Immune Cells Are DifferentiallyAffected by SARS-CoV-2 Viral Loads in K18-hACE2 Mice

Viral load and the duration of viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are important determinants of the transmission of coronavirus disease 2019.In this study, we examined the effects of viral doses on the lung and spleen of K18-hACE2 transgenic mice by temporal histological and transcriptional analyses. Approximately, 1×105 plaque-forming units (PFU) of SARS-CoV-2 induced strong host responses in the lungs from 2 days post inoculation (dpi) which did not recover until the mice died, whereas responses to the virus were obvious at 5 days, recovering to the basal state by 14 dpi at 1×102 PFU. Further, flow cytometry showed that number of CD8+ T cells continuously increased in 1×102 PFU-virusinfected lungs from 2 dpi, but not in 1×105 PFU-virus-infected lungs. In spleens, responses to the virus were prominent from 2 dpi, and number of B cells was significantly decreased at 1×105PFU; however, 1×102 PFU of virus induced very weak responses from 2 dpi which recovered by 10 dpi. Although the defense responses returned to normal and the mice survived, lung histology showed evidence of fibrosis, suggesting sequelae of SARS-CoV-2 infection. Our findings indicate that specific effectors of the immune response in the lung and spleen were either increased or depleted in response to doses of SARS-CoV-2. This study demonstrated that the response of local and systemic immune effectors to a viral infection varies with viral dose, which either exacerbates the severity of the infection or accelerates its elimination.

The Risk of COVID-19 and Its Outcomes in Korean Patients With Gout: A Multicenter, Retrospective, Observational Study

This retrospective cohort study aimed to compare coronavirus disease 2019 (COVID-19)-related clinical outcomes between patients with and without gout. Electronic health recordbased data from two centers (Seoul National University Hospital [SNUH] and Boramae Medical Center [BMC]), from January 2021 to April 2022, were mapped to a common data model. Patients with and without gout were matched using a large-scale propensityscore algorithm based on population-level estimation methods. At the SNUH, the risk for COVID-19 diagnosis was not significantly different between patients with and without gout (hazard ratio [HR], 1.07; 95% confidence interval [CI], 0.59–1.84). Within 30 days after COVID-19 diagnosis, no significant difference was observed in terms of hospitalization (HR, 0.57; 95% CI, 0.03–3.90), severe outcomes (HR, 2.90; 95% CI, 0.54–13.71), or mortality (HR, 1.35; 95% CI, 0.06–16.24). Similar results were obtained from the BMC database, suggesting that gout does not increase the risk for COVID-19 diagnosis or severe outcomes.

Successful treatment of hemophagocytic lymphohistiocytosis in a patient with systemic lupus erythematosus with ruxolitinib: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hematological disorder characterized by uncontrolled activation of CD8+ T and natural killer cells, leading to a cytokine storm and severe organ dysfunction. Although secondary HLH related to autoimmune diseases usually demonstrates a good treatment response to immunosuppressive therapy for underlying conditions, there is no consensus regarding the treatment in case of unresponsiveness to the treatment. Herein, we present a case of HLH that was unresponsive to high-dose glucocorticoid and cyclosporine treatment in a patient with newly diagnosed systemic lupus erythematosus. The patient’s clinical features and laboratory abnormalities rapidly improved with ruxolitinib, an oral Janus kinase 1 and 2 (JAK1/2) inhibitor. This result suggests that blocking JAK-STAT pathway may be a potential treatment option in patients with refractory HLH secondary to autoimmune diseases.

Clinical characteristics and courses of Korean patients with giant cell arteritis: a multi-center retrospective study

Objective@#Giant cell arteritis (GCA) is a large-vessel vasculitis that primarily affects elderly individuals. However, data regarding Korean patients with GCA are scarce owing to its extremely low prevalence in East Asia. This study aimed to investigate the clinical characteristics of Korean patients with GCA and their outcomes, focusing on relapse. @*Methods@#The medical records of 27 patients with GCA treated at three tertiary hospitals between 2007 and 2022 were retrospectively reviewed. @*Results@#Seventeen (63.0%) patients were females, and the median age at diagnosis was 75 years. Large vessel involvement (LVI) was detected in 12 (44.4%) patients, and polymyalgia rheumatica (PMR) was present in 14 (51.9%) patients. Twelve (44.4%) patients had fever at onset. The presence of LVI or concurrent PMR at diagnosis was associated with a longer time to normalization of the C-reactive protein level (p=0.039) or erythrocyte sedimentation rate (p=0.034). During follow-up (median: 33.8 months), four (14.8%) patients experienced relapse. Kaplan-Meier analyses showed that relapse was associated with visual loss (p=0.008) and the absence of fever (p=0.004) at onset, but not with LVI or concurrent PMR. @*Conclusion@#Concurrent PMR and LVI were observed in approximately half of Korean patients with GCA, and the elapsed time to normalization of inflammatory markers in these patients was longer. The relapse rate in Korean GCA is lower than that in Western countries, and afebrile patients or patients with vision loss at onset have a higher risk of relapse, suggesting that physicians should carefully monitor patients with these characteristics.

Treatment Sequence After Initiating Biologic Therapy for Patients With Rheumatoid Arthritis in Korea: A Nationwide Retrospective Cohort Study

Objective@#To evaluate treatment patterns and healthcare resource utilization (HCRU) after initiating biologic disease-modifying antirheumatic drugs (bDMARDs) in Korean patients with rheumatoid arthritis (RA). @*Methods@#Patients newly diagnosed with RA in 2014 were identified and followed up on using the Korean National Health Insurance Database until 2018. The initial line of therapy (LOT) or LOT1 included patients treated with conventional DMARDs (cDMARD). Patients who started a bDMARD were assigned to LOT2 bDMARD. Those who moved from a bDMARD to a Janus kinase inhibitor were assigned to LOT3. Analyzed outcomes were treatment patterns and HCRU in LOT2 bDMARD. @*Results@#The most prescribed initial bDMARD was a tumor necrosis factor inhibitor. Seventy-five percent of patients had changes in treatment after starting a bDMARD, such as addition/removal or switch of a DMARD, and transition to LOT3. For the first and second changes in LOT2 bDMARD, adding a cDMARD to a bDMARD was more common than switching to another bDMARD (7.98% vs. 2.93% for the first change, and 17.10% vs. 6.51% for the second change). Tocilizumab was the most common bDMARD that was switched to. Forty-eight percent of patients had at least one hospitalization after initiating bDMARDs. Of these patients, 64.3% were admitted due to RA-related reasons. @*Conclusion@#This real-world study provides information on treatment characteristics of RA patients in Korea after starting a bDMARD. In contrary to guidelines, cDMARD addition was more often than bDMARD switches in daily clinical practice.

Concomitant ankylosing spondylitis can increase the risk of biologics or small molecule therapies to control inflammatory bowel disease

Background/Aims@#Patients with inflammatory bowel disease (IBD) are diagnosed with ankylosing spondylitis (AS) often. However, the disease course of patients with both IBD and AS is not well understood. This study aims to evaluate the effect of concomitant AS on IBD outcomes. @*Methods@#Among the 4,722 patients with IBD who were treated in 3 academic hospitals from 2004 to 2021, 55 were also diagnosed with AS (IBD-AS group). Based on patients’ electronic medical records, the outcomes of IBD in IBD-AS group and IBD group without AS (IBD-only group) were appraised. @*Results@#The proportion of patients treated with biologics or small molecule therapies was significantly higher in IBD-AS group than the proportion in IBD-only group (27.3% vs. 12.7%, P= 0.036). Patients with both ulcerative colitis and AS had a significantly higher risk of biologics or small molecule therapies than patients with only ulcerative colitis (P< 0.001). For univariable logistic regression, biologics or small molecule therapies were associated with concomitant AS (odds ratio, 4.099; 95% confidence interval, 1.863–9.021; P< 0.001) and Crohn’s disease (odds ratio, 3.552; 95% confidence interval, 1.590–7.934; P= 0.002). @*Conclusions@#Concomitant AS is associated with the high possibility of biologics or small molecule therapies for IBD. IBD patients who also had AS may need more careful examination and active treatment to alleviate the severity of IBD.

Korean treatment recommendations for patients with axial spondyloarthritis

We aimed to develop evidence-based recommendations for treating axial spondylarthritis (axSpA) in Korea. The development committee was constructed, key clinical questions were determined, and the evidence was searched through online databases including MEDLINE, Embase, Cochrane, KoreaMed, and KMbase. Systematic literature reviews were conducted, quality of evidence was determined, and draft recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluations methodology. Recommendations that reached 80% consensus among a voting panel were finalized. Three principles and 21 recommendations were determined. Recommendations 1 and 2 pertain to treatment strategies, regular disease status assessment, and rheumatologist-steered multidisciplinary management. Recommendations 3 and 4 strongly recommend patient education, exercise, and smoking cessation. Recommendations 5~12 address pharmacological treatment of active disease using nonsteroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, biologics, and Janus kinase inhibitors.Recommendations 13~16 address treatment in stable disease. We suggest against spa and acupuncture as therapies (Recommendation 17). Recommendations 18 and 19 pertain to total hip arthroplasty and spinal surgery. Monitoring of comorbidities and drug toxicities are recommended (Recommendations 20 and 21). Recommendations for axSpA treatment in a Korean context were developed based on comprehensive clinical questions and evidence. These are intended to guide best practice in the treatment of axSpA.

SARS‑CoV‑2 Omicron variant causes brain infection with lymphoid depletion in a mouse COVID‑19 model / 한국실험동물학회지

Background@#The Omicron variant has become the most prevalent SARS-CoV-2 variant. Omicron is known to induce milder lesions compared to the original Wuhan strain. Fatal infection of the Wuhan strain into the brain has been well documented in COVID-19 mouse models and human COVID-19 cases, but apparent infections into the brain by Omicron have not been reported in human adult cases or animal models. In this study, we investigated whether Omicron could spread to the brain using K18-hACE2 mice susceptible to SARS-CoV-2 infection. @*Results@#K18-hACE2 mice were intranasally infected with 1 × 105 PFU of the original Wuhan strain and the Omicron variant of SARS-CoV-2. A follow-up was conducted 7 days post infection. All Wuhan-infected mice showed > 20% body weight loss, defined as the lethal condition, whereas two out of five Omicron-infected mice (40%) lost > 20% body weight. Histopathological analysis based on H&E staining revealed inflammatory responses in the brains of these two Omicron-infected mice. Immunostaining analysis of viral nucleocapsid protein revealed severe infection of neuron cells in the brains of these two Omicron-infected mice. Lymphoid depletion and apoptosis were observed in the spleen of Omicron-infected mice with brain infection. @*Conclusion@#Lethal conditions, such as severe body weight loss and encephalopathy, can occur in Omicron-infected K18-hACE2 mice. Our study reports, for the first time, that Omicron can induce brain infection with lymphoid depletion in the mouse COVID-19 model.

Korean treatment recommendations for patients with axial spondyloarthritis

We aimed to develop evidence-based recommendations for treating axial spondylarthritis (axSpA) in Korea. The development committee was constructed, key clinical questions were determined, and the evidence was searched through online databases including MEDLINE, Embase, Cochrane, KoreaMed, and Kmbase. Systematic literature reviews were conducted, quality of evidence was determined, and draft recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluations methodology. Recommendations that reached 80% consensus among a voting panel were finalized. Three principles and 21 recommendations were determined. Recommendations 1 and 2 pertain to treatment strategies, regular disease status assessment, and rheumatologist-steered multidisciplinary management. Recommendations 3 and 4 strongly recommend patient education, exercise, and smoking cessation. Recommendations 5–12 address pharmacological treatment of active disease using nonsteroidal anti-inflammatory drugs, glucocorticoids, sulfasalazine, biologics, and Janus kinase inhibitors. Recommendations 13–16 address treatment in stable disease. We suggest against spa and acupuncture as therapies (Recommendation 17). Recommendations 18 and 19 pertain to total hip arthroplasty and spinal surgery. Monitoring of comorbidities and drug toxicities are recommended (Recommendations 20 and 21). Recommendations for axSpA treatment in a Korean context were developed based on comprehensive clinical questions and evidence. These are intended to guide best practice in the treatment of axSpA.

Laboratory information management system for COVID-19 non-clinical efficacy trial data / 한국실험동물학회지

Background@#As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. @*Results@#In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. @*Conclusions@#This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

Practical Utility of D-dimer Test for Venous Thromboembolism in Systemic Lupus Erythematosus Depends on Disease Activity: a Retrospective Cohort Study

Background@#The D-dimer test is a screening tool for venous thromboembolism (VTE);however, its utility for patients with systemic lupus erythematosus (SLE) remains unclear.Here, we examined the utility of the D-dimer test as a screening tool for VTE in SLE patients. @*Methods@#SLE patients (n = 276) and age- and sex-matched patients with non-rheumatic disease (n = 1,104), all of whom underwent D-dimer testing to screen for VTE, were enrolled.The sensitivity and specificity and receiver operating characteristics curve of the D-dimer test were compared in both groups. Then, subgroup of SLE patients in whom the D-dimer test can be useful was sought. @*Results@#The incidence of VTE was more common in SLE patients than controls (10.9% vs.4.0%). Although the sensitivity of the D-dimer test was comparable between SLE patients and controls (93.3% vs. 90.9%), the specificity of the test was profoundly lower in SLE patients compared to controls (28.4% vs. 84.4%). The area under the curve (AUC) of the D-dimer for VTE was 0.669 in SLE patients and 0.90 in control group. Multiple linear regression analysis demonstrated that SLE disease activity index-2000 (SLEDAI-2K) was significantly associated with D-dimer levels in SLE patients (β = 0.155; P = 0.022). Subgroup analysis showed that the AUC is moderate (0.768) with low disease activity, while it is low (0.518) with high SLEDAI-2K. @*Conclusion@#The D-dimer test may not be a useful screening tool for VTE in patients with active SLE. D-dimer test for predicting VTE in SLE patients should be differentially applied according to disease activity of SLE.

Erratum: Endoscopic Features of Upper Gastrointestinal Tract in Patients with Systemic Sclerosis Compared to the Healthy Control

The original version of this article contained an error of the acknowledgement (funding source).

Endoscopic Features of Upper Gastrointestinal Tract in Patients with Systemic Sclerosis Compared to the Healthy Control

OBJECTIVE: To characterize the endoscopic features of upper gastrointestinal tract in patients with systemic sclerosis (SSc) compared with those in the healthy controls. METHODS: Data on esophagogastroduodenoscopy (EGD) in 180 patients with SSc (SSc group) were compared with that from the 181 age- and sex-matched healthy control who underwent EGD for routine check-up (control group). Clinical data of participants at the time of EGD (defined as baseline) were collected from electric medical record. Endoscopic findings were evaluated by two experts with blinded to their clinical features. Primary outcome of the study was prevalence of each endoscopic lesion between the two groups. RESULTS: The mean±standard deviation age and disease duration in the SSc group at baseline were 55.3±11.8 and 2.9±3.7 years, respectively. Compared to the control group, SSc group more frequently showed reflux esophagitis (32.8% vs. 9.4%, p < 0.001). In contrast, prevalence of atrophic gastritis was significantly lower in the SSc group (8.3% vs. 29.3%, p < 0.001). This result was consistent in the multivariable analysis where patients' age and concomitant proton pump inhibitor use were adjusted. There was no case of gastric antral vascular ectasia (GAVE) in both groups. However, 29 (16.1%) patients in SSc group showed a clinically significant anemia (hemoglobin < 10 mg/dL), with none of the endoscopic features showed significant associations with the outcome. CONCLUSION: Patients with SSc showed significantly lower prevalence of atrophic gastritis. There was no case of GAVE, which suggests that clinical phenotype of the SSc could be different according to the ethnicity or geographic region.

Clinical factors and treatment outcomes associated with failure in the detection of urate crystal in patients with acute gouty arthritis

BACKGROUND/AIMS: To investigate the rate of detection of monosodium urate (MSU) crystals in the synovial fluid (SF) of patients with acute gouty arthritis and factors associated with false-negative results. METHODS: A total of 179 patients with acute gouty arthritis who had undergone SF crystal examination were identified from the data warehouse of two university hospitals. Clinical and laboratory data were obtained from the medical records. RESULTS: The overall rate of detection of MSU crystals was 78.8%. In univariate analyses, the only significant differences between the variables of crystal-negative and crystal-positive patients were a lower C-reactive protein level (p = 0.040) and fewer patients undergoing emergent surgery in the crystal-positive group (p = 4.5 x 10(-6)). In logistic regression analyses, MSU crystal-negative results were significantly associated with the interval from arthritis onset to crystal examination (p = 0.042), and this was the most significant risk factor for arthroscopic surgery (p = 2.1 x 10(-4)). Seventeen patients who underwent arthroscopic surgery had a significantly longer hospital stay (p = 0.007) and a significant delay in gout treatment (p = 8.74 x 10(-5)). The distribution of crystal-negative patients differed significantly between the SF samples that were evaluated by both the laboratory medicine and the rheumatology departments (p = 1.2 x 10(-14)), and the kappa value was 0.108. CONCLUSIONS: Although several clinical features were associated with detection failure, SF MSU crystal identification was critically dependent on the observer. Considering the impact on the treatment outcomes, implementation of a quality control program is essential.

A Case of Relapsing Polychondritis Improved by Infliximab Treatment

Relapsing polychondritis is an episodic, systemic inflammation of the cartilage with unknown autoimmune etiology. It leads to the destruction of cartilaginous structures of the ear, eye, nose, respiratory tract, joints, skin, and heart valve, and its presented symptoms are diverse. It can be improved mainly by corticosteroid or immunosuppressive agents. Recently, the use of biologic agents (TNF inhibitors, rituximab, tocilizumab et al) was reported from abroad. However, there is no reported case of relapsing polychondritis, which is treated by biologic agents in Korea. We report this first case of refractory relapsing polychondritis, which was improved with a treatment of Infliximab.

Preclinical Efficacy Testing for Stomach and Liver Cancers / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Hollow fiber assays offer an early in vivo method of anticancer drug screening. The assays have been optimized for human cancers originating from the lung, breast, colon, ovary, and brain, but not from the stomach and liver. The current study focused on optimization of hollow fiber assays for gastric and hepatocellular carcinoma cell lines. MATERIALS AND METHODS: Gastric (SNU-16, SNU-484, SNU-668) and hepatocellular (HepG2, SK-Hep-1, Hep3B) carcinoma cell lines in hollow fibers were transplanted subcutaneously and intraperitoneally into mice, which were subsequently treated with a standard anticancer agent, paclitaxel. The hollow fiber activity of paclitaxel in each cell line was compared with the xenograft activity. RESULTS: Using optimized inoculation densities and schedules, treatment with paclitaxel was effective in gastric carcinoma cell lines, SNU-16 and SNU-484, but not in SNU-668. In the hollow fiber assays, paclitaxel was effective in hepatocellular carcinoma cell lines, HepG2 and SK-Hep-1, but not in Hep3B. Consistent with the results of the hollow fiber assay, SNU-16 and SNU-484, but not SNU-668, showed tumor regression, and HepG2 and SK-Hep-1, but not Hep3B, showed effective tumor responses following treatment with paclitaxel in xenograft models. When EW7197, a novel compound, and flavopiridol were tested in SNU-16 cells under optimized conditions, the hollow fiber activity showed good correlation with the xenograft activity of each compound. CONCLUSION: Our protocols may be useful for screening candidate small molecules that may exhibit activity against stomach and liver cancers, both of which are common in Korea.

Treatment with Rituximab in a Patient with Refractory Felty Syndrome and Low Rheumatoid Arthritis Disease Activity: A Case Report

Felty syndrome (FS) is a rare manifestation in rheumatoid arthritis (RA) characterized by neutropenia and splenomegaly. Treatment for FS is not well established because there has been no randomized controlled study. A few recent reports found rituximab effective in patients with refractory FS. According to those reports, most patients with RA and FS had active arthritis. Here we report a case of a patient with glucocorticoid dependent and disease-modifying anti-rheumatic drugs (DMARDs) refractory FS and quiescent RA who was successfully treated with rituximab.

Rituximab Treatment for the Patients with Refractory Inflammatory Myopathy

OBJECTIVE: To assess the efficacy and safety of rituximab (RTX) on disease activity and muscle strength in patients with inflammatory myopathies refractory to conventional therapy. METHODS: Four inflammatory myopathy patients who had been refractory to glucocorticoids, one or more immunosuppressive therapies and intravenous immunoglobulin were treated on an open-label basis. Each patient received two 500 mg doses of RTX 2 weeks apart in one cycle. In one patient who did not respond after the first cycle of RTX, the infusion schedule was modified by the physician. We measured muscle enzyme including CPK, LDH and assessed muscle strength individually to evaluate RTX response. Additionally anti-CD19 antibody was measured. RESULTS: Three patients responded to the first cycle of RTX treatment with improvements in muscle enzyme and muscle strength, and then maintained physical function over the duration of several infusion cycles. In one patient, muscle enzyme did not decrease after the first cycle of RTX, and a high dose glucocorticoid was given. After modifying the treatment schedule with monthly RTX infusion, his muscle enzyme level and muscle strength improved. Anti-CD19 antibody decreased after RTX generally, but responses were variable. Herpes zoster infection occurred in two patients. CONCLUSION: Rituximab may be a therapeutic choice in refractory inflammatory myopathy. However a further trial is needed to confirm the efficacy and prove the safety.

A Case of Pneumatosis Cystoides Intestinalis in a Patient with Systemic Lupus Erythematosus / 대한내과학회지

Pneumatosis cystoides intestinalis, which is characterized by multiple air-filled cysts in the intestinal mucosa, submucosa, and subserosa, is associated with autoimmune disorders, including systemic sclerosis, inflammatory myopathy and, rarely, systemic lupus erythematosus (SLE). Here, we report the case of a 57-year-old female with a 2-year history of SLE who developed pneumatosis cystoides intestinalis. The patient's symptoms were improved with conservative management. Although pneumatosis cystoides intestinalis is an uncommon manifestation of SLE, and follows a mainly benign course, it can be associated with vasculitis, which has a poor prognosis.

Altered Expression of Metabotropic Glutamate Receptors mGluR1, mGluR5, and mGluR2/3 in the Diabetic Rat Retina / 대한해부학회지

An excitatory neurotransmitter glutamate is engaged in slow transmission by activating the secondary signal transduction pathway through metabotropic receptors of the target cells. The present study has been investigated the localization of group I (mGluR1 and mGluR5) and II (mGluR2/3) metabotropic glutamate receptors in the retina and their altered expression patterns following long-term diabetes using immunohistochemistry, in order to clarify the involvement of the slow transmission of glutamate in diabetic retinopathy. Insulin-dependent diabetes was induced by a single intravenous injection of streptozotocin. Experimental periods were set at 1, 4, 12 and 24 weeks after the onset of diabetes. MGluR1 and mGluR5 were expressed in the outer plexiform layer, 1, 3, and 5 strata of the inner plexiform layer, and the photoreceptor layer in the retina at normal state. In the early periods of diabetes, the expression pattern of group I receptors was no large change. The expression level in the photoreceptor layer of 12 and 24 weeks diabetic retinas was increased, while that in the IPL was decreased. MGluR2/3 was expressed in the amacrine cells, in the displaced amacrine cells, and in two bands in the inner plexiform layer at normal retina. In later diabetic periods, the expression level of mGluR2/3 was increased in the two bands especially. These results demonstrate that diabetes induces the activation of I and II mGluRs in the retina, and may suggest the involvement of slow transmission of glutamate via metabotropic receptors in progression of diabetic retinopathy.