RESUMEN
OBJECTIVES: Observational studies have suggested that a higher 25-hydroxyvitamin D concentration may be associated with longer telomere length; however, this has not been investigated in randomised controlled trials. We conducted an ancillary study within a randomised, double-blind, placebo-controlled trial of monthly vitamin D (the D-Health Trial) for the prevention of all-cause mortality, conducted from 2014 to 2020, to assess the effect of vitamin D supplementation on telomere length (measured as the telomere to single copy gene (T/S) ratio). DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: Participants were Australians aged 60-84 years and we randomly selected 1,519 D-Health participants (vitamin D: n=744; placebo: n=775) for this analysis. We used quantitative polymerase chain reaction to measure the relative telomere length (T/S ratio) at 4 or 5 years after randomisation. We compared the mean T/S ratio between the vitamin D and placebo groups to assess the effect of vitamin D supplementation on relative telomere length, using a linear regression model with adjustment for age, sex, and state which were used to stratify the randomisation. RESULTS: The mean T/S ratio was 0.70 for both groups (standard deviation 0.18 and 0.16 for the vitamin D and placebo groups respectively). The adjusted mean difference (vitamin D minus placebo) was -0.001 (95% CI -0.02 to 0.02). There was no effect modification by age, sex, body mass index, or predicted baseline 25-hydroxyvitamin D concentration. CONCLUSION: In conclusion, routinely supplementing older adults, who are largely vitamin D replete, with monthly doses of vitamin D is unlikely to influence telomere length.
Asunto(s)
Vitamina D , Vitaminas , Humanos , Anciano , Australia , Vitaminas/farmacología , Vitaminas/uso terapéutico , Calcifediol , Telómero , Suplementos Dietéticos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Vitamin D, specifically serum 25(OH)D has been associated with mortality, cancer and multiple other health endpoints in observational studies, but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population-wide supplementation. We have therefore launched the D-Health Trial, a randomized trial of vitamin D supplementation for prevention of mortality and cancer. Here we report the methods and describe the trial cohort. METHODS: The D-Health Trial is a randomized placebo-controlled trial, with planned intervention for 5years and a further 5years of passive follow-up through linkage with health and death registers. Participants aged 65-84years were recruited from the general population of Australia. The intervention is monthly oral doses of 60,000IU of cholecalciferol or matching placebo. The primary outcome is all-cause mortality. Secondary outcomes are total cancer incidence and colorectal cancer incidence. RESULTS: We recruited 21,315 participants to the trial between February 2014 and May 2015. The participants in the two arms of the trial were well-balanced at baseline. Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health, to be current smokers or to have diabetes than the Australian population. However, the proportion overweight or with health conditions such as arthritis and angina was similar. CONCLUSIONS: Observational data cannot be considered sufficient to support interventions delivered at a population level. Large-scale randomized trials such as the D-Health Trial are needed to inform public health policy and practice.
Asunto(s)
Colecalciferol/uso terapéutico , Mortalidad , Neoplasias/prevención & control , Vitaminas/uso terapéutico , Anciano , Anciano de 80 o más Años , Australia/epidemiología , Causas de Muerte , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/prevención & control , Método Doble Ciego , Humanos , Incidencia , Masculino , Neoplasias/epidemiología , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: Thyroid cancer incidence has been increasing worldwide. Some suggest greater ascertainment of indolent tumours is the only driver, but others suggest there has been a true increase. Increases in Australia appear to have been among the largest in the world, so we investigated incidence trends in the Australian state of Queensland to help understand reasons for the rise. METHODS: Thyroid cancers diagnoses in Queensland 1982-2008 were ascertained from the Queensland Cancer Registry. We calculated age-standardized incidence rates (ASR) and used Poisson regression to estimate annual percentage change (APC) in thyroid cancer incidence by socio-demographic and tumour-related factors. RESULTS: Thyroid cancer ASR in Queensland increased from 2·2 to 10·6/100 000 between 1982 and 2008 equating to an APC of 5·5% [95% confidence interval (CI) 4·7-6·4] in men and 6·1% (95% CI 5·5-6·6) in women. The rise was evident, and did not significantly differ, across socio-economic and remoteness-of-residence categories. The largest increase seen was in the papillary subtype in women (APC 7·9%, 95% CI 7·3-8·5). Incidence of localized and more advanced-stage cancers rose over time although the increase was greater for early-stage cancers. CONCLUSION: There has been a marked increase in thyroid cancer incidence in Queensland. The increase is evident in men and women across all adult age groups, socio-economic strata and remoteness-of-residence categories as well as in localized and more advanced-stage cancers. Our results suggest 'overdiagnosis' may not entirely explain rising incidence. Contemporary aetiological data and individual-level information about diagnostic circumstances are required to further understand reasons for rising thyroid cancer incidence.
RESUMEN
AIMS: To assess associations between maternal serum vitamin D concentration and glucose metabolism in a cohort of pregnant women living in an Australian subtropical environment. METHODS: Cross-sectional assessment of 25-hydroxy vitamin D concentrations in 399 Hyperglycemia and Adverse Pregnancy Outcome ancillary study participants, treated at an obstetric teaching hospital in Brisbane, Australia. All patients underwent a blinded 75-g oral glucose tolerance test at 24-32 (target 28) weeks' gestation. RESULTS: The mean (± standard deviation) fasting plasma glucose was 4.5 ± 0.4 mmol/l. Mean (± standard deviation) serum 25-hydroxy vitamin D was 132.5 ± 44.0 nmol/l. A difference of one standard deviation in maternal 25-hydroxy vitamin D was inversely related to fasting glucose (fasting glucose lower by 0.047 mmol/l, P=0.012) when assessed with multiple linear regression after adjusting for confounders. Maternal 25-hydroxy vitamin D correlated with ß-cell function as estimated by the log-transformed homeostasis model assessment-ß-cell function equation (r=0.131, P=0.009), but not with the homeostasis model assessment of insulin resistance. CONCLUSIONS: An association between mid-gestational 25-hydroxy vitamin D and fasting glucose was confirmed in a largely normoglycaemic and vitamin D-replete pregnant population. The correlation between 25-hydroxy vitamin D and ß-cell function suggests that vitamin D may influence glucose metabolism through this mechanism. Intervention studies are required to determine causality and the role of vitamin D replacement in deficient individuals.
Asunto(s)
Glucemia/metabolismo , Hiperglucemia/etiología , Complicaciones del Embarazo/etiología , Deficiencia de Vitamina D/complicaciones , Vitamina D/análogos & derivados , Adulto , Índice de Masa Corporal , Estudios Transversales , Diabetes Gestacional/sangre , Diabetes Gestacional/etiología , Ayuno/sangre , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Embarazo , Complicaciones del Embarazo/sangre , Resultado del Embarazo , Vitamina D/sangreRESUMEN
During eye development, apoptosis is vital to the maturation of highly specialized structures such as the lens and retina. Several forms of apoptosis have been described, including anoikis, a form of apoptosis triggered by inadequate or inappropriate cell-matrix contacts. The anoikis regulators, Bit1 (Bcl-2 inhibitor of transcription-1) and protein kinase-D (PKD), are expressed in developing lens when the organelles are present in lens fibers, but are downregulated as active denucleation is initiated. We have previously shown that in rats with a spontaneous mutation in the Cryba1 gene, coding for ßA3/A1-crystallin, normal denucleation of lens fibers is inhibited. In rats with this mutation (Nuc1), both Bit1 and PKD remain abnormally high in lens fiber cells. To determine whether ßA3/A1-crystallin has a role in anoikis, we induced anoikis in vitro and conducted mechanistic studies on astrocytes, cells known to express ßA3/A1-crystallin. The expression pattern of Bit1 in retina correlates temporally with the development of astrocytes. Our data also indicate that loss of ßA3/A1-crystallin in astrocytes results in a failure of Bit1 to be trafficked to the Golgi, thereby suppressing anoikis. This loss of ßA3/A1-crystallin also induces insulin-like growth factor-II, which increases cell survival and growth by modulating the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR and extracellular signal-regulated kinase pathways. We propose that ßA3/A1-crystallin is a novel regulator of both life and death decisions in ocular astrocytes.
Asunto(s)
Anoicis/fisiología , Astrocitos/citología , Cristalinas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Apoptosis/fisiología , Astrocitos/enzimología , Astrocitos/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
We report the case of a 56-year-old man with the rare autoimmune pathologies of alternating hypothyroidism and hyperthyroidism due to thyroid-stimulating hormone receptor antibodies, and rheumatoid arthritis as manifestations of a human immunodeficiency virus-related immune reconstitution inflammatory syndrome. The patient also developed overt progression of a pre-existing skin malignancy that may also be related. This case highlights immune reconstitution syndrome as an important differential diagnosis following antiretroviral therapy commencement, and that a high index of suspicion should be maintained for this rare but important cluster of conditions. Furthermore, the patient's genetic predisposition to autoimmunity provides helpful insights into the pathogenesis of these disorders.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Progresión de la Enfermedad , Síndrome Inflamatorio de Reconstitución Inmune/diagnóstico , Neoplasias Cutáneas/diagnóstico , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/patología , Diagnóstico Diferencial , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/complicaciones , Síndrome Inflamatorio de Reconstitución Inmune/patología , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/patologíaRESUMEN
The immunolocalization of the low density lipoprotein receptor-related protein 1 (LRP1) and its ligand alpha 2-Macroglobulin (alpha(2)M) was examined in tissues from human donor eyes of normal, diabetic and sickle cell disease subjects. Streptavidin alkaline phosphatase immunohistochemistry was performed with a mouse anti-human LRP1 and rabbit anti-human alpha(2)M antibodies. Retinal and choroidal blood vessels were labeled with mouse anti-human CD34 antibody in adjacent tissue sections. Mean scores for immunostaining from the pathological and control eyes were statistically compared. LRP1 immunoreactivity was very weak to negative in the neural retina of normal subjects except in scattered astrocytes. LRP1 expression in diabetic eyes was detected in the internal limiting membrane (ILM), astrocytes, inner photoreceptor matrix, choriocapillaris and choroidal stroma. The ligand alpha(2)M, however, was limited mainly to blood vessel walls, some areas of the inner nuclear layer (INL), photoreceptors, RPE-Bruch's membrane-choriocapillaris complex, intercapillary septa, and choroidal stroma. In sickle cell eyes, avascular and vascular retina as well as choroidal neovascularization (CNV) were analyzed. In avascular areas, LRP1 immunoreactivity was in innermost retina (presumably ILM, astrocytes, and Muller cells) and INL as well as RPE-Bruch's membrane-choriocapillaris complex and choroidal stroma. alpha(2)M was very weak in avascular peripheral retina compared to vascularized areas and limited to stroma in choroid. In contrast, in areas with CNV, LRP1 immunoreactivity was significantly decreased in overlying retina and in RPE-Bruch's membrane and choroidal stroma compared to the controls, while alpha(2)M was elevated in RPE-Bruch's membrane near CNV compared to normal areas in sickle cell choroid. The mean scores revealed that LRP1 and alpha(2)M in neural retina were significantly elevated in astrocytes and ILM in diabetic eyes (p < or = 0.05), whereas in sickle cell eyes scores were elevated in ILM and INL (p < or = 0.05). In addition, alpha(2)M immunoreactivity was in photoreceptors in both ischemic retinopathies. In choroid, the patterns of LRP1 and alpha(2)M expression were different and not coincident. This is the first demonstration of the presence of LRP1 and alpha(2)M in human proliferative retinopathies. Elevated LRP1 expression in sickle cell neural retina and diabetic inner retina and choroid suggests that LRP1 plays an important role in ischemic neovascular diseases.
Asunto(s)
Anemia de Células Falciformes/metabolismo , Coroides/metabolismo , Retinopatía Diabética/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Retina/metabolismo , Neovascularización Retiniana/metabolismo , alfa-Macroglobulinas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Vasos Retinianos/metabolismoRESUMEN
Vasculogenesis and/or angiogenesis are thought to be the major mechanisms for new vessel formation during development. A third mechanism, haemo-vasculogenesis, has been described in which blood vessel and blood cells (haematopoiesis (expression of CD34(+)) and erythropoiesis (presence of epsilon chain of haemoglobin or Hb-epsilon(+))) differentiate from a common precursor, the haemangioblast. This review describes the mechanism(s) for development of human choroidal vascular from 6 until 22 weeks gestation (WG). Endothelial cell or EC (CD31, CD34, CD39, VEGFR-2) and angioblast (CD39, VEGFR-2) markers were present in choriocapillaris (CC) by 7 WG through 22 WG. From 6 to 8 WG, many erythroblasts (nucleated Hb-epsilon(+) RBCs) were observed in the CC layer. Erythroblasts (Hb-epsilon(+)) were also positive for CD34, CD31, and/or VEGFR-2. Proliferation of vascular cells (Ki67+), suggesting angiogenesis, was not observed until 12 WG. TEM analysis demonstrated that CC was structurally immature even at 11 WG: no basement membrane, absence of pericytes, and poorly formed lumens that were filled with filopodia. Contiguous fenestrations and significant PV-1 (protein in diaphragms of fenestrations) were not observed until 21-22 WG. Smooth muscle actin was prominent at 20 WG and the maturation of pericytes was confirmed by TEM. Therefore, the embryonic CC appears to form initially by haemo-vasculogenesis (Hb-epsilon(+)/CD31(+) cells), whereas angiogenesis (CD34(+)/Ki67(+)) appears to be the mode of intermediate and large choroidal vessel development later in the foetus. Contiguous fenestrations, mature pericytes, and EC basal lamina occur late in development, around 22 WG, which coincides with photoreceptors developing inner segments.
Asunto(s)
Coroides/irrigación sanguínea , Neovascularización Fisiológica/fisiología , Antígenos CD/metabolismo , Proliferación Celular , Coroides/embriología , Coroides/metabolismo , Células Endoteliales/citología , Células Endoteliales/metabolismo , Edad Gestacional , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Retina/citología , Retina/embriología , Retina/metabolismo , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/metabolismoRESUMEN
Subclinical hypothyroidism (SCH), thyroid autoimmunity and isolated maternal hypothyroxinaemia are diagnoses made on laboratory findings. The two former conditions are commonly identified in the general population, while the term isolated maternal hypothyroxinaemia was developed to highlight potential neurodevelopmental risks in progeny. Each entity has been associated with either obstetric, perinatal and/or child developmental harm in observational studies, although few interventional trials have been performed to guide diagnostic and therapeutic approaches. Once diagnosed, treatment of SCH is recommended by endocrine groups to limit potential risk, given that harm from appropriate therapy is unlikely. Screening for thyroid disorders in pregnancy has traditionally been controversial. Definitive trials are expected to report over coming years and updated consensus guidelines will hopefully resolve this issue.
RESUMEN
AIM: To examine the immunolocalisation of stromal cell derived factor 1 (SDF-1) and its receptor CXCR4 in aged control human donor eyes and eyes with age related macular degeneration (AMD). METHODS: Postmortem eyes from eight aged control donors (mean age 79.8 years) and from 12 donors with AMD (mean age 83.9 years) were cryopreserved and sectioned through the macular region. SDF-1 and CXCR4 were localised using streptavidin alkaline phosphatase immunohistochemistry and then sections were bleached. Three independent masked observers scored the immunohistochemical reaction product. RESULTS: In aged control retinas, SDF-1 immunoreactivity was most intense in inner photoreceptor matrix (IPM). CXCR4 showed a similar pattern of immunostaining, but was more prominent in inner segments of photoreceptors. In aged control and AMD choroid, SDF-1 and CXCR4 localisations were most prominent in retinal pigment epithelial (RPE) cells and choroidal stroma. However, the intensity for SDF-1 was significantly reduced in RPE (p < 0.0001) and choroidal stroma (p < 0.05) in late AMD eyes. SDF-1 and CXCR4 immunoreactivities were weak or nearly absent in disciform scars with choroidal neovascularisation (CNV). Circulating cells, presumably leucocytes, were most intensely positive for CXCR4. CONCLUSIONS: These results show that changes in distribution and relative levels of SDF-1/CXCR4 were not evident in early AMD. This suggests that SDF-1/CXCR4 may not contribute to the formation of CNV in AMD, in that CXCR4+ cells were not incorporated into neovascularisation. However, the examples of CNV studied were within disciform scars, so the authors cannot comment on the role of SDF-1/CXCR4 in the early stages of CNV formation.
Asunto(s)
Quimiocinas CXC/análisis , Coroides/química , Degeneración Macular/metabolismo , Receptores CXCR4/análisis , Retina/química , Anciano , Anciano de 80 o más Años , Biomarcadores/análisis , Quimiocina CXCL12 , Neovascularización Coroidal/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Fotorreceptoras/química , Epitelio Pigmentado Ocular/químicaRESUMEN
AIMS: This study investigated the expression and localisation of thrombospondin-1 (TSP-1), a known anti-angiogenic extracellular matrix protein, in normal aged control human eyes and eyes with age related macular degeneration (AMD). METHODS: Immunohistochemical analysis with mouse anti-human TSP-1 antibody and mouse anti-human CD 34 antibody, as a blood vessel marker, was performed on frozen sections from macular and peripheral blocks of aged control donor eyes (n = 12; mean age 78.8 years), and eyes with AMD (n = 12; mean age 83.9 years). Pigment in retinal pigment epithelium (RPE) and choroidal melanocytes was bleached. Three independent observers scored the immunohistochemical reaction product. RESULTS: In the macular region, TSP-1 expression was observed intensely in Bruch's membrane and weakly in RPE basement membrane, choriocapillaris, and the wall of large choroidal blood vessels in the aged control eyes. In eyes with AMD, TSP-1 immunoreactivity was significantly lower in all structures except RPE basement membrane (p<0.01). There was significantly lower TSP-1 in the far periphery than the equator and submacular regions in all eyes. TSP-1 immunoreactivity was low in choroidal neovascularisation (CNV), but it was high and diffuse in adjacent scar tissue. CONCLUSION: These findings suggest that decreased TSP-1 in Bruch's membrane and choroidal vessels during AMD may permit the formation of CNV.
Asunto(s)
Ojo/metabolismo , Degeneración Macular/metabolismo , Trombospondina 1/metabolismo , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Lámina Basal de la Coroides/metabolismo , Preescolar , Coroides/metabolismo , Neovascularización Coroidal/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Retina/metabolismoRESUMEN
Diabetes mellitus develops spontaneously in middle-aged, obese rhesus monkeys, thus making them a good model for examining the effects of co-morbid factors on the development of end-organ damage. Changes in structure and function in the eyes of one monkey who spontaneously developed type 2 diabetes are reported here. This animal had concomitant hypertension, high levels of triglycerides and serum cholesterol, and a low fraction of high-density lipoprotein. The eyes showed intraretinal hemorrhages and large areas of retinal capillary nonperfusion. Indo-cyanin green (ICG) angiography revealed a large area of non- or poorly perfused choriocapillaris in one eye, and immunohistochemistry showed loss of viable choriocapillaries in this region. Both basal laminar deposits and hard drusen were present on areas of Bruch's membrane adjacent to nonviable choriocapillaris. Blood flow via the nasal posterior ciliary arteries to this section of choroid was not detectable by color duplex Doppler ultrasound, indicating contribution of extraocular vascular disease to ischemia in this eye. There was a severe decline in number of photoreceptor inner and outer segments, and corresponding reductions in the multifocal electroretinogram (ERG), in the areas of choriocapillaris loss. The ganzfeld ERG indicated loss in both inner and outer retinal function. Much of the ganglion cell layer was absent throughout the retina, possibly reflecting the effect of diabetes as well as chronic open angle glaucoma; the latter diagnosis supported by elevated intraocular pressures and excavated optic disks. In summary, high resolution, enzyme histochemical and histopathological analyses of a diabetic hypertensive monkey retina and choroid after serial functional in vivo analyses have demonstrated the relationship between vascular dysfunction and visual function loss. Choroidal vascular dysfunction in both large and small vessels was associated with age-related macular degeneration-like changes in Bruch's membrane and photoreceptor degeneration.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Ojo/patología , Fenómenos Fisiológicos Oculares , Envejecimiento/fisiología , Angiografía/métodos , Animales , Velocidad del Flujo Sanguíneo/fisiología , Capilares/patología , Coroides/patología , Coroides/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Retinopatía Diabética/complicaciones , Retinopatía Diabética/patología , Retinopatía Diabética/fisiopatología , Modelos Animales de Enfermedad , Electrorretinografía/métodos , Células Endoteliales/patología , Células Endoteliales/fisiología , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Femenino , Inmunohistoquímica/métodos , Macaca mulatta , Hipertensión Ocular/complicaciones , Hipertensión Ocular/patología , Hipertensión Ocular/fisiopatología , Drusas Retinianas/patología , Drusas Retinianas/fisiopatología , Hemorragia Retiniana/patología , Hemorragia Retiniana/fisiopatología , Vasos Retinianos/patología , Vasos Retinianos/fisiopatologíaRESUMEN
AIMS: The expression of the adhesion molecules ICAM-1, VCAM-1, and P-selectin, and the distribution and number of polymorphonuclear leucocytes (PMNs) were investigated in sickle cell retinopathy (SCR) and compared to the normal retina. METHODS: Postmortem ocular tissue was obtained from five subjects (16, 21, 28, 40, and 41 years of age) with sickle haemoglobinopathies and from one control subject. Tissue was cryopreserved, and streptavidin peroxidase immunohistochemistry was performed with antibodies against ICAM-1, VCAM-1, and P-selectin. Immunohistochemical reaction product was scored, and PMN numbers were counted in sections stained with non-specific esterase. RESULTS: Increased ICAM-1, VCAM-1, and P-selectin immunoreactivities were observed in sickle cell subjects compared to the control subject. The highest ICAM and P-selectin immunoreactivity was associated with intraretinal vessels adjacent to the preretinal neovascular formation in subjects with proliferative retinopathy. This was not the case with VCAM-1 immunoreactivity, which was highest in intraretinal vessels adjacent to the sea fan when the sea fan was still "in statu nascendi." Fully formed, "older" sea fans had the highest levels of VCAM-1. The increase in adhesion molecule immunoreactivity was paralleled by an increase in intraretinal PMNs. The number of intraretinal PMNs increased with progression of the disease and the numbers surpassed those in control subjects by threefold. In the sea fan with the greatest VCAM-1 immunoreactivity, there were 20 times more PMNs were observed than in the rest of the retina in the same subject. CONCLUSION: These data suggest that adhesion molecule mediated leucocyte adhesion might play an important part in the vaso-occlusive phase of sickle cell retinopathy and in autoinfarction of sea fan formations.
Asunto(s)
Anemia de Células Falciformes/metabolismo , Moléculas de Adhesión Celular/metabolismo , Enfermedades de la Retina/metabolismo , Adolescente , Adulto , Anciano , Anemia de Células Falciformes/complicaciones , Progresión de la Enfermedad , Femenino , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Recuento de Leucocitos , Masculino , Selectina-P/metabolismo , Enfermedades de la Retina/etiología , Neovascularización Retiniana/etiología , Neovascularización Retiniana/metabolismo , Vasos Retinianos/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
The role of genetic and environmental influences on the relationship between combat exposure, posttraumatic stress disorder (PTSD) symptoms, and alcohol use were examined in 4072 male-male twin pairs who served in the United States military during the Vietnam era (1965-1975). Results indicate that the relationship between combat and alcohol use and between PTSD symptom factors and alcohol use were both substantially influenced by genetic factors. Findings are most consistent with a shared vulnerability model for the etiology of the association between PTSD symptoms and alcohol use. Specific unique environmental factors were more important than genetic factors for PTSD symptoms, and both factors were equally important for alcohol use. Further support is also found for the role of the unique environment in PTSD symptoms.
Asunto(s)
Alcoholismo/etiología , Trastornos de Combate/etiología , Enfermedades en Gemelos/etiología , Ambiente , Predisposición Genética a la Enfermedad/genética , Trastornos por Estrés Postraumático/etiología , Alcoholismo/diagnóstico , Alcoholismo/epidemiología , Análisis por Conglomerados , Trastornos de Combate/diagnóstico , Trastornos de Combate/epidemiología , Enfermedades en Gemelos/epidemiología , Análisis Factorial , Humanos , Funciones de Verosimilitud , Masculino , Modelos Genéticos , Modelos Estadísticos , Fenotipo , Sistema de Registros , Factores de Riesgo , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/epidemiología , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Vietnam , GuerraRESUMEN
PURPOSE: Patients with sickle cell disease have elevated circulating levels of cytokines including tumor necrosis factor (TNF) alpha. TNF-alpha stimulates expression by endothelial cells of adhesion molecules, including vascular cell adhesion molecule (VCAM) 1. Others have demonstrated that VLA-4 (alpha(4)beta(1)), a ligand for VCAM-1 or fibronectin, is present on a fraction of sickle reticulocytes. The intent of this study was to determine, using a rat model, if TNF-alpha increases retention of sickle erythrocytes in retina and if that retention can be inhibited. METHODS: TNF-alpha was given intraperitoneally to rats 5 hours before IV administration of FITC-labeled, density-separated sickle erythrocytes. After 5 minutes, rats were exsanguinated, and retinas were excised and incubated for ADPase activity, permitting the determination of the number and location of retained cells. RESULTS: TNF-alpha caused a three- to fourfold increase in retention of sickle erythrocytes in retinal capillaries (P < 0.05) but not of normal human erythrocytes. Preincubation of sickle erythrocytes with TBC772, a peptide that blocks the binding of alpha(4)beta(1) and alpha(4)beta(7), or a monoclonal antibody against VLA-4 (19H8), significantly inhibited the TNF-alpha-induced retention (P < or = 0.02), whereas a control cyclic peptide and antibody had no effect. IV TBC772 also inhibited sickle erythrocyte retention (P = 0.01). Two intravenously administered anti-fibronectin antibodies inhibited sickle cell retention as well, but an anti-rat VCAM-1 antibody did not inhibit retention. CONCLUSIONS: The authors conclude that TNF-alpha stimulates retention of sickle erythrocytes in the retinal vasculature. This increased retention can be blocked by a VLA-4 antagonist, suggesting that the cells retained after cytokine stimulation are reticulocytes. The counter-receptor for VLA-4 in this rat retina model appears to be fibronectin and not VCAM-1, based on data obtained using antibodies against these molecules.
Asunto(s)
Anemia de Células Falciformes/sangre , Eritrocitos Anormales/metabolismo , Integrinas/antagonistas & inhibidores , Receptores Mensajeros de Linfocitos/antagonistas & inhibidores , Vasos Retinianos/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Adhesión Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Humanos , Inyecciones Intraperitoneales , Integrina alfa4beta1 , Integrinas/inmunología , Integrinas/metabolismo , Masculino , Microscopía Fluorescente , Péptidos Cíclicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Mensajeros de Linfocitos/inmunología , Receptores Mensajeros de Linfocitos/metabolismo , Reticulocitos/efectos de los fármacos , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
Endothelial-monocyte-activating polypeptide (EMAP) is a proinflammatory cytokine and a mediator of programmed endothelial cell death. To gain insight into its possible functions during retinal development and degeneration, the cellular distribution of EMAP protein was compared in control and retinal degeneration (rd) mice. EMAP immunoreactivity was confined to the ganglion cell layer (GCL) and the inner nuclear layer (INL). There were significant differences in the intensity of EMAP labeling in the GCL and the INL when comparing control and rd mouse retinas. Rd retinas contain much more EMAP immunoreactivity in the GCL and the INL than the control retinas at postnatal day 14, which is the time point immediately after the onset of the degeneration of the rd retina. Histopathologic examination showed no significant abnormalities in the GCL and INL in the rd mouse, despite a great degree of photoreceptor cell death from P12 to P18. Light and electron microscopic studies immunolocalize EMAP protein to the cytoplasm of retinal ganglion cells, amacrine cells, and horizontal cells. The data suggests that EMAP is synthesized and accumulated as an intracellular precursor protein that has a functional role in translation and protein synthesis as a cofactor for tRNA synthetase. The increased expression of EMAP precursor levels in rd mouse retina may reflect the enhanced rate of translation and protein synthesis in the production of endogenous factors that promote survival in the GCL and INL.
Asunto(s)
Citocinas/inmunología , Degeneración Retiniana/inmunología , Células Ganglionares de la Retina/inmunología , Animales , Calbindinas , Citocinas/análisis , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Sistema Hipotálamo-Hipofisario/inmunología , Proteínas de la Membrana/análisis , Ratones , Ratones Endogámicos C3H , Ratones Mutantes , Microscopía Electrónica , Hidrolasas Diéster Fosfóricas/genética , Proteínas Qa-SNARE , Degeneración Retiniana/genética , Células Ganglionares de la Retina/química , Células Ganglionares de la Retina/ultraestructura , Proteína G de Unión al Calcio S100/análisisRESUMEN
The purpose of this study was to develop an in vivo, noninvasive method to assess the velocities of normal and sickle red blood cells (RBCs) in the retinal and choroidal vasculatures of rats. Human and rat RBCs were isolated from whole blood, labeled with fluorescein isothiocyanate (FITC), and administered intravenously to anesthetized rats. A Rodenstock scanning laser ophthalmoscope (SLO) was used to image the FITC-labeled RBCs as an NTSC video signal. Video sequences of RBC transit in the retinal (pigmented rats) and choroidal (albino rats) vessels were captured directly to digital format. Following in vivo angiography, the animals were sacrificed, the eyes enucleated, and retinas prepared by our adenosine diphosphatase vascular labeling technique for viewing by conventional optical microscopy. Although rat and normal human RBCs differ slightly in size, their velocities were similar in the retinal arteries and capillaries (within 4%). Velocities of RBCs from sickle cell patients (sRBCs) were slower by 12 and 9% in arteries and by 38 and 25% in capillaries, compared to rat and normal human RBCs, respectively. Compared to velocities in retinal capillaries, the velocities in choroidal capillaries were much slower for rat RBCs (77%), normal human RBCs (79%), and sRBCs (67%). In contrast to normal human RBCs, sRBCs were often retained transiently in retinal capillaries at preferred sites, but in choroidal capillaries large numbers of cells were retained for extended periods. SLO imaging of FITC-labeled RBCs in rat retina and choroid provided a reliable method for evaluating normal and abnormal hemodynamics.
Asunto(s)
Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/fisiopatología , Coroides/irrigación sanguínea , Eritrocitos Anormales/fisiología , Eritrocitos/fisiología , Vasos Retinianos/fisiología , Animales , Velocidad del Flujo Sanguíneo , Fluoresceína-5-Isotiocianato , Colorantes Fluorescentes , Humanos , Masculino , Oftalmoscopía , Ratas , Ratas Endogámicas BN , Ratas Sprague-DawleyRESUMEN
We studied the retinal effects of 1.25 GHz high peak power microwaves in Rhesus monkeys. Preexposure fundus photographs, retinal angiograms, and electroretinograms (ERG) were obtained to screen for normal ocular structure and function and, after exposure, as endpoints of the study. Histopathology of the retina was an additional endpoint. Seventeen monkeys were randomly assigned to receive sham exposure or pulsed microwave exposures. Microwaves were delivered anteriorly to the face at 0, 4.3, 8.4, or 20.2 W/kg spatially and temporally averaged retinal specific absorption rates (R-SAR). The pulse characteristics were 1.04 MW ( approximately 1.30 MW/kg temporal peak R-SAR), 5.59 micros pulse length at 0, 0.59, 1. 18, and 2.79 Hz pulse repetition rates. Exposure was 4 h per day and 3 days per week for 3 weeks, for a total of nine exposures. The preexposure and postexposure fundus pictures and angiograms were all within normal limits. The response of cone photoreceptors to light flash was enhanced in monkeys exposed at 8.4 or 20.2 W/kg R-SAR, but not in monkeys exposed at 4.3 W/kg R-SAR. Scotopic (rod) response, maximum (combined cone and rod) response, and Naka-Rushton R(max) and log K of scotopic b-waves were all within normal range. Retinal histopathology revealed the presence of enhanced glycogen storage in photoreceptors among sham (2/5), 8.4 W/kg (3/3), and 20.2 W/kg (2/5) exposed monkeys, while enhanced glycogen storage was not observed in the 4.3 W/kg (0/4) exposed group. Supranormal cone photoreceptor b-wave was R-SAR dependent and may be an early indicator of mild injury. However no evidence of degenerative changes and ERG depression was seen. We concluded that retinal injury is very unlikely at 4 W/kg. Functional changes that occur at higher R-SAR are probably reversible since we saw no evidence of histopathologic correlation with ERG changes. Bioelectromagnetics 21:439-454, 2000. Published 2000 Wiley-Liss, Inc.
Asunto(s)
Microondas/efectos adversos , Retina/efectos de la radiación , Absorción , Angiografía , Animales , Colorantes , Electrorretinografía , Exposición a Riesgos Ambientales , Femenino , Angiografía con Fluoresceína , Glucógeno/efectos de la radiación , Verde de Indocianina , Macaca mulatta , Masculino , Dosis de Radiación , Distribución Aleatoria , Retina/patología , Células Fotorreceptoras Retinianas Conos/patología , Células Fotorreceptoras Retinianas Conos/efectos de la radiación , Células Fotorreceptoras Retinianas Bastones/patología , Células Fotorreceptoras Retinianas Bastones/efectos de la radiación , Vasos Retinianos/diagnóstico por imagenRESUMEN
PURPOSE: 5' nucleotidase (5'N) is a major source of the vasogenic substance adenosine in most tissues. The distribution and relative levels of 5'N and adenosine were examined in neonatal dog inner retina during normal vasculogenesis and oxygen-induced retinopathy (OIR). METHODS: Animals ranging in age from 1 to 22 days of age were used in this study. Adenosine immunolocalization was performed on frozen sections with an antibody against adenosine conjugated to laevulinic acid using a streptavidin peroxidase technique. Triplicate room air control animals at different postnatal ages and triplicate oxygen-treated animals at different time points during or after hyperoxic insult were analyzed. Adenosine immunoreactivity (AI) and 5'N enzyme histochemical reaction product were quantified using microdensitometry. Adjacent sections were incubated for von Willebrand factor to label blood vessels. RESULTS: During normal vasculogenesis, AI was most prominent within the inner retina. The peak of immunoreactivity was located at the border of vascularized retina throughout the period of primary retinal vasculogenesis (1-15 days of age). At 22 days when vasculogenesis was complete, AI decreased within the inner retina. The highest 5'N activity was localized to inner Muller cell processes in inner retina and decreased after vasculogenesis was complete. In animals killed after 4 days of oxygen breathing, the vasoobliterative stage of OIR, AI and 5'N activity were reduced throughout the retina. During the vasoproliferative stage, AI was markedly elevated at the edge of reforming vasculature as well as throughout the more posterior inner retina where 5'N activity also was elevated. AI was also in intravitreal neovascularization. CONCLUSIONS: Peak adenosine levels in the inner retina correlated temporally with active vasculogenesis. Adenosine and 5'N levels were reduced in hyperoxia and then returned to above normal levels during the vasoproliferative stage of OIR.
Asunto(s)
5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Retina/metabolismo , Neovascularización Retiniana/metabolismo , Vasos Retinianos/metabolismo , Retinopatía de la Prematuridad/metabolismo , Animales , Animales Recién Nacidos , Densitometría , Modelos Animales de Enfermedad , Perros , Histocitoquímica , Humanos , Hiperoxia/complicaciones , Técnicas para Inmunoenzimas , Recién Nacido , Oxígeno , Retina/patología , Neovascularización Retiniana/etiología , Neovascularización Retiniana/patología , Vasos Retinianos/patología , Retinopatía de la Prematuridad/etiología , Retinopatía de la Prematuridad/patología , Factor de von Willebrand/metabolismoRESUMEN
PURPOSE: To investigate the association of adenosine A2a receptors (A2aR) with retinal vasculogenesis and angiogenesis that occurs in the canine model of oxygen-induced retinopathy (OIR). METHODS: One-day-old dogs were exposed to 100/o oxygen for 4 days and killed in oxygen (5 days old) and at 3, 10, 17, and 23 days after exposure to hyperoxia. Room air control animals were killed at 1, 5, 8, 15, 22, and 28 days of age. Immunolocalization of A2aR was performed on frozen sections, and reaction product density was quantified using microdensitometry. Cell types were identified in serial sections using antibodies against von Willebrand factor (endothelial cells) and GFAP (astrocytes), and enzyme histochemistry for menadione-dependent a-glycerophosphate dehydrogenase (M-a-GPDH) (to label angioblasts and developing blood vessels). RESULTS: A2aR immunoreactivity was associated with forming blood vessels and angioblasts in the nerve fiber layer (NFL) of peripheral retina. As development progressed, vascular labeling decreased, whereas labeling of neuronal elements increased. In OIR, A2aR immunoreactivity in the NFL was reduced after exposure to hyperoxia and significantly elevated in the inner retina throughout vascularized retina and in advance of forming vasculature in all oxygen-treated animals returned to room air. A2aR immunoreactivity was also prominent in fronds of intravitreal neovascularization. CONCLUSIONS: A2aR immunoreactivity was associated with developing retinal vessels. As development progressed, vascular-associated A2aR labeling decreased and, concomitantly, labeling of neuronal elements increased. A2aR immunoreactivity was significantly elevated at the edge of forming vasculature in all animals returned to room air after hyperoxia and in intravitreal neovas cular formations. These results provide additional evidence for the importance of A2aR and its ligand adenosine in retinal vascular development and in the vasoproliferative stage of canine OIR.