Changes in Density of Peripapillary and Intrapapillary Capillaries on OCT Angiography in Acute Retinal Necrosis Treated by Pharmacotherapy Alone without Surgery.

PURPOSE: To analyze radial peripapillary capillaris (RPC) and intra-papillary capillaris (IPC) using optical coherence tomography angiography (OCTA) in acute retinal necrosis (ARN) with good outcome. METHODS: RPC and IPC were analyzed by OCTA in patients diagnosed with ARN and treated with pharmacotherapy alone without surgery at the Tokyo Medical University Hospital. RESULTS: A total of 13 patients were studied. Ophthalmoscopic examination showed no abnormality in the optic disc in 12 of the 13 patients. However, OCTA findings of the affected eye compared with the unaffected fellow eye revealed morphological abnormalities in RPC in nine cases (69%) and decrease in capillary network in RPC or IPC in eight cases (62%). CONCLUSION: In ARN, RPC and IPC were impaired even in eyes that were healed with medical treatment only without requiring surgical intervention and had no abnormal findings on ophthalmoscopic examination. This result suggests the presence of some degrees of optic neuropathy even in mild cases with good visual prognosis.

The Differences of Mechanisms in Antihypertensive and Anti-Obesity Effects of Eucommia Leaf Extract between Rodents and Humans.

In the 1970s, Eucommia leaf tea, known as Tochu-cha in Japanese, was developed from roasted Eucommia leaves in Japan and is considered as a healthy tea. The antihypertensive, diuretic, anti-stress, insulin resistance improving, and anti-obesity effects of Eucommia leaf extract have been reported. However, the identification and properties of the active components as well as the underlying mechanism of action are largely unknown. In this review, we summarize studies involving the oral administration of geniposidic acid, a major iridoid component of Eucommia leaf extract which increases plasma atrial natriuretic peptide (ANP) on the atria of spontaneously hypertensive rats (SHR) by activating the glucagon-like peptide-1 receptor (GLP-1R). To achieve the antihypertensive effects of the Eucommia leaf extract through ANP secretion in humans, combining a potent cyclic adenosine monophosphate phosphodiesterase (cAMP-PDE) inhibitor, such as pinoresinol di-ß-d-glucoside, with geniposidic acid may be necessary. Changes in the gut microbiota are an important aspect involved in the efficacy of asperuloside, another component of the Eucommia leaf extract, which improves obesity and related sequelae, such as insulin resistance and glucose intolerance. There are species differences of mechanisms associated with the antihypertensive and anti-obesity effects between rodents and humans, and not all animal test results are consistent with that of human studies. This review is focused on the mechanisms in antihypertensive and anti-obesity effects of the Eucommia leaf extract and summarizes the differences of mechanisms in their effects on rodents and humans based on our studies and those of others.

Anti-TNF-α Therapy for Refractory Uveitis Associated with Behçet's Syndrome and Sarcoidosis: A Single Center Study of 131 Patients.

PURPOSE: The efficacy of infliximab (IFX) and adalimumab (ADA) for treating Behçet's syndrome (BS) and sarcoidosis has not been compared adequately. METHODS: We reviewed the medical records of patients with uveitis diagnosed at Tokyo Medical University Hospital and compared the efficacy of IFX and ADA for BS and the efficacy of ADA for sarcoidosis and BS. RESULTS: 68 patients in IFX group and 63 patients in ADA group were analyzed. In BS patients, IFX and ADA were both effective in improving uveitic macular edema (UME). ADA improved UME in BS but not in sarcoidosis patients. The efficacy of ADA in reducing doses of corticosteroids and glaucoma medications was better in sarcoidosis than in the BS group. CONCLUSION: Both IFX and ADA are efficacious in improving UME in BS patients. The reason that ADA improves UME better in BS than in sarcoidosis may be due to the difference in pathogenesis between these diseases.

The Biological Effects of Forsythia Leaves Containing the Cyclic AMP Phosphodiesterase 4 Inhibitor Phillyrin.

Forsythia fruit (Forsythia suspensa Vahl (Oleaceae)) is a common component of Kampo medicines for treating the common cold, influenza, and allergies. The main polyphenolic compounds in the leaves of F. suspensa are pinoresinol ß-d-glucoside, phillyrin and forsythiaside, and their levels are higher in the leaves of the plant than in the fruit. It is known that polyphenolic compounds stimulate lipid catabolism in the liver and suppress dyslipidemia, thereby attenuating diet-induced obesity and polyphenolic anti-oxidants might attenuate obesity in animals consuming high-fat diets. Recently, phillyrin was reported as a novel cyclic AMP phosphodiesterase 4 (PDE4) inhibitor derived from forsythia fruit. It was expected that the leaves of F. suspensa might display anti-obesity effects and serve as a health food material. In this review, we summarized our studies on the biological effects of forsythia leaves containing phillyrin and other polyphenolic compounds, particularly against obesity, atopic dermatitis, and influenza A virus infection, and its potential as a phytoestrogen.

Changes in Etiology of Uveitis in a Single Center in Japan.

Purpose: We investigated the changes in etiology of uveitis at the Uveitis Clinic of Tokyo Medical University Hospital in recent years.Methods: Medical records of patients with uveitis diagnosed between 2011 and 2017 (Group A) and between 2001 and 2007 (Group B) were reviewed.Results: 1,587 patients in group A and 1,507 patients in group B were analyzed. For noninfectious uveitis, frequencies of Vogt-Koyanagi-Harada disease, intraocular lymphoma (IOL) and iridocyclitis in young girls increased, while those of sarcoidosis and Behçet's disease decreased in the recent era. For infectious uveitis, herpetic iridocyclitis, ocular toxoplasmosis, ocular syphilis, and bacterial endophthalmitis increased, while acute retinal necrosis and ocular toxocariasis decreased. Unclassified uveitis decreased, whereas infectious uveitis and IOL increased due to the availability of new diagnostic tests.Conclusion: Etiologies of uveitis have changed over the years. Further development of novel tests and diagnostic criteria would increase definitive diagnosis for unclassified uveitis. (147/150 words).

An unusual case of Behcet disease with posterior scleritis: A case report.

RATIONALE: Posterior scleritis is an ocular inflammatory disorder that can be associated with both infectious and non-infectious immune reactions. Behcet disease is a chronic, relapsing, multisystemic inflammatory disorder with uveitis. There are no reported cases of posterior scleritis with Bechet disease. PATIENT CONCERNS: A 50-year-old man previously diagnosed with systemic Behcet disease presented with ocular pain and decreased vision in the left eye. DIAGNOSIS: Posterior scleritis associated with Behcet disease was diagnosed based on optical coherence tomography showing choroidal folds, as well as contrast computed tomography and ultrasound sonography demonstrating thickening of the posterior sclera. INTERVENTIONS: Treatment with systemic corticosteroids was initiated. Since inflammation relapsed during steroid tapering, anti-tumor necrosis factor-alpha (TNF-α) therapy was used in combination, and tapering of steroids was possible without recurrence of inflammation for 12 months. OUTCOMES: Posterior scleritis was resolved and visual acuity improved. With the continuation of TNF-α therapy, oral prednisolone was successfully tapered and discontinued. No relapse of inflammation was observed at follow-up 1 year after discontinuation of prednisolone. LESSONS: Ophthalmologists should be aware of the possibility of rare manifestation of posterior scleritis in patients with Behcet disease, and that combined use of systemic steroids and anti-TNF-α therapy may resolve the scleritis without recurrence of inflammation.

Clinical features of anterior uveitis caused by three different herpes viruses.

PURPOSE: To compare the clinical findings in patients with anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). METHODS: We retrospectively analyzed the clinical profiles of HSV-AU (14 patients), VZV sine herpete (ZSH-AU: 21 patients), and CMV-AU (17 patients) diagnosed by the detection of corresponding viral DNA in aqueous humor samples by polymerase chain reaction. Further, five patients with Posner-Schlossman (P-S) syndrome were selected as controls for CMV-AU. RESULTS: Patients with CMV-AU were predominately male or older in age, and all cases were unilateral except for three patients with CMV-AU. Mutton-fat keratic precipitates (KPs) were found mostly in patients with HSV-AU and ZSH-AU. Severities of AU and viral load were the highest in ZSH-AU, followed by HSV-AU and CMV-AU. Iris atrophy was observed in HSV-AU (50%) and ZSH-AU (76%), with typical morphology of round type and sector type, respectively. In patients with CMV-AU, a ring-shaped KP was found in 53% patients, 76% of whom showed a decreased number of corneal endothelial cells. CMV was not detected in the aqueous humor of patients with typical P-S syndrome. CONCLUSION: Clinical findings of HSV-AU and VZV-AU were similar; however, more inflammatory findings were observed in VZV-AU. Iris atrophy morphologically differed in HSV-AU and VZV-AU. Inflammatory findings in CMV-AU were mild, and clinical features of iritis differed from those of the two former groups. A difference in the etiology between CMV-AU and P-S syndrome was observed.

Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration.

We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities.

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2-4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2-4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.

Quantitative Analysis of Southern rice black-streaked dwarf virus in Sogatella furcifera and Virus Threshold for Transmission.

We investigated Southern rice black-streaked dwarf virus (SRBSDV) accumulation in a vector insect, the whitebacked planthopper (Sogatella furcifera), to elucidate the association of virus accumulation in the vector with virus transmission efficiency. Real-time quantitative reverse transcription polymerase chain reaction analysis confirmed that this virus is transmitted in a persistent-propagative manner. SRBSDV was successfully transmitted by S. furcifera males in which RNA accumulation of the capsid protein gene of SRBSDV was >10(3) in the whole body of S. furcifera, indicating that the threshold accumulation of the virus RNA for virus transmission is 10(3) in an S. furcifera male. The SRBSDV detection rate in the immigrant population of S. furcifera was high in 2011 (39.5%); however, most of the insects contained fewer than 10(3) RNAs of the capsid protein gene. This result indicates that the risk of SRBSDV epidemics could be estimated from the proportion of virus-transmissible S. furcifera (i.e., S. furcifera that contained more than 10(3) RNAs of the virus capsid protein gene) rather than the SRBSDV detection rate in S. furcifera.

A case of herpes zoster uveitis with severe hyphema.

BACKGROUND: Uveitis sometimes causes hyphema, but severe hyphema as a complication following herpes zoster uveitis has rarely been reported. We report a rare case of zoster sine herpete with unusually severe hyphema. CASE PRESENTATION: A 41-year-old Japanese female developed hyphema filling almost one-half of the depth of the anterior chamber after a two-week history of unilateral anterior uveitis. Hyphema persisted for four weeks while sectorial iris atrophy became gradually apparent. Systemic prednisolone and valaciclovir resulted in prompt resolution of uveitis and hyphema. Serum anti-varicella zoster virus (VZV) IgG measured by enzyme immunoassay was 116 at presentation and decreased to 20.3 four month later. In addition, the antibody level in aqueous humor was almost 10-fold higher than that in serum examined 9 months after presentation. Because there was no skin lesion, this case was diagnosed as zoster sine herpete. The patient underwent cataract operation due to secondary cataract. The final visual acuity in decimal notation was 1.0, but complications such as severe iris atrophy, wide anterior synechiae, corneal opacity, and decrease in corneal endothelial cell count remained. CONCLUSION: Zoster sine herpete is an important differential diagnosis in a case of acute anterior uveitis with severe hyphema, although such cases are quite rare. Measurement of anti-VZV IgG levels by enzyme immunoassay in aqueous humor and serum would be useful in the diagnosis of VZV reactivation. Prompt diagnosis and administration of corticosteroids and anti-herpes virus medication may improve the outcome.

Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts.

Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia-reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia-reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5×10(-8) M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca(2+)([Ca(2+)]m) uptake induced by changes in the Ca(2+) content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff-perfused hearts. Fluvoxamine inhibited the increase in [Ca(2+)]m induced by changes in the Ca(2+) content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca(2+)]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia-reperfusion hearts.

Biological and genetic diversity of Wheat yellow mosaic virus (Genus Bymovirus).

The biological and genetic diversity of Wheat yellow mosaic virus (WYMV) isolates in Japan was characterized. On the basis of wheat cultivar reactions, 14 WYMV isolates from various places were classified into pathotypes I, II, or III. These were distributed in central, northern, and southern areas of Japan, respectively. WYMV isolates comprised three genotypes (A, A' and B) based on amino acid differences in RNA1 and two genotypes (a and b) based on amino acid differences in RNA2. A correlation was found between the WYMV RNA1-based genotype and pathotype, suggesting that factors associated with pathogenicity map to RNA1. Genotype Aa and A'a were distributed mainly in the central to southern areas of Japan, and genotype Bb was found in northern areas of Japan, as shown by reverse-transcription polymerase chain reaction restriction fragment length polymorphism analysis. Chinese isolates YA and YZ were closely related to genotypes Bb and Aa, respectively. Wheat was introduced from China to Japan in the 4th and 5th centuries, and the two genotypes of WYMV might also have been introduced with the crop from China and later adapted to local wheat cultivars in Japan.

Dynamics of Southern rice black-streaked dwarf virus in rice and implication for virus acquisition.

A novel viral disease of rice caused by Southern rice black-streaked dwarf virus (SRBSDV) has spread throughout East and Southeast Asia since the mid-2000s. Outbreaks of this viral disease occur yearly in southern parts of Japan concurrently with overseas migration of the planthopper vector Sogatella furcifera from southern China during the rainy season (from late June to early July). We examined the dynamics (changes in titer and localization) of SRBSDV on rice using reverse-transcription real-time polymerase chain reaction and determined the relationship between virus titer in plants and virus acquisition by S. furcifera. Under a constant temperature of 27°C, a substantial increase of SRBSDV titer in the leaf sheath together with typical symptoms (stunted growth and twisting of leaf tips) was observed at 20 days after the end of a 7-day exposure of viruliferous S. furcifera. Approximately 40% of S. furcifera acquired SRBSDV through feeding for 5 days on rice plants that were infected following exposure to viruliferous vectors for 10 to 15 days. These results suggest that rice infected by S. furcifera can be a source of SRBSDV before the next generation of S. furcifera emerges.

Inhibition of hydrogen embrittlement of Ni-Ti superelastic alloy in acid fluoride solution by hydrogen peroxide addition.

Inhibition of the hydrogen embrittlement of Ni-Ti superelastic alloy in an acidulated phosphate fluoride (APF) solution has been attempted by adding various amounts of H(2)O(2). In a 0.2% APF solution, hydrogen absorption is markedly inhibited by adding H(2)O(2), although corrosion is slightly enhanced by increasing the amount of added H(2)O(2). By adding a small amount of H(2)O(2) (0.001 M), in the early stage of immersion, hydrogen embrittlement is inhibited and corrosion is only slightly enhanced. Upon adding H(2)O(2), it appears that the dominant cathodic reactions change from hydrogen evolution to H(2)O(2) reduction reactions, or the surface conditions of the alloy are changed by H(2)O(2) with a high oxidation capability, thereby inhibiting hydrogen absorption. The present study clearly indicates that infinitesimal addition of H(2)O(2) into acid fluoride solutions is effective for the inhibition of the hydrogen embrittlement of the alloy.

The structure of a new cardenolide diglycoside and the biological activities of eleven cardenolide diglycosides from Nerium oleander.

A new cardenolide diglycoside (1) was isolated from Nerium oleander together with ten known cardenolide diglycosides 2-11. The structure of compound 1 was established on the basis of their spectroscopic data. The in vitro anti-inflammatory activity of compounds 1-11 was examined on the basis of inhibitory activity against the induction of the intercellular adhesion molecule-1 (ICAM-1). Compounds 2-5 were active at an IC(50) value of less than 0.8 µM. The cytotoxicity of compounds 1-11 was evaluated against three human cell lines normal human fibroblast cells (WI-38), malignant tumor cells induced from WI-38 (VA-13), and human liver tumor cells (HepG2). Compound 3 was active toward VA-13 cells, and compounds 2-5 were active toward HepG2 cells at IC(50) values of less than 1.3 µM. The multidrug resistance (MDR)-reversal activity of compounds 1-11 was evaluated on the basis of the amount of calcein in MDR human ovarian cancer 2780AD cells in the presence of each compound. Compounds 1 and 8 showed moderate effects on calcein accumulation.

Three new cardenolides from methanol extract of stems and twigs of Nerium oleander.

Two new cardenolide monoglycosides, cardenolides B-1 (1) and B-2 (2) were isolated from Nerium oleander, together with oleagenin (3) which is the first isolated compound from natural sources. The structure of compounds 1-3 were established on the basis of their spectroscopic data.

[Pars plana vitrectomy in patients with acute retinal necrosis syndrome: surgical results in 52 patients].

PURPOSE: To analyze results of pars plana vitrectomy for acute retinal necrosis (ARN) syndrome. METHODS: We reviewed the records of 52 eyes with ARN syndrome who underwent pars plana vitrectomy at the Tokyo Medical University Hospital from 1989 to 2007. The mean age was 50.1 +/- 10.2 years and the mean follow-up duration was 75.3 months. The causative virus was herpes simplex virus in 7 cases and varicella zoster virus in 45 cases. In all cases, treatment with acyclovir and corticosteroids was started from presentation. During the follow-up period, vitrectomy was done in patients who developed retinal detachment, and in those who developed posterior vitreous detachment exerting marked traction on the retina, even though retinal detachment had not occurred. In these cases, preoperative and postoperative visual acuities were compared and reoperation, retinal detachment preventive surgery and age-stratified visual prognosis after vitrectomy were analyzed. RESULTS: Visual acuity was improved by 2 lines or more in 13 eyes (25.0%), remained unchanged in 16 eyes (30.8%), and deteriorated by 2 lines or more in 23 eyes (44.2%). Thirty-seven of 52 eyes (71.2%) required re-operation. No significant differences were detected when the patients were stratified according to whether they were treated either with or without combined use of silicon oil, or according to whether they were treated either with or without prophylactic surgery for retinal detachment, as well as by age of vitrectomy. A combination of lens extraction, silicon oil and encircling sclera buckling procedure was associated with a significantly higher frequency of final visual acuity. CONCLUSION: Despite the advances in vitrectomy achieved today, the visual prognosis of acute retinal necrosis remains unsatisfactory. The present study found no significant improvement in the prognostic relevance of prophylactic vitrectomy. Improvement in pharmacotherapy may help improve the prognosis. Further prospective large-scale studies to compare other treatment modalities are also required.

Comparison of patients with ocular tuberculosis in the 1990s and the 2000s.

PURPOSE: To compare clinical findings in patients with ocular tuberculosis experienced during two different decades. METHODS: Thirty-four patients with ocular tuberculosis were divided into two groups: a 1990s group (n = 18) and a 2000s group (n = 16), according to the dates of their first outpatient visit. The clinical profiles of the two groups were then compared. RESULTS: More cases of the 1990s group had complications involving extraocular tuberculosis than those of the 2000s group. While various ophthalmic manifestations were observed clinically in the 1990s group, all retinal periphlebitis cases presented in the 2000s group. The proportion of patients who received antituberculous treatment was higher in the 1990s group, but the proportion who received oral corticosteroid therapy did not differ between the two periods. However, more patients underwent laser photocoagulation in the 2000s group. The percentage of eyes with final visual acuity better than 20/20 increased in the 2000s group. CONCLUSIONS: The clinical outcome of patients with ocular tuberculosis was improved in the 2000s group, which may be attributable to the increase in active use of laser photocoagulation therapy.

Immune responses to interphotoreceptor retinoid-binding protein and S-antigen in Behcet's patients with uveitis.

PURPOSE: Immune responses to retina-specific autoantigens, including S antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP), have been suggested to be involved in the pathogenesis of human uveitis, including Behçet's disease (BD). In this study, the authors examined whether immune responses to IRBP and S-Ag in BD patients can be characterized by cytokine production profiles. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from BD patients with uveitis and healthy controls, and each sample was cultured with IRBP, S-Ag, or purified protein derivative (PPD). At the end of culture, IL-2, IL-4, IL-6, IL-10, IL-17, IFN-gamma, and TNF-alpha concentrations in supernatants were measured. RESULTS: PBMCs from BD patients and healthy controls produced IL-6, IL-10, IL-17, IFN-gamma, and TNF-alpha on stimulation with IRBP or S-Ag, as well as PPD stimulation, immunity against which was acquired by Bacille Calmette-Guérin immunization. IL-17 and IFN-gamma production was significantly higher when PBMCs were stimulated with IRBP than with S-Ag, whereas the reverse was observed for IL-6 production. IRBP-stimulated IL-6, IFN-gamma, and IL-17 production was higher in BD patients than in healthy controls, though IL-10 production was not different between them. In particular, IRBP-stimulated IFN-gamma production was significantly higher in BD patients with active uveitis than in BD patients with uveitis in remission. CONCLUSIONS: Immune responses to both IRBP and S-Ag were observed even in PBMCs of healthy controls. However, the present results suggested that retinal autoantigen-stimulated IL-6, IL-17, and especially IFN-gamma production would be involved in the development of uveitis in BD.