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1.
FASEB J ; 34(5): 6757-6768, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32223016

RESUMO

Nuclear YAP1 plays a critical role in regulation of stem cell proliferation, tissue regeneration, and organ size in many types of epithelia. Due to rapid turnover of most epithelial cell types, the cytoplasmic function of YAP1 in epithelial cells has not been well studied. The retinal pigment epithelium (RPE) is a highly polarized epithelial cell type maintained at a senescence state, and offers an ideal cell model to study the active role of YAP1 in maintenance of the adult epithelial phenotype. Here, we show that the cytoplasmic function of YAP1 is essential to maintain adult RPE differentiation. Knockout of Yap1 in the adult mouse RPE caused cell depolarization and tight junction breakdown, and led to inhibition of RPE65 expression, diminishment of RPE pigments, and retraction of microvilli and basal infoldings. These changes in RPE further prompted the loss of adjacent photoreceptor outer segments and photoreceptor death, which eventually led to decline of visual function in older mice between 6 and 12 months of age. Furthermore, nuclear ß-catenin and its activity were significantly increased in mutant RPE. These results suggest that YAP1 plays an important role in active inhibition of Wnt/ß-catenin signaling, and is essential for downregulation of ß-catenin nuclear activity and prevention of dedifferentiation of adult RPE.

2.
J Hum Genet ; 65(2): 193-197, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31767933

RESUMO

Biallelic pathogenic variants in POC1A are ultra rare. They have been reported in 13 families as causing either Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis (SOFT) syndrome, or a milder partially overlapping phenotype, variant POC1A-related syndrome. This pleiotropic effect is likely precipitated by the variant's location and respective affected protein domain. Here, we describe seven patients from two consanguineous Omani families with classic SOFT syndrome and a novel homozygous POC1A variant (c.64G>T; p.(Val22Phe)), which is the first one described for the alternative exon 2. This result refines the POC1A mutational spectrum relevant for exertion of the described pleiotropic effect. Furthermore, six of our patients experienced recurrent mild to severe respiratory difficulties that have not been previously reported for SOFT syndrome and may be an underdiagnosed or a genotype-specific complication that warrants attention in future studies. Thus, our study unravels new aspects of the genotype-phenotype correlation suggested by previous reports.

3.
Cell Rep ; 28(5): 1323-1334.e4, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31365873

RESUMO

Retinitis pigmentosa (RP) initiates with diminished rod photoreceptor function, causing peripheral and night-time vision loss. However, subsequent loss of cone function and high-resolution daylight and color vision is most debilitating. Visual pigment-rich photoreceptor outer segments (OS) undergo phagocytosis by the retinal pigment epithelium (RPE), and the RPE also acts as a blood-outer retinal barrier transporting nutrients, including glucose, to photoreceptors. We provide evidence that contact between externalized phosphatidylserine (PS) on OS tips and apical RPE receptors activates Akt, linking phagocytosis with glucose transport to photoreceptors for new OS synthesis. As abundant mutant rod OS tips shorten in RP, Akt activation is lost, and onset of glucose metabolism in the RPE and diminished glucose transport combine to cause photoreceptor starvation and accompanying retinal metabolome changes. Subretinal injection of OS tip mimetics displaying PS restores Akt activation, glucose transport, and cone function in end-stage RP after rods are lost.

4.
J Clin Neurosci ; 67: 139-144, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31182267

RESUMO

Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM #607250), an exceedingly rare disorder having been documented in only a single family from Saudi Arabia, is the result of an unusual mutation in the tyrosyl DNA phosphodiesterase 1 gene (TDP1). We performed high-throughput sequencing (whole exome and ataxia gene panel) in two apparently unrelated Omani families segregating sensorimotor neuropathy and ataxia in an autosomal recessive fashion. Following validation by Sanger sequencing, all affected subjects (n = 4) were confirmed to carry the known SCAN1 pathogenic homozygous variant in the TDP1 gene, NM_001008744.1:c.1478A > G (p.His493Arg). In keeping with the initial description, our patients demonstrated progressive ataxia, cerebellar atrophy and disabling axonal sensori-motor neuropathy (n = 4), hypercholesterolemia (n = 2) and elevated serum alpha fetoprotein (n = 3). In addition, our patients also had mild cognitive deficits in multiple domains (n = 3), a feature not previously reported. Our findings independently revalidate the phenotype of TDP1 mutation and expand the clinical spectrum to include mild cognitive deficits. Haplotype sharing, as determined by DNA microarray (CytoScan HD), attests to a possible common founder mutation in the Arab population.


Assuntos
Ataxias Espinocerebelares/genética , Adolescente , Adulto , Exoma , Feminino , Humanos , Masculino , Mutação , Doenças do Sistema Nervoso Periférico/genética , Diester Fosfórico Hidrolases , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/psicologia , Adulto Jovem
5.
Eur J Med Genet ; 62(1): 39-43, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29709712

RESUMO

BACKGROUND: Clinical whole exome sequencing (WES) yields a diagnosis in approximately 30% of patients evaluated for presumed genetic disorders. For unsolved cases, periodic reanalysis is usually predicated on the availability of improved bioinformatics tools or new gene discoveries. METHODS: Exome data reanalysis was independently performed on unsolved cases that had underwent trio analysis by an external service provider. The retrieved exome data was reannotated using wANNOVAR and reanalysed following standard filtering criteria. RESULTS: Independent reanalysis led to the identification of a disease-causing variation in two families segregating predominantly a neurological phenotype. As the causative genes were relatively well established at the time the WES referral was made, misinterpretation of the functional impact of the variant and/or underappreciation of the gene's associated phenotype are the most probable causes of the discrepancy in reporting. CONCLUSION: Non-diagnostic clinical exome resulting from variant misinterpretation is probably under appreciated. These results emphasise the relevance of implement a policy for the reanalysis of high-throughput sequencing data, especially in a clinical context given the implications.


Assuntos
Deficiências do Desenvolvimento/genética , Testes Genéticos/normas , Sequenciamento Completo do Exoma/normas , Alelos , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Reações Falso-Negativas , Feminino , Testes Genéticos/métodos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Linhagem , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Sequenciamento Completo do Exoma/métodos
6.
Case Rep Genet ; 2018: 6737938, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30473892

RESUMO

The autosomal recessive cerebellar ataxias (ARCA) affect both the central and the peripheral nervous systems. They are also characterized by a relatively high level of genetic heterogeneity with well over 40 genes already implicated. The present study aimed to identify the gene mutation responsible for a complex phenotype comprising cerebellar ataxia and intellectual disability segregating in an Omani consanguineous family. Homozygosity-guided exome data analysis identified a novel frameshift mutation (c.2319_2322del) within the sorting nexin 14 gene (SNX14), which predicts complete absence of the SNX14 encoded protein. Segregation within the family of the sequence variation is consistent with its pathogenic role. Importantly, loss-of-function mutations in SNX14 have recently been described as a cause of a clinically distinguishable recessive syndrome consisting of cerebellar atrophy, ataxia, coarsened facial features, and intellectual disability. This study expands the genetic diversity of ataxia genes in the Omani population and have important implications for the clinical and molecular diagnosis of this condition in affected individuals.

7.
Anat Rec (Hoboken) ; 301(11): 1955-1967, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30288945

RESUMO

The domestic swine eye resembles the human eye both anatomically and physiologically. Xenotransplantation of the swine cornea to humans in need of full keratoplasty shows promise as a potential therapeutic strategy to restore vision in individuals with advanced corneal disease, especially those residing in developing nations. That said, we characterized the morphology of corneas from miniature swine, which are smaller in size, easier to handle, and more cost-effective compared to domestic swine. Eyes (N = 15) were harvested from miniature swine from different age groups: 1 month (N = 3), 2 month (N = 3), 4 month (N = 3), 8 month (N = 3), as well as 24 month old adult domestic swine (N = 3). They were immediately submerged in fixative and processed for histological examination at the light and transmission electron microscopic level. Gross anatomic measurements of the cornea were significantly less (P value ≤ 0.05) in miniature swine versus domestic swine. Corneal strata exhibited morphological characteristics similar to the domestic swine cornea. Adult miniature swine corneas show similar overall corneal thickness at 8 months of age versus domestic swine. Miniature swine exhibit similar corneal morphology with the domestic pig and humans, with the exception of Bowman's layer, which is absent in pigs. Therefore, miniature pigs may be a useful resource of corneal tissue for humans in need of full keratoplasty, as well as serve as a large eye model for ophthalmology residents to develop surgical skills and for development and testing of ocular therapeutic strategies that translate to humans. Anat Rec, 301:1955-1967, 2018. © 2018 Wiley Periodicals, Inc.


Assuntos
Córnea/anatomia & histologia , Córnea/ultraestrutura , Fatores Etários , Animais , Córnea/fisiologia , Suínos , Porco Miniatura
8.
Can J Public Health ; 109(3): 327-337, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29981098

RESUMO

OBJECTIVES: During the period of June-September 2014, the Northwest Territories (NWT) experienced its worst wildfire season on record, with prolonged smoke events and poor air quality. In the context of climate change, this study sought to qualitatively explore the lived experience of the 2014 wildfire season among four communities in the NWT. METHODS: Our team conducted 30 semi-structured interviews in four communities (Yellowknife, N'Dilo, Detah, and Kakisa). Interviewees were purposively sampled to include a broad cross-section of backgrounds and experiences. Interviews were video recorded, and the audio portion of each interview was transcribed to facilitate analysis and theme generation. RESULTS: Interviewees reported how their experiences of evacuation and isolation as well as feelings of fear, stress, and uncertainty contributed to acute and long-term negative impacts for their mental and emotional well-being. Prolonged smoke events were linked to extended time indoors and respiratory problems. Livelihood and land-based activities were disrupted for some interviewees, which had negative consequences for mental, emotional, and physical well-being. Individual and community stories of adaptation and resilience prior to and during the summer, including the opening of indoor recreational spaces, were shared; however, there was consensus about the need for improved risk communication and coordination at the community and territorial levels to address similar events in the future. CONCLUSION: Coordinated community-based education, communication, and adaptation initiatives that are inclusive of local knowledge, values, and context are needed to address the expressed needs of community members associated with prolonged smoke events and wildfire seasons.


Assuntos
Adaptação Psicológica , Desastres , Estresse Psicológico/psicologia , Incêndios Florestais , Poluição do Ar/estatística & dados numéricos , Feminino , Humanos , Masculino , Saúde Mental/estatística & dados numéricos , Territórios do Noroeste , Pesquisa Qualitativa , Estações do Ano , Fumaça/efeitos adversos
9.
Sch Psychol Q ; 33(3): 439-447, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29565608

RESUMO

Repeated readings (RR) and listening passage preview (LPP) are commonly used reading fluency interventions. However, relatively little is known about the behavioral changes that occur in children's reading in response to these interventions and what reading behavior, if any, students engage in during LPP. As such, in the current study, 57 third-grade students were randomly assigned to either a RR or LPP + RR condition. Intervention effects were evaluated by measuring students' oral reading fluency and eye-movement (EM) behaviors. Results revealed similar outcomes across measures. Students in both conditions significantly increased their words read correctly per minute and decreased the number of errors made in reading, total fixation time, frequency of fixations, and percentage of words fixated. EM measures indicated students' reading improved particularly on low-frequency words because of a reduction in time spent on high-level text processing. Results have implications for the classroom as well as future EM research. (PsycINFO Database Record


Assuntos
Dislexia/reabilitação , Leitura , Percepção da Fala/fisiologia , Ensino , Criança , Medições dos Movimentos Oculares , Feminino , Humanos , Masculino
10.
J Perinat Med ; 46(9): 968-974, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-28822227

RESUMO

OBJECTIVE: The purpose of this study was to determine the frequency of non-immune hydrops fetalis (NIHF) among all pregnancies referred for prenatal care at Sultan Qaboos University Hospital (SQUH) during the study period and to evaluate the underlying etiologies of NIH. STUDY DESIGN: All pregnancies referred to SQUH between February 2014 and December 2015 were identified, and all pregnancies meeting the diagnosis of NIHF were included in this study. All cases of NIHF referred to our center during this period underwent standard systematic diagnostic work-up that included biochemical and molecular studies in addition to the standard investigations for hydrops fetalis. Clinical characteristics and results of the diagnostic work-up were retrospectively reviewed. RESULTS: A total of 3234 pregnancies were referred for prenatal care at SQUH during the study period, and 12 pregnancies were affected by NIHF. An underlying diagnosis was established in nine cases, and the majority of cases (7/9) were caused by inborn errors of metabolism (IEM). These included a novel homozygous variant in the AARS2 gene (5/7) and two cases of galactosialidosis (2/7). CONCLUSION: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.


Assuntos
Aspartato-tRNA Ligase/genética , Hidropisia Fetal , Doenças por Armazenamento dos Lisossomos , Erros Inatos do Metabolismo , Adulto , Feminino , Homozigoto , Humanos , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/epidemiologia , Hidropisia Fetal/etiologia , Hidropisia Fetal/genética , Doenças por Armazenamento dos Lisossomos/complicações , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/epidemiologia , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Omã/epidemiologia , Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco
11.
Sultan Qaboos Univ Med J ; 17(3): e355-e357, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29062563

RESUMO

Spinal muscular atrophy (SMA) is a genetic lower motor neuron disease. It usually involves all of the skeletal muscles innervated by the anterior horn cells of the spinal cord. In rare cases, there is also localised involvement of the spinal cord. We report a 10-year-old boy who presented to the Sultan Qaboos University Hospital, Muscat, Oman, in 2015 with muscle weakness restricted to the lower limbs. The presence of a homozygous deletion within the survival of motor neuron 1 gene confirmed the diagnosis of SMA. To the best of the authors' knowledge, this is the first report of an Omani patient with segmental SMA involving only the lower limbs. Treatment for this rare and relatively benign form of SMA is symptomatic and includes physiotherapy.


Assuntos
Deleção de Genes , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Criança , Mãos , Humanos , Extremidade Inferior , Masculino , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/epidemiologia , Omã/epidemiologia , Pé Cavo
12.
Ophthalmic Genet ; 38(6): 544-548, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28511025

RESUMO

AIM: To report co-occurrence of two rare recessive conditions, the membrane frizzled-related protein (MFRP)-related ocular phenotype and glycogen storage disease type 1b (GSD-1b), in three siblings in an Omani family. BACKGROUND: Biallelic mutations in the MFRP gene (chromosome 11q23) result in a distinct ocular phenotype characterized by retinitis pigmentosa, foveoschisis, optic nerve head drusen, and posterior microphthalmos. GSD-1b is an autosomal-recessive disorder caused by mutations in SLC37A4 gene located in the same chromosomal region. METHODS: An Omani family with three siblings diagnosed with GSD-1b presented with ocular manifestations of progressive visual impairment and diminution of night vision. All siblings underwent a standard ophthalmic and clinical genetic evaluation. Full sequencing of the MFRP and SLC37A4 genes and haplotype analysis was carried out. RESULTS: The three children (2F:1M) aged 13, 17, and 18 years were born to consanguineous parents. Their best-corrected visual acuity ranged from 20/60 to 20/15. Ophthalmic exam revealed bilateral optic disc drusen, foveoschisis, and pigmentary retinopathy, hyperopia of +12 to +15.5 diopters, and decreased axial length (15.8-16.39 mm) in all affected siblings. Full-field electroretinography showed rod-cone dysfunction. Sequence analysis revealed two novel variants in a homozygous state in the SLC37A4 and MFRP genes in all the affected patients. CONCLUSIONS: We report the MFRP-related ocular phenotype in three siblings with GSD-1b. Molecular genetic studies identified novel mutations in the MFRP and SLC37A4 genes. Co-inheritance of a haplotype harboring mutations in both loci on chromosome 11q23 resulted in co-occurrence of the MFRP-related ocular phenotype and GSD-1b. This has not been reported previously.


Assuntos
Antiporters/genética , Oftalmopatias/genética , Doença de Depósito de Glicogênio Tipo I/genética , Proteínas de Membrana/genética , Proteínas de Transporte de Monossacarídeos/genética , Mutação , Adolescente , Cromossomos Humanos Par 11/genética , Consanguinidade , Eletrorretinografia , Feminino , Genes Recessivos , Humanos , Masculino , Microftalmia/genética , Drusas do Disco Óptico/genética , Linhagem , Fenótipo , Retinite Pigmentosa/genética , Retinosquise/genética , Irmãos , Acuidade Visual/fisiologia
13.
Transl Vis Sci Technol ; 6(2): 4, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28316877

RESUMO

PURPOSE: We characterize the progression of retinopathy in Filial 1 (F1) progeny of a transgenic (Tg) founder miniswine exhibiting severe Pro23His (P23H) retinopathy. METHODS: The F1 TgP23H miniswine progeny were created by crossing TgP23H founder miniswine 53-1 with wild type (WT) inbred miniature swine. Scotopic (rod-driven) and photopic (cone-driven) retinal functions were evaluated in F1 TgP23H and WT littermates using full field electroretinograms (ffERGs) at 1, 2, 3, 6, 9, 12, and 18 months of age, as well as the Tg founder miniswine at 6 years of age. Miniswine were euthanized and their retinas processed for morphologic evaluation at the light and electron microscopic level. Retinal morphology of a 36-month-old Tg miniswine also was examined. RESULTS: Wild type littermates reached mature scotopic and photopic retinal function by 3 months, while TgP23H miniswine showed abnormal scotopic ffERGs at the earliest time point, 1 month, and depressed photopic ffERGs after 2 months. Rod and cone photoreceptors (PR) exhibited morphologic abnormalities and dropout from the outer nuclear layer at 1 month, with only a monolayer of cone PR somata remaining after 2 months. The retinas showed progressive neural remodeling of the outer retina that included dendritic retraction of rod bipolar cells and glial seal formation by Müller cells. The TgP23H founder miniswine showed cone PR with relatively intact morphology exclusive to the area centralis. CONCLUSIONS: The F1 Tg miniswine and the TgP23H founder miniswine exhibit similar retinopathy. TRANSLATIONAL RELEVANCE: TgP23H miniswine are a useful large-eye model to study pathogenesis and preservation cone PRs in humans with retinitis pigmentosa.

14.
Oman Med J ; 31(3): 227-30, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27162595

RESUMO

Charcot-Marie-Tooth neuropathy type 4B1 (CMT4B1) disease is a rare subtype of CMT4 with reported association of facial weakness, vocal cord paresis, chest deformities, and claw hands. We report the unusual occurrence of optic neuritis and cervical cord schwannoma in a male individual with confirmed CMT4B1 disease. Sequencing of the MTMR2 gene revealed a novel nonsense homozygous mutation c.1768C>T (p.Gln590*). The mutation was identified in affected relatives of the proband and a second, apparently unrelated, family. The rare association of optic neuritis or schwannoma with genetically confirmed CMT1A has been individually observed, but never with recessive CMT. To the best of our knowledge, the occurrence of optic neuritis and cervical cord schwannoma in the same patient has never been reported with any form of CMT including CMT4B1. In similar cases, we recommend immediate medical attention to rule out the possibility of schwannomas in patients with all demyelinating CMT subtypes in case of the development of focal neurological signs or acute worsening of clinical status.

15.
Cell Rep ; 15(2): 372-85, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-27050517

RESUMO

Most retinitis pigmentosa (RP) mutations arise in rod photoreceptor genes, leading to diminished peripheral and nighttime vision. Using a pig model of autosomal-dominant RP, we show glucose becomes sequestered in the retinal pigment epithelium (RPE) and, thus, is not transported to photoreceptors. The resulting starvation for glucose metabolites impairs synthesis of cone visual pigment-rich outer segments (OSs), and then their mitochondrial-rich inner segments dissociate. Loss of these functional structures diminishes cone-dependent high-resolution central vision, which is utilized for most daily tasks. By transplanting wild-type rods, to restore glucose transport, or directly replacing glucose in the subretinal space, to bypass its retention in the RPE, we can regenerate cone functional structures, reactivating the dormant cells. Beyond providing metabolic building blocks for cone functional structures, we show glucose induces thioredoxin-interacting protein (Txnip) to regulate Akt signaling, thereby shunting metabolites toward aerobic glucose metabolism and regenerating cone OS synthesis.


Assuntos
Células Fotorreceptoras Retinianas Cones/patologia , Retinite Pigmentosa/patologia , Animais , Modelos Animais de Doenças , Ácidos Graxos/biossíntese , Glucose/farmacologia , Proteínas de Fluorescência Verde/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Interferente Pequeno/metabolismo , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/transplante , Segmento Interno das Células Fotorreceptoras da Retina/efeitos dos fármacos , Segmento Interno das Células Fotorreceptoras da Retina/metabolismo , Segmento Externo das Células Fotorreceptoras da Retina/efeitos dos fármacos , Segmento Externo das Células Fotorreceptoras da Retina/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/patologia , Células Fotorreceptoras Retinianas Bastonetes/transplante , Retinite Pigmentosa/fisiopatologia , Rodopsina/metabolismo , Sus scrofa , Tiorredoxinas/metabolismo
16.
Transl Vis Sci Technol ; 4(5): 5, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26396931

RESUMO

PURPOSE: Rhodopsin localization and rod photoreceptor (PR) morphology is altered in embryonic transgenic (Tg) Pro23His (P23H) miniswine. At birth, the Tg P23H swine retina lacks rod driven signaling. Curcumin, a neuroprotective food additive, has been shown to rescue Tg P23H rat rod PRs and promote normal trafficking of rhodopsin. We tested the hypothesis that prenatal exposure to curcumin would prevent PR morphological changes in Tg P23H miniswine retinae. METHODS: A domestic sow was inseminated with semen from a Tg P23H miniswine founder. Her daily diet was supplemented with curcumin (100 mg/Kg body weight) from embryonic (E) day 80 to E112. The same diet without curcumin was fed to a second inseminated control sow. At E112, 2 days before parturition, both sows were euthanized. Their embryos were harvested, genotyped, and their eyes enucleated and prepared for morphological evaluation. RESULTS: In all pigs, we measured mean outer retinal thickness, localization of rhodopsin, and rod PR morphology. Curcumin-treated Tg P23H swine embryonic retinas were similar to WT. Untreated Tg P23H embryonic retinas show significant degenerative effects; their outer retina was thinner, rod PR morphology was abnormal, and rhodopsin was mislocalized to the outer nuclear layer (ONL). CONCLUSIONS: These data support a role for curcumin as a neuroprotective agent that prevents/delays morphological abnormalities associated with rod PR degeneration in this Tg P23H swine model of retinitis pigmentosa (RP). TRANSLATIONAL RELEVANCE: Curcumin, a Food and Drug Administration-approved dietary supplement, may arrest/delay PR degeneration if ingested by individuals at risk for developing RP.

17.
J Med Biogr ; 23(4): 196-204, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24585614

RESUMO

John Armstrong, the first honours graduate of the University of Edinburgh School of Medicine, was famous in his day for a lengthy didactic poem entitled The Art of Preserving Health (1744). He is now obscure except to scholars specializing in the 18th century and, when discussed at all, often dismissed as a failed physician who wrote mediocre poetry in a quest for money and fame. A new exegesis by Adam Budd exhumes Armstrong as an original voice who offered timely and reassuring advice to Britons as they braced for another epidemic of plague; who depicted illness through the lens of a vulnerable and sympathetic physician, and who was perhaps above all else a leveller of medical knowledge. Elaborating on Budd's thesis, it would seem that Armstrong, a complicated man, has frequently been misread and was in some ways ahead of his time.


Assuntos
História do Século XVIII , Médicos/história , Poesia como Assunto/história , Humanos , Literatura Moderna/história , Escócia
18.
JBJS Essent Surg Tech ; 5(1): e3, 2015 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30473911

RESUMO

Introduction: The correct usage of preoperative and intraoperative imaging allows fixation of posterior pelvic ring injuries with safely positioned iliosacral screws in the setting of sacral dysmorphism. Step 1 Preoperative Planning: Obtain CT reformats along the longitudinal axis of the sacrum to determine the orientation and diameter of the osseous corridor for selection of the ideal screw size, length, and trajectory. Step 2 Patient Positioning: Proper positioning enables reduction and accurate iliosacral screw placement. Step 3 Fracture Reduction: Reduction of the posterior pelvic ring confers stability; if closed reduction is unsuccessful, proceed with open reduction. Step 4 Identification of the Entry Point: The entry point for an iliosacral screw into the upper sacral segment of a dysmorphic pelvis lies more posterior and caudal on the outer table of the posterior ilium than does a transsacral screw; adjust the entry point on the basis of inlet and outlet fluoroscopic views. Step 5 Drilling Technique: Insert a stout cannulated drill bit of 4.5 to 5 mm (depending on the core diameter of the intended iliosacral screw) over the Kirschner wire and drill it into the sacral body under fluoroscopic guidance, in accordance with the preoperative plan. Step 6 Screw Insertion: With the guidewire in the ideal position, measure the screw length off the inserted guidewire and advance a tap into the pathway; insert the screw and verify its position on the inlet, outlet, and lateral sacral views. Results: Understanding the three-dimensional anatomy of the posterior pelvic ring is essential to successful reduction and fixation of unstable pelvic injuries with use of percutaneous iliosacral screws.IndicationsContraindicationsPitfalls & Challenges.

19.
Invest Ophthalmol Vis Sci ; 55(4): 2452-9, 2014 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-24618321

RESUMO

PURPOSE: Functional studies have detected deficits in retinal signaling in asymptomatic children from families with inherited autosomal dominant retinitis pigmentosa (RP). Whether retinal abnormalities are present earlier during gestation or shortly after birth in a subset of children with autosomal dominant RP is unknown and no appropriate animal RP model possessing visual function at birth has been available to examine this possibility. In a recently developed transgenic P23H (TgP23H) rhodopsin swine model of RP, we tracked changes in pre- and early postnatal retinal morphology, as well as early postnatal retinal function. METHODS: Domestic swine inseminated with semen from a TgP23H miniswine founder produced TgP23H hybrid and wild type (Wt) littermates. Outer retinal morphology was assessed at light and electron microscopic levels between embryonic (E) and postnatal (P) day E85 to P3. Retinal function was evaluated using the full field electroretinogram at P3. RESULTS: Embryonic TgP23H rod photoreceptors are malformed and their rhodopsin expression pattern is abnormal. Consistent with morphological abnormalities, rod-driven function is absent at P3. In contrast, TgP23H and Wt cone photoreceptor morphology (E85-P3) and cone-driven retinal function (P3) are similar. CONCLUSIONS: Prenatal expression of mutant rhodopsin alters the normal morphological and functional development of rod photoreceptors in TgP23H swine embryos. Despite this significant change, cone photoreceptors are unaffected. Human infants with similarly aggressive RP might never have rod vision, although cone vision would be unaffected. Such aggressive forms of RP in preverbal children would require early intervention to delay or prevent functional blindness.


Assuntos
DNA/genética , Mutação , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinite Pigmentosa/genética , Rodopsina/biossíntese , Animais , Animais Geneticamente Modificados , Análise Mutacional de DNA , Modelos Animais de Doenças , Eletrorretinografia , Genótipo , Humanos , Imuno-Histoquímica , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase , Células Fotorreceptoras Retinianas Bastonetes/ultraestrutura , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Rodopsina/genética , Suínos , Porco Miniatura
20.
Invest Ophthalmol Vis Sci ; 55(4): 2460-8, 2014 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-24618325

RESUMO

PURPOSE: Human and swine retinas have morphological and functional similarities. In the absence of primate models, the swine is an attractive model to study retinal function and disease, with its cone-rich visual streak, our ability to manipulate their genome, and the differences in susceptibility of rod and cone photoreceptors to disease. We characterized the normal development of cone function and its subsequent decline in a P23H rhodopsin transgenic (TgP23H) miniswine model of autosomal dominant RP. METHODS: Semen from TgP23H miniswine 53-1 inseminated domestic swine and produced TgP23H and Wt hybrid littermates. Retinal function was evaluated using ERGs between postnatal days (P) 14 and 120. Retinal ganglion cell (RGC) responses were recorded to full-field stimuli at several intensities. Retinal morphology was assessed using light and electron microscopy. RESULTS: Scotopic retinal function matures in Wt pigs up to P60, but never develops in TgP23H pigs. Wt and TgP23H photopic vision matures similarly up to P30 and diverges at P60 where TgP23H cone vision declines. There are fewer TgP23H RGCs with visually evoked responses at all ages and their response to light is compromised. Photoreceptor morphological changes mirror these functional changes. CONCLUSIONS: Lack of early scotopic function in TgP23H swine suggests it as a model of an aggressive form of RP. In this mammalian model of RP, normal cone function develops independent of rod function. Therefore, its retina represents a system in which therapies to rescue cones can be developed to prolong photopic visual function in RP patients.


Assuntos
Células Fotorreceptoras Retinianas Cones/ultraestrutura , Células Fotorreceptoras Retinianas Bastonetes/ultraestrutura , Retinite Pigmentosa/patologia , Rodopsina/metabolismo , Animais , Animais Geneticamente Modificados , Contagem de Células , Modelos Animais de Doenças , Eletrorretinografia , Microscopia Eletrônica de Transmissão , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/fisiopatologia , Suínos , Porco Miniatura
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