-
Investigative Ophthalmology & Visual... Feb 2024To sequence, identify, and perform phylogenetic and recombination analysis on three clinical adenovirus samples taken from the vitreous humor at the Bascom Palmer Eye...
PURPOSE
To sequence, identify, and perform phylogenetic and recombination analysis on three clinical adenovirus samples taken from the vitreous humor at the Bascom Palmer Eye Institute.
METHODS
The PacBio Sequel II was used to sequence the genomes of the three clinical adenovirus isolates. To identify the isolates, a full genome-based multiple sequence alignment (MSA) of 722 mastadenoviruses was generated using multiple alignment using fast Fourier transform (MAFFT). MAFFT was also used to generate genome-based human adenovirus B (HAdV-B) MSAs, as well as HAdV-B fiber, hexon, and penton protein-based MSAs. To examine recombination within HAdV-B, RF-Net 2 and Bootscan software programs were used.
RESULTS
In the course of classifying three new atypical ocular adenovirus samples, taken from the vitreous humor, we found that all three isolates were HAdV-B species. The three Bascom Palmer HAdV-B genomes were then combined with over 300 HAdV-B genome sequences, including nine ocular HAdV-B genome sequences. Attempts to categorize the penton, hexon, and fiber serotypes using phylogeny of the three Bascom Palmer samples were inconclusive due to incongruence between serotype and phylogeny in the dataset. Recombination analysis using a subset of HAdV-B strains to generate a hybridization network detected recombination between nonhuman primate and human-derived strains, recombination between one HAdV-B strain and the HAdV-E outgroup, and limited recombination between the B1 and B2 clades.
CONCLUSIONS
The discordance between serotype and phylogeny detected in this study suggests that the current classification system does not accurately describe the natural history and phylogenetic relationships among adenoviruses.
Topics: Humans; Animals; Adenoviridae; Vitreous Body; Phylogeny; Serogroup; Adenoviruses, Human; Hexamethonium; Recombination, Genetic
PubMed: 38319669
DOI: 10.1167/iovs.65.2.12 -
Biomedicines Dec 2023In the early stages of Alzheimer-Perusini's disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast... (Review)
Review
In the early stages of Alzheimer-Perusini's disease (AD), individuals often experience vision-related issues such as color vision impairment, reduced contrast sensitivity, and visual acuity problems. As the disease progresses, there is a connection with glaucoma and age-related macular degeneration (AMD) leading to retinal cell death. The retina's involvement suggests a link with the hippocampus, where most AD forms start. A thinning of the retinal nerve fiber layer (RNFL) due to the loss of retinal ganglion cells (RGCs) is seen as a potential AD diagnostic marker using electroretinography (ERG) and optical coherence tomography (OCT). Amyloid beta fragments (Aβ), found in the eye's vitreous and aqueous humor, are also present in the cerebrospinal fluid (CSF) and accumulate in the retina. Aβ is known to cause tau hyperphosphorylation, leading to its buildup in various retinal layers. However, diseases like AD are now seen as mixed proteinopathies, with deposits of the prion protein (PrP) and α-synuclein found in affected brains and retinas. Glial cells, especially microglial cells, play a crucial role in these diseases, maintaining immunoproteostasis. Studies have shown similarities between retinal and brain microglia in terms of transcription factor expression and morphotypes. All these findings constitute a good start to achieving better comprehension of neurodegeneration in both the eye and the brain. New insights will be able to bring the scientific community closer to specific disease-modifying therapies.
PubMed: 38137479
DOI: 10.3390/biomedicines11123258 -
Heliyon Jan 2024N6-methyladenosine (mA) modification, as the most common modification method in eukaryotes, is widely involved in numerous physiological and pathological processes, such... (Review)
Review
N6-methyladenosine (mA) modification, as the most common modification method in eukaryotes, is widely involved in numerous physiological and pathological processes, such as embryonic development, malignancy, immune regulation, and premature aging. Under pathological conditions of ocular diseases, changes in mA modification and its metabolism can be detected in aqueous and vitreous humor. At the same time, an increasing number of studies showed that mA modification is involved in the normal development of eye structures and the occurrence and progress of many ophthalmic diseases, especially ocular neovascular diseases, such as diabetic retinopathy, age-related macular degeneration, and melanoma. In this review, we summarized the latest progress regarding mA modification in ophthalmic diseases, changes in mA modification-related enzymes in various pathological states and their upstream and downstream regulatory networks, provided new prospects for mA modification in ophthalmic diseases and new ideas for clinical diagnosis and treatment.
PubMed: 38192819
DOI: 10.1016/j.heliyon.2023.e23668 -
Journal of Vitreoretinal Diseases 2023To describe a case of T-cell lymphoma with bilateral vitreous involvement. A case report was reviewed, and a literature review, including search terms such as...
To describe a case of T-cell lymphoma with bilateral vitreous involvement. A case report was reviewed, and a literature review, including search terms such as "anaplastic large-cell lymphoma (ALCL)" and "T-cell lymphoma with ocular involvement", was performed. A 56-year-old man presented with slurred speech, left-sided weakness, and floaters in his right eye. He was found to have an enhancing right frontal lobe mass with biopsy positive for ALCL. The right eye demonstrated 2+ vitreous cell, with a vitreous biopsy consistent with ALCL. His floaters resolved, and the patient was asymptomatic until he developed floaters in his left eye 1½ years later. A subsequent vitreous biopsy revealed recurrence of ALCL in the fellow eye. ALCL is a rare T-cell lymphoma uncommonly reported as having vitreous infiltration.
PubMed: 37974916
DOI: 10.1177/24741264231191668 -
Heliyon Feb 2024Assessment and validation of endothelial-mesenchymal transition (EndoMT) in the retinal endothelium of patients with proliferative diabetic retinopathy (PDR) at the...
BACKGROUND
Assessment and validation of endothelial-mesenchymal transition (EndoMT) in the retinal endothelium of patients with proliferative diabetic retinopathy (PDR) at the level of retinal and vitreous specimens, and preliminary discussion of its regulatory mechanisms.
METHODS
Transcriptome sequencing profiles of CD31 cells from 9 retinal fibrovascular mem-branes (FVMs) and 4 postmortem retinas were downloaded from GEO databases to analyze EndoMT-related differentially expressed genes (DEGs). Then, 42 PDR patients and 34 idiopathic macular holes (IMH) patients were enrolled as the PDR and control groups, respectively. Vitreous humor (VH) samples were collected, and the expression of EndoMT-related proteins was quantified by enzyme-linked immunosorbent assay.
RESULTS
A total of 5845 DEGs were identified, and we subsequently focused on the analysis of 24 EndoMT-related marker genes, including the trigger of EndoMT, endothelial genes, mesenchymal genes, transcription factors, inflammatory factors, and autophagy markers. Six of these genes were selected for protein assay validation in VH, showing increased mesenchymal marker (type I collagen α 2 chain, COL1A2) and decreased endothelial marker (VE-cadherin, CDH5) accompanied by increased TGFβ, IL-1β, LC3B and P62 in PDR patients. In addition, anti-VEGF therapy could enhance EndoMT-related phenotypes.
CONCLUSIONS
EndoMT may underlie the pathogenesis of PDR, and the induction and regulation correlate with autophagy defects and the inflammatory response.
PubMed: 38327444
DOI: 10.1016/j.heliyon.2024.e25166 -
Journal of Pharmaceutical Sciences Aug 2023Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection,...
Mice are rarely used in pharmacokinetic (PK) studies of ocular therapeutics due to the small size of their eyes and challenges in drug administration, tissue collection, and analysis of drug concentrations. Therefore, ocular PK of protein therapeutics in mouse eye following intravitreal (IVT) administration is not known. Here, we have presented the first of its kind investigation, to study the PK of 4 different size non-binding protein therapeutics in mouse plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) following IVT administration. Administered proteins include trastuzumab (150 kDa) and F(ab) (100 kDa), Fab, and scFv (27 kDa) fragments of trastuzumab. An imaging and injection apparatus suitable for performing small (50 nL) IVT injections in mice was developed, and techniques for enucleation of the eye and dissection of ocular tissues were developed. Furthermore, a sensitive enzyme-linked immunosorbent assay (ELISA) for detection of proteins in very small amounts of ocular tissues were developed. It was observed that elimination from the vitreous chamber was the primary driver of PK in the cornea/ICB, retina, posterior cup, and plasma. Trastuzumab displays first-order kinetics in the vitreous humor with a half-life of 18.8 h. F(ab), Fab, and ScFv show biphasic PK profiles with distribution phases becoming more rapid as molecular weight decreases, and terminal elimination becoming longer as molecular weight decreases, with terminal half-lives of 16.3, 20.6, and 48.9 h, respectively. The mean residence times of trastuzumab, F(ab), Fab, and scFv in the vitreous humor were 26.0, 12.2, 10.7, and 8.16 h, respectively. It was found that the mean residence time in vitreous humor doubles with an increase in molecular weight of ∼69 kDa. Interestingly, the PK of proteins measured in the un-injected eye suggest the presence of a pathway for drug transfer between the eyes, which needs to be further validated. Overall, the findings presented here pave the way for drug discovery and development studies of protein therapeutics for ophthalmic indications in mice.
Topics: Mice; Animals; Antibodies, Monoclonal; Intravitreal Injections; Eye; Vitreous Body; Trastuzumab; Immunoglobulin Fragments
PubMed: 37062415
DOI: 10.1016/j.xphs.2023.04.006 -
Survey of Ophthalmology 2024Primary vitreoretinal lymphoma is a potentially aggressive intraocular malignancy with poor systemic prognosis and sometimes significant diagnostic delays as it may... (Review)
Review
Primary vitreoretinal lymphoma is a potentially aggressive intraocular malignancy with poor systemic prognosis and sometimes significant diagnostic delays as it may masquerade as chronic uveitis. Despite the variety of diagnostic techniques, it is unclear which modality is most accurate in the diagnosis of PVRL. A systematic literature search was conducted on Ovid MEDLINE, EMBASE and the Cochrane Controlled Register of Trials for studies published between January, 2000, and June, 2023. Randomized controlled trials (RCTs) reporting on the following diagnostic tools used to diagnose patients with PVRL were included: cytology, flow cytometry, MYD88 L265P mutation, CD79B mutation, interleukin 10/interleukin-6 (IL-10/IL-6) ratio, polymerase chain reaction (PCR) for monoclonal immunoglobulin heavy chain (IgH) and immunoglobulin kappa light chain (IgK) rearrangements, and imaging findings. The aggregated sensitivity of each diagnostic modality was reported and compared using the chi-squared (χ2) test. A total of 662 eyes from 29 retrospective studies reporting on patients diagnosed with PVRL were included. An IL-10/IL-6 ratio greater than 1 had the highest sensitivity (89.39%, n = 278/311 eyes, n = 16 studies) for PVRL, where the sensitivity was not significantly different when only vitreous samples were drawn (88.89%, n = 232/261 eyes, n = 13 studies) compared to aqueous samples (83.33%, n = 20/24, n = 2) (p = 0.42). Flow cytometry of vitreous samples gave a positive result in 66/75 eyes (88.00%, n = 6 studies) with PVRL, and monoclonal IgH rearrangements on PCR gave a positive result in 354/416 eyes (85.10%, n = 20 studies) with PVRL. MYD88 L265P and CD79B mutation analysis performed poorly, yielding a positive result in 63/90 eyes (70.00%, n = 8 studies) with PVRL, and 20/57 eyes (35.09%, n = 4 studies) with PVRL, respectively. Overall, our systematic review found that an IL-10/IL-6 ratio greater or equal to one may provide the highest sensitivity in identifying patients with PVRL. Future studies are needed to employ multiple diagnostic tools to aid in the detection of PVRL and to further establish nuanced guidelines when determining the optimal diagnostic tool to use in diverse patient populations.
Topics: Humans; Retinal Neoplasms; Vitreous Body; Interleukin-10; Intraocular Lymphoma; Flow Cytometry; Interleukin-6; Myeloid Differentiation Factor 88; Diagnostic Techniques, Ophthalmological; Biomarkers, Tumor; CD79 Antigens; Polymerase Chain Reaction
PubMed: 38163550
DOI: 10.1016/j.survophthal.2023.12.001 -
Die Ophthalmologie Oct 2023Age-related changes in vitreous molecular and anatomic morphology begin early in life and involve two major processes: vitreous liquefaction and weakening of... (Review)
Review
Age-related changes in vitreous molecular and anatomic morphology begin early in life and involve two major processes: vitreous liquefaction and weakening of vitreo-retinal adhesion. An imbalance in these two processes results in anomalous posterior vitreous detachment (PVD), which comprises, among other conditions, vitreo-macular adhesion (VMA) and traction (VMT). VMA is more common in patients with neovascular age-related macular degeneration (nAMD) than age-matched control patients, with the site of posterior vitreous adherence to the inner retina correlating with location of neovascular complexes. The pernicious effects of an attached posterior vitreous on age-related macular degeneration (AMD) progression involve mechanical forces, enhanced fluid influx and inflammation in and between the retinal layers, hypoxia leading to an accumulation of vascular endothelial growth factor (VEGF) and other stimulatory cytokines, and probably an infiltration of hyalocytes. It has been shown that vitrectomy not only mitigates progression to end-stage AMD, but existing choroidal neovascularization regresses after surgery. Thus, surgical PVD induction during vitrectomy or by pharmacologic vitreolysis may be considered in non-responders to anti-VEGF treatment with concomitant VMA.
Topics: Humans; Vitreous Body; Vascular Endothelial Growth Factor A; Vitreous Detachment; Macular Degeneration; Retinal Diseases
PubMed: 37801159
DOI: 10.1007/s00347-023-01934-1 -
Ceska a Slovenska Oftalmologie :... 2024Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments,... (Review)
Review
Retinoblastoma is the most common primary malignant intraocular tumor in children. Seeding, specifically the dispersion of the tumor into the adjacent compartments, represents a major parameter determining the degree of retinoblastoma according to the International Classification of Retinoblastoma. In this article we focused on vitreous seeding, one of the main limiting factors in the successful "eye preservation treatment" of retinoblastoma. This article presents an overview of the history of vitreous seeding of retinoblastoma, established treatment procedures and new-research modalities. The introduction of systemic chemotherapy in the treatment of retinoblastoma at the end of the 1990s represented a significant breakthrough, which enabled the progressive abandonment of radiotherapy with its attendant side effects. However, the attained concentrations of chemotherapeutics in the vitreous space during systemic chemotherapy are not sufficient for the treatment of vitreous seeding, and the toxic effects of systemic chemotherapy are not negligible. A significant change came with the advent of chemotherapy in situ, with the targeted administration of chemotherapeutic drugs, namely intra-arterial and intravitreal injections, contributing to the definitive eradication of external radiotherapy and a reduction of systemic chemotherapy. Although vitreous seeding remains the most common reason for the failure of intra-arterial chemotherapy, this technique has significantly influenced the original treatment regimen of children with retinoblastoma. However, intravitreal chemotherapy has made the greatest contribution to increasing the probability of preservation of the eyeball and visual functions in patients with advanced findings. Novel local drug delivery modalities, gene therapy, oncolytic viruses and immunotherapy from several ongoing preclinical and clinical trials may represent promising approaches in the treatment of vitreous retinoblastoma seeding, though no clinical trials have yet been completed for routine use.
Topics: Child; Humans; Retinoblastoma; Retinal Neoplasms; Melphalan; Antineoplastic Agents, Alkylating; Vitreous Body; Intravitreal Injections; Retrospective Studies
PubMed: 38538290
DOI: 10.31348/2023/35 -
Diabetes Research and Clinical Practice Apr 2024To evaluate and summarize the association between interleukin (IL) concentrations and diabetes mellitus (DM) and its complications. (Review)
Review
OBJECTIVE
To evaluate and summarize the association between interleukin (IL) concentrations and diabetes mellitus (DM) and its complications.
METHODS
Meta-analyses and eligible individual studies of observational studies investigating the associations between IL and DM and its complications were included. The random-effects model was used to estimate the summary effect, and the heterogeneity among studies was assessed using the Q-statistic and the I metric; The Egger's regression and the χ test were used to test for small study effects and excess significance bias.
RESULTS
This overview identified 34 meta-analyses that investigated the association between IL concentrations and DM and its complications. Meta-analyses of prospective studies indicated that elevated circulating IL-6 and IL-1β had predictive value for the incident of type 2 diabetes mellitus (T2DM), type 1 diabetes mellitus (T1DM) as well as gestational diabetes mellitus (GDM), and the overall Hazard Ratio (HR) of T2DM was 1.28 (95 % CI: 1.17, 1.40; P<0.001) per 1 log pg/ml increment in IL-6 levels, however, there was no correlation between circulating IL-10 levels and DM. Meanwhile, the increased level of IL-6 was significantly associated several diabetic complications (Diabetic kidney disease[DKD], diabetic peripheral neuropathy[DPN], and cognitive impairment[CI]), and for the diabetic retinopathy (DR), the levels of IL-1β, IL-8 and IL-10 in the aqueous humor and vitreous humor, but not the blood were significantly correlated with it.
CONCLUSION
Multiple ILs, such as the IL-6 and IL-1β, are definitively linked to DM and its complications, and they may be new targets for the diagnosis and treatment, but stronger evidence needs to be confirmed by prospective studies with larger sample sizes and longer observation periods.
Topics: Humans; Diabetes Mellitus, Type 2; Interleukin-10; Interleukin-6; Prospective Studies; Systematic Reviews as Topic; Diabetic Retinopathy; Interleukin-1beta
PubMed: 38513987
DOI: 10.1016/j.diabres.2024.111615