scholarly journals Pathological processes in aqueous humor due to iris atrophy predispose to early corneal graft failure in humans and mice

2020 ◽  
Vol 6 (20) ◽  
pp. eaaz5195 ◽  
Author(s):  
Takefumi Yamaguchi ◽  
Kazunari Higa ◽  
Yukari Yagi-Yaguchi ◽  
Koji Ueda ◽  
Hisashi Noma ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Aqueous Humor ◽  
Murine Model ◽  
Graft Failure ◽  
Cellular Response ◽  
Energy Homeostasis ◽  
Corneal Transplantation ◽  
Full Spectrum ◽  
Therapeutic Modalities ◽  
Iris Atrophy

Corneal endothelial cell (CEnC) loss after corneal transplantation is the major cause of graft failure and remains a clinically relevant challenge to overcome. Accumulated knowledge derived from long-term clinical outcomes suggested that elevated protein levels in the aqueous humor are associated with CEnC loss. However, the full spectrum of driver proteins and molecular processes remains to be determined. Here, we defined the somatic microenvironmental landscape and cellular response across human aqueous humor in samples with poor corneal transplantation clinical outcomes using multiomics analyses and clarified specific driver alterations, including complement activation and disturbed energy homeostasis. These driver alterations were also confirmed in aqueous humor from a novel murine model that spontaneously develops iris atrophy, leading to CEnC loss. The application of the integrative multiomics performed in human samples to the novel murine model will help the development of therapeutic modalities for patients with CEnC loss after corneal transplantation.

Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer’s Disease

2021 ◽  
pp. 1-5
Author(s):  
Hesam Khodadadi ◽  
Évila Lopes Salles ◽  
Abbas Jarrahi ◽  
Vincenzo Costigliola ◽  
MB Khan ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cognitive Decline ◽  
Murine Model ◽  
Early Onset ◽  
Behavioral Tests ◽  
Translational Model ◽  
Therapeutic Modalities ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
Motor Outcomes

There is a dire need for due innovative therapeutic modalities to improve outcomes of AD patients. In this study, we tested whether cannabidiol (CBD) improves outcomes in a translational model of familial AD and to investigate if CBD regulates interleukin (IL)-33 and triggering receptor expressed on myeloid cells 2 (TREM2), which are associated with improved cognitive function. CBD was administered to 5xFAD mice, which recapitulate early onset, familial AD. Behavioral tests and immunoassays were used to evaluate cognitive and motor outcomes. Our findings suggest that CBD treatment enhanced IL-33 and TREM2 expression, ameliorated the symptoms of AD, and retarded cognitive decline.

scholarly journals Differential Persistence among Genomovars of the Burkholderia cepacia Complex in a Murine Model of Pulmonary Infection

2002 ◽  
Vol 70 (5) ◽  
pp. 2715-2720 ◽  
Author(s):  
Karen K. Chu ◽  
Donald J. Davidson ◽  
T. Keith Halsey ◽  
Jacqueline W. Chung ◽  
David P. Speert
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Outcomes ◽  
Murine Model ◽  
Burkholderia Cepacia ◽  
Pulmonary Infection ◽  
Burkholderia Cepacia Complex ◽  
Clinical Infection ◽  
Minimal Toxicity

ABSTRACT Cystic fibrosis patients infected with strains from different genomovars of the Burkholderia cepacia complex can experience diverse clinical outcomes. To identify genomovar-specific determinants that might be responsible for these differences, we developed a pulmonary model of infection in BALB/c mice. Mice were rendered leukopenic by administration of cyclophosphamide prior to intranasal challenge with 1.6 × 104 bacteria. Five of six genomovar II strains persisted at stable numbers in the lungs until day 16 with minimal toxicity, whereas zero of seven genomovar III strains persisted but resulted in variable toxicity. We have developed a chronic pulmonary model of B. cepacia infection which reveals differences among genomovars in terms of clinical infection outcome.

Effectiveness of Histocompatibility Matching in High-Risk Corneal Transplantation

2020 ◽  
pp. 1-8
Author(s):  
Alan D. Penman ◽  
Kimberly W. Crowder ◽  
William M. Watkins
Keyword(s):  
High Risk ◽  
Graft Failure ◽  
Corneal Transplantation ◽  
Corneal Graft ◽  
Hla Dr ◽  
Risk Patients ◽  
Graft Success ◽  
Group Matching ◽  
Corneal Graft Failure

The Collaborative Cornea Transplant Studies (CCTS) comprised two randomized, double-masked, clinical trials, the Antigen Matching Study (AMS) and the Crossmatch Study (CS), designed to determine whether matching HLA-A, -B, and/or HLA-DR antigens, donor-recipient crossmatching, or ABO compatibility reduced the risk of corneal allograft rejection and failure in high-risk patients. The studies showed that for patients needing a corneal graft with uncompromised immune systems and at high risk for corneal graft rejection: (1) neither HLA-A, -B, nor HLA-DR antigen matching substantially reduces the likelihood of corneal graft failure; (2) a positive donor-recipient crossmatch does not dramatically increase the risk of corneal graft failure; and (3) ABO blood group matching may be effective in reducing the risk of graft failure. Intensive steroid therapy after transplantation, frequent follow-up, medication and follow-up compliance, and patient education appear to play a significant role in corneal graft success.

scholarly journals Quantifying Donor Effects on Transplant Outcomes Using Kidney Pairs from Deceased Donors

2019 ◽  
Vol 14 (12) ◽  
pp. 1781-1787
Author(s):  
Kathleen F. Kerr ◽  
Eric R. Morenz ◽  
Heather Thiessen-Philbrook ◽  
Steven G. Coca ◽  
F. Perry Wilson ◽  
...  
Keyword(s):  
Relative Risk ◽  
Clinical Outcomes ◽  
Graft Failure ◽  
Absolute Risk ◽  
Graft Function ◽  
Delayed Graft Function ◽  
Kidney Donor ◽  
Excess Absolute Risk ◽  
Deceased Donors ◽  
Concordance Measures

Background and objectivesIn kidney transplantation, the relative contribution of donor versus other factors on clinical outcomes is unknown. We sought to quantify overall donor effects on transplant outcomes for kidney donations from deceased donors.Design, setting, participants, & measurementsFor paired donations from deceased donors resulting in transplants to different recipients, the magnitude of donor effects can be quantified by examining the excess of concordant outcomes within kidney pairs beyond chance concordance. Using data from the Organ Procurement and Transplantation Network between the years 2013 and 2017, we examined concordance measures for delayed graft function, death-censored 1-year graft failure, and death-censored 3-year graft failure. The concordance measures were excess relative risk, excess absolute risk, and the fixation index (where zero is no concordance and one is perfect concordance). We further examined concordance in strata of kidneys with similar values of the Kidney Donor Profile Index, a common metric of organ quality.ResultsIf the transplant of the kidney mate resulted in delayed graft function, risk for delayed graft function was 19% higher (95% confidence interval [95% CI], 18% to 20%), or 1.76-fold higher (95% CI, 1.73- to 1.80-fold), than baseline. If a kidney graft failed within 1 year, then the kidney mate’s risk of failure was 6% higher (95% CI, 4% to 9%), or 2.85-fold higher (95% CI, 2.25- to 3.48-fold), than baseline. For 3-year graft failure, the excess absolute risk was 7% (95% CI, 4% to 10%) but excess relative risk was smaller, 1.91-fold (95% CI, 1.56- to 2.28-fold). Fixation indices were 0.25 for delayed graft function (95% CI, 0.24 to 0.27), 0.07 for 1-year graft failure (95% CI, 0.04 to 0.09), and 0.07 for 3-year graft failure (95% CI, 0.04 to 0.10). Results were similar in strata of kidneys with a similar Kidney Donor Profile Index.ConclusionsOverall results indicated that the donor constitution has small or moderate effect on post-transplant clinical outcomes.

scholarly journals Approaches toward enhancing survival probability following deep anterior lamellar keratoplasty

2020 ◽  
Vol 12 ◽  
pp. 251584142091301
Author(s):  
Sepehr Feizi ◽  
Amir A Azari
Keyword(s):  
Graft Rejection ◽  
Graft Failure ◽  
Corneal Transplantation ◽  
Corneal Neovascularization ◽  
Lamellar Keratoplasty ◽  
Deep Anterior Lamellar Keratoplasty ◽  
Vernal Keratoconjunctivitis ◽  
Full Thickness ◽  
Appropriate Treatment ◽  
Anterior Lamellar Keratoplasty

The greatest advantage of deep anterior lamellar keratoplasty over full-thickness corneal transplantation is the elimination of graft failure caused by endothelial rejection. Despite this advantage, a deep anterior lamellar keratoplasty graft can fail because of several factors, such as complications related to the donor–recipient interface, graft epithelial abnormalities, graft vascularization, stromal graft rejection, and recurrence of herpetic keratitis. Increased deep anterior lamellar keratoplasty graft survival is mainly built upon optimization of the ocular surface to provide a hospitable environment for the graft. Any predisposing factors for graft epithelial abnormalities, corneal neovascularization, and preexisting vernal keratoconjunctivitis should be identified and treated preoperatively. Prompt recognition and appropriate treatment of interface-related complications and stromal graft rejection usually result in good anatomic outcomes, with no detrimental effects on vision.

scholarly journals Meta-Analysis and Potential Role of Preexisting Heterosubtypic Cellular Immunity Based on Variations in Disease Severity Outcomes for Influenza Live Viral Challenges in Humans

2015 ◽  
Vol 22 (8) ◽  
pp. 949-956 ◽  
Author(s):  
Olga Pleguezuelos ◽  
Stuart Robinson ◽  
Ana Fernandez ◽  
Gregory A. Stoloff ◽  
Wilson Caparrós-Wanderley
Keyword(s):  
Placebo Group ◽  
Clinical Outcomes ◽  
Disease Severity ◽  
Cellular Response ◽  
Influenza Pandemic ◽  
Meta Analysis ◽  
Antiviral Agents ◽  
Test Group ◽  
Investigational Agent ◽  
Viral Shedding

ABSTRACTInfluenza live viral challenges in humans are valuable models for testing the efficacy of vaccines and antiviral agents. Volunteers are treated with an investigational agent, and their clinical outcomes postchallenge are compared to those of placebo-treated volunteers. Despite using a common protocol, similar recruitment criteria, and similar doses of the same challenge strain, we noticed differences in disease severity outcomes between the placebo groups from different studies. We investigated whether these differences were significant and, if so, whether any pattern and its possible causes could be identified. We compared the clinical outcomes postchallenge in placebo groups from five clinical studies carried out between 2008 and 2013. Correlations between the prechallenge heterosubtypic cellular response (gamma interferon [IFN-γ]) and postchallenge clinical outcomes were also investigated in one study. Placebo groups from studies carried out between 2009 and 2010 attained significantly reduced (P< 0.05) symptom scores postchallenge compared to those of placebo groups from studies carried out in either 2008 or 2013. Also, in a 2010 study, the frequency of high-influenza heterosubtypic cellular responders prevaccination was significantly lower in the test group (FLU-v) than that in the placebo group (P= 0.04). Moreover, the increased preexisting heterosubtypic cellular response of the placebo group correlated with reductions in symptom score and viral shedding postchallenge (P≤ 0.023). Only postvaccination did the test group display an equivalent correlation. The last influenza pandemic coincided with a significant reduction in disease severity outcomes. This reduction also appears to correlate with increased preexisting influenza heterosubtypic cellular responses. (This study is registered at ClinicalTrials.gov under registration number NCT01226758.)

Prevalence and clinical consequences of cytomegalovirus DNA in the aqueous humour and corneal transplants

2018 ◽  
Vol 103 (5) ◽  
pp. 666-671 ◽  
Author(s):  
Ching-Hsi Hsiao ◽  
Yih-Shiou Hwang ◽  
Wen-Yu Chuang ◽  
David H K Ma ◽  
Lung-Kun Yeh ◽  
...  
Keyword(s):  
Medical Records ◽  
Graft Failure ◽  
Corneal Transplantation ◽  
Diagnostic Value ◽  
Pcr Analysis ◽  
High Prevalence ◽  
Corneal Transplants ◽  
Clinical Consequences ◽  
Patients At Risk

AimTo determine the prevalence and clinical consequences of cytomegalovirus (CMV) DNA in the aqueous and corneal tissues obtained at the time of corneal transplantation to evaluate the diagnostic value of PCR analysis in identifying patients at risk of postkeratoplasty CMV endotheliitis.MethodsThirty patients who underwent corneal transplantation were included in 2011. The aqueous, excised recipient corneas and donor corneoscleral rims were analysed by PCR for the presence of CMV DNA. The medical records of the patients were retrospectively reviewed and linked with PCR results.ResultsCMV DNA was detected in three (10%) aqueous, eight (26.7%) recipient corneas and six (20.0%) donor corneas obtained during keratoplasty from the 30 patients. Postoperatively, four patients, who had CMV DNA in either aqueous (3) or recipient cornea (1), were diagnosed with CMV endotheliitis based on clinical features and repeat aqueous tapping for real-time PCR analysis. At the median 60.5 months follow-up, 8 (72.7%), including 4 with postkeratoplasty CMV endotheliitis, of the 11 patients with CMV positivity in any one sample had graft failure, while 9 (47.3%) of the 19 patients without evidence of CMV DNA experienced graft failure.ConclusionsWe found a relatively high prevalence of CMV DNA in the aqueous and corneas obtained during keratoplasty. All the patients who had CMV positivity in aqueous developed CMV endotheliitis postoperatively and experienced graft failure eventually. Aqueous tapping at the time of corneal transplantation for PCR analysis may help to improve the diagnosis and follow-up management of postkeratoplasty CMV endotheliitis.

scholarly journals Metagenomic alterations in gut microbiota precede and predict onset of colitis in the IL10 gene-deficient murine model

2020 ◽  
Author(s):  
Jun Miyoshi ◽  
Sonny T. M. Lee ◽  
Megan Kennedy ◽  
Mora Puertolas ◽  
Mary Frith ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Clinical Outcomes ◽  
Murine Model ◽  
Inflammatory Bowel Diseases ◽  
Gut Microbiome ◽  
Predictive Biomarkers ◽  
Disease Outcomes ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Robust Measures

AbstractBackground & AimsInflammatory bowel diseases (IBD) are chronic inflammatory disorders where predictive biomarkers for the disease development and clinical course are sorely needed for development of prevention and early intervention strategies that can be implemented to improve clinical outcomes. Since gut microbiome alterations can reflect and/or contribute to impending host health changes, we examined whether gut microbiota metagenomic profiles would provide more robust measures for predicting disease outcomes in colitis-prone hosts.MethodsUsing the IL-10 gene-deficient (IL-10 KO) murine model where early life dysbiosis from antibiotic (cefoperozone, CPZ) treated dams vertically-transferred to pups increases risk for colitis later in life, we investigated temporal metagenomic profiles in the gut microbiota of post-weaning offspring and determined their relationship to eventual clinical outcomes.ResultsCompared to controls, offspring acquiring maternal CPZ-induced dysbiosis exhibited a restructuring of intestinal microbial membership both in bacteriome and mycobiome that were associated with alterations in specific functional subsystems. Furthermore, among IL-10 KO offspring from CPZ-treated dams, several functional subsystems, particularly nitrogen metabolism, diverged between mice that developed spontaneous colitis (CPZ-colitis) versus those that did not (CPZ-no-colitis) at a time point prior to eventual clinical outcome.ConclusionsOur findings provide support that functional metagenomic profiling of gut microbes has potential and promise meriting further study for development of tools to assess risk and manage human IBD.SynopsisCurrently, predictive markers for the development and course of inflammatory bowel diseases (IBD) are not available. This study supports the notion that gut microbiome metagenomic profiles could be developed into a useful tool to assess risk and manage human IBD.

Securing Transplanted Meniscal Allografts Using Bone Plugs Results in Lower Risks of Graft Failure and Reoperations: A Meta-analysis

2021 ◽  
pp. 036354652110420
Author(s):  
Zachariah Gene Wing Ow ◽  
Chin Kai Cheong ◽  
Hao Han Hai ◽  
Cheng Han Ng ◽  
Dean Wang ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Lower Risk ◽  
Graft Failure ◽  
Meta Analysis ◽  
Young Patients ◽  
Bone Bridge ◽  
Risk Of Failure ◽  
Meniscal Allograft ◽  
Bone Plug

Background: Meniscal allograft transplant (MAT) is an important treatment option for young patients with deficient menisci; however, there is a lack of consensus on the optimal method of allograft fixation. Hypothesis: The various methods of MAT fixation have measurable and significant differences in outcomes. Study Design: Meta-analysis; Level of evidence, 4. Methods: A single-arm meta-analysis of studies reporting graft failure, reoperations, and other clinical outcomes after MAT was performed. Studies were stratified by suture-only, bone plug, and bone bridge fixation methods. Proportionate rates of failure and reoperation for each fixation technique were pooled with a mixed-effects model, after which reconstruction of relative risks with confidence intervals was performed using the Katz logarithmic method. Results: A total of 2604 patients underwent MAT. Weighted mean follow-up was 4.3 years (95% CI, 3.2-5.6 years). During this follow-up period, graft failure rates were 6.2% (95% CI, 3.2%-11.6%) for bone plug fixation, 6.9% (95% CI, 4.5%-10.3%) for suture-only fixation, and 9.3% (95% CI, 6.2%-13.9%) for bone bridge fixation. Transplanted menisci secured using bone plugs displayed a lower risk of failure compared with menisci secured via bone bridges (RR = 0.97; 95% CI, 0.94-0.99; P = .02). Risks of failure were not significantly different when comparing suture fixation to bone bridge (RR = 1.02; 95% CI, 0.99-1.06; P = .12) and bone plugs (RR = 0.99; 95% CI, 0.96-1.02; P = .64). Allografts secured using bone plugs were at a lower risk of requiring reoperations compared with those secured using sutures (RR = 0.91; 95% CI, 0.87-0.95; P < .001), whereas allografts secured using bone bridges had a higher risk of reoperation when compared with those secured using either sutures (RR = 1.28; 95% CI, 1.19-1.38; P < .001) or bone plugs (RR = 1.41; 95% CI, 1.32-1.51; P < .001). Improvements in Lysholm and International Knee Documentation Committee scores were comparable among the different groups. Conclusion: This meta-analysis demonstrates that bone plug fixation of transplanted meniscal allografts carries a lower risk of failure than the bone bridge method and has a lower risk of requiring subsequent operations than both suture-only and bone bridge methods of fixation. This suggests that the technique used in the fixation of a transplanted meniscal allograft is an important factor in the clinical outcomes of patients receiving MATs.

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