A Case of Corneal Thinning During S-1 Oral Administration.

We experienced a case of bilateral corneal thinning during the oral taking of S-1, a combination anti-cancer drug of tegafur, gimeracil, and oteracil-potassium. A 69-year-old man was prescribed oral S-1 for the treatment of duodenal papilla adenocarcinoma and intraductal papillary mucinous neoplasm. However, he developed a decrease in visual acuity in both eyes after three cycles of S-1 oral taking, and ophthalmic examination revealed corneal thinning exceeding 100 µm and an increase in high-order irregularity of cornea in both eyes. After one month after discontinuation of S-1, his visual acuity and corneal thickness returned to its previous levels. Besides corneal ulcers and perforations, corneal thinning can be recognized as a potential corneal side effect necessitating monitoring during S-1 treatment.

Assessment of Mild Cognitive Impairment Using CogEvo: A Computerized Cognitive Function Assessment Tool.

INTRODUCTION/OBJECTIVES: To assess the utility of the computerized cognitive function assessment tool, CogEvo, as a screening tool for mild cognitive impairment in primary care, we explored the relationship between CogEvo performance, age, and the severity of cognitive dysfunction evaluated by the Mini-Mental State Examination (MMSE). METHODS: The observational cross-sectional study included 209 individuals' data (mean age 79.4 ± 8.9 years). We conducted a correlation analysis between CogEvo and MMSE scores, compared the performance among the 3 cognitive function groups (MMSE ≥ 28 group; MMSE24-27 group; MMSE ≤ 23 group) using the MMSE cut-off, and evaluated CogEvo's predictive accuracy for cognitive dysfunction through ROC analysis. RESULTS: Both total CogEvo and MMSE scores significantly decreased with age. A significant positive correlation was observed between total CogEvo and MMSE scores, but a ceiling effect was detected in MMSE performance. Significant differences were observed in the total CogEvo score, including orientation and spatial cognitive function scores, among the 3 groups. CogEvo showed no educational bias. ROC analyses indicated moderate discrimination between the MMSE ≥ 28 group and the MMSE24-27 and MMSE ≤ 23 groups. CONCLUSIONS: The computer-administered CogEvo has the advantage of not exhibiting ceiling effects or educational bias like the MMSE, and was found to be able to detect age-related cognitive decline and impairment.

Two different types of giant bleb formation following Ahmed Glaucoma valve implantation.

Purpose: This study aims to present two different types of giant bleb formation following Ahmed Glaucoma Valve (AGV) implantation: an anterior enlarged giant bleb and a posterior enlarged giant bleb. Observations: In Case 1, a 70-year-old Japanese male underwent AGV implantation for neovascular glaucoma in his right eye (OD). Preoperatively, the patient's intraocular pressure (IOP) and best corrected visual acuity (BCVA) were 23 mmHg and 0.6, respectively, OD, while using 3 antiglaucoma topical medications. Two months post-surgery, the patient began experiencing double vision. Slit lamp evaluation revealed no abnormalities, IOP and BCVA were 24.0 mmHg and 0.8, respectively, OD. A posteriorly enlarged bleb in the superotemporal quadrant OD was found to be causing displacement on T2-weighted orbital MRI. The patient underwent surgical excision of the anterior bleb wall. By three weeks post-surgery, the double vision resolved; IOP and BCVA were 17 mmHg and 0.7, respectively, and a normal bleb in the slit lamp evaluation was identified OD. In Case 2, a 10-year-old Japanese female underwent AGV implantation for childhood glaucoma associated with congenital cataract OD. Preoperatively, IOP and BCVA were 30 mmHg and 0.5, respectively, OD, while using 3 antiglaucoma topical medications. She underwent pars plana vitrectomy (PPV) in addition to AGV implantation. Seven months post-surgery, slip lamp evaluation revealed an anteriorly enlarged giant bleb that only cause her a cosmetic concern. Conclusions and Importance: There are two types of giant bleb formation following AGV implantation based on the direction of the enlargement: an anterior enlarged giant bleb and a posterior enlarged giant bleb. The introduction of this classification contribute to better understanding and management of this unusual surgical complication.

Dislocation of the PreserFlo MicroShunt During a Postsurgical Needling Procedure.

We report a case of PreserFlo MicroShunt (PFM) dislocation following a postsurgical needling procedure. A 58-year-old woman underwent PFM implantation for exfoliation glaucoma in her left eye (OS). There were no intraoperative complications. Preoperatively, her best-corrected visual acuity (BCVA) was 0.6, and her intraocular pressure (IOP) was 25 mmHg with three antiglaucoma medications in the OS. On postoperative day 21, the IOP was 21 mmHg OS, and the filtration bleb had shrunk. A needling procedure was performed using a sharp 26-gauge needle to lower the IOP. On postoperative day 29, the BCVA was 0.02, and the IOP was 60 mmHg OS. Gonioscopy revealed no device tip in the anterior chamber, and peripheral anterior synechia was observed at the site of PFM insertion. Anterior segment optical coherence tomography showed a dislocated device in the subconjunctival space. On postoperative day 35, the dislocated PFM was removed, and a new device was inserted. Following the reoperation, no further complications were observed, and bleb formation was obtained. In conclusion, like other glaucoma filtering surgeries, PFM may require postsurgical needling procedures. Needling procedures may cause PFM dislocation and IOP rise, resulting in the requirement for further IOP-reducing procedures.

Validity and reliability of a computerized cognitive function evaluation battery (CogEvo) as a screening tool.

Aim: The aim of this study was to determine the validity and reliability of cognitive function evaluation battery, CogEvo, a recently developed computerized cognitive function evaluation battery, as a screening tool for decreased cognitive function. Methods: The study sample comprised 123 (age: 57-97 years) community-dwelling elderly people. They were required to perform five CogEvo tasks and complete two questions-based neuropsychological tests, including the Mini-Mental State Examination, so that the correlations could be analyzed. The validity and reliability of CogEvo were examined using factor analysis, MacDonald's omega reliability coefficient, logistic regression analysis, and receiver operating characteristic curve analysis. Results: Exploratory factor analysis revealed the orientation/spatial cognitive function (orientation and spatial cognition) and attention/executive function (attention, memory, and execution) factors. Structural validity was supported by confirmatory factor analysis. All two-factor-based subtasks showed adequate internal consistency (MacDonald's omega ≥0.6). The total CogEvo score and two-factor scores were significantly correlated with neuropsychological test results. Based on the total CogEvo score, the cognitively normal and cognitive decline groups were identified by receiver operating characteristic curve analysis with a moderate predictive performance. The cognitive decline group was well identified using the orientation/spatial cognitive function factor. Conclusions: CogEvo is a valid and reliable screening tool for cognitive function evaluation. It proved useful in the early identification of cognitive decline in our study sample.

Structure and electrochemical properties of (µ-O)2Mn2(iii,iii) and (µ-O)2Mn2(iii,iv) complexes supported by pyridine-, quinoline-, isoquinoline- and quinoxaline-based tetranitrogen ligands.

Seven new bis(µ-oxo)dimanganese complexes with Mn2(iii,iii) or Mn2(iii,iv) oxidation states were prepared using quinoline- and isoquinoline-based tetraamine ligands. The structures of the ligands include ethylenediamine, trans-1,2-cyclohexanediamine and tripodal amine, bearing two or three nitrogen-containing heteroaromatics. Regardless of the skeleton and number of aliphatic nitrogen atoms in the ligands, quinoline complexes stabilize the Mn2(iii,iii) oxidation state, whereas, isoquinoline ligands afford Mn2(iii,iv) complexes. A systematic comparison of the differences in structural parameters and redox potentials of a total of 14 complexes with a (µ-O)2Mn2 diamond core, which includes corresponding pyridine and quinoxaline derivatives as supporting ligands, highlights the distinct deviation of quinoline and tripodal amine motifs in this ligand series.

Hippocampal Cholinergic Neurostimulating Peptide Suppresses LPS-Induced Expression of Inflammatory Enzymes in Human Macrophages.

Hippocampal cholinergic neurostimulating peptide (HCNP) is a secreted undecapeptide produced through proteolytic cleavage of its precursor protein, HCNPpp. Within hippocampal neurons, HCNP increases gene expression of choline acetyltransferase (ChAT), which catalyzes acetylcholine (ACh) synthesis, thereby modulating neural activity. HCNPpp also appears to be expressed in various immune cells. In the present study, we observed that HCNPpp is expressed in U937 human macrophage-like cells and that HCNP exposure suppresses lipopolysaccharide (LPS)-induced gene expression of ChAT. The opposite action is also seen in T lymphocytes, which suggest that HCNP appear to suppress cholinergic system in immune cells. In addition, HCNP suppresses LPS-induced gene expression of inflammatory enzymes including cyclooxygenase 2 (COX2) and inducible nitric oxide (NO) synthase (iNOS). The suppressive effect of HCNP may reflect suppression of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling activated by LPS. Thus, HCNP may have therapeutic potential as an anti-inflammatory drug.

Cigarette Smoke Extract Modulates Functions of Peroxisome Proliferator-Activated Receptors.

Cigarette smoke extract (CSE) contains many toxicants and may derange the physiological processes, such as cholesterol metabolism. We examined the impact of CSE on transcriptional regulation mediated peroxisome proliferator-activated receptors (PPARs) and its interaction with cofactors to elucidate differences in the molecular mechanism between CSE and other agonists of PPARs. We constructed several mutant PPARs (mPPARs) with amino acid substitution in the ligand-binding domain, which according to the molecular modeling, may affect the binding of agonists. In transient expression assays, each wild-type peroxisome proliferator-activated receptor (PPAR) mediated transcription stimulated by CSE was faintly yet significantly elevated compared to the control. The CSE-induced transcriptional activation was abolished in the H323A, H323Y, S342A, and H449A mPPARγs, although the activation elevated by pioglitazone was reserved. In the mPPARγ with Y473A and mPPARß/δs with H286Y and Y436A, the pioglitazone-induced or L165041-activated transcriptional elevations were decreased and were lower than that of CSE-induced stimulation. These results suggested that CSE activated both mutant PPARs to be selectively different from those ligands. Mammalian two-hybrid assay illustrated that CSE could mildly recruit SRC1 or GRIP1 to the wild-type PPARγ. Representative ingredients, such as acrolein and crotonaldehyde present in CSE, could stimulate PPAR isoforms even at the toxicological concentrations and might possibly contribute to stimulatory effects. CSE mildly regulates the cholesterol metabolism-related genes, such as low density lipoprotein (LDL) receptor and Liver X receptor (LXR)ß. In conclusion, these CSE effects the nuclear hormone receptors and their cofactors thereby disturbing metabolic phenomena. Therefore, CSE might be involved in cholesterol metabolism.

Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation.

Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor-nuclear factor erythroid 2-related factor 2 (Nrf2)-has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.

Insulin-like growth factor-1 directly mediates expression of mitochondrial uncoupling protein 3 via forkhead box O4.

OBJECTIVE: The objective of our study was to examine the direct action of insulin-like growth factor-1(IGF-1) signaling on energy homeostasis in myocytes. DESIGN: We studied the IGF-1 stimulation of mitochondrial uncoupling protein 3 (UCP3) expression in the HEK 293 derived cell line TSA201, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal myoblasts. We also investigated the direct effect of IGF-1 on the Insulin/IGF-1 receptor (IGF-1R)/phosphatidylinositol 3 (PI3)-Akt/forkhead box O4 (FOXO4) pathway using a combination of a reporter assay, semi-quantitative polymerase chain reaction, western blotting, and animal experiments. RESULTS: We demonstrated that IGF-1 regulates UCP3 expression via phosphorylation of FOXO4, which is a downstream signal transducer of IGF-1. UCP3 expression increased with activated FOXO4 in a dose-dependent manner. We also examined the functional FOXO4 binding site consensus sequences and identified it as the -1922 bp site in the UCP3 promoter region. UCP3 was also found to be concomitantly expressed with IGF-1 during differentiation of C2C12 myoblasts. Our animal experiments showed that high fat diet induced IGF-1 levels which likely influenced UCP3 expression in the skeletal muscle. CONCLUSION: Our findings demonstrate that that IGF-1 directly stimulates UCP3 expression via the IGF-1/IGF-1R/PI3-Akt/FOXO4 pathway.

Hippocampal Cholinergic Neurostimulating Peptide Suppresses Acetylcholine Synthesis in T Lymphocytes.

Lymphocytic cholinergic system has important roles in T cell functions, including immune responses and proliferation and differentiation of immune cells. T lymphocytes exclusively produces acetylcholine (ACh) via choline acetyltransferase (ChAT), activating their muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively) in an autocrine and paracrine manners. Hippocampal cholinergic neurostimulating peptide (HCNP) is an undecapeptide cleaved from N-terminal of phosphatidylethanolamine-binding protein 1 (PEBP1). HCNP enhances ACh synthesis through upreglation of ChAT expression in septo-hippocampal cholinergic neurons and participates in neuronal development and differentiation. Although PEBP1 and HCNP appears to be distributed ubiquitously in tissues and cells including spleen, its functions in immune cells have not been understood. In the present study, we observed that PEBP1 is also expressed in human and murine T cells. Long-term exposure to HCNP suppressed ChAT expression in MOLT3 human leukemic T cells, resulting in decreased release of ACh. HCNP also decreased the expression of extracellular signal-regulated kinase (ERK). Thus, HCNP appears to suppress lymphocytic cholinergic signaling, which might act as an immune modulator.

Surveys of Food Intake Just after the Nuclear Accident at the Fukushima Daiichi Nuclear Power Station.

As a result of the nuclear accident at the Fukushima Daiichi nuclear power station (FDNPS) after the Great East Japan Earthquake on March 11, 2011, volatile radionuclides including iodine-131 were released into the environment and contaminated open-field vegetables, raw milk, tap water, etc. It is important for the health care of residents to correctly comprehend the level of their exposure to radioactive substances released following the accident. However, an evaluation of the internal exposure doses of residents of Fukushima Prefecture as a result of the ingestion of foods, which is indicated in the report issued by United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)1 is based on a number of assumptions. For instance, the estimation assumes that foods were ingested as usual, without regard to the places to which residents were evacuated after the accident, the places where food shipment restrictions were imposed, and so forth. The present report aims to improve the accuracy of estimation of the amount of food actually ingested at evacuation areas, in order to reduce as much as possible the level of uncertainty in conventional values estimated directly after the accident, which were in fact values based on conservative assumptions. More concretely, as basic source material to more accurately estimate internal exposure doses from food ingestion, various patterns of evacuation and dietary habits at the time of the accident of the residents of 13 municipalities in Fukushima Prefecture who were evacuated during the period from directly after the accident of March 11, 2011 until the end of March are clarified in this report. From survey results, most of the food that evacuees took immediately after the accident was confirmed to have been sourced from either stockpiles prepared before the accident, or relief supplies from outside of the affected areas. The restriction orders of food supplies such as contaminated vegetables and milk, and tap water intake were implemented within several days after the major release of radionuclides on March 15, 2011. In addition, collapse in supply chains, i.e., damage to distribution facilities, lack of transportation vehicles or electricity, and the closure of retail stores, contributed to a situation where food or supplies contaminated with iodine -131 were not consumed in large quantities in general, even before the food restriction order. Since people consumed tap water and water from other sources before the implementation of restriction orders in affected areas, we surveyed the status of water as a potential route of internal exposure.

Antiviral Activity and Molecular Geometry of Some New Symmetrical Tris(aminoalkyl)amine Derivatives.

We report the preparation of new tripodal receptor-type C3- and CS-symmetrical molecules constructed on a tris(2-aminoethyl)amine (TAEA) template. Both the anti-herpes simplex virus type 1 (anti-HSV-1) activity and cytotoxic activity of synthesized receptor-type derivatives were evaluated in order to find a characteristic structural feature for these bioactivities of compounds. Among the compounds of synthesized symmetrical TAEA-related derivatives, compound 13k showed high anti-HSV-1 activity (50% effective concentration (EC50)=16.7 µM) and low cytotoxicity (50% cytotoxic concentration (CC50)=>200 µM). The presence of a hydrogen bond donor proton in the molecule is thought to be an important structural factor for expressing potential anti-HSV-1 activities.

Cleavage pattern and development of isolated D blastomeres in bivalves.

Although bivalves develop through spiral cleavage patterns, similar to other lophotrochozoans, the cleavage pattern of D lineage blastomeres is unique, since 2d shows four rounds of stereotypic unequal cleavage before bilateral cleavage of the largest derivative of 2d: 2d(1121) . This unique modification of spiral cleavage is directly associated with the characteristic morphology of bivalves, namely, bilaterally separated shell plates, because the bilateral shell plates are thought to be derived from the bilateral derivatives of 2d(1121) . In this report, to determine whether the unique cleavage pattern of bivalves is regulated depending on the interaction with other cells or by cell autonomous mechanisms, we performed cell isolation experiments and observed subsequent cleavage patterns of isolated blastomeres. When focusing on the largest derivatives of D blastomeres, 8% of isolated D blastomeres followed the cleavage pattern of normal development up to bilateral cleavage. Importantly, the remainder of the partial embryos ended cleavage before that stage, and none of the isolated blastomeres showed abnormal cleavage patterns. We also examined the development of isolated blastomeres and found that isolated D blastomeres could develop shell plates, whereas larvae developed from AB blastomeres never had shell plates. Based on these observations, we concluded that D blastomeres control their unique cleavage pattern through intrinsic mechanisms and develop shell glands autonomously without any cell-cell interaction with other lineages.

Cytokeratin localization and basal cell differentiation in the epididymal epithelium during postnatal development of the mouse.

The epididymis is a male genital organ that has plays various functions, including sperm concentration, maturation, and storage. The epididymal epithelium consists of principal cells, clear cells, and basal cells. To comprehensively understand the occurrence and morphological differentiation of basal cells, we examined the expression and localization of cytokeratins (CKs) in the epididymal epithelium during postnatal development of the mouse. Immunohistochemical staining showed that, in adult mice, CK5 and CK14 were exclusively expressed in the cytoplasm of basal cells. During postnatal development, basal cells that stained positive for CK5 and CK14 first appeared in immature columnar epithelial cells in mice aged 1 week. The immunoreactivity became progressively stronger in mice aged 2-3 weeks. In mice aged 3 weeks, the immunoreactivity was strong in regions IV and V. In mice aged ≥ 4 weeks, strong immunoreactivity was observed in all epididymal regions. CK5 and CK14 could be useful markers of differentiation in epididymal basal cells. These basal cells originate from immature columnar epithelial cells and are of two types­dome-shaped and flask-shaped­. The flask-shaped cells are mainly located in the initial segment of the mouse epididymis.

Transcription activity of individual rrn operons in Bacillus subtilis mutants deficient in (p)ppGpp synthetase genes, relA, yjbM, and ywaC.

In Bacillus subtilis a null mutation of the relA gene, whose gene product is involved in the synthesis and/or hydrolysis of (p)ppGpp, causes a growth defect that can be suppressed by mutation(s) of yjbM and/or ywaC coding for small (p)ppGpp synthetases. All 35 suppressor mutations newly isolated were classified into two groups, either yjbM or ywaC, by mapping and sequencing their mutations, suggesting that there are no (p)ppGpp synthetases other than RelA, YjbM, and YwaC in B. subtilis. In order to understand better the relation between RelA and rRNA synthesis, we studied in the relA mutant the transcriptional regulation of seven rRNA operons (rrnO, -A, -J, -I, -E, -D, or -B) individually after integration of a promoter- and terminatorless cat gene. We identified the transcriptional start sites of each rrn operon (a G) and found that transcription of all rrn operons from their P1 promoters was drastically reduced in the relA mutant while this was almost completely restored in the relA yjbM ywaC triple mutant. Taken together with previous results showing that the intracellular GTP concentration was reduced in the relA mutant while it was restored in the triple mutant, it seems likely that continuous (p)ppGpp synthesis by YjbM and/or YwaC at a basal level causes a decrease in the amounts of intracellular GTP.

Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12.

We show that selection of drug-resistant bacterial mutants allows the discovery of antibacterial compounds. Mutant strains of a soil-isolated Streptomyces species that does not produce antibacterials synthesize a previously unknown class of antibacterial, which we name piperidamycin. Overall, 6% of non-Streptomyces actinomycetes species and 43% of Streptomyces species that do not produce antibacterials are activated to produce them. The antibacterial-producing mutants all carried mutations in RNA polymerase and/or the ribosomal protein S12.

Identification and functional analysis of novel (p)ppGpp synthetase genes in Bacillus subtilis.

Bacterial alarmone (p)ppGpp, is a global regulator responsible for the stringent control. Two homologous (p)ppGpp synthetases, RelA and SpoT, have been identified and characterized in Escherichia coli, whereas Gram-positive bacteria such as Bacillus subtilis have been thought to possess only a single RelA-SpoT enzyme. We have now identified two genes, yjbM and ywaC, in B. subtilis that encode a novel type of alarmone synthetase. The predicted products of these genes are relatively small proteins ( approximately 25 kDa) that correspond to the (p)ppGpp synthetase domain of RelA-SpoT family members. A database survey revealed that genes homologous to yjbM and ywaC are conserved in certain bacteria belonging to Firmicutes or Actinobacteria phyla but not in other phyla such as Proteobacteria. We designated the proteins as small alarmone synthetases (SASs) to distinguish them from RelA-SpoT proteins. The (p)ppGpp synthetase function of YjbM and YwaC was confirmed by genetic complementation analysis and by in vitro assay of enzyme activity. Molecular genetic analysis also revealed that ywaC is induced by alkaline shock, resulting in the transient accumulation of ppGpp. The SAS proteins thus likely function in the biosynthesis of alarmone with a mode of action distinct from that of RelA-SpoT homologues.

FR258900, a novel glycogen phosphorylase inhibitor isolated from Fungus No. 138354. II. Anti-hyperglycemic effects in diabetic animal models.

A novel glycogen phosphorylase inhibitor FR258900 was isolated from the cultured broth of a fungal strain No. 138354. We examined the hypoglycemic effects of FR258900 in diabetic animal models. FR258900 treatment significantly reduced the plasma glucose concentrations during oral glucose tolerance tests in diabetic mice models, including db/db mice and STZ-induced diabetic mice. Furthermore, FR258900 treatment resulted in rapid decrease in the plasma glucose levels in db/db mice. These improvements in glucose disposal were accompanied by increased liver glycogen contents, suggesting that the glucose lowering effects of FR258900 were attributed to suppressed hepatic glycogen breakdown and increased hepatic glycogen synthesis. Taken together, our results suggest that glycogen phosphorylase is a potentially useful target in new therapies against diabetes.