Kernicterus e icterícia neonatal : revisão teórica a propósito de um caso clínico

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population

Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middle-aged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (≤165 cm for males; ≤155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A>G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A>G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.

Defining Atoh1 function and regulation in avian supporting cells during auditory hair cell regeneration

Thesis (Ph.D.)--University of Washington, 2016-06

Mutation in mitochondrial DNA as a cause of presbyacusis

Much of the hearing loss that occurs in old age is likely to be due to the long-term deterioration of the mitochondria in the different structures of the cochlea. The current review surveys some of the basic information on mitochondria and mitochondrial DNA, as a background to their possible involvement in presbyacusis. It is likely that oxygen radicals damage mitochondrial DNA and other components of the mitochondria, such as their proteins and lipids. This further compromises both oxidative phosphorylation and the repair processes in mitochondria, setting up a vicious cycle of degradation. Evidence is presented from inherited point mutations on the possibly most critical sites for mutations in mitochondrial DNA associated with hearing loss. It is suggested that random sorting and clonal expansion of mutations both maintain the integrity of the pool of mitochondrial DNA molecules and give rise to the apoptosis that leads to loss of vulnerable cells, and hence to deafness. It is moreover suggested that apoptosis of the vulnerable cells of the inner ear may to some extent be preventable, or at least delayed. Copyright (C) 2004 S. Karger AG, Basel.

Successes and failures in assessing acquired language disorders using an Internet-based telerehabilitation system

We have used a telerehabilitation system (eREHAB) to remotely assess acquired language disorders via the Internet. The system was used to establish a 128 kbit/s videoconference between two sites and allowed a remote language assessment to be conducted using the standardized Boston Diagnostic Aphasia Examination (BDAE). The system had the capacity to display text and images, and could play pre-recorded instructions to the participant via various built-in tools. A touch screen allowed tasks involving picture identification to be completed easily. Eighteen participants with a diagnosis of an acquired language disorder were simultaneously assessed using the eREHAB system, and in the traditional face-to-face manner by two speech pathologists. There was very high agreement between the two assessors, with weighted kappa scores of 0.8–1.0 for 88% of the sub-tests of the BDAE. There was also high agreement (80–100%) and high kappa scores (0.67–0.90) between assessors on the six rating scales relating to language characteristics. The agreement between the two assessors for the diagnosis of the type of aphasia was 83%. Limitations of the system related mainly to problems inherent in IP videoconferencing. The inability to maintain the preferred speed of 128 kbit/s for the duration of the videoconference and the resultant increase in video and audio breakup and latency affected the clinician’s ability to administer the BDAE with the same ease and accuracy as in face-to-face administration. These difficulties were exacerbated when participants presented with a moderate to severe language disorder, auditory comprehension deficits or significant hearing loss. Despite these limitations, a valid assessment of language disorder was found to be feasible via this telerehabilitation application.

Foundations of an intervention package to improve communication in residential care settings:a mixed methods study

Background: The prevalence of hearing loss is considerably higher in individuals in residential care than in people within the community-dwelling population, and yet hearing aids and hearing services are relatively underused. Care staff have a key role in supporting access to services. Objectives: This study identifies staff perspectives on hearing loss and their views about potential hearing service improvements. Study design: A four-stage mixed methods study was used, made up of qualitative interviews, observation, a survey and a stakeholder involvement meeting. Results: The qualitative stages indicated that staff were concerned about their levels of interaction with residents. Staff considered maximizing communication as part of their professional role. The quantitative survey indicated that these views were widely held by staff, and the stakeholder stage identified the need for social support and dedicated staff training opportunities. Conclusion: Care home staff regard communication as a shared issue. Future interventions could enhance access to hearing services and provide care home staff with training in hearing loss and hearing aid management. © 2013 Informa Healthcare.

The identification of early factors related to academic achievement among deaf students

The purpose of this research study was to examine specific factors believed to be related to academic achievement in deaf children. More specifically, this research sought to determine whether there was a significant difference in achievement between those students whose parents use oral communication only and those whose parents use some type of sign language. An additional purpose of this research was to determine if there was a significant difference in academic achievement with those deaf students who used amplification devices early in life. This study also sought to determine whether providing early intervention program which emphasizes and enables parents to develop a language rich environment had a significant impact on the academic achievement of deaf children and whether the age at which initial services are received influence deaf student's subsequent academic achievement. This study examined the relationship, if any, between intellectual ability and academic achievement among deaf children. Finally, this study sought to investigate the relationship between the degree of hearing loss and academic achievement. ^ Purposive sampling was used to select subjects for this study. All 228 eligible Deaf/Hard of Hearing (DHH) students enrolled in a Broward County Public School were included in the original sample. Sixty-one students actually participated in this study. A correlational method of statistical analysis as well as a cross classification (crosstabs) was used to analyze the data. ^ The results show that academic achievement in the areas of reading and mathematics was significantly related to parental mode of communication and the mode of communication used in school. Academic achievement, in the area of reading, was also signficantly related to intellectual ability. The reading achievement was also found to be significantly related to degree of hearing loss. Written language was not significantly related to any factors investigated in this study. ^ Additional research should be conducted to further investigate the low academic achievement among deaf children. The diversity among signing systems at school and between home and school should also be analyzed. Finally, future studies should examine curriculum and instruction methods to increase the academic achievement of deaf children. ^

Endothelin receptor B and neural crest derived melanocyte development

Neural Crest cells (NCC) constitute a unique embryonic cell population that arises between the prospective epidermis and the dorsal aspect of the neural tube of vertebrates. NCC migrate ventromedially and dorsolaterally throughout the developing embryo giving rise to the peripheral nervous system constituents and melanocytes that ultimately reside in the skin and hair follicles respectively. Mice and humans with mutations in the Endothelin receptor b (Ednrb) gene manifest strikingly similar phenotypes characterized by hypopigmentation, hearing loss and megacolon these are due to absence of melanocytes in the skin and inner ear and lack of enteric ganglia in the distal part of the gut, respectively. Piebald lethal mice and humans with Hirschsprung's disease or Waardenburg syndrome carry different mutations in the Ednrb gene. The major goals of this project were to determine whether the action of Ednrb in NCC is required prior to commitment of these cells to the melanocytic lineage and to investigate its potential participation in the actual process of commitment. In order to achieve these goals transgenic mice that express Ednrb under two different regulatory elements were created. The first, Dct-Ednrb, expresses Ednrb under the control of the DOPAchrome tautomerase (Dct) promoter to direct expression to already committed melanocyte precursors. The second, Nes-Ednrb, expresses Ednrb under the regulation of the human nestin gene second enhancer to direct expression to pre-migratory NCC. Crosses of the Dct-Ednrb mouse with piebald lethal showed that the transgene was capable of rescuing the hypopigmentation phenotype of the later. This result indicates that the action of Ednrb after NCC commit to the melanocytic lineage is sufficient for normal melanocyte development. The Dct-Ednrb was further crossed with two other hypopigmentation mutants that carry mutations in the transcription factors Sox10 and Pax3. The transgene rescued the phenotype of the Sox10 mutant only. This suggests that Ednrb interacts with Sox10 but not with Pax3 during melanocyte development. The Nes-Ednrb mice developed a hypopigmentation phenotype that was augmented when crossed with piebald lethal or lethal spotting (mutation in Edn3, the ligand for Ednrb) mice but was rescued by over expression of Edn3. These results suggest that alterations in Ednrb expression early in development affect melanocyte development. This study provides novel information necessary to better understand the early embryonic development of NCC, clarifies specific interactions between different melanogenic genes and, could eventually help in the implementation of therapies for human pigmentary genetic disorders. ^

Transgenic Expression of Endothelin Receptor-B Rescues the Aganglionosis Phenotype of Piebald Lethal Mice

Neural crest cells (NCC) are a unique population of cells in vertebrates that arise between the presumptive epidermis and the dorsal most region of the neural tube. During neurulation, NCC migrate to many regions of the body to give rise to a wide variety of cell types. NCC that originate from the neural tube at the levels of somite 1-7 colonize the gut and give rise to the enteric ganglia. The endothelin signaling pathway has been shown to be crucial for proper development of some neural crest derivatives. Mice and humans with mutations in the Endothelin receptor b (Ednrb) gene exhibit similar phenotypes characterized by hypopigmentation, hearing loss, and megacolon. Thesephenotypes are due to lack of melanocytes in the skin, inner ear and enteric ganglia in the distal portion of the colon, respectively. It is well established that Ednrb is required early during the embryonic development for normal innervation of the gut. However, it is not clear if Ednrb acts on enteric neuron precursor cells or in pre-committed NC precursors. Additionally, it is controversial whether the action of Ednrb is cell autonomous or non- autonomous. We generated transgenic mice that express Ednrb under the control of the Nestin second intron enhancer (Nes) which drives expression to pre-migrating NCC. These mice were crosses to the spontaneous mouse mutant piebald lethal, which carriers a null mutation in Ednrb and exhibits enteric aganglionosis. The Nes-Ednrb was capable of rescuing the aganglianosis phenotype of piebald lethal mutants demonstrating that expression of Ednrb in pre-committed precursors is sufficient for normal enteric ganglia development. This study provides insight in early embryonic development of NCC and could eventually have potential use in cellular therapies for Hirschsprung's disease.

Percepção da equipe de saúde, discentes e usuários sobre a comunicação com indivíduos surdos na atenção primária

The study aimed to identify in the professionals and students of health courses that work in a health Basic Unit in the city of Natal/RN their perceptions of the care of deaf patients, and with the population's needs with hearing loss in relation to health care. This is a cross-sectional, exploratory, descriptive study, conducted between April to July 2014, with a population composed of 21 health professionals, 17 students and 8 deaf users. For data collection, we used a structured questionnaire with open and closed questions applied to groups composed of health professionals (doctors, dentists, nurses and health workers) and students of medical schools, nursing, physical education, nutrition and social service. The professionals/students answered a semi-structured questionnaire with open and closed questions concerning the possible difficulties the care of the deaf and hearing impaired. Data collection with deaf users was conducted through filmed interview for the Brazilian Sign Language (Libras) could be interpreted as to the Portuguese by the researcher. With the latter it was conducted a survey of their reactions when looking for a care in the health service. Regarding the profile of identification of the subjects, it was analyzed by simple descriptive statistics (absolute and relative frequencies). The open questions were analyzed through the content analysis technique which allowed the categorization process preserving all the points raised in the discussion so that the lines were representative of the whole. When asked about the professionals and students attitude used to communicate with deaf patients possible the following categories emerged: the "writing", the "gestures" and the "third party assistance". With regard of the deaf, when asked about their experiences in seeking care in health, the elucidated categories were: "quality of care to the hearing impaired", "communication with the hearing impaired adequacy" and "dependence on third parties." The closed questions were measured and adapted to the 5 degrees of variation Likert Scale, which comprised three of these issues: degree of difficulty in communication to meet a patient with hearing loss (minimum to great difficulty); feeling of comfort while using sign language (minimum to severe discomfort); and knowledge of the Law 10.436, which provides for the Brazilian Sign Language (Libras) (low knowledge to entirely clear). The data collected with professionals and students revealed some misunderstanding and discomfort in health care for deaf patients, reality also evidenced in the opinion of the deaf participants. This study revealed problems in communication, resulting in negative consequences in serving this population. This diagnosis may be relevant to public policy development and curriculum guidelines essential to the training of health professionals, inclusion and improving assistance to deaf.

Prevalência e fatores associados à alteração vocal em idosos institucionalizados com capacidade cognitiva preservada

Voice disorders (VD) in the elderly can interfere negatively in communication, emotional well-being and quality of life, conditions that correspond to greater exposure to illness and social isolation bringing consequent economic impact for the health system. It is assumed that institutionalized confinement, weakness and morbidity associated to nursing home (NH) contribute to transform VD an especially prevalent condition in institutionalized elderly, including those without cognitive impairment. Thus, the aim of this study was to determine the prevalence and associated factors of VD in NH elderly residents without cognitive impairment. There is no epidemiological diagnostic instruments of VD for elderly populations, so the first step of this study was dedicated to prepare and analyze the psychometric properties of a short, inexpensive and easy to use questionnaire named Screening for Voice Disorders in Older Adults (Rastreamento de Alterações Vocais em Idosos—RAVI). The methodological procedures of this step followed the guidelines of the Standards for Educational and Psychological Testing and contemplated validity evidence based on test content, based on response processes, based on internal structure and based on relations with other variables, as well as reliability analysis and clinical consistency. The result of the validation process showed that the RAVI final score generate valid and reliable interpretations for the epidemiological diagnosis of VD in the elderly, which endorsed the use of the questionnaire in the second stage of the study, performed in ten NH located in the city of Natal, Rio Grande do Norte. At this stage, data from socioeconomic and demographic variables, lifestyle, general health conditions and characterization of the institution were collected. It was performed a bivariate analysis and it was calculated the prevalence ratio as a magnitude association measure, with a confidence interval of 95%. The variables with p-value less than 0.20 were included in the multiple logistic regression model that followed the Forward selection method. The odds ratio found in the multivariate model was converted into prevalence ratio and the level of significance was 5%. The sample consisted of 117 subjects with predominance of females and average of 79.68 (± 7.92) years old. The prevalence of VD was 39.3% (95% CI: 30.4-48.1%). The multivariate model showed statistically significant association between VD and depressive symptoms, smoking for a year or more and selfreported hearing loss. In conclusion, VD is a prevalent health condition in NH elderly residents without cognitive impairment and is associated with factors involving psychosocial, lifestyle and communicative disability that require attention of managers and professionals involved with NH environment. Strategies to encourage communication and social integration, actions to combat smoking and minimizing the effects of hearing loss could stimulate the physical well-being, emotional and mental health of institutionalized elderly population, contributing to the vocal and communicative maintenance, a more effective social inclusion and better overall health condition.

The Excess Burden of Cytomegalovirus in African American Communities: A Geospatial Analysis.

Background.  Cytomegalovirus (CMV) is a common cause of birth defects and hearing loss in infants and opportunistic infections in the immunocompromised. Previous studies have found higher CMV seroprevalence rates among minorities and among persons with lower socioeconomic status. No studies have investigated the geographic distribution of CMV and its relationship to age, race, and poverty in the community. Methods.  We identified patients from 6 North Carolina counties who were tested in the Duke University Health System for CMV immunoglobulin G. We performed spatial statistical analyses to analyze the distributions of seropositive and seronegative individuals. Results.  Of 1884 subjects, 90% were either white or African American. Cytomegalovirus seropositivity was significantly more common among African Americans (73% vs 42%; odds ratio, 3.31; 95% confidence interval, 2.7-4.1), and this disparity persisted across the life span. We identified clusters of high and low CMV odds, both of which were largely explained by race. Clusters of high CMV odds were found in communities with high proportions of African Americans. Conclusions.  Cytomegalovirus seropositivity is geographically clustered, and its distribution is strongly determined by a community's racial composition. African American communities have high prevalence rates of CMV infection, and there may be a disparate burden of CMV-associated morbidity in these communities.

Meniere’s, Migraine & Motion Sickness

CONCLUSION Elevated MSS in MD is likely to be a consequence of the onset of MD and not migraine per se. OBJECTIVES Pathologies of the vestibular system influence motion sickness susceptibility (MSS). Bilateral vestibular deficits lower MSS, vestibular neuritis or benign paroxysmal positional vertigo have little overall effect, whereas vestibular migraine elevates MSS. However, less is known about MSS in Meniere’s disease (MD), a condition in which many patients experience vestibular loss and migraine symptoms. METHODS We conducted an online survey that posed diagnostic and disease questions before addressing frequency of headaches, migraines, visual display dizziness (VDD), syncope, social life and work impact of dizziness (SWID4) and motion sickness susceptibility (MSSQ). The two groups were: diagnosed MD individuals with hearing loss (n=751) and non-MD individuals in the control group (n=400). RESULTS The MD group showed significantly elevated MSS, more headache and migraine, increased VDD, higher SWID4 scores, and increased syncope. MSS was higher in MD than controls only after the development of MD but not before, nor in childhood. Although elevated in MD compared with controls, MSS was lower than migraine patients from past data. Multivariate analysis revealed VDD, SWID4 and MSS in adulthood as the strongest predictors of MD, but not headache nor migraine.

Accelerated age-related olfactory decline among type 1 Usher patients

Usher Syndrome (USH) is a rare disease with hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. A phenotype heterogeneity is reported. Recent evidence indicates that USH is likely to belong to an emerging class of sensory ciliopathies. Olfaction has recently been implicated in ciliopathies, but the scarce literature about olfaction in USH show conflicting results. We aim to evaluate olfactory impairment as a possible clinical manifestation of USH. Prospective clinical study that included 65 patients with USH and 65 normal age-gender-smoking-habits pair matched subjects. A cross culturally validated version of the Sniffin' Sticks olfaction test was used. Young patients with USH have significantly better olfactory scores than healthy controls. We observe that USH type 1 have a faster ageing olfactory decrease than what happens in healthy subjects, leading to significantly lower olfactory scores in older USH1 patients. Moreover, USH type 1 patients showed significantly higher olfactory scores than USH type 2, what can help distinguishing them. Olfaction represents an attractive tool for USH type classification and pre diagnostic screening due to the low cost and non-invasive nature of the testing. Olfactory dysfunction should be considered among the spectrum of clinical manifestations of Usher syndrome.

Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome

Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.