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1.
Sci Rep ; 12(1): 2507, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35190596

RESUMO

Genetic testing for cancer predisposition has been curtailed by the cost of sequencing, and testing has been restricted by eligibility criteria. As the cost of sequencing decreases, the question of expanding multi-gene cancer panels to a broader population arises. We evaluated how many additional actionable genetic variants are returned by unrestricted panel testing in the private sector compared to those which would be returned by adhering to current NHS eligibility criteria. We reviewed 152 patients referred for multi-gene cancer panels in the private sector between 2014 and 2016. Genetic counselling and disclosure of all results was standard of care provided by the Consultant. Every panel conducted was compared to current eligibility criteria. A germline pathogenic / likely pathogenic variant (P/LP), in a gene relevant to the personal or family history of cancer, was detected in 15 patients (detection rate of 10%). 46.7% of those found to have the P/LP variants (7 of 15), or 4.6% of the entire set (7 of 152), did not fulfil NHS eligibility criteria. 46.7% of P/LP variants in this study would have been missed by national testing guidelines, all of which were actionable. However, patients who do not fulfil eligibility criteria have a higher Variant of Uncertain Significance (VUS) burden. We demonstrated that the current England NHS threshold for genetic testing is missing pathogenic variants which would alter management in 4.6%, nearly 1 in 20 individuals. However, the clinical service burden that would ensue is a detection of VUS of 34%.


Assuntos
Biomarcadores Tumorais/genética , Aconselhamento Genético/normas , Testes Genéticos/normas , Neoplasias/epidemiologia , Medicina Estatal/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inglaterra/epidemiologia , Feminino , Aconselhamento Genético/estatística & dados numéricos , Predisposição Genética para Doença , Testes Genéticos/estatística & dados numéricos , Mutação em Linhagem Germinativa , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/genética , Estudos Retrospectivos , Medição de Risco/normas , Medição de Risco/estatística & dados numéricos , Adulto Jovem
2.
Materials (Basel) ; 14(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34279333

RESUMO

Pultruded fiber-reinforced polymer composites are susceptible to microstructural nonuniformity such as variability in fiber volume fraction (Vf), which can have a profound effect on process-induced residual stress. Until now, this effect of non-uniform Vf distribution has been hardly addressed in the process models. In the present study, we characterized the Vf distribution and accompanying nonuniformity in a unidirectional fiber-reinforced pultruded profile using optical light microscopy. The identified nonuniformity in Vf was subsequently implemented in a mesoscale thermal-chemical-mechanical process model, developed explicitly for the pultrusion process. In our process model, the constitutive material behavior was defined locally with respect to the corresponding fiber volume fraction value in different-sized representative volume elements. The effect of nonuniformity on the temperature and cure degree evolution, and residual stress was analyzed in depth. The results show that the nonuniformity in fiber volume fraction across the cross-section increased the absolute magnitude of the predicted residual stress, leading to a more scattered residual stress distribution. The observed Vf gradient promotes tensile residual stress at the core and compressive residual stress at the outer regions. Consequently, it is concluded that it is essential to take the effects of nonuniformity in fiber distribution into account for residual stress estimations, and the proposed numerical framework was found to be an efficient tool to study this aspect.

3.
Health Qual Life Outcomes ; 18(1): 196, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571342

RESUMO

PURPOSE: There have been few systematic reports of vision-related activity limitations of people with retinitis pigmentosa (RP). We report a merging of data from the National Eye Institute Visual Function Questionnaire (NEI-VFQ) obtained in five previous studies. We asked whether the Vision Function Scale (VFS; Pesudovs et al., 2010) which was developed for cataract patients would apply in this new population (condition). METHODS: Five hundred ninety-four individuals completed a total of 1753 questionnaires, with 209 participants providing responses over at least 4 years. Rasch analysis showed that the 15-item VFS was poorly targeted. A new instrument created by adding four driving-related items to the VFS had better targeting. As an indirect validation, VFS-plus person scores were compared to visual field area measured using a Goldmann perimeter, to the summed score for the combined 30-2 and 30/60-1 Humphrey Field Analyzer programs (HFA), to 30-Hz full-field cone electroretinogram (ERG) amplitude, and to ETDRS visual acuity. Changes in VFS-plus person scores with age and between four common heredity groups were also examined. RESULTS: The Rasch model of responses to the 19 VFS-plus items had person and item separation of 2.66 and 24.43 respectively. The VFS-plus person scores were related to each vision measure (p < 0.001). Over a five-year period, there was a reduction in person scores of 0.5 logits (p < 0.001). Person scores fell by an average of 0.34 logits per decade (p < 0.0001). Participants with an X-linked hereditary pattern had, on average, lower person scores (p < 0.001). CONCLUSIONS: The VFS-plus instrument quantified a highly-significant annual reduction in perceived vision-related ability over a five-year period. The outcome was consistent with clinical measures of vision, and detected lower perceived vision-related ability in participants with X-linked disease. It may be of use in future studies, but this needs to be tested in a representative population sample.


Assuntos
Atividades Cotidianas , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/terapia , Inquéritos e Questionários/normas , Avaliação de Sintomas/normas , Baixa Visão/terapia , Acuidade Visual/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Eye Institute (U.S.) , Reprodutibilidade dos Testes , Estados Unidos
4.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-30783616

RESUMO

The membrane guanylate cyclase, ROS-GC, that synthesizes cyclic GMP for use as a second messenger for visual transduction in retinal rods and cones, is stimulated by bicarbonate. Bicarbonate acts directly on ROS-GC1, because it enhanced the enzymatic activity of a purified, recombinant fragment of bovine ROS-GC1 consisting solely of the core catalytic domain. Moreover, recombinant ROS-GC1 proved to be a true sensor of bicarbonate, rather than a sensor for CO2. Access to bicarbonate differed in rods and cones of larval salamander, Ambystoma tigrinum, of unknown sex. In rods, bicarbonate entered at the synapse and diffused to the outer segment, where it was removed by Cl--dependent exchange. In contrast, cones generated bicarbonate internally from endogenous CO2 or from exogenous CO2 that was present in extracellular solutions of bicarbonate. Bicarbonate production from both sources of CO2 was blocked by the carbonic anhydrase inhibitor, acetazolamide. Carbonic anhydrase II expression was verified immunohistochemically in cones but not in rods. In addition, cones acquired bicarbonate at their outer segments as well as at their inner segments. The multiple pathways for access in cones may support greater uptake of bicarbonate than in rods and buffer changes in its intracellular concentration.


Assuntos
Bicarbonatos/metabolismo , Guanilato Ciclase/metabolismo , Receptores de Superfície Celular/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Visão Ocular/fisiologia , Acetazolamida/farmacologia , Ambystoma , Animais , Células COS , Dióxido de Carbono/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Bovinos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Chlorocebus aethiops , GMP Cíclico/metabolismo , Expressão Gênica , Guanilato Ciclase/genética , Camundongos , Proteínas Recombinantes/metabolismo , Células Fotorreceptoras Retinianas Cones/citologia , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/citologia , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Visão Ocular/efeitos dos fármacos
5.
Comput Methods Biomech Biomed Engin ; 21(12): 684-692, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30406680

RESUMO

In the present study, the free fall impact test in accordance with the EN1078 standard for certification of bicycle helmets is replicated using numerical simulations. The impact scenario is simulated using an experimentally validated, patient-specific head model equipped with and without a bicycle helmet. Head accelerations and intracranial biomechanical injury metrics during the impacts are recorded. It is demonstrated that wearing the bicycle helmet during the impact reduces biomechanical injury metrics, with the biggest reduction seen in the metric for skull fracture.


Assuntos
Ciclismo , Análise de Elementos Finitos , Dispositivos de Proteção da Cabeça , Aceleração , Fenômenos Biomecânicos , Cabeça , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
6.
Stat Med ; 37(17): 2586-2598, 2018 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-29855067

RESUMO

Retinitis pigmentosa is one of the most common forms of inherited retinal degeneration. The electroretinogram (ERG) can be used to determine the severity of retinitis pigmentosa-the lower the ERG amplitude, the more severe the disease is. In practice for career, lifestyle, and treatment counseling, it is of interest to predict the ERG amplitude of a patient at a future time. One approach is prediction based on the average rate of decline for individual patients. However, there is considerable variation both in initial amplitude and in rate of decline. In this article, we propose an empirical Bayes (EB) approach to incorporate the variations in initial amplitude and rate of decline for the prediction of ERG amplitude at the individual level. We applied the EB method to a collection of ERGs from 898 patients with 3 or more visits over 5 or more years of follow-up tested in the Berman-Gund Laboratory and observed that the predicted values at the last (kth) visit obtained by using the proposed method based on data for the first k-1 visits are highly correlated with the observed values at the kth visit (Spearman correlation =0.93) and have a higher correlation with the observed values than those obtained based on either the population average decline rate or those obtained based on the individual decline rate. The mean square errors for predicted values obtained by the EB method are also smaller than those predicted by the other methods.


Assuntos
Teorema de Bayes , Progressão da Doença , Eletrorretinografia , Retinose Pigmentar/fisiopatologia , Simulação por Computador , Humanos
7.
JAMA Ophthalmol ; 136(5): 490-495, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29596553

RESUMO

Importance: While oral vitamin A supplementation is considered to potentially slow loss of retinal function in adults with retinitis pigmentosa and normal liver function, little data from children with this disease are available. Objective: To compare disease courses in children with retinitis pigmentosa taking or not taking vitamin A supplementation. Design, Setting, and Participants: Retrospective, nonrandomized comparison of vitamin A and control cohorts followed up for a mean of 4 to 5 years by the Electroretinography Service of the Massachusetts Eye and Ear Infirmary. The study included children with different genetic types of typical retinitis pigmentosa: 55 taking vitamin A and 25 not taking vitamin A. The dates for patient evaluations ranged from June 1976 to July 2016, and the data analysis occurred in October 2016. Interventions: Age-adjusted dose of oral vitamin A palmitate (≤15 000 IU/d). Main Outcomes and Measures: Mean exponential rates of change of full-field cone electroretinogram amplitude to 30-Hz flashes estimated by repeated-measures longitudinal regression without and with adjusting for potential confounders. Results: Of the 55 children in the vitamin A cohort, 38 (69%) were male; the mean [SD] age was 9.1 [1.9] years; and 48 (87%) were white , 6 (11%) were Asian, and 1 (2%) was black. Of the 25 members of the control cohort, 19 (76%) were male; the mean [SD] age was 9.2 [1.7] years; and 25 (100%) were white. The estimated mean rates of change with the unadjusted model were -0.0713 loge unit/y (-6.9% per year) for the vitamin A cohort and -0.1419 loge unit per year (-13.2% per year) for the control cohort (difference, 0.0706 loge unit per year; 95% CI for the difference, 0.0149-0.1263 loge unit per year; P = .01). The adjusted model confirmed a slower mean rate of decline in the vitamin A cohort (difference, 0.0771 loge-unit per year; 95% CI for the difference, 0.0191-0.1350 loge-unit per year; P = .009). With respect to ocular safety, the mean exponential rates of change of visual field area and visual acuity and the incidences of falling to a visual field diameter of 20° or less or a visual acuity of 20/200 or less in at least 1 eye did not differ by cohort. Conclusions and Relevance: A vitamin A palmitate supplement was associated with a slower loss of cone electroretinogram amplitude in children with retinitis pigmentosa. Although the relatively small-sample, retrospective, nonrandomized design does not allow a test of causation and is subject to possible biases, these findings support consideration of an age-adjusted dose of vitamin A in the management of most children with the common forms of retinitis pigmentosa.


Assuntos
Antioxidantes/administração & dosagem , Células Fotorreceptoras Retinianas Cones/fisiologia , Retinose Pigmentar/fisiopatologia , Vitamina A/análogos & derivados , Adolescente , Estudos de Casos e Controles , Criança , Progressão da Doença , Diterpenos , Eletrorretinografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Retinose Pigmentar/diagnóstico , Ésteres de Retinil , Estudos Retrospectivos , Acuidade Visual/fisiologia , Vitamina A/administração & dosagem
8.
Genes (Basel) ; 8(10)2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28981474

RESUMO

Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes.

9.
Curr Eye Res ; 41(11): 1498-1506, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27158920

RESUMO

PURPOSE: Anterior ischemic optic neuropathy (AION) is the most common cause of non-glaucomatous optic nerve head (ONH) injury among older adults. AION results from a sudden ischemic insult to the proximal portion of the optic nerve, typically leading to visual impairment. Here, we present an experimental model of photodynamically induced ONH injury that can be used to study neuroprotective modalities. METHODS: Intraperitoneal injection of mesoporphyrin IX was followed by photodynamic treatment of the ONH in one eye of Brown-Norway rats; the fellow eye received the reverse sequence as a sham control. Fluorescein angiography (FA), spectral domain optical coherence tomography (SD-OCT), and visual evoked potential (VEP) recordings were performed at different time points following laser treatment. Immunohistochemistry was used to monitor apoptotic cell death (TUNEL) and macrophage infiltration (CD68). Cytokine levels were evaluated using enzyme-linked immunosorbent assay (ELISA). RESULTS: FA showed early hyperfluorescence and late leakage of the ONH, while SD-OCT revealed optic nerve edema. No leakage or other abnormalities were detected in control eyes. VEPs were significantly reduced in amplitude and showed prolonged responses compared to sham eyes. The number of apoptotic retinal ganglion cells was elevated one day after laser treatment (13.77 ± 4.49, p < 0.01) and peaked on day 7 (57.22 ± 11.34, p < 0.01). ONH macrophage infiltration also peaked on day 7 (101.8 ± 9.8, p < 0.05). ELISAs performed showed upregulation of macrophage chemoattractant protein-1 and macrophage inflammatory protein-2 on days 3 and 1, respectively. CONCLUSIONS: Photodynamic treatment of the ONH after administration of mesoporphyrin IX leads to macroscopic, histologic, and physiologic evidence of ONH injury. Given the long half-life of mesoporphyrin IX and the ease of intraperitoneal injections, this new model of photodynamically induced ONH injury may be a useful tool for studying optic nerve injury and possible neuroprotective treatments.


Assuntos
Disco Óptico/patologia , Neuropatia Óptica Isquêmica/patologia , Fotoquimioterapia/efeitos adversos , Células Ganglionares da Retina/patologia , Animais , Apoptose , Modelos Animais de Doenças , Potenciais Evocados Visuais , Angiofluoresceinografia , Fundo de Olho , Masculino , Neuropatia Óptica Isquêmica/etiologia , Neuropatia Óptica Isquêmica/fisiopatologia , Ratos , Ratos Endogâmicos BN , Tomografia de Coerência Óptica/métodos
10.
Ophthalmology ; 122(9): 1899-906, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26143542

RESUMO

PURPOSE: To determine the frequency and severity of visual function loss in female carriers of X-linked retinitis pigmentosa (XLRP). DESIGN: Case series. PARTICIPANTS: Two hundred seventy-six XLRP carriers with cross-sectional data (n = 242) and longitudinal data (n = 34; median follow-up, 16 years; follow-up range, 3-37 years). Half of the carriers were from RPGR- or RP2-genotyped families. METHODS: Retrospective medical records review. MAIN OUTCOME MEASURES: Visual acuities, visual field areas, final dark adaptation thresholds, and full-field electroretinography (ERG) responses to 0.5-Hz and 30-Hz flashes. RESULTS: In genotyped families, 40% of carriers showed a baseline abnormality on at least 1 of 3 psychophysical tests. There was a wide range of function among carriers. For example, 3 of 121 (2%) genotyped carriers were legally blind because of poor visual acuity, some as young as 35 years. Visual fields were less affected than visual acuity. In all carriers, the average ERG amplitude to 30-Hz flashes was approximately 50% of normal, and the average exponential rate of amplitude loss over time was half that of XLRP males (3.7%/year vs. 7.4%/year, respectively). Among obligate carriers with affected fathers, sons, or both, 53 of 55 (96%) had abnormal baseline ERG results. Some carriers who initially had completely normal fundi in both eyes went on to experience moderately decreased vision, although not legal blindness. Among carriers with RPGR mutations, those with mutations in ORF15, compared with those in exons 1-14, had worse final dark adaptation thresholds and lower 0.5-Hz and 30-Hz ERG amplitudes. CONCLUSIONS: Most carriers of XLRP had mildly or moderately reduced visual function but rarely became legally blind. In most cases, obligate carriers could be identified by ERG testing. Carriers of RPGR ORF15 mutations tended to have worse visual function than carriers of RPGR exon 1 through 14 mutations. Because XLRP carrier ERG amplitudes and decay rates over time were on average half of those of affected men, these observations were consistent with the Lyon hypothesis of random X-inactivation.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Heterozigoto , Retinose Pigmentar/genética , Retinose Pigmentar/fisiopatologia , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Adaptação à Escuridão , Eletrorretinografia , Proteínas do Olho/genética , Feminino , Proteínas de Ligação ao GTP , Estudos de Associação Genética , Técnicas de Genotipagem , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Estimulação Luminosa , Retina/fisiopatologia , Estudos Retrospectivos
11.
Neuron ; 86(1): 247-63, 2015 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-25801704

RESUMO

Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/metabolismo , Células Fotorreceptoras/fisiologia , Retina/citologia , Transativadores/metabolismo , Adaptação Ocular/genética , Fatores Etários , Animais , Animais Recém-Nascidos , Imunoprecipitação da Cromatina , Eletrorretinografia , Embrião de Mamíferos , Proteínas do Olho/metabolismo , Genoma , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Retina/crescimento & desenvolvimento
12.
Nat Neurosci ; 17(9): 1190-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25086610

RESUMO

Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Envelhecimento/fisiologia , Proteínas Serina-Treonina Quinases/genética , Segmento Externo da Célula Bastonete/patologia , Segmento Externo da Célula Bastonete/fisiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Envelhecimento/patologia , Células Amácrinas/patologia , Células Amácrinas/fisiologia , Animais , Eletrorretinografia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Células Bipolares da Retina/patologia , Células Bipolares da Retina/fisiologia , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/fisiologia , Especificidade por Substrato , Sinapses/patologia , Sinapses/fisiologia
13.
JAMA Ophthalmol ; 132(10): 1209-14, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24993773

RESUMO

IMPORTANCE: Current treatments for cystoid macular edema (CME) in retinitis pigmentosa (RP) are not always effective, may lead to adverse effects, and may not restore visual acuity. The present research lays the rationale for evaluating whether an iodine supplement could reduce CME in RP. OBJECTIVE: To determine whether central foveal thickness (CFT) in the presence of CME is related to dietary iodine intake inferred from urinary iodine concentration (UIC) in nonsmoking adults with RP. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional observational study of 212 nonsmoking patients aged 18 to 69 years referred to our institution for RP with visual acuity of no worse than 20/200 in at least 1 eye. EXPOSURE: Retinitis pigmentosa with or without CME. MAIN OUTCOMES AND MEASURES: With the eye as the unit of analysis, the relationship of log CFT measured by optical coherence tomography to UIC measured from multiple spot samples and represented as a 3-level classification variable (<100, 100-199, and ≥200 µg/L), assigning greater weight to patients with more reliable UIC estimates. RESULTS: Analyses were limited to 199 patients after excluding 11 who failed to return urine samples for measuring UIC and 2 outliers for UIC. Of the 199 patients, 36.2% had CME in 1 or both eyes. Although log CFT was inversely related to UIC based on findings from all eyes (P = .02), regression of log CFT on UIC separately for eyes with and without CME showed a strong inverse significant relationship for the former group (P < .001) and no significant relationship for the latter group (P = .66) as tested. For the eyes with CME, CFT ranged from a geometric mean of 267 µm for a median UIC of less than 100 µg/L to a geometric mean of 172 µm for a median UIC of 200 µg/L or greater. In contrast, we found no significant association between CME prevalence and UIC based on the entire sample as tested (odds ratio, 1.01 [95% CI, 0.38-2.67]; P = .99). CONCLUSIONS AND RELEVANCE: A higher UIC in nonsmoking adults with RP was significantly associated with less central foveal swelling in eyes with CME. Additional study is required to determine whether an iodine supplement can limit or reduce the extent of CME in patients with RP.


Assuntos
Fóvea Central/patologia , Iodo/urina , Edema Macular/urina , Retinose Pigmentar/urina , Adolescente , Adulto , Idoso , Estudos Transversais , Dieta , Feminino , Humanos , Edema Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Retinose Pigmentar/diagnóstico , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
15.
Arch Ophthalmol ; 130(7): 901-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22410627

RESUMO

OBJECTIVE: To determine whether mutations in different Bardet-Biedl syndrome (BBS) genes result in different ocular phenotypes. METHODS: Thirty-seven patients from 31 families were enrolled who met the clinical criteria for BBS and for whom a BBS mutation had been identified. Seventeen patients harbored mutations in BBS1, 10 in BBS10, and 10 in other genes (BBS2, BBS3, BBS5, BBS7, and BBS12). All the patients underwent ocular examination; 36 patients had computerized full-field electroretinograms (ERGs). RESULTS: Visual acuity was significantly better in BBS1 patients than in patients with other BBS mutations (P=.01), and a larger proportion of BBS1 patients had good (≥20/50) visual acuity (P=.01). The ERG amplitudes were significantly higher in BBS1 patients than in patients with other BBS mutations in response to 0.5-Hz and 30-Hz flashes (P<.001 for both). All the BBS1 patients harbored at least 1 missense mutation compared with only 45% of patients with mutations in other BBS genes (P<.001); the rest harbored only null alleles. However, multivariate analysis demonstrated that visual acuity or ERG amplitude did not depend on the type of mutation present (missense or null) when controlling for BBS gene. Prevalences of bone spicule pigmentation and cataract were comparable in BBS subtypes. CONCLUSIONS: Patients with BBS1 mutations had a milder phenotype than did patients with mutations in other BBS genes. Clinically, this manifested as significantly better visual acuity and larger ERG amplitudes. CLINICAL RELEVANCE: These phenotypic differences can help guide genetic testing and genetic counseling for patients with this syndrome.


Assuntos
Síndrome de Bardet-Biedl/genética , Estudos de Associação Genética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Retina/fisiopatologia , Adolescente , Adulto , Síndrome de Bardet-Biedl/fisiopatologia , Chaperoninas , Criança , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Chaperoninas do Grupo II/genética , Humanos , Masculino , Pessoa de Meia-Idade , Acuidade Visual/fisiologia , Adulto Jovem
16.
Am J Pathol ; 180(5): 1917-27, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22429967

RESUMO

The increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies.


Assuntos
Integrases/fisiologia , Epitélio Pigmentado da Retina/enzimologia , Animais , Atrofia/enzimologia , Atrofia/patologia , Modelos Animais de Doenças , Eletrorretinografia/métodos , Regulação da Expressão Gênica , Integrases/genética , Integrases/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiologia , Camundongos , Camundongos Transgênicos , Microglia/patologia , Microglia/fisiologia , Microscopia Eletrônica , Oxirredutases/genética , Oxirredutases/fisiologia , Fenótipo , Células Fotorreceptoras de Vertebrados/fisiologia , Proteínas Recombinantes de Fusão/genética , Distrofias Retinianas/enzimologia , Distrofias Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/fisiopatologia , Epitélio Pigmentado da Retina/ultraestrutura
17.
Arch Ophthalmol ; 130(6): 707-11, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22332205

RESUMO

OBJECTIVE: To evaluate whether a diet high in long chain ω-3 fatty acids can slow the rate of visual acuity loss among patients with retinitis pigmentosa receiving vitamin A palmitate. METHODS: We calculated dietary intake from questionnaires completed annually by 357 adult patients from 3 randomized trials who were all receiving vitamin A, 15 000 IU/d, for 4 to 6 years. Rates of visual acuity decline were compared between those with high (≥0.20 g/d) vs low (<0.20 g/d) ω-3 intake. Analyses took age into account. RESULTS: Mean rates of decline of acuity were slower among those with high ω-3 intake: Early Treatment Diabetic Retinopathy Study distance acuity: high intake=0.59 letter per year, low intake=1.00 letter per year,P=.001; Snellen retinal acuity: high intake=1.5% per year, low intake=2.8% per year, P=.03. CONCLUSIONS: We conclude that mean annual rates of decline in distance and retinal visual acuities in adults with retinitis pigmentosa receiving vitamin A, 15 000 IU/d,are slower over 4 to 6 years among those consuming a diet rich in ω-3 fatty acids. To our knowledge, this is the first report that nutritional intake can modify the rate of decline of visual acuity in retinitis pigmentosa.


Assuntos
Antioxidantes/administração & dosagem , Dieta , Ácidos Graxos Ômega-3/administração & dosagem , Retinose Pigmentar/fisiopatologia , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Vitamina A/análogos & derivados , Adolescente , Adulto , Diterpenos , Ácidos Docosa-Hexaenoicos/metabolismo , Membrana Eritrocítica/metabolismo , Comportamento Alimentar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Fosfatidiletanolaminas/metabolismo , Retinose Pigmentar/dietoterapia , Ésteres de Retinil , Inquéritos e Questionários , Transtornos da Visão/dietoterapia , Campos Visuais/fisiologia , Vitamina A/administração & dosagem , Adulto Jovem
18.
J Clin Neurosci ; 19(2): 316-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22133816

RESUMO

We describe a case of acute transverse myelitis following Campylobacter diarrhoea in an adult. The patient presented with diplegia due to a longitudinal spinal cord lesion. The CSF demonstrated an aseptic meningitis. Oligoclonal bands and C. jejuni-specific IgG were detected in serum and cerebrospinal fluid at the beginning of the neurological illness. The patient was treated with antimicrobial therapy and steroids. A near full recovery was made and there were no relapses. C. jejuni is strongly implicated in the aetiology of acute motor axonal neuropathy and Miller Fisher syndrome through molecular mimicry of neuronal gangliosides. These gangliosides are expressed throughout the nervous system yet C. jejuni related central nervous system disease is exceedingly rare. We conclude that disruption of the blood-brain barrier was the key event in the pathogenesis of immune mediated post-infectious myelitis in our patient.


Assuntos
Barreira Hematoencefálica/diagnóstico por imagem , Infecções por Campylobacter/diagnóstico por imagem , Diarreia/diagnóstico por imagem , Mielite Transversa/diagnóstico por imagem , Adulto , Barreira Hematoencefálica/microbiologia , Infecções por Campylobacter/complicações , Diarreia/complicações , Diarreia/microbiologia , Humanos , Masculino , Mielite Transversa/complicações , Mielite Transversa/microbiologia , Radiografia
19.
Invest Ophthalmol Vis Sci ; 52(12): 9244-9, 2011 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-21989720

RESUMO

PURPOSE: To evaluate the change in ocular function by eye in patients with unilateral pigmentary retinopathy. METHODS: Longitudinal regression was used to estimate mean exponential rates of change in Goldmann visual field area (V4e white test light) and in full-field electroretinogram (ERG) amplitudes to 0.5- and 30-Hz white flashes in 15 patients with unilateral pigmentary retinopathy. Snellen visual acuity was assessed case by case. RESULTS: Mean annual rates of change for the affected eyes were -4.9% for visual field area, -4.7% for ERG amplitude to 0.5-Hz flashes, and -4.6% for ERG amplitude to 30-Hz flashes. All three rates were faster than the corresponding age-related rates of change for the fellow normal eyes (P = 0.0006, P = 0.003, P = 0.03, respectively). An initial cone ERG implicit time to 30-Hz flashes in affected eyes ≥ 40 ms predicted a faster mean rate of decline of visual field area and of ERG amplitude to 0.5- and 30-Hz flashes (P < 0.0001 for all three measures). The visual acuity of affected eyes was more likely to decrease in patients presenting at >35 years of age than in patients presenting at a younger age (P = 0.0004). CONCLUSIONS: The affected eye in unilateral pigmentary retinopathy shows a progressive loss of peripheral retinal function that cannot be attributed to aging alone and that is faster in eyes with a more prolonged initial cone ERG implicit time. Patients presenting at >35 years of age are at greater risk for losing visual acuity.


Assuntos
Retina/fisiologia , Retinose Pigmentar/fisiopatologia , Escotoma/fisiopatologia , Adulto , Progressão da Doença , Eletrorretinografia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto Jovem
20.
Retin Cases Brief Rep ; 5(1): 62-3, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-25389683

RESUMO

PURPOSE: The purpose of this study was to improve the clarity of retinal images photographed through small pupils. METHODS: Retinal photographs were taken with a Topcon TRC-NW100 digital nonmydriatic camera centered and decentered about the pupillary axis. Four hundred and twelve consecutive individuals (age, 8-95 years) were screened for eye disease with nonmydriatic retinal photography in the District 33N Lions Eyemobile during a 1-year period. RESULTS: Twenty-nine percent of the eyes photographed had pupillary diameters <4 mm and yielded or would have yielded poor-quality images of the posterior pole with standard, on-axis alignment. In 78% of these eyes with small pupils, photography with off-axis alignment produced images of sufficient clarity for clinical assessment of retinal appearance. CONCLUSION: Off-axis alignment increases the percentage of gradable images of the posterior pole in individuals with small pupils.

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