RESUMEN
OBJECTIVE: To estimate age-related macular degeneration (AMD) incidence/progression across a wide age range. METHODS AND ANALYSIS: AMD at baseline and follow-up (colour fundus imaging, Three Continent AMD Consortium Severity Scale, 3CACSS, clinical classification, CC) was assessed for 1513 individuals aged 35-95 years at baseline from three jointly designed population-based cohorts in Germany: Kooperative Gesundheitsforschung in der Region Augsburg (KORA-Fit, KORA-FF4) and Altersbezogene Untersuchungen zur Gesundheit der Universität Regensburg (AugUR) with 18-year, 14-year or 3-year follow-up, respectively. Baseline assessment included lifestyle, metabolic and genetic markers. We derived cumulative estimates, rates and risk factor association for: (1) incident early AMD, (2) incident late AMD among no AMD at baseline (definition 1), (3) incident late AMD among no/early AMD at baseline (definition 2), (4) progression from early to late AMD. RESULTS: Incidence/progression increased by age, except progression in 70+-year old. We observed 35-55-year-old with 3CACSS-based early AMD who progressed to late AMD. Predominant risk factor for incident late AMD definition 2 was early AMD followed by genetics and smoking. When separating incident late AMD definition 1 from progression (instead of combined as incident late AMD definition 2), estimates help judge an individual's risk based on age and (3CACSS) early AMD status: for example, for a 65-year old, 3-year late AMD risk with no or early AMD is 0.5% or 7%, 3-year early AMD risk is 3%; for an 85-year old, these numbers are 0.5%, 21%, 12%, respectively. For CC-based 'early/intermediate' AMD, incidence was higher, but progression was lower. CONCLUSION: We provide a practical guide for AMD risk for ophthalmology practice and healthcare management and document a late AMD risk for individuals aged <55 years.
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Degeneración Macular , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Fondo de Ojo , Humanos , Incidencia , Degeneración Macular/diagnóstico , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Individuals with Autism Spectrum Disorder (ASD) and the Broad Autism Phenotype (BAP) are more likely than individuals with typical development (TD) to report a sexual minority orientation (e.g., Bejerot and Eriksson, PLoS ONE 9:1-9, 2014; DeWinter et al., Journal of Autism and Developmental Disorders 47:2927-2934, 2017; Qualls et al., Journal of Autism and Developmental Disorders 48:3974-3983, 2018). This study operationalized and tested the fit of an existing model of sexual orientation to examine which factors are associated with increased sexual minority orientation (Worthington et al., The Counseling Psychologist 30:496-531, 2002) in individuals with TD, BAP, and ASD. The model was found to have adequate fit, χ2 (130) = 374.04, p < 0.001; RMSEA = 0.07; CFI = 0.95; SRMR = 0.08. Heterosexism was found to be the only predictor of sexual minority orientation and a significant predictor in the BAP and ASD groups, with increased daily heterosexist experiences predicting greater sexual minority orientation in these groups.
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Trastorno del Espectro Autista , Trastorno Autístico , Minorías Sexuales y de Género , Trastorno del Espectro Autista/complicaciones , Trastorno Autístico/complicaciones , Femenino , Humanos , Masculino , Fenotipo , Conducta Sexual/psicologíaRESUMEN
The heart rate-based lactate minimum test is a highly reproducible exercise test. However, the relation between lactate minimum determined by this test and maximal lactate steady state in running and cycling is still unclear. Twelve endurance-trained men performed this test in running and cycling. Exercise intensity at maximal lactate steady state was determined by performing several constant heart rate endurance tests for both exercise modes. Heart rate, power output, lactate concentration, oxygen uptake and rating of perceived exertion at lactate minimum, maximal lactate steady state and maximal performance were analysed. All parameters were significantly higher at maximal lactate steady state compared to lactate minimum for running and cycling. Significant correlations (p<0.05) between maximal lactate steady state and lactate minimum data were found. Peak heart rate and peak oxygen uptake were significantly higher for running versus cycling. Nevertheless, the exercise mode had no influence on relative (in percentage of maximal values) heart rate at lactate minimum (p=0.099) in contrast to relative power output (p=0.002). In conclusion, all measured parameters at lactate minimum were significantly lower but highly correlated with values at maximal lactate steady state in running and cycling, which allows to roughly estimate exercise intensity at maximal lactate steady state with one single exercise test.
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Ciclismo/fisiología , Frecuencia Cardíaca , Ácido Láctico/sangre , Carrera/fisiología , Adulto , Prueba de Esfuerzo , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Resistencia Física , Adulto JovenRESUMEN
STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the effect of chronic motor complete spinal cord injury (SCI) and sex on bone densitometry parameters of the hip, femoral neck, tibial epiphysis, and diaphysis and on long bone fractures. SETTING: SCI rehabilitation center. METHODS: Women and men with long-term (≥7 years) motor complete SCI were compared with able-bodied women and men. Dual-energy X-ray absorptiometry was used to assess bone densitometry parameters at the hip and femoral neck, whereas peripheral quantitative computed tomography was used for the tibial epiphysis and diaphysis. RESULTS: The data of 18 women and 25 men with SCI with a mean age of 54.7 ± 12.4 and 53.5 ± 8.6 years, respectively, were analyzed. As reference groups, 74 able-bodied women and 46 men with a mean age of 51.0 ± 13.1 and 50.9 ± 11.2 years were evaluated. Most bone densitometry values were significantly (p ≤ 0.033) lower in the SCI compared with the reference groups, including total bone mineral density at the distal tibial epiphysis (-58.0% in SCI women and -53.6% in SCI men). Fracture rates per 100 patient-years were 3.17 and 2.66 in women and men with SCI compared with 0.85 and 0.21 in able-bodied women and men, respectively. CONCLUSIONS: Compared with able-bodied women and men, individuals with chronic motor complete SCI showed considerably lower bone densitometry values and a higher historical fracture rate. These findings support the need for preventative and therapeutic strategies against bone loss in individuals with SCI.
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Densidad Ósea , Osteoporosis/etiología , Fracturas Osteoporóticas/etiología , Traumatismos de la Médula Espinal/complicaciones , Absorciometría de Fotón , Adulto , Enfermedad Crónica , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/diagnóstico por imagen , Factores Sexuales , Tomografía Computarizada por Rayos XRESUMEN
Individuals on the autism spectrum experience difficulties in social relationships and emotion regulation. The aim of the present exploratory research study was to develop and explore the effectiveness of a manualized emotion regulation group intervention for autistic adults to improve emotion regulation and social communication. The group participants included seven young adults (age > 18 years) on the autism spectrum. Primary outcome measures were the Social Responsiveness Scale (SRS-2) and the Emotion Regulation Questionnaire (ERQ). Group participants reported significant improvements on the Social Communication and Interaction subscale (SCI; t = 2.601, p = .041), the Social Awareness (AWR; t = 3.163, p = .019), and the Social Cognition (COG; t = 4.861, p = .003) subscales of the SRS-2: Self Report. Overall, this study provides preliminary evidence of the effectiveness of a group treatment approach that focuses on emotion regulation to improve social interactions for young adults on the autism spectrum.
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Trastorno del Espectro Autista/terapia , Regulación Emocional , Psicoterapia de Grupo/métodos , Adulto , Femenino , Humanos , Masculino , Evaluación de Resultado en la Atención de Salud , Adulto JovenRESUMEN
Previous research indicates that although those with ASD desire sexual relationships, they may not effectively engage in romantic and intimate interactions. The purpose of this study was to compare reports from young adults with ASD and parents from the same families on the young adult's sexual behavior, experiences, knowledge, and communication. 100 young adults (18-30 years) and parents completed an online survey. Results indicated that young adults reported more typical privacy and sexual behaviors, and higher sexual victimization than their parents reported on their behalf. Our findings indicated that individuals with ASD desire and pursue sexual relationships typical of most people and suggest the need for sex education and communication about topics generally covered for neurotypically developing young adults.
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Trastorno del Espectro Autista/psicología , Conducta Sexual/psicología , Adolescente , Adulto , Víctimas de Crimen/psicología , Femenino , Humanos , Masculino , Padres/psicología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Diagnoses of autism spectrum disorder (ASD) have increased considerably over the past 20â¯years. Because of this rise and the inherent complexity of ASD, there is a need for an increased number of scientifically valid basic and clinical research studies addressing this disorder. This manuscript serves as an introduction to the clinical presentation of ASD as well as the unique challenges and modifications required to conduct clinical research with this population. This includes detailing the current diagnostic criteria, process of receiving an ASD diagnosis, information on assessment measures, and special considerations when developing research. It is the hope that this information will provide researchers interested in conducting clinical trials with those with ASD with baseline information and considerations when developing their research topics and methodology.
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Trastorno del Espectro Autista/diagnóstico , Ensayos Clínicos como Asunto/métodos , Selección de Paciente , Trastorno del Espectro Autista/epidemiología , HumanosRESUMEN
The purpose of the present study was to understand how caregiver stress and coping behaviors impact African American and Euro-American families differently when caring for a child with autism. This study used discriminate function analysis to contrast the stress and coping profiles of Euro-American caregivers who are more acculturated with the majority culture with African American caregivers who ascribe to more traditional values. A sample of 103 families was recruited (52 Euro-American, 51 African American). African American families reported significantly more stress and utilizing more varied coping strategies than their Euro-American counterparts. Additional differences were found between the high and low acculturated African American groups such that low acculturated African Americans were more likely to engage in religious coping.
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Adaptación Psicológica , Trastorno del Espectro Autista/psicología , Negro o Afroamericano/psicología , Cuidadores/psicología , Estrés Psicológico/psicología , Población Blanca/psicología , Adaptación Psicológica/fisiología , Adulto , Negro o Afroamericano/etnología , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/etnología , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Socioeconómicos , Estados Unidos/etnología , Población Blanca/etnologíaRESUMEN
INTRODUCTION: The present study provides pilot data investigating relationships between severity of autism spectrum disorder (ASD) traits, community supports, and other family variables as reported by caregivers of children with ASD in Chile. METHOD: An anonymous caregiver survey was developed based on previous ASD survey studies conducted in the United States and direct input from collaborators residing in Chile. Participants included Chilean caregivers of individuals with ASD (N = 50; Mchild age = 6.98). The survey addressed topics regarding the child's ASD traits, the caregiver's beliefs and perceptions of ASD, and community supports and engagement. RESULTS: Correlational analyses indicated associations between ASD traits, physician support, family stress, stigma, and community engagement. DISCUSSION: Results from this study highlight the importance of future research to better understand and treat Latin American children with ASD and their families. (PsycINFO Database Record
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Trastorno del Espectro Autista/complicaciones , Cuidadores/psicología , Calidad de la Atención de Salud/normas , Adaptación Psicológica , Trastorno del Espectro Autista/psicología , Niño , Preescolar , Chile , Femenino , Humanos , Masculino , Estigma Social , Encuestas y CuestionariosRESUMEN
Individuals with higher levels of the broad autism phenotype (BAP) have some symptoms of autism spectrum disorder (ASD). Like individuals with ASD, people with higher-BAP may have fewer sexual experiences and may experience more same-sex attraction. This study measured BAP traits, sexual experiences, and sexual orientation in typically developing (TD) individuals to see if patterns of sexual behavior and sexual orientation in higher-BAP resemble those in ASD. Although BAP characteristics did not predict sexual experiences, one BAP measure significantly predicted sexual orientation, ß = 0.22, t = 2.72, p = .007, controlling for demographic variables (R2 change = .04, F = 7.41, p = .007), showing individuals with higher-BAP also reported increased same-sex attraction. This finding supports the hypothesis that individuals with higher-BAP resemble ASD individuals in being more likely than TD individuals to experience same-sex attraction.
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Trastorno del Espectro Autista/psicología , Fenotipo , Conducta Sexual/psicología , Encuestas y Cuestionarios , Adolescente , Adulto , Trastorno del Espectro Autista/diagnóstico , Femenino , Humanos , Masculino , Conducta Sexual/fisiología , Adulto JovenRESUMEN
INTRODUCTION: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤ 0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33,000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER: NCT01962571.
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Protocolos Clínicos , Eritropoyetina/administración & dosificación , Neuritis Óptica/tratamiento farmacológico , Retina/fisiopatología , Agudeza Visual , Adolescente , Adulto , Método Doble Ciego , Eritropoyetina/efectos adversos , Femenino , Alemania , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: To evaluate the morphological and functional outcome of wet age-related macular degeneration (AMD) during antivascular endothelial growth factor therapy with bevacizumab using SLO microperimetry (SLO-MP) with eye tracking. PATIENTS AND METHODS: First, reproducibility was tested over the choroidal neovascularization (CNV) in 21 eyes of 19 patients with wet AMD. Second, 21 eyes of 19 patients with active CNV were studied longitudinally during bevacizumab therapy. Best-corrected visual acuity, SLO-MP, spectral-domain optical coherence tomography and fluorescein angiography were performed. RESULTS: There was good reproducibility with a concordance correlation coefficient of 0.85. In the longitudinal study, eyes with anatomical response demonstrated a significant increase of retinal sensitivity. Non-responders showed no change in SLO-MP. Retinal sensitivity at baseline had a significant predictive value for the change in retinal sensitivity during therapy with bevacizumab (P=.032). CONCLUSION: SLO-MP is able to analyze retinal function overlying lesions in wet AMD and can be a useful tool to monitor therapy in patients with macular diseases.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Retina/fisiopatología , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Trastornos de la Visión/fisiopatología , Pruebas del Campo Visual , Degeneración Macular Húmeda/fisiopatología , Anciano , Femenino , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Oftalmoscopía , Tomografía de Coherencia Óptica , Agudeza Visual/fisiología , Campos Visuales/fisiología , Degeneración Macular Húmeda/tratamiento farmacológicoRESUMEN
Autism spectrum disorders are difficult for older adolescents and young adults as impaired social communication affects the transition to adult life. d-Cycloserine, a partial glycine agonist at the N-methyl-d-aspartic acid receptor, was tested in a double-blind randomized trial in 20 older adolescents and young adults with autism spectrum disorders using two dosing strategies (50 mg daily versus 50 mg weekly) for 8 weeks with a 2-week follow-up after discontinuation. d-Cycloserine caused statistically and clinically significant improvement with no differentiation between dosing strategies on the Social Responsiveness Scale and the Aberrant Behavior Checklist before and after d-cycloserine administration.
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Antimetabolitos/uso terapéutico , Trastorno del Espectro Autista/complicaciones , Cicloserina/uso terapéutico , Trastorno de Comunicación Social/tratamiento farmacológico , Trastorno de Comunicación Social/etiología , Adolescente , Adulto , Trastorno del Espectro Autista/psicología , Método Doble Ciego , Femenino , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Escala del Estado Mental , Pruebas Neuropsicológicas , Escalas de Valoración Psiquiátrica , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: Autism spectrum disorders (ASDs) have core impairments in social communication as well as the presence of repetitive, stereotypic behaviors and restricted interests. Older adolescents and young adults are particularly impacted by these deficits. Preclinical data implicate glutamatergic dysfunction in the pathophysiology of ASDs. D-Cycloserine (DCS), a partial glycineB agonist at the N-methyl-D-aspartic acid receptor site, has been shown to improve sociability in mouse models and a small human study. The sensitivity of the obligatory glycineB co-agonist binding site may change with daily administration of DCS as a result of agonist-induced desensitization. The efficacy of a "pulsed" once-weekly administration versus "daily" administration of DCS was compared. METHODS: Males and females, ages 14 to 25 years, with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis of an ASD were enrolled in a double-blind, randomized 10-week trial consisting of 8 weeks of active drug with either weekly or daily administration of 50 mg of DCS followed by a 2-week follow-up visit. RESULTS: For the purposes of this study, no statistical or clinical differences existed between the 2 dosage groups on the Aberrant Behavior Checklist subscale 3, which measures stereotypies/repetitive movements. When combining groups, a statistically significant decrease of 37% was found from baseline to week 8 when study drug was completed using a linear mixed effects model (P = 0.003). CONCLUSIONS: D-Cycloserine was shown to be effective in improving stereotypic symptoms in older adolescents and young adults with ASDs measured by the Aberrant Behavior Checklist subscale 3. In addition, DCS was safe and well tolerated.
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Antimetabolitos/uso terapéutico , Trastornos Generalizados del Desarrollo Infantil/tratamiento farmacológico , Cicloserina/uso terapéutico , Receptores de N-Metil-D-Aspartato/agonistas , Trastorno de la Conducta Social/prevención & control , Trastorno de Movimiento Estereotipado/prevención & control , Adolescente , Conducta del Adolescente/efectos de los fármacos , Adulto , Antimetabolitos/administración & dosificación , Antimetabolitos/efectos adversos , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Cicloserina/administración & dosificación , Cicloserina/efectos adversos , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Proyectos Piloto , Escalas de Valoración Psiquiátrica , Trastorno de la Conducta Social/etiología , Conducta Estereotipada/efectos de los fármacos , Trastorno de Movimiento Estereotipado/etiología , Adulto JovenRESUMEN
PURPOSE: To evaluate the morphologic restoration of retinal anatomy after surgery for epiretinal membrane (ERM) peeling using spectral domain optical coherence tomography. Correlation of retinal structure with visual outcome. DESIGN: Retrospective consecutive case series. METHODS: Thirty-four consecutive eyes with ERM underwent surgery with 1 year follow-up examination. Spectral domain optical coherence tomography scans were analyzed preoperatively and 1, 3, 6, 9, and 12 months postoperative. Best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study charts was measured at each visit. RESULTS: All eyes showed a significant improvement of BCVA after ERM peeling (P = 0.002). The time point of BCVA and retinal restoration seen on spectral domain optical coherence tomography occurred simultaneously and varied between individuals (occurrence of BCVA: mean, 4.82 months; retinal restoration: mean, 4.24 months). At 3 months, the retinal anatomical restoration rate was 70% and 88% at 6 months. CONCLUSION: Restoration of the retinal anatomical structure predominantly occurs within the first 3 months post-ERM peeling. An improvement of BCVA and anatomical retinal restoration after ERM removal varies in individuals. If retinal layers fully restore in their anatomical structure, BCVA improves at the same time point.
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Membrana Epirretinal/cirugía , Procedimientos Quirúrgicos Oftalmológicos , Retina/fisiopatología , Agudeza Visual/fisiología , Anciano , Membrana Epirretinal/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Tomografía de Coherencia Óptica , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate temporal changes and predictors of accuracy in the alignment between simultaneous near-infrared image and optical coherence tomography (OCT) scan on the Heidelberg Spectralis using a model eye. DESIGN: Laboratory investigation. METHODS: After calibrating the device, 6 sites performed weekly testing of the alignment for 12 weeks using a model eye. The maximum error was compared with multiple variables to evaluate predictors of inaccurate alignment. Variables included the number of weekly scanned patients, total number of OCT scans and B-scans performed, room temperature and its variation, and working time of the scanning laser. A 4-week extension study was subsequently performed to analyze short-term changes in the alignment. RESULTS: The average maximum error in the alignment was 15 ± 6 µm; the greatest error was 35 µm. The error increased significantly at week 1 (P = .01), specifically after the second imaging study (P < .05); reached a maximum after the eighth patient (P < .001); and then varied randomly over time. Predictors for inaccurate alignment were temperature variation and scans per patient (P < .001). For each 1 unit of increase in temperature variation, the estimated increase in maximum error was 1.26 µm. For the average number of scans per patient, each increase of 1 unit increased the error by 0.34 µm. CONCLUSION: Overall, the accuracy of the Heidelberg Spectralis was excellent. The greatest error happened in the first week after calibration, and specifically after the second imaging study. To improve the accuracy, room temperature should be kept stable and unnecessary scans should be avoided. The alignment of the device does not need to be checked on a regular basis in the clinical setting, but it should be checked after every other patient for more precise research purposes.
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Modelos Biológicos , Oftalmoscopios/normas , Retina/anatomía & histología , Tomografía de Coherencia Óptica/instrumentación , Calibración , Humanos , Imagenología Tridimensional , Rayos Infrarrojos , Reproducibilidad de los ResultadosRESUMEN
PURPOSE: To evaluate in vivo ocular safety of an intravitreal hydrosilylated porous silicon (pSi) drug delivery system along with the payload of daunorubicin (DNR). METHODS: pSi microparticles were prepared from the electrochemical etching of highly doped, p-type Si wafers and an organic linker was attached to the Si-H terminated inner surface of the particles by thermal hydrosilylation of undecylenic acid. DNR was bound to the carboxy terminus of the linker as a drug-loading strategy. DNR release from hydrosilylated pSi particles was confirmed in the excised rabbit vitreous using liquid chromatography-electrospray ionization-multistage mass spectrometry. Both empty and DNR-loaded hydrosilylated pSi particles were injected into the rabbit vitreous and the degradation and safety were studied for 6 months. RESULTS: The mean pSi particle size was 30×46×15 µm with an average pore size of 15 nm. Drug loading was determined as 22 µg per 1 mg of pSi particles. An ex vivo drug release study showed that intact DNR was detected in the rabbit vitreous. An in vivo ocular toxicity study did not reveal clinical or pathological evidence of any toxicity during a 6-month observation. Hydrosilylated pSi particles, either empty or loaded with DNR, demonstrated a slow elimination kinetics from the rabbit vitreous without ocular toxicity. CONCLUSIONS: Hydrosilylated pSi particles can host a large quantity of DNR by a covalent loading strategy and DNR can be slowly released into the vitreous without ocular toxicity, which would appear if an equivalent quantity of free drug was injected.
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Daunorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Silicio/química , Inhibidores de Topoisomerasa II/administración & dosificación , Animales , Cromatografía Liquida , Daunorrubicina/farmacocinética , Daunorrubicina/toxicidad , Inyecciones Intravítreas , Tamaño de la Partícula , Porosidad , Conejos , Espectrometría de Masa por Ionización de Electrospray , Factores de Tiempo , Inhibidores de Topoisomerasa II/farmacocinética , Inhibidores de Topoisomerasa II/toxicidadRESUMEN
PURPOSE: The objectives of this study were to synthesize and characterize two types of cytarabine (Ara-C) lipid produgs and evaluate the prodrugs for sustained intraocular delivery after administration by intravitreal injection. METHODS: Hexadecyloxypropyl cytarabine 5'-monophosphate (HDP-P-Ara-C) and hexadecyloxypropyl cytarabine 3',5'-cyclic monophosphate (HDP-cP-Ara-C) were synthesized starting from cytarabine (1-ß-D-arabinofuranosylcytosine). Their vitreal clearance profile was simulated using a custom dissolution chamber, in vitro cytotoxicity was evaluated using cell proliferation assays, and in vivo ocular properties in rat and rabbit eyes were assessed using biomicroscopy, indirect ophthalmoscopy, tonometry, electroretinography, and histology. RESULTS: HDP-P-Ara-C was cleared from the dissolution chamber (flow rate 2 µL/min) within 7 days. In contrast, HDP-cP-Ara-C, a much more insoluble prodrug, was still detectable 36 days after the dissolution process was started. HDP-P-Ara-C had a 50% cytotoxicity concentration of 52±2.6 µM in human retinal pigment epithelium (ARPE-19) and 32±2.2 µM in a rat Müller cell line, rMC-1. The 50% cytotoxicity concentration values for HDP-cP-Ara-C in ARPE-19 and rMC-1 cells were 50 µM and 25 µM, respectively. HDP-P-Ara-C was not detectable 2 weeks after the highest intravitreal dose (228 µg/rat eye) was injected, and no ocular toxicity was found. With HDP-cP-Ara-C, the drug depot was visible for 26 weeks following a single intravitreal injection (800 µg/rabbit eye). For both compounds, the electroretinogram, intraocular pressure, and other toxicity studies were negative except for the highest dose of HDP-cP-Ara-C (800 µg/eye), which had focal toxicity from the direct touch of the retina and decreased dark adapted a-waves and decreased flicker electroretinogram amplitudes (generalized estimating equations, p=0.039 and 0.01). CONCLUSIONS: The cyclic monophosphate prodrug, HDP-cP-Ara-C, was found to have physiochemical properties better suited for sustained delivery of cytarabine to posterior segments of the eye. These properties included limited aqueous solubility, in vitro antiproliferative activity, and good tolerability after injection into rabbit eyes.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Arabinonucleotidos/administración & dosificación , Citidina Monofosfato/análogos & derivados , Preparaciones de Acción Retardada/administración & dosificación , Profármacos/administración & dosificación , Retina/efectos de los fármacos , Vitreorretinopatía Proliferativa/tratamiento farmacológico , Cuerpo Vítreo/efectos de los fármacos , Animales , Antimetabolitos Antineoplásicos/síntesis química , Arabinonucleotidos/síntesis química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citidina Monofosfato/administración & dosificación , Citidina Monofosfato/síntesis química , Preparaciones de Acción Retardada/síntesis química , Cámaras de Difusión de Cultivos , Electrorretinografía , Humanos , Inyecciones Intravítreas , Cinética , Oftalmoscopía , Profármacos/síntesis química , Conejos , Ratas , Retina/metabolismo , Retina/patología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/patología , Solubilidad , Vitreorretinopatía Proliferativa/metabolismo , Vitreorretinopatía Proliferativa/patología , Cuerpo Vítreo/metabolismo , Cuerpo Vítreo/patologíaRESUMEN
PURPOSE: To evaluate the integrity of photoreceptor inner segment/outer segment (IS/OS) junction after change of drusen size in age-related macular degeneration using spectral-domain optical coherence tomography. METHODS: Drusen volume raster scans were performed with the Spectralis spectral-domain optical coherence tomography (Heidelberg Engineering) through 2,624 drusen in 14 eyes with clinically dry age-related macular degeneration, which had been longitudinally followed-up between 23 and 28 months without intervention (mean, 26.3 months). All eyes had Early Treatment Diabetic Retinopathy Study visual acuity. A total of 416 of 2,624 drusen were analyzed. RESULTS: Of 416 drusen, 83 (20%) were found to have regressed spontaneously (Group A), 212 (51%) showed no change in size (Group B), and 121 (29%) progressed (Group C). Mean drusen size of all drusen was 63.7 ± 25.7 µm. Cross-sectional analysis of drusen morphology showed a correlation between drusen size and disrupted IS/OS junction/photoreceptor integrity (r = -0.48, P < 0.001). Of the drusen that regressed over time, there was intact IS/OS junction integrity. Even drusen that caused a major disruption showed IS/OS restoration in 74% of the drusen (P < 0.001). CONCLUSION: Progression of drusen shows structural disruption of the IS/OS junction. After drusen regression, the IS/OS junction is either able to restore as drusen regress or was artifactitiously compressed and not initially visible because of the initial drusen compression of the IS/OS junctional line. Therefore, drusen evolution may play an important role in affecting the photoreceptor IS/OS junction integrity.
Asunto(s)
Atrofia Geográfica/diagnóstico , Drusas Retinianas/diagnóstico , Segmento Interno de las Células Fotorreceptoras Retinianas/patología , Segmento Externo de las Células Fotorreceptoras Retinianas/patología , Humanos , Tomografía de Coherencia Óptica , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To correlate surgical difficulty of epiretinal membrane (ERM) removal with characteristics of ERM adherence seen by spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective observational case series. METHODS: Surgical difficulty was correlated with extent of ERM adherence by SD-OCT using masked observers in consecutive eyes undergoing ERM removal (N=31). Surgical videos were analyzed and difficulty of ERM removal (grade 1-3) was determined in 4 quadrants as well as the fovea by consensus of observers masked to SD-OCT findings. Extent of ERM adhesion was categorized (focal, broad, or complete) by masked observers using SD-OCT. The presence of fibrillary changes between the ERM and retinal nerve fiber layer (RNFL) was also evaluated. Surgical difficulty of ERM removal for each quadrant and fovea was compared to extent of ERM adherence and presence of fibrillary changes. RESULTS: Assessment of ERM adherence using SD-OCT between masked observers was highly concordant (kappa=0.9178). Surgical difficulty of ERM removal was strongly associated with more extensive ERM adherence to the retina observed by SD-OCT. Complete ERM adherence correlated with an 8.6-fold increased surgical difficulty of ERM removal compared to focal adherence (P<.0001). The presence of fibrillary changes between the ERM and RNFL also correlated with a 25.5-fold increased difficulty of surgical removal compared to the absence of fibrillary changes (P<.0001). CONCLUSION: Extent of ERM-retinal adhesion and presence of fibrillary changes determined by SD-OCT provide reliable preoperative assessment of surgical difficulty. Furthermore, SD-OCT analysis may help localize surgically advantageous coordinates to initiate ERM removal.