Endocrine journal最新文献

{"title":"Initial validation of the clinical significance of the NETest in Japanese gastroenteropancreatic neuroendocrine tumor patients","authors":"Hao Zhang, Takahiro Tsuchikawa, Satoshi Takeuchi, Kenji Hirata, Kimitaka Tanaka, Aya Matsui, Yoshitsugu Nakanishi, Toshimichi Asano, Takehiro Noji, Toru Nakamura, Shintaro Takeuchi, Masataka Wada, Satoshi Hirano","doi":"10.1507/endocrj.ej24-0090","DOIUrl":"https://doi.org/10.1507/endocrj.ej24-0090","url":null,"abstract":"</p><p>As novel biomarkers for gastroenteropancreatic neuroendocrine tumors (GEPNET) are in demand, we aimed to validate the clinical value of the NETest in Japanese patients. Between 2021 and 2023, blood and clinical data were collected from patients with GEPNET. Among 35 patients (median age: 59 [49–66] years), 27 cases originated from the pancreas and eight from the gastrointestinal tract. Of 69 samples sent to the laboratory, 56 (81.2%) underwent NETest. The diagnostic sensitivity was 97.1%. Among three patients who underwent R0 resection and four treated with peptide receptor radionuclide therapy, the changes in NETest scores closely correlated with disease progression. The NETest demonstrated high diagnostic efficacy and accurate therapeutic monitoring capabilities in a Japanese population.</p>\u0000<p></p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":"393 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141785137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between COVID-19 severity and relatively high serum adiponectin levels at the time of admission.","authors":"Ryohei Mineo, Shiro Fukuda, Shigehito Suzuki, Yoshito Ito, Sachiko Tamba, Takuya Sugiyama, Yuya Fujishima, Hitoshi Nishizawa, Iichiro Shimomura, Koji Yamamoto, Yuji Matsuzawa","doi":"10.1507/endocrj.EJ24-0072","DOIUrl":"10.1507/endocrj.EJ24-0072","url":null,"abstract":"<p><p>At the beginning of 2020, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to epidemics worldwide. Obesity and visceral fat accumulation have been reported to be independent risk factors for severe COVID-19. Several reports have focused on the levels of adipocytokines/adipokines, including adiponectin (APN), which is exclusively secreted from adipocytes, although the importance of these factors in acute disease conditions remains unclear. Therefore, we investigated the relationship between serum adiponectin levels and COVID-19 severity. Patients with COVID-19 who were admitted to Sumitomo Hospital (Osaka, Japan) from May through October 2021 were included. A total of 107 patients were enrolled in this study. We obtained the anthropometric and clinical laboratory data of the patients at the time of admission and examined the associations between various parameters and COVID-19 severity. The mean period from onset to admission was 6.5 ± 2.8 days. We divided the patients into \"non-severe\" (mild, moderate-I and moderate-II) (n = 80) and \"severe\" (n = 27) groups. The \"severe\" patients were significantly older than \"non-severe\" patients. Additionally, no significant differences were observed in BMI, sex, or the period from onset to admission. The serum adiponectin levels of \"severe\" patients at the time of admission were significantly greater than those of \"non-severe\" patients even after adjusting for age, sex, and BMI. These results suggest that the serum APN levels at the time of admission can predict COVID-19 severity. However, further investigations on the changes in APN levels in acute diseases are needed.</p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":" ","pages":"705-711"},"PeriodicalIF":1.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140911637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHOX and sex difference in height: a hypothesis","authors":"Tsutomu Ogata, Atsushi Hattori, Maki Fukami","doi":"10.1507/endocrj.ej24-0249","DOIUrl":"https://doi.org/10.1507/endocrj.ej24-0249","url":null,"abstract":"</p><p>The mean height is taller in males than in females, except for early teens. In this regard, previous studies have revealed that (1) distribution of the mean adult heights in subjects with disorders accompanied by discordance between sex chromosome complement and bioactive sex steroids and in control subjects (the British height standards) indicates that, of the ~12.5 cm of sex difference in the mean adult height, ~9 cm is accounted for by the difference in the sex chromosome complement and the remaining ~3.5 cm is explained by the dimorphism in sex steroids (primarily due to the growth-promoting effect of gonadal androgens); (2) according to the infancy-childhood-puberty growth model, the sex difference in the childhood growth function produces height differences of ~1 cm in childhood and 8–10 cm at 18–20 years of age, whereas the sex difference in the pubertal growth function yields height difference of ~4.5 cm at 18–20 years of age; and (3) <i>SHOX</i> expression and methylation analyses using knee cartilage tissues and cultured chondrocytes have shown lower <i>SHOX</i> expression levels in female samples than in male samples and methylation patterns consistent with partial spreading of X-inactivation affecting <i>SHOX</i> in female samples. These findings suggest that small but persistent sex difference in <i>SHOX</i> expression dosage leads to the variation in the sex steroid independent childhood growth function, thereby yielding the sex difference in height which remains small in childhood but becomes obvious in adulthood.</p>\u0000<p></p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":"19 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141568989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of insulin signaling with FOXO and FOXK transcription factors","authors":"Masaji Sakaguchi","doi":"10.1507/endocrj.ej24-0205","DOIUrl":"https://doi.org/10.1507/endocrj.ej24-0205","url":null,"abstract":"</p><p>Insulin is an essential hormone for animal activity and survival, and it controls the metabolic functions of the entire body. Throughout the evolution of metazoan animals and the development of their brains, a sustainable energy supply has been essential to overcoming the competition for survival under various environmental stresses. Managing energy for metabolism, preservation, and consumption inevitably involves high oxidative stress, causing tissue damage in various organs. In both mice and humans, excessive dietary intake can lead to insulin resistance in various organs, ultimately displaying metabolic syndrome and type 2 diabetes. Insulin signals require thorough regulation to maintain metabolism across diverse environments. Recent studies demonstrated that two types of forkhead-box family transcription factors, FOXOs and FOXKs, are related to the switching of insulin signals during fasting and feeding states. Insulin signaling plays a role in supporting higher activity during periods of sufficient food supply and in promoting survival during times of insufficient food supply. The insulin receptor depends on the tyrosine phosphatase feedback of insulin signaling to maintain adipocyte insulin responsiveness. α4, a regulatory subunit of protein phosphatase 2A (PP2A), has been shown to play a crucial role in modulating insulin signaling pathways by regulating the phosphorylation status of key proteins involved in these pathways. This short review summarizes the current understanding of the molecular mechanism related to the regulation of insulin signals.</p>\u0000<p></p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":"69 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141568972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoimmunity related to anti-Nax and anti-ZSCAN1 autoantibodies in adipsic hypernatremia","authors":"Akari Nakamura-Utsunomiya","doi":"10.1507/endocrj.ej24-0058","DOIUrl":"https://doi.org/10.1507/endocrj.ej24-0058","url":null,"abstract":"</p><p>“Adipsic hypernatremia” is clinically characterized by chronic elevation of plasma [Na⁺] with an inappropriate lack of thirst and upward resetting of the osmotic set point for arginine vasopressin (AVP) secretion, combined with a relative deficiency of AVP, thereby resulting in persistent hypernatremia. Many cases are accompanied by structural lesions in the hypothalamus, pituitary gland, and circumventricular organs (CVOs). On the other hand, cases without structural lesions have been reported since the 1970s, but the pathophysiology was unknown for a long time. In 2010, Hiyama <i>et al.</i> reported that an anti-Na_x antibody response caused adipsic hypernatremia in a pediatric case with ganglioblastoma. In recent years, advances in clinical research have led researchers to recognize that an autoimmunological pathogenic mechanism might be associated with periventricular organs such as the subfornical organ (SFO). In addition, in pediatric cases diagnosed as ROHHAD (rapid-onset obesity with hypoventilation, hypothalamic dysfunction, autonomic dysregulation) syndrome, it has been reported that half of the cases have abnormal serum Na levels, and some research findings indicated an autoimmune mechanism acting on the organs of the hypothalamus and CVOs. Then, anti-ZSCAN1 antibody response was detected in cases diagnosed as ROHHAD-NET in 2022. In this review, by summarizing a series of studies on Na_x and ZSCAN1, which are expressed in the hypothalamus, pituitary gland, and SFO, I would like to describe the current findings of the autoimmune pathogenesis of adipsic hypernatremia.</p>\u0000<p></p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":"7 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141550246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between diabetes diet-related quality of life and dietary fiber intake among people with type 2 diabetes: a cross-sectional study.","authors":"Fuyuko Takahashi, Yoshitaka Hashimoto, Ayumi Kaji, Ryosuke Sakai, Yuka Kawate, Yuriko Kondo, Takuro Okamura, Naoko Nakanishi, Saori Majima, Takafumi Osaka, Hiroshi Okada, Takafumi Senmaru, Emi Ushigome, Mai Asano, Masahide Hamaguchi, Masahiro Yamazaki, Eiko Sato, Michiaki Fukui","doi":"10.1507/endocrj.EJ23-0320","DOIUrl":"10.1507/endocrj.EJ23-0320","url":null,"abstract":"<p><p>Diet therapy is one of the most important treatments for people with type 2 diabetes (T2D). However, dietary restrictions due to diet therapy may reduce quality of life (QOL). This cross-sectional study aimed to investigate the association between diabetes diet-related QOL and dietary fiber intake in 238 people with T2D. The Diabetes Diet-related Quality of Life-Revised version (DDRQOL-9-R) and the brief-type self-administered diet history questionnaire were used to evaluate diabetes diet-related QOL and nutritional intake, respectively. Higher scores of each DDRQOL-9-R subscale means greater satisfaction with diet, perceived merits of diet therapy, and lower burden of diet therapy, which indicates good QOL. The median scores for perceived merits of diet therapy, satisfaction with diet, and burden of diet therapy were 58.3 [41.7-75.0], 75.0 [66.7-91.7], and 66.7 [50.0-75.0] points, respectively. HbA1c levels in people with high perceived merits of diet therapy (7.3 [6.7-7.8] vs. 7.5 [7.1-8.2] %, p = 0.007) and people with high satisfaction with diet (7.3 [6.8-7.8] vs. 7.5 [7.1-8.4] %, p = 0.010) were lower than those without. Dietary fiber intake was higher in people with high perceived merits of diet therapy (11.6 [8.8-16.7] vs. 10.0 [7.9-13.8] g/day, p = 0.010), high satisfaction with diet (11.4 [8.8-16.1] vs. 9.7 [7.8-13.2] g/day, p = 0.007), and low burden of diet therapy (11.8 [8.7-16.5] vs. 9.7 [7.8-12.6] g/day, p = 0.004) than in those without. Dietary fiber intake was related to perceived merits of diet therapy (Odds ratio [OR]1.07 [95%CI: 1.00-1.15], p = 0.049), burden of diet therapy (OR 0.90 [95%CI: 0.82-0.98], p = 0.022), and satisfaction with diet (OR 1.18 [95%CI: 1.09-1.27], p < 0.001) after adjusting for covariates. Dietary fiber intake is associated with diabetes diet-related QOL in people with T2D.</p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":" ","pages":"583-592"},"PeriodicalIF":2.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140331607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of the anterior pituitary: diverse lineages of the stem/progenitor cells.","authors":"Yukio Kato, Takako Kato","doi":"10.1507/endocrj.EJ23-0676","DOIUrl":"10.1507/endocrj.EJ23-0676","url":null,"abstract":"<p><p>The pituitary gland is endocrine tissue composed of two distinct parts with different origins: the adenohypophysis (adenohypophyseal placode origin) and the neurohypophysis (neuroectoderm origin). Differentiation of endocrine cells in the pituitary gland leads to hormone synthesis, secretion into the capillary network, and transportation to target organs. In 1988, the discovery of the pituitary transcription factor PIT1 sparked research on endocrine cell differentiation. In the twenty-first century, the discovery that SOX2-positive stem/progenitor cells give rise to all types of pituitary endocrine cells advanced research on differentiation processes using diverse marker molecules. Lineage tracing using specific marker genes from early embryos revealed that during construction of the anterior pituitary from the adenohypophyseal placodal cells the developing anterior pituitary incorporates diverse cell types originating from the neural crest-derived and ectodermal-derived cells. Consequently, the postnatal anterior pituitary becomes a mosaic of terminally differentiated cells of different origin and with different life histories. It has also been revealed that most of the postnatal stem/progenitor cells form at least solid clusters in the parenchyma. Moreover, the classification and role of S100β-positive cells had been ambiguous, but now they are identified as a major component of postnatal stem/progenitor cells. This paper provides an updated overview of pituitary development.</p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":" ","pages":"547-559"},"PeriodicalIF":2.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between DNA methylation levels of thioredoxin-interacting protein (TXNIP) and changes in glycemic traits: a longitudinal population-based study.","authors":"Keisuke Maeda, Ryosuke Fujii, Hiroya Yamada, Eiji Munetsuna, Mirai Yamazaki, Yoshitaka Ando, Genki Mizuno, Hiroaki Ishikawa, Koji Ohashi, Yoshiki Tsuboi, Yuji Hattori, Yuya Ishihara, Nobuyuki Hamajima, Shuji Hashimoto, Koji Suzuki","doi":"10.1507/endocrj.EJ23-0629","DOIUrl":"10.1507/endocrj.EJ23-0629","url":null,"abstract":"<p><p>Thioredoxin-interacting protein (TXNIP) plays an important role in glucose metabolism, and its expression is regulated by DNA methylation (DNAm). Although the association between TXNIP DNAm and type 2 diabetes mellitus has been demonstrated in studies with a cross-sectional design, prospective studies are needed. We therefore examined the association between TXNIP DNAm levels and longitudinal changes in glycemic traits by conducting a longitudinal study involving 169 subjects who underwent two health checkups in 2015 and 2019. We used a pyrosequencing assay to determine TXNIP DNAm levels in leukocytes (cg19693031). Logistic regression analyses were performed to assess the associations between dichotomized TXNIP DNAm levels and marked increases in glycemic traits. At four years, the TXNIP DNA hypomethylation group had a higher percentage of changes in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) compared to those in the hypermethylation group. The adjusted odds ratios for FPG and HbA1c levels were significantly higher in the TXNIP DNA hypomethylation group than in the hypermethylation group. We found that TXNIP DNA hypomethylation at baseline was associated with a marked increase in glycemic traits. Leukocyte TXNIP DNAm status could potentially be used as an early biomarker for impaired glucose homeostasis.</p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":" ","pages":"593-601"},"PeriodicalIF":1.3,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Super paramagnetic iron oxide contrast-enhanced magnetic resonance imaging was useful in differentiating an insulinoma from an accessory spleen: a case report with review of literature","authors":"Ema Toyokuni, Hiroshi Okada, Goji Hasegawa, Mayuko Kadono, Sayaka Kato, Mari Yoneda, Michiaki Fukui","doi":"10.1507/endocrj.ej24-0142","DOIUrl":"https://doi.org/10.1507/endocrj.ej24-0142","url":null,"abstract":"</p><p>When a neuroendocrine tumor with abundant blood flow is located in the pancreatic tail, it is difficult to distinguish it from accessory spleen. The patient was a 71-year-old woman who was admitted with impaired consciousness and hypoglycemia, raising suspicion of insulinoma. The selective arterial calcium injection test suggested a lesion in the pancreatic tail. Contrast-enhanced computed tomography and magnetic resonance imaging (MRI) showed a mass in the splenic hilum; however, its continuity with the pancreas was unclear. Contrast-enhanced MRI using super paramagnetic iron oxide (SPIO) showed no SPIO uptake in the splenic hilar mass. SPIO contrast-enhanced MRI is considered useful for differentiating pancreatic endocrine tumors from paraspleen tumors.</p>\u0000<p></p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":"36 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141189707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-traumatic pituitary stalk transection syndrome (PSTS) expeditiously manifested after a fall from a height combined with acute traumatic spinal cord injury: a rare case report with review of literature","authors":"Yohei Ishiki, Atsuko Tamaki, Ken-ichiro Honma, Ken Yonaha, Takamitsu Yabiku, Taiki Teruya, Moriyuki Uehara, Yoshiro Nakayama, Rei Chinen, Tsugumi Uema, Sawako Nakachi, Shiki Okamoto, Hiroaki Masuzaki","doi":"10.1507/endocrj.ej24-0091","DOIUrl":"https://doi.org/10.1507/endocrj.ej24-0091","url":null,"abstract":"</p><p>Post-traumatic pituitary stalk transection syndrome (PSTS) is an extremely rare cause of combined pituitary hormone deficiency (CPHD), affecting approximately 9 per 100,000 cases of traumatic brain injury. In contrast, pituitary stalk interruption syndrome (PSIS) is also a rare cause of CPHD. Importantly, these conditions are often confused due to their similar names and resembling findings on magnetic resonance imaging (MRI). PSIS has been thought to be a prenatal developmental event resulting from a couple of genetic aberrations. In typical PSIS, anterior pituitary hormone deficiencies are restricted to growth hormone (GH) and gonadotropin during the pediatric age, gradually and generally progressing to panhypopituitarism in most cases. In contrast, global deficiencies of the anterior pituitary hormones in PSTS are temporally associated with trauma. To the best of our knowledge, no case reports of PSTS combined with acute traumatic spinal cord injury have been reported. A 34-year-old female was transferred to our hospital after jumping from the fourth building floor. She was diagnosed as an acute traumatic spinal cord injury and underwent the operation of elective posterior spinal fusion. On postoperative day 7, the blood tests revealed considerable hyperkalemia, hyponatremia and eosinophilia. Notably, menstruation stopped after falling from a height. Pituitary function tests revealed GH deficiency, hypogonadism, hypothyroidism and hypoadrenocorticism. MRI revealed loss of the pituitary stalk, whilst the hyperintense signal from distal axon of hypothalamus was still identified. Based on these findings, she was diagnosed as PSTS. Our case highlights endocrinological landscape of transection of the pituitary stalk by acute trauma.</p>\u0000<p></p>","PeriodicalId":11631,"journal":{"name":"Endocrine journal","volume":"19 1","pages":""},"PeriodicalIF":2.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141170496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}