Prph2 knock-in mice recapitulate human central areolar choroidal dystrophy retinal degeneration and exhibit aberrant synaptic remodeling and microglial activation.

Central areolar choroidal dystrophy is an inherited disorder characterized by progressive choriocapillaris atrophy and retinal degeneration and is usually associated with mutations in the PRPH2 gene. We aimed to generate and characterize a mouse model with the p.Arg195Leu mutation previously described in patients. Heterozygous (Prph2WT/KI) and homozygous (Prph2KI/KI) mice were generated using the CRISPR/Cas9 system to introduce the p.Arg195Leu mutation. Retinal function was assessed by electroretinography and optomotor tests at 1, 3, 6, 9, 12, and 20 months of age. The structural integrity of the retinas was evaluated at the same ages using optical coherence tomography. Immunofluorescence and transmission electron microscopy images of the retina were also analyzed. Genetic sequencing confirmed that both Prph2WT/KI and Prph2KI/KI mice presented the p.Arg195Leu mutation. A progressive loss of retinal function was found in both mutant groups, with significantly reduced visual acuity from 3 months of age in Prph2KI/KI mice and from 6 months of age in Prph2WT/KI mice. Decreased amplitudes in the electroretinography responses were observed from 1 month of age in Prph2KI/KI mice and from 6 months of age in Prph2WT/KI mice. Morphological analysis of the retinas correlated with functional findings, showing a progressive decrease in retinal thickness of mutant mice, with earlier and more severe changes in the homozygous mutant mice. We corroborated the alteration of the outer segment structure, and we found changes in the synaptic connectivity in the outer plexiform layer as well as gliosis and signs of microglial activation. The new Prph2WT/KI and Prph2KI/KI murine models show a pattern of retinal degeneration similar to that described in human patients with central areolar choroidal dystrophy and appear to be good models to study the mechanisms involved in the onset and progression of the disease, as well as to test the efficacy of new therapeutic strategies.

Ischemia-Reperfusion Increases TRPM7 Expression in Mouse Retinas.

Ischemia is the main cause of cell death in retinal diseases such as vascular occlusions, diabetic retinopathy, glaucoma, or retinopathy of prematurity. Although excitotoxicity is considered the primary mechanism of cell death during an ischemic event, antagonists of glutamatergic receptors have been unsuccessful in clinical trials with patients suffering ischemia or stroke. Our main purpose was to analyze if the transient receptor potential channel 7 (TRPM7) could contribute to retinal dysfunction in retinal pathologies associated with ischemia. By using an experimental model of acute retinal ischemia, we analyzed the changes in retinal function by electroretinography and the changes in retinal morphology by optical coherence tomography (OCT) and OCT-angiography (OCTA). Immunohistochemistry was performed to assess the pattern of TRPM7 and its expression level in the retina. Our results show that ischemia elicited a decrease in retinal responsiveness to light stimuli along with reactive gliosis and a significant increase in the expression of TRPM7 in Müller cells. TRPM7 could emerge as a new drug target to be explored in retinal pathologies associated with ischemia.

Microglia activation and neuronal alterations in retinas from COVID-19 patients: correlation with clinical parameters.

BACKGROUND: Different ocular alterations have been described in patients with coronavirus disease 2019 (COVID-19). Our aim was to determine whether COVID-19 affected retinal cells and establish correlations with clinical parameters. METHODS: Retinal sections and flat-mount retinas from human donors with COVID-19 (n = 16) and controls (n = 15) were immunostained. The location of angiotensin-converting enzyme 2 (ACE2) and the morphology of microglial cells, Müller cells, astrocytes, and photoreceptors were analyzed by confocal microscopy. Microglial quantification and the area occupied by them were measured. Correlations among retinal and clinical parameters were calculated. RESULTS: ACE2 was mainly located in the Müller cells, outer segment of cones and retinal pigment epithelium. Cell bodies of Müller cells in COVID-19 group showed greater staining of ACE2 and cellular retinaldehyde-binding protein (CRALBP). The 81.3% of COVID-19 patients presented disorganization of honeycomb-like pattern formed by Müller cells. Gliosis was detected in 56.3% of COVID-19 patients compared to controls (40%) as well as epiretinal membranes (ERMs) or astrocytes protruding (50%). Activated or ameboid-shape microglia was the main sign in the COVID-19 group (93.8%). Microglial migration towards the vessels was greater in the COVID-19 retinas (P < 0.05) and the area occupied by microglia was also reduced (P < 0.01) compared to control group. Cone degeneration was more severe in the COVID-19 group. Duration of the disease, age and respiratory failure were the most relevant clinical data in relation with retinal degeneration. CONCLUSIONS: The retinas of patients with COVID-19 exhibit glial activation and neuronal alterations, mostly related to the inflammation, hypoxic conditions, and age.

A longitudinal study on coping and emotional well-being in cardiac patients.

Emotions and coping play a role in the prognosis of cardiac patients. This two-wave longitudinal study aims to analyze the ability of adaptive and maladaptive coping to predict the emotional well-being of cardiac patients after controlling for their functional physical capacity. Emotional well-being (positive and negative affect), coping strategies, and functional physical capacity were evaluated both at Time 1 (n = 253) and at Time 2 (n = 186), 8 weeks later. At Time 1, positive affect was positively predicted by adaptive coping and negatively predicted by maladaptive coping, while the opposite pattern was found when negative affect was considered. At Time 2, after controlling for sociodemographic variables and for negative affect and functional physical capacity at T1, negative affect was negatively predicted by adaptive coping and positively predicted by maladaptive coping. In addition, positive affect was only predicted by adaptive coping after controlling for functional physical capacity and positive affect at Time 1. Relationships between coping and emotional well-being remain after controlling for the functional physical capacity of cardiac patients, which has a big impact on their emotional state. Finally, it is suggested that specific modules to improve coping and emotional state of cardiac patients should be included in Cardiac Rehabilitation Programs.

UVA induces retinal photoreceptor cell death via receptor interacting protein 3 kinase mediated necroptosis.

Ultraviolet light A (UVA) is the only UV light that reaches the retina and can cause indirect damage to DNA via absorption of photons by non-DNA chromophores. Previous studies demonstrate that UVA generates reactive oxygen species (ROS) and leads to programmed cell death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor interacting protein 1 and 3 (RIPK1 and RIPK3) kinases, key signaling molecules of PCD, in UVA-induced photoreceptor injury using in vitro and ex vivo models. UVA irradiation activated RIPK3 but not RIPK1 and mediated necroptosis through MLKL that lie downstream of RIPK3 and induced apoptosis through increased oxidative stress. Moreover, RIPK3 but not RIPK1 inhibition suppresses UVA-induced cell death along with the downregulation of MLKL and attenuates the levels of oxidative stress and DNA fragmentation. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced necroptosis cell death in photoreceptors and highlight RIPK3 potential as a neuroprotective target.

Neuroprotective Effects of Tauroursodeoxicholic Acid Involves Vascular and Glial Changes in Retinitis Pigmentosa Model.

Purpose: Retinitis pigmentosa is primarily characterized by a massive photoreceptor loss. But a global retinal remodeling occurs in later stages of the disease. At that phase, glial cells and retinal vasculature are also strongly affected. The main aim of the present work is to assess if the bile acid Tauroursodeoxicholic acid (TUDCA), which has a demonstrated neuroprotective effect in numerous neurodegenerative diseases, is able to prevent glial and vascular degeneration in the P23H rat retina. Methods: Homozygous P23H (line 3) animals were injected weekly with a TUDCA (500 mg/kg, i.p.) or vehicle solution, from the postnatal day (P) 21 to P120. Sprague-Dawley rats (SD) were used as control. Retinal cross-sections and wholemounts were immunostained using different glial and vascular markers and visualized with confocal microscopy. Retinal blood vessels were stained with nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry and retinal vascular networks were drawn by hand using a camera lucida. Results: At P120, the photoreceptor degeneration observed in P23H rats was accompanied by a reduction in the vascular network density and complexity at the deep capillary plexus. In addition, astrocytes showed gliotic features and the outer processes of Müller cells displayed an aberrant distribution in ring-shaped structures. When treated with TUDCA, P23H rats displayed better-preserved vessels and capillary loops in the deep capillary plexus which are associated with the partial preservation of photoreceptors. TUDCA treatment also increased the number of astrocytes and reduced the presence of Müller cell process clusters in the outer retina. Conclusion: This work suggests that, besides its neuroprotective effect on photoreceptor cells, TUDCA treatment also protects from vascular and glial degeneration, a fact that encourages the use of TUDCA as a powerful therapy for neurodegenerative diseases.

Phenotypic Differences in a PRPH2 Mutation in Members of the Same Family Assessed with OCT and OCTA.

Choroidal dystrophies comprise a group of chorioretinal degenerations. However, the different findings observed among these patients make it difficult to establish a correct clinical diagnosis. The objective of this study was to characterize new clinical findings by optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) in these patients. Four family members with a PRPH2 gene mutation (p.Arg195Leu) were included. OCT was performed at the macula, and the thickness of the outer and inner retina, total retina, and choroid was measured. The features of the vascular network were analyzed by OCTA. Patients showed a decreased outer nuclear layer in the avascular area compared with the controls. Two patients presented greater foveal and parafoveal degeneration of the outer retina, whereas the most degenerated area in the rest was the perifovea. Disruption of the third outer band at the foveola is one of the first-altered outer bands. Slow blood flow areas or capillary dropout were main signs in the deep capillary plexus. Microaneurysms were frequently observed in less degenerated retinas. Vascular loops and intraretinal microvascular abnormalities (IRMAs) were present in the superficial plexus. Extensive degeneration of the choriocapillaris was detected. Phenotypic differences were found between patients: two showed central areolar choroidal dystrophy and the rest had extensive chorioretinal atrophy. These signs observed in OCT and OCTA can help to more appropriately define the clinical disease in patients with choroidal dystrophies.

Optical Coherence Tomography Angiography in Diabetic Patients: A Systematic Review.

BACKGROUND: Diabetic retinopathy (DR) is the leading cause of legal blindness in the working population in developed countries. Optical coherence tomography (OCT) angiography (OCTA) has risen as an essential tool in the diagnosis and control of diabetic patients, with and without DR, allowing visualisation of the retinal and choroidal microvasculature, their qualitative and quantitative changes, the progression of vascular disease, quantification of ischaemic areas, and the detection of preclinical changes. The aim of this article is to analyse the current applications of OCTA and provide an updated overview of them in the evaluation of DR. METHODS: A systematic literature search was performed in PubMed and Embase, including the keywords "OCTA" OR "OCT angiography" OR "optical coherence tomography angiography" AND "diabetes" OR "diabetes mellitus" OR "diabetic retinopathy" OR "diabetic maculopathy" OR "diabetic macular oedema" OR "diabetic macular ischaemia". Of the 1456 studies initially identified, 107 studies were screened after duplication, and those articles that did not meet the selection criteria were removed. Finally, after looking for missing data, we included 135 studies in this review. RESULTS: We present the common and distinctive findings in the analysed papers after the literature search including the diagnostic use of OCTA in diabetes mellitus (DM) patients. We describe previous findings in retinal vascularization, including microaneurysms, foveal avascular zone (FAZ) changes in both size and morphology, changes in vascular perfusion, the appearance of retinal microvascular abnormalities or new vessels, and diabetic macular oedema (DME) and the use of deep learning technology applied to this disease. CONCLUSION: OCTA findings enable the diagnosis and follow-up of DM patients, including those with no detectable lesions with other devices. The evaluation of retinal and choroidal plexuses using OCTA is a fundamental tool for the diagnosis and prognosis of DR.

Interpretation of OCT and OCTA images from a histological approach: Clinical and experimental implications.

Optical coherence tomography (OCT) and OCT angiography (OCTA) have been a technological breakthrough in the diagnosis, treatment, and follow-up of many retinal diseases, thanks to its resolution and its ability to inform of the retinal state in seconds, which gives relevant information about retinal degeneration. In this review, we present an immunohistochemical description of the human and mice retina and we correlate it with the OCT bands in health and pathological conditions. Here, we propose an interpretation of the four outer hyperreflective OCT bands with a correspondence to retinal histology: the first and innermost band as the external limiting membrane (ELM), the second band as the cone ellipsoid zone (EZ), the third band as the outer segment tips phagocytosed by the pigment epithelium (PhaZ), and the fourth band as the mitochondria in the basal portion of the RPE (RPEmitZ). The integrity of these bands would reflect the health of photoreceptors and retinal pigment epithelium. Moreover, we describe how the vascular plexuses vary in different regions of the healthy human and mice retina, using OCTA and immunohistochemistry. In humans, four, three, two or one plexuses can be observed depending on the distance from the fovea. Also, specific structures such as vascular loops in the intermediate capillary plexus, or spider-like structures of interconnected capillaries in the deep capillary plexus are found. In mice, three vascular plexuses occupy the whole retina, except in the most peripheral retina where only two plexuses are found. These morphological issues should be considered when assessing a pathology, as some retinal diseases are associated with structural changes in blood vessels. Therefore, the analysis of OCT bands and OCTA vascular plexuses may be complementary for the diagnosis and prognosis of retinal degenerative processes, useful to assess therapeutic approaches, and it is usually correlated to visual acuity.

Benefit Finding in Cardiac Patients: Relationships with Emotional Well-Being and Resources after Controlling for Physical Functional Impairment.

Benefit finding (BF) is defined as the individual's perception of positive change as a result of coping with an adverse life event. The beneficial effects of BF on well-being could be because BF favors the improvement of resources like self-efficacy, social support and effective coping. The main objective of this longitudinal 8 week study was to explore, in a sample of cardiac patients (n = 51), the combined contribution of BF and these resources to the positive affect. Moreover, we wanted to check whether these resources were derived from BF or, on the contrary, these resources were antecedents of BF. Results showed that after controlling for functional capacity, only effective coping could predict the positive affect at Time 1 (ß = .32, p < .05), while the BF predicted it at Time 2 (ß = .23, p < .001). Only social support predicted BF (ß = .26, p < .05), but not the opposite. We discussed the desirability of promoting these processes to improve the emotional state of cardiac patients.

A Randomised Trial of a Positive Intervention to Promote Well-Being in Cardiac Patients.

BACKGROUND: Negative emotions are linked to the onset and development of coronary heart diseases (CHD), whereas positive emotions are associated with better health and lower mortality rates among patients with these diseases. The objective of this randomised trial was to improve cardiac patients' emotional states using a Programme to Improve Well-being (PIW) based exclusively on positive interventions (those that promote intentional behaviours and thoughts to improve well-being). METHODS: Cardiac patients (n = 108) were randomly assigned to two parallel groups. In the control group, they participated in only a Cardiac Rehabilitation Programme (CRP group), whereas the intervention group also participated in the PIW (CRP+PIW group). Physical functional capacity, depressive symptoms, hostility, and negative and positive affect were assessed at T1 (baseline) and T2 (8 weeks later). RESULTS: At T2, after controlling for functional capacity, the CRP+PIW group reported a significantly less negative affect than the CRP group. Moreover, the CRP group did not change from T1 to T2, whereas the CRP+PIW group reported more positive emotions and fewer negative emotions and hostility at T2 than at T1. CONCLUSIONS: Positive interventions effectively improve the emotional state of cardiac patients. We suggest that specific modules should be included in the CRP to improve well-being.

Benefit finding in cardiac patients: relationships with emotional well-being and resources after controlling for physical functional impairment

Benefit finding (BF) is defined as the individual’s perception of positive change as a result of coping with an adverse life event. The beneficial effects of BF on well-being could be because BF favors the improvement of resources like self-efficacy, social support and effective coping. The main objective of this longitudinal 8 week study was to explore, in a sample of cardiac patients (n = 51), the combined contribution of BF and these resources to the positive affect. Moreover, we wanted to check whether these resources were derived from BF or, on the contrary, these resources were antecedents of BF. Results showed that after controlling for functional capacity, only effective coping could predict the positive affect at Time 1 (β = .32, p < .05), while the BF predicted it at Time 2 (β = .23, p < .001). Only social support predicted BF (β = .26, p < .05), but not the opposite. We discussed the desirability of promoting these processes to improve the emotional state of cardiac patients (AU)

No disponible

Effect of negative attributions on depressive symptoms of patients with coronary heart disease after controlling for physical functional impairment.

OBJECTIVES: Negative attributional style (NAS), or tendency to explain negative events through internal, stable, and global causes, has proved to be an important predictor of depressive symptoms and poor health, including coronary heart disease (CHD). The goal of this two-wave longitudinal study was to look at whether depressive symptoms are caused by or are a consequence of this style in a sample of patients with CHD while controlling for the effect of physical functional impairment on the development of these symptoms. METHODS: Ninety-one patients, who had just suffered a first cardiac episode, were evaluated on NAS, depressive symptoms and functional capacity (measured in metabolic equivalent levels or METs) both on the first and on last day of an 8-week cardiac rehabilitation programme. RESULTS: Globality dimension of NAS at Time 1 predicted depressive symptoms at Time 2 after controlling for both depressive symptoms and METs at Time 1. However, depressive symptoms at Time 1 could not predict any dimension of this style at Time 2. CONCLUSIONS: These results seem to support that negative attributions about the disease are one of the causes contributing to the development of depression and not a consequence of it, and also suggest that intervention programme should be aimed not only at reducing depressive symptoms, but also at replacing stable and global attributions of negative situations with more unstable and specific explanations. STATEMENT OF CONTRIBUTION: What is already known on this subject? Negative attributional style (NAS) is an important predictor of depressive symptoms.Depressive symptoms worsen the diagnosis of coronary heart disease (CHD) patients. What does this study add? Globality dimension predicts depression in patients with CHD after controlling for functional capacity. Negative attributions contribute to the development of depression and are not a consequence of it.

Pessimistic attributions and coping strategies as predictors of depressive symptoms in people with coronary heart disease.

This two-wave longitudinal study examines the ability of pessimistic attributional style and coping strategies to predict depressive symptoms in a sample of 99 patients with coronary heart disease (CHD). After the cardiac episode, the globality dimension of this style was associated with increased depressive symptoms, and this association was mediated by the low use of effective coping strategies. Stability and globality dimensions of pessimistic attributional style could also predict depressive symptoms eight weeks later. Cardiac intervention programmes should include the treatment of these symptoms and promote effective coping strategies as well as the modification of these stable and global attributions.

Cambios psicológicos e intervenciones basadas en mindfulness para los supervivientes de un cáncer / No disponible

La población de supervivientes de cáncer va en aumento gracias a los avances de la medicina. Lograr solo años de supervivencia no es ya suficiente y el interés está en mejorar la calidad de vida en todas sus dimensiones incluidas las psicológicas y espirituales. Surgen nuevas necesidades psicosociales a atender para esta población. En general los trastornos mentales graves, tales como depresión mayor o Trastorno de Estrés Postraumático son raros entre los supervivientes siendo más frecuentes los trastornos adaptativos menos graves como los depresivos, ansiosos o mixtos. Pero junto a estos cambios negativos para la calidad de vida, también se han descrito cambios psicológicos positivos englobados en el concepto de crecimiento postraumático. Las afinidades entre las descripciones de los cambios de las personas que experimentan crecimiento postraumático y la actitud que promueve Mindfulness nos hace plantear que el entrenamiento en Mindfulness o Atención Plena podría promover crecimiento postraumático en los supervivientes de cáncer (AU)

The population of cancer survivors is increasing due to advances in medicine. Achieving an increase in survival is not enough and the focus is on improving the quality of life in all its dimensions, including psychological and spiritual. New psychosocial needs arise in this population. In general, major mental disorders such as major depression or PTSD are rare among survivors, while less severe adjustment disorders such as depression, anxiety or mixed are relatively common. But not only negative changes in quality of life have been described, there are also several positive psychological changes included in the concept of posttraumatic growth. The similarities between descriptions of change in people experiencing posttraumatic growth and the attitude that Mindfulness promotes suggest that Mindfulness training may promote posttraumatic growth in cancer survivors (AU)