Publications by authors named "Yoshihiro Yokoyama"

35 Publications

Gastrointestinal involvement in a patient with familial Mediterranean fever mimicking Crohn's disease: a case report.

Clin J Gastroenterol 2021 May 11. Epub 2021 May 11.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.

Familial Mediterranean fever (FMF) in gastrointestinal involvement has been considered rare, but resent reports suggest that FMF causes enterocolitis which is similar endoscopic findings to inflammatory bowel disease. The clinical characteristics and endoscopic findings of FMF with enterocolitis remain unclear. Here, we report a case of an FMF patient who had enterocolitis with stricture of the terminal ileum whose endoscopic and clinical features mimicked Crohn's disease. A 23-year-old man who was diagnosed with FMF 10 years ago presented with abdominal pain and diarrhea. Colonoscopy showed terminal ileitis and aphthous colitis; however, these findings, including the histopathology, did not confirm Crohn's disease. Therefore, we diagnosed FMF with enterocolitis and administered anti-interleukin-1β monoclonal antibody (canakinumab). The patient's symptoms improved with treatment, but after 1 year, lower abdominal pain recurred. Colonoscopy revealed a stricture of the terminal ileum. Endoscopic balloon dilation relieved his symptoms. At present, he has been followed up without surgical treatment by endoscopic balloon dilation every 6 month. Clinicians should be aware that FMF accompanied with enterocolitis may resemble Crohn's disease.
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http://dx.doi.org/10.1007/s12328-021-01426-2DOI Listing
May 2021

The characteristics of gastrointestinal symptoms in patients with severe COVID-19: a systematic review and meta-analysis.

J Gastroenterol 2021 05 23;56(5):409-420. Epub 2021 Mar 23.

Department of Gastroenterology and Hepatology, Sapporo Medical University of Medicine, S-1, W16, Chuoku, Sapporo, Hokkaido, 060-8543, Japan.

Although primarily a respiratory illness, several studies have shown that COVID-19 causes elevation of liver enzymes and various gastrointestinal (GI) symptoms. The aim of this study was to undertake a systematic review and meta-analysis to determine whether the presence of gastrointestinal (GI) symptoms contributed toward COVID-19 severity, and identify the GI symptoms characteristic of severe COVID-19. We conducted a literature search of PubMed from December 1, 2019, to June 30, 2020, and identified all reports with GI symptoms reported. A meta-analysis comparing the severity of COVID-19 with the presence of liver enzyme elevation and GI symptoms was performed using RevMan version 5.4. Pooled data from 15,305 unique reverse transcriptase-polymerase chain reaction positive COVID-19 patients from 44 studies were analyzed. We found that the severe COVID-19 patients significantly had abdominal pain compared to the non-severe COVID-19 patients (OR = 2.70, 95% CI 1.17-6.27, Z = 2.32, p = 0.02, I = 0%) by analyzed 609 patients of 4 studies who reported both abdominal pain and COVID-19 severity. However, there was no significant difference in the incidence of diarrhea, nausea, or vomiting between the two groups. Thus, this systematic review and meta-analysis demonstrated that abdominal pain could be characteristic of severe COVID-19 infections. Compared with other viral infections that primarily infect the respiratory system, patients with COVID-19 have a slightly lower frequency of diarrheal symptoms with abdominal pain. However, to confirm this, further studies with COVID-19 patients across various countries and ethnicities are required.
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http://dx.doi.org/10.1007/s00535-021-01778-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987120PMC
May 2021

Autophagy and Autophagy-Related Diseases: A Review.

Int J Mol Sci 2020 Nov 26;21(23). Epub 2020 Nov 26.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Autophagy refers to the process involving the decomposition of intracellular components via lysosomes. Autophagy plays an important role in maintaining and regulating cell homeostasis by degrading intracellular components and providing degradation products to cells. In vivo, autophagy has been shown to be involved in the starvation response, intracellular quality control, early development, and cell differentiation. Recent studies have revealed that autophagy dysfunction is implicated in neurodegenerative diseases and tumorigenesis. In addition to the discovery of certain disease-causing autophagy-related mutations and elucidation of the pathogenesis of conditions resulting from the abnormal degradation of selective autophagy substrates, the activation of autophagy is essential for prolonging life and suppressing aging. This article provides a comprehensive review of the role of autophagy in health, physiological function, and autophagy-related disease.
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http://dx.doi.org/10.3390/ijms21238974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729615PMC
November 2020

Artificial intelligence-assisted endoscopy changes the definition of mucosal healing in ulcerative colitis.

Dig Endosc 2020 Sep 10. Epub 2020 Sep 10.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Hokkaido, Japan.

The relevance of endoscopic monitoring of ulcerative colitis (UC) has been translated into the new concept of "mucosal healing (MH)" as the therapeutic goal to achieve because a large amount of scientific data have revealed the favorable prognostic value of a healed mucosa in determining the clinical outcome of UC. Recent interest in MH has skewed toward not only endoscopic remission but also histological improvement (so called histological MH). However, we should recognize that there have been no prospectively validated endoscopic scoring systems of UC activity in previous clinical trials. Artificial intelligence (AI)-assisted endoscopy has been developed for gastrointestinal cancer surveillance. Recently, several AI-assisted endoscopic systems have been developed for assessment of MH in UC. In the future, the development of a new endoscopic scoring system based on AI might standardize the definition of MH. Therefore, "The road to an exact definition of MH in the treatment of UC has begun only now".
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http://dx.doi.org/10.1111/den.13825DOI Listing
September 2020

Expert Opinions on the Current Therapeutic Management of Inflammatory Bowel Disease during the COVID-19 Pandemic: Japan IBD COVID-19 Taskforce, Intractable Diseases, the Health and Labor Sciences Research.

Digestion 2020 Sep 4:1-9. Epub 2020 Sep 4.

Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan.

Background: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as a dramatic challenge for all healthcare systems worldwide. This outbreak immediately affected gastroenterologists as well as global physicians worldwide because COVID-19 can be associated with not only triggering respiratory inflammation but also gastrointestinal (GI) inflammation based on the mechanism by which SARS-CoV-2 enters cells via its receptor the angiotensin-converting enzyme 2, which is expressed on GI cells. However, the comorbidity spectrum of digestive system in patients with COVID-19 remains unknown. Because the inflammatory bowel disease (IBD) management involves treating uncontrolled inflammation with immune-based therapies, physicians, and patients have great concern about whether IBD patients are more susceptible to SARS-CoV-2 infection and have worsened disease courses.

Summary: It is necessary to precisely ascertain the risk of SARS-CoV-2 infection and the COVID-19 severity in IBD patients and to acknowledge the IBD management during the COVID-19 pandemic with clinically reliable information from COVID-19 cohorts and IBD experts' opinions. In this review, we highlight clinical questions regarding IBD management during the COVID-19 pandemic and make comments corresponding to each question based on recent publications. Key Messages: We propose that there is (1) no evidence that IBD itself increases the risk of SARS-CoV-2 infection, (2) to basically prioritize the control of disease activity of IBD, (3) no need for physicians to suddenly discontinue immunomodulatory or biologic therapy in patients with quiescent IBD, and (4) a need for careful observation of elderly (>60 years old) and IBD patients receiving corticosteroid treatment during the COVID-19 pandemic.
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http://dx.doi.org/10.1159/000510502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573907PMC
September 2020

Immunological Mechanisms in Inflammation-Associated Colon Carcinogenesis.

Int J Mol Sci 2020 Apr 26;21(9). Epub 2020 Apr 26.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo 060-8543, Japan.

Patients with chronic inflammatory bowel diseases are at an increased risk of developing colitis-associated cancer (CAC). Chronic inflammation positively correlates with tumorigenesis. Similarly, the cumulative rate of incidence of developing CAC increases with prolonged colon inflammation. Immune signaling pathways, such as nuclear factor (NF)-κB, prostaglandin E2 (PGE2)/cyclooxygenase-2 (COX-2), interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), and IL-23/T helper 17 cell (Th17), have been shown to promote CAC tumorigenesis. In addition, gut microbiota contributes to the development and progression of CAC. This review summarizes the signaling pathways involved in the pathogenesis following colon inflammation to understand the underlying molecular mechanisms in CAC tumorigenesis.
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http://dx.doi.org/10.3390/ijms21093062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247693PMC
April 2020

Current Diagnostic and Therapeutic Approaches to Cytomegalovirus Infections in Ulcerative Colitis Patients Based on Clinical and Basic Research Data.

Int J Mol Sci 2020 Mar 31;21(7). Epub 2020 Mar 31.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus (the human herpesvirus 5) and an opportunistic pathogen that primarily infects HIV-positive and other immuno-compromised patients. Retrospective studies in the field of inflammatory bowel disease (IBD) have suggested a relationship between a concomitant colonic HCMV infection and poor outcomes in patients with an ulcerative colitis (UC) due to the presence of HCMV in surgical specimens of patients with a toxic megacolon or a steroid-resistant UC. Therefore, gastroenterologists have focused on the contribution of HCMV infections in the exacerbation of UC. Numerous studies have addressed the benefits of treating colonic HCMV reactivation in UC using an antiviral treatment. However, its clinical relevance remains uncertain as only a few prospective studies have assessed the direct relationship between clinical outcomes and the viral load of HCMV in colonic tissues. HCMV reactivation can be triggered by inflammation according to fundamental research studies. Thus, optimal control of intestinal inflammation is essential for preventing an HCMV reactivation in the intestinal mucosa. Indeed, several reports have indicated the effectiveness of an anti-tumor necrosis factor-alpha (TNFα) treatment in patients with an active UC and concomitant HCMV infections. In this review, we describe the mechanism of HCMV reactivation in UC cases and discuss the current issues regarding diagnosis and treatment of HCMV infections in UC patients.
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http://dx.doi.org/10.3390/ijms21072438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177554PMC
March 2020

[Primary biliary cholangitis complicated by primary hepatic extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue].

Rinsho Ketsueki 2019 ;60(11):1532-1537

Department of Gastrointestinal Medicine, Hakodate Goryokaku Hospital.

An 89-year-old woman was admitted to our hospital owing to liver dysfunction and ascites. Enhanced computed tomography (CT) revealed hepatomegaly and heterogeneous density in the liver. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) /CT revealed diffuse accumulation of FDG throughout the liver. Histopathology of a biopsy specimen revealed hepatic mucosa-associated lymphoid tissue (MALT) lymphoma. Complete remission (CR) was achieved with two cycles of rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone. Because a second CT demonstrated liver cirrhosis and a test for anti-mitochondrial antibody was positive, liver biopsy was repeated, and pathological examination confirmed primary biliary cholangitis (PBC). The lymphoma recurred after 18 months and was treated with rituximab, which again resulted in CR. Over the subsequent 7 years, the patient had no liver dysfunction or recurrent lymphoma. Interestingly, despite the underlying PBC, liver dysfunction in this case appeared only with the MALT lymphoma.
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http://dx.doi.org/10.11406/rinketsu.60.1532DOI Listing
December 2019

The Etiology of Pancreatic Manifestations in Patients with Inflammatory Bowel Disease.

J Clin Med 2019 Jun 26;8(7). Epub 2019 Jun 26.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Inflammatory bowel disease (IBD) is an idiopathic chronic and recurrent condition that comprises Crohn's disease and ulcerative colitis. A pancreatic lesion is one of the extraintestinal lesions in patients with IBD. Acute pancreatitis is the representative manifestation, and various causes of pancreatitis have been reported, including those involving adverse effects of drug therapies such as 5-aminosalicylic acid and thiopurines, gall stones, gastrointestinal lesions on the duodenum, iatrogenic harm accompanying endoscopic procedures such as balloon endoscopy, and autoimmunity. Of these potential causes, autoimmune pancreatitis (AIP) is a relatively newly recognized disease and is being increasingly diagnosed in IBD. AIP cases can be divided into type 1 cases involving lymphocytes and IgG4-positive plasma cells, and type 2 cases primarily involving neutrophils; the majority of AIP cases complicating IBD are type 2. The association between IBD and chronic pancreatitis, exocrine pancreatic insufficiency, pancreatic cancer, etc. has also been suggested; however, studies with high-quality level evidence are limited, and much remains unknown. In this review, we provide an overview of the etiology of pancreatic manifestation in patients with IBD.
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http://dx.doi.org/10.3390/jcm8070916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679036PMC
June 2019

Impact of Autophagy of Innate Immune Cells on Inflammatory Bowel Disease.

Cells 2018 12 22;8(1). Epub 2018 Dec 22.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.

Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed the contribution of autophagy to the innate immune response, and relationships between this process and various diseases have been reported. Inflammatory bowel disease is an intractable disorder with unknown etiology; however, immunological abnormalities in the intestines are known to be involved in the pathology of inflammatory bowel disease, as is dysfunction of autophagy. In Crohn's disease, many associations with autophagy-related genes, such as , , , and others, have been reported. Abnormalities in the gene, in particular, have been reported to cause autophagic dysfunction, resulting in enhanced production of inflammatory cytokines by macrophages as well as abnormal function of Paneth cells, which are important in intestinal innate immunity. In this review, we provide an overview of the autophagy mechanism in innate immune cells in inflammatory bowel disease.
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http://dx.doi.org/10.3390/cells8010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356773PMC
December 2018

Monosodium glutamate ingestion during the development period reduces aggression mediated by the vagus nerve in a rat model of attention deficit-hyperactivity disorder.

Brain Res 2018 07 9;1690:40-50. Epub 2018 Apr 9.

Department of Neurophysiology & Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan. Electronic address:

We used an umami substance, monosodium glutamate (MSG), as a simple stimulant to clarify the mechanism of the formation of emotional behavior. A 60 mM MSG solution was fed to spontaneously hypertensive rats (SHR), used as a model of attention-deficit hyperactivity disorder, from postnatal day 25 for 5 weeks kept in isolation. Emotional behaviors (anxiety and aggression) were then assessed by the open-field test, cylinder test and social interaction test. MSG ingestion during the developmental period resulted in a significant reduction in aggressive behavior but had few effects on anxiety-like behavior. Several experiments were performed to identify the reason for the reduced aggression with MSG intake. Blood pressure in the MSG-treated SHR was comparable to that of the controls during development. Argyrophil III staining to detect the very early phase of neuronal damage revealed no evidence of injury by MSG in aggression-related brain areas. Assessment of plasma amino acids revealed that glutamate levels remained constant (∼80 μM) with MSG ingestion, except for a transient increase after fasting (∼700 μM). However, lactate dehydrogenase assay in an in vitro blood-brain barrier model showed that cell toxicity was not induced by indirect MSG application even at 700 μM, confirming that MSG ingestion caused minimal neuronal damage. Finally, vagotomy at the sub-diaphragmatic level before MSG ingestion blocked its effect on aggressive behavior in the isolated SHR. The data suggest that MSG ingestion during the developmental period can reduce aggressive behavior in an attention deficit-hyperactivity disorder model rat, mediated by gut-brain interaction.
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http://dx.doi.org/10.1016/j.brainres.2018.04.006DOI Listing
July 2018

Hepatic portal venous gas due to polystyrene sulfonate-induced enteritis.

Clin J Gastroenterol 2018 Jun 22;11(3):220-223. Epub 2018 Jan 22.

Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan.

A 78-year-old man with acute right lower abdominal pain and nausea was referred to our hospital. Computed tomography (CT) demonstrated hepatic portal venous gas and a thickened wall of the terminal ileum, and colonoscopy demonstrated ulcers and erosions of the ileocecal region. Histological examination of biopsy samples revealed basophilic crystals consistent with the component of calcium polystyrene sulfonate (CPS). This patient started taking CPS 2 months prior for chronic hyperkalemia. The symptoms resolved soon after ceasing CPS, and subsequent imaging studies confirmed the disappearance of the portal venous gas and ileocolitis.
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http://dx.doi.org/10.1007/s12328-018-0818-8DOI Listing
June 2018

Analysis of genes encoding high-antigenicity polypeptides in three serotypes of Miamiensis avidus.

Parasitol Int 2018 Apr 26;67(2):196-202. Epub 2017 Oct 26.

Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan; Center for Marine Environmental Studies (CMES), Ehime University, Matsuyama 790-8577, Japan. Electronic address:

The ciliate Miamiensis avidus causes scuticociliatosis in Japanese flounder Paralichthys olivaceus. We previously reported three serotypes of this ciliate distinguishable by serotype-specific antigenic polypeptides (serotype I, 30kDa; serotype II, 38kDa; serotype III, 34kDa). In this study, we determined the localization site of the serotype-specific polypeptides in the ciliate and determined the genes encoding the polypeptides, using the isolates IyoI (serotype I), Nakajima (serotype II), and Mie0301 (serotype III). SDS-PAGE and immunoblot analysis of cilia, membrane proteins, and cytoskeletal elements of the ciliates revealed that the polypeptides were abundant in the former two. Scanning electron microscopy of ciliates immobilized by homologous antiserum showed morphological changes in the cilia. These evidences suggested that the polypeptides were ciliary membrane immobilization antigens. The ciliary genes identified showed low identity scores-<51.5% between serotypes. To differentiate the serotypes, we designed serotype-specific PCR primer sets based on the DNA sequences. The PCR-based serotyping results were completely consistent with conventional serotyping methods (immobilization assay and immunoblot analysis). Twenty of 21 isolates were classified as either serotype I or II, and one isolate was undistinguishable. The combination of species-specific PCR previously reported and three serotype-specific PCR could be useful for identifying, serotyping, and surveillance for occurrences of new serotypes of M. avidus.
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http://dx.doi.org/10.1016/j.parint.2017.10.007DOI Listing
April 2018

Elevation of Plasmin-α2-plasmin Inhibitor Complex Predicts the Diagnosis of Systemic AL Amyloidosis in Patients with Monoclonal Protein.

Intern Med 2018 Mar 11;57(6):783-788. Epub 2017 Oct 11.

Department of Gastroenterology, Rheumatology, and Clinical Immunology, Sapporo Medical University School of Medicine, Japan.

Objective The complication of systemic immunoglobulin light chain (AL) amyloidosis in patients with monoclonal immunoglobulin affects the prognosis, but amyloid deposition in tissues is sometimes difficult to detect due to bleeding tendencies and preferential distributions. However, fibrinolysis is known to be exacerbated in patients with systemic AL amyloidosis specifically. We therefore explored new biomarkers for predicting a diagnosis of systemic AL amyloidosis focusing on coagulation and fibrinolysis markers. Methods We reviewed the clinical features and treatment outcomes of patients with serum monoclonal protein, including primary systemic AL amyloidosis and multiple myeloma (MM), treated at our hospital between January 2008 and December 2014. Results Among several biomarkers, only the serum level of plasmin-α2-plasmin inhibitor complex (PIC) in patients with systemic AL amyloidosis (n=26) at the diagnosis was significantly higher than in patients with MM without AL amyloidosis (n=26) (mean±standard deviation, 3.69±2.82 μg/mL vs. 1.23±0.97 μg/mL, p<0.01). The cut-off for predicting a diagnosis of systemic AL amyloidosis in patients with serum monoclonal protein was 1.72 μg/mL with 84.6% sensitivity and 80.8% specificity. Hepatic involvement resulted in a significantly higher PIC level than no involvement in patients with systemic AL amyloidosis. The serum PIC level was also associated with the hematological response of systemic AL amyloidosis. Conclusion PIC is a useful biomarker for the diagnosis and management of patients with systemic AL amyloidosis.
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http://dx.doi.org/10.2169/internalmedicine.8999-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891514PMC
March 2018

A case of adenosquamous carcinoma of the lower bile duct diagnosed preoperatively via transpapillary biopsy.

Nihon Shokakibyo Gakkai Zasshi 2016 08;113(8):1425-32

Department of Gastroenterology, Muroran City General Hospital.

A 78-year-old man presented to our hospital with fever and brownish urine. Upon thorough examination, a diagnosis of obstructive jaundice and acute cholangitis associated with a lower bile duct tumor was made. Endoscopic retrograde cholangiopancreatography revealed entire circumferential stenosis of the lower bile duct. Examination of a transpapillary biopsy specimen of the lesion suggested adenosquamous carcinoma. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination revealed adenocarcinoma of the lower bile duct and squamous cell carcinoma components;a case of adenosquamous carcinoma was accordingly diagnosed. The lower bile duct tumor directly extended into the pancreatic parenchyma for approximately 1mm. We performed radical surgery and administered adjuvant chemotherapy with gemcitabine because of advanced neural invasion after consulting with the patient. There was no sign of recurrence 46 months after surgery. As adenosquamous carcinoma of the extrahepatic bile duct is rare, it is difficult to preoperatively diagnose the condition. Only a few cases have been reported till date.
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http://dx.doi.org/10.11405/nisshoshi.113.1425DOI Listing
August 2016

Tofacitinib can decrease anti-DNA antibody titers in inactive systemic lupus erythematosus complicated by rheumatoid arthritis.

Mod Rheumatol 2016 07 3;26(4):633-4. Epub 2015 Aug 3.

a Division of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo , Hokkaido, Japan.

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http://dx.doi.org/10.3109/14397595.2015.1069473DOI Listing
July 2016

CCAAT/enhancer binding protein α (C/EBPα)(+) M2 macrophages contribute to fibrosis in IgG4-related disease?

Mod Rheumatol 2015 May 2;25(3):484-6. Epub 2014 Sep 2.

Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo , Japan.

IgG4-related disease (IgG4-RD) is a new disease entity characterized by type 2 helper T (Th2)-dominant inflammation and progressive fibrosis. We found the infiltration of strange cell populations in the fibrotic lesions of submandibular gland specimens obtained from 15 patients with IgG4-RD. These cells expressed CCAAT/enhancer binding protein a (C/EBPα). Many of the cell populations were identified with M2 macrophages. The degrees of infiltration of C/EBPα(+)M2 macrophages and the ratio of fibrotic lesions in the specimens were correlated (r(2) = 0.83, p < 0.01). We also analyzed the expression of C/EBPα in other chronic inflammatory disorders: synovium in rheumatoid arthritis (RA), liver tissue in chronic viral hepatitis, and mucosa in ulcerative colitis. The specimens from RA and chronic viral hepatitis showed infiltration of C/EBPα(+) cells, but there were few C/EBPα-positive cells in ulcerative colitis. Fibrosis is not a major issue in ulcerative colitis. In conclusion, we found the remarkable infiltration of C/EBPα(+)M2 macrophages in cases of chronic inflammation with fibrosis, including IgG4-RD. This primitive study also disclosed that most of C/EBPα(+)M2 macrophages localized in fibrotic lesions, and the degree of the infiltration and the ratio of fibrotic area were correlated.
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http://dx.doi.org/10.3109/14397595.2014.950826DOI Listing
May 2015

Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: results from the SMART database.

Mod Rheumatol 2015 Mar 27;25(2):199-204. Epub 2014 Aug 27.

Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo , Japan.

Abstract Objective. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a new disease entity that has only been identified this century. Clinical information is thus lacking. We established the Sapporo Medical University and Related Institutes Database for Investigation and Best Treatments of IgG4-related Disease (SMART) to clarify the clinical features of IgG4-RD and provide useful information for clinicians. Methods. Participants comprised 122 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), representing lacrimal and/or salivary lesions of IgG4-RD, followed-up in December 2013. We analyzed the sex ratio, mean age at onset, organ dysfunction, history or complications of malignancy, treatments, rate of clinical remission, and relapse. Results. The sex ratio was roughly equal. Mean age at diagnosis was 59.0 years. Positron emission tomography revealed that the ratio of other organ involvements was 61.4%. Complications of malignancy were observed in 7.4% of cases. Glucocorticoid was used to treat 92.1% of cases, and the mean maintenance dose of prednisolone was 4.8 mg/day. Rituximab was added in three cases, and showed good steroid-sparing effect. The clinical remission rate was 73.8%, and the annual relapse rate was 11.5%. Half of the cases experienced relapses within 7 years of initial treatment. Conclusion. We analyzed the clinical features and treatments of IgG4-DS using SMART, providing useful information for everyday clinical practice.
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http://dx.doi.org/10.3109/14397595.2014.950036DOI Listing
March 2015

Identification of relapse predictors in IgG4-related disease using multivariate analysis of clinical data at the first visit and initial treatment.

Rheumatology (Oxford) 2015 Jan 6;54(1):45-9. Epub 2014 Jun 6.

Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Division of Advanced Medicine Promotion, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo and Center for Antibody and Vaccine Therapy, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

Objectives: Inducting clinical remission by glucocorticoid treatment is relatively easy in IgG4-related disease (IgG4-RD), but relapse also occurs easily with tapering of the steroid dose. The present study tried to analyse the cases to extract predictors of relapse present at the diagnosis of IgG4-RD.

Methods: Subjects comprised 79 patients with IgG4-related dacryoadenitis and sialadenitis, known as Mikulicz's disease, who were diagnosed between April 1997 and October 2013 and followed-up for >2 years from the initial induction treatment. They were applied to Cox proportional hazard modelling, based on the outcome of interval to relapse. We performed multivariate analysis for the clinical factors of these cases and identified predictors of relapse.

Results: Identified factors were male sex and younger onset in cases without organ involvement at diagnosis and low levels of serum IgG4 in cases with organ dysfunction at diagnosis. Complication with autoimmune pancreatitis and low steroid dose at initial treatment also tended to be associated with recurrence.

Conclusion: Follow-up is important in cases with recognized risk factors for relapse, including male sex and younger onset in cases without organ damage.
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http://dx.doi.org/10.1093/rheumatology/keu228DOI Listing
January 2015

Cloning and expression of cDNA encoding lysyl hydroxylase 1, 2 and 3 in tiger puffer Takifugu rubripes.

Comp Biochem Physiol B Biochem Mol Biol 2013 Oct 13;166(2):123-32. Epub 2013 Aug 13.

Laboratory of Food Chemistry, Department of Marine Bioscience, Faculty of Biotechnology, Fukui Prefectural University, Obama, Fukui 917-0003, Japan.

Lysyl hydroxylase (LH) catalyzes the hydroxylation of lysine residues in collagens, and contributes to the formation of more stable collagen cross-links. However, in teleost, there is little information about collagen modification enzymes including lysyl oxidase (LOX) family members. Here, we cloned cDNAs encoding LH1, 2 and 3 from tiger puffer Takifugu rubripes. To determine the mRNA expressions of LH family members in a tiger puffer, we performed a northern blot analysis. Results showed that both fgLH1 and fgLH3 mRNAs were almost constitutively expressed in tissues, but highly expressed in muscle and ovary, respectively. However, fgLH2 mRNA was detected only in RT-PCR, indicating that expression level of fgLH2 is very low in tissues. It may be that low expression level of fgLH2 contributes to the fewer contents of stable collagen cross-links in tiger puffer tissues. To further investigate expression profiles of fgLHs, we examined gene expressions in embryos during development. In embryos, expression profiles differ among three fgLHs, indicating that there are functional differences among the three fgLHs. This is the first report that examined gene expression patterns of three LHs in emrbyos and adult tissues in teleost.
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http://dx.doi.org/10.1016/j.cbpb.2013.08.001DOI Listing
October 2013

Role of hypoxia-inducible factor α in response to hypoxia and heat shock in the Pacific oyster Crassostrea gigas.

Mar Biotechnol (NY) 2012 Feb 6;14(1):106-19. Epub 2011 Jul 6.

Department of Marine Bioscience, Faculty of Marine Bioscience, Fukui Prefectural University, Obama, Fukui 917-0003, Japan.

The Pacific oyster Crassostrea gigas inhabits the intertidal zone and shows tolerance to stress conditions such as hypoxia and heat shock. Although some information is available about the genes expressed in response to hypoxia, little is known about the molecular mechanism of the regulation of their expression in mollusks, including the Pacific oyster. Hypoxia-inducible factor 1α (HIF-1α) is a master regulator of hypoxia-responsive transcription. In this study, we cloned HIF-α from the oyster and investigated its response to unique stress conditions, including air exposure, for the first time in mollusks. The cDNA of oyster Hif-α is 3,182 bp long, of which 2,094 bp encodes a protein of 698 amino acid residues. Northern and Western blot analysis showed that expression of oyster HIF-α mRNA and protein were induced by air exposure, and that expression was induced periodically during air exposure. In addition, induction of Hif-α mRNA increased by a maximum 8.0-fold by heat shock. Under heat shock at 35°C (lethal temperature for the oyster), however, it was induced later than at 30°C. After recovery from hypoxia and/or heat shock, Hif-α mRNA also upregulated. These data suggest that the oyster has a strategy to induce Hif-α mRNA in order to survive hypoxia and heat shock, and that HIF signaling is necessary for recovery from stress.
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http://dx.doi.org/10.1007/s10126-011-9394-3DOI Listing
February 2012

Novel isoforms of heat shock transcription factor 1 are induced by hypoxia in the Pacific oyster Crassostrea gigas.

J Exp Zool A Ecol Genet Physiol 2011 Aug 31;315(7):394-407. Epub 2011 Mar 31.

Department of Marine Bioscience, Faculty of Marine Bioscience, Fukui Prefectural University, Fukui, Japan.

The Pacific oyster Crassostrea gigas inhabits the intertidal zone and shows tolerance to various stress conditions such as hypoxia and heat shock. However, little is known about the cellular mechanism of responses to these stresses. Heat shock transcription factor 1 (HSF1) regulates the transcription of several genes, including heat shock proteins (HSPs). In this study, we cloned HSF1 from the oyster and investigated its response to air-exposure. The cDNA of oyster Hsf1 contains 2,931 bp, of which 1,389 bp encode a protein of 463 amino acid residues. Moreover, we found that the oyster has seven novel alternatively spliced isoforms, Hsf1b-h, consisting of insertion A with 48 bp, insertion B with 42 bp and/or insertion C with 42 bp. We determined the sequences of oyster genomic DNA containing Hsf1 insertions A, B and C. The results indicated that eight isoforms of Hsf1 are generated from a single Hsf1 gene by alternative splicing without frameshifting. Real-time PCR analysis showed that Hsf1a is expressed constitutively, and the expression of Hsf1b-h and Hsp70 mRNA is induced by air exposure and/or hypoxia. In addition, we found that 11 putative hypoxia response elements, which are hypoxia-inducible factor 1 (HIF-1) binding sequences, are located in the Hsf1 promoter region. These data suggest that the oyster has an HIF-HSF pathway in which HSPs are induced in an HIF-dependent manner, and that it also has a novel mechanism of alternative splicing of Hsf1 in response to hypoxia.
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http://dx.doi.org/10.1002/jez.685DOI Listing
August 2011

Molecular cloning of calnexin and calreticulin in the Pacific oyster Crassostrea gigas and its expression in response to air exposure.

Mar Genomics 2010 Mar 2;3(1):19-27. Epub 2010 Feb 2.

Department of Marine Bioscience, Fukui Prefectural University, Obama, Japan.

Calnexin (CNX) and calreticulin (CRT) are endoplasmic reticulum (ER) chaperones. CNX is a type I transmembrane protein and CRT is a soluble CNX homologue. In the ER, CNX and CRT are important for Ca(2+) homeostasis and protein maturation. Here, we describe the full-length cDNA of the first mollusk CNX (cgCNX) and a second mollusk CRT (cgCRT) from the oyster Crassostrea gigas. CgCNX, containing 3255bp, was composed of a 1764bp open reading frame (ORF) that encodes a 588-amino acid protein. CgCRT, containing 1727bp, was composed of a 1242bp ORF that encodes a 414-amino acid protein. CgCNX and cgCRT contains an N-terminal 21- and 16-amino acid sequence, respectively, which is characteristic of a signal sequence. At the C-terminus, cgCRT also contains the KDEL (-Lys-Asp-Glu-Leu) peptide motif suggesting that cgCRT localizes in the ER. Northern blot analysis showed that both cgCNX and cgCRT mRNAs are induced by air exposure. The expression patterns of cgCNX mRNA differed from those of cgCRT during air exposure. This suggests that these two molecular chaperones have different roles in the response to air exposure.
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http://dx.doi.org/10.1016/j.margen.2010.01.002DOI Listing
March 2010

Purification, characterization and cDNA cloning of a novel lectin from the jellyfish Nemopilema nomurai.

Comp Biochem Physiol B Biochem Mol Biol 2010 May 25;156(1):12-8. Epub 2010 Jan 25.

Department of Marine Bioscience, Fukui Prefectural University, Obama, Japan.

A lectin (designated NnL) from a jellyfish Nemopilema nomurai was purified by ion-exchange chromatography followed by affinity chromatography. The apparent molecular mass of NnL was 28kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing and nonreducing conditions. NnL agglutinated horse erythrocytes, the gram-positive bacterium Bacillus subtilis and gram-negative bacterium Escherichia coli K12. The hemagglutinating activity of NnL was inhibited by N-acetyl-D-galactosamine N-acetylneuraminic acid and N-glycolylneuraminic acid. Bovine submaxillary mucin was the potent inhibitor of the hemagglutinating activity of NnL among the glycoproteins tested. cDNA cloning of NnL revealed that its primary structure contained part of a fibrinogen-like domain. The deduced amino acid sequence of NnL showed no significant sequence identities to other known lectins. On the other hand NnL showed high sequence identity to a predicted protein of the sea anemone Nematostella vectensis suggesting that NnL may belong to a novel lectin family in metazoans. This is the first report to describe the purification characterization and cDNA cloning of a jellyfish lectin.
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http://dx.doi.org/10.1016/j.cbpb.2010.01.008DOI Listing
May 2010

Cell growth-promoting activity of fluid from eye sacs of the bubble-eye goldfish (Carassius auratus).

Zoolog Sci 2009 Apr;26(4):254-8

Bioscience and Biotechnology Center, Nagoya University, Nagoya, Aichi 464-8601, Japan.

The growth-promoting effects of fish body fluids, such as serum and embryonic extract, on fish cell cultures have been widely demonstrated. The bubble-eye variety of aquarium goldfish is characterized as having a large sac filled with fluid (sac fluid) under each eye. These sacs are believed to contain lymph, which is similar in composition to serum or blood plasma. In order to test whether the sac fluid can be used as an additive for fetal bovine serum (FBS) in growth factor supplements, we compared cell growth in media containing FBS together with different concentrations of sac fluid. A dose-dependent growth-promotion effect was observed in early passage caudal fin cells from both medaka and zebrafish. Cell-growth promotion was also confirmed in early passage medaka blastula cells and in a zebrafish embryonic cell line (ZF4). Replacement of the fluid in the eye sacs of bubble-eyes occurs within a couple of months after the sac fluid has been harvested, and the cell-growth promoting activity of the new fluid is similar to that of the fluid that was tapped initially. These findings suggest that sac fluid can be used as a growth-promoting supplement for fish cell culture. Importantly, the ability of the goldfish to replace the fluid combined with the fact that equipotent fluid can be repeatedly harvested from the eye sacs means that a sustainable source of the fluid can be obtained without needing to sacrifice the fish.
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http://dx.doi.org/10.2108/zsj.26.254DOI Listing
April 2009

cDNA cloning and expression of grp94 in the Pacific oyster Crassostrea gigas.

Comp Biochem Physiol B Biochem Mol Biol 2009 Nov 10;154(3):290-7. Epub 2009 Jul 10.

Laboratory of Food Chemistry, Department of Marine Bioscience, Faculty of Biotechnology, Fukui Prefectural University, Obama, Fukui 917-0003, Japan.

The 94-kDa glucose-regulated protein (GRP94) is an endoplasmic reticulum (ER) chaperone. We cloned the first mollusk grp94 from a cDNA library of the Pacific oyster Crassostrea gigas. Analysis of C. gigas grp94 (cggrp94) clone containing 3212 bp DNA revealed that the cDNA contains a 2391 bp open reading frame that encodes a 797 amino acid protein of 91.6 kDa. The deduced amino acid sequence of cgGRP94 is 67%, 68%, and 67% homologous to the GRP94 of Homo sapiens, GP96 of Strongylocentrotus purpuratus, and GP96 of Xenopus laevis, respectively. CgGRP94 contains an N-terminal 22 amino acid sequence, which is characteristic of a signal sequence. It also contains a HATPase_c domain. In addition, it contains the KDEL (-Lys-Asp-Glu-Leu) peptide motif at the C-terminus, which suggests that cgGRP94 localizes in the ER. Northern blot analysis showed that cggrp94 mRNA is expressed at high levels in the gill which cggrp94 mRNA is induced during air exposure condition. Expression patterns of cggrp94 mRNA differed between gill and mantle, and cggrp94 mRNA was induced at high temperature during air exposure condition. These indicate that cggrp94 mRNA is induced by hypoxia and heat shock stress, and there are different strategies for air exposure condition between gill and mantle.
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http://dx.doi.org/10.1016/j.cbpb.2009.07.001DOI Listing
November 2009

Estimation of the impact of particulate organic matter drained from a freshwater reservoir on the sea using diatom tracking.

Water Sci Technol 2008 ;58(11):2109-15

National Institute for Rural Engineering, Tsukuba Science City, 305-8609, Japan.

We estimated the extent of suspended solids (SS) and particulate organic matter (POM) discharged from a freshwater reservoir, called the Isahaya Reservoir, into a sea area by tracking the diatom frustules produced in the reservoir. The estimation method is based on the fact that Skeletonema subsalsum and S. costatum, are the predominant diatoms in the reservoir and the sea, respectively, and the discharged SS and POM contain the freshwater diatom, S. subsalsum, and that the diatom frustules remain undecomposed in the environment even after the plankton decays. The results of the sediment trap experiment and bottom sediment survey showed that the distribution of diatom frustules in the bottom sediment had good agreement with that in the water column in the sea, and the greatest amounts of the drained SS and POM were estimated to have reached and settled down on the bottom sediment in the sea area within approximately 2 km from the drainage gates of the reservoir.
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http://dx.doi.org/10.2166/wst.2008.811DOI Listing
March 2009

Expression and distribution of fugu TIMP-2s (fgTIMP-2a and fgTIMP-2b) mRNAs in tissues and embryos.

Comp Biochem Physiol B Biochem Mol Biol 2007 Nov 16;148(3):225-30. Epub 2007 Aug 16.

Laboratory of Food Chemistry, Department of Marine Bioscience, Faculty of Biotechnology, Fukui Prefectural University, Obama, Fukui 917-0003, Japan.

In teleosts, two distinct types of TIMP-2s occur, TIMP-2a and TIMP-2b, but little is known about their locations and quantitative expressions. Here, we examined pufferfish (Takifugu rubripes) TIMP-2a (fgTIMP-2a) and TIMP-2b (fgTIMP-2b) quantities and locations in fugu adult tissues and embryos. To compare the quantitative expression of fgTIMP-2s, we performed a quantitative real-time PCR (qPCR). FgTIMP-2a mRNA was constitutively expressed and significant differences in expression were not observed among adult tissues. Whereas, fgTIMP-2b mRNA was significantly differently expressed in ordinary muscle and gill compared to the expression level in whole blood (P<0.05). Although significant difference was not observed between brain and other tissues, both fgTIMP-2s mRNAs were abundant in the brain. In addition, we examined embryos during development using qPCR. Both fgTIMP-2s mRNAs gradually increased during embryonic development from 48 hpf. However, fgTIMP-2b mRNA was obviously abundant compared to fgTIMP-2a mRNA in embryos. We also examined the specific mRNA distribution in embryos. The fgTIMP-2s mRNAs showed the same distribution during development. Both fgTIMP-2s are expressed in adult fugu tissues and embryos but their expression levels clearly differ, suggesting that there is a predominance of fgTIMP-2b over fgTIMP-2a in vivo.
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http://dx.doi.org/10.1016/j.cbpb.2007.02.016DOI Listing
November 2007

Molecular cloning and expression of gelatinases (MMP-2 and MMP-9) in the pufferfish Takifugu rubripes.

Comp Biochem Physiol B Biochem Mol Biol 2007 Nov 27;148(3):295-302. Epub 2007 Jun 27.

Laboratory of Food Chemistry, Department of Marine Bioscience, Faculty of Biotechnology, Fukui Prefectural University, Obama, Fukui 917-0003, Japan.

To determine the metabolism location of the extra-cellular matrix proteins in fugu (Takifugu rubripes), we cloned the cDNAs of the fugu gelatinases, matrix metalloproteinase-2 (MMP-2) and MMP-9, and examined their expressions in various adult tissues using a quantitative real-time PCR. The expression profiles of fugu gelatinases were different among tissues. FgMMP-9 mRNA was abundant in tissues that contain blood cells abundantly where fgMMP-2 mRNA was little expressed. We also examined the expression of these genes in fugu embryos during development using a whole mount in situ hybridization. Fugu MMP-2 mRNA was expressed in the pharyngeal area and mesenchyme in embryos at 80 hours post fertilization (hpf). While fugu MMP-9 mRNA was expressed in the vent at 140 hpf and the caudal end of the fin fold at 172 hpf. Although fugu MMP-2 mRNA was expressed in the pectoral fin bud at 120 hpf, fugu MMP-9 mRNA did not appear in this tissue until 10 days post fertilization (dpf). These data show expression profiles differ between the fugu gelatinases and suggest expressions of these genes are controlled at the matrix protein degradation site in fugu embryos during development.
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http://dx.doi.org/10.1016/j.cbpb.2007.06.007DOI Listing
November 2007