The Intraocular Pressure-Lowering Effect of Persimmon leaves (Diospyros kaki) in a Mouse Model of Glaucoma.

The aim of this study was to evaluate the pharmacological efficacy of persimmon leaves in two glaucoma models, microbeads-induced ocular hypertension (OHT) and DBA/2 mouse. Thus, we demonstrated that Ethanol Extract of Diospyros kaki (EEDK) reduced elevated intraocular pressure (IOP) in both mouse models of glaucoma by measurements with a tonometer. In particular, we revealed that retinal ganglion cell loss and optic nerve damage caused by IOP elevation were markedly diminished as assessed by TUNEL assay, H&E staining, and fluorescent staining, while the expression of soluble guanylate cyclase (sGCα-1) increased, when EEDK was administered, as revealed by western blot. Moreover, the b-wave magnitude indicating functional scotopic vision was significantly improved in EEDK-administered DBA/2 mice during the 10-week follow-up study, as observed with electroretinography. Collectively, our results suggested that EEDK could be an effective therapeutic and IOP-lowering agent for preventing and treating retinal degenerative diseases such as glaucoma.

ASK1/JNK-mediated TAp63 activation controls the cell survival signal of baicalein-treated EBV-transformed B cells.

Transcriptionally active p63 (TAp63) promotes cell cycle arrest, senescence, and apoptosis in several cancer cells. Migration inhibitory factor (MIF)/CD74 regulates B-cell survival through nuclear factor (NF)-κB-dependent TAp63 expression. In this study, we investigated how the level of TAp63 expression influences the induction of apoptosis in baicalein-treated EBV-transformed B cells. Baicalein induced the expression of TAp63 and apoptosis signal-regulating kinase 1 (ASK1), as well as cytotoxicity, by disrupting the mitochondrial membrane and inhibiting the activation of phosphoinositide 3-kinase (PI3K)/Akt and NF-κB. Genetic knockdown of TAp63 or ASK1 by small interfering RNA resulted in protection from apoptosis accompanied by the recovery of CD74, CD44, α4 integrin, Bcl-2, and NF-κB activation. Baicalein-induced reactive oxygen species activated the ASK1/JNK pathway with subsequent expression of TAp63. Pre-engagement with MIF/CD74 maintained the expression of CD74, CD44, and α4 integrin, as well as Syk/Src-mediated PI3K/Akt activation, in baicalein-treated EBV-transformed B cells. Meanwhile, ASK1/JNK-dependent TAp63 expression was efficiently suppressed after pre-treatment with MIF. Our results suggest that baicalein-mediated ASK1/JNK activation regulates the mitochondria-dependent apoptosis pathway through the up-regulation of TAp63 and down-regulation of NF-κB and CD74/CD44 in B-cell malignancies.

TLR3/TRIF signalling pathway regulates IL-32 and IFN-ß secretion through activation of RIP-1 and TRAF in the human cornea.

Toll-like receptor-3 (TLR3) and RNA helicase retinoic-acid-inducible protein-1 (RIG-I) serve as cytoplasmic sensors for viral RNA components. In this study, we investigated how the TLR3 and RIG-I signalling pathway was stimulated by viral infection to produce interleukin (IL)-32-mediated pro-inflammatory cytokines and type I interferon in the corneal epithelium using Epstein-Barr virus (EBV)-infected human cornea epithelial cells (HCECs/EBV) as a model of viral keratitis. Increased TLR3 and RIG-I that are responded to EBV-encoded RNA 1 and 2 (EBER1 and EBER2) induced the secretion of IL-32-mediated pro-inflammatory cytokines and IFN-ß through up-regulation of TRIF/TRAF family proteins or RIP-1. TRIF silencing or TLR3 inhibitors more efficiently inhibited sequential phosphorylation of TAK1, TBK1, NF-κB and IRFs to produce pro-inflammatory cytokines and IFN-ß than RIG-I-siRNA transfection in HCECs/EBV. Blockade of RIP-1, which connects the TLR3 and RIG-I pathways, significantly blocked the TLR3/TRIF-mediated and RIG-I-mediated pro-inflammatory cytokines and IFN-ß production in HCECs/EBV. These findings demonstrate that TLR3/TRIF-dependent signalling pathway against viral RNA might be a main target to control inflammation and anti-viral responses in the ocular surface.

Effects of chondrocyte-derived extracellular matrix in a dry eye mouse model.

PURPOSE: The occurrence of repetitive dry eye is accompanied by inflammation. This study investigated the anti-inflammatory effects of chondrocyte-derived extracellular matrix (CDECM) on the cornea and conjunctiva in a dry eye mouse model. METHODS: Dry eyes were experimentally induced in 12- to 16-week-old NOD.B10.H2(b) mice (Control) via subcutaneous injections of scopolamine (muscarinic receptor blocker) and exposure to an air draft for 10 days (desiccation stress [DS] 10D group). Tear volume and corneal smoothness were measured at 3, 5, 7, and 10 days after the instillation of PBS (PBS group) or CDECM (CDECM group). The corneas and conjunctivas were sectioned and stained with hematoxylin and eosin (H&E) and periodic acid Schiff (PAS). The expression of inflammatory markers (i.e., tumor necrosis factor-α [TNF-α], matrix metalloproteinase-2 [MMP-2], MMP-9, intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion molecule-1 [VCAM-1]) was detected by quantitative real-time (qRT)-PCR and western blotting. All data were statistically processed using SPSS version 18.0. RESULTS: The instillation of CDECM after the removal of the DS increased tear production by up to 3.0-fold, and corneal smoothness improved to 80% compared to the PBS group (p<0.05). In the CDECM group, the detachment of the corneal epithelial cells was reduced by 73.3% compared to the PBS group, and the conjunctival goblet cell density was significantly recovered to the control levels (p<0.05). The expression of inflammatory factors was decreased in the cornea and conjunctiva of the CDECM group compared to the PBS group. CONCLUSIONS: These observations suggest that CDECM induced effective anti-inflammatory improvements in the cornea and conjunctiva in this experimental model of dry eye.

Caffeic acid phenethyl ester lessens disease symptoms in an experimental autoimmune uveoretinitis mouse model.

Experimental autoimmune uveoretinitis (EAU) is an autoimmune disease that models human uveitis. Caffeic acid phenethyl ester (CAPE), a phenolic compound isolated from propolis, possesses anti-inflammatory and immunomodulatory properties. CAPE demonstrates therapeutic potential in several animal disease models through its ability to inhibit NF-κB activity. To evaluate these therapeutic effects in EAU, we administered CAPE in a model of EAU that develops after immunization with interphotoreceptor retinal-binding protein (IRBP) in B10.RIII and C57BL/6 mice. Importantly, we found that CAPE lessened the severity of EAU symptoms in both mouse strains. Notably, treated mice exhibited a decrease in the ocular infiltration of immune cell populations into the retina; reduced TNF-α, IL-6, and IFN-γ serum levels: and inhibited TNF-α mRNA expression in retinal tissues. Although CAPE failed to inhibit IRBP-specific T cell proliferation, it was sufficient to suppress cytokine, chemokine, and IRBP-specific antibody production. In addition, retinal tissues isolated from CAPE-treated EAU mice revealed a decrease in NF-κB p65 and phospho-IκBα. The data identify CAPE as a potential therapeutic agent for autoimmune uveitis that acts by inhibiting cellular infiltration into the retina, reducing the levels of pro-inflammatory cytokines, chemokine, and IRBP-specific antibody and blocking NF-κB pathway activation.

Inhibitory effects of the platelet-activating factor receptor antagonists, CV-3988 and Ginkgolide B, on alkali burn-induced corneal neovascularization.

PURPOSE: Platelet-activating factor (PAF) has been found in various ocular tissues; the activity of PAF depends on the binding to its specific receptor, PAF-receptor. We investigated the therapeutic effects of PAF-receptor antagonists (CV-3988 and Ginkgolide B) on alkali burn-induced corneal neovascularization (CNV). METHODS: CNV was induced by applying a 0.2 N sodium hydroxide (3 µl, NaOH) solution directly on mice corneas. CV-3988 (1 mM/10 µl) and Ginkgolide B (1 mM/10 µl) were administered topically on the corneas three times daily for three consecutive days. CNV was evaluated under a slit-lamp microscope. Corneas were processed for histological, immunohistochemical and reverse transcription polymerase chain reaction analysis. Human umbilical vein endothelial cells were used for the migration and tube formation assay. RESULTS: Application of CV-3988 and Ginkgolide B inhibited CNV caused by alkali burn. CV-3988 and Ginkgolide B attenuated the expression of PAF-receptor mRNA. Alkali injury induced a massively increased intraocular mRNA expression of an angiogenic factor in cornea tissues, whereas these increments were attenuated by the application of CV-3988 and Ginkgolide B. CONCLUSIONS: CV-3988 and Ginkgolide B reversed opacity and neovascularization in alkali burn-induced corneas. Our findings suggest that CV-3988 and Ginkgolide B may be therapeutically useful in the treatment of CNV and inflammation.

Effect of porcine chondrocyte-derived extracellular matrix on the pterygium in mouse model.

PURPOSE: To investigate the effect of porcine chondrocyte-derived extracellular matrix (PCDECM) on an experimental mouse model of human pterygial epithelial cells. METHODS: Cultured human pterygial epithelial cells (hPECs) were stained with pan-cytokeratin (CK), CK3/2p, vimentin, and CK13 antibodies to characterize the cells. A pterygium mouse model was developed by injecting 1X104 hPECs into the nasal subconjunctival space in athymic nude mice. PCDECM (25 mg/mL, 10 µL) was injected into the nasal subconjunctival space in the right eye 7, 10 and 14 days after the epithelial cell injection (PCDECM group). Image analysis was performed using ImageJ® to compare the lesion size. A histopathological analysis of the cornea was conducted to evaluate the state of the epithelium and the expression of pterygial epithelial cell markers. RESULTS: The isolated pterygial cells were positive for pan-CK, CK3/2p and vimentin, and they were negative for CK13 under immunofluorescence microscopy. On day 17 after epithelial cell injection, the size of the lesion compared to the entire cornea was increased to 37.1 % in the control group. However, in the PCDECM group, the lesion covered only 26.3 % of the entire cornea. The corneas of the pterygium mice showed an epithelium of irregular thickness, proliferation of the stroma, extracellular matrix breakdown and overexpression of pterygium-positive markers. However, these changes were significantly suppressed by the application of PCDEDM. CONCLUSIONS: Our findings suggest that PCDECM seems to suppress pterygial epithelial cell growth and it could be used as a promising biomaterial for the noninvasive treatment of pterygium.

Anti-neovascular effect of chondrocyte-derived extracellular matrix on corneal alkaline burns in rabbits.

PURPOSE: We investigated the effect of a chondrocyte-derived extracellular matrix (CDECM) on experimental corneal alkaline burns in rabbits. METHODS: Corneal neovascularization (NV) was induced by applying an 8-mm filter paper soaked in 1 N NaOH to the right central corneas of rabbits for 1 minute. Ten days later, the rabbits were randomly divided into three groups: the alkaline burn group, the CDECM transplantation group, and the human amniotic membrane (HAM) transplantation group. The left eyes were used as controls. CDECM and HAM were transplanted onto the corneal surface to completely cover the resected area and were subsequently sutured. On the 10th day after transplantation, the structural changes of the cornea were analyzed histologically. We examined the effects of CDECM on clinical NV features and on the expression of corneal NV markers. RESULTS: The alkaline burn produced significant NV and increased the corneal thickness. On day 10 after transplantation, the thickness, NV and opacity of the cornea were markedly decreased in the CDECM group (p < 0.001). However, the HAM transplantation group did not exhibit improvements in these clinical parameters, and there were no significant differences relative to the burn group. In addition, the use of CDECM improved the healing of the cornea following the alkaline burn by disrupting the corneal epithelial proliferation and reducing the fibrotic changes of the stroma. The hallmarks of NV were significantly induced in the subepithelium by the alkaline burn, and these levels were also suppressed by CDECM. The CDECM suppressed corneal NV by inhibiting nuclear factor-kappa B (NF-κB) activation by blocking the PKC and Akt signaling pathways. CONCLUSIONS: CDECM transplantation was markedly effective in healing alkali-burned corneas by modulating the translocation of NF-κB to the nucleus, thereby representing a promising material for the noninvasive treatment of ocular surface disease.

MiR-9 regulates the post-transcriptional level of VEGF165a by targeting SRPK-1 in ARPE-19 cells.

PURPOSE: To investigate the effect of the overexpression of miRNA-9 to the ratio of pro- and anti-angiogenic isoforms of vascular endothelial growth factor (VEGF) in human retinal pigment cells (ARPE-19). METHODS: Oxidative stress was induced to ARPE-19 cells by 4-hydroxynonenal (4-HNE), tert-butyl hydroperoxide (t-BH), and hypoxia chamber with 1% O2. Expression patterns of miRNAs were validated by qPCR. Relative mRNA levels of VEGF and PEDF were measured by semi-quantitative PCR. After the transfection of miR-9 mimic and inhibitor, transcriptional levels of VEGF165a, VEGF 165b, and SRPK-1 were measured by qPCR. RESULTS: We demonstrated that miR-9 expression is decreased in ARPE-19 human retinal pigment cells under hypoxic stress induced by 4-HNE, a lipid peroxidation end-product. We observed that miR-9 mimic transfection of ARPE-19 inhibited one of its targets, serine-arginine protein kinase-1 (SRPK-1), modulating the transcriptional level of VEGF165b. Transfection of miR-9 reduced the alternative splicing of VEGF165a mRNA in ARPE-19 cells under hypoxic conditions, suggesting that miR-mediated regulation of alternative splicing could be a potential therapeutic target in neovascular pathologies. CONCLUSIONS: Hypoxic stress decreased the miR-9 level in ARPE-19 cells, which increased the transcriptional level of SRPK-1, resulting in alternative splicing shift to pro-angiogenic isoforms of VEGF165 in human retinal pigment epithelial cells.

Caffeic acid phenethyl ester inhibits the inflammatory effects of interleukin-1ß in human corneal fibroblasts.

CONTEXT: Expression of various inflammatory mediators in corneal fibroblasts contributes to corneal inflammation. OBJECTIVE: The purpose of this study was to assess the possible effects of caffeic acid phenethyl ester (CAPE) on the expression of inflammatory mediators during an inflammatory response in human corneal fibroblasts. MATERIALS AND METHODS: The levels of interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule-1 (ICAM-1) from IL-1ß-exposed human corneal fibroblasts were measured with enzyme-linked immunosorbent assays (ELISA). The regulatory mechanisms of CAPE on cellular signaling pathways were examined using Western blot and electrophoretic mobility shift assays. A functional validation was carried out by evaluating the inhibitory effects of CAPE on neutrophil and monocyte migration in vitro. RESULTS: CAPE inhibited the expression of IL-6, MCP-1 and ICAM-1 induced by the pro-inflammatory cytokine IL-1ß in corneal fibroblasts. The activation of AKT and NF-κB by IL-1ß was markedly inhibited by CAPE, whereas the activity of mitogen-activated protein kinases (MAPKs) was not affected. CAPE significantly suppressed the IL-1ß-induced migration of differentiated (d)HL-60 and THP-1 cells. DISCUSSION: These anti-inflammatory effects of CAPE may be expected to inhibit the infiltration of leukocytes into the corneal stroma in vivo.

The transconjunctival approach a minimally invasive approach to various kinds of retrobulbar tumors.

PURPOSE: Orbital tumors, particularly those within the retrobulbar space, were approached by maxillofacial, ophthalmic, and neurological surgeons. Less traumatic approaches in this functionally and cosmetically important region are desirable. We describe another method to remove orbital tumor in the retrobulbar space by a transconjunctival approach with lateral canthotomy and transient extraocular muscle severing without lateral orbitotomy. METHODS: We report 5 retrobulbar tumors operated with a transconjunctival approach, 2 of which were intraconal. Contrast-enhanced computed tomography and magnetic resonance imaging scans were used to determine precise location of the retrobulbar tumor. RESULTS: Retrobulbar tumors could be removed successfully through a transconjunctival approach. Three pleomorphic adenomas, 1 carvenous hemangioma, and 1 pseudotumor were the pathologic findings encountered. These patients were free from visible scars, proptosis, and any other noticeable complications at last follow-up, 6 months after surgery. CONCLUSIONS: The transconjunctival approach, which involves lateral canthotomy and transient extraocular muscle severing without lateral orbitotomy, is an unconventional procedure for retrobulbar tumor and results in a successful outcome. The indications for this approach depend on the size, location, and nature of the tumor. In this regard, contrast-enhanced computed tomography and magnetic resonance imaging scans give useful information for planning operative strategy.

Success rate and complications of endonasal dacryocystorhinostomy with unciformectomy.

BACKGROUND: Endonasal dacryocystorhinostomy (DCR) has been widely used to treat nasolacrimal duct obstruction. Here, we evaluated the anatomical advantages of the uncinate process as a landmark and to study the effect of unciformectomy on success rate and complications of endonasal DCR . METHODS: In total, 288 eyes of 265 adult patients who underwent endonasal DCR between January 2003 and February 2010 were reviewed retrospectively. The eyes were classified into two groups, according to whether unciformectomy was performed or not. All surgical procedures and surgical indications were the same except unciformectomy and endonasal DCR was performed by one surgeon. Unciformectomy was performed by resecting the anterior part of uncinate process. RESULTS: One hundred and eighty-six eyes of 168 patients received endonasal DCR with unciformectomy, and 102 eyes of 97 patients received endonasal DCR alone. The average success rate of endonasal DCR with unciformectomy was 97.8 % and that of endonasal DCR alone was 90.2 %, with statistically significant difference (Student's t-test, p-value < 0.05). There were 14 eyes with post-operative nasolacrimal obstruction, caused by granuloma in five eyes, intranasal synechia in two eyes, membranous obstruction in six eyes, and canalicular stenosis in one eye. There were no serious complications such as orbital fat prolapse, cerebrospinal fluid leak, or delayed hemorrhage. CONCLUSIONS: Anterior resection of the uncinate process gives improved access to the lacrimal bone by exposing the medial aspect of the lacrimal fossa and forming the precise location of the osteotomy on the lacrimal bone during endonasal DCR. Thus, the uncinate process can be used as an anatomical landmark for endonasal DCR. The unciformian endonasal DCR improves operation success rate by allowing access to the large space of the nasal cavity and reducing the synechiae of the nasal cavity.

Expression of Stat3 and indoleamine 2, 3-dioxygenase in cornea keratocytes as factor of ocular immune privilege.

PURPOSE: Ocular immune privilege is a multifactorial phenomenon evolutionally selected to prevent immunogenic inflammation from disrupting the visual axis and causing blindness. Here, we investigated the role of signal transducers and activators of transcription (Stat3) and indoleamine 2,3-dioxygenase (IDO) in ocular immune privilege in corneal stromal cells. METHODS: Human keratocytes were isolated and cultured in vitro, and Stat3 and IDO expression on keratocytes was investigated by reverse transcription polymerase chain reaction (RT-PCR). The active form of Stat3 was detected by flow-cytometry, and IDO enzyme activity following IFN-γ stimulation of keratocytes was measured by tryptophan to kynurenine conversion with photometric determination of kynurenine concentration in the supernatant. RESULTS: Stat3 was constitutively expressed in cultured keratocytes and up-regulated following IFN-γ stimulation. The active form of Stat3 was also up-regulated following IFN-γ stimulation. IDO expression and enzyme activity was markedly induced following IFN-γ stimulation, but this induction was prevented by the IDO specific inhibitor, 1-methyl tryptophan (1-MT). CONCLUSIONS: On the basis of this study, Stat3 and IDO may act as a factor of ocular immune privilege in corneal keratocytes. Thus, focus on these inhibitory molecules should be considered in studies aimed at developing therapeutic agents for controlling ocular inflammatory or immune diseases.

Effect of lipoic acid on expression of angiogenic factors in diabetic rat retina.

BACKGROUND: This study evaluated the effect of a lipoic acid on reactive oxygen species formation and the simultaneous changes of several angiogenic factors in an experimental diabetic rat retina. METHODS: Diabetes was induced chemically by intraperitoneal injection of streptozotocin in 30 Sprague-Dawley rats. After inducing diabetes, lipoic acid (10 mg/kg) was administered to 10 rats orally. The rats were divided into normal, diabetes mellitus, and lipoic acid-treated groups (each group n = 10). The eyeballs were harvested 8 weeks after inducing diabetes. The expression of vascular endothelial growth factor, erythropoietin, angiopoietin 1 and 2 and NADPH oxidase was examined in the rat retina using reverse transcription-polymerase chain reaction and Western blot. Superoxide formation was examined using dihydroethidium stain. RESULTS: Dihydroethidium analyses showed increased superoxide formation in the retina of the diabetic group. The superoxide formation was suppressed with lipoic acid treatment. Western blot analysis showed that NADPH oxidase was decreased in the diabetic group and returned to normal level in the lipoic acid-treated group. Treatment with lipoic acid blocked hyperglycaemia induced increases of vascular endothelial growth factor, angiopoietin 2 and erythropoietin shown by reverse transcription-polymerase chain reaction and Western blot analysis. CONCLUSIONS: Lipoic acid treatment suppressed expression of vascular endothelial growth factor, angiopoietin 2 and erythropoietin via blockade of superoxide formation. Antioxidant treatment is suspected to have an antiangiogenic effect.

Giant epidermal cyst of the periorbital area.

Epidermal cysts of periorbit and intraorbit are common problems to ophthalmologists, but giant periorbital epidermal cyst is exceedingly rare. Only a few cases have been reported previously. A 62-year-old woman presented with a large right periorbital area mass that resulted in right upper lid complete ptosis and severe gaze limitation in all directions. Visual acuity of right eye was finger count (20/2000). Computed tomography and magnetic resonance imaging revealed a bone-destroying mass involving the lateral side of the right superior orbital limb. Complete surgical removal was performed through skin incision. The superior-lateral orbital limb was reconstructed with bone cement and Leibinger plate. Pathologic examination revealed a giant epidermal cyst (9.8×5.2×4.0 cm) of the periorbital area. After surgery, there was near-complete resolution of ptosis and gaze limitation. In addition, marked elevation of visual acuity was observed (20/125 on best-corrected visual acuity).

Clinical Treatment Efficacy Using One-snip Punctoplasty and Irrigation Technique in Primary Canaliculitis Patients.

PURPOSE: This study aims to report the efficacy and safety of one-snip punctoplasty and 18-gauge irrigation technique in patients with primary canaliculitis. METHODS: All patients diagnosed with primary canaliculitis between January 2020 and August 2021 at Inje University Busan Paik Hospital are included. All patients underwent one-snip punctoplasty and 18-gauge irrigation technique. After the procedure, patients had topical antibiotics. The resolution of symptoms and inflammatory signs and complications were evaluated 3 weeks after the procedure. RESULTS: A total of 11 patients (eight female patients and three male patients, 14 canaliculi) aged 34 to 82 years with a mean age of 63.8 ± 15.7 years were participated. Common symptoms were epiphora, mucopurulent discharge, and injection, and common signs were discharge from punctum, pouting punctum, punctal erythema, and swellling. Among 14 canaliculi, 12 (85.7%) had complete resolution and two underwent second treatment which showed completed resolution after the treatment. CONCLUSIONS: One-snip punctoplasty and 18-gauge irrigation technique are minimally invasive to punctum and canaliculi and are a highly effective surgical procedure for patients with primary canaliculitis.

Longitudinal association of thyroid-stimulating immunoglobulin levels with clinical characteristics in thyroid eye disease.

OBJECTIVES: The clinical course of thyroid eye disease (TED) is heterogeneous and predicting patients who may develop the severe sequelae of the disease is difficult. In this study, we evaluated the longitudinal association between changes in serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb) levels and course of disease activity and severity over time. DESIGN: This was a multicentre, prospective, observational study. SETTING: Fifteen tertiary care oculoplastic service centres in Korea. PARTICIPANTS: Seventy-six patients with newly diagnosed TED were included and followed up for 12 months. METHODS: We evaluated clinical characteristics and serum TRAb levels at baseline, 6 and 12 months of TED diagnosis. Additionally, we analysed longitudinal associations between the serum TRAb levels and clinical activity score (CAS), no signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, sight loss (NOSPECS) score and proptosis. RESULTS: Thyroid-stimulating immunoglobulin (TSI) and TSH-binding inhibitory immunoglobulin (TBII) levels decreased during the 1-year follow-up, whereas disease activity measured using CAS decreased mainly in the first 6 months. Disease severity measured using NOSPECS score and proptosis remained unchanged. Moreover, inter-person differences in TBII levels were associated with CAS, NOSPECS score and proptosis over time, whereas inter-person differences in TSI levels were associated with NOSPECS score. Subgroup analysis of patients with a baseline CAS≥4 demonstrated that within-person changes in TSI levels affected the CAS and NOSPECS score. CONCLUSIONS: Follow-up measurement of serum TSI and TBII levels may help evaluate TED prognosis and enable accurate clinical decision-making.

Relapse in patients with limited-stage ocular adnexal lymphoma treated by chemoimmunotherapy: Extended follow-up of a phase 2 study.

BACKGROUND: Approximately 50% of limited-stage ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) patients with adverse prognostic factors relapse after radiotherapy. Chemoimmunotherapy has been proposed as an alternative frontline therapy. However, only a few studies have reported its long-term treatment outcome. METHODS: In 2011, we commenced a phase 2 trial to investigate the efficacy of rituximab, cyclophosphamide, doxorubicin, and prednisolone (R-CVP) in bilateral and non-conjunctival limited-stage OAML patients. Results of the clinical trial showed a response rate of 100% and a 4-year progression-free survival of 90.3% without significant toxicity. We extended the study period to December 2020 to determine the long-term efficacy of R-CVP chemoimmunotherapy. RESULTS: At a median observation period of 66.0 months, eight of 33 study patients had relapsed. The cumulative incidence of relapse was 18.9% at 5 years and 44.7% at 8 years. The majority of relapses developed more than 4 years after treatment. Local relapse was more prevalent than distant relapse. The relapse risk of orbital and lacrimal diseases was likely to be higher than that of conjunctival and eyelid diseases (HR: 2.5, 95% CI: 0.498-12.500, p = 0.25). CONCLUSION: Although the response rate was remarkable for chemoimmunotherapy, the risk of late relapse was considerable. Based on our findings, clinical trials for limited-stage OAML patients should have a long-term observation period. To minimize radiation toxicity and reduce the risk of delayed relapse (local relapse and distant relapse), a future study with sequential or combination treatment of local low-dose radiation and systemic chemoimmunotherapy can be considered.

The pharmacokinetics of enteric-coated mycophenolate sodium and its gastrointestinal side effects in de novo renal transplant recipients of Hispanic ethnicity.

OBJECTIVE: The aim of the study is to characterize the pharmacokinetics and the gastrointestinal side effect profiles of enteric-coated mycophenolate sodium (EC-MPS) in de novo kidney transplant patients of Hispanic ethnicity. MATERIALS AND METHODS: The pharmacokinetic study of EC-MPS was conducted in 11 de novo kidney transplant patients of Hispanic ethnicity. Eight blood samples were obtained after EC-MPS was given at the steady state. Blood concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were measured. RESULTS: The mean age (± standard deviation) was 39.4 (± 12.3) years. The mean daily dose of EC-MPS at the time of the pharmacokinetic study was 1408 ± 108 mg. For MPA and MPAG, the time to peak concentration was 2.5 ± 1.3 hours and 4.6 ± 3.1 hours, respectively; the peak concentration (Cmax) was 19.3 ± 17.2 mg/L and 109.4 ± 49.2 mg/L; and the area under the curve from 6 to 12 hours (AUC6-12) was 32.2 ± 19.3 mg·hr/L and 373.7 ± 235.8 mg·hr/L, respectively, which represents 41.3% and 43.0% of AUC0-12. The AUC0-12 for MPA measured 77.8 ± 53.1 mg·hr/L and for MPAG 869.2 ± 388.8 mg·hr/L. Seven patients (64%) exhibited a second peak at approximately 8.3 hours after the dose at a mean concentration (± standard deviation) of 10.3 ± 7.6 mg/L. The Cmax or AUC of MPA does not correlate with overall Gastrointestinal Symptom Rating Scale scores or subscale scores, but the Cmax of MPAG correlates with indigestion subscale (P = 0.022), diarrhea (P = 0.032), and overall scores (P = 0.028). The AUC of MPAG also correlates with acid reflux (P = 0.024) and indigestion (P = 0.032). DISCUSSION AND CONCLUSION: The pharmacokinetics of EC-MPS has a high variability in de novo kidney transplant patients of the Hispanic ethnicity, which was similar to other ethnic groups. The MPA exposure expressed by the AUC appears to be higher in Hispanic patients than those reported in other ethnic groups, which may be the result of various factors such as difference of the uridine diphosphate glucuronosyltransferase enzyme genotypes, but gastrointestinal side effects were acceptable and the Cmax or AUC of MPAG showed correlations with gastrointestinal symptoms.

Gene polymorphism of vascular endothelial growth factor -1154 G>A is associated with hypertensive nephropathy in a Hispanic population.

The aim of this study was to determine the association between hypertensive nephropathy and gene polymorphisms of vascular endothelial growth factor (VEGF) in a self-reported Hispanic patient group. A total of 155 Hispanic living kidney donors as controls and a total of 86 Hispanic kidney transplant patients, whose renal failure was attributed to hypertensive nephropathy after ruling out diabetes mellitus or other causes, were genotyped for four different single nucleotide polymorphisms of VEGF: -2578 C>A (rs699947), -1154 G>A (rs1570360), -460 C>T (rs833061), and +936 C>T (rs3025039). The homozygous mutant type (AA) of VEGF -1154 G>A (rs1570360) was found with significantly higher frequency in the hypertensive nephropathy patients than in controls. On the other hand, homozygous wild type (GG) was found less frequently in the hypertensive nephropathy patient group than in the control group. Linkage disequilibrium (LD) analyses revealed a high degree of LD among VEGF -2578 C>A (rs699947), VEGF -1154 G>A (rs1570360), and VEGF -460 C>T (rs833061). The haplotype analysis revealed that two haplotypes, CGTC and CATC (in the order of VEGF -2578 C>A (rs699947), -1154 G>A (1570360), -460 C>T (rs833061), and +936 C>T (3025039)), were significantly associated with hypertensive nephropathy in Hispanic patients. Hence, the -1154 G>A polymorphism (rs1570360) and two haplotypes (CGTC and CATC) of VEGF appear to be associated with hypertensive nephropathy in Hispanic patients who developed end-stage renal disease requiring kidney transplant.