Reappraisal of a Renovated Cell-free and Concentrated Ascites Reinfusion Therapy for Malignant Ascites.

BACKGROUND/AIM: Cell-free and concentrated ascites reinfusion therapy (CART) was established for refractory ascites and renovated CART (Keisuke Matsusaki (KM) -CART) has been recently developed especially for malignant ascites; however, the actual clinical efficacy of KM-CART has been rarely reported. PATIENTS AND METHODS: We performed 226 KM-CART procedures in 104 patients with malignant ascites in three hospitals from August 2013 to September 2018. Medical records were retrospectively reviewed for ascites data, related complications, symptoms before and after each CART and prognosis after the first CART. The modified Glasgow Prognostic Score (mGPS) was reviewed before every procedure, as an indicator of nutritional status. RESULTS: Pancreatic cancer was the most common indication for the KM-CART procedure, followed by gastric cancer, hepatocellular carcinoma, ovarian cancer, and cholangiocarcinoma (five major diseases). The 50% survival times of these five major diseases after the first procedure were 25, 39, 31, 49, and 33 days, respectively. The mean survival time for all patients was 73.5 days, and 75.6 days for those with the five major diseases. All patients experienced symptomatic relief, and complications were rare. Repeated KM-CART was performed in 47.1% of the patients, most often in those with ovarian cancer (66.7%). Regarding the mGPS at the first CART procedure, 89% of patients were in the group with the poorest nutritional status. Patients who underwent KM-CART three or more times had longer survival than those who were treated once or twice. CONCLUSION: Repeated KM-CART provides a survival benefit for patients with malignant ascites, even in cases of poor nutritional status.

Exosomes in ascites from patients with human pancreatic cancer enhance remote metastasis partially through endothelial-mesenchymal transition.

BACKGROUND: Despite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis. METHODS: Exosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro. RESULTS: Distant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro. CONCLUSION: Exosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition.

Comparison of phrenic nerve injury and its effect on the extrapulmonary vein structures with cryoballoon and hot-balloon ablation systems: considering the lesion created on the superior vena cava as a surrogate marker.

Preventing phrenic nerve injury (PNI) during balloon-based ablation is essential. The superior vena cava-right atrial (SVC-RA) junction is located just opposite the balloon position during right superior pulmonary vein (RSPV) ablation, and the phrenic nerve runs nearby on the lateral side. We compared the occurrence of PNI between the two balloon-based ablation systems and also the lesions created at the SVC-RA junction, which were expected to represent the effect on extra-PV structures. Cryoballoon ablation (CBA, n = 110) and hot-balloon ablation (HBA, n = 90) were performed in atrial fibrillation patients. High-density maps of the SVC-RA junction were created in 93 patients (CBA = 53, HBA = 40), and the damaged area (< 1.0 mV) was determined as an "SVC lesion". CBA had a higher occurrence of transient PNI (7.3% vs 1.1%, p = 0.035), but all recovered during the 6-month follow-up. An apparent SVC lesion was documented in 43% of the patients (40/93), and all patients with PNI had this lesion. CBA created a frequent (CBA vs HBA = 55% vs 28%, p = 0.008) and wider (0.8[0.4-1.7] cm2 vs 0.5[0.3-0.7] cm2, p = 0.005) SVC lesion than HBA. A multivariate analysis revealed that the use of a CBA system was a predictive factor of the occurrence of SVC lesions. CBA had a higher occurrence of transient PNI but not a permanent form. Every patient with PNI had lesions on the SVC-RA junction, and CBA revealed more substantial ablation effects at the SVC-RA junction than HBA. This may be caused by the different characteristics of the two balloon-based ablation systems and their balloon positions.

Efficacy and Safety of the Long-Acting Diquafosol Ophthalmic Solution DE-089C in Patients with Dry Eye: A Randomized, Double-Masked, Placebo-Controlled Phase 3 Study.

INTRODUCTION: DE-089C is a newly developed long-acting formulation of diquafosol ophthalmic solution with less frequent administration (three times daily) than the currently approved and clinically used diquafosol ophthalmic solution (six times daily), hereinafter referred to as DQS. DE-089C is desirable for achieving better patient adherence in clinical practice for dry eye therapy. The objective of this study was to confirm the efficacy and safety of DE-089C in patients with dry eye compared to placebo. METHODS: This randomized, multicenter, double-masked, placebo-controlled, parallel-group phase 3 study was conducted in Japan. Patients with aqueous-deficient dry eye satisfying Schirmer's test I results ≤ 5 mm/5 min were included. A total of 337 patients with dry eye were randomized in an equal ratio to treatment with DE-089C or placebo ophthalmic solution, three times daily for 4 weeks. The primary endpoint for efficacy was change in fluorescein corneal staining score from baseline to week 4. The incidence of adverse drug reactions was investigated for safety evaluation. RESULTS: The background characteristics of patients in the two groups were similar. Primary endpoint of change in fluorescein corneal staining score at week 4 in the DE-089C group was significantly improved compared with the placebo group (least squares mean difference - 0.51, 95% CI - 0.754 to - 0.269, P < 0.0001). The secondary endpoint of the Lissamine green conjunctival staining score was also significantly improved in the DE-089C group compared to that in the placebo group, while other secondary endpoints were not achieved in this study. Commonly (incidence ≥ 1%) reported adverse drug reactions in the DE-089C group were eye irritation (3.6%) and eye discharge (1.8%) with mild severity, and the incidences of these two events were not higher than those in previous clinical studies on DQS. CONCLUSION: The efficacy and safety of DE-089C administered three times daily at half the dosage of DQS in patients with dry eye were confirmed in this study. TRIAL REGISTRATION: Japan Pharmaceutical Information Center ID, JapicCTI-205177.

Pancreatic cancer cell-derived exosomes induce epithelial-mesenchymal transition in human pancreatic cancer cells themselves partially via transforming growth factor ß1.

Distant metastasis is a dismal prognostic factor of pancreatic cancer. Metastasis is established in several steps, but the mechanism underlying the very early stages remains unclear. Epithelial-mesenchymal transition (EMT) is involved in these stages. Although signaling molecules have been reported to induce EMT, the mechanism underlying their origin is unclear. In this study, we hypothesized that pancreatic cancer cell-derived exosomes induce EMT in cancer cells themselves, a notion we entertained because we found EMT in in vitro three-dimensional colonies of cancer cells, with vimentin-positive cells observed in some of the budding pancreatic cancer cells and in single cells outside the colony as well. First, we clarified that pancreatic cancer cell-derived exosomes induce EMT in cancer cells themselves. Next, we examined the involvement of transforming growth factor-ß1 (TGF-ß1), and TGF-ß1 knock-down in pancreatic cancer cells with TGF-ß1 siRNA significantly suppressed TGF-ß1 gene expression in cancer cells, and exosomal TGF-ß1 was significantly reduced in the secretory exosomes. Exosomes from TGF-ß1 knock-down cells suppressed EMT induction in cancer cells themselves and TGF-ß1 protein expression in target cells. Taken together, these findings suggest that TGF-ß1 is involved in EMT induction via exosomes, results that may support the production of effective metastasis inhibitors.

Pathogenic Mechanism of Dry Eye-Induced Chronic Ocular Pain and a Mechanism-Based Therapeutic Approach.

Purpose: Dry eye-induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye-induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy. Methods: We used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α2δ-1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye-induced ocular neuropathic pain. Results: Dry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α2δ-1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α2δ-1 subunit upregulation, and astrocyte activation. Conclusions: These results suggest that dry eye-induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α2δ-1 subunit. Here, we showed that pregabalin is effective for treating dry eye-induced ocular neuropathic pain even after chronic pain has been established.

Cryofreezing for slow-pathway modification in patients with slow-fast AVNRT: Efficacy, safety, and electroanatomical relation between sites of transient AV block and sites of successful cryoablation.

INTRODUCTION: Cryoablation has emerged as an alternative to radiofrequency ablation for treating atrioventricular nodal reentrant tachycardia (AVNRT). The aim of this prospective study was to evaluate the efficacy and safety of cryoapplication at sites within the mid/high septal region of Koch's triangle and the relation between sites of transient AV block (AVB) and sites of successful cryoablation. METHODS AND RESULTS: Included were 45 consecutive patients undergoing slow-fast AVNRT cryoablation. Initial delivery of cryoenergy was to the mid-septal to high septal region of Koch's triangle. Transient AVB occurred during cryoenergy delivery in 62% (28/45) of patients. Median distance between sites at which cryofreezing successfully eliminated slow pathway conduction and sites of AVB was 4.0 (3.25-5.0) mm. Sites of successful cryoablation tended to be to the left and inferior to the AVB sites. The atrial/ventricular electrogram ratio was significantly lower at sites of successful cryoablation than at AVB sites (0.25 [0.17-0.56] vs. 0.80 [0.36-1.25], p < .001). Delayed discrete or fractionated atrial electrograms were recorded more frequently at sites of successful cryoablation than at AVB sites (78% vs. 20%, p < .001). No persistent AV conduction disturbance occurred, and 96% (43/45) of patients showed absence of recurrence at a median follow-up time of 25.0 months. CONCLUSION: Cryoablation of slow-fast AVNRT and targeting the mid/high septal region of Koch's triangle was highly successful. AVB frequently emerged near the site at which the slow pathway was eliminated but always resolved by regulating the energy delivery under careful monitoring, and it may be distinguishable by its local electrogram features.

Utility of hot-balloon-based pulmonary vein isolation under balloon surface temperature monitoring: First clinical experience.

INTRODUCTION: A new hot balloon system that registers balloon surface temperature (BST) during energy delivery is now available for clinical use in Japan. This study sought to investigate the utility of BST measurement for achievement of pulmonary vein isolation (PVI) by a single-shot energy delivery strategy during hot balloon ablation (HBA). METHODS: We applied and tested the system in 30 consecutive patients undergoing HBA for paroxysmal or early-persistent atrial fibrillation (AF). We also performed real-time PV potential monitoring using a circular catheter. RESULTS: Acute PVI was achieved with single hot balloon shots in 88% (106/120) of the PVs. Real-time BSTs and PV potentials were recorded in all cases. Mean BST at documentation of PVI was 49.4°C, and acute reconnections were observed in most cases (86%, 12/14) in which the single-shot technique was ineffective. Time-to-isolation (TTI) (23.1 ± 8.7 s vs. 36.3 ± 9.3 s, p < .01) and median BST (59.9 ± 2.6°C vs. 55.7 ± 1.9°C, p < .01) differed significantly between cases in which PVI was achieved (vs. those in which PVI was not achieved). Multivariable analysis revealed strong association between both TTI and median BST and acute PVI. The best median BST cutoff value for achieving PVI with a single shot was >58.7°C (sensitivity 67.0%, specificity 100%). CONCLUSION: Our data suggest that real-time BST monitoring during energy applications is useful for predicting achievement of acute PVI by a single shot during HBA.

The influence of hemorrhagic shock on ocular microcirculation by obtained by laser speckle flowgraphy in a white rabbit model.

PURPOSE: To clarify the continuous changes in the retinal vessels' and choroid's microcirculation during hemorrhagic shock and resuscitation in a rabbit model. METHODS: Hemorrhagic shock by the removal of blood (30 mL) and resuscitation by a blood-return technique was induced in anesthetized male New Zealand White rabbits (n = 10). We evaluated the retinal vessel blood flow (relative flow volume: RFV) and choroidal blood flow (mean blur rate in the choroid area: MBR-CH) by laser speckle flowgraphy (LSFG), with simultaneous measurements of systemic hemodynamics and laboratory parameters. RESULTS: RFV and MBR-CH showed significant decreases immediately after the initiation of blood removal and recovered by blood return. The lactate concentration tended to increase from baseline by the blood-removal operation, and it was significantly higher at the end of observation period. The %RFV and %MBR-CH each showed a significant positive correlation with mean arterial blood pressure, cardiac output, carotid blood flow, and central venous pressure. %RFV showed a significant positive correlation with %central venous oxygen saturation and negatively correlated with %lactate. The %hemoglobin did not show a significant correlation with %RFV or %MBR-CH. CONCLUSION: This rabbit hemorrhagic shock model confirmed that ocular microcirculation measurements by LSFG feasibly reflect variations in systemic hemodynamics during hemorrhagic shock and recovery.

Hot balloon versus cryoballoon ablation for persistent atrial fibrillation: Lesion area, efficacy, and safety.

INTRODUCTION: The clinical efficacy and safety of hot balloon ablation (HBA) for the treatment of persistent AF (PerAF) remain unclear. We aimed to evaluate the clinical efficacy and safety of HBA versus cryoballoon ablation (CBA) as a treatment for PerAF. METHODS: Of 195 consecutive patients who underwent initial catheter ablation for PerAF (AF lasting for longer than 7 days but shorter than 12 months), 158 propensity score-matched (79 HBA and 79 CBA) patients were included in our retrospective study. All patients who underwent HBA received applications of energy to the upper posterior LA wall with a larger balloon in addition to single shots to each pulmonary vein (PV) ostium, whereas those who underwent CBA received simple single-shot applications. The electrically isolated surface area (ISA), including the PV antrum and part of the posterior LA wall, was assessed by high-resolution mapping. RESULTS: The success of the PV isolation with balloon shots alone did not differ between HBA and CBA (81% vs. 85%; p = .52). The ISA was generally wide in both groups and significantly larger in the HBA group than in the CBA group (61 ± 16% vs. 51 ± 12%; p < .001). The incidence of procedure-related complications did not differ significantly (HBA 4% vs. CBA 1%; p = .62) nor did the arrhythmia recurrence rate (HBA 11% vs. CBA 18% at 18 months; p = .26). CONCLUSION: Despite the difference in protocols, HBA and CBA performed for PerAF appear comparable in terms of wide antral lesion creation, clinical efficacy, and safety. Further prospective studies, based on a unified methodology, are needed.

Effectiveness of Photodynamic Screening Using 5-Aminolevulinic Acid for the Diagnosis of Pancreatic Cancer.

BACKGROUND/AIM: We evaluated urinary levels of porphyrin metabolites, such as uroporphyrin (UP) and coproporphyrin (CP), after 5-Aminolevulinic acid (ALA) administration in patients with or without pancreatic cancer (PaC). PATIENTS AND METHODS: Sixty-seven subjects with PaC, 11 with pancreatitis, and 9 with normal pancreas (NP) were enrolled. Urine samples from all subjects were collected prior to ALA administration and at more than 4 hours after ALA administration. We measured the urinary levels of UP and CP by high-performance liquid chromatography analysis. RESULTS: The PaC group showed significantly higher UP levels compared to NP groups (104.9 nmol/g Cre vs. 53.4 nmol/g Cre, p=0.014). Moreover, PaC patients with long-term survival had significantly lower urinary levels of UP at diagnosis (98.8 nmol/gCre) than the short-term survival group (125.2 nmol/gCre) (p=0.042). CONCLUSION: The urinary levels of UP after ALA administration might serve as a promising biomarker for diagnosis and prognosis prediction of PaC.

Role of phosphorylated Smad3 signal components in intraductal papillary mucinous neoplasm of pancreas.

BACKGROUND: Malignant intraductal papillary mucinous neoplasm (IPMN) has poor prognosis. The carcinogenesis of IPMN is not clear. The aim of this study was to clarify transitions in phosphorylated Smad3 signaling during IPMN carcinogenesis. METHODS: By using immunohistochemistry, we examined the expression of pSmad3C and pSmad3L from 51 IPMN surgical specimens resected at our institution between 2010 and 2013. We also examined the expression of Ki-67, c-Myc and p-JNK. RESULTS: The median immunostaining index of pSmad3C was 79.2% in low-grade dysplasia, 74.9% in high-grade dysplasia, and 42.0% in invasive carcinoma (P < 0.01), whereas that of pSmad3L was 3.4%, 4.3%, and 42.4%, respectively (P < 0.01). There was a negative relationship between the expression of pSmad3C and c-Myc (P < 0.001, r = -0.615) and a positive relationship between the expression of pSmad3L and c-Myc (P < 0.001, r = 0.696). Negative relationship between the expression of pSmad3C and Ki-67 (P < 0.01, r = -0.610) and positive relationship between the expression of pSmad3L and Ki-67 (P < 0.01, r = 0.731) were confirmed. p-JNK-positive cells were frequently observed among pSmad3L-positive cancer cells. The median of pSmad3L/pSmad3C ratio in the non-recurrence group and the recurrence group were 0.58 (range, 0.05-0.93), 3.83 (range, 0.85-5.96), respectively (P = 0.02). The median immunostaining index of c-Myc in the non-recurrence group and the recurrence group were 2.91 (range, 0-36.9) and 82.1 (range, 46.2-97.1), respectively (P = 0.02). The median immunostaining index of Ki-67 in the non-recurrence group and the recurrence group were 12.9 (range 5.7-30.8) and 90.9 (range 52.9-98.5), respectively (P = 0.02). CONCLUSIONS: pSmad3L was upregulated in malignant IPMN. pSmad3L/pSmad3C ratio may be a useful prognostic factor in IPMN.

Clinical implications of elevated serum interleukin-6 in IgG4-related disease.

INTRODUCTION: Some patients with IgG4-related disease (IgG4-RD) exhibit elevated serum interleukin (IL)-6 with excessive inflammatory reactions or with repeating relapse. To date few reports pertaining to clinical implications of elevated serum IL-6 in IgG4-RD patients have been published. The aims of the current retrospective study were to investigate the clinical implications of elevated serum IL-6 in IgG4-RD patients, and to examine whether IL-6 can predict the activity and/or relapse of the disease. MATERIALS AND METHODS: We examined the clinical picture at the onset of 43 patients who were diagnosed with IgG4-RD in our hospital and were able to measure serum IL-6 before steroid treatment. RESULTS: The median level of serum IL-6 was 2.2 pg/mL. There was a significant correlation between IL-6 and C-reactive protein (CRP) level (r = 0.397, p = 0.008), hemoglobin level (r = -0.390, p = 0.010) and albumin level (r = -0.556, p < 0.001). When 43 patients were divided into two groups by using a cut-off IL-6 of 4 pg/mL, the high IL-6 group showed higher age, lower albumin, higher CRP and higher aspartate aminotransferase (AST) (age p = 0.014, albumin p = 0.006, CRP p <0.001, AST p = 0.009). Hepatic swelling and splenomegaly were significantly more prevalent in the high IL-6 group than it was in the low IL-6 group (liver p < 0.001, spleen p = 0.020). Biliary tract involvement tended to admit more in the high IL-6 group (p = 0.060). CONCLUSION: Serum IL-6 level at the onset of IgG4-RD may be significantly correlated with clinical inflammatory parameters and it may also be associated with involvement of the bile duct, liver, and spleen.

Xenografts Derived From Patients' Ascites Recapitulate the Gemcitabine Resistance Observed in Pancreatic Cancer Patients.

OBJECTIVES: Most patient-derived pancreatic ductal adenocarcinoma (PDAC) xenografts have been established from surgical specimens of patients who have not received chemotherapy. However, xenografts have rarely been established from chemotherapy-resistant, advanced PDACs, because such cases are usually inoperable. The purpose of this study is to establish patient-derived xenografts using PDAC cells refractory to chemotherapy. METHODS: Clinical PDAC cells obtained from ascites of patients who had received continuous chemotherapy were implanted into the flanks of immunocompromised mice. Growth and histological features of the xenografts with and without gemcitabine treatment were then analyzed. RESULTS: Ascites-derived PDAC cells were successfully expanded through serial xenograft passage without changes in histological appearance. While treatment with gemcitabine substantially inhibited the growth of all PDAC xenografts tested, the tumor volume gradually increased, and the tumors showed marked regrowth even under continued gemcitabine treatment. These findings are consistent with the actual clinical course of the corresponding patients for each xenograft. CONCLUSIONS: Ascites-derived xenograft models represent a valuable experimental system for testing the efficacy of currently available therapeutic compounds on chemotherapy-resistant PDAC cells and for elucidation of the mechanisms underlying chemotherapy resistance.

Association among Blink Rate, Changes in Ocular Surface Temperature, Tear Film Stability, and Functional Visual Acuity in Patients after Cataract Surgery.

PURPOSE: To investigate the association among the ocular surface temperature (OST), tear film stability, functional visual acuity (FVA), and blink rate in patients after cataract surgery. METHODS: We recruited 98 eyes of 69 patients (mean age, 73.7 ± 5.2 years) 1 month after phacoemulsification with implantation of acrylic intraocular lenses and assessed slit-lamp microscopy, corrected distance VA, FVA, noninvasive tear breakup time (NIBUT), and OST. We defined the changes in the OST from 0 to 10 seconds after eye opening as the ΔOST. We measured the FVA and blink rate using the FVA measurement system. We divided the patients into two groups based on tear film stability: stable tear film (NIBUT, >5.0 seconds) and unstable tear film (NIBUT, ≤5.0 seconds). We evaluated the differences between the two groups and the association between the blink rate and other clinical parameters. RESULTS: The unstable tear film group (56 eyes) had significantly (p < 0.0001, unpaired t-test) shorter NIBUTs than the stable tear film group (42 eyes). The ΔOSTs and blink rates were significantly (p < 0.0001) higher in the unstable tear film group than in the stable group. Linear single regression analysis showed that the ΔOST (r = -0.430, p < 0.0001), NIBUT (r = -0.392, p < 0.0001), and gender (r = -0.370, p=0.0002) were correlated significantly with the blink rate. Multiple regression analysis showed that the ΔOST independently contributed to the blink rate. CONCLUSIONS: The frequency of blinks is associated with tear film stability in patients after cataract surgery. The blink rate may be useful for evaluating the tear film stability in clinical practice. The ΔOST should be an important contributing factor to the blink rate. [This trial is registered with UMIN000026970].

Secreted Mucins on the Ocular Surface.

Mucins, which play important roles on the ocular surface in wettability, lubrication, and barrier function, are classified into two categories: secreted mucins and membrane-associated mucins. The most important secreted mucin on the ocular surface is MUC5AC, which is secreted by the conjunctival goblet cells. In the human conjunctiva, goblet cells are present in higher concentrations in the fornix, inferior nasal bulbar, and the lid wiper on the lid margin. The number of conjunctival goblet cells and MUC5AC expression/secretion are decreased in a patient with dry eye. In Japan, drugs that stimulate mucin secretion or increase the number of conjunctival goblet cells are commercially available. A P2Y2 receptor, diquafosol, stimulates tear fluid secretion from conjunctival epithelial cells and promotes mucin secretion from conjunctival goblet cells. Rebamipide was marketed originally as an oral therapeutic drug to treat gastritis in Japan. Topical rebamipide increases numbers of goblet cells in the bulbar conjunctiva and the lid wiper area of palpebral conjunctiva. Many researchers have reported decreases in the ocular surface mucin expression including MUC5AC secreted by goblet cells in patients with dry eye. However, it is unknown whether changes in mucin expression on the ocular surface cause or result from dry eye. Further study is needed to determine the true mechanism of dry eye disease.

Relationships between retinal break locations and the shapes of the detachments.

PURPOSE: Detecting primary breaks and confirming detachment preoperatively are important. Lincoff stated that retinal detachments progress according to gravity; his law has become popular. We evaluated Lincoff's law with a slight modification to determine whether it remains suitable for present cases independent of refractive error and previous cataract surgery. PATIENTS AND METHODS: Group 1 included superior region detachments not exceeding the 12 o'clock midline; the original break was within 1 1/2 clock hours of the highest detachment border. Group 2 included shallow inferior detachment; the original break corresponded to the more spread side of the 6 o'clock midline. Group 3 detachments were beyond 12 o'clock; the original break was within a triangle with a 12 o'clock apex (A) or within 1 1/2 hours of 12 o'clock (B); (A) and (B) were stated in the original report. Another five classifications were applied for small numbers of detachments. Consecutive initial rhegmatogenous retinal detachment surgery patients were included; medical records and detachment charts were examined. Eyes were classified into categories and rates were calculated. Eyes that had never undergone previous cataract surgery besides those in which the macula remained attached were divided into groups at a -6 D cutoff (Groups 1, 2, and 3[B]); we compared groups in each category. We compared phakic eyes, pseudophakic eyes, and eyes ruptured at the posterior capsule (Groups 1, 2, and 3[B]). RESULTS: Finally, 747 eyes were categorized. In Groups 1, 2, 3(A), and 3(B), corresponding rates were 92, 86, 70, and 89%, respectively. Between the above and below -6 D groups, there was no significant difference in rate in any category. There were no significant differences between phakic, pseudophakic, and ruptured eyes. CONCLUSION: Lincoff's law was suitable for the present cases and independent of refractive error and previous cataract surgery.

Intravitreal bevacizumab treatment reduces ocular blood flow in retinopathy of prematurity: a four-case report.

PURPOSE: To evaluate the relationship between ocular blood flow, expressed as mean blur rate (MBR) by laser speckle flowgraphy, and intravitreal bevacizumab (IVB) therapy in neonates with retinopathy of prematurity (ROP). METHODS: This was a case series study of 4 neonates with ROP under sedation before and after IVB and evaluated 8 eyes, in which the circulation could be measured three times consecutively. We performed optic nerve head blood flow measurement and fluorescein angiography (FA) before and 1 week after treatment. Blood flow was analyzed separately for MBR-A (mean of all values), MBR-V (vessel mean), and MBR-T (tissue mean). Comparisons between the MBR (-A, -V, -T), body weight, and other systemic and ocular parameters before and after treatment were performed using a paired t test. RESULTS: The MBR values after IVB were lower than the pre-treatment values in all cases. All eyes showed leakage at neovascularization on FA before treatment. Although leakage improved 1 week after treatment, the neovascularization did not completely regress. CONCLUSIONS: IVB improves vein dilation and artery tortuosity, while reducing ocular blood flow in neonates with ROP. We suggest that neovascularization might not be involved in reducing ocular blood flow in the early stage of IVB treatment.

The evaluation of dry eye mobile apps for screening of dry eye disease and educational tear event in Japan.

PURPOSE: To evaluate the usefulness of a dry eye mobile application (app) for screening dry eye disease (DED) at educational tear events in Japan. METHODS: In this cross-sectional study, Japanese subjects visiting a "Tears Day" event were selected randomly. They completed questionnaires and underwent ophthalmic evaluations for DED (using Japanese revised diagnostic criteria) including a functional visual acuity (FVA) test. The app calculated FVA using the average of the continuous VA over 30 s. RESULTS: Sixty-three general-population subjects were included: 25 men and 38 women (average age, 50.8 ±â€¯15.9 years). The prevalence of DED was 66.7% (42 subjects); age was significantly higher among subjects with DED (55.2 ±â€¯3.4 vs. 48.1 ±â€¯2.7 years, p = 0.04; men, 54.0 ±â€¯7.3 vs. 47.0 ±â€¯3.0 years, p = 0.36; women, 55.5 ±â€¯3.9 vs. 50.6 ±â€¯3.8 years, p = 0.4). The prevalence of DED was significantly higher in women (p = 0.04). Tear film breakup time was significantly shorter (3.8 ±â€¯2.4 vs. 8.7 ±â€¯2.0, p = 0.04) and the meibum score was significantly higher (p = 0.02) among subjects with DED. Regarding the tear film breakup pattern, line and random breaks were most prevalent among DED. FVA showed a significant negative correlation with DED (r = -0.25, p = 0.047). CONCLUSIONS: The app might motivate people to perform quick tests with the expectation of getting easy DED screening. The number of subjects diagnosed with DED was relatively high.