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1.  Anterior capsule contraction and intraocular lens decentration and tilt after hydrogel lens implantation 
The British Journal of Ophthalmology  2001;85(11):1294-1297.
AIM—To prospectively investigate changes in the area of the anterior capsule opening, and intraocular lens (IOL) decentration and tilt after implantation of a hydrogel IOL.
METHODS—100 patients underwent implantation of a hydrogel IOL in one eye and an acrylic IOL implantation in the opposite eye. The area of the anterior capsule opening, and the degree of IOL decentration and tilt were measured using the Scheimpflug videophotography system at 3 days, and at 1, 3, and 6 months postoperatively.
RESULTS—The mean anterior capsule opening area decreased significantly in both groups. At 6 months postoperatively, the area in the hydrogel group was significantly smaller than that in the acrylic group. The mean percentage of the area reduction in the hydrogel group was also significantly greater than that in the acrylic group, being 16.9% in the hydrogel group and 8.8% in the acrylic group. In contrast, IOL decentration and tilt did not progress in either group. No significant differences were found in the degree of IOL decentration and tilt throughout the follow up period.
CONCLUSIONS—Contraction of the anterior capsule opening was more extensive with the hydrogel IOL than with the acrylic IOL, but the degree of IOL decentration and tilt were similar for the two types of lenses studied.

PMCID: PMC1723752  PMID: 11673291
2.  Anterior capsule contraction and intraocular lens dislocation in eyes with pseudoexfoliation syndrome 
The British Journal of Ophthalmology  1998;82(12):1429-1432.
AIMS—To examine the extent of anterior capsule contraction as well as intraocular lens (IOL) decentration and tilt following implant surgery in eyes with pseudoexfoliation syndrome (PE).
METHODS—53 eyes from 53 patients with PE and 53 control eyes from 53 age matched patients, undergoing phacoemulsification and implant surgery, were recruited. The anterior capsule opening area and the amounts of IOL decentration and tilt after undergoing continuous curvilinear capsulorhexis were measured using the Scheimpflug videophotography system at 1 week and 1, 3, 6, 9, and 12 months postoperatively.
RESULTS—The mean area of the anterior capsule opening in the PE group was significantly smaller than that in the control group at 1 month postoperatively and later. The percentage reductions in the PE group were approximately 25%, while they were less than 10% in the control group. The degree of IOL tilt was also larger in the PE group than in the control group. Five eyes (9.4%) in the PE group underwent a neodymium:YAG laser anterior capsulotomy, but none in the control group underwent a capsulotomy.
CONCLUSIONS—The contraction of the anterior capsule opening was more extensive in the PE eyes than in the control eyes, thus resulting in a high Nd:YAG laser anterior capsulotomy rate. The IOL tilt was also greater in the PE eyes than in the control eyes.

 Keywords: anterior capsule contraction; intraocular lens dislocation; pseudoexfoliation syndrome; continuous curvilinear capsulorhexis
PMCID: PMC1722461  PMID: 9930277
3.  Comparison of decentration and tilt between one piece and three piece polymethyl methacrylate intraocular lenses 
BACKGROUND—The extent of the decentration and tilt was prospectively compared between one piece polymethyl methacrylate (PMMA) and three piece PMMA intraocular lenses (IOLs) which were implanted in the capsular bag after performing continuous curvilinear capsulorhexis.
METHODS—91 patients underwent a one piece PMMA IOL implantation in one eye as well as the implantation of the three piece PMMA IOL with polyvinylidene fluoride loops in the opposite eye. The length of the lens decentration and the angle of the tilt were quantitated using the anterior eye segment analysis system (EAS-1000) at 1 week as well as 1, 3, and 6 months postoperatively.
RESULTS—The mean length of the decentration in the one piece IOL was smaller than that in the three piece IOL at 1 week (p=0.0092), 1 month (p=0.0044), 3 months (p=0.0069), and 6 months (p=0.0010) postoperatively. However, no significant difference was found in the degree of the tilt between the two types of IOLs throughout the observation periods.
CONCLUSION—These results clarified that the one piece PMMA IOL with rigid PMMA haptics implanted in the capsular bag provides a better centration than the three piece PMMA IOL with flexible haptics, whereas the tilt was the same between the two types of IOLs.

 Keywords: intraocular lens; decentration; tilt; continuous curvilinear capsulorhexis
PMCID: PMC1722563  PMID: 9640193
4.  A Low-Testosterone State Associated with Endometrioma Leads to the Apoptosis of Granulosa Cells 
PLoS ONE  2014;9(12):e115618.
Although endometriosis is suspected to be a cause of premature ovarian insufficiency (POI), the mechanism(s) underlying this process have not been elucidated. Recently, androgens were shown to promote oocyte maturation and to play a role in folliculogenesis. In addition, several reports have documented low testosterone levels in the follicular fluid obtained from endometriosis patients. We therefore examined whether the low levels of serum testosterone are associated with the apoptosis of granulosa cells in follicles obtained from endometriosis patients. Serum samples were collected from 46 patients with endometriosis and from 62 patients without endometriosis who received assisted reproductive therapy. Specimens of the ovaries obtained from 10 patients with endometrioma were collected using laparoscopy. The mean serum testosterone concentration in the patients with endometriosis was significantly lower than that observed in the patients without endometriosis. Furthermore, high expression of a pro-apoptotic Bcl-2 member, BimEL, in the follicles was found to be associated with a low serum testosterone level. We clarified the underlying mechanisms using a basic approach employing human immortalized granulosa cells derived from a primary human granulosa cell tumor, the COV434 cell line. The in vitro examination demonstrated that testosterone inhibited apoptosis induced by sex steroids depletion via the PI3K/Akt-FoxO3a pathway in the COV434 cells. In conclusion, we elucidated the mechanism underlying the anti-apoptotic effects of testosterone on granulosa cells, and found that a low-testosterone status is a potentially important step in the development of premature ovarian insufficiency in patients with endometriosis.
PMCID: PMC4275210  PMID: 25536335
5.  Frequency of HER2 expression of circulating tumour cells in patients with metastatic or recurrent gastrointestinal cancer 
British Journal of Cancer  2013;109(11):2829-2832.
The clinical significance of circulating tumour cell (CTC) detection in gastrointestinal (GI) cancer remains controversial and the molecular biological characteristics of CTCs are poorly understood.
A total of 87 patients with metastatic or recurrent GI cancer were prospectively enrolled. Circulating tumour cells and their HER2 status were assessed using the CellSearch System.
Among the 62 CTC-positive cases, we found 22 discordant cases (35.5%). Among the HER2-negative primary tumours, 17 of 54 developed HER2-positive CTCs. Five of eight had HER2-negative CTCs among the HER2-positive primary tumours.
The findings in the current study suggest that it is critical to evaluate the HER2 status of not only the primary tumour but also the CTCs because the metastasising tumour cells are the primary target of systemic therapy.
PMCID: PMC3844922  PMID: 24201755
gastrointestinal cancer; circulating tumour cells; HER2
6.  Novel Positively Charged Nanoparticle Labeling for In Vivo Imaging of Adipose Tissue-Derived Stem Cells 
PLoS ONE  2014;9(11):e110142.
Stem cell transplantation has been expected to have various applications for regenerative medicine. However, in order to detect and trace the transplanted stem cells in the body, non-invasive and widely clinically available cell imaging technologies are required. In this paper, we focused on magnetic resonance (MR) imaging technology, and investigated whether the trimethylamino dextran-coated magnetic iron oxide nanoparticle -03 (TMADM-03), which was newly developed by our group, could be used for labeling adipose tissue-derived stem cells (ASCs) as a contrast agent. No cytotoxicity was observed in ASCs transduced with less than 100 µg-Fe/mL of TMADM-03 after a one hour transduction time. The transduction efficiency of TMADM-03 into ASCs was about four-fold more efficient than that of the alkali-treated dextran-coated magnetic iron oxide nanoparticle (ATDM), which is a major component of commercially available contrast agents such as ferucarbotran (Resovist), and the level of labeling was maintained for at least two weeks. In addition, the differentiation ability of ASCs labeled with TMADM-03 and their ability to produce cytokines such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2), were confirmed to be maintained. The ASCs labeled with TMADM-03 were transplanted into the left kidney capsule of a mouse. The labeled ASCs could be imaged with good contrast using a 1T MR imaging system. These data suggest that TMADM-03 can therefore be utilized as a contrast agent for the MR imaging of stem cells.
PMCID: PMC4217721  PMID: 25365191
7.  Decorin induced by progesterone plays a crucial role in suppressing endometriosis 
The Journal of Endocrinology  2014;223(2):203-216.
Dienogest, a synthetic progestin, has been shown to be effective against endometriosis, although it is still unclear as to how it affects the ectopic endometrial cells. Decorin has been shown to be a powerful endogenous tumor repressor acting in a paracrine fashion to limit tumor growth. Our objectives were to examine the direct effects of progesterone and dienogest on the in vitro proliferation of the human ectopic endometrial epithelial and stromal cell lines, and evaluate as to how decorin contributes to this effect. We also examined DCN mRNA expression in 50 endometriosis patients. The growth of both cell lines was inhibited in a dose-dependent manner by both decorin and dienogest. Using a chromatin immunoprecipitation assay, it was noted that progesterone and dienogest directly induced the binding of the decorin promoter in the EMOsis cc/TERT cells (immortalized human ovarian epithelial cells) and CRL-4003 cells (immortalized human endometrial stromal cells). Progesterone and dienogest also led to significant induced cell cycle arrest via decorin by promoting production of p21 in both cell lines in a dose-dependent manner. Decorin also suppressed the expression of MET in both cell lines. We confirmed that DCN mRNA expression in patients treated with dienogest was higher than that in the control group. In conclusion, decorin induced by dienogest appears to play a crucial role in suppressing endometriosis by exerting anti-proliferative effects and inducing cell cycle arrest via the production of p21 human ectopic endometrial cells and eutopic endometrial stromal cells.
PMCID: PMC4198121  PMID: 25244916
decorin; progesterone; dienogest; endometriosis; cell cycle arrest; p21
8.  Is d-aspartate produced by glutamic-oxaloacetic transaminase-1 like 1 (Got1l1): a putative aspartate racemase? 
Amino Acids  2014;47:79-86.
d-Aspartate is an endogenous free amino acid in the brain, endocrine tissues, and exocrine tissues in mammals, and it plays several physiological roles. In the testis, d-aspartate is detected in elongate spermatids, Leydig cells, and Sertoli cells, and implicated in the synthesis and release of testosterone. In the hippocampus, d-aspartate strongly enhances N-methyl-d-aspartate receptor-dependent long-term potentiation and is involved in learning and memory. The existence of aspartate racemase, a candidate enzyme for d-aspartate production, has been suggested. Recently, mouse glutamic-oxaloacetic transaminase 1-like 1 (Got1l1) has been reported to synthesize substantially d-aspartate from l-aspartate and to be involved in adult neurogenesis. In this study, we investigated the function of Got1l1 in vivo by generating and analyzing Got1l1 knockout (KO) mice. We also examined the enzymatic activity of recombinant Got1l1 in vitro. We found that Got1l1 mRNA is highly expressed in the testis, but it is not detected in the brain and submandibular gland, where d-aspartate is abundant. The d-aspartate contents of wild-type and Got1l1 KO mice were not significantly different in the testis and hippocampus. The recombinant Got1l1 expressed in mammalian cells showed l-aspartate aminotransferase activity, but lacked aspartate racemase activity. These findings suggest that Got1l1 is not the major aspartate racemase and there might be an as yet unknown d-aspartate-synthesizing enzyme.
PMCID: PMC4282708  PMID: 25287256
Glutamic-oxaloacetic transaminase-1 like 1; d-Aspartate; Knockout mice; Testis; Hippocampus; Recombinant protein expression
9.  Efficacy and safety of febuxostat in elderly female patients 
Maintenance of low serum urate levels is important for the management of gout. Achieving the recommended serum urate levels of less than 6.0 mg/dL is difficult in elderly (65 years of age or older) patients with renal impairment. Xanthine oxidase inhibitors allopurinol and febuxostat are used for this purpose. Although febuxostat had been shown to be efficacious in elderly patients, its safety and efficacy in elderly female patients with hyperuricemia remain unclear.
The aim of this study was to assess the efficacy and safety of febuxostat in elderly female patients.
We studied a retrospective cohort study. The study included elderly Japanese patients (65 years of age or older) who were treated with febuxostat at Fujita Health University Hospital from January 2012 to December 2013. The treatment goal was defined as achievement of serum urate levels of 6.0 mg/dL or lower within 16 weeks; this was the primary endpoint in the present study. Adverse events of febuxostat were defined as more than twofold increases in Common Terminology Criteria for adverse events scores from baseline.
We evaluated 82 patients treated with febuxostat during the observation period and classified them into male (n=53) and female (n=29) groups. The mean time to achievement of the treatment goal was significantly shorter in the female group (53 days) than in the male group (71 days). There were no significant differences in adverse events between the 2 groups.
Our findings suggest that the efficacy of febuxostat in elderly female patients is superior to that in elderly male patients and that the safety is equivalent.
PMCID: PMC4158997  PMID: 25214776
febuxostat; elderly female patients; hyperuricemia
10.  Effect of methylglyoxal on multidrug-resistant Pseudomonas aeruginosa 
Honey has a complex chemistry, and its broad-spectrum antimicrobial activity varies with floral source, climate, and harvesting conditions. Methylglyoxal was identified as the dominant antibacterial component of manuka honey. Although it has been known that methylglyoxal has antibacterial activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, there is not much information describing its activity against gram-negative bacteria. In this study, we report the effect of methylglyoxal against multidrug-resistant Pseudomonas aeruginosa (MDRP) using 53 clinically isolated strains. We also assessed the effect of deleting the five multidrug efflux systems in P. aeruginosa, as well as the efflux systems in Escherichia coli and Salmonella enterica serovar Typhimurium, on MICs of methylglyoxal. Our results indicate that methylglyoxal inhibits the growth of MDRP at concentrations of 128–512 μg/ml (1.7–7.1 mM) and is not recognized by drug efflux systems.
PMCID: PMC4029012  PMID: 24860556
manuka honey; methylglyoxal; drug efflux system; multidrug resistance; Pseudomonas aeruginosa
11.  Risk factors for an early dialysis start in patients with diabetic nephropathy end-stage renal disease 
Patients with end-stage renal disease (ESRD) have symptoms related to severe anemia, edema, and heart failure. Although dialysis improves ESRD syndromes, the optimum timing for initiation of dialysis is unclear. Recent observational studies have suggested that early commencement of dialysis can be harmful. Given that early dialysis may increase the risk of death, avoiding an early start to dialysis is recommended. Patients with diabetic nephropathy (DN) may have risk factors for early dialysis. However, the risk factors for early dialysis are unclear in ESRD patients with DN. The aim of this study was to elucidate the risk factors for early initiation of dialysis in patients with DN and ESRD.
From April 2009 to December 2012, we identified Japanese DN patients with an estimated glomerular filtration rate of less than 15 mL/minute/1.73 m2. The patients were divided into late or early dialysis groups based on the timing of start of dialysis.
We evaluated 52 patients who commenced dialysis during the observation period, including 33 in the late dialysis group and 19 in the early dialysis group. There was a significant association between early dialysis and age ≥65 years (odds ratio 4.59). The incidence of pneumonia before starting dialysis was significantly higher in elderly patients than in nonelderly patients.
Our findings suggest that elderly patients with DN and ESRD have an increased risk of early initiation of dialysis, and occurrence of pneumonia is also associated with early dialysis. To avoid early commencement of dialysis, booster pneumococcal vaccination could be useful in elderly DN patients with ESRD.
PMCID: PMC3913608  PMID: 24511237
early dialysis; diabetes mellitus; nephropathy; elderly patients; estimated glomerular filtration rate
12.  Selection of Rodent Species Appropriate for mtDNA Transfer to Generate Transmitochondrial Mito-Mice Expressing Mitochondrial Respiration Defects 
Experimental Animals  2014;63(1):21-30.
Previous reports have shown that transmitochondrial mito-mice with nuclear DNA from Mus musculus and mtDNA from M. spretus do not express respiration defects, whereas those with mtDNA from Rattus norvegicus cannot be generated from ES cybrids with mtDNA from R. norvegicus due to inducing significant respiration defects and resultant losing multipotency. Here, we isolated transmitochondrial cybrids with mtDNA from various rodent species classified between M. spretus and R. norvegicus, and compared the O2 consumption rates. The results showed a strong negative correlation between phylogenetic distance and reduction of O2 consumption rates, which would be due to the coevolution of nuclear and mitochondrial genomes and the resultant incompatibility between the nuclear genome from M. musculus and the mitochondrial genome from the other rodent species. These observations suggested that M. caroli was an appropriate mtDNA donor to generate transmitochondrial mito-mice with nuclear DNA from M. musculus. Then, we generated ES cybrids with M. caroli mtDNA, and found that these ES cybrids expressed respiration defects without losing multipotency and can be used to generate transmitochondrial mito-mice expressing mitochondrial disorders.
PMCID: PMC4160931  PMID: 24521860
interspecies mtDNA transfer; multipotency; Mus caroli mtDNA; respiration defects; transmitochondrial ES cybrids
13.  Restructuring the Ikeda City school urinary screening system: report of a screening survey 
Annual urinary screening is conducted at municipal kindergartens, elementary schools, and junior high schools in Ikeda City, Osaka, Japan (Ikeda City School System), and the results are reviewed by a general physician, but standards for when to recommend specialist referral have not been clear.
In all children attending the Ikeda City School System in 2012, dipstick urinalysis of a first-morning urine specimen was recommended once or twice, and if a second urinalysis showed proteinuria (≥1+), the urinary protein/creatinine ratio was measured. If this showed ≥0.2 g/g of creatinine (g/gCr), it was recommended that the child be evaluated by a specialist at Ikeda City Hospital.
Urinary screening was performed in about 20% (388) of kindergarten, about 90% (5363) of elementary school, and about 86% (2523) of junior high school children living in Ikeda City. Urine samples were obtained from 387, 5349, and 2476 children, respectively. The urinary protein/creatinine ratio was ≥0.2 g/gCr in 13 children, including 1 elementary and 12 junior high children. In these 13 children, chronic nephritic syndrome (CNS) was suspected in 6 junior high school children, and of these, this was a new finding in 5, and renal biopsy was indicated in 3. In Ikeda City, the prevalence of CNS in elementary school children was <0.03%, the prevalence of CNS in junior high school children was 0.29%, and a renal biopsy was indicated in 0.14%. By eliminating the costs associated with assessment of the results by the Ikeda Medical Association, and by directly contracting with the testing company, the expenses paid by Ikeda City for the system itself decreased from 2,508,619 yen to 966,157 yen.
Incorporating the urinary protein/creatinine ratio into the school urinary screening system in the Ikeda City School System and clarifying standards for specialist referral has enabled restructuring of the system so that is efficient and its effectiveness can be assessed.
PMCID: PMC4028752  PMID: 24330222
Chronic glomerulonephritis; Chronic nephritic syndrome; Prevalence; Renal biopsy; School urinary screening; Urinary protein/creatinine ratio
14.  A New Protocol to Detect Multiple Foodborne Pathogens with PCR Dipstick DNA Chromatography after a Six-Hour Enrichment Culture in a Broad-Range Food Pathogen Enrichment Broth 
BioMed Research International  2013;2013:295050.
A quick foodborne pathogen screening method after six-hour enrichment culture with a broad-range food pathogen enrichment broth is described. Pathogenic factors of Salmonella enterica, Shigella spp., enteroinvasive Escherichia coli, and enterohemorrhagic E. coli are amplified with a cocktail primer and rapid polymerase chain reaction (PCR), which finishes amplification in 30 min. The PCR amplicon was differentiated with a dipstick DNA chromatography assay in 5–10 min. Starting from a four- to six-hour enrichment culture, this assay was finished within 45 min. Detection sensitivity of this protocol was less than 2.5 CFU/25 g for S. enterica and 3.3 CFU/25 g for enterohemorrhagic E. coli in spiked ground meat experiments.
PMCID: PMC3865639  PMID: 24364031
15.  Renal thrombotic microangiopathy in a patient with septic disseminated intravascular coagulation 
BMC Nephrology  2013;14:260.
The mechanism for the development of thrombotic microangiopathy (TMA) during sepsis has only been partially elucidated. TMA is recognized as a disease caused by various factors, and may be involved in the emergence of organ damage in severe sepsis. Here we report a case of TMA that followed disseminated intravascular coagulation (DIC) due to severe infection in a patient with a reduced ADAMTS-13 activity level.
Case presentation
An 86-year-old Japanese woman was admitted to our hospital because of low back pain and fever. A careful evaluation led to a diagnosis of acute obstructive pyelonephritis due to a ureteral stone. Proteus mirabilis was isolated from both blood and urine cultures. The patient developed systemic inflammatory response syndrome and DIC, and was treated with antibiotics and daily continuous hemodiafiltration. Although infection and the coagulation abnormalities due to DIC were successfully controlled, renal failure persisted and her consciousness level deteriorated progressively in association with severe thrombocytopenia and microangiopathic hemolytic anemia. We therefore suspected the presence of TMA and started plasma exchange, which resulted in an impressive improvement in consciousness as well as the laboratory abnormalities. The ADAMTS-13 activity was 44% and the patient tested negative for the ADAMTS-13 inhibitor prior to the initiation of plasma exchange. A renal biopsy was performed to determine the etiology of acute renal injury, which revealed findings that were interpreted to be compatible with the sequelae of TMA. The follow-up studies performed after the successful treatment of TMA showed that her plasma ADAMTS-13 activity level remained persistently low. It is surmised that septic DIC occurring in the presence of preexisting reduced ADAMTS-13 activity have led to the development of secondary TMA in the present case.
The present case suggests that TMA can be superimposed on sepsis-induced DIC, and plasma exchange is expected to be beneficial in such situations. Clinicians should consider the possibility of secondary TMA that follows sepsis-induced DIC in certain indicative clinical settings.
PMCID: PMC4222681  PMID: 24279773
Thrombotic microangiopathy; Cortical necrosis; DIC; Sepsis; Renal biopsy; TTP; HUS; Plasma exchange; ADAMTS-13
16.  Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages 
Cell Death and Differentiation  2012;19(11):1856-1869.
Anti-apoptotic Bcl-2 family proteins, which inhibit the mitochondrial pathway of apoptosis, are involved in the survival of various hematopoietic lineages and are often dysregulated in hematopoietic malignancies. However, their involvement in the megakaryocytic lineage is not well understood. In the present paper, we describe the crucial anti-apoptotic role of Mcl-1 and Bcl-xL in this lineage at multistages. The megakaryocytic lineage-specific deletion of both, in sharp contrast to only one of them, caused apoptotic loss of mature megakaryocytes in the fetal liver and systemic hemorrhage, leading to embryonic lethality. ABT-737, a Bcl-xL/Bcl-2/Bcl-w inhibitor, only caused thrombocytopenia in adult wild-type mice, but further induced massive mature megakaryocyte apoptosis in the Mcl-1 knockout mice, leading to severe hemorrhagic anemia. All these phenotypes were fully restored if Bak and Bax, downstream apoptosis executioners, were also deficient. In-vitro study revealed that the Jak pathway maintained Mcl-1 and Bcl-xL expression levels, preventing megakaryoblastic cell apoptosis. Similarly, both were involved in reticulated platelet survival, whereas platelet survival was dependent on Bcl-xL due to rapid proteasomal degradation of Mcl-1. In conclusion, Mcl-1 and Bcl-xL regulate the survival of the megakaryocytic lineage, which is critically important for preventing lethal or severe hemorrhage in both developing and adult mice.
PMCID: PMC3469054  PMID: 22790873
Bcl-xL; Mcl-1; apoptosis; megakaryocyte; platelet; reticulated platelet
17.  Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival 
PLoS ONE  2013;8(10):e76941.
The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.
PMCID: PMC3799859  PMID: 24204710
18.  Regression of cerebellar tonsillar descent and hydrocephalus after endoscopic third ventriculostomy in a patient with a quadrigeminal arachnoid cyst 
Posterior fossa arachnoid cysts, including quadrigeminal cistern arachnoid cysts, can occasionally cause compression of the quadrigeminal plate, leading to Sylvian aqueduct stenosis and induction of cerebellar tonsillar descent into the foramen magnum. This, in turn, can result in obstructive hydrocephalus. In such cases, the characteristic of hydrocephalus is generally considered to be hypertensive.
Case Description:
We present the case of a 28-year-old female complaining of chronic and progressively worsening headaches following the delivery of her first child. Magnetic resonance imaging revealed marked tri-ventriculomegaly, the arachnoid cyst located in the quadrigeminal cistern, and cerebellar tonsillar descent. Ophthalmoscopy revealed bilateral papilledema indicating a long-standing elevation of intracranial pressure. Endoscopic third ventriculostomy (ETV) was performed successfully and resulted in complete recovery from her headaches and papilledema. Postoperative MRI revealed resolution of ventriculomegaly and cerebellar tonsillar descent, suggesting that the fourth ventricle outlet obstruction was associated with the development of the hydrocephalus in this patient.
Our case is the first report that a quadrigeminal arachnoid cyst associated with both cerebellar tonsillar descent and hydrocephalus was well treated with ETV. It was indicated that the patient's hydrocephalus and cerebellar tonsillar descent were secondary and synergistic events, caused by the arachnoid cyst located in the quadrigeminal cistern.
PMCID: PMC3815032  PMID: 24232572
Arachnoid cyst; endoscopic third ventriculostomy; hydrocephalus; tonsillar descent
19.  Identification of Substituted Pyrimido[5,4-b]indoles as Selective Toll-Like Receptor 4 Ligands 
Journal of Medicinal Chemistry  2013;56(11):4206-4223.
A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.
PMCID: PMC3722616  PMID: 23656327
20.  Thallium group poisoning incident in Japan 2011 
Critical Care  2013;17(Suppl 2):P269.
PMCID: PMC3642765
21.  Orbital Cystic Schwannoma Originating from the Frontal Nerve 
Schwannomas of the orbit are very rare benign neoplasms. Intraorbital cystic schwannomas originating from the frontal nerve are even rarer, with only 1 case reported to date. This is most likely due to the fact that, in most cases, the origin of the orbital schwannoma cannot be identified intraoperatively. The nerve origin is usually speculated from histological examination of the specimen and the postoperative neurological deficits of the patient. Here, we present the case of a 65-year-old woman with a one-month history of exophthalmos, whose orbital cystic lesion was completely removed by microsurgical transcranial operation. Intraoperatively, the continuity between the tumor and frontal nerve was seen macroscopically, leading us to confirm the frontal nerve as an origin of the tumor, which was consistent with the postoperative neurological findings. The diagnosis of the tumor was established as schwannoma from the histological examination. As a differential diagnosis of the orbital cystic lesions, the possibility of schwannomas should be kept in mind.
PMCID: PMC3540697  PMID: 23320224
22.  -449 C>G polymorphism of NFKB1 gene, coding nuclear factor-kappa-B, is associated with the susceptibility to ulcerative colitis 
AIM: To clarify the association between a polymorphism -449 C>G (rs72696119) in 5’-UTR of NFKB1 with ulcerative colitis (UC).
METHODS: The studied population comprised 639 subjects, including patients with UC (UC cases, n = 174) and subjects without UC (controls, n = 465). We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism.
RESULTS: The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%, respectively (P = 0.10). Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls (P = 0.017), and the GG homozygote was significantly associated with susceptibility to UC [odds ratio (OR), 1.88; 95%CI, 1.13-3.14]. In male subjects, the GG homozygote was associated with an increased risk for UC (OR, 3.10; 95%CI, 1.47-6.54; P = 0.0053), whereas this association was not found in female subjects. In addition, the GG homozygote was significantly associated with the risk of non-continuous disease (OR, 2.06; 95%CI, 1.12-3.79; P = 0.029), not having total colitis (OR, 2.40; 95%CI, 1.09-3.80, P = 0.040), disease which developed before 20 years of age (OR, 2.80; 95%CI, 1.07-7.32, P = 0.041), no hospitalization (OR, 2.28; 95%CI, 1.29-4.05; P = 0.0090) and with a maximum of 8 or less on the UCDAI score (OR, 2.45; 95%CI, 1.23-4.93; P = 0.022).
CONCLUSION: Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC. This polymorphism influences the susceptibility to and pathophysiological features of UC.
PMCID: PMC3531683  PMID: 23322997
Genetic polymorphism; NFKB1; Ulcerative colitis
23.  Role of Histamine and Its Receptor Subtypes in Stimulation of Conjunctival Goblet Cell Secretion 
The purpose of this study was to determine the effect of histamine and its receptors on goblet cell secretion.
Cultured rat and human goblet cells were grown in RPMI 1640. Goblet cell secretion of high molecular weight glycoconjugate was measured by an enzyme-linked lectin assay. Cultured rat goblet cells were homogenized and either RNA was isolated for RT-PCR or proteins were isolated for Western blot analysis for presence of histamine receptors subtypes H1 through H4. The localization of these receptors was determined in rat and human goblet cells by immunofluorescence microscopy.
Histamine stimulated goblet cell secretion in a concentration- and time-dependent manner. All four histamine receptors were present in cultured rat and human goblet cells. Use of agonists specific to individual histamine receptor subtypes indicated that the rank order of agonist stimulation was H1 = H3 > H4 > H2. Using antagonists specific to individual histamine receptor subtypes determined that H2 and H3, but not the H1 and H4, antagonists, inhibited histamine-stimulated conjunctival goblet cell secretion.
Rat and human conjunctival goblet cells are a direct target of histamine, which induces secretion. All four histamine receptors are present in rat and human conjunctiva and are active in rat conjunctival goblet cells. These findings suggest that all four histamine receptor subtypes are important for conjunctival goblet cell secretion. Blockage of histamine receptor subtypes could prevent the excess mucus production associated with ocular allergy.
The study demonstrated that all four histamine receptors are present and active in rat conjunctival goblet cells.
PMCID: PMC3376076  PMID: 22467574
24.  Dienogest increases the progesterone receptor isoform B/A ratio in patients with ovarian endometriosis 
The resistance of endometriotic tissue to progesterone can be explained by alterations in the distribution of progesterone receptor (PR) and estrogen receptor (ER) isoforms. The aims of this study were to examine the expressions of PR-A, PR-B, ERα and ERβ in endometrioma and assess whether these expressions are affected by dienogest or leuprolide acetate (LA) treatment.
We enrolled 60 females, including 43 patients with endometriosis (14 who received no medical treatment, 13 who received dienogest and 16 who received LA before undergoing laparoscopic surgery) and 17 patients with leiomyoma. The expression levels of PR and ER isoforms in eutopic and ectopic endometrium were assayed with quantitative real-time PCR, and confirmed with immunohistochemistry.
A decreased PR-B/PR-A ratio and an increased ERβ/ERα ratio were demonstrated in ectopic endometrium derived from females with endometriosis compared with the ratios observed in eutopic endometrium obtained from females without endometriosis. Although LA treatment did not affect the PR-B/PR-A and ERβ/ERα ratios, dienogest treatment increased the PR-B/PR-A ratio and decreased the ERβ/ERα ratio in patients with endometriomas.
Dienogest may improve progesterone resistance in endometriotic tissue by increasing the relative expressions of PR-B and PR-A, and decreasing the relative expressions of ERβ and ERα.
PMCID: PMC3541078  PMID: 23113924
Dienogest; Progesterone receptor isoforms; Estrogen receptor isoforms; Ovarian endometriosis; Progesterone resistance
25.  Inhibitory effects of carbon dioxide insufflation on pneumoperitoneum and bowel distension after percutaneous endoscopic gastrostomy 
AIM: To evaluate the inhibitory effects of carbon dioxide (CO2) insufflation on pneumoperitoneum and bowel distension after percutaneous endoscopic gastrostomy (PEG).
METHODS: A total of 73 consecutive patients who were undergoing PEG were enrolled in our study. After eliminating 13 patients who fitted our exclusion criteria, 60 patients were randomly assigned to either CO2 (30 patients) or air insufflation (30 patients) groups. PEG was performed by pull-through technique after three-point fixation of the gastric wall to the abdominal wall using a gastropexy device. Arterial blood gas analysis was performed immediately before and after the procedure. Abdominal X-ray was performed at 10 min and at 24 h after PEG to assess the extent of bowel distension. Abdominal computed tomography was performed at 24 h after the procedure to detect the presence of pneumoperitoneum. The outcomes of PEG for 7 d post-procedure were also investigated.
RESULTS: Among 30 patients each for the air and the CO2 groups, PEG could not be conducted in 2 patients of the CO2 group, thus they were excluded. Analyses of the remaining 58 patients showed that the patients’ backgrounds were not significantly different between the two groups. The elevation values of arterial partial pressure of CO2 in the air group and the CO2 group were 2.67 mmHg and 3.32 mmHg, respectively (P = 0.408). The evaluation of bowel distension on abdominal X ray revealed a significant decrease of small bowel distension in the CO2 group compared to the air group (P < 0.001) at 10 min and 24 h after PEG, whereas there was no significant difference in large bowel distension between the two groups. Pneumoperitoneum was observed only in the air group but not in the CO2 group (P = 0.003). There were no obvious differences in the laboratory data and clinical outcomes after PEG between the two groups.
CONCLUSION: There was no adverse event associated with CO2 insufflation. CO2 insufflation is considered to be safer and more comfortable for PEG patients because of the lower incidence of pneumoperitoneum and less distension of the small bowel.
PMCID: PMC3400858  PMID: 22826621
Percutaneous endoscopic gastrostomy; Carbon dioxide insufflation; Pneumoperitoneum; Abdominal distension; Randomized control study

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