A phase 3, randomized, double-blind, clinical study to evaluate the long-term safety and efficacy of gefapixant in Japanese adult participants with refractory or unexplained chronic cough.

BACKGROUND: In two phase 3, global clinical trials (COUGH-1 and COUGH-2), the P2X3-receptor antagonist gefapixant significantly reduced objective 24-h cough frequency in participants with refractory or unexplained chronic cough (RCC or UCC) at a dosage of 45 mg twice daily (BID), with an acceptable safety profile. The primary objective of this phase 3, randomized, double-blind, parallel-group study was to assess the safety and tolerability of gefapixant in Japanese participants with RCC or UCC (ClinicalTrials.gov, NCT03696108; JAPIC-CTI, 184154). METHODS: Participants aged ≥20 years with chronic cough lasting ≥4 months and a diagnosis of RCC or UCC despite treatment in accordance with Japanese Respiratory Society guidelines were randomized 1:1 to receive gefapixant 15 or 45 mg BID for 52 weeks. The primary objective was to evaluate the safety and tolerability of gefapixant, including adverse events (AEs) and discontinuations due to AEs. Cough-specific quality of life was assessed using the Leicester Cough Questionnaire as a secondary objective. RESULTS: Of 169 randomized and treated participants, 63% were female and mean age was 58 years. Adverse events were reported by 79 (94%) and 82 (96%) participants in the 15- and 45-mg BID groups, respectively. Most treatment-related AEs were taste related. Discontinuations due to AEs occurred in 6 (7%) and 17 (20%) participants receiving gefapixant 15 or 45 mg BID, respectively. There were no serious treatment-related AEs or deaths. Leicester Cough Questionnaire total scores improved from baseline through Week 52. CONCLUSIONS: Gefapixant had an acceptable safety profile, with no serious treatment-related AEs in Japanese participants.

Web-based survey to evaluate the prevalence of chronic and subacute cough and patient characteristics in Japan.

BACKGROUND: Cough lasting 3-8 weeks and more than 8 weeks are defined as subacute/prolonged cough and chronic cough, respectively. Japanese chronic cough population has not been well studied. This study aimed to describe the prevalence and characteristics of chronic cough and subacute cough patients in Japan. This study also sought to compare between chronic cough patients who were not greatly satisfied with treatment effectiveness for resolving cough and other chronic cough patients. METHODS: Data from a cross-sectional online 2019 Japan National Health and Wellness Survey and a supplemental chronic cough survey were used to understand respondents' chronic cough status and their cough-specific characteristics and experience. The prevalence, patient characteristics and cough-specific characteristics were summarised descriptively. Patients who were not greatly satisfied with treatment effectiveness and other chronic cough patients were compared for their characteristics and cough severity. RESULTS: The point prevalence of chronic cough was 2.89% and 12-month period prevalence was 4.29%. Among all chronic cough patients analysed, the average age was 56 years old, 61.1% were males and 29.4% were current smokers. Patients were most frequently told by a physician that cough was related to allergic rhinitis, asthma and cough variant asthma. Only 44.2% of chronic cough patients had spoken with a physician about their cough, and half of chronic cough patients did not use any medications. Patients who were not greatly satisfied with treatment effectiveness had significantly greater cough severity during past 2 weeks compared with other chronic cough patients (Visual Analogue Scale 45.34 vs 39.63). CONCLUSIONS: This study described the prevalence and patient characteristics information of chronic cough patients in Japan. Furthermore, the study highlighted an unmet need for better diagnosis and treatments for chronic cough patients, especially among patients who were not greatly satisfied with treatment effectiveness and reported significantly worse cough severity.

Disease burden and quality of life of patients with chronic cough in Japan: a population-based cross-sectional survey.

BACKGROUND: Cough lasting 3-8 and >8 weeks are defined as subacute/prolonged cough and chronic cough (CC), respectively. Studies have revealed that CC negatively impact patients' quality of life (QoL). In Japan, there is limited data on the impact of CC on health-related quality of life (HRQoL), work productivity and activity impairment (WPAI) and healthcare resource utilisation (HRU) using validated instruments. This study aimed to estimate the burden of CC and to compare the burden among patients with CC between subgroups. METHODS: Data from two cross-sectional online surveys conducted between September and November 2019 were combined for the analysis. Eligible patients with cough were propensity score matched to non-cough respondents. Comparisons of general HRQoL, WPAI, HRU and other symptoms experienced were conducted between matched non-cough respondents and patients with cough. Among patients with CC, subgroup comparisons were performed to understand general HRQoL, WPAI, HRU, cough-related QoL (Leicester Cough Questionnaire and Hull Airway Reflux Questionnaire) between patients with CC of different severities, patients with refractory CC and patients with non-refractory CC and patients with CC whose underlying diseases were unknown and others. RESULTS: Patients with CC (n=568) in Japan reported significantly poorer HRQoL, increased WPAI, more HRU and higher proportion of psychological and sleep problems, compared with matched non-cough respondents selected from 21 415 non-cough respondents. More patients with severe CC reported significantly poorer HRQoL, increased WPAI and worse cough-related QoL. Patients with refractory CC experienced significantly greater burden measured by cough-related QoL. No significant differences were observed between patients with CC whose underlying diseases were unknown and other patients with CC in terms of general HRQoL and cough-related QoL. CONCLUSIONS: This study showed that patients with CC in Japan experienced significant burden compared with non-cough respondents. Patients with more severe cough and refractory CC experienced worse cough-related QoL. These results highlighted the unmet need for better interventions and treatments to reduce the burden among patients with CC.

Biphenyl degradation by recombinant photosynthetic cyanobacterium Synechocystis sp. PCC6803 in an oligotrophic environment using unphysiological electron transfer.

Cyanobacteria are potentially useful photosynthetic microorganisms for bioremediation under oligotrophic environments. Here, the biphenyl degradation pathway genes of ß-proteobacterium Acidovorax sp. strain KKS102 were co-expressed in cyanobacterium Synechocystis sp. PCC6803 cells under control of the photo-inducible psbE promoter. In the KKS102 cells, biphenyl is dioxygenated by bphA1 and bphA2 gene products complex using electrons supplied from NADH via bphA4 and bphA3 gene products (BphA4 and BphA3, respectively), and converted to benzoic acid by bphB, bphC and bphD gene products. Unexpectedly, biphenyl was effectively hydroxylated in oligotrophic BG11 medium by co-expressing the bphA3, bphA1 and bphA2 genes without the bphA4 gene, suggesting that endogenous cyanobacteria-derived protein(s) can supply electrons to reduce BphA3 at the start of the biphenyl degradation pathway. Furthermore, biphenyl was converted to benzoic acid by cyanobacterial cells co-expressing bphA3, bphA1, bphA2, bphB, bphC and bphD. Structural gene-screening using recombinant Escherichia coli cells co-expressing bphA3, bphA1, bphA2, bphB and bphC suggested that petH, which encodes long- and short-type NADP-ferredoxin oxidoreductase isomers (FNRL and FNRS, respectively), and slr0600, which is annotated as an NADPH-thioredoxin reductase gene in CyanoBase, were BphA3-reducible proteins. Purified FNRL and FNRS, and the slr0600 gene product showed BphA3 reductase activity dependent on NADPH and the reduced form of glutathione, respectively, potentially shedding light on the physiological roles of the slr0600 gene product in cyanobacterial cells. Collectively, our results demonstrate the utility of Synechocystis sp. PCC6803 cells as a host for bioremediation of biphenyl compounds under oligotrophic environments without an organic carbon source.

Current Landscape of Late-Phase Clinical Trials for Alzheimer's Disease: Comparing Regional Variation Between Subjects in Japan and North America.

INTRODUCTION: Over the last few decades, numerous late-phase multi-regional clinical trials have been conducted to develop a novel treatment for Alzheimer's disease (AD), with no effective results. OBJECTIVE: To inform the design and interpretation of future clinical trials, the aim of this study was first to examine the current landscape of late-phase clinical trials to determine key study design characteristics, and then assess the regional variation between Japan and North America for the most utilized clinical efficacy endpoint in the most targeted stage of the disease. METHODS: The study design and the mechanism of action of the interventional drugs tested in the late-phase clinical trials initiated in the last 5 years (2014-2018) were assessed based on the records in ClinicalTrials.gov database. The regional variation of the most utilized clinical efficacy endpoint in the most targeted population was assessed using data from two similarly designed observational studies conducted in Japan (Japanese Alzheimer's Disease Neuroimaging Initiative, J-ADNI) and North America (Alzheimer's Disease Neuroimaging Initiative, ADNI). For the most utilized clinical efficacy endpoint, the change from baseline (CFB) at Month 6, Year 1 and Year 2 was estimated using the growth curve model with a random intercept and slope, including gender as a fixed factor and age, apolipoprotein E ε4 genotype and years of education as covariates. RESULTS: Of 48 Phase III trials that were initiated during the study period, 25 were disease-modifying treatment trials in which individuals with early AD were the most studied (56%) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) was the most frequently utilized primary clinical efficacy endpoint (64%). The baseline characteristics of the early AD population between J-ADNI and ADNI were generally comparable, except for years of education. When comparing CDR-SB in early AD, J-ADNI had generally better baseline scores and the overall progression was similar (CFB at Year 2, ADNI 2.7 and J-ADNI 2.3, p = 0.190), despite slower progression in functional domains (CFB at Year 2, ADNI 1.4 and J-ADNI 1.0, p = 0.031). CONCLUSION: Over the years, the target population has shifted toward early stage of the disease, wherein the clinical progression is slower and difficult to measure. Moreover, our results suggest that regional variation could have an impact on functional measurements due to cultural differences in pivotal clinical trials. Therefore, caution should be exercised according to the characteristics of the endpoint used.

MTF Measurement of MR Blurring in Liver Dynamic MRI with Gd-EOB-DTPA.

During the arterial phase acquisition of Gd-EOB-DTPA examinations, use of a small volume of the Gd-EOB-DTPA may make it difficult the encoding center of the k-space, and produce blurring. The previous studies revealed the encoding technique of the k-space was one of the most important reasons. However, there is no report to discuss the reasons with quantitative evaluations. The purpose of this study was to quantitatively evaluate the characteristics of the artifacts using different k-space encoding techniques (centric-view ordering (CVO) and sequential-view ordering (SVO)) for liver dynamic MRI in computer simulation study. This simulation study consists of the following steps. First of all, the creation of a time intensity curve, and original simulation images at certain points among the one phase dynamic scanning. Secondly, creation-simulated MR echo data from the created original images using FFT, and encoding simulated k-space using the simulated MR echo data. Finally, a reconstruction of simulated dynamic MR images from the simulated k-space, and to evaluate each simulated MR images, we measured modulation transfer functions (MTFs) from the bar patterns of the reconstructed images. The results of the CVO simulation indicated that the bar patterns were blurring compared to the images encoded by the SVO. The results of the SVO simulation indicated that the bar patterns were not enhanced at late scan timings. In addition, the results of MTFs indicated that there was no edge enhancement at all scan timings and both encoding techniques. In conclusion, it is possible to quantitatively evaluate the characteristics of artifacts using MTF, which was measured by the bar patterns, in liver dynamic MRI.

Adjunctive preladenant: A placebo-controlled, dose-finding study in Japanese patients with Parkinson's disease.

BACKGROUND: Preladenant, an adenosine 2A antagonist, reduced daily OFF time when administered as adjunctive treatment in a previous phase 2 trial in non-Japanese Parkinson's disease (PD) patients on stable doses of levodopa. This study aimed to evaluate preladenant as adjunctive therapy in Japanese patients with PD. METHODS: In this randomized, placebo-controlled, double-blind, 12-week, dose-ranging, phase 2 study, Japanese patients with moderate to severe PD on a stable regimen of levodopa were randomly assigned 1:1:1:1 to preladenant 2 mg, 5 mg, or 10 mg BID or placebo. The primary efficacy end point was change from baseline to week 12 in mean OFF time, recorded using a PD diary. Safety and tolerability were also assessed. RESULTS: In total, 111 patients were randomly assigned to receive preladenant 2 mg, and 113 each received preladenant 5 mg, 10 mg, or placebo. In contrast to previous data, preladenant in this study did not demonstrate statistically significant efficacy; the primary outcome was -0.7 h (P = 0.0564), -0.5 h (P = 0.1844), and -0.3 h (P = 0.3386), respectively, for preladenant 2 mg, 5 mg, and 10 mg BID versus placebo. Overall, preladenant was well tolerated, and the frequency of adverse events appeared to be dose related. CONCLUSIONS: In this phase 2 study, preladenant used as adjunctive therapy in PD patients on stable doses of levodopa did not reduce mean OFF time; treatment was well tolerated at doses between 2 and 10 mg BID.

Orthostatic response of cephalic blood flow using a mini laser Doppler blood flowmeter and hemodynamics of a new active standing test.

PURPOSE: Cephalic hemodynamic assessment is important in initial orthostatic hypotension. We sought to investigate cephalic blood flow (CBF) in the earlobe using a mini laser Doppler flowmeter (LDF) during orthostatic challenge. In addition, we clarified hemodynamic differences during a new active standing protocol using a footstool standing test (FST) with bending of the legs on the footstool in the sitting position to reduce the load of the squatting posture in the conventional squat standing test (SST). METHODS: Ten healthy men (21 ± 0.5 years) performed the SST after a 1 min squat and the FST after a 1 min load consisting of bending the legs on a footstool in the sitting position. Earlobe CBF, beat-to-beat arterial blood pressure (ABP), mean arterial blood pressure (MAP), and heart rate (HR) were recorded during each test. RESULTS: Earlobe CBF showed a transient fall synchronized with the ABP during each test. No significant differences in the recovery times (RTs) of CBF and MAP were observed during the SST (CBF 12.9 ± 0.6 s vs. MAP 12.1 ± 0.5 s, P = 0.313) and FST (CBF 10.6 ± 0.4 s vs. MAP 10.1 ± 0.8 s, P = 0.552). Although the CBF and ABP decreases were not different in each test, the HR increase was significantly lower with the FST (24 ± 2 bpm) than with the SST (31 ± 3 bpm, P < 0.005). CONCLUSIONS: Earlobe CBF reflects the compensatory ABP regulatory response during standing and is potentially useful for estimating the orthostatic ABP response indirectly. Furthermore, the FST is a low-load protocol that can be an effective protocol for a standing test of cardiac function.

Purtscher's retinopathy followed by neovascular glaucoma.

We report the case of a 66-year-old Japanese man who developed neovascular glaucoma secondary to Purtscher's retinopathy following a head injury. The patient presented at our hospital with blurred vision and a visual field abnormality in his left eye 1 month after suffering from a head injury. Upon initial presentation, his best-corrected visual acuity on a decimal chart was 1.5 oculus dexter and 0.6 oculus sinister. The intraocular pressure (IOP) was 12 mmHg in both eyes. Fundus examination of the left eye revealed multiple white lesions in the posterior pole. Optical coherence tomography demonstrated retinal edema, particularly in the inner retina. On the basis of these findings, a diagnosis of Purtscher's retinopathy was made. One month after the initial examination, the visual acuity in the left eye deteriorated to 0.01 in decimal chart, and the IOP increased to 37 mmHg. Gonioscopy showed angle neovascularization. The patient received an intravitreal bevacizumab injection and panretinal photocoagulation. Subsequently, the IOP normalized and the angle neovascularization regressed.

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with dyslipidemia.

OBJECTIVE: This study evaluated the effects of anacetrapib (ANA) on lipids and safety when administered as monotherapy or in combination with atorvastatin (ATV) in Japanese patients with dyslipidemia. METHODS: Patients (n = 407) were randomized equally to 1 of 10 groups: placebo, ATV 10 mg, ANA 10, 40, 100, or 300 mg once daily, and the same ANA doses in combination with ATV 10 mg. Patients were treated with study medication for 8 weeks and followed for an additional 8 weeks, during which ANA was switched to placebo. RESULTS: For the placebo and ANA monotherapy groups (10, 40, 100, and 300 mg), least squares mean percent changes from baseline at Week 8 for low-density lipoprotein cholesterol (LDL-C) calculated by the Friedewald equation were 3%, -12%, -27%, -32%, and -32%, respectively, and for high-density lipoprotein-cholesterol (HDL-C) were 1%, 56%, 116%, 134%, and 159%, respectively (p < 0.001 vs. placebo for all doses). All ANA doses co-administered with ATV 10 mg produced significantly greater LDL-C reductions and HDL-C increases compared with ATV 10 mg monotherapy. ANA was well tolerated, and dose-dependent relationships for adverse events were not observed across treatment groups. Changes from baseline in blood pressure and electrolytes were not significantly different between the active and control treatment groups. CONCLUSION: ANA, as monotherapy or co-administered with ATV, produced significant reductions in LDL-C and increases in HDL-C. ANA was generally well tolerated in Japanese patients with dyslipidemia.

Quantitative evaluation of iris convexity in primary angle closure.

PURPOSE: In eyes with primary angle closure (PAC), we quantitatively evaluated anterior bowing of the iris by means of ultrasound biomicroscopy (UBM). DESIGN: Retrospective, observational, and consecutive case series. METHODS: A total of 203 phakic eyes with PAC that had not undergone any surgical or laser treatment were included. Using UBM, we measured anterior chamber depth (ACD) and iris convexity (IC): the maximum distance from the posterior surface of the iris to the iris plane passing through the pupillary margin of the iris and iris root. RESULTS: The average IC was 0.22 +/- 0.1 mm, although there was considerable individual variation. The IC value was correlated weakly, albeit significantly, with age (r = 0.22, P < .01), and strongly with ACD (r = -0.57, P < .0001). CONCLUSIONS: In eyes with PAC, older age and a more shallow ACD appear to be important causes of increased forward bowing of the iris resulting from pupillary block.

Fellow eye of patients with retinal detachment associated with macular hole and bilateral high myopia.

PURPOSE: To estimate the risk of retinal detachment in the fellow eye of patients with bilateral high myopia who had retinal detachment associated with macular hole (MH-RD) in one eye. METHODS: The present study examined retrospectively 56 patients with bilateral high myopia who had MH-RD. To determine the incidence of involvement of the fellow eye, patients who completed a follow up of 12 months or longer were eligible for the current study. RESULTS: Of 56 patients with MH-RD due to high myopia, 54 had unilateral detachment at presentation and two had bilateral detachment. Of the 54 highly myopic fellow eyes without retinal detachment at presentation, 37 eyes underwent 12 or more months of documented follow up. Mean follow up after initial surgery to the primary eye was 6.5 +/- 4.9 years. During follow up, a macular hole without retinal detachment was noted in one (2.7%) of these 37 eyes. Three other eyes (8.1%) had MH-RD at 1, 2 and 7 years, respectively, after the initial surgery to the primary eye. At the final visit, 12 eyes (32%) had visual acuity of > or =6/9, whereas 12 eyes (32%) had visual acuity of < or =6/60. CONCLUSIONS: When patients with bilateral high myopia have MH-RD in one eye, they would be expected to be at increased risk of retinal detachment in the fellow eye.

Methanol-induced retinal toxicity patient examined by optical coherence tomography.

BACKGROUND: Methanol is a highly toxic substance used as an industrial solvent and automotive antifreeze. Human consumption of methanol may result in severe visual disturbances. Because optical coherence tomography (OCT) is very useful for evaluating retinal edema and nerve fiber swelling, we used OCT to examine a patient with methanol-induced retinal toxicity. CASE: A 37-year-old man who drank industrial alcohol (100 ml/day) for 4 days. OBSERVATIONS: The retinal profiles were evaluated by OCT and fluorescein angiography during the course of treatment. OCT demonstrated peripapillary nerve fiber swelling and accumulation of intraretinal fluid in the acute phase. In the chronic phase, the retinal thickness was diffusely decreased. Steroid pulse therapy was not effective, and his visual acuity was 6/200 OD and 4/100 OS 2 years after the event. CONCLUSION: OCT was very useful for evaluating the severity of the retinal edema and the temporal changes in the retinal profile.

Visual field defect after radial optic neurotomy for central retinal vein occlusion.

PURPOSE: To evaluate visual field defects after radial optic neurotomy (RON) in eyes with central retinal vein occlusion (CRVO). METHODS: Eight patients (eight eyes) underwent RON for macular edema associated with CRVO. Goldmann perimetry was performed on each patient both before and after surgery. RESULTS: Postoperative Goldmann perimetry showed a temporally located wedge-shaped visual field defect consistent with neural damage secondary to RON in seven eyes (88%). After surgery, the visual field decreased from preoperative values by 7% at 3 months (P = 0.30) and by 21% at 12 months (P = 0.0023). Although three patients (38%) were aware of the postoperative visual field defect, only one patient (13%) considered this defect to be a visual disability. CONCLUSIONS: After RON, most patients showed a postoperative defect in the temporal visual field consistent with the incision to the optic disk. However, this visual field defect appears to be well tolerated by most patients.

Angle widening and alteration of ciliary process configuration after cataract surgery for primary angle closure.

PURPOSE: To evaluate quantitatively, by means of ultrasound biomicroscopy (UBM), changes in the anterior segment configuration, including the ciliary processes, induced by cataract surgery in eyes with primary angle closure. DESIGN: Retrospective interventional case series. PARTICIPANTS: Thirty-one eyes of 31 patients with primary angle closure or primary angle-closure glaucoma were treated with cataract surgery. Before cataract surgery, 10 eyes had been treated with laser peripheral iridotomy, and 1 with laser peripheral iridoplasty. METHODS: Configuration of the anterior chamber was examined by means of UBM before and at 3 months after cataract surgery. MAIN OUTCOME MEASURES: Using UBM, anterior chamber depth (ACD), angle opening distance at points 500 mum from the scleral spur (AOD500), and trabecular-ciliary process distance (TCPD) were measured. RESULTS: Not only ACD and AOD500, but also TCPD, increased significantly after cataract surgery, compared with measurements obtained before surgery (P<0.001). Postoperative AOD500 was correlated significantly with postoperative TCPD (r = 0.72, P<0.001) and with the amount of change of TCPD caused by cataract surgery (Delta TCPD) (r = 0.52, P<0.01). CONCLUSIONS: Cataract surgery attenuated anterior positioning of the ciliary processes in eyes with primary angle closure, concomitant with significant widening of the angle. Cataract surgery resulted in not only complete dissolution of lens volume and pupillary block, but also attenuation of the anterior positioning of the ciliary processes, all of which contributed to postoperative widening of the angle in eyes with primary angle closure.

Synthesis and characterization of a novel reagent containing dansyl group, which specifically alkylates sulfhydryl group: an example of application for protein chemistry.

We have synthesized a novel reagent containing dansyl group, iodoacethyl dansylcadaverine (IADC), which specifically alkylates sulfhydryl groups. The carboxyl group of iodoacetic acid was activated with dicyclohexylcarbodiimide and was condensed with amino group of dansylcadaverine. Purity and chemical structure of IADC was confirmed with mass spectrometry (MS) and NMR. IADC alkylated GSH but not GSSG, which was confirmed by MS. The reactivity of IADC with proteins was also investigated with Western blotting using anti-dansyl antibody. IADC reacted only with sulfhydryl-containing proteins. The specificity of the interaction of IADC with sulfhydryl groups in proteins was confirmed by adding excessive amount of a well-known sulfhydryl-specific reagent, 5, 5'-dithiobis(2-nitrobenzoic acid), which led to a complete inhibition. To show the usefulness of IADC, the cysteines in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from chicken muscle were modified with this reagent, and GAPDH was then digested by lysyl endopeptidase. The peptides generated from digestion of IADC-incorporated GAPDH were applied to an anti-dansyl immunoaffinity column. The peptide fragments bound and eluted from the column were separated by HPLC, and the amino acid sequence of each peptide was analyzed, and peptide was identified as the one containing a Cys residue(s). These data showed that IADC is a useful reagent to specifically identify the positions of a Cys residue(s) in proteins.

Cataract surgery for residual angle closure after peripheral laser iridotomy.

PURPOSE: To investigate the frequency of residual angle closure after resolution of pupillary blocking by laser peripheral iridotomy and the effects of subsequent cataract surgery to resolve angle closure completely. DESIGN: Retrospective, consecutive, interventional study. PARTICIPANTS: Among 70 eyes treated with laser iridotomy, 13 with residual angle closure were treated with cataract surgery. METHODS: The provocative test of angle closure by prone position in a dark room for 1 hour was performed; increases in tension of > or =8 mmHg, 6 or 7 mmHg, and < or =5 mmHg were considered to be positive, suspected positive, and negative, respectively. Configuration of the anterior chamber was examined using ultrasound biomicroscopy (UBM). MAIN OUTCOME MEASURES: Intraocular pressure (IOP), response to the dark room prone position test, and morphologic analysis by UBM were evaluated before and 3 months after cataract surgery. RESULTS: Residual angle closure after iridotomy was seen in 27 (38.6%) of 70 eyes; this was confirmed functionally by the dark room prone position test and morphologically by UBM. Eyes with IOP of > or =20 mmHg or with a glaucomatous visual field defect before iridotomy had a significantly higher incidence of residual angle closure after iridotomy than eyes without these findings (P<0.05). In all the eyes with residual angle closure after iridotomy, the response to the prone position test became negative after cataract surgery, with significant lowering of IOP (P<0.01). CONCLUSIONS: Residual angle closure after iridotomy was common, especially in eyes with primary angle closure and poorly controlled IOP or glaucomatous optic neuropathy. Cataract surgery was effective to resolve completely the residual angle closure after iridotomy and lower IOP.

[Natural killer-cell lymphoma of the iris with a normal fundus].

BACKGROUND: Intraocular lymphoma is a relatively uncommon malignancy, rarely presenting with exclusively anterior segment findings in a normal fundus. CASE: A 38-year-old male, previously diagnosed with nasal lymphoma, currently in complete remission after chemotherapy and radiotherapy, presented with blurring of vision in his left eye, which initially responded to local steroid therapy. However, the patient developed resistance to steroid therapy and developed nodular masses in the left iris. Ultrasound biomicroscopy revealed diffuse thickenings leading to a complex and uneven shape of the left iris. An iris biopsy was done which led to the diagnosis of natural killer(NK)-cell lymphoma. Radiation therapy was instituted which led to rapid resolution of both the nodular masses and iritis. CONCLUSION: This is a case of malignant lymphoma presenting as metastasis to the iris without involvement of the chorioretinal tissues. When encountering a patient with iritis resistant to the steroid therapy, clinical ophthalmologists should consider metastatic malignancy in the differential diagnosis.

A novel function of tissue-type transglutaminase: protein disulphide isomerase.

We have found that tissue-type transglutaminase (tTG), also called TGc, TGase2 and Galpha(h), has the activity of protein disulphide isomerase (PDI). We have shown that tTG converts completely reduced/denatured inactive RNase A molecule to the native active enzyme. The PDI activity of tTG was strongly inhibited by bacitracin, which is a frequently used inhibitor of conventional PDI activity. It was substantially inhibited by the simultaneous presence of other potential substrate proteins such as completely reduced BSA, but not by native BSA. This activity was especially high in the presence of GSSG, but not GSH. The addition of GSH to the reaction mixture in the presence of GSSG at a fixed concentration up to at least 200-fold excess did not very substantially inhibit the PDI activity. It is possible that tTG can exert PDI activity in a fairly reducing environment like cytosol, where most of tTG is found. It is quite obvious from the following observations that PDI activity of tTG is catalysed by a domain different from that used for the transglutaminase reaction. Although the alkylation of Cys residues in tTG completely abolished the transglutaminase activity, as was expected, it did not affect the PDI activity at all. This PDI activity did not require the presence of Ca(2+). It was not inhibited by nucleotides including GTP at all, unlike the other activity of tTG.

New insight into the functional role of acetylcholine in developing embryonic rat retinal neurons.

PURPOSE: To examine the effects of acetylcholine (ACh) on glutamate-induced neurotoxicity in embryonic rat retinal neurons. METHODS: Primary cultures were obtained from rat retinas at embryonic days 17 to 19. Cultured cells were exposed to glutamate for 10 minutes, followed by incubation in glutamate-free medium for 1 hour. Drugs were added to the incubation medium for 1 to 24 hours until immediately before glutamate exposure and were removed from culture medium during glutamate exposure and the postincubation period. The neurotoxic effects on retinal cultures were quantitatively assessed by the trypan blue exclusion method. RESULTS: Cell viability was markedly reduced by 10-minute exposure to 500 microM glutamate followed by a 1-hour incubation in glutamate-free medium. Incubating the cultures with 1 microM ACh for 12 hours before glutamate exposure reduced glutamate neurotoxicity. A similar effect was induced by application of carbachol (1 microM). The protective effect of ACh against glutamate neurotoxicity was inhibited by a nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine (0.5 microM), whereas a muscarinic acetylcholine receptor (mAChR) antagonist, atropine (0.5 microM) did not affect ACh-induced protection. In addition, a similar protection was induced by application of nicotine (1 microM), but not by muscarine (1 microM). Pretreatment with nicotine induced a protective effect in a time-dependent manner, ranging from 1 to 12 hours. Pretreatment with nicotine at concentrations ranging from 0.001 to 1 microM induced dose-dependent protection against glutamate neurotoxicity. Furthermore, the protective action of nicotine was inhibited by simultaneous application of dopamine D1 receptor antagonist, SCH23390 (1 microM), with nicotine, whereas a dopamine D2 receptor antagonist, domperidone (1 microM), did not affect nicotine-induced protection. CONCLUSIONS: These results suggest that pretreatment of cultured rat retinal neurons with ACh or the nAChR agonists, nicotine and carbachol, has a protective action against glutamate neurotoxicity through nAChRs and that the dopamine release induced by nicotinic stimulation subsequently protects the retinal neurons by way of dopamine D1 receptors.