Stages Of Degeneration Research Articles

Contributions of Lipid-Related Metabolites and Complement Proteins to Early and Intermediate Age-Related Macular Degeneration

ObjectiveOur objective was to determine the effects of lipids and complement proteins on early and intermediate age-related macular degeneration (AMD) stages using machine learning models by integrating metabolomics and proteomic data. DesignNested case-control study. Subjects, Participants, and/or ControlsThe analyses were performed in a subset of the Singapore Indian Chinese Cohort (SICC) Eye Study. Among the 6,753 participants, we randomly selected 155 AMD Indian and 155 Chinese cases and matched them with 310 controls on age, sex and ethnicity. MethodsWe measured 35 complement proteins and 56 lipid-related metabolites using Mass Spectrometry and Nuclear Magnetic Resonance, respectively. We first selected the most contributing lipids and complement proteins to early and intermediate AMD using random forest models. Then we estimated their effects using a multinomial model adjusted for potential confounders. Main Outcome MeasuresAMD was classified using the Beckman classification system. ResultsAmong the 310 individuals with AMD, 166 (53.5%) had early and 144 (46.5%) intermediate AMD. Firstly, high-density lipoprotein (HDL) particle diameter was positively associated with both early and intermediate AMD (ORearly=1.69 [1.11, 2.55] and ORintermediate=1.72 [1.11, 2.66] per 1-SD increase in HDL diameter). Secondly, five complement proteins: complement protein 2 (C2), complement C1 inhibitor (ICI1), complement protein 6 (C6), complement protein 1QC (C1QC) and complement factor H-related protein 1 (FHR1), were associated with AMD. C2 was positively associated with both early and intermediate AMD (ORearly=1.58 [1.08, 2.30] and ORintermediate=1.56 [1.04, 2.34]). C6 was positively (ORearly=1.41 [1.03, 1.93]) associated with early AMD. However, IC1 was negatively associated with early AMD (ORearly=0.62 [0.38, 0.99]), while C1QC (ORintermediate=0.63 [0.42, 0.93]) and FHR1 (ORintermediate=0.73 [0.54, 0.98) were both negatively associated with intermediate AMD. ConclusionsWhile both HDL diameter and C2 levels show associations with both early and intermediate AMD, dysregulations of IC1, C6, C1QC, and FHR1 are only observed at specific stages of AMD. These findings underscore the complexity of complement system dysregulation in AMD, which appears to vary depending on the disease severity.

HDACi vorinostat protects muscle from degeneration after acute rotator cuff injury in mice.

Rotator cuff (RC) injuries are characterized by tendon rupture, muscle atrophy, retraction, and fatty infiltration, which increase injury severity and jeopardize adequate tendon repair. Epigenetic drugs, such as histone deacetylase inhibitors (HDACis), possess the capacity to redefine the molecular signature of cells, and they may have the potential to inhibit the transformation of the fibro-adipogenic progenitors (FAPs) within the skeletal muscle into adipocyte-like cells, concurrently enhancing the myogenic potential of the satellite cells. HDACis were added to FAPs and satellite cell cultures isolated from mice. The HDACi vorinostat was additionally administered into a RC injury animal model. Histological analysis was carried out on the isolated supra- and infraspinatus muscles to assess vorinostat anti-muscle degeneration potential. Vorinostat, a HDACi compound, blocked the adipogenic transformation of muscle-associated FAPs in culture, promoting myogenic progression of the satellite cells. Furthermore, it protected muscle from degeneration after acute RC in mice in the earlier muscle degenerative stage after tenotomy. The HDACi vorinostat may be a candidate to prevent early muscular degeneration after RC injury.

Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b+ cells and astrocytes in the α-synuclein overexpression mouse model of Parkinson´s disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b+ cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b+ cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.Graphical abstract

An injectable anti-vascularization functionalized hydrogel for degenerative nucleus pulposus repair

Neovascularization and inflammatory cell invasion within the nucleus pulposus (NP) constitute pivotal pathological changes during the acceleration stage of intervertebral disc degeneration (IDD). Mesenchymal stem cells (MSCs), renowned for their remarkable capacity in intervertebral disc (IVD) regeneration, also exhibit the capability to secrete pro-angiogenic factors, expediting IDD progression under hypoxic conditions. Consequently, we developed a hydrogel comprised of methacrylated hyaluronic acid (HAMA), rat tail collagen I (COL), and MSCs, incorporating the vascular endothelial growth factor receptor (VEGFR) inhibitor cabozantinib (Cabo@HAMA-COL/MSCs hydrogel). This innovative construct aimed to facilitate NP regeneration while mitigating vascularization and inflammation. Our findings revealed that the hydrogel aptly mimicked the mechanical characteristics of NP tissue, exhibiting injectability, low cytotoxicity, and the preservation of the cellular phenotype of NP cells. Co-culturing of MSCs and human umbilical vein endothelial cells (HUVECs) promoted migration, tube formation, and sprouting of HUVECs, which will be inhibited by cabozantinib. In vivo experiments demonstrated that Cabo@HAMA-COL/MSCs hydrogel maintained disc height, protected NP, and alleviated vascularization and inflammation in a puncture-induced rat caudal IDD model. Consequently, our results substantiate that Cabo@HAMA-COL/MSCs hydrogel can prevent IDD degeneration by ameliorating the vascularization-inflammation pathological microenvironment, offering a promising therapeutic strategy for IDD.

Nutritional Supplements for Healthy Aging: A Critical Analysis Review

Background: Healthy aging is defined as survival to advanced age while retaining autonomy in activities of daily living, high societal participation, and good quality of life. Sarcopenia, insomnia, cognitive impairment, and changes in sensation can be key hinderances to healthy aging, but nutritional supplements may abate their impact. As research advances, an updated review on their efficacy on age-related conditions is warranted. Results: Sarcopenia can be mitigated through proper protein intake, supplements like creatine, and in certain situations Branched-Chain Amino Acids and Vitamin D, in adults over 65. Melatonin supplementation has moderate evidence for improving sleep, while valerian root lacks evidence. Magnesium, tart cherry, and kiwifruits have shown promising impacts on sleep in limited articles. Magnesium, Vitamin D, and B vitamin supplementation have been shown to improve cognition in those with mild cognitive impairment and Alzheimer’s disease but require further study prior to recommendation. The Age-Related Eye Disease Study supplement combination is routinely recommended to reduce risk of progression to advance stages of age-related macular degeneration. Alpha-Lipoic Acid and Folate have been investigated for their roles in mitigating age-related hearing losses. Conclusions: Nutritional supplements and lifestyle changes may mitigate disabilities across multiple domains of age-related illnesses and promote healthy aging.

A novel in-vitro model of intervertebral disc degeneration using hyperphysiological loading

Intervertebral disc (IVD) degeneration includes changes in tissue biomechanics, physical attributes, biochemical composition, disc microstructure, and cellularity, which can all affect the normal function of the IVD, and ultimately may lead to pain. The purpose of this research was to develop an in-vitro model of degeneration that includes the evaluation of physical, biomechanical, and structural parameters, and that does so over several load/recovery periods. Hyperphysiological loading was used as the degenerative initiator with three experimental groups employed using bovine coccygeal IVD specimens: Control; Single-Overload; and Double-Overload. An equilibrium stage comprising a static load followed by two load/recovery periods was followed by six further load/recovery periods. In the Control group all load/recovery periods were the same, comprising physiological cyclic loading. The overload groups differed in that hyperphysiological loading was applied during the 4th loading period (Single-Overload), or the 4th and 5th loading period (Double-Overload). Overloading led to a significant reduction in disc height compared to the Control group, which was not recovered in subsequent physiological load/recovery periods. However, there were no significant changes in stiffness. Overloading also led to significantly more microstructural damage compared to the Control group. Taking all outcome measures into account, the overload groups were evaluated as replicating clinically relevant aspects of moderate IVD degeneration. Further research into a potential dose–effect, and how more severe degeneration can be replicated would provide a model with the potential to evaluate new treatments and interventions for different stages of IVD degeneration.

Stroke-Induced Secondary Neurodegeneration of the Corticospinal Tract-Time Course and Mechanisms Underlying Signal Changes in Conventional and Advanced Magnetic Resonance Imaging.

Secondary neurodegeneration refers to the final result of several simultaneous and sequential mechanisms leading to the loss of substance and function in brain regions connected to the site of a primary injury. Stroke is one of the most frequent primary injuries. Among the subtypes of post-stroke secondary neurodegeneration, axonal degeneration of the corticospinal tract, also known as Wallerian degeneration, is the most known, and it directly impacts motor functions, which is crucial for the motor outcome. The timing of its appearance in imaging studies is usually considered late (over 4 weeks), but some diffusion-based magnetic resonance imaging (MRI) techniques, as diffusion tensor imaging (DTI), might show alterations as early as within 7 days from the stroke. The different sequential pathological stages of secondary neurodegeneration provide an interpretation of the signal changes seen by MRI in accordance with the underlying mechanisms of axonal necrosis and repair. Depending on the employed MRI technique and on the timing of imaging, different rates and thresholds of Wallerian degeneration have been provided in the literature. In fact, three main pathological stages of Wallerian degeneration are recognizable-acute, subacute and chronic-and MRI might show different changes: respectively, hyperintensity on T2-weighted sequences with corresponding diffusion restriction (14-20 days after the injury), followed by transient hypointensity of the tract on T2-weighted sequences, and by hyperintensity and atrophy of the tract on T2-weighted sequences. This is the main reason why this review is focused on MRI signal changes underlying Wallerian degeneration. The identification of secondary neurodegeneration, and in particular Wallerian degeneration, has been proposed as a prognostic indicator for motor outcome after stroke. In this review, the main mechanisms and neuroimaging features of Wallerian degeneration in adults are addressed, focusing on the time and mechanisms of tissue damage underlying the signal changes in MRI.

Enhancing Readability and Detection of Age-Related Macular Degeneration Using Optical Coherence Tomography Imaging: An AI Approach.

Artificial intelligence has been used effectively in medical diagnosis. The objective of this project is to examine the application of a collective AI model using weighted fusion of predicted probabilities from different AI architectures to diagnose various retinal conditions based on optical coherence tomography (OCT). A publicly available Noor dataset, comprising 16,822, images from 554 retinal OCT scans of 441 patients, was used to predict a diverse spectrum of age-related macular degeneration (AMD) stages: normal, drusen, or choroidal neovascularization. These predictions were compared with predictions from ResNet, EfficientNet, and Attention models, respectively, using precision, recall, F1 score, and confusion matric and receiver operating characteristics curves. Our collective model demonstrated superior accuracy in classifying AMD compared to individual ResNet, EfficientNet, and Attention models, showcasing the effectiveness of using trainable weights in the ensemble fusion process, where these weights dynamically adapt during training rather than being fixed values. Specifically, our ensemble model achieved an accuracy of 91.88%, precision of 92.54%, recall of 92.01%, and F1 score of 92.03%, outperforming individual models. Our model also highlights the refinement process undertaken through a thorough examination of initially misclassified cases, leading to significant improvements in the model's accuracy rate to 97%. This study also underscores the potential of AI as a valuable tool in ophthalmology. The proposed ensemble model, combining different mechanisms highlights the benefits of model fusion for complex medical image analysis.

Association of eGFR with stages of diabetic retinopathy and age-related macular degeneration in Indian population.

To investigate the influence of glomerular filtration rate in renal disease decline and its association with diabetic retinopathy (DR) and age-related macular degeneration (ARMD) in patients in South India. A population-based cross-sectional study was conducted including participants with DR and ARMD recruited from urban and rural populations. The data collection included medical history, anthropometric measurements, and ophthalmic work-up. The estimated glomerular filtration rate (eGFR) was calculated using the equation of chronic kidney disease-epidemiology collaboration (CKD-EPI). The grading of AMD was done by a single experienced (more than 5 years) vitreoretinal surgeon as per the International ARM Epidemiological Study Group and it was staged based on grading in the worsened eye. A decline in eGFR was observed as the severity of DR increased ( P < 0.001). Baseline characteristics such as age ( P < 0.001), duration of diabetes ( P < 0.001), gender ( P < 0.001), creatinine ( P < 0.001), albumin to creatinine ratio (ACR; P < 0.001), albuminuria ( P = 0.023), blood urea ( P < 0.001), and high-density lipoprotein (HDL; P = 0.003) were found to be statistically significant. The risk for developing DR with CKD was found to be 5 times higher in male patients compared to female patients. Age and high blood urea level, diastolic blood pressure, mild and moderate DR were the risk factors associated with CKD. A decline in eGFR was observed as the severity of ARMD increased ( P < 0.001). The risk factors associated with CKD were age, gender, smoking, alcohol consumed, presence of hypertension, duration of diabetes, systolic and diastolic blood pressure, history of diabetes, body mass index (BMI), serum triglycerides, and serum HDL cholesterol. Reduced eGFR values were associated with an increase in the severity of DR and ARMD.

Potential of Dual-Energy CT-Based Collagen Maps for the Assessment of Disk Degeneration in the Lumbar Spine

Rationale and ObjectivesLumbar disk degeneration is a common condition contributing significantly to back pain. The objective of the study was to evaluate the potential of dual-energy CT (DECT)-derived collagen maps for the assessment of lumbar disk degeneration. Patients and MethodsWe conducted a retrospective analysis of 127 patients who underwent dual-source DECT and MRI of the lumbar spine between 07/2019 and 10/2022. The level of lumbar disk degeneration was categorized by three radiologists as follows: no/mild (Pfirrmann 1&2), moderate (Pfirrmann 3&4), and severe (Pfirrmann 5). Recall (sensitivity) and accuracy of DECT collagen maps were calculated. Intraclass correlation coefficient (ICC) was used to evaluate inter-reader reliability. Subjective evaluations were performed using 5-point Likert scales for diagnostic confidence and image quality. ResultsWe evaluated a total of 762 intervertebral disks from 127 patients (median age, 69.7 (range, 23.0 – 93.7), female, 56). MRI identified 230 non/mildly degenerated disks (30.2%), 484 moderately degenerated disks (63.5%), and 48 severely degenerated disks (6.3%). DECT collagen maps yielded an overall accuracy of 85.5% (1955/2286). Recall (sensitivity) was 79.3% (547/690) for the detection of no/mild lumbar disk degeneration, 88.7% (1288/1452) for the detection of moderate disk degeneration, and 83.3% (120/144) for the detection of severe disk degeneration (ICC=0.9). Subjective evaluations of DECT collagen maps showed high diagnostic confidence (median 4) and good image quality (median 4). ConclusionThe use of DECT collagen maps to distinguish different stages of lumbar disk degeneration may have clinical significance in the early diagnosis of disk-related pathologies in patients with contraindications for MRI or in cases of unavailability of MRI.

Self-Reported Utilization of International (ACVIM Consensus) Guidelines and the Latest Clinical Trial Results on the Treatment of Dogs with Various Stages of Myxomatous Mitral Valve Degeneration: A Survey among Veterinary Practitioners.

Myxomatous mitral valve degeneration is the most common canine heart disease. Several clinical trials have investigated various treatments. The latest recommendations are published in the ACVIM consensus guidelines (2019). Our study aimed to investigate how closely veterinary practitioners apply the treatment recommendations of these guidelines and the latest clinical trials. An online survey was sent to Dutch and Belgian veterinary practices via digital channels. The data from 363 fully completed surveys were analyzed. For stage B1 disease, 93% recommended, correctly, no treatment. For stage B2 disease, 67% of the respondents recommended starting pimobendan as monotherapy. For chronic treatment of stage C disease, 16 different drug combinations were mentioned, but nobody recommended surgery. Only 48% of the respondents recommended the only evidence-based drug combination: a loop diuretic with pimobendan. A concerning finding was the simultaneous prescription of two loop diuretics, by 19% of the respondents. Treatment recommendations showed an increasing variation with more advanced disease stages from B1 through B2 to C. This reflects the increasing disagreement among the panelists who prepared the ACVIM consensus guidelines. Practitioners of our study seem to practice more evidence-based medicine than veterinary cardiologists, as it was reported in a recent survey-based study.

Connecting the ends: signaling via receptor tyrosine kinases and cytoskeletal degradation in neurodegeneration

Receptor tyrosine kinases (RTKs) are known to perform versatile roles in disease landscapes, which determine the fate of the cell. Although much has been discussed from the perspective of proliferation, this review focuses on the impact of RTK-mediated signaling and its role in cytoskeletal degradation, the penultimate stage of cellular degeneration. In the case of degenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), age-related macular degeneration (AMD), and type 2 diabetes mellitus (T2DM), RTK signaling has been reported to be perturbed in several studies. The implications of downstream signaling via these receptors through canonical and noncanonical pathways alter the status of actin filaments that provide structural integrity to cells. Degenerative signaling leads to the altered status of rat sarcoma (Ras), Ras homologous (Rho), Ras-related C3 botulinum toxin substrate (Rac), and cell division control protein 42 (Cdc42), the best-characterized components of the cytoskeleton remodeling machinery. RTKs, along with their diverse adaptor partners and other membrane receptors, affect the functionality of Rho family guanosine triphosphate hydrolases (GTPases), which are discussed in this review. To conclude, this review focuses on therapeutic strategies targeting RTKs and Rho GTPase-mediated pathways that can be more effective due to their combined multifactorial impact on neurodegenerative cascades.

POLITICAL COMMUNICATION PROCESS IN THE FACTIONALISM OF ISLAMIC POLITICAL PARTIES: CASE STUDY OF PROSPEROUS JUSTICE PARTY (PKS) (1999-2023)

This research wants to know the process of political communication in factionalism that occurs in Islamic Parties, namely Prosperous Justice Party (PKS). The approach taken in this research is qualitative with case study research type and interview method as data collection technique. Interviews were conducted with 12 (twelve) resource persons. The theories used in this research are political communication theory, conflict theory, and faction theory. The results showed that there are stages in Prosperous Justice Party factionalism, namely cooperative factionalism, competitive factionalism, and degenerative factionalism. In these three stages, each stage was analyzed in accordance with the elements of political communication, namely sender, encoding, message, channel, decoding, receiver, feedback, and noise. In the cooperative factionalism stage, there are justice and welfare factions. At the competitive factionalism stage, there are conflicts between factions and at the degenerative factionalism stage marked by the birth of a new party, namely the Gelombang Rakyat Indonesia party. The generation system in Prosperous Justice Party as a recipient communication element, palys a role in political communication and strengthens the party’s ability to overcome persistent conflicts and has saved the party from prolonged conflict. In addition to regeneration, PKS leaders and the Majelis Syuro as sender elements or communicators, have a central role in the political communication process. Their role covers various aspects, from formulating party messages to communicating with the public, party members, and other stakeholders.

Imaging mass cytometry analysis of Becker muscular dystrophy muscle samples reveals different stages of muscle degeneration

Becker muscular dystrophy (BMD) is characterised by fiber loss and expansion of fibrotic and adipose tissue. Several cells interact locally in what is known as the degenerative niche. We analysed muscle biopsies of controls and BMD patients at early, moderate and advanced stages of progression using Hyperion imaging mass cytometry (IMC) by labelling single sections with 17 markers identifying different components of the muscle. We developed a software for analysing IMC images and studied changes in the muscle composition and spatial correlations between markers across disease progression. We found a strong correlation between collagen-I and the area of stroma, collagen-VI, adipose tissue, and M2-macrophages number. There was a negative correlation between the area of collagen-I and the number of satellite cells (SCs), fibres and blood vessels. The comparison between fibrotic and non-fibrotic areas allowed to study the disease process in detail. We found structural differences among non-fibrotic areas from control and patients, being these latter characterized by increase in CTGF and in M2-macrophages and decrease in fibers and blood vessels. IMC enables to study of changes in tissue structure along disease progression, spatio-temporal correlations and opening the door to better understand new potential pathogenic pathways in human samples.

Effect of Ultraviolet Radiation on the Enzymolytic and Biomechanical Profiles of Abdominal Aortic Adventitia Tissue.

The abdominal aortic aneurysm (AAA) is defined as an increase in aortic diameter by more than 50% and is associated with a high risk of rupture and mortality without treatment. The aim of this study is to analyze the role of aortic adventitial collagen photocrosslinking by UV-A irradiation on the biomechanical profile of the aortic wall. This experimental study is structured in two parts: the first part includes in vitro uniaxial biomechanical evaluation of porcine adventitial tissue subjected to either short-term elastolysis or long-term collagenolysis in an attempt to duplicate two extreme situations as putative stages of aneurysmal degeneration. In the second part, we included biaxial biomechanical evaluation of in vitro human abdominal aortic adventitia and human AAA adventitia specimens. Biomechanical profiles were examined for porcine and human aortic tissue before and after irradiation with UV-A light (365 nm wavelength). On the porcine aortic sample, the enhancing effect of irradiation was evident both on the tissue subjected to elastolysis, which had a high collagen-to-elastin ratio, and on the tissue subjected to prolonged collagenolysis despite being considerably depleted in collagen. Further, the effect of irradiation was conclusively demonstrated in the human adventitia samples, where significant post-irradiation increases in Cauchy stress (longitudinal axis: p = 0.001, circumferential axis: p = 0.004) and Young's modulus (longitudinal axis: p = 0.03, circumferential axis: p = 0.004) were recorded. Moreover, we have a stronger increase in the strengthening of the AAA adventitia samples following the exposure to UV-A irradiation (p = 0.007) and a statistically significant but not very important increase (p = 0.021) regarding the stiffness in the circumferential axis. The favorable effect of UV irradiation on the strength and stiffness of degraded aortic adventitia in experimental situations mimicking early and later stages of aneurysmal degeneration is essential for the development and potential success of procedures to prevent aneurysmal ruptures. The experiments on human normal and aneurysmal adventitial tissue confirmed the validity and potential success of a procedure based on exposure to UV-A radiation.

Fluorescence spectroscopic profiling of urine samples for predicting kidney transplant rejection

Rejection is the primary factor affecting the functionality of a kidney post-transplant, where its prompt prediction of risk significantly influences therapeutic strategies and clinical outcomes. Current graft health assessment methods, including serum creatinine measurements and transplant kidney puncture biopsies, possess considerable limitations. In contrast, urine serves as a direct indicator of the graft's degenerative stage and provides a more accurate measure than peripheral blood analysis, given its non-invasive collection of kidney-specific metabolite. This research entailed collecting fluorescent fingerprint data from 120 urine samples of post-renal transplant patients using hyperspectral imaging, followed by the development of a learning model to detect various forms of immunological rejection. The model successfully identified multiple rejection types with an average diagnostic accuracy of 95.56 %.Beyond proposing an innovative approach for predicting the risk of complications post-kidney transplantation, this study heralds the potential introduction of a non-invasive, rapid, and accurate supplementary method for risk assessment in clinical practice.

Alterations in glutamate and nitric oxide metabolism in the RdS mice

Aims/Purpose: Nitric oxide (NO) is an essential signalling molecule, with gaseous nature. NO is synthesized by the conversion of L‐arginine to L‐citrulline. This reaction is catalysed by the enzyme nitric oxide synthase (NOS). There are three NOS isoforms, but nNOS reflects most of the production of NO in the retina. Although NO is employed in the retina to maintain ocular function, it has also been related to different visual diseases. Increased levels of NO have been associated with ocular diseases involving increased glutamate concentrations, ischaemia, oxidative stress and inflammation (such as retinitis pigmentosa (RP)). The main purpose of this work was to determine glutamate retinal concentrations at different stages of the retinal degeneration that occurs in the rds mice and to study possible NO metabolism alterations.Methods: Rds mice were treated in accordance with the ARVO statement for the use of animals in ophthalmic and vision research. Mice were sacrificed at different postnatal days (11, 17, 21 and 28). Retinal glutamate concentrations were determined by high pressure liquid chromatography (HPLC). The expression of different enzymes related with NO metabolism (nNOS, guanylate cyclase (GC) and arginase) was determined by histochemistry.Results: Glutamate as well as nNOS was observed to be increased in the retina of rds mice mainly between the peak of rods and cones death. GC was observed to be decreased in the rds mice compared to control ones and no significant changes were observed in arginase expression when we compared rds and control mice.Conclusions: There are alterations in the expression of glutamate, nNOS and GC in rds mice retina compared to control mice. RP is a disease with no effective treatment to date and NO metabolism may be a new target in RP treatment.

Role of Autophagy and Pyroptosis in Intervertebral Disc Degeneration.

Intervertebral disc degeneration is a chronic degenerative disease caused by the interaction of genetic and environmental factors, mainly manifested as lower back pain. At present, the diagnosis of intervertebral disc degeneration mainly relies on imaging. However, early intervertebral disc degeneration is usually insidious, and there is currently a lack of relevant clinical biomarkers that can reliably reflect early disease progression. Pyroptosis is a regulatory form of cell death triggered by the activation of inflammatory bodies and caspase, which can induce the formation of plasma membrane pores and cell swelling or lysis. Previous studies have shown that during the progression of intervertebral disc degeneration, sustained activation of inflammasomes leads to nuclear cell pyroptosis, which can occur in the early stages of intervertebral disc degeneration. Moreover, intervertebral disc nucleus pulposus cells adapt to the external environment through autophagy and maintain cellular homeostasis and studying the mechanism of autophagy in IDD and intervening in its pathological and physiological processes can provide new ideas for the clinical treatment of IDD. This review analyzes the effects of pyroptosis and autophagy on IDD by reviewing relevant literature in recent years, in order to explore the relationship between pyroptosis, autophagy and IDD.

Multifocal electroretinography in the diagnosis and monitoring of early and intermediate stages of age-related macular degeneration

Multifocal electroretinography is a valuable diagnostic method for the objective localization and quantitative assessment of functional disorders of the central retina in age-related macular degeneration. It is used to detect early changes, monitor the course of the disease and treatment outcomes. In many cases, multifocal electroretinography is a more sensitive method for detecting functional disorders at the early/intermediate stage of age-related macular degeneration compared to morphological (optical coherence tomography) and subjective (visual acuity, perimetry) testing methods.

Early-Stage Moderate Alcohol Feeding Dysregulates Insulin-Related Metabolic Hormone Expression in the Brain: Potential Links to Neurodegeneration Including Alzheimer's Disease.

Alzheimer's disease (AD), one of the most prevalent causes of dementia, is mainly sporadic in occurrence but driven by aging and other cofactors. Studies suggest that excessive alcohol consumption may increase AD risk. Our study examined the degree to which short-term moderate ethanol exposure leads to molecular pathological changes of AD-type neurodegeneration. Long Evans male and female rats were fed for 2 weeks with isocaloric liquid diets containing 24% or 0% caloric ethanol (n = 8/group). The frontal lobes were used to measure immunoreactivity to AD biomarkers, insulin-related endocrine metabolic molecules, and proinflammatory cytokines/chemokines by duplex or multiplex enzyme-linked immunosorbent assays (ELISAs). Ethanol significantly increased frontal lobe levels of phospho-tau, but reduced Aβ, ghrelin, glucagon, leptin, PAI, IL-2, and IFN-γ. Short-term effects of chronic ethanol feeding produced neuroendocrine molecular pathologic changes reflective of metabolic dysregulation, together with abnormalities that likely contribute to impairments in neuroplasticity. The findings suggest that chronic alcohol consumption rapidly establishes a platform for impairments in energy metabolism that occur in both the early stages of AD and alcohol-related brain degeneration.