereas no effect was observed on CYP26A1 expression, the major enzyme involved in RA degradation, Moreover, MYT1 variants impacted significantly the expression of these genes, further supporting their pathogenicity. In conclusion, a third variant affecting function in MYT1 was identified as a cause of OAVS. Furthermore, we confirmed MYT1 connection to RA signaling pathway.


Assuntos
Proteínas de Ligação a DNA/genética , Síndrome de Goldenhar/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo , Feminino , Síndrome de Goldenhar/diagnóstico , Células HEK293 , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/metabolismo
19.
PLoS Pathog ; 13(2): e1006220, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28241052

RESUMO

Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.


Assuntos
Metabolismo dos Lipídeos/genética , Receptores de Esteroides/genética , Receptor X Retinoide alfa/genética , Dengue Grave/genética , Grupo com Ancestrais do Continente Africano/genética , Cuba/etnologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Dengue Grave/etnologia
20.
Cytogenet Genome Res ; 150(1): 17-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27842301

RESUMO

Wolf-Hirschhorn syndrome (WHS) is a contiguous gene and multiple malformation syndrome that results from a deletion in the 4p16.3 region. We describe here a 6-month-old girl that presented with WHS features but also displayed unusual findings, such as epibulbar dermoid in the left eye, ear tags, and left microtia. Although on G-banding her karyotype appeared to be normal, chromosomal microarray analysis revealed an ∼13-Mb 4p16.3p15.33 deletion and an ∼9-Mb Xp22.33p22.31 duplication, resulting from a balanced maternal t(X;4)(p22.31;p15.33) translocation. The patient presented with functional Xp disomy due to an unbalanced X-autosome translocation, a rare cytogenetic finding in females with unbalanced rearrangements. Sequencing of both chromosome breakpoints detected no gene disruption. To the best of our knowledge, this is the first patient described in the literature with WHS and epibulbar dermoid, a typical characteristic of the oculoauriculovertebral spectrum (OAVS). Our data suggest that possible candidate genes for OAVS may have been deleted along with the WHS critical region.


Assuntos
Deleção Cromossômica , Duplicação Cromossômica/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos X/genética , Cisto Dermoide/genética , Translocação Genética/genética , Síndrome de Wolf-Hirschhorn/genética , Adulto , Criança , Bandeamento Cromossômico , Pontos de Quebra do Cromossomo , Feminino , Humanos , Lactente , Idade Materna
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