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.

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.

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.

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.

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.

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.