Hypoxia increases persulfide and polysulfide formation by AMP kinase dependent cystathionine gamma lyase phosphorylation.

Hydropersulfide and hydropolysulfide metabolites are increasingly important reactive sulfur species (RSS) regulating numerous cellular redox dependent functions. Intracellular production of these species is known to occur through RSS interactions or through translational mechanisms involving cysteinyl t-RNA synthetases. However, regulation of these species under cell stress conditions, such as hypoxia, that are known to modulate RSS remain poorly understood. Here we define an important mechanism of increased persulfide and polysulfide production involving cystathionine gamma lyase (CSE) phosphorylation at serine 346 and threonine 355 in a substrate specific manner, under acute hypoxic conditions. Hypoxic phosphorylation of CSE occurs in an AMP kinase dependent manner increasing enzyme activity involving unique inter- and intramolecular interactions within the tetramer. Importantly, both cellular hypoxia and tissue ischemia result in AMP Kinase dependent CSE phosphorylation that regulates blood flow in ischemic tissues. Our findings reveal hypoxia molecular signaling pathways regulating CSE dependent persulfide and polysulfide production impacting tissue and cellular response to stress.

Spinal Cord Subependymoma: A Subanalysis of the Neurospinal Society of Japan's Multicenter Study of Intramedullary Spinal Cord Tumors.

OBJECTIVE: This study aimed to analyze the clinical characteristics, treatment strategies, and surgical outcomes of subependymoma patients from the 2022 Neurospinal Society of Japan multicenter intramedullary spinal cord tumor study. METHODS: Twenty-six patients with spinal cord subependymoma who were included in the index study of 1,033 patients were retrospectively analyzed. RESULTS: Mean patient age was 49.4 years. Seventeen patients were men and 9 were women. Sensory disturbance was reported in 22 patients and motor weakness in 18. Median duration of symptoms was 24 months. The tumor was eccentrically located in 19 patients (73.1%) and unilateral in 17 (65.4%). Gross total resection was achieved in 6 patients (23.1%). The same rate for ependymoma patients in the index study was significantly higher (74.8%). Median follow-up was 40.5 months (interquartile range, 18-68 months). In 2 patients who underwent only partial resection, reoperation was required owing to progression 68 and 90 months after surgery, respectively. No recurrence occurred in patients who underwent gross total resection. Five patients experienced neurological worsening after surgery. CONCLUSION: Although spinal cord subependymoma can be difficult to distinguish from other intramedullary spinal cord lesions before surgery, it is characterized by an indolent clinical course and eccentric location. Surgical treatment should prioritize functional preservation because the prognosis is good even after subtotal resection.

Hemorrhagic cervical juxta-facet cyst presenting with Brown-Séquard syndrome: illustrative case.

BACKGROUND: Intraspinal juxta-facet cysts of the spine are known to predominate at the lumbar level and is relatively rare at the cervical level. Most cervical spinal lesions are found incidentally, but they sometimes cause myelopathy or radiculopathy in a chronic course. OBSERVATIONS: The authors present a rare case of hemorrhagic cervical juxta-facet cyst presenting with Brown-Séquard syndrome. An 86-year-old woman presented with acute-onset right hemiparesis following neck pain and was admitted to the local hospital. She was started on antithrombotic therapy with a suspected diagnosis of cerebral infarction, but quadriplegia progressed 2 days later. Cervical magnetic resonance imaging revealed an intraspinal mass at the C4-5 level and she was referred to the authors' hospital. Her neurological findings on admission revealed right Brown-Séquard syndrome. In emergency surgery, the mass was resected with a posterior approach. Pathological findings showed hemosiderin deposition and fibroblast proliferation, consistent with a juxta-facet cyst with intracystic hemorrhage. The patient recovered well and returned to an independent daily life. LESSONS: Rarely, juxta-facet cyst of the cervical spine can cause acute Brown-Séquard syndrome due to intraspinal hemorrhage. In a case of hemiparesis that develops following neck pain, hemorrhagic cervical juxta-facet cyst should be taken into consideration as a differentiation.

A mouse model of weight gain after nicotine withdrawal.

Smoking cessation increases body weight. The underlying mechanisms, however, have not been fully understood. We here report an establishment of a mouse model that exhibits an augmented body weight gain after nicotine withdrawal. High fat diet-fed mice were infused with nicotine for two weeks, and then with vehicle for another two weeks using osmotic minipumps. Body weight increased immediately after nicotine cessation and was significantly higher than that of mice continued on nicotine. Mice switched to vehicle consumed more food than nicotine-continued mice during the first week of cessation, while oxygen consumption was comparable. Elevated expression of orexigenic agouti-related peptide was observed in the hypothalamic appetite center. Pair-feeding experiment revealed that the accelerated weight gain after nicotine withdrawal is explained by enhanced energy intake. As a showcase of an efficacy of pharmacologic intervention, exendin-4 was administered and showed a potent suppression of energy intake and weight gain in mice withdrawn from nicotine. Our current model provides a unique platform for the investigation of the changes of energy regulation after smoking cessation.

Maturity-onset diabetes of the young type 5, presenting as diabetic ketoacidosis with alkalemia: A report of a case.

A 34-year-old man visited our Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, because of dry mouth and weight loss. His plasma glucose level was 32.8 mmol/L and serum levels of ketone bodies were increased, but with metabolic alkalemia. He was also suffering from renal tubular hypomagnesemia and hypokalemia. Abdominal computed tomography showed bilateral renal cysts. These findings were suggestive of maturity-onset diabetes of the young type 5. Genetic testing showed heterozygous hepatocyte nuclear factor 1 beta gene deletion. In the present case, it seemed reasonable to view hepatocyte nuclear factor 1 beta gene deletion as the common cause of maturity-onset diabetes of the young type 5-associated diabetic ketoacidosis and tubular malfunction-induced hypokalemic alkalosis. This case exemplifies the importance of hepatocyte nuclear factor 1 beta gene abnormality as a potential cause of diabetic ketoacidosis with alkalemia.

Primary Spinal Intradural Extramedullary Mesenchymal Chondrosarcoma.

BACKGROUND: Among chondrosarcomas arising from bones and soft tissues, mesenchymal chondrosarcoma (MCS), especially primary spinal intradural extramedullary MCS, is extremely rare, and only 18 cases have been reported to date. We report an adult case of this rare condition mimicking meningioma. CASE DESCRIPTION: A 42-year-old woman presented with paraplegia and sensory disturbance associated with right-sided Brown-Séquard syndrome following back pain. Magnetic resonance imaging showed an intradural mass in the right dorsal spinal canal with homogeneous enhancement and dural tail sign at the T8 level. Computed tomography demonstrated a calcified portion in the mass. Following T7-8 laminectomies, an intradural extramedullary tumor was completely removed after detaching the tumor from the dura mater. The histopathologic diagnosis was MCS, and positron emission tomography showed no metastatic lesions at other sites. The patient did not receive adjuvant therapy, and magnetic resonance imaging revealed no evidence of recurrence during 2-year follow-up. CONCLUSIONS: Primary spinal intradural extramedullary MCS has been reported to have a better prognosis than MCS occurring in other regions. In a case with early complete surgical resection, adjuvant therapy should be considered at the time of recurrence.

Metastasis of Carcinoma to a Cerebral Arteriovenous Malformation.

BACKGROUND: Although carcinoma metastasis to primary intracranial neoplasms has occasionally been reported, metastasis to a cerebral arteriovenous malformation (AVM) has been exceedingly rare, with only 5 cases reported to date. In the present study, we have reported a case of lung carcinoma that had metastasized to a cerebral AVM. To the best of our knowledge, the present report is the first case in which the pathological examination detected the bleeding mechanism of this rare condition, showing destruction of the feeders by the metastatic tumor. CASE DESCRIPTION: A 61-year-old man who had had a tumor shadow in the right middle lung field identified at a medical examination 5 weeks previously had suddenly experienced a disturbance of consciousness. Head computed tomography and computed tomography angiography revealed a right occipital subcortical hemorrhage with abnormal vessels, suggesting a ruptured AVM. Magnetic resonance imaging with gadolinium-based contrast agents did not show any other lesions. Cerebral angiography revealed a Spetzler-Martin grade III AVM in the right occipital lobe. Endovascular feeder embolization and subsequent removal of the AVM were performed. Histopathological examination of the resected mass showed a small cell carcinoma that had metastasized to the AVM. The tumor cells had infiltrated to the vessel walls of the feeders, which might have elicited the bleeding. CONCLUSION: Although rare, clinicians should recognize that undifferentiated carcinomas can metastasize to AVMs and cause bleeding. Because the preoperative diagnosis can be difficult, even using the latest imaging modalities, careful examination of the resected specimen is required to reveal such pathological conditions.

Role of growth hormone signaling pathways in the development of atherosclerosis.

OBJECTIVE: The direct actions of growth hormone (GH) in the development of atherosclerosis are unclear. The goal of this study was to characterize GH-induced changes in expression of signaling pathway elements and other proteins that may be related to atherosclerosis. METHODS: Human umbilical vein endothelial cells (HUVEC) and THP-1, a human acute monocytic leukemia cell line, were stimulated by exposure to 10-9 M or 10-8 M human GH with or without pretreatment with a mitogen-activated protein kinase kinase (MEK) 1 inhibitor. Levels of transcripts encoding vascular cell adhesion molecule (VCAM) -1, E-selectin, monocyte chemotactic protein (MCP-1), interleukin (IL) -6, and IL-8 were investigated by reverse transcription (RT) -PCR. For the quantitative adhesion assay, THP-1 cells or human primary monocytes were fluorescently labeled with 3'-O-acetyl-2',7'-bis(carboxyethyl) -4 diacetoxymethyl ester (BCECF/AM). HUVEC treated with human GH were co-incubated with BCECF-labeled THP-1 cells. One hour later, the number of BCECF-labeled THP-1 cells was assessed. An equivalent experiment was performed using BCECF-labeled primary monocytes, and the number of monocytes adhering to HUVEC was counted. RESULTS: Treatment with hGH increased the levels of E-selectin- and VCAM-1-encoding mRNAs in HUVEC. This effect was attenuated by pretreatment with a MEK1 inhibitor. Furthermore, hGH treatment increased adhesion of BCECF-labeled THP-1 cells or primary monocytes to HUVEC, and this effect was attenuated by pretreatment with a MEK1 inhibitor. CONCLUSIONS: VCAM-1 and E-selectin expression was stimulated by GH via the mitogen-activated protein kinase pathway, resulting in augmented adhesion of THP-1 cells and monocytes to HUVEC. These data suggested that GH directly stimulates the development of atherosclerosis.

Construction of reporter gene assays using CWP and PDR mutant yeasts for enhanced detection of various sex steroids.

BACKGROUND: Sex steroid hormone receptors are classified into three classes of receptors: estrogen receptors (ER) α and ß, androgen receptor (AR), and progesterone receptor (PR). They belong to the nuclear receptor superfamily and activate their downstream genes in a ligand-dependent manner. Since sex steroid hormones are involved in a wide variety of physiological processes and cancer development, synthetic chemical substances that exhibit sex steroid hormone activities have been applied as pharmaceuticals and consumed in large amounts worldwide. They are potentially hazardous contaminants as endocrine disruptors in the environment because they may induce inappropriate gene expression mediated by sex steroid hormone receptors in vivo. RESULTS: To develop simple reporter gene assays with enhanced sensitivity for the detection of sex steroid hormones, we newly established mutant yeast strains lacking the CWP and PDR genes encoding cell wall mannoproteins and plasma membrane drug efflux pumps, respectively, and expressing human ERα, ERß, AR, and PR. Reporter gene assays with mutant yeast strains responded to endogenous and synthetic ligands more strongly than those with wild-type strains. Sex steroid hormone activities in some pharmaceutical oral tablets and human urine were also detectable in these yeast assays. CONCLUSIONS: Yeast reporter gene assay systems for all six steroid hormone receptors, including previously established glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) assay yeasts, are now available. Environmental endocrine disrupters with steroid hormone activity will be qualitatively detectable by simple and easy procedures. The yeast-based reporter gene assay will be valuable as a primary screening tool to detect and evaluate steroid hormone activities in various test samples. Our assay system will strongly support the detection of agonists, antagonists, and inverse agonists of steroid hormone receptors in the field of novel drug discovery and assessments of environmental pollutants.

Detection of Transient Increase of Cerebral Blood Flow and Reversible Neuronal Dysfunction by Iodine-123-Iomazenil Single Photon Emission Computed Tomography After Cerebral Hyperperfusion Syndrome After Revascularization Surgery for Moyamoya Disease.

BACKGROUND: Early and late images of single photon emission computed tomography (SPECT) using 123I-iomazenil (123I-IMZ) can demonstrate cerebral blood flow and cortical neuronal viability. Hyperperfusion syndrome is one of the serious complications after revascularization surgery for moyamoya disease; therefore, the real-time observation of the hemodynamics and neuronal viability is important for the treatment after the revascularization. Here we report, a case of moyamoya disease where 123I-IMZ SPECT had a significant efficacy to delineate the hemodynamics and transient neuronal dysfunction in hyperperfusion state after revascularization. CASE DESCRIPTION: A 47-year-old woman presented with motor aphasia 3 days after superficial temporal artery-middle cerebral artery anastomosis with indirect revascularization. Magnetic resonance imaging (MRI) on the same day showed no new ischemic changes but high intensities along the left frontal sulci observed on fluid-attenuated inversion recovery images, and 123I-IMZ SPECT demonstrated the increased uptake on the early images and the decreased uptake on the late images around the anastomosis site. The patient was completely recovered 1 month after surgery, and abnormal changes on MRI and 123I-IMZ SPECT returned to normal along with the symptom withdrawal. CONCLUSIONS: These findings indicate that 123I-IMZ SPECT could be the index for the treatment of revascularization for obstructive vascular diseases such as moyamoya disease.

Growth hormone increases regulator of calcineurin 1-4 (Rcan1-4) mRNA through c-JUN in rat liver.

Growth hormone (GH) activates multiple signal transduction pathways. To investigate these pathways, we identified novel genes whose transcription was induced by GH in the liver of hypophysectomized (HPX) rats using the suppression subtractive hybridization technique. We found that regulator of calcineurin 1 (Rcan1) mRNA was upregulated by GH administration. RCAN1 regulates the activity of calcineurin, a Ca/calmodulin-dependent phosphatase. Rcan1 encodes two major transcripts, Rcan1-1 and Rcan1-4, resulting from differential promoter use and first exon choice. We found that a single injection of GH increased the levels of Rcan1-4 mRNA and RCAN1-4 protein transiently, but did not increase Rcan1-1 mRNA in HPX rat liver. Then the molecular mechanism of GH to induce Rcan1-4 transcription was examined in rat hepatoma H4IIE cells. Experiments using inhibitors suggested that c-JUN N-terminal kinase was required for the induction of Rcan1-4 mRNA by GH. GH increased the levels of phosphorylated c-JUN protein and c-Jun mRNA in HPX rat liver. The luciferase and electrophoretic mobility shift assays showed that c-JUN upregulated Rcan1-4 mRNA by binding to the cAMP-responsive element in the upstream of Rcan1 exon 4. These results indicate that GH activates c-JUN to affect the activity of calcineurin by the induction of Rcan1-4 in rat liver.

Genotyping of a gene cluster for production of colibactin and in vitro genotoxicity analysis of Escherichia coli strains obtained from the Japan Collection of Microorganisms.

INTRODUCTION: Colibactin is a small genotoxic molecule produced by enteric bacteria, including certain Escherichia coli (E. coli) strains harbored in the human large intestine. This polyketide-peptide genotoxin is considered to contribute to the development of colorectal cancer. The colibactin-producing (clb +) microorganisms possess a 54-kilobase genomic island (clb gene cluster). In the present study, to assess the distribution of the clb gene cluster, genotyping analysis was carried out among E. coli strains randomly chosen from the Japan Collection of Microorganisms, RIKEN BRC, Japan. FINDINGS: The analysis revealed that two of six strains possessed a clb gene cluster. These clb + strains JCM5263 and JCM5491 induced genotoxicity in in vitro micronucleus (MN) tests using rodent CHO AA8 cells. Since the induction level of MN by JCM5263 was high, a bacterial umu test was carried out with a cell extract of the strain, revealing that the extract had SOS-inducing potency in the umu tester bacterium. CONCLUSION: These results support the observations that the clb gene cluster is widely distributed in nature and clb + E. coli having genotoxic potencies is not rare among microorganisms.

Anterior Approach Combined with Endoscopic Fluorescence Video Angiography for a Cervical Perimedullary Arteriovenous Fistula.

BACKGROUND: Perimedullary arteriovenous fistulas (pAVFs) of the anterior cervical spinal cord are rare and difficult to eradicate by surgery because of the limitations of the approach routes. Because of the anatomic relationships, an anterior approach with corpectomy can provide direct observation. However, a narrow corridor to the lesion is the drawback of this approach. Therefore, to overcome this limitation, we introduced angled endoscopes integrated with fluorescence video angiography to observe the real-time blood flow. CASE DESCRIPTION: A 47-year-old woman was incidentally found to have a pAVF fed by multiple radicular arteries, and she underwent direct surgery via the anterior approach. Although observation of the entire lesion was difficult with the microscope alone, the introduction of the angled endoscope made it possible to observe the lateral portion of the spinal cord hidden behind the dura mater. Furthermore, endoscopic fluorescein video angiography visualized residual fine feeding arteries that were then electrocoagulated, which contributed to complete obliteration of the shunt. CONCLUSIONS: The anterior approach with endoscopic assistance is a reasonable strategy for the treatment of ventrally located cervical pAVFs. Furthermore, integration of a fluorescence video angiography system with the endoscope enables confirmation of the complicated real-time hemodynamics of the pAVFs, contributing to reliable treatment.

Endoscope-Integrated Fluorescence Video Angiography for the Surgery of Ventrally Located Perimedullary Arteriovenous Fistula at Craniocervical Junction.

BACKGROUND: Intraoperative confirmation of the vascular anatomy and blood flow contributes to the safety of the surgery for perimedullary arteriovenous fistulas (PAVF). However, because the PAVF at the craniocervical junction (CCJ) is mainly located on the ventral spinal cord surface, it is difficult to observe the entire pathology by a conventional surgical approach. To achieve increased viewing angle and visualization of real time blood flow, we introduced endoscope-integrated fluorescein video angiography in the treatment for PAVF at the CCJ for the first time. CASE DESCRIPTION: A 63-year-old man presented with subarachnoid hemorrhage due to rupture of PAVF at the CCJ, fed by both the right C1 radiculomedullary artery and the anterior spinal artery (ASA). Suboccipital craniotomy and C1 hemilaminotomy was performed and microscopic observation revealed partial anatomy of the PAVF covered by subarachnoid clots on the ventrolateral surface at the right C1 nerve root level. However, pathology ventral to the C1 nerve root was obscure and an endoscope-integrated fluorescein video angiography was introduced, which clearly demonstrated the PAVF components and the ASA. CONCLUSIONS: According to these findings, the PAVF was coagulated and the ASA was preserved. Endoscope-integrated fluorescein video angiography allowed to visualize its real-time blood flow, leading to a safe and reliable treatment.

Growth hormone activates X-box binding protein 1 in a sexually dimorphic manner through the extracellular signal-regulated protein kinase and CCAAT/enhancer-binding protein ß pathway in rat liver.

Growth hormone (GH) has multiple physiological roles, acting on many organs. In order to investigate its roles in rat liver, we tried to identify novel genes whose transcription was regulated by GH. We identified X-box binding protein 1 (Xbp1) as a candidate gene. XBP1 is a key transcription factor activated in response to endoplasmic reticulum (ER) stress. The purpose of this study was to investigate the mode of action of GH on XBP1, including the relation with ER stress, sex-dependent expression of the mRNA, and the signaling pathway. Intravenous administration of GH rapidly and transiently increased Xbp1 mRNA in hypophysectomized rat livers. Neither phosphorylated inositol-requiring-1α (IRE1α) nor phosphorylated PKR-like ER kinase (PERK) increased, suggesting that Xbp1 expression is induced by an ER stress-independent mechanism. The active form of XBP1(S) protein was increased by GH administration and was followed by an increased ER-associated dnaJ protein 4 (ERdj4) mRNA level. XBP1(S) protein levels were predominantly identified in male rat livers with variations among individuals similar to those of phosphorylated signal transducer and activator of transcription 5B (STAT5B), suggesting that XBP1(S) protein levels are regulated by the sex-dependent secretary pattern of GH. The GH signaling pathway to induce Xbp1 mRNA was examined in rat hepatoma H4IIE cells. GH induced the phosphorylation of CCAAT/enhancer-binding protein ß (C/EBPß) following extracellular signal-regulated protein kinase (ERK) phosphorylation. Taken together, the results indicated that XBP1 is activated by GH in rat liver in a sexually dimorphic manner via ERK and C/EBPß pathway.

In vitro genotoxicity analyses of colibactin-producing E. coli isolated from a Japanese colorectal cancer patient.

Colibactin is a polyketide-peptide genotoxin produced by enteric bacteria such as E. coli, and is considered to contribute to the development of colorectal cancer. We previously isolated E. coli strains from Japanese colorectal cancer patients, and in the present study we investigated the genotoxic potency of the colibactin-producing (clb+) E. coli strains that carry the polyketide synthases "pks" gene cluster (pks+) and an isogenic clb- mutant in which the colibactin-producing ability is impaired. Measurement of phosphorylated histone H2AX indicated that DNA double strand breaks were induced in mammalian CHO AA8 cells infected with the clb+ E. coli strains. Induction of DNA damage response (SOS response) by crude extract of the clb+ strains was 1.7 times higher than that of the clb- E. coli in an umu assay with a Salmonella typhimurium TA1535/pSK1002 tester strain. Micronucleus test with CHO AA8 cells revealed that infection with the clb+ strains induced genotoxicity, i.e., the frequencies of micronucleated cells infected with clb+ strain were 4-6 times higher than with the clb- strain. Since the intestinal flora are affected by dietary habits that are strongly associated with ethnicity, these data may contribute to both risk evaluation and prevention of colorectal cancer in the Japanese population.

Efficacy of Intraarterial Fluorescence Video Angiography in Surgery for Dural and Perimedullary Arteriovenous Fistula at Craniocervical Junction.

OBJECTIVE: Confirming the exact location of a fistula and the origins of draining veins during surgery for dural and perimedullary arteriovenous fistulas (AVFs) is crucial but sometimes inadequately performed, which can result in incomplete elimination of the lesion. Intraoperative digital subtraction angiography (DSA) is the gold standard for confirming the hemodynamics of an AVF; however, it cannot reveal the location of an AVF in the operative field. In this study, the efficacy of intraoperative intraarterial fluorescence video angiography during surgery for craniocervical junction dural and perimedullary AVFs was investigated. METHODS: We repeatedly employed this technology to evaluate its usefulness in revealing the flow dynamics and anatomy of AVFs and to confirm complete elimination of the fistula. RESULTS: Seven AVFs were included in this study. Their locations were C1 in 5 cases and C2 in 2 cases. Intraarterial fluorescence video angiography precisely revealed the locations of 3 dural AVFs, 1 perimedullary AVF, and 3 co-occurring dural and perimedullary AVFs. Frame-by-frame review of the fluorescence video angiography clearly demonstrated that fluorescence appeared earlier in the perimedullary AVF than in the draining vein through the dural AVF after intraarterial injection in all 3 co-occurring cases. Complete elimination of the AVF was also confirmed in all cases by fluorescence video angiography, as well as intraoperative and follow-up DSA. CONCLUSIONS: Intraarterial fluorescence video angiography, particularly frame-by-frame review, enables surgeons to distinguish the flow dynamics of AVFs and contributes to the planning of effective surgical strategies for optimal results.

Proton-pump inhibitor-induced fundic gland polyps with hematemesis.

Fundic gland polyps (FGPs) are generally considered benign. Proton-pump inhibitors (PPIs) are used worldwide as first-line therapy for gastroesophageal reflux disease and nonsteroidal anti-inflammatory drug-induced ulcer treatment. Long-term use of PPIs increases the risk of FGP development. We report an extremely rare case of PPI-induced FGPs with hematemesis. A 37-year-old woman taking daily rabeprazole presented to the hospital with a complaint of hematemesis and tarry stools. Esophagogastroduodenoscopy (EGD) revealed > 20 pedunculated polyps in the gastric body and fundus. Histological examination showed multiple fragments of fundic gland mucosa with dilated glands. Based on these findings and the clinical history, FGPs were diagnosed. Rabeprazole use was discontinued. Repeat EGD performed 9 months later showed a significant decrease in the number and size of the polyps. FGPs are small polyps typically located in the gastric corpus and fundus. They are commonly reported in patients in their 60s and predominantly in females. We conclude that PPI use is a risk factor for the development of FGPs and hematemesis.

PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.

Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element-binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain (PHD)3, which suppressed stress signalling through inhibition of the IκB kinase-nuclear factor-κB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator-activated receptor γ coactivator 1α-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.

A Case of Euthyroid Graves' Ophthalmopathy in a Patient Sero-Negative for TSH Receptor Autoantibody.

We report of a case of Graves' ophthalmopathy presented solely with symptoms of the eyes with normal thyroid function tests and negative immunoreactive TSH receptor autoantibody. 40-year-old male was referred to our hospital due to 2-month history of ocular focusing deficit without any signs or symptoms of hyper- or hypothyroidism. Serum thyroid function tests and 99mTc uptake were both within the normal range. Anti-thyroid autoantibodies were all negative except for the cell-based assay for serum TSH receptor stimulating activity. Since orbital CT scan and MRI gave typical results compatible with Graves' ophthalmopathy, we treated the patients with corticosteroid pulse therapy and orbital radiation therapy, leading to a partial improvement of the symptoms. This case gives insights into the potential pathophysiologic mechanism underlying Graves' ophthalmopathy and casts light upon the difficulties of establishing the diagnosis in a euthyroid case with minimal positive results for anti-thyroid autoantibodies.