A brief step-by-step guide on conducting a systematic review and meta-analysis of prognostic model studies.

Prognostic models provide an avenue to predict the risk of individual patients and support shared-decision making. Many prognostic models are published annually, and systematic reviews provide an avenue to collate the existing evidence behind prognostic models to determine whether a model demonstrates adequate predictive performance and is ready for real-world use. This article provides a brief step-by-step guide on how to conduct a systematic review and meta-analysis of prognostic model studies and how these reviews differ from systematic reviews of therapy and diagnosis.

Clinical and pathological predictors for FDG-PET/CT avidity in patients with marginal zone lymphoma-a retrospective cohort study.

BACKGROUND: The clinical value of FDG-PET/CT for staging and monitoring treatment response in patients with aggressive lymphoma is well established. Conversely, its role in the assessment and management of marginal zone lymphoma (MZL) is less conclusive. We aimed to assess clinical, laboratory, and pathological predictors for FDG uptake in these patients, in an attempt to identify MZL patients whose management will benefit from this imaging modality. METHODS: In this single-center, retrospective cohort study, we included all adult patients diagnosed with MZL at the Rabin Medical Center between January 2006 and December 2020 who underwent FDG-PET/CT at the time of diagnosis. Primary outcomes were FDG avidity (defined as a visual assessment of at least moderate intensity), SUVmax, and SUVliver. Variables such as advanced clinical stage, primary disease site, hemoglobin level (Hb), platelet count (Plt), serum albumin, LDH level, ß-2 microglobulin, and Ki 67 index were evaluated univariate and multivariate analysis using logistic and linear regression models. Association between FDG avidity and progression-free and overall survival was evaluated using Kaplan-Meier curves and Cox regression analysis. RESULTS: A total of 207 MZL patients were included in this study, 76 of whom (36.7%) had FDG-avid disease. Baseline patients' characteristics such as age, gender, and comorbid conditions were similar between patients with and without significant FDG uptake. In a multivariate logistic regression model, non-gastric MALT (OR 4.2, 95% CI 1.78-10), Ki 67 index ≥ 15% (OR 3.64, 95% CI 1.36-9.76), and elevated LDH level (OR 8.6, 95% CI 3.2-22.8) were all associated with positive FDG avidity. In a multivariate linear regression model, a combination of advanced clinical stage, specific disease subtypes, LDH level, and Ki 67 index predicted the value of SUVmax (P value < 0.001; adjusted R2 = 33.8%) and SUVmax/SUVliver (P value < 0.001; adjusted R2 = 27%). Baseline FDG avidity was associated to PFS and OS only in univariate analyses. CONCLUSIONS: In this retrospective cohort study, we present prediction models for positive FDG uptake and SUVmax in MZL patients. These models aim to help clinicians choose patients suitable for incorporation of FDG-PET/CT for staging and monitoring disease and reduce the costs of redundant tests.

Clinicians and Older Adults' Perceptions of the Utility of Patient-Generated Health Data in Caring for Older Adults: Exploratory Mixed Methods Study.

BACKGROUND: Many people are motivated to self-track their health and optimize their well-being through mobile health apps and wearable devices. The diversity and complexity of these systems have evolved over time, resulting in a large amount of data referred to as patient-generated health data (PGHD), which has recently emerged as a useful set of data elements in health care systems around the world. Despite the increased interest in PGHD, clinicians and older adults' perceptions of PGHD are poorly understood. In particular, although some clinician barriers to using PGHD have been identified, such as concerns about data quality, ease of use, reliability, privacy, and regulatory issues, little is known from the perspectives of older adults. OBJECTIVE: This study aims to explore the similarities and differences in the perceptions of older adults and clinicians with regard to how various types of PGHD can be used to care for older adults. METHODS: A mixed methods study was conducted to explore clinicians and older adults' perceptions of PGHD. Focus groups were conducted with older adults and health care providers from the Greater Toronto area and the Kitchener-Waterloo region. The participants were asked to discuss their perceptions of PGHD, including facilitators and barriers. A questionnaire aimed at exploring the perceived usefulness of a range of different PGHD was also embedded in the study design. Focus group interviews were transcribed for thematic analysis, whereas the questionnaire results were analyzed using descriptive statistics. RESULTS: Of the 9 participants, 4 (44%) were clinicians (average age 38.3 years, SD 7 years), and 5 (56%) were older adults (average age 81.0 years, SD 9.1 years). Four main themes were identified from the focus group interviews: influence of PGHD on patient-provider trust, reliability of PGHD, meaningful use of PGHD and PGHD-based decision support systems, and perceived clinical benefits and intrusiveness of PGHD. The questionnaire results were significantly correlated with the frequency of PGHD mentioned in the focus group interviews (r=0.42; P=.03) and demonstrated that older adults and clinicians perceived blood glucose, step count, physical activity, sleep, blood pressure, and stress level as the most useful data for managing health and delivering high-quality care. CONCLUSIONS: This embedded mixed methods study generated several important findings about older adults and clinicians' perceptions and perceived usefulness of a range of PGHD. Owing to the exploratory nature of this study, further research is needed to understand the concerns about data privacy, potential negative impact on the trust between older adults and clinicians, data quality and quantity, and usability of PGHD-related technologies for older adults.

Using Consumer-Grade Physical Activity Trackers to Measure Frailty Transitions in Older Critical Care Survivors: Exploratory Observational Study.

BACKGROUND: Critical illness has been suggested as a sentinel event for frailty development in at-risk older adults. Frail critical illness survivors are affected by increased adverse health outcomes, but monitoring the recovery after intensive care unit (ICU) discharge is challenging. Clinicians and funders of health care systems envision an increased role of wearable devices in monitoring clinically relevant measures, as sensor technology is advancing rapidly. The use of wearable devices has also generated great interest among older patients, and they are the fastest growing group of consumer-grade wearable device users. Recent research studies indicate that consumer-grade wearable devices offer the possibility of measuring frailty. OBJECTIVE: This study aims to examine the data collected from wearable devices for the progression of frailty among critical illness survivors. METHODS: An observational study was conducted with 12 older survivors of critical illness from Kingston General Hospital in Canada. Frailty was measured using the Clinical Frailty Scale (CFS) at ICU admission, hospital discharge, and 4-week follow-up. A wearable device was worn between hospital discharge and 4-week follow-up. The wearable device collected data on step count, physical activity, sleep, and heart rate (HR). Patient assessments were reviewed, including the severity of illness, cognition level, delirium, activities of daily living, and comorbidity. RESULTS: The CFS scores increased significantly following critical illness compared with the pre-ICU frailty level (P=.02; d=-0.53). Survivors who were frail over the 4-week follow-up period had significantly lower daily step counts than survivors who were not frail (P=.02; d=1.81). There was no difference in sleep and HR measures. Daily step count was strongly correlated with the CFS at 4-week follow-up (r=-0.72; P=.04). The average HR was strongly correlated with the CFS at hospital discharge (r=-0.72; P=.046). The HR SD was strongly correlated (r=0.78; P=.02) with the change in CFS from ICU admission to 4-week follow-up. No association was found between the CFS and sleep measures. The pattern of increasing step count over the 4-week follow-up period was correlated with worsening of frailty (r=.62; P=.03). CONCLUSIONS: This study demonstrated an association between frailty and data generated from a consumer-grade wearable device. Daily step count and HR showed a strong association with the frailty progression of the survivors of critical illness over time. Understanding this association could unlock a new avenue for clinicians to monitor and identify a vulnerable subset of the older adult population that might benefit from an early intervention.

Consumer-Grade Wearable Device for Predicting Frailty in Canadian Home Care Service Clients: Prospective Observational Proof-of-Concept Study.

BACKGROUND: Frailty has detrimental health impacts on older home care clients and is associated with increased hospitalization and long-term care admission. The prevalence of frailty among home care clients is poorly understood and ranges from 4.0% to 59.1%. Although frailty screening tools exist, their inconsistent use in practice calls for more innovative and easier-to-use tools. Owing to increases in the capacity of wearable devices, as well as in technology literacy and adoption in Canadian older adults, wearable devices are emerging as a viable tool to assess frailty in this population. OBJECTIVE: The objective of this study was to prove that using a wearable device for assessing frailty in older home care clients could be possible. METHODS: From June 2018 to September 2019, we recruited home care clients aged 55 years and older to be monitored over a minimum of 8 days using a wearable device. Detailed sociodemographic information and patient assessments including degree of comorbidity and activities of daily living were collected. Frailty was measured using the Fried Frailty Index. Data collected from the wearable device were used to derive variables including daily step count, total sleep time, deep sleep time, light sleep time, awake time, sleep quality, heart rate, and heart rate standard deviation. Using both wearable and conventional assessment data, multiple logistic regression models were fitted via a sequential stepwise feature selection to predict frailty. RESULTS: A total of 37 older home care clients completed the study. The mean age was 82.27 (SD 10.84) years, and 76% (28/37) were female; 13 participants were frail, significantly older (P<.01), utilized more home care service (P=.01), walked less (P=.04), slept longer (P=.01), and had longer deep sleep time (P<.01). Total sleep time (r=0.41, P=.01) and deep sleep time (r=0.53, P<.01) were moderately correlated with frailty. The logistic regression model fitted with deep sleep time, step count, age, and education level yielded the best predictive performance with an area under the receiver operating characteristics curve value of 0.90 (Hosmer-Lemeshow P=.88). CONCLUSIONS: We proved that a wearable device could be used to assess frailty for older home care clients. Wearable data complemented the existing assessments and enhanced predictive power. Wearable technology can be used to identify vulnerable older adults who may benefit from additional home care services.

Checklist for the Systemic Treatment of Psoriasis Using Biologics: A Delphi Study.

BACKGROUND: Despite the complexity of psoriasis treatment using biologic therapy, there does not exist a standardized synoptic reporting form for the initiation of this population. The purpose of this study was to use a modified Delphi approach to develop a standard checklist for the standardized documentation of patients receiving systemic biologic therapy for psoriasis. METHODS: A modified Delphi survey was conducted over 3 rounds (February 2017 through January 2018). An expert panel generated a 51-item checklist that was proposed to participants. Items were rated on an anchored 1-7 Likert scale. Consensus was defined apriori as ≥ 70% agreement by respondents. RESULTS: A total of 58, 17, and 18 dermatologists participated in 3 consecutive Delphi rounds, respectively. Only half of the dermatologists surveyed reported using a checklist for the management of psoriasis. The final checklist comprised 19, 5, 6, and 9 items pertaining to patient history; physical exam and history of systemic therapy; vaccinations; and lab investigations and bloodwork, respectively. CONCLUSIONS: Given the increasing availability and complexity of biologic agents for psoriasis treatment, there is a need to promote standardized documentation for this population. The Checklist for the Systemic Treatment of Psoriasis presents 38 items that should be considered when initiating patients with psoriasis on biologic therapy.

Consumer Mobile Apps for Potential Drug-Drug Interaction Check: Systematic Review and Content Analysis Using the Mobile App Rating Scale (MARS).

BACKGROUND: General consumers can now easily access drug information and quickly check for potential drug-drug interactions (PDDIs) through mobile health (mHealth) apps. With aging population in Canada, more people have chronic diseases and comorbidities leading to increasing numbers of medications. The use of mHealth apps for checking PDDIs can be helpful in ensuring patient safety and empowerment. OBJECTIVE: The aim of this study was to review the characteristics and quality of publicly available mHealth apps that check for PDDIs. METHODS: Apple App Store and Google Play were searched to identify apps with PDDI functionality. The apps' general and feature characteristics were extracted. The Mobile App Rating Scale (MARS) was used to assess the quality. RESULTS: A total of 23 apps were included for the review-12 from Apple App Store and 11 from Google Play. Only 5 of these were paid apps, with an average price of $7.19 CAD. The mean MARS score was 3.23 out of 5 (interquartile range 1.34). The mean MARS scores for the apps from Google Play and Apple App Store were not statistically different (P=.84). The information dimension was associated with the highest score (3.63), whereas the engagement dimension resulted in the lowest score (2.75). The total number of features per app, average rating, and price were significantly associated with the total MARS score. CONCLUSIONS: Some apps provided accurate and comprehensive information about potential adverse drug effects from PDDIs. Given the potentially severe consequences of incorrect drug information, there is a need for oversight to eliminate low quality and potentially harmful apps. Because managing PDDIs is complex in the absence of complete information, secondary features such as medication reminder, refill reminder, medication history tracking, and pill identification could help enhance the effectiveness of PDDI apps.

User Acceptance of Wrist-Worn Activity Trackers Among Community-Dwelling Older Adults: Mixed Method Study.

BACKGROUND: Wearable activity trackers are newly emerging technologies with the anticipation for successfully supporting aging-in-place. Consumer-grade wearable activity trackers are increasingly ubiquitous in the market, but the attitudes toward, as well as acceptance and voluntary use of, these trackers in older population are poorly understood. OBJECTIVE: The aim of this study was to assess acceptance and usage of wearable activity trackers in Canadian community-dwelling older adults, using the potentially influential factors as identified in literature and technology acceptance model. METHODS: A mixed methods design was used. A total of 20 older adults aged 55 years and older were recruited from Southwestern Ontario. Participants used 2 different wearable activity trackers (Xiaomi Mi Band and Microsoft Band) separately for each segment in the crossover design study for 21 days (ie, 42 days total). A questionnaire was developed to capture acceptance and experience at the end of each segment, representing 2 different devices. Semistructured interviews were conducted with 4 participants, and a content analysis was performed. RESULTS: Participants ranged in age from 55 years to 84 years (mean age: 64 years). The Mi Band gained higher levels of acceptance (16/20, 80%) compared with the Microsoft Band (10/20, 50%). The equipment characteristics dimension scored significantly higher for the Mi Band (P<.05). The amount a participant was willing to pay for the device was highly associated with technology acceptance (P<.05). Multivariate logistic regression with 3 covariates resulted in an area under the curve of 0.79. Content analysis resulted in the formation of the following main themes: (1) smartphones as facilitators of wearable activity trackers; (2) privacy is less of a concern for wearable activity trackers, (3) value proposition: self-awareness and motivation; (4) subjective norm, social support, and sense of independence; and (5) equipment characteristics matter: display, battery, comfort, and aesthetics. CONCLUSIONS: Older adults were mostly accepting of wearable activity trackers, and they had a clear understanding of its value for their lives. Wearable activity trackers were uniquely considered more personal than other types of technologies, thereby the equipment characteristics including comfort, aesthetics, and price had a significant impact on the acceptance. Results indicated that privacy was less of concern for older adults, but it may have stemmed from a lack of understanding of the privacy risks and implications. These findings add to emerging research that investigates acceptance and factors that may influence acceptance of wearable activity trackers among older adults.

Smart Devices for Older Adults Managing Chronic Disease: A Scoping Review.

BACKGROUND: The emergence of smartphones and tablets featuring vastly advancing functionalities (eg, sensors, computing power, interactivity) has transformed the way mHealth interventions support chronic disease management for older adults. Baby boomers have begun to widely adopt smart devices and have expressed their desire to incorporate technologies into their chronic care. Although smart devices are actively used in research, little is known about the extent, characteristics, and range of smart device-based interventions. OBJECTIVE: We conducted a scoping review to (1) understand the nature, extent, and range of smart device-based research activities, (2) identify the limitations of the current research and knowledge gap, and (3) recommend future research directions. METHODS: We used the Arksey and O'Malley framework to conduct a scoping review. We identified relevant studies from MEDLINE, Embase, CINAHL, and Web of Science databases using search terms related to mobile health, chronic disease, and older adults. Selected studies used smart devices, sampled older adults, and were published in 2010 or after. The exclusion criteria were sole reliance on text messaging (short message service, SMS) or interactive voice response, validation of an electronic version of a questionnaire, postoperative monitoring, and evaluation of usability. We reviewed references. We charted quantitative data and analyzed qualitative studies using thematic synthesis. To collate and summarize the data, we used the chronic care model. RESULTS: A total of 51 articles met the eligibility criteria. Research activity increased steeply in 2014 (17/51, 33%) and preexperimental design predominated (16/50, 32%). Diabetes (16/46, 35%) and heart failure management (9/46, 20%) were most frequently studied. We identified diversity and heterogeneity in the collection of biometrics and patient-reported outcome measures within and between chronic diseases. Across studies, we found 8 self-management supporting strategies and 4 distinct communication channels for supporting the decision-making process. In particular, self-monitoring (38/40, 95%), automated feedback (15/40, 38%), and patient education (13/40, 38%) were commonly used as self-management support strategies. Of the 23 studies that implemented decision support strategies, clinical decision making was delegated to patients in 10 studies (43%). The impact on patient outcomes was consistent with studies that used cellular phones. Patients with heart failure and asthma reported improved quality of life. Qualitative analysis yielded 2 themes of facilitating technology adoption for older adults and 3 themes of barriers. CONCLUSIONS: Limitations of current research included a lack of gerontological focus, dominance of preexperimental design, narrow research scope, inadequate support for participants, and insufficient evidence for clinical outcome. Recommendations for future research include generating evidence for smart device-based programs, using patient-generated data for advanced data mining techniques, validating patient decision support systems, and expanding mHealth practice through innovative technologies.

Human gingival fibroblasts display a non-fibrotic phenotype distinct from skin fibroblasts in three-dimensional cultures.

Scar formation following skin injury can be a major psychosocial and physiological problem. However, the mechanisms of scar formation are still not completely understood. Previous studies have shown that wound healing in oral mucosa is faster, associates with a reduced inflammatory response and results to significantly reduced scar formation compared with skin wounds. In the present study, we hypothesized that oral mucosal fibroblasts from human gingiva are inherently distinct from fibroblasts from breast and abdominal skin, two areas prone to excessive scar formation, which may contribute to the preferential wound healing outcome in gingiva. To this end, we compared the phenotype of human gingival and skin fibroblasts cultured in in vivo-like three-dimensional (3D) cultures that mimic the cells' natural extracellular matrix (ECM) niche. To establish 3D cultures, five parallel fibroblast lines from human gingiva (GFBLs) and breast skin (SFBLs) were seeded in high density, and cultured for up to 21 days in serum and ascorbic acid containing medium to induce expression of wound-healing transcriptome and ECM deposition. Cell proliferation, morphology, phenotype and expression of wound healing and scar related genes were analyzed by real-time RT-PCR, Western blotting and immunocytochemical methods. The expression of a set of genes was also studied in three parallel lines of human abdominal SFBLs. Findings showed that GFBLs displayed morphologically distinct organization of the 3D cultures and proliferated faster than SFBLs. GFBLs expressed elevated levels of molecules involved in regulation of inflammation and ECM remodeling (MMPs) while SFBLs showed significantly higher expression of TGF-ß signaling, ECM and myofibroblast and cell contractility-related genes. Thus, GFBLs display an inherent phenotype conducive for fast resolution of inflammation and ECM remodeling, characteristic for scar-free wound healing, while SFBLs have a profibrotic, scar-prone phenotype.

Use of spectral domain-optical coherence tomography to visualize photoreceptor abnormalities in cone-rod dystrophy 6.

PURPOSE: The purpose of this study was to describe the spectral domain-optical coherence tomography findings in a patient with cone-rod dystrophy 6. METHODS: This is a case report of a 13-year-old girl who presented with progressive loss of vision. Fundus photography, a fluorescein angiogram, an electroretinogram, autofluorescence imaging, spectral domain-optical coherence tomography, and genetic testing were performed. RESULTS: The patient's fundi showed mild granularity of the perifoveal retinal pigment epithelium. An electroretinogram showed cone dysfunction and normal rod function. Genetic testing showed a heterozygous CGC>CAC nucleotide substitution at codon 838 of the GUCY2D gene. This results in an amino acid change of Arg838His and provides a molecular diagnosis of cone-rod dystrophy 6. The spectral domain-optical coherence tomography showed abnormalities at the inner segment/outer segment junction and the outer segment layer suggestive of loss or disease of photoreceptor outer segments. Autofluorescence imaging showed a perifoveal ring of hyperfluorescence that correlated with abnormallities on spectral domain-optical coherence tomography. CONCLUSION: Spectral domain-optical coherence tomography can show photoreceptor abnormalities that correlate with the perifoveal ring seen with autofluorescence imaging of patients with cone-rod dystrophy 6. Spectral domain-optical coherence tomography has significant potential for understanding and following the natural history of diseases such as cone-rod dystrophy 6.

Comprehensive analysis of complement factor H and LOC387715/ARMS2/HTRA1 variants with respect to phenotype in advanced age-related macular degeneration.

PURPOSE: To examine the interaction of genotypic variation of 16 single-nucleotide polymorphisms (SNP) in the complement factor H (CFH) and LOC387715/ARMS2/HTRA1 loci with clinical characteristics of age-related macular degeneration (AMD). DESIGN: Retrospective cohort study. METHODS: Eighty-four patients with neovascular AMD were genotyped using direct sequencing or Sequenom iPLEX technology. The Fisher exact test, Cochran-Mantel-Haenszel statistics, and Mann-Whitney U test were used to assess the effect of each SNP with respect to the following phenotypic manifestations: age at diagnosis, gender, affected eye, study and fellow eye visual acuity at diagnosis and at last follow-up, study eye best acuity during follow-up, presence of large drusen and retinal pigment epithelium (RPE) hyperpigmentation in study and fellow eye, choroidal neovascularization (CNV) angiographic subtype (classic vs occult), CNV size, presence of wet AMD in fellow eye, presence of dry AMD in fellow eye, and smoking history. RESULTS: Only SNPs in the LOC387715/ARMS2/HTRA1 (10q26) region were associated with disease phenotypes. The polymorphisms rs10664316 and rs1049331 were associated with a decreased risk of poor visual acuity during follow-up and at diagnosis; rs2672598 and rs2293870 were associated with a decreased risk of RPE hyperpigmentation; rs10664316 was associated with a decreased risk of RPE hyperpigmentation with large drusen in the study eye, but an increased risk of large drusen in the fellow eye; rs11200638 was associated with an increased risk of larger CNV; rs10490924 and rs11200638 were associated with younger age of diagnosis. CONCLUSIONS: Several polymorphisms examined in the LOC387715/ARMS2/HTRA1 locus, but none in the CFH region, correlated with specific phenotypic attributes of AMD.

Elevated erythropoietin and vascular endothelial growth factor levels in an adolescent with retinal neovascularization from a chronic rhegmatogenous retinal detachment.

PURPOSE: To evaluate the role of erythropoietin and vascular endothelial growth factor (VEGF) in a patient with retinal neovascularization from a rhegmatogenous retinal detachment of long duration. METHODS: Fundus photography, fluorescein angiography, and vitreous analysis were performed. The vitreous concentrations of erythropoietin and VEGF were measured by enzyme-linked immunosorbent assays and compared with control levels. RESULTS: An adolescent with a history of mild retinopathy of prematurity presented with a retinal detachment found by routine examination. The patient had a rhegmatogenous retinal detachment with signs of chronicity and extensive retinal neovascularization. The patient's erythropoietin level was higher than those of patients with proliferative diabetic retinopathy. The patient's VEGF level was not as high as those of patients with proliferative diabetic retinopathy but was elevated compared with those of patients without neovascularization. CONCLUSION: Vitreous concentrations of erythropoietin and VEGF can be elevated in patients with neovascularization secondary to a rhegmatogenous retinal detachment of long duration.

The genetics and ocular findings of Alagille syndrome.

Alagille syndrome is an autosomal dominant disorder caused by mutations in the JAG1 gene. The JAG1 gene encodes a ligand for the Notch receptor and thus is part of a critical signaling pathway during development. The ophthalmologist can play an important role in the diagnosis of Alagille syndrome by identifying the characteristic ocular findings. These include a posterior embryotoxon, optic disc drusen, angulated retinal vessels, and a pigmentary retinopathy. Despite recent advances in the genetics of Alagille syndrome, the correlations between genotypes and phenotypes remain incompletely defined.

Littoral cell angioma.

Littoral cell angioma (LCA) is an extremely rare primary splenic tumor. There are few MRI and scintigraphic characteristics described. These characteristics may be most helpful in differentiating LCA from other primary vascular tumors. We present a 54-year-old woman found on CT to have a 7-cm mass within an enlarged spleen. LCA was diagnosed by ultrasound (US)-guided biopsy. She was successfully treated with laparoscopic splenectomy. The CT, MRI, US, and Tc99m-RBC scan characteristics are described along with histologic and immunohistochemical correlation.

Constitutive and cytokine-induced GITR ligand expression on human retinal pigment epithelium and photoreceptors.

PURPOSE: The glucocorticoid-induced TNF-related receptor (GITR) plays a pivotal role in regulating the suppressive function of CD4+CD25+ regulatory T cells. GITR is also involved in the inhibition of T-cell receptor-induced apoptosis and the upregulation of inducible nitric oxide synthase (iNOS). GITR expression on CD4+ T cells has been shown to correlate with the disease course of noninfectious uveitis. The current study was conducted to examine the expression of glucocorticoid-induced TNF-related receptor ligand (GITRL) and its regulation by ocular tissue. METHODS: Immunohistochemistry and confocal immunofluorescence microscopy were performed on human ocular tissue to examine the in vivo protein expression of GITRL. The regulation of GITRL was investigated by culturing retinal pigment epithelium (RPE) with proinflammatory cytokines and performing immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR). The in vivo mRNA expression of GITRL was studied by RT-PCR on RNA from microdissected tissue sections. RESULTS: Both immunohistochemistry and confocal immunofluorescence microscopy demonstrated that GITRL was expressed constitutively on RPE and photoreceptor inner segments. Immunocytochemistry demonstrated that in vitro stimulated RPE cells expressed GITRL at the protein level, and RT-PCR showed that GITRL was upregulated at 24 hours by proinflammatory cytokines. Constitutive GITRL mRNA expression in vivo was confirmed by RT-PCR analysis of microdissected tissue. CONCLUSIONS: GITRL is expressed constitutively on RPE and in high levels on photoreceptor inner segments. The upregulation of GITRL by proinflammatory cytokines suggests that GITRL may play an important role in ocular immunity. The high level of constitutive GITRL expression on photoreceptor inner segments suggests that photoreceptors participate in the regulation of ocular inflammation.

Expression of glucocorticoid induced TNF receptor family related protein (GITR) on peripheral T cells from normal human donors and patients with non-infectious uveitis.

The expression of the glucocorticoid induced TNF receptor family related gene (GITR) in subsets of T lymphocytes from human peripheral blood was studied. In normal human peripheral blood mononuclear cells, GITR expression on the resting CD4+ T cells was low but markedly increased after activation. The percentage of GITR+ T cells in the CD4+CD25+ T cell subpopulation (15.1%) was significantly higher than that in the CD4+CD25- T cell subpopulation (5.2%, P<0.01), suggesting a preferential co-expression of GITR with CD25. In a group of patients with non-infectious uveitis, a proposed T helper cell mediated autoimmune ocular disease, the GITR expression on the CD4+ T cells in both the active patients (34.5%) and the inactive patients (19.6%) was significantly higher as compared to that in the normal donors (10.7%; P<0.01 vs. active, P<0.05 vs. inactive). This increased GITR expression in T cells was only seen in the CD4 positive T helper cell subpopulation but not in the CD4 negative T cell subpopulation. GITR expression on the CD4+ T cells decreased when the patients became clinically quiescent. Therefore, GITR is an activation marker for the CD4+ T cells and preferentially co-expressed with CD25 on the CD4+ T cells in human peripheral blood. Its expression correlates with the clinical course of non-infectious uveitis.