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Abstract Background Anisakiasis is a parasitic infection caused by Anisakis worms found in raw fish. Most cases of anisakiasis occur in the stomach and rarely occur in the intestine. It is extremely rare for live larvae to break through the intestine into the mesentery and cause severe intestinal ischemia. Anisakiasis can be treated conservatively, because the larvae will die in approximately 1 week, but, sometimes, a serious condition can arise, as in this case. We report the first case of extraluminal anisakiasis in which a live Anisakis worm caused severe intestinal ischemia. Case presentation The patient was a 26-year-old woman who ate squid a week prior. She had abdominal pain and was admitted to our emergency department. On physical examination, abdominal guarding and rebound tenderness were present in her lower abdomen. Contrast-enhanced computed tomography showed ascites, the whirl sign, localized submucosal edema of the intestinal wall, and a dilated small bowel segment with edema. We suspected the strangulated small bowel obstruction based on the CT-scan findings. To rule out the strangulated small bowel obstruction, laparoscopic exploration was performed. Bloody ascites in the pouch of Douglas and severe inflammation in 20 cm of the ileum were observed. An Anisakis larva had perforated the intestinal wall and was found alive in the mesentery. The ileum had developed a high degree of ischemia, so the affected section was resected. Histopathological examination revealed that the Anisakis worm body was in the inflamed mesentery and caused a high degree of ischemia in the intestinal tract. The patient was discharged 9 days after surgery. Conclusions A living Anisakis larva punctured the mesentery of the small intestine, resulting in severe intestinal ischemia. As seen in this case, intestinal anisakiasis may cause serious symptoms, and a low threshold for performing diagnostic laparoscopy for the early diagnosis of bowel ischemia secondary to anisakiasis can be useful in determining the definite diagnosis and indications for resection.

Abstract Background Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs) including thyroid dysfunction. There are only a few reports on Graves’ disease induced by ICIs. We report a case of new-onset Graves’ disease after the initiation of nivolumab therapy in a patient receiving gastric cancer treatment. Case presentation The patient was a 66-year-old Japanese man, who was administered nivolumab (240 mg every 3 weeks) as a third-line therapy for stage IVb gastric cancer. His thyroid function was normal before the initiation of nivolumab therapy. However, he developed thyrotoxicosis before the third administration of nivolumab. Elevated, bilateral, and diffuse uptake of radioactive tracer was observed in the 99mTc-pertechnetate scintigraphy. Furthermore, the thyroid-stimulating hormone receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) test results, which were negative before the first administration of nivolumab, were positive after starting the therapy. The patient was diagnosed with Graves’ disease, and the treatment with methimazole and potassium iodide restored thyroid function. Conclusions This is the first complete report of a case of new-onset Graves’ disease after starting nivolumab therapy, confirmed by diffusely increased thyroid uptake in scintigraphy and the positive conversion of antibodies against thyroid-stimulating hormone receptor. It is important to perform thyroid scintigraphy and ultrasonography to accurately diagnose and treat ICI-induced thyrotoxicosis, because there are various cases in which Graves’ disease is developed with negative and positive TRAb titres.

Tolvaptan, a vasopressin V2 receptor antagonist, was initially approved in Japan for treatment of autosomal dominant polycystic kidney disease (ADPKD). Recently, a retrospective study showed that the effect of tolvaptan on kidney function could be sustained for a long period. However, the long-term efficacy and safety of high-dose tolvaptan (120 mg/day) in individual cases remain unknown. We report here 2 Japanese ADPKD patients (males, 36 and 29 years old) treated with tolvaptan (120 mg/day) for 9 years, during which time determinations of estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were performed. In these 2 patients, eGFR prior to therapy was 57.3 and 76.3 mL/min/1.73 m2, respectively, and 30.2 and 43.5 mL/min/1.73 m2, respectively, after 9 years of tolvaptan treatment, for a relatively constant annual decline of –3.01 and –3.64 mL/min/1.73 m2, respectively. As compared to the predicted (calculated) eGFR without tolvaptan treatment, eGFR actually measured was higher by 15.3 and 12.6 mL/min/1.73 m2, respectively, after the 9-year therapy period. In addition, the rate of TKV increase was gradual, 2.4 and 4.7%, respectively, per year during the initial 3-year period, to 6.5 and 12.5%, respectively, per year in the following 6-year period. During the 9 years of treatment, neither patient showed tolvaptan-related adverse events. Our findings suggest that long-term administration of tolvaptan at a high dose is both safe and effective to preserve kidney function, though a gradual increase in TKV was seen in both of the present cases, particularly during the later phase.

Background: The severe asthma and severe, uncontrolled asthma (SUA) populations in Japan are not well-studied. We investigated the prevalence of continuously treated severe asthma and SUA patients, their disease burden, and the treatment reality via a Japanese health insurance claims database. Methods: Continuously treated asthma patients (patients prescribed inhaled corticosteroids for asthma ≥4 times in the past year) aged ≥17 years at the index date (latest visit between April 2014 and March 2015 for asthma treatment) were included in this analysis (KEIFU study, UMIN000027695). Asthma severity and control status at the index date were defined using modified criteria of ERS/ATS guidelines. Asthma hospitalization, oral corticosteroid (OCS) use, and total medical expenses were calculated using data up to 12 months post–index date. Results: We identified 10,579 patients as continuously treated asthma patients. Of these, 823 (7.8%) had severe asthma; 267 (2.5%) and 556 (5.3%) patients had SUA and severe, controlled asthma (SCA), respectively. Compared with SCA and mild to moderate asthma patients, a greater percentage of SUA patients required hospitalization (13.7%, 6.2%, and 3.0%, respectively) and were prescribed OCSs (67.4%, 45.9%, and 16.2%, respectively). Yearly total medical expenses were also greater for SUA patients (mean [standard deviation]: 8346 [12,280], vs 5989 [10,483] and 3422 [8800] USD, respectively). Conclusions: The percentages of severe asthma and SUA patients continuously treated in Japan were obtained through this large-scale analysis using a health insurance claims database. SUA patients had greater medical and economic burdens, suggesting more appropriate treatment is required according to the treatment guidelines. Keywords: Asthma, Burden of illness, Database, Insurance claim reporting, Prevalence

The selection of dialysate calcium concentration (D-Ca) is still controversial among chronic hemodialysis (HD) regimens. We examined the trajectories of CKD MBD parameters among the J-DAVID trial participants to see the effect of D-Ca and alfacalcidol. The trial was an open-label randomized clinical trial including 976 HD patients with intact PTH of 180 pg/mL or lower which compared the users of vitamin D receptor activator (oral alfacalcidol) and non-users over a median of 4 years. The main D-Ca used at baseline were 3.0 mEq/L in 70% and 2.5 mEq/L in 25%, respectively. The primary endpoint was the composite of fatal and non-fatal cardiovascular events and the secondary endpoint was all-cause mortality. Multivariable Cox proportional hazard regression analyses in which D-Ca was included as a possible effect modifier and serum laboratory data as time-varying covariates showed no significant effect modification for composite cardiovascular events or all-cause mortality. This post hoc analysis showed that the effects of alfacalcidol on cardiovascular outcomes were not significantly modified by D-Ca.

Many patients worldwide suffer from constipation, which reduces their quality of life (QOL) over the long term. Carbonated water intake is expected to improve constipation by improving intestinal motility. Conversely, carbonated water intake is believed to alter bowel status via the intestinal contents (gas and liquid) and intestinal distension, and these changes may be reflected in bowel sound (BS) peak-frequency histograms. In this study, to identify changes in intestinal conditions before and after the ingestion of liquid (i.e., water/carbonated water intake), we used a novel evaluation index, namely peak-frequency histogram similarity (PFHS), which measures the changes in the peak-frequency histogram before and after liquid intake. We considered 13 subjects who participated in a liquid intake test, and PFHS values before and after carbonated water intake were found to be significantly lower than those before and after cold water intake (p < 0.01). However, when using conventional frequency-domain features, this difference was not identified. The results obtained in this study suggest that PFHS can identify changes in bowel status (including intestinal gas and distension) that could not be found using conventional BS frequency domain features. Our findings provide a novel method of research for investigators to non-invasively monitor and evaluate intestinal conditions such as the intestinal gas volume and intestinal distention, which are associated with constipation, using a BS-based approach.

Endoplasmic reticulum (ER) stress is a key pathogenic factor in type 1 and 2 diabetes. Glycogen synthase kinase 3 (Gsk-3) contributes to β-cell loss in mice. However, the mechanism by which Gsk-3 leads β-cell death remains unclear. ER stress was pharmacologically induced in mouse primary islets and insulinoma cells. We used insulinoma cells derived from Akita mice as a model of genetic ER stress. Gsk-3 activity was blocked by treating with Gsk-3 inhibitors or by introducing catalytically inactive Gsk-3β. Gsk-3 inhibition prevented proteasomal degradation of activating transcriptional factor 4 (ATF4) and alleviated apoptosis. We found that ATF4-S214 was phosphorylated by Gsk-3, and that this was required for a binding of ATF4 with βTrCP, which mediates polyubiquitination. The anti-apoptotic effect of Gsk-3 inhibition was attenuated by introducing DN-ATF4 or by knockdown of ATF4. Mechanistically, Gsk-3 inhibition modulated transcription targets of ATF4 and in turn facilitated dephosphorylation of eIF2α, altering the protein translational dynamism under ER stress. These observations were reproduced in the Akita mouse-derived cells. Thus, these results reveal the role of Gsk-3 in the regulation of the integrated stress response, and provide a rationale for inhibiting this enzyme to prevent β-cell death under ER stress conditions.

Although dual endothelin receptor antagonists (ERAs) show great promise for treating various conditions, their propensity to induce liver injury limits their clinical usage. Inflammation and fibrosis are important processes in liver responses to injury and it has been suggested that they and dual ERA-induced liver injury are mediated by the proteoglycan component chondroitin sulfate (CS), which is synthesized by CHST3 and CHST13. In this study, we investigated whether dual ER inhibition in the liver could alter CHST3 and CHST13 expression and thus CS production and whether liver CS content could prevent inflammatory and fibrosis responses after liver injury. We observed increased CHST3 and CHST13 expression after liver injury in bile duct ligated mice and histologically confirmed abundant CS deposition in the injured liver. Moreover, treating Hep3B cells with a dual ERA mimic significantly increased CHST3 and CHST13 expression, inflammatory cytokine levels, and glycosaminoglycan deposition. Furthermore, pro-inflammatory and pro-fibrotic markers were observed after dual ERA treatment, while treatment with CS-degrading chondroitinase ABC was able to successfully reverse these phenotypes. These observations suggest that CHST3- and CHST13-induced CS production can mediate liver injury responses caused by dual ER inhibition and thus could be an alternative pathway for treating ERA-induced liver injury. Key words: endothelin, endothelin receptor antagonists, liver injury, chondroitin sulfate, inflammation, fibrosis, chondroitinase ABC. Bien que les doubles antagonistes des recepteurs de l'endotheline (ARE) soient tres prometteurs en vue du traitement de diverses maladies, leur propension a engendrer des lesions hepatiques limite leur utilisation en clinique. L'inflammation et la fibrose sont d'importants processus dans la reaction du foie a des lesions et on a laisse entrevoir que le sulfate de chondroitine (SC), un composant proteoglycane synthetise par CHST3 et CHST13, participe a la mediation de celles-la et des lesions hepatiques engendrees par les doubles ARE. Dans ces travaux, nous avons etudie si l'inhibition double des RE dans le foie pourrait alterer l'expression de CHST3 et de CHST13, et par consequent la production de SC, et si les taux de SC dans le foie pourraient permettre de prevenir des reactions inflammatoires et de fibrose a la suite de lesions hepatiques. Nous avons observe une augmentation de l'expression de CHST3 et de CHST13 a la suite de lesions hepatiques provoquees par une ligature du canal choledoque chez la souris et confirme par l'histologie la presence de depots abondants de SC dans le foie lese. En outre, l'exposition de cellules Hep3B a un double ARE mime une augmentation notable de l'expression de CHST3 et de CHST13, des taux de cytokines inflammatoires et du depot de glycosaminoglycanes. De plus, nous avons observe des marqueurs pro-inflammatoires et profibrotiques apres l'administration d'un double ARE, tandis que l'administration de chondroitinase ABC degradant le SC permettait d'inverser ces phenotypes avec succes. Ces observations laissent entendre que la production de SC engendree par le CHST3 et le CHST13 pourrait participer a la mediation de reactions lesionnelles hepatiques engendrees par l'inhibition par des double ARE, et qu'elle pourrait donc constituer un autre choix de voie de signalisation en vue du traitement de lesions hepatiques engendrees par des ARE. [Traduit par la Redaction] Mots-cles: endotheline, antagonistes des recepteurs de l'endotheline, lesions hepatiques, sulfate de chondroitine, inflammation, fibrose, chondroitinase ABC., Introduction The vasoconstrictor endothelin (ET) exerts a variety of functions in addition to its main role; thus, many studies have investigated ET receptor antagonists (ERAs) as therapeutic agents (Maguire and [...]

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line medication for the treatment of pulmonary arterial hypertension (PAH). It has been shown to improve symptoms of hypertension, exercise capacity, and hemodynamics and prolong time to clinical worsening. However, liver dysfunction is a major side effect of bosentan treatment that could hamper the optimal management of patients with PAH. Previously, we demonstrated, using drug metabolism enzymes and transporters analysis, that the carbohydrate sulfotransferase 3 (CHST3) and CHST13 alleles are significantly more frequent in patients with elevated aminotransferases during therapy with bosentan than they are in patients without liver toxicity. In addition, we constructed a pharmacogenomics model to predict bosentan-induced liver injury in patients with PAH using two single-nucleotide polymorphisms and two nongenetic factors. The purpose of the present study was to externally validate the predictive model of bosentan-induced liver toxicity in Japanese patients. We evaluated five cases of patients treated with bosentan, and one presented with liver dysfunction. We applied mutation alleles of CHST3 and CHST13, serum creatinine, and age to our model to predict liver dysfunction. The sensitivity and specificity were calculated as 100% and 50%, respectively. Considering that PAH is a rare disease, multicenter collaboration would be necessary to validate our model. Key words: bosentan, pulmonary arterial hypertension, pharmacogenomics, CHST3, CHST13. Le bosentan, un antagoniste des recepteurs de l'endotheline, est un medicament qui a ete largement utilise en premiere ligne dans le traitement de l'hypertension arterielle pulmonaire (HAP). On a montre qu'il permet d'attenuer les symptomes de l'hypertension ainsi que d'ameliorer la capacite a l'effort physique et les parametres hemodynamiques, avec une augmentation du temps ecoule avant de presenter une aggravation sur le plan clinique. Cependant, le dysfonctionnement hepatique represente un effet indesirable majeur du bosentan qui pourrait nuire a la prise en charge optimale des patients atteints d'HAP. Anterieurement, a l'aide de l'etude des enzymes et des transporteurs de la biotransformation des medicaments, nous avons montre que les alleles de la sulfotransferase carbohydrique 3 (CHST3) et CHST13 sont nettement plus frequents chez les patients presentant une hausse des aminotransferases au cours du traitement par le bosentan que chez ceux qui ne presentaient pas de toxicite hepatique. De plus, nous avons construit un modele pharmacogenomique en vue de predire la presence de lesions hepatiques engendrees par le bosentan chez les patients atteints d'HAP a l'aide de deux polymorphismes mononucleotidiques et de deux facteurs non genetiques. La presente etude avait pour but de valider exterieurement le modele predictif de toxicite hepatique engendree par le bosentan chez des patients japonais. Nous avons evalue cinq cas de patients traites par le bosentan, dont l'un d'entre eux presentait un dysfonctionnement hepatique. En vue de predire le dysfonctionnement hepatique, nous avons applique a notre modele des alleles de mutation de CHST3 et de CHST13, la creatinine serique et l'age. Nous avons calcule une sensibilite et une specificite de 100 % et de 50 %, respectivement. Etant donne que l'HAP est une maladie rare, une collaboration multicentrique serait necessaire pour valider notre modele. [Traduit par la Redaction] Mots-cles: bosentan, hypertension arterielle pulmonaire, pharmacogenomique, CHST3, CHST13., Introduction Pulmonary arterial hypertension (PAH) is a rare disease with a high mortality rate (Galie et al. 2016). Treatment options have improved in the last two decades including prostanoids, phosphodiesterase-5 [...]

The Sixteenth International Conference on Endothelin (ET-16) was held September 22-25, 2019, in Kobe Port Oasis, Kobe, Japan, and co-chaired by Noriaki Emoto, MD, PhD, from Kobe Pharmaceutical University and Bambang Widyantoro, MD, PhD, from the University of Indonesia. As the sixteenth iteration of this biannual conference that has been held since 1988, ET-16 provided a platform for researchers of all generations from all parts of the world to present novel discoveries in the field of endothelin. ET-16 returned to Asia and to Kobe, Japan, after 6 years of alternating venues with North America and Europe, with over 100 participants attending, sharing, and discussing the newest findings on endothelin and endothelin receptor antagonists in science and medicine. Key words: clinical medicine, disease, endothelin, endothelium, endothelin receptor antagonists, clinical studies, molecular biology, Paul Vanhoutte, physiology. Le Seizieme congres international sur l'endotheline (ET-16) s'est tenu au centre Port Oasis de Kobe au Japon du 22 au 25 septembre 2019, et etait copreside par le Docteur Noriaki Emoto, MD, PhD de l'Universite pharmaceutique de Kobe et le Docteur Bambang Widyantoro, MD, PhD de l'Universite de l'Indonesie. Seizieme edition de ce congres semestriel tenu depuis 1988, l'ET-16 a offert une plateforme aux chercheurs de toutes les generations et de toutes les parties du monde pour leur permettre de presenter de nouvelles decouvertes dans le domaine de l'endotheline. L'ET-16 est retourne en Asie et a Kobe, au Japon apres s'etre tenu en alternance entre l'Amerique du Nord et l'Europe pendant 6 ans, avec plus de 100 participants se communiquant sur place les plus recents resultats sur l'endotheline et les antagonistes des recepteurs de l'endotheline en science et en medecine. [Traduit par la Redaction] Mots-cles: medecine clinique, maladie, endotheline, endothelium, antagonistes des recepteurs de l'endotheline, etudes cliniques, biologie moleculaire, Paul Vanhoutte, physiologie., In 1988, the discovery of the structure and function of a novel 21-amino acid peptide named endothelin made a tremendous impact on biomedical science and medicine (Yanagisawa et al. 1988; [...]