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Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic disorder characterized by tissue eosinophilic infiltration and vasculitis. Although EGPA causes multiple organ damage, it causes cholecystitis less frequently. We herein report a case of acute cholecystitis associated with EGPA in which successful treatment with glucocorticoid therapy allowed surgery to be avoided. EGPA can present as acute cholecystitis. It is important not to overlook acute cholecystitis associated with EGPA in patients with abdominal pain with peripheral eosinophilia. Furthermore, in cases of mild cholecystitis associated with EGPA that are diagnosed preoperatively, cholecystectomy might be avoided with conservative glucocorticoid treatment.

Cholesterol crystal embolization (CCE) shows a poor prognosis and it can cause ischemic organ damage due to a cholesterol embolism from atherosclerotic lesions in large blood vessels. Such an embolism mainly affects the kidneys and skin, although cases involving digestive organs have also been reported. We encountered an autopsy case of CCE with damage mainly to the digestive organs, including the pancreas. The patient had non-specific abdominal symptoms or image findings. Symptomatic therapy failed to save him. CCE can involve the digestive organs, and so must be differentiated from abdominal pathologies. Moreover, conventional treatments may be ineffective, and new treatments might thus be necessary.

BACKGROUND AND AIM Improvement of atrophic gastritis and intestinal metaplasia (IM) is considered to reduce the gastric cancer risk, but whether it can be achieved by H. pylori eradication (HPE) remains controversial. To evaluate the effect of HPE, we observed the gastric mucosa for up to17 years after HPE and sex differences in gastric mucosa. METHODS In total, 172 patients (94 males, 78 females) with HPE were enrolled. Annual histological evaluations were performed for up to 17 years. The grades of mononuclear cells, neutrophils, atrophy, IM in the antrum and corpus were evaluated using the updated Sydney system. RESULTS Relative to the pre-HPE period, atrophy had improved significantly 1 year after HPE in the antrum (1.50 ± 0.75 vs. 1.21 ± 1.25, P

In this study, the level of cell damage were analyzed immuno-histochemically to clarify the association between nodular gastritis and undifferentiated gastric cancer. Thirty patients of nodular gastritis were enrolled as the nodular gastritis group. Thirty patients of non-nodular gastritis were enrolled as the control group. They were evaluated according to the updated Sydney system and used for immunohistochemical staining (p53, Ki-67, E-cadherin, and 8-OHdG). The scores based on the updated Sydney system were significantly higher in the nodular group than in the non-nodular group for histologically assessed inflammation and activity in the gastric corpus (1.91 ± 0.77 vs 1.58 ± 0.60, p = 0.049, 0.83 ± 0.81 vs 0.44 ± 0.64, p = 0.032). On immunostaining, the detection of E-cadherin was lower in the nodular group for both the antrum (1.0 ± 0.62 vs 1.47 ± 0.85, p = 0.047) and the corpus (1.16 ± 0.81 vs 1.48 ± 0.71, p = 0.043) and the p53 labeling index of the gastric corpus was higher in the nodular group than in the non-nodular group (3.06 ± 1.94 vs 2.03 ± 1.99, p = 0.015). Nodular gastritis showed significant severe inflammation and immunohistochemical cell damage compared with non-nodular gastritis. These findings may play an important role in the oncogenesis of undifferentiated gastric cancer in nodular gastritis.

Hematin is a state in which hemoglobin, as petechiae, is discolored to a brown coffee color by gastric hydrochloric acid. Given the nature of hematin, a close relationship between hematin and acidity has been suggested, but has not been confirmed. We investigated the clinical significance of endoscopic finding of hematin with respect to gastric acidity.A total of 501 patients were assessed for both hematin and fasting gastric juice pH by endoscopy. Endpoints were as follows: 1) the relationship between the presence of hematin and the fasting gastric juice pH; and 2) the diagnostic performance of endoscopic hematin. In addition, we performed a supplementaryThe prevalence of hematin was 31.1% (142/206), 4.6% (5/109) and 45.2% (84/186) in theEndoscopic finding of hematin represent strong gastric acidity.

Stratification of gastric cancer risk by measuring serological biomarkers is useful for screening of gastric cancer. However, this method has problem such as overlooking past infected patients. We aimed to evaluate the association between

Background Although eradication therapy for chronic Helicobacter pylori reduces the risk of gastric cancer (GC), its effectiveness is incomplete. Therefore, it is critically important to identify those patients who remain at high risk after H. pylori eradication therapy. Accumulation of protein methylation is strongly implicated in cancer, and a recent study showed that dimethylation of eEF1A lysine 55 (eEF1AK55me2) promotes carcinogenesis in vivo. We aimed to investigate the relationship between eEF1A dimethylation and H. pylori status in gastric mucosa and to reveal potential downstream molecules of eEF1A dimethylation in H. pylori-eradicated mucosa. Methods Records of 115 patients (11 H. pylori-negative, 29 H. pylori-positive, 75 post-eradication patients) who underwent upper gastrointestinal endoscopy were retrospectively reviewed. The eEF1A dimethyl level was evaluated in each functional cell type of gastric mucosa by immunofluorescent staining. We also investigated the relationship between eEF1AK55me2 downregulation by CRISPR/Cas9-mediated deletion of Mettl13, which is known as a dimethyltransferase of eEF1AK55me2. Results The level of eEF1A dimethylation significantly increased in the surface and basal areas of H. pylori-positive mucosa compared with -negative mucosa (surface, p=0.0031; basal, pp=0.005), but those in the basal area were maintained even after eradication therapy. Multivariate analysis revealed that high dimethylation of eEF1A in the basal area of the mucosa was the independent factor related to GC incidence (odds ratio=3.6611, 95% confidence interval=1.0350–12.949, p=0.0441). We also showed the relationship between eEF1A dimethylation and expressions of reprogramming factors Oct4 and Nanog by immunohistochemistry and in vitro genome editing experiments. Conclusions The results indicated that H. pylori infection potently induced eEF1A dimethylation in gastric mucosa. The accumulation of dimethyl-eEF1A in the basal area of the mucosa might contribute to GC risk via regulation of reprograming factors in H. pylori-eradicated gastric mucosa.

A 72-year-old man was followed as an outpatient at our hospital for 6 years after surgery for small cell carcinoma of left adrenal gland origin. Follow-up abdominal computed tomography showed a 6-cm mass in the left lower mesentery. The patient underwent open laparotomy. The histological diagnosis was sclerosing mesenteritis. The previous specimens of the left adrenal mass were then re-examined with a microscope, and panniculitis was found around the small cell carcinoma. Both lesions were histologically similar to IgG4-related disease (RD), but they did not completely meet the diagnostic criteria of IgG4-RD clinically or histologically.

The Helicobacter pylori infection and functional dyspepsia are often coexisted. The effect of acotiamide, a drug for functional dyspepsia, on the result of Helicobacter pylori diagnosis has yet to be studied. We evaluated the influence of acotiamide on the results of Helicobacter pylori diagnosis in the 13C-urea breath test. Twenty patients with Helicobacter pylori-positive functional dyspepsia were treated with 100 mg of acotiamide three times a day for two weeks. Changes in 13C-urea breath test were investigated before and after administration, and two weeks after administration as the follow-up period. The 13C-urea breath test and the medical questionnaire of modified frequency scale for the symptoms of gastroesophageal reflux disease were conducted at every period. Nineteen patients were included for analysis. No patients showed negative in 13C-urea breath test at Weeks 2 and 4. On the symptom scale, dyspepsia and total scores decreased from Week 0 to Week 2 and increased from Week 2 to Week 4, and the improvement rates of the dyspepsia score at Week 2 was 63%. In conclusion, we confirmed that acotiamide is unlikely to influence the result of 13C-urea breath test and it may improve the symptoms of functional dyspepsia during Helicobacter pylori eradication treatment.

Prediction of tissue origin of esophagogastric junction (EGJ) adenocarcinomas can be important for therapeutic decision, but no molecular marker is available. Here, we aimed to develop such a marker taking advantage of tissue-specific profiles of DNA methylation. DNA methylation profiles of gastric adenocarcinomas (GACs) were obtained by an Infinium HumanMethylation450 BeadChip array, and those of esophageal adenocarcinoma (EACs) were obtained from the TCGA database. DNA from formalin-fixed paraffin-embedded (FFPE) samples was analyzed by bisulfite pyrosequencing. In the screening set, 51 of 145,841 CpG sites in CpG islands were methylated at significantly higher levels in 30 GACs compared to those in 30 EACs. Among them, SLC46A3 and cg09177106 were unmethylated in all the 30 EACs. Predictive powers of these two markers were successfully confirmed in an independent validation set (18 GACs and 18 EACs) (SLC46A3, sensitivity = 77.8%, specificity = 100%; cg09177106, sensitivity = 83.3%, specificity = 94.4%), and could be applied to FFPE samples (37 GACs and 18 EACs) (SLC46A3, P = 0.0001; cg09177106, P = 0.0028). On the other hand, EAC-specific markers informative in the FFPE samples could not be isolated. Using these GAC-specific markers, nine of 46 (19.6%) TCGA EGJ adenocarcinomas were predicted to be GACs. Two GAC-specific markers, SLC46A3 and cg09177106, had a high specificity for identifying the tissue origin of EGJ adenocarcinoma.

In this study, the level of cell damage were analyzed immuno­histochemically to clarify the association between nodular gastritis and undifferentiated gastric cancer. Thirty patients of nodular gastritis were enrolled as the nodular gastritis group. Thirty patients of non-nodular gastritis were enrolled as the control group. They were evaluated according to the updated Sydney system and used for immunohistochemical staining (p53, Ki-67, E-cadherin, and 8-OHdG). The scores based on the updated Sydney system were significantly higher in the nodular group than in the non-nodular group for histologically assessed inflammation and activity in the gastric corpus (1.91 ± 0.77 vs 1.58 ± 0.60, p = 0.049, 0.83 ± 0.81 vs 0.44 ± 0.64, p = 0.032). On immunostaining, the detection of E-cadherin was lower in the nodular group for both the antrum (1.0 ± 0.62 vs 1.47 ± 0.85, p = 0.047) and the corpus (1.16 ± 0.81 vs 1.48 ± 0.71, p = 0.043) and the p53 labeling index of the gastric corpus was higher in the nodular group than in the non-nodular group (3.06 ± 1.94 vs 2.03 ± 1.99, p = 0.015). Nodular gastritis showed significant severe inflammation and immunohistochemical cell damage compared with non-nodular gastritis. These findings may play an important role in the oncogenesis of undifferentiated gastric cancer in nodular gastritis.

A fundic gland polyp (FGP) is a common gastric polyp. Intraepithelial neoplasia in FGPs, referred to as FGP with dysplasia, is often seen in patients with familial adenomatous polyposis (FAP). In sporadic FGPs, low-grade dysplasia (LGD) is rare, and high-grade dysplasia (HGD) or carcinoma arising from sporadic FGPs is extremely rare. Because of this rarity, the prognosis and appropriate management of these lesions have not been clarified. In the present case, a sporadic FGP with LGD did not develop into invasive carcinoma, but contained foci of HGD 14 years after diagnosis. The biopsy specimen of the polyp taken at the first esophagogastroduodenoscopy 15 years earlier was diagnosed as FGP without dysplasia. At the second histological examination, LGD was found. Because the polyp increased in size during proton pump inhibitor therapy for 14 years, endoscopic mucosal resection was performed. The pathological diagnosis of the resected specimen was FGP with HGD mixed in LGD, with no invasive carcinoma. Dysplasia in FGPs might have less malignant potential regardless of dysplasia or size.

Cap polyposis is a rare intestinal disorder. Characteristic endoscopic findings are multiple inflammatory polypoid lesions covered by caps of fibrous purulent exudate. Although a specific treatment has not been established, some studies have suggested that eradication therapy for Helicobacter pylori (H. pylori) is effective. We report a case of a 20-year-old man with cap polyposis presenting with hematochezia. Colonoscopy showed the erythematous polyps with white caps from the sigmoid colon to rectum. Histopathological findings revealed elongated, tortuous, branched crypts lined by hyperplastic epithelium with a mild degree of fibromusculosis in the lamina propria. Although H. pylori eradication was instituted, there was no improvement over six months. We then performed en bloc excision of the polyps by endoscopic submucosal dissection (ESD), which resulted in complete resolution of symptoms. ESD may be a treatment option for cap polyposis refractory to conservative treatments. We review the literature concerning treatment for cap polyposis and clinical outcomes.

Background: We previously reported the development of pancreatic acinar cell metaplasia (PACM) in the glandular stomach of a duodenal contents reflux model (reflux model)., Aims: We aimed to investigate the characteristics and histogenesis of PACM using a reflux model., Methods: A reflux model was created using 8-week-old male Wistar rats, which were killed up to 30 weeks postoperatively. Histological examination was performed to analyze the glandular stomach-jejunal anastomosis. Furthermore, electron microscopic images of PACM samples were compared with pancreatic and gastric glands removed from rats that had not undergone surgery. Immunostaining for α-amylase, HIK1083, TFF2, and Ki-67 was performed, and double fluorescent staining was carried out using antibodies against α-amylase and HIK1083, or α-amylase and TFF2., Results: In all reflux model rats, PACM was observed proximal to the glandular stomach-jejunal anastomosis, surrounded by pseudopyloric metaplasia. The number of chief cells was decreased in the deep part of the gland, where PACM occurred. Electron microscopy showed that PACM cells had greater numbers of rough endoplasmic reticulum tubules than chief cells, and exhibited pancreatic acinar cell morphology. Upon immunochemical staining, the regenerative foveolar epithelium and part of the pseudopyloric glands stained strongly positive for TFF2, whereas PACM cells were only weakly positive. Double fluorescent staining identified early lesions of PACM in the neck, which were double positive for α-amylase and TFF2, but negative for HIK1083., Conclusions:PACM could be induced by duodenal contents reflux. PACM originates from stem cells located in the neck of oxyntic glands during gastric mucosal regeneration.

The Helicobacter pylori infection and functional dyspepsia are often coexisted. The effect of acotiamide, a drug for functional dyspepsia, on the result of Helicobacter pylori diagnosis has yet to be studied. We evaluated the influence of acotiamide on the results of Helicobacter pylori diagnosis in the 13C-urea breath test. Twenty patients with Helicobacter pylori-positive functional dyspepsia were treated with 100 mg of acotiamide three times a day for two weeks. Changes in 13C-urea breath test were investigated before and after administration, and two weeks after administration as the follow-up period. The 13C-urea breath test and the medical questionnaire of modified frequency scale for the symptoms of gastroesophageal reflux disease were conducted at every period. Nineteen patients were included for analysis. No patients showed negative in 13C-urea breath test at Weeks 2 and 4. On the symptom scale, dyspepsia and total scores decreased from Week 0 to Week 2 and increased from Week 2 to Week 4, and the improvement rates of the dyspepsia score at Week 2 was 63%. In conclusion, we confirmed that acotiamide is unlikely to influence the result of 13C-urea breath test and it may improve the symptoms of functional dyspepsia during Helicobacter pylori eradication treatment.

Pyloric metaplasia (PM) and pseudopyloric metaplasia (PPM) are metaplastic changes resulting in pyloric-type glands in the gastric oxyntic mucosa that mainly occur in chronic gastritis caused by Helicobacter pylori (H. pylori) infection. Focusing on PM and PPM, we classified the histological changes in gastric mucosa according to the Updated Sydney System, using 314 biopsy specimens of gastric greater curvature of the middle body before H. pylori eradication (HPE). Next, the numbers of PM and PPM glands were counted in 47 specimens, and subjects were followed up over 10 years after HPE. PPM was recognized jointly with inflammation, activity, atrophy, and intestinal metaplasia, but PM was recognized more frequently than PPM as atrophy and intestinal metaplasia progressed. Both PM and PPM regressed significantly within 6 years after HPE. Additionally, we demonstrated that PM and PPM are not always coincident with spasmolytic polypeptide-expressing metaplasia (SPEM). In conclusion, PM and PPM are considered different modulations of the same line of differentiation, which are both reversible, with PM potentially emerging from PPM upon progression.

Aims The aim of this study was to clarify the histopathological features of fundic gland polyps (FGPs) in patients treated with proton pump inhibitors (PPIs) and to investigate the mechanism of enlargement of FGPs after PPI treatment. Methods and results A total of 196 biopsy specimens of FGPs, which consisted of 87 FGPs in patients treated with PPIs (PPI group) and 109 FGPs in patients treated without PPIs (non-PPI group) were compared histologically using haematoxylin and eosin staining, Ki67 immunohistochemistry and multiplex immunohistochemical stain with Ki67, MUC5AC and MUC6. The significant histological features of FGPs in the PPI group were: larger size of dilated fundic gland cysts, larger number of foveolar and mixture type fundic gland cysts, foveolar cell hyperplasia, parietal cell protrusion, mononuclear cell infiltration and a higher percentage of Ki67-positive cells in the deeper layers of the glands. Multiplex immunohistochemical stain showed that Ki67-positive cells were also positive for MUC5AC, and the Ki67-positive rate was significantly higher in MUC5AC-positive cells of the PPI group than of the non-PPI group. Gene mutations of β-catenin were found in only 9.7% of FGPs in the PPI group. Conclusions Enlargement of fundic gland cysts due to foveolar cell proliferation and parietal cell protrusion might promote the enlargement of FGPs in patients treated with PPIs. β-catenin gene mutations might not be associated with these histological changes of FGPs after PPI treatment.

A fundic gland polyp (FGP) is a common gastric polyp. Intraepithelial neoplasia in FGPs, referred to as FGP with dysplasia, is often seen in patients with familial adenomatous polyposis (FAP). In sporadic FGPs, low-grade dysplasia (LGD) is rare, and high-grade dysplasia (HGD) or carcinoma arising from sporadic FGPs is extremely rare. Because of this rarity, the prognosis and appropriate management of these lesions have not been clarified. In the present case, a sporadic FGP with LGD did not develop into invasive carcinoma, but contained foci of HGD 14 years after diagnosis. The biopsy specimen of the polyp taken at the first esophagogastroduodenoscopy 15 years earlier was diagnosed as FGP without dysplasia. At the second histological examination, LGD was found. Because the polyp increased in size during proton pump inhibitor therapy for 14 years, endoscopic mucosal resection was performed. The pathological diagnosis of the resected specimen was FGP with HGD mixed in LGD, with no invasive carcinoma. Dysplasia in FGPs might have less malignant potential regardless of dysplasia or size.

A 62-year-old man with epigastralgia was referred to our hospital for the evaluation of an intractable duodenal ulcer, which did not improve following proton pump inhibitor treatment. An upper gastrointestinal endoscopy revealed that the base of the ulcer was gray-white in color with conspicuous fibrosis tissue, unlike the appearance of common ulcers. A contrast-enhanced abdominal CT scan and angiography revealed tortuous and dilated vascular structures in the pancreatic head. This was diagnosed as a pancreatic arteriovenous malformation. We suggest that the intractable duodenal ulcer was caused by the pancreatic arteriovenous malformation. Therefore, we performed a pancreaticoduodenectomy. Pancreatic arteriovenous malformations should be considered as one of the causes of treatment-resistant duodenal ulcers.

Mizuki Tagami, Ryuto Sai, Masahide Fukuda, Atsushi Azumi Ophthalmology Department, Eye Center, Kobe Kaisei Hospital, Kobe, Hyogo, Japan Purpose: This study was conducted to investigate the outcome of switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO) in daily practice. Materials and methods: This retrospective study enrolled 15 eyes in 15 Japanese patients with ME secondary to BRVO who had been receiving a pro re nata regimen of ranibizumab and had provided written informed consent to switch to aflibercept therapy. The intravitreal injection interval, central retinal thickness, and visual acuity were evaluated before and after switching. Results: The mean period of ranibizumab treatment was 11.8±4.2 months. The mean observation period after switching to aflibercept was 10.6±3.4 months, and seven patients were observed for more than 12 months after switching. The mean intravitreal injection interval was prolonged by 23.6 days with aflibercept (68.2±26.4 days with ranibizumab vs 91.8±33.2 days with aflibercept; P=0.0011). The mean intravitreal injection interval just before the switch was 81.3±35.6 days and was significantly prolonged to 100.8±34.2 days just after the switch to aflibercept (P=0.0309). The mean central retinal thickness did not change before or after the switch to aflibercept (295±55 µm with ranibizumab vs 276±25 µm with aflibercept; P=0.12). The mean visual acuity also remained at an improved level after the switch. No systemic or ocular side effects were evident during the study period. Conclusion: Switching therapy from ranibizumab to aflibercept in Japanese patients with ME secondary to BRVO prolonged the intravitreal injection interval without anatomical or functional degradation. Keywords: branch retinal vein occlusion, macular edema, ranibizumab, aflibercept

Behçet's disease (BD) is a systemic inflammatory disorder polarised to the Th1 and Th17 immune systems. Allergic diseases are polarised to the Th2 immune system. The aim of the present study is to investigate the prevalence of allergic diseases in patients who have BD.The study involved a large-scale interview survey of Japanese patients with BD at 21 institutes of ophthalmology; 353 patients (255 males and 98 females) were recruited for this study. We analysed the history of allergic diseases such as atopic dermatitis (AD), allergic rhinitis (AR), bronchial asthma (BA) and drug/food allergies (FA).Oral aphthous ulcers, ocular lesions, skin lesions, genital ulcers, arthritis, neurological lesions, intestinal lesions, deep vein thrombosis and epididymitis were reported in 95.8%, 98.6%, 72.5%, 44.8%, 13.9%, 6.8%, 6.2%, 3.7% and 1.4% of the patients, respectively. It was also reported that 73 patients (20.7%) had histories of allergic diseases: AD (5 cases, 1.4%), AR (36 cases, 10.2%), BA (19 cases, 5.4%) and FA (30 cases, 8.5%). This percentage was significantly lower than in a survey that Japan's Ministry of Health, Labour and Welfare conducted for healthy population (47.6%) (odds ratio = 0.29, 95% confidence interval = 0.22-0.38, p=4.9×10-22). Frequencies of posterior/pan-uveitis, relatively severe ocular findings, and visual prognosis were not affected by a history of allergic diseases in BD.Patients with BD had fewer complications from allergic diseases than did the entire population of Japan.

Diabetes redistributes the expression of glial aquaporin (AQP) water channels in the retina. However, it is not known whether diabetes also affects retinal AQP-0 expression. This study examined the effects of the development of diabetes on the expression of retinal AQP-0 in spontaneously diabetic Torii (SDT) rats. Male SDT rats at 10 and 40 weeks of age and age-matched male Sprague-Dawley (SD) rats were used. The localization of AQP-0 was assessed immunohistochemically using sagittal cryosections of the rats’ retinas and optic nerves. Fold changes in AQP-0 gene expression relative to controls were assessed by real-time RT-PCR. All SDT rats spontaneously developed diabetes by 40 weeks of age (the mean hemoglobin (Hb) A1c levels were 2.8 ± 0.2% and 11.2 ± 1.0% at 10 and 40 weeks, respectively). SD rats did not develop diabetes (the HbA1c levels were 2.7 ± 0.2% and 2.6 ± 0.3% at 10 and 40 weeks, respectively). In the retinas of SD rats and in those of SDT rats at 10 weeks of age, immunoreactivity for AQP-0 was confined predominantly to the inner nuclear layer and to the border between the inner plexiform layer and the ganglion cell layer (GCL), where AQP-0 colocalized with protein kinase C-α. AQP-0 immunoreactivity was also observed in the GCL to a lesser degree, which colocalized with the neuronal nuclei. In the 40-week-old SDT rat retinas, additional AQP-0 immunoreactivity was observed in the GCL and colocalized with neurofilaments, indicating expression of AQP-0 in ganglion cell axons. However, the axonal AQP-0 immunoreactivity was restricted to the retinal nerve fibers, whereas the optic nerve axons were devoid of AQP-0. Retinal blood vessels did not express AQP-0. AQP-0 gene expression was 3.4-fold higher in SDT rat retinas than in SD rat retinas at 40 weeks of age. AQP-0 was predominantly expressed in the bipolar cells of the non-diabetic rat retinas, whereas it was also expressed in the retinal nerve fibers of diabetic rat retinas. The disrupted water transport between astrocytes and retinal nerve fibers may be associated with the known accelerated apoptosis of retinal ganglion cells induced by diabetes.

Evidence is mounting that not only microangiopathy, but also neurodegenerative events occur in the retinas of humans and rodents with early diabetes. Diverse pathologies are known to alter the amount and/or location of glial expression of the water-selective channels aquaporins (AQPs) 1 and 4. However, the temporal relationships among glial activation, the altered expression of the AQP proteins and neuronal death in the retinas of diabetic animals remains to be investigated. Male spontaneously diabetic Torii (SDT) rats reportedly develop diabetes by 40 weeks of age at the latest and manifest proliferative diabetic retinopathy at 50 weeks or later. This study compared temporal changes in neuroretinal apoptosis, glial fibrillary acidic protein (GFAP) expression and the expression of AQPs 1 and 4 between SDT rat retinas and age-matched Sprague-Dawley (SD) rat retinas. Cell death was detected by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling on retinal flatmounts and activated caspase 3 immunofluorescence of retinal cryosections. The expression of GFAP and AQPs 1 and 4 was assessed by immunohistochemistry of cryosections and retinal flatmounts. Diabetes started to develop around 15 weeks in SDT rats. Apoptotic cells in the ganglion cell layer and the inner nuclear layer were significantly more numerous in 40-week-old SDT rat retinas than in either age-matched SD rat retinas or 10-week-old SDT rats. GFAP immunoreactivity was confined to the nerve fiber layer both in SD and SDT rats at 10 weeks, whereas it spanned the whole retina in SDT rats, but not in SD rats, at 40 weeks. AQP1 was expressed in the outer retina, whereas AQP4 was expressed in the perivascular and end feet of Muller cells and astrocytes in the inner retina in the control SD rats and the SDT rats at 10 weeks. The perivascular AQPs shifted from AQP4 to AQP1 in 40-week-old SDT rats that exhibited marked hyperglycemia. Thus, the development of diabetes increases neuroretinal apoptosis, and this coincides with an altered expression pattern of GFAP and water-selective channels AQPs 1 and 4 in SDT rats.

To investigate whether tafluprost, which is a prostaglandin-related compound and an anti-glaucoma drug, has a direct anti-apoptotic effect in cultured retinal ganglion cells (RGCs) and rat RGCs in retinas with optic nerve crush (ONC).RGC-5 cells were induced to undergo apoptosis by a serum deprivation and by exogenous glutamate. The level of cell death with or without tafluprost was monitored by an XTT assay and by immunocytochemistry with activated caspase-3. Changes in intracellular calcium ([Ca(2+)]i) levels were measured with fluo-4 fluorescence. Rat RGCs were degenerated by ONC. After topical instillation of tafluprost for 7 and 14 days, the numbers of retrograde-labeled RGCs were counted. Retinal flatmounts were subjected to terminal dUTP nick end labeling (TUNEL) staining to detect apoptotic cells.Tafluprost dose-dependently promoted RGC-5 cell viability with an optimum concentration of 3 microM (p = 0.006). Tafluprost significantly reduced caspase-3-positive cells and suppressed [Ca(+2)]i evoked by exogenous glutamate. The cGMP-dependent protein kinase inhibitor and KT-5823 partially blocked the rescue effect of tafluprost (p = 0.002). The survival rate of RGCs significantly increased in eyes treated with tafluprost (p = 0.01), and the prevalence of TUNEL-positive cells was significantly decreased 14 days after ONC (p0.001).These data suggest that tafluprost has an anti-apoptotic effect in RGCs.

This study was conducted to investigate the outcome of switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO) in daily practice.This retrospective study enrolled 15 eyes in 15 Japanese patients with ME secondary to BRVO who had been receiving a pro re nata regimen of ranibizumab and had provided written informed consent to switch to aflibercept therapy. The intravitreal injection interval, central retinal thickness, and visual acuity were evaluated before and after switching.The mean period of ranibizumab treatment was 11.8±4.2 months. The mean observation period after switching to aflibercept was 10.6±3.4 months, and seven patients were observed for more than 12 months after switching. The mean intravitreal injection interval was prolonged by 23.6 days with aflibercept (68.2±26.4 days with ranibizumab vs 91.8±33.2 days with aflibercept;Switching therapy from ranibizumab to aflibercept in Japanese patients with ME secondary to BRVO prolonged the intravitreal injection interval without anatomical or functional degradation.

A quantitative analysis of the tetragonal phase in Mg-PSZ by a standard X-ray powder diffraction method was carried out using the diffraction intensities with the Miller indices (311). The volume fraction of the tetragonal phase is shown to be given byVt=2.92/(1+0.991 X), where X={It(311)+Ic(311)}/It(113) which involves the diffraction intensities It and Ic of the corresponding tetragonal and cubic phases. The standard error of this method was estimated to be 4.5%. The present result is applicable to evaluate the tetragonal phase and the cubic phase in Mg-PSZ which contains the monoclinic phase less than 37%.

Sintered body of ZrO2-3.3mass%MgO was prepared, and the bulk density, pore size, transverse-rupture strength (TRS) and the fracture origin were studied in relation with the average particle size ranged from 1.1 to 0.6μm of the powder specimen, which was prepared by an attrition mill with 2-propanol solvent and zirconia ball. The test sample was obtained by sintering at 1680°C×2hr and aging at 1080°C×20hr. TRS was measured by the 3 point-bending and the fracture origin was extensively studied for the samples sintered with three different size particles: 1.1, 0.8 and 0.6μm.As the particle size was lowered, the bulk density increased from 5.60 to 5.82g/cm3 and both the pore size and its number decreased. TRS of 661, 700 and 623MPa was obtained for 1.1, 0.8 and 0.6μm powders, respectively. Through the observation of transverse-ruptured surface by SEM, the pore was concluded to be responsible as the fracture origin, and the corresponding pore size was measured on each fracture. It was concluded that the 0.8μm sample, in comparison with the 1.1μm sample, increased in TRS by improved solidification and pore size, while the 0.6μm sample lowered in TRS by an over grown grain size in spite of its highly solidified body.

The sintered WC compact was machined by electric discharge machining, and then annealed in vacuum at 800-1300°C for the time up to 80hrs. The phase change of different phases (β-WC1-x, W2C) appearing along the machining surface was studied as functions of annealing temperature and time. It was found that the different phases had a tendency to disappear and finally change to WC. Such a phase change could be explained by assuming that two sorts of eutectoid reactions, that is, β-WC1-xW2C+WC and W2CW+WC took place during annealing, and that the formed W2C or W changed to WC, because they reacted with the free carbon remaining in non-equilibrium state in the surface layer. Microstructural changes of surface layer due to annealing were in detail studied.

The transverse-rupture strength of WC-(10, 20)%Co alloys oxidized in air at the temperature of 973-1173 K for the time of 0.3-1.8 ks was studied as a function of Co content, carbon content of alloys, WC grain size and r-domain size. It was found that the strength of the alloy decreased owing to the surface oxidation and the strength decrease became larger with rising temperature and increasing time. It was noted that the strength decrease was enhanced with increasing r-domain size. It was also found that the rate of oxidation was faster in the domain boundary than inside the domain, so that the domain boundary after oxidation acted as a notch during transverse-rupture test, leading to the strength decrease.

We investigated whether latanoprost has a direct anti-apoptotic effect in retinal ganglion cell (RGC) line and RGCs in the rat. RGC-5 cells were induced to undergo apoptosis by serum deprivation and exogenous glutamate. The level of cell death with or without latanoprost acid was monitored by an XTT assay and by immunocytochemistry with activated caspase-3. Changes in the level of intracellular calcium ([Ca(2+)]i) were measured with fluo-4 fluorescence. The XTT assay revealed that latanoprost acid increased RGC-5 cell viability. Latanoprost acid significantly reduced caspase-3 positive cells and suppressed [Ca(2+)]i evoked by glutamate. U0126, a mitogen-activated protein/extracellular signal-regulated kinase 1 and 2 inhibitor, partially blocked the rescue effect of latnanoprost acid (p=0.013). In vivo, rat RGCs were degenerated by optic nerve crush. After topical instillation of latanoprost for 7days, RGCs labeled with fluorogold were significantly. Retinal flatmounts were subjected to terminal dUTP nick end labeling (TUNEL) staining to detect apoptotic cells. TUNEL-positive cells were significantly decreased in eyes with topically instilled latanoprost (p=0.015). These data suggest that latanoprost has an neuroprotective ability in RGCs.

High carbon WC-(10, 20)mass%Co micro-grained alloys containing no Cr3C2 or 5.0 mass%Cr3C2 in binder, were prepared by solid-phase sintering, that is, vacuum sintering at 1473-1553K and then HIP-treatment at 1523 K. Some properties such as microstructure and mechanical properties were studied. It was found that the alloys prepared by solid-phase sintering, for instance, sintering at 1523K for 10.8ks and then HIP-treatment, reached full density and showed excellent mechanical properties. As to the transverse-rupture strength, the alloys, having grain size of 0.5-0.6 μm, exhibited the value so high as about 3.5 GPa or more, independent of binder content or Cr3C2 addition. It was noted that WC grains recrystallized during solid-phase sintering.

The WC-(10, 20, 30)%Co alloys were minutely vacuum-sintered, so that the defect acting as a fracture source in each alloy might almost consist of coarse WC grains smaller than about 20μ. Two sorts of cooling rates after sintering, about 15°and 0.5°C/min, were adopted in the temperature range from 1360°to 1300°C for 10%Co alloy, 1350°to 1300°C for 20%Co alloy and 1340°to 1300°C for 30%Co alloy, respectively. Two sorts of specimens different in cooling rates in each alloy were ground with a diamond wheel, and transverse-ruptured according to JIS. After the test, the dimension (2a) and location of coarse WC grains as a fracture source were measured on the ruptured surface.The results obtained were as follows: 1) The average transverse-rupture strength (σm), and also the external stress (σd) corresponding to σm were always higher in rapidly cooled specimen (R-specimen) than in slowly cooled specimen (S-specimen). 2) The 2a of R-specimen was generally smaller than that of S-specimen, showing that of an anomalous grain growth of WC also occurred during the time of cooling specimens, when the cooling rate was decreased. 3) The distance from the tension surface to the defect (Δt) of R-specimen was larger in 10%Co alloy than that of S-specimen. However, the difference in Δt was hardly observed in (20, 30)%Co alloys. It was found in a slowly cooled 30% Co alloy that the location of the defect was always on the domain boundary of binder phase. 4) The increase in Δm and σd due to increasing cooling rate was considered to be affected mainly by the increase in the strength of WC-Co matrix including that of the domain boundary, and partially by the changes in 2a and Δt.

The WC-(6-30)%Co high carbon alloys with mean grain size of about 1.7μ were in vacuum sintered, and subsequently four side surfaces of specimens were ground by diamond wheel to prepare the bending test pieces, or further polished to remove the surface layer associated with the residual compressive stress due to grinding. Two sorts of test pieces in each alloy were Vickers-indentated under various loads at the span center, and used for the transverse-rupture test. The difference in strength between two sorts of test piece was examined in each alloy and the residual compressive stress, which may effectively suppress the crack propagation in WC-Co alloys, was estimated.The results obtained were as follows: 1) A linear relationship between the difference in strength and the depth of Vickers indentation was observed within the accuracy of this experiment, and the value obtained by extrapolating the straight line to zero depth of indentation was considered to he an effective compressive stress (σre) on the surface of ground specimen. The σre of 6, 10 and 30%Co alloys, for example, was about 160, 100 and 10 kg/mm2, respectively; showing that the value decreased sharply with increasing Co content of the alloy. 2) The difference in strength was not almost affected in each alloy by the depth of Vickers indentation. Namely, the strength of ground specimens having indentation was usually higher by about are than that of polished specimens. Under the same depth of indentation, the strength of ground specimens did not almost change with the Cc content, although that of polished specimens decreased by a large amount with decreasing Co contents. Discussions on those results as well as on are were made.

It was previously reported by the present authors that flaky structures consisting of βt often appeared and acted as fracture sources in WC-βt-Co alloy, the structures being caused by the agglomerated flaky powder formed during ball-milling. The mechanism why the flaky structures developed during sintering was studied. It was suggested that the flaky structures were formed, as the result of different kinds of massflows such as liquid flow, and solution and precipitation of WC and βt particles, taking place in or near the region of flaky powder during sintering.