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.

Inhibitors of cyclo-oxygenase-2 and secretory phospholipase A2 preserve bone architecture following ovariectomy in adult rats

Epidemiological evidence and in vitro data suggest that COX-2 is a key regulator of accelerated remodeling. Accelerated states of osteoblast and osteoclast activity are regulated by prostaglandins in vitro, but experimental evidence for specific roles of cyclooxygenase-2 (COX-2) and secretory phospholipase A(2) (sPLA(2)) in activated states of remodeling in vivo is lacking. The aim of this study was to determine the effect of specific inhibitors of sPLA(2)-IIa and COX-2 on bone remodeling activated by estrogen deficiency in adult female rats. One hundred and twenty-four adult female Wistar rats were ovariectomized (OVX) or sham-operated. Rats commenced treatment 14 days after surgery with either vehicle, a COX-2 inhibitor (DFU at 0.02 mg/kg/day and 2.0 mg/kg/day) or a sPLA(2)-group-IIa inhibitor (KH064 at 0.4 mg/kg/day and 4.0 mg/kg/day). Treatment continued daily until rats were sacrificed at 70 days or 98 days post-OVX. The right tibiae were harvested, fixed and embedded in methylmethacrylate for structural histomorphometric bone analysis at the proximal tibial metaphysis. The specific COX-2 or sPLA(2) inhibitors prevented ovariectomy-induced (OVX-induced) decreases in trabecular connectivity (P < 0.05); suppressed the acceleration of bone resorption; and maintained bone turnover at SHAM levels following OVX in the rat. The sPLA2 inhibitor significantly suppressed increases in osteoclast surface induced by OVX (P < 0.05), while the effect of COX-2 inhibition was less marked. These findings demonstrate that inhibitors of COX-2 and sPLA(2)-IIa can effectively suppress OVX-induced bone loss in the adult rat by conserving trabecular bone mass and architecture through reduced bone remodeling and decreased resorptive activity. Moreover, we report an important role of sPLA(2)-IIa in osteoclastogenesis that may be independent of the COX-2 metabolic pathway in the OVX rat in vivo. (c) 2006 Elsevier Inc. All rights reserved.

Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination

Enhancement of oligodendrocyte survival through activation of leukemia inhibitory factor receptor (LIFR) signaling is a candidate therapeutic strategy for demyelinating disease. However, in other cell types, LIFR signaling is under tight negative regulation by the intracellular protein suppressor of cytokine signaling 3 (SOCS3). We, therefore, postulated that deletion of the SOCS3 gene in oligodendrocytes would promote the beneficial effects of LIFR signaling in limiting demyelination. By studying wild-type and LIF-knockout mice, we established that SOCS3 expression by oligodendrocytes was induced by the demyelinative insult, that this induction depended on LIF, and that enclogenously produced LIF was likely to be a key determinant of the CNS response to oligodendrocyte loss. Compared with wild-type controls, oligo-dendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3. Moreover, these SOCS3-deficient mice were protected against cupri-zone-induced oligodendrocyte loss relative to wild-type animals. These results indicate that modulation of SOCS3 expression could facilitate the endogenous response to CNS injury.

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.

Uso do protocolo no serviço de psicologia e avaliação psicodinâmica em candidatos à cirurgia bariátrica

A clínica da Obesidade Mórbida e a Cirurgia Bariátrica exige estudos e acompanhamentos do paciente. Os benefícios e riscos do emagrecimento por tratamento cirúrgico devem servir como ponto de alerta aos profissionais da saúde. O uso do questionário no serviço de psicologia é norteado pela escuta psicológica. Objetivos: 1) Descrever o perfil sócio-demográfico candidatos à cirurgia bariátrica. 2) Analisar a percepção dos pacientes sobre características de personalidade associadas à obesidade e transtornos alimentares. 3) Descrever os conteúdos psicodinâmicos da narrativa do sujeito e avaliar o sistema tensional inconsciente de dois pacientes por meio do Teste das Relações Objetais de Phillipson (TRO). Método: O delineamento metodológico com análise de dados pelo método epidemiológico e estudo de caso clínico, orientação psicanalítica. Na primeira etapa foram consultados 300 questionários do serviço de psicologia e na segunda dois pacientes com ganho de peso após 24 meses. São pacientes que procuraram tratamento em clínica especializada, em uma metrópole do sudeste brasileiro, sob consentimento pós-informado. Os questionários foram preenchidos por 227 mulheres e 73 homens; com média de idade igual a 36 anos; escolaridade ensino médio e superior, 53%; maioria casados; IMC entre grave e super mórbido (94,3%). Técnicas cirúrgicas indicadas Capella Bypass e Fobi-Capella (67%). Resultados: características psicológicas referidas pelos pacientes, a ansiedade apontou em 93,7% das respostas, seguidas por impulsividade, depressão, tolerância à frustração, baixa auto-estima, resolvedor de problemas dos outros (mais de 50%). No histórico familiar da obesidade está em mais de 70% depressão e uso do álcool em 30%; realização de psicoterapia (30%) e medicamentos para depressão e ansiedade (10%). Na segunda etapa, foi realizado o diagnóstico psicodinâmico, por meio do Teste das Relações Objetais de Phillipson com duas pacientes, cuja análise indicou necessidade de psicoterapia psicanalítica, pois tinham fixações na posição esquizoparanóide e apresentavam dificuldade em lidar com perdas e baixa motivação para mudança e insigth. Conclusões: Com a aplicação do questionário e o registro das observações empíricas, este questionário de entrevista semidirigida preenche condições de melhor acessar e avaliar os conteúdos revelados pelos pacientes. As contradições entre as respostas e o discurso, no contato individual com o psicólogo, apontam a necessidade de investimento no preparo do paciente para a cirurgia e mais acentuadamente o acompanhamento psicológico no primeiro ano do pós-operatório. Há um pensamento mágico a ser trabalhado durante a aplicação do questionário sobre as crenças frente à cirurgia e o emagrecimento e assim convocar o paciente a ocupar o lugar do sujeito implicado em seu processo pré e pós-operatório. O TRO contribuiu na compreensão do diagnóstico psicodinâmico de pacientes com ganho de peso após cirurgia e reforçou a necessidade de maior investimento no pré-operatório.(AU)

Mechanism of the attenuation of proteolysis-inducing factor stimulated protein degradation in muscle by β-hydroxy-β-methylbutyrate

The leucine metabolite β-hydroxy-β-methylbutyrate (HMB) prevents muscle protein degradation in cancer-induced weight loss through attenuation of the ubiquitin-proteasome proteolytic pathway. To investigate the mechanism of this effect, the action of HMB on protein breakdown and intracellular signaling leading to increased proteasome expression by the tumor factor proteolysis-inducing factor (PIF) has been studied in vitro using murine myotubes as a surrogate model of skeletal muscle. A comparison has been made of the effects of HMB and those of eicosapentaenoic acid (EPA), a known inhibitor of PIF signaling. At a concentration of 50 μmol/L, EPA and HMB completely attenuated PIF-induced protein degradation and induction of the ubiquitin-proteasome proteolytic pathway, as determined by the "chymotrypsin-like" enzyme activity, as well as protein expression of 20S proteasome α- and β-subunits and subunit p42 of the 19S regulator. The primary event in PIF-induced protein degradation is thought to be release of arachidonic acid from membrane phospholipids, and this process was attenuated by EPA, but not HMB, suggesting that HMB might act at another step in the PIF signaling pathway. EPA and HMB at a concentration of 50 μmol/L attenuated PIF-induced activation of protein kinase C and the subsequent degradation of inhibitor κBα and nuclear accumulation of nuclear factor κB. EPA and HMB also attenuated phosphorylation of p42/44 mitogen-activated protein kinase by PIF, thought to be important in PIF-induced proteasome expression. These results suggest that HMB attenuates PIF-induced activation and increased gene expression of the ubiquitin-proteasome proteolytic pathway, reducing protein degradation.

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.

Microstructural study of aluminide surface coatings on single crystal nickel base superalloy substrates

Aluminide diffusion coatings are frequently employed to enhance the oxidation resistance of nickel base superalloys. However, there is a concern that the presence of an aluminide coating could influence the properties of the coated superalloy, especially in respect of fatigue behaviour. To understand the nature of the effects of surface coatings on the fatigue properties of superalloys, an understanding of microstructural development within both the coating and the coating/substrate interfacial zone during high temperature fatigue testing is necessary. This paper is concerned with microstructural changes in aluminide diffusion coatings on single crystal γ′ strengthened superalloy substrates during the course of high temperature fatigue testing. The 'edge on' transmission electron microscopy technique is employed to study cross-sections of two stage (aluminization plus diffusion treatment) coated superalloy samples. The paper examines the degradation of the coating produced by phase transformations induced by loss of aluminum from the coating and/or aging of the coating. Aluminum removal both by interdiffusion with the substrate and by oxidation of the coating surface is considered. Microstructural development in the portion of the substrate influenced by interdiffusion with the coating is also discussed.

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.