Development of a New De Novo Design Algorithm for Exploring Chemical Space.

In the first stage of development of new drugs, various lead compounds with high activity are required. To design such compounds, we focus on chemical space defined by structural descriptors. New compounds close to areas where highly active compounds exist will show the same degree of activity. We have developed a new de novo design system to search a target area in chemical space. First, highly active compounds are manually selected as initial seeds. Then, the seeds are entered into our system, and structures slightly different from the seeds are generated and pooled. Next, seeds are selected from the new structure pool based on the distance from target coordinates on the map. To test the algorithm, we used two datasets of ligand binding affinity and showed that the proposed generator could produce diverse virtual compounds that had high activity in docking simulations.

[Progress in imaging techniques].

Today it is common to perform real-time diagnosis and treatment via live broadcast as a method of education and to spread new technology for diagnosis and therapy in medical fields. Live medical broadcasts have developed along with broadcast technology. In the early days, live video feeds were sent from operating rooms to classrooms and lecture halls in universities and hospitals. However, the development of imaging techniques and communication networks enabled live broadcasts that bi-directionally link operating rooms and meeting halls during scientific meetings and live demonstration courses. Live broadcasts therefore became an important method for education and the dissemination of new medical technologies. The development of imaging techniques has contributed to more realistic live broadcasts through such innovative techniques as three-dimensional viewing and higher-definition 4K technology. In the future, live broadcasts will be transmitted on personal computers using regular Internet connections. In addition to the enhancement of image delivery technology, it will also be necessary to examine the entire image delivery environment carefully, including issues of security and privacy of personal information.

Reversible visual disturbance due to cryptococcal uveitis in a non-HIV individual.

A 52-year-old man without underlying diseases visited a local hospital with symptoms of memory deficit and mild headache. Radiological examination of the brain with computed tomography (CT) revealed hydrocephalus. Etiology was not revealed by cerebrospinal fluid (CSF) analysis and a ventricular-atrial (V-A) shunt was installed. The patient had congestion and dacryorrhea of the right eye and uveitis was diagnosed three months after placement of the V-A shunt. The serum cryptococcal antigen (CrAg) tested positive at a titration of 64 times. Additionally, samples of the right eye anterior chamber aqueous humor (ACAH), cerebrospinal fluid (CSF) and prostate fluid were positive for Cryptococcus antigen at a titration of 128 times. In addition, Cryptococcus neoformans var. grubii was isolated from the peripheral blood, CSF and ACAH, resulting in a diagnosis of disseminated cryptococcosis. Fluconazole (FLCZ) at 800 mg/day was administered for the first two days, followed by a 400 mg/day maintenance dose. After six months of treatment, his visual power recovered. This is a rare case of disseminated cryptococcosis involving uveitis, which was successfully treated by FLCZ. Disseminated cryptococcosis should be considered in cases with mild symptoms and V-A shunt installation for hydrocephalus.

Acute corneal epithelial change after instillation of benzalkonium chloride evaluated using a newly developed in vivo corneal transepithelial electric resistance measurement method.

OBJECTIVE: Acute corneal permeability change after instillation of benzalkonium chloride (BAC) was evaluated using a newly developed in vivo corneal transepithelial electric resistance (TER) measurement method. METHOD: Corneal TER was measured by Ag/AgCl electrodes placed in the anterior aqueous chamber and on the cornea of live rabbit eyes. TER was measured and TER change after instillation of 0.05% BAC solution was monitored. After TER measurement, cornea was excised and fixed for transmission and scanning electron microscopy. For the control study, physiologic saline was used instead of BAC. RESULTS: The TER of normal rabbit cornea was 602.3 +/- 195.0 Omega cm(2). TER decreased instantly after instillation of 0.05% BAC. In 5 s, TER decreased to 58.3 +/- 5.2%. In 60 s, TER decreased to 18.5 +/- 3.2%. At all time points, TER after instillation of 0.05% BAC was significantly lower than that of the control (p < 0.0001). Dissociation of tight junctions and the destruction of superficial cell membranes were observed under electron microscopy. CONCLUSION: Corneal epithelial change with increased permeability is rapid and intense after the instillation of highly concentrated BAC solution, accompanied by disorder of tight junctions and cell membranes of superficial cells. The newly developed in vivo corneal TER measurement method is suitable for assessing acute corneal change after drug instillation.

All-trans-retinol generated by rhodopsin photobleaching induces rapid recruitment of TIP47 to lipid droplets in the retinal pigment epithelium.

PURPOSE: To investigate the effect of light stimulation on lipid droplets (LDs) and LD proteins in the retinal pigment epithelium (RPE). METHODS: Dark-adapted mouse eyes were exposed to intense flashes of light, and ARPE-19 cells were treated with all-trans-retinol. The two specimens were labeled with BODIPY493/503 for LDs and with antibodies for three LD proteins: adipocyte differentiation-related protein (ADRP), TIP47, and Rab18. The labeling intensity in fluorescence microscopy was quantified by image analysis. Localization of mutated TIP47 was also examined. Immunoelectron microscopy was performed for ADRP in mouse RPE. Expression of TIP47 in ARPE-19 cells was knocked down by RNA interference (RNAi), and its effect on retinyl ester storage was measured by HPLC. RESULTS: Both flashes of light on mouse eyes and all-trans-retinol on ARPE-19 cells caused rapid translocation of TIP47 from the cytosol to LDs, whereas ADRP distributed constitutively in LDs. The density of LDs did not show visible changes by any treatment. The localization of TIP47 to LDs was abolished when either the amino-terminal or the carboxyl-terminal half of the molecule was deleted, but was enhanced by a short deletion in the carboxyl terminus. Manipulation of TIP47 expression by RNAi or cDNA transfection did not affect the retinyl ester amounts in ARPE-19 cells significantly. CONCLUSIONS: All-trans-retinol generated by photobleaching in the retina induces rapid translocation of TIP47 to LDs in the RPE.

Visual field defects after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling.

PURPOSE: To report visual field defects after macular hole surgery with indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling. DESIGN: Interventional consecutive case series. METHODS: A retrospective review of 140 eyes with macular hole after vitrectomy with ILM peeling. The group with 0.25% of ICG for ILM peeling consisted of 96 eyes. The group without ICG consisted of 44 eyes. RESULTS: Nasal visual field defects occurred in 11 eyes, temporal visual field defects in seven eyes, and concentric visual field defects in one eye. In the group with ICG, nasal visual field defects were far higher in the left eye than in the right eye. CONCLUSIONS: We speculate that the postoperative nasal visual field defects were caused by the enhanced toxicity of ICG resulting from the exposure to illumination.

A case of uveal, palpebral, and orbital invasions in adult T-Cell leukemia.

BACKGROUND: Patients with adult T-cell leukemia (ATL) may have eyelid lymphoma, uveitis, or cytomegalovirus retinitis due to being immunocompromised. However, there have been few reports on the invasion of multiple ocular lesions. We treated 1 unusual ATL patient with uveitis in whom multiple ocular invasions were suspected. CASE: A woman in whom ATL was diagnosed 10 years previously complained of blurred vision and decreased visual acuity in the right eye. Anterior uveitis of the right eye was suspected. One week later the cells increased in the anterior chamber, and fibrin exudates and hyphema appeared. She was admitted to our hospital. OBSERVATIONS: The visual acuity was 0.04 in the right eye and finger-counting from 30 cm in the left. She was treated with systemic steroid therapy. Inflammation disappeared, but both eyelids became swollen and multiple ocular lesions appeared. She was given carcinostatic therapy once more and the mass lesions decreased. Mass lesions appeared in the iris and in the bulbar conjunctiva. Computed tomography and magnetic resonance imagining (MRI) showed that the mass lesions extended to the right orbit and both nasal cavities. MRI also demonstrated choroidal thickening in the left eye. CONCLUSION: This case documents that ATL cells may cause severe uveitis and invade multiple ocular tissues such as the iris, eyelid, choroids, and orbit.