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- Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene: Influence of modifiers on 35delG/35delG phenotypePublication . Hilgert, Nele; Caria, Helena; Van Camp, GuyHereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 x 10(-3) and 1 x 10(-4). This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.
- Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association.Publication . Matos, T. D.; Simões-Teixeira, H.; Caria, Helena; Cascão, R.; Rosa, H.; O'Neill, A.; Dias, O.; Andrea, M.E.; Kelsell, D. P.; Fialho, G.Involvement of GJB2 noncoding regions in hearing loss (HL) has not been extensively investigated. However, three noncoding mutations, c.-259C>T, c.-23G>T, and c.-23+1G>A, were reported. Also, c.-684 -675del, of uncertain pathogenicity, was found upstream of the basal promoter. We performed a detailed analysis of GJB2 noncoding regions in Portuguese HL patients (previously screened for GJB2 coding mutations and the common GJB6 deletions) and in control subjects, by sequencing the basal promoter and flanking upstream region, exon 1, and 3’UTR. All individuals were genotyped for c.-684 -675del and 14 SNPs. Novel variants (c.-731C>T, c.-26G>T, c.∗45G>A, and c.∗985A>T) were found in controls. A hearing individual homozygous for c.-684 - 675del was for the first time identified, supporting the nonpathogenicity of this deletion. Our data indicate linkage disequilibrium (LD) between SNPs rs55704559 (c.∗168A>G) and rs5030700 (c.∗931C>T) and suggest the association of c.[∗168G;∗931T] allele with HL. The c.∗168A>G change, predicted to alter mRNA folding, might be involved in HL.
- Prevalência da algaliação sem indicação: um factor de risco evitávelPublication . Caramujo, Natércia; Carvalho, Manuel; Caria, HelenaA Infecção Associada aos Cuidados de Saúde constitui um problema com consequências importantes a nível socio-económico em todo o Mundo. A Infecção do Tracto Urinário é uma das Infecções Associadas aos Cuidados de Saúde com maior importância pela grande repercussão em termos de morbilidade, de impacto pessoal para os doentes e suas familias além do impacto económico para as instituições. A algaliação é reconhecida como o principal factor de risco associado à infecção do tracto urinário. No entanto, a sua utilização é, por vezes, essencial na prestação de cuidados de saúde. A frequência com que os doentes são algaliados e o tempo de algaliação determina o maior ou menor risco de infecção do tracto urinário. Se o doente estiver inapropriadamente algaliado então esse risco é evitável. O objectivo do presente estudo foi determinar a frequência da algaliação evitável num Departamento de Medicina, o que envolveu a análise de todos os doentes internados para determinar a presença de algaliação, em dois dias diferentes, e ainda a posterior consulta dos processos clínicos dos doentes algaliados para identificar os casos onde tinham surgido infecções do tracto urinário. Dos 160 doentes internados no período do estudo, 20% tinham catéter vesical. A indicação da algaliação foi na sua maioria (84,4%) médica. Nos indivíduos estudados, foi observado que 25% não tinham indicação apropriada para estarem algaliados naquele dia, verificando-se como justificações para a permanência da algália a gestão da incontinência (6,2%) e a ausência de indicação para a sua remoção (18,8%). Verificámos que doze dos indivíduos da amostra (37,5%) desenvolveram Infecção do Tracto Urinário e que cinco desses casos não tinham indicação apropriada para estarem algaliados. Concluiu-se que cinco casos de Infecção do Tracto Urinário eram potencialmente evitáveis. Este número corresponde a 41,7% do total das Infecções do Tracto Urinário identificadas. Este é um dado relevante se considerarmos o objectivo de melhorar continuamente a prestação de cuidados, bem como todos os custos associados ao tratamento de infecções do tracto urinário.
- Two portuguese cochlear implanted dizygotic twins: a case report.Publication . Chora, J.; Simões-Teixeira, H.; Matos, T. D.; Martins, J. H.; Alves, M.; Ferreira, R.; Silva, L.; Ribeiro, C.; Fialho, G.; Caria, H.
- Spectrum and frequency of gjb2 mutations in a cohort of 264 portuguese nonsyndromic sensorineural hearing loss patientsPublication . Matos, T. D.; Simões-Teixeira, H.; Caria, Helena; Gonçalves, A. C.; Chora, J.; Correia, M. C.; Moura, C.; Rosa, H.; Monteiro, L.; O'Neill, A.; Dias, O.; Andrea, M.; Fialho, G.Objective: To assess the spectrum and prevalence of mutations in the GJB2 gene in Portuguese nonsyndromic sensorineural hearing loss (NSSHL) patients. Design: Sequencing of the coding region, basal promoter, exon 1 and donor splice site of the GJB2 gene; screening for the presence of the two common GJB6 deletions. Study sample: A cohort of 264 Portuguese NSSHL patients. Results: At least one out of 21 different GJB2 variants was identified in 80 (30.2%) of the 264 patients analysed. Two mutant alleles were found in 53 (20%) of these probands, of which 83% (44/53) harboured at least one c.35delG allele. Twenty-seven (10.2%) of the probands harboured only one mutant allele. Subsequent analysis revealed that the GJB6 deletion del(GJB6-D13S1854) was present in at least 7.4% (2/27) of the patients carrying only one mutant GJB2 allele. Overall, one in five (55/264) of the patients were diagnosed as having DFNB1-related NSSHL, of which the vast majority (53/55) harboured only GJB2 mutations. Conclusions: This study provides clear demonstration that mutations in the GJB2 gene are an important cause of NSSHL in Portugal, thus representing a valuable indicator as regards therapeutical and rehabilitation options, as well as genetic counseling of these patients and their families.
- A Novel p.Leu213X Mutation in GJB2 Gene in a Portuguese FamilyPublication . Gonçalves, A. C.; Chora, J.; Matos, T. D.; O'Neill, A.; Escada, P.; Fialho, G.; Caria, H.
- Rubella in sub-saharan Africa and sensorineural hearing loss: a case control studyPublication . Caroça, Cristina; Vicente, Vera; Campelo, Paula; Chasqueira, Maria; Caria, Helena; Silva, Susana; Paixão, Paulo; Paço, JoãoBackground: Rubella infection can affect several organs and cause birth defects that are responsible for congenital rubella syndrome (CRS). Congenital hearing loss is the most common symptom of this syndrome, occurring in approximately 60% of CRS cases. Worldwide, over 100 000 babies are born with CRS every year. There is no specific treatment for rubella, but the disease is preventable by vaccination. Since 1969, the rubella vaccine has been implemented in many countries, but in Africa, only a few countries routinely immunize against rubella. The aim of this study was to estimate the rate of infection from the wild-type rubella virus in São Tomé and Príncipe by determining rubella seroprevalence with a DBS method. The goal of this study was to reinforce the need for implementation of the rubella vaccine in this country. As secondary objectives, the validation of a DBS method was first attempted and an association between seroprevalence and hearing loss was assessed. Methods: We collected samples from individuals observed during humanitarian missions in São Tomé and Príncipe. All individuals underwent an audiometric evaluation, and a drop of blood was collected for the dried blood spot (DBS). We define two groups: the case group (individuals with unilateral or bilateral hearing loss (HL)) and the control group (individuals with two normal ears). Patients were excluded if they suffered from conductive HL, if they showed evidence of possible causes of HL, if they had developmental delay or if they refused to participate in the study. Results: Among the 315 subjects, we found 64.1% individuals with IgG for the rubella virus, 32.1% without immunity for the rubella virus and 3.8% who were borderline. In the control group, 62.6% were positive for the rubella IgG, whereas in the case group, 72% were positive. Analyzing both groups, with ages ranging from 2 to 14 years of age and from 15 to 35 years of age, we found a seroprevalence of 50.3% to rubella in the younger group and 82.1% in the older group, with a significant difference between cases and control group noted within the younger patients (p = 0.025). Conclusions: Rubella is a disease that can be prevented. Rubella infections are still very common in São Tomé and Príncipe, and women of child-bearing age are still at risk for rubella infection during pregnancy, justifying the urgency of vaccination against rubella. A statistically significant association between the group of children under 14 years of age with HL and immunity for rubella was observed in this country, although this study did not allow us to establish a cause-effect relationship between rubella infection and SNHL.
- G6PD variants, malaria and sensorineural hearing loss in São Tomé and Príncipe: a case-control studyPublication . Caroça, Cristina; Campelo, Paula; Caria, Helena; Paço, João; Silva, SusanaBackground: São Tomé and Príncipe (STP) is a least developed country (LDC) on Sub-Saharan Africa, in which was detected a high prevalence of sensorineural Hearing Loss (SNHL). HL is a common condition with both genetic and environmental causes, and it greatly impacts on global health. STP population has leading with additional health problems over the years, such as anaemia and malaria infection. The present study aims to identify the correlation between the most prevalent G6PD variants and the high prevalence of HL in STP population. Methods: A sample of 316 individuals collected during Humanitarian Missions in STP, was retrospectively studied in a case-control approach to evaluate the role of G6PD gene variants in individual susceptibility to HL and it correlation with other potential risk factors. Results: The results obtained showed an increased risk for those cases that have reported malaria infection (OR 1.867, CI 95% [1.107-3.48]) in global population. The same effect of increased risk was found after stratification for male gender (OR 3.721 CI 95% [1.631-8.489]). Conclusions: Our results did not allow us to correlate any specific variant of G6PD gene with HL. However, emphasize the hypothetical correlation between malaria infection and the increased risk for HL.
- Pathophysiology, diagnosis and treatment of somatosensory tinnitus: a scoping reviewPublication . Haider, H. F.; Hoare, D. J.; Costa, R. F.; Potgieter, Iskra; Kikidis, D.; Lapira, A.; Nikitas, C.; Caria, H.; Cunha, N.; Paço, J.
- Despite reproductive interference, the net outcome of reproductive interactions among spider mite species is not necessarily costlyPublication . Clemente, Salomé; Santos, Inês; Ponce, Rita; Rodrigues, Leonor; Varela, Susana; Magalhães, SaraReproductive interference is considered a strong ecological force, potentially leading to species exclusion. This supposes that the net effect of reproductive interactions is strongly negative for one, or both, of the species involved. Testing this requires a comprehensive analysis of interspecific reproductive interactions, accounting for the order and timing of mating events, and for their effects on either fertility or fecundity. To this aim, we measured reproductive interactions among spider mites, using a focal species, Tetranychus urticae, and an invasive (T. evansi) and a resident (T. ludeni) species, varying the mating sequence and interval, and measuring the effect of such crosses on fecundity and offspring sex ratio (a measure of fertility, as these species are haplodiploid). We found that mating with heterospecifics affected fecundity and sex ratio negatively or positively, depending on the species involved, and on the order and timing of mating events. Overall, the net effect of reproductive interactions was weak despite strong effects of particular events. In natural situations, the outcome of reproductive interactions will thus hinge upon the frequency of each event.