scholarly journals Identification of Arhgef12 and Prkci as Genetic Modifiers of Retinal Dysplasia in the Crb1rd8 Mouse Model

2021 ◽  
Author(s):  
Sonia M. Weatherly ◽  
Gayle B. Collin ◽  
Jeremy R. Charette ◽  
Lisa Stone ◽  
Nattaya Damkham ◽  
...  
Keyword(s):  
Severe Disease ◽  
Functional Decline ◽  
Retinal Disease ◽  
Underlying Disease ◽  
Chemical Mutagenesis ◽  
Macular Dystrophy ◽  
Genetic Modifiers ◽  
Epistasis Analysis ◽  
Clinical Variation ◽  
Retinal Dysplasia

AbstractMutations in the apicobasal polarity gene CRB1 lead to diverse retinal diseases, such as Leber congenital amaurosis, cone-rod dystrophy, retinitis pigmentosa (with and without Coats-like vasculopathy), foveal retinoschisis, macular dystrophy, and pigmented paravenous chorioretinal atrophy. Limited correlation between disease phenotypes and CRB1 alleles, and evidence that patients sharing the same alleles often present with different disease features, suggest that genetic modifiers contribute to clinical variation. Similarly, the retinal phenotype of mice bearing the Crb1 retinal degeneration 8 (rd8) allele varies with genetic background. Here, we initiated a sensitized chemical mutagenesis screen in B6.Cg-Crb1rd8/Pjn, a strain with a mild clinical presentation, to identify genetic modifiers that cause a more severe disease phenotype. Two models from this screen, Tvrm266 and Tvrm323, exhibited increased retinal dysplasia. Genetic mapping with high-throughput exome and candidate-gene sequencing identified causative mutations in Arhgef12 and Prkci, respectively. Epistasis analysis of both strains indicated that the increased dysplastic phenotype required homozygosity of the Crb1rd8 allele. Retinal dysplastic lesions in Tvrm266 mice were smaller and caused less photoreceptor degeneration than those in Tvrm323 mice, which developed an early, large diffuse lesion phenotype. In both models at one month of age, Müller glia and microglia mislocalization at dysplastic lesions was similar to that in B6.Cg-Crb1rd8/Pjn mice, while photoreceptor cell mislocalization was more extensive. External limiting membrane disruption was comparable in Tvrm266 and B6.Cg- Crb1rd8/Pjn mice but milder in Tvrm323 mice. Immunohistological analysis of mice at postnatal day 0 indicated a normal distribution of mitotic cells in Tvrm266 and Tvrm323 mice, suggesting normal early development. Aberrant electroretinography responses were observed in both models but functional decline was significant only in Tvrm323 mice. These results identify Arhgef12 and Prkci as modifier genes that differentially shape Crb1-associated retinal disease, which may be relevant to understanding clinical variability and underlying disease mechanisms.

scholarly journals Retinitis pigmentosa is associated with shifts in the gut microbiome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Oksana Kutsyr ◽  
Lucía Maestre-Carballa ◽  
Mónica Lluesma-Gomez ◽  
Manuel Martinez-Garcia ◽  
Nicolás Cuenca ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Gut Microbiome ◽  
Functional Decline ◽  
Retinal Disease ◽  
Photoreceptor Cells ◽  
Amplicon Sequencing ◽  
Rrna Gene ◽  
Sequencing Data ◽  
Alpha And Beta Diversity ◽  
Potential Biomarker

AbstractThe gut microbiome is known to influence the pathogenesis and progression of neurodegenerative diseases. However, there has been relatively little focus upon the implications of the gut microbiome in retinal diseases such as retinitis pigmentosa (RP). Here, we investigated changes in gut microbiome composition linked to RP, by assessing both retinal degeneration and gut microbiome in the rd10 mouse model of RP as compared to control C57BL/6J mice. In rd10 mice, retinal responsiveness to flashlight stimuli and visual acuity were deteriorated with respect to observed in age-matched control mice. This functional decline in dystrophic animals was accompanied by photoreceptor loss, morphologic anomalies in photoreceptor cells and retinal reactive gliosis. Furthermore, 16S rRNA gene amplicon sequencing data showed a microbial gut dysbiosis with differences in alpha and beta diversity at the genera, species and amplicon sequence variants (ASV) levels between dystrophic and control mice. Remarkably, four fairly common ASV in healthy gut microbiome belonging to Rikenella spp., Muribaculaceace spp., Prevotellaceae UCG-001 spp., and Bacilli spp. were absent in the gut microbiome of retinal disease mice, while Bacteroides caecimuris was significantly enriched in mice with RP. The results indicate that retinal degenerative changes in RP are linked to relevant gut microbiome changes. The findings suggest that microbiome shifting could be considered as potential biomarker and therapeutic target for retinal degenerative diseases.

Coronavirus Disease (COVID-19): 10 Questions and Discussion Points for Diabetes and COVID-19

2021 ◽  
Author(s):  
Mahbube Ebrahimpur ◽  
Moloud Payab ◽  
Mahnaz Pejman Sani ◽  
Bagher Larijani
Keyword(s):  
High Risk ◽  
General Population ◽  
Severe Disease ◽  
Underlying Disease ◽  
Serious Illness ◽  
Risk Categories

The COVID-19 pandemic is now an international concern. COVID-19 is first reported in Wuhan, China on 31 December 2019 and affects different people in different ways. Evidence suggests that people with underlying disease are at higher risk for more severe disease. People with diabetes are not only more likely than the general population to have COVID-19 but also they are among those high-risk categories that can have serious illness if they get the virus.

Abstract 15937: Gender Disparities in Presentation and Outcomes for Patients Undergoing Endovascular Lower Extremity Interventions for Peripheral Artery Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Elizabeth M Lancaster ◽  
Bian Wu ◽  
Joel Ramirez ◽  
James Iannuzzi ◽  
Michael S Conte ◽  
...  
Keyword(s):  
Lower Extremity ◽  
Hospital Mortality ◽  
Peripheral Artery Disease ◽  
Severe Disease ◽  
Functional Decline ◽  
Multivariable Analysis ◽  
National Database ◽  
Peripheral Artery ◽  
Artery Disease ◽  
Gender Based

Introduction: Although data suggests higher rates of functional decline and inferior outcomes in women compared to men after interventions for peripheral artery disease (PAD), women remain underrepresented in contemporary studies. We used a large national database to better understand gender-based differences in presentation and outcomes for patients undergoing endovascular treatment for PAD. Methods: Patients in the Vascular Quality Initiative (VQI) database that underwent lower extremity (LE) endovascular interventions for symptomatic PAD from 2010-2019 were included. Descriptive statistics and multivariable analysis were performed. Results: 128,688 patients (40% female) underwent endovascular LE interventions for symptomatic PAD. Women were more likely to have chronic limb threatening ischemia compared to men (54% vs 51%) and more likely to have a preoperative ABI <0.4 (20% vs 14%). Compared to men, women were older (mean [SD]: 68 [11] vs 70 [12]), more likely to be Black (19% vs 14%), and less likely to be smokers (34% vs 36%), diabetic (50% vs 54%), have CAD (28% vs 35%), or be on dialysis (8% vs 9%) (Table 1). Women were less likely to have exclusively infrapopliteal interventions (8% vs 14%) compared to men (p<0.001 for all). Despite shorter procedural times in women, female gender was an independent predictor of in hospital mortality (OR 1.25, 95% CI 1.09-1.44) in a hierarchical multivariable model adjusting for age, race, smoking, and comorbidities. Women were more likely to be discharged to a rehab or nursing home (11% vs 10%, p< 0.001) and less likely to be taking a statin medication (73% vs 78%, p<0.001). Conclusions: Compared to men, women undergoing endovascular LE interventions for PAD are older, present with more severe disease, and have higher adjusted rates of in hospital mortality. More aggressive screening and medical treatment for PAD in women is needed to address these gender-based differences in disease presentation and clinical outcomes.

scholarly journals A gyermekkori uveitis klinikai jellemzői és terápiája

2019 ◽  
Vol 160 (34) ◽  
pp. 1335-1339
Author(s):  
Judit Kiss ◽  
Valéria Gaál ◽  
Zoltán Nyul ◽  
Bernadett Mosdósi
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Autoimmune Diseases ◽  
Single Case ◽  
Severe Disease ◽  
Significant Proportion ◽  
Middle Layer ◽  
Underlying Disease ◽  
Posterior Uveitis ◽  
Study Data ◽  
Multidisciplinary Cooperation

Abstract: Introduction: Uveitis is characterized by inflammation of the middle layer of the eye. Its overall incidence is low. Autoimmune diseases and infections are the most common underlying diseases. Out of the autoimmune diseases, juvenile idiopathic arthritis is associated most frequently with uveitis. The topical ophthalmological treatment may fail in a significant proportion of the patients and immunomodulatory therapy may be required. Aim and method: In a retrospective study, data of 33 children diagnosed and treated with uveitis at the Department of Pediatrics and Ophthalmology, University of Pécs during the last 5 years were collected and analyzed. Results: The mean age of the patients was 9.3 (0.3–17.8) years. Boys and girls were equally affected with an exception of patients with juvenile idiopathic arthritis where female predominance was found. An underlying disease could be identified in 60% of the cases (20/33). Uveitis was associated in 12 patients with juvenile idiopathic arthritis, in 2 patients with Behcet’s disease and in a single case with inflammatory bowel disease. Infections have been proven in 5 patients. The autoimmune diseases caused an eye inflammation typically in anterior localization, in contrast to the infections that resulted in posterior uveitis. The majority of the patients required systemic treatment. 3 of them received systemic corticosteroid and 18 patients methotrexate as disease-modifying antirheumatic drug. 13 children with severe disease activity required biological therapy (adalimumab injection). Remission could be achieved in 1.45 (0.75–2.5) months. Conclusion: Pediatric uveitis is of great importance. Early diagnosis, adequate therapy and follow-up require multidisciplinary cooperation. Orv Hetil. 2019; 160(34): 1335–1339.

scholarly journals Extending the Spectrum of EYS-Associated Retinal Disease to Macular Dystrophy

2019 ◽  
Vol 60 (6) ◽  
pp. 2049 ◽  
Author(s):  
Laurence H. M. Pierrache ◽  
Muriël Messchaert ◽  
Alberta A. H. J. Thiadens ◽  
Lonneke Haer-Wigman ◽  
Yvonne de Jong-Hesse ◽  
...  
Keyword(s):  
Retinal Disease ◽  
Macular Dystrophy

scholarly journals Reduction in CD11c+ microglia promotes clinical progression in autoimmune demyelination

2018 ◽  
Author(s):  
Florian Mayrhofer ◽  
Zhanna Dariychuk ◽  
Anthony Zhen ◽  
Daniel J. Daugherty ◽  
Peter Bannerman ◽  
...  
Keyword(s):  
Immune Cell ◽  
Severe Disease ◽  
Underlying Disease ◽  
Perivascular Spaces ◽  
Clinical Progression ◽  
Autoimmune Encephalomyelitis ◽  
Progressive Decline ◽  
Demyelinating Disorder ◽  
Relapsing Remitting ◽  
Autoimmune Demyelination

AbstractMultiple sclerosis (MS) is a chronic autoimmune demyelinating disorder. Most people with MS show a relapsing-remitting disease course that over time transitions into progressive decline of neurologic function. The mechanisms underlying disease progression in MS remain poorly understood. Here we demonstrate that reduction in CD11c+ microglia promotes dispersed coalescent parenchymal infiltration and clinical progression in chronic mild experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found sex-dependent differences in EAE progression mediated by p38α signaling, a key regulator of inflammation. CD11c promoter-driven knockout of p38α (KO) reduced CD11c+ microglia proliferation in female mice and promoted CNS infiltration and transition of chronic mild to severe disease. In protected KO males, immune cells were trapped within perivascular spaces and prevented from crossing the glia limitans closely surrounded by dendritic cell-like CD11c+ microglia. Together, our study provides the first evidence that in chronic mild EAE, CD11c+ microglia interact with astrocytes to control CNS immune cell parenchymal infiltration.

scholarly journals Stromelysin-1 polymorphism as a new potential risk factor in progression of chronic obstructive pulmonary disease

2016 ◽  
Vol 71 (1) ◽  
Author(s):  
P. Santus ◽  
F. Casanova ◽  
M.L. Biondi ◽  
F. Blasi ◽  
F. Di Marco ◽  
...  
Keyword(s):  
Risk Factor ◽  
Severe Disease ◽  
Functional Decline ◽  
Chronic Obstructive Lung Disease ◽  
Allelic Frequency ◽  
Airflow Limitation ◽  
Nucleotide Sequencing ◽  
Chronic Obstructive ◽  
Genotype Distribution ◽  
Stable Conditions

Background. Chronic obstructive lung disease (COPD) is characterised by partially reversible usually progressive airflow limitation caused by inflammation and remodelling. Stromelysin-1 (MMP-3) has regulatory activity on other matrix-metalloproteinases. Altered MMP-3 activity has been described in different diseases. We investigated the role of a promoter MMP-3 polymorphism in determining susceptibility and severity of COPD. Methods. We studied 147 patients with COPD in stable conditions and distinguished two groups based on FEV1 values. In 100 patients functional modifications across a two-year period were noted. 133 healthy subjects were used as controls. Genotyping for the –1171 5A/6A MMP-3 polymorphism was performed using nucleotide sequencing. Results. No difference was noted in the genotype distribution between COPD patients and controls. However, among patients with severe disease 6A/6A genotype and 6A allelic frequency were significantly more represented than among mild-moderate patients (p &lt; 0.05). The 6A/6A genotype was also associated with a higher FEV1 decline over time. Conclusions. Our data suggests that –1171 6A allele does not represent a risk factor for the development of COPD while it is associated with more severe disease and different functional decline. We hypothesise that a disregulation of MMP-3, possibly caused by the –1171 5A/6A polymorphism or other linked variants, may lead to different progression in COPD.

scholarly journals Optical Coherence Tomography Angiography Imaging in Inherited Retinal Diseases

2019 ◽  
Vol 8 (12) ◽  
pp. 2078 ◽  
Author(s):  
Ong ◽  
Patel ◽  
Singh
Keyword(s):  
Optical Coherence Tomography ◽  
Optical Coherence Tomography Angiography ◽  
Imaging Modality ◽  
Retinal Disease ◽  
Macular Dystrophy ◽  
Retinal Diseases ◽  
Optical Coherence ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Powerful Research Tool

Optical coherence tomography angiography (OCTA) is a novel, noninvasive imaging modality that allows depth-resolved imaging of the microvasculature in the retina and the choroid. It is a powerful research tool to study the pathobiology of retinal diseases, including inherited retinal dystrophies. In this review, we provide an overview of the evolution of OCTA technology, compare the specifications of various OCTA devices, and summarize key findings from published OCTA studies in inherited retinal dystrophies including retinitis pigmentosa, Stargardt disease, Best vitelliform macular dystrophy, and choroideremia. OCTA imaging has provided new data on characteristics of these conditions and has contributed to a deeper understanding of inherited retinal disease.

scholarly journals Hepatobiliary and Pancreatic Manifestations of Coronavirus Disease 2019

2020 ◽  
Vol 11 (01) ◽  
pp. 21-23
Author(s):  
Vikas Singla ◽  
Anil Arora
Keyword(s):  
Diabetes Mellitus ◽  
Liver Disease ◽  
Liver Injury ◽  
Islet Cells ◽  
Severe Disease ◽  
Specific Treatment ◽  
Pulmonary Involvement ◽  
Underlying Disease ◽  
Biliary Cirrhosis ◽  
Pancreatic Involvement

AbstractCoronavirus disease 2019 (COVID-19) is a new infectious disease that has spread rapidly throughout the world. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the Coronaviridae family. Though the pulmonary involvement is a major cause of morbidity and mortality, involvement of the gastrointestinal tract, liver, and pancreas has been explained in these patients. The literature is rapidly changing because of influx of new information with every passage of time. The most common hepatic presentation is mild elevation of aspartate transaminase and alanine transaminase, which does not require specific treatment. Occasionally, patients can have severe liver injury. Because of underlying predisposing factors such as diabetes mellitus, hypertension, and obesity, patients with nonalcoholic liver disease may be at risk of severe disease. Patients with decompensated liver disease may also be vulnerable to severe disease. Behavior of SARS-CoV-2 in patients with chronic hepatitis B and C, autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis is yet to be seen. The prevalence and severity of COVID-19 patients with the aforementioned diseases may be different. The effect of SARS-CoV-2 on an underlying liver disease is not known. COVID-19 may complicate the peritransplant period and throw new challenges in these patients. Drugs used to treat severe COVID-19 may cause liver injury and may have an effect on the underlying disease activity. Both hepatic and pancreatic involvement is related to the severity of COVID-19 disease. Serum amylase and lipase levels may be elevated in patients with severe COVID-19 disease. The involvement of pancreatic islet cells may lead to deranged blood sugar levels and potentially predispose to future diabetes mellitus. There are many unknown facts that will unfold with the passage of time.

The ABC of Alzheimer's Disease: ADL and Improving Day-to-Day Functioning of Patients

2002 ◽  
Vol 14 (S1) ◽  
pp. 7-26 ◽  
Author(s):  
Steven G. Potkin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Severe Disease ◽  
Functional Decline ◽  
Behavioral Changes ◽  
Therapeutic Interventions ◽  
Slow Decline ◽  
Moderate Disease ◽  
Home Placement ◽  
Che Inhibitors

Alzheimer's disease (AD) is characterized by deterioration in the ability to perform activities of daily living (ADL) in addition to loss of cognitive function and behavioral changes. This decline in day-to-day functioning is increasingly recognized as a source of considerable social, health, and economic costs. Inability to perform ADL results in growing caregiver burden and may lead to the eventual need for alternative care or nursing home placement. The measurement of ADL, which enables monitoring of the effectiveness of therapeutic interventions, can be performed using a number of inventories including the Progressive Deterioration Scale (PDS), the Disability Assessment for Dementia (DAD), and the Alzheimer Disease Cooperative Study ADL (ADCS/ADL) assessment scale. Clinical studies using these and other scales have indicated that cholinesterase (ChE) inhibitors offer an effective approach to treating the functional decline of AD. Donepezil, rivastigmine, and galantamine have been shown in some studies to prevent or slow decline in ADL over treatment periods of one to two years. For instance, in a 24-week study in subjects with moderate to severe AD, donepezil-treated patients remained stable compared with the placebo-treated patients. Rivastigmine has shown improvement or stabilization of PDS scores in patients with mild to moderate disease following 26 weeks of treatment and slowed deterioration in patients with more severe disease. Evidence to date suggests that these agents may not be equally effective at slowing or stabilizing loss in ADL over time and that these differences may reflect differences in pharmacology. In addition to inhibition of acetylcholinesterase (AChE), these compounds have other putative differences in mechanisms of action. Galantamine allosterically modulates the nicotinic receptor and may prevent the loss of ADL. Rivastigmine robustly inhibits butyrylcholinesterase in addition to AChE and therefore acts as a dual ChE inhibitor. Comparative studies evaluating the differential effects of these ChE inhibitors on ADL are awaited.

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