A M Lapshina, E A Bazarova, E G Przhialkovskaya, P M Khandaeva, V N Azizyan, A Yu Grigoriev, O V Ivashchenko, N V Tarbaeva, Zh E Belaya
{"title":"[Metastatic pituitary lesion].","authors":"A M Lapshina, E A Bazarova, E G Przhialkovskaya, P M Khandaeva, V N Azizyan, A Yu Grigoriev, O V Ivashchenko, N V Tarbaeva, Zh E Belaya","doi":"10.14341/probl13395","DOIUrl":"https://doi.org/10.14341/probl13395","url":null,"abstract":"<p><p>Metastatic lesion of pituitary is a rare condition and is diagnosed in 1.8-4% of cases. Monitoring and treatment of such patients is a complex task and requires increased attention from a multidisciplinary team of specialists. The authors represent three patients with metastatic pituitary lesion who underwent neurosurgical treatment at the National Research Center of the National Research Institute of Endocrinology with subsequent pathomorphological confirmation of the diagnosis. The primary tumors were breast cancer, lung carcinoid, and clear cell kidney cancer. Two patients had distant metastases other than the pituitary gland. The clinical manifestation consisted in the appearance of symptoms of panhypopituitarism, chiasmal syndrome and mass effect in all cases. The follow-up period after surgical treatment was 0.25-2.5 years. Progression of the underlying disease was noted in two patients. One of them carried out stereotactic radiosurgical treatment and stereotactic oriented irradiation. One patient has a stable condition.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"46-53"},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"[The role of leptin in endometrium disorders: literature review].","authors":"K D Ievleva, I N Danusevich, L V Suturina","doi":"10.14341/probl13397","DOIUrl":"https://doi.org/10.14341/probl13397","url":null,"abstract":"<p><p>Leptin is not only the main regulator of energy balance, but also it affects the reproductive and immune systems. Leptin and its receptors are expressed in the endometrium and are actively involved in the embryo implantation. According to numerous studies, expression and level changes of leptin are associated with the inflammatory and autoimmune diseases, including endometriosis and chronic endometritis. Hyperplastic and inflammatory diseases of the uterus are accompanied by a violation of the receptivity of the endometrium due to the dysregulation of many factors involved in proliferation, vascularization and decidualization of cells. Activity of most of these factors is due to the leptin action, however, there are no studies of the direct effect of leptin in the pathogenesis of disorders of the endometrium in hyperplastic and inflammatory diseases.Thus, the purpose of this literature review was to describe the putative molecular mechanisms of the effect of leptin on the development of endometrial pathology.Literature search was carried out from 03/20/2023 to 05/11/2023 using scientific literature databases: NCBI PubMed, Google Scholar (foreign sources), Cyberleninka, Elibrary (domestic sources): references for the period 1995-2023 were analyzed. The following keywords were used for the search: leptin, endometrial dysfunction, endometrial receptivity, inflammation, pelvic inflammatory disease.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"106-114"},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D V Sazonova, M A Perepelova, A S Shutova, L V Nikankina, G S Kolesnikova, E A Pigarova, L K Dzeranova
{"title":"[Combination of macro-TSH and macroprolactinemia phenomena in a patient with autoimmune thyroiditis and vitiligo].","authors":"D V Sazonova, M A Perepelova, A S Shutova, L V Nikankina, G S Kolesnikova, E A Pigarova, L K Dzeranova","doi":"10.14341/probl13390","DOIUrl":"https://doi.org/10.14341/probl13390","url":null,"abstract":"<p><p>Laboratory diagnostic methods are the main tools in the practice of a doctor of any specialty, including an endocrinologist. Factors were identified that could change the concentration of the biologically active fraction of the test substance, subsequently complicating the interpretation of laboratory results and making the right clinical decision. The literature describes a variety of circulating autoantibodies involved in binding to pituitary hormones (prolactin (PRL), thyroid-stimulating hormone (TSH), growth hormone, luteinizing, follicle-stimulating, and adrenocorticotropic hormones), hypothalamus (vasopressin and oxytocin), pancreas (insulin and glucagon) , parathyroid glands (parathyroid hormone), as well as with thyroid hormones. As a rule, the resulting macromolecules lead to an increase in laboratory parameters, in which the prevailing fraction of the hormone does not have biological activity, which determines the main problem of this phenomenon. The most common variants include immune complexes with PRL and TSH, causing the phenomena of macroprolactinemia and macrothyrotropinemia (macro-TSH-emia/macro-TSH), respectively. Most laboratory test systems used in clinical practice are capable of determining only the total amount of PRL and TSH. The presented clinical observation describes a combination of the phenomena of macro-TSH and macroprolactinemia in a patient with autoimmune thyroiditis (AIT) and vitiligo.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"34-39"},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A V Strelkova, F A Bichkaeva, O S Vlasova, E V Nesterova, B A Shengof, T B Gretskaya
{"title":"[Insulin level, glycemia, insulin resistance and β-cell function in relation to the lifestyle of Arctic indigenous people. Are there conditions for diabetes and which type?]","authors":"A V Strelkova, F A Bichkaeva, O S Vlasova, E V Nesterova, B A Shengof, T B Gretskaya","doi":"10.14341/probl13411","DOIUrl":"https://doi.org/10.14341/probl13411","url":null,"abstract":"<p><strong>Background: </strong>Modern studies suggest that lifestyle changes of the indigenous Arctic residents lead to the loss of the \"adaptive polar type of metabolism\", which is characterized by the intensification of protein metabolism, optimization of lipid metabolism, and minimization of carbohydrate metabolism at low insulin concentrations. How to survive the era of change?</p><p><strong>Aim: </strong>To assess insulinemia, glycemia, β-cell secretory activity, and insulin sensitivity in Arctic indigenous people in relation to their lifestyle.</p><p><strong>Materials and methods: </strong>A cross-sectional study of a population of indigenous Arctic residents (Nenets, Komi) aged from 22 to 60 years was conducted. Insulin levels were studied in blood serum using ELISA, and glucose levels using the spectrophotometric method. Insulin resistance (HOMA-IR) and β-cell function (HOMA1-%β) indices were calculated.</p><p><strong>Results: </strong>397 people were examined; 89 (22%) of them were nomadic people (NP) and 44 (49%) were male. Another 308 (78%) were sedentary people (SP), and 69 (22%) were male. The insulin level was significantly lower in NP (6.0 [3.5-11.8] µU/ml) compared to SP (8.3 [4.6-13.1] µU/ml), p=0.006. There was no difference in glycemia (4.6 [4.2-5.0] in NP and 4.6 [4.1-5.2] in SP) between lifestyles.The HOMA-IR was significantly lower in NP (1.3 [0.7-2.4]) than in SP (1.8 [0.95-2.8]), p=0.013. IR-HOMA >2 units was 1.8 times more frequent in the SP than in NP, with adjusted for sex, age, and BMI OR=0.56; 95% CI: 0.33-0.96, p=0.034. The median HOMA1-%β was 128 [67-241] % in NP and 144 [93-236]% in SP with no significant differences between groups. The proportion of individuals with HOMA1-%β <48.9 was 17% in NP versus 5% in SP, p<0.001. The adjusted odds of having HOMA1-%β <48.9 in NP are 3.5 times higher than in SP; 95% CI: 1.56-7.92, p=0.002. Fifty-six cases of glycemia ≥5.6 mmol/l were identified: 13.5% in NP and 14.3% in SP. The ratio IR-HOMA >2/ HOMA1-%β <48.9/BMI was 1.8 units/45%/25.2 kg/m2 in NP and 3.0 units/88%/29.6 kg/m2 in SP.</p><p><strong>Conclusion: </strong>Maintaining a nomadic lifestyle helps keep lower insulin concentrations; at the same time, glycemic levels in the groups were similar. In the NP group, there was a high proportion of individuals with low β-cell secretory activity, predominantly men; in the SP group, more individuals were insulin-resistant. Analysis of cases of glycemia ≥5.6 mmol/l confirmed, that hyperglycemia in a nomadic lifestyle was associated with β-cell hypofunction and the absence of obesity; on the contrary, in a sedentary lifestyle, it was associated with increased insulin resistance and obesity.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"54-69"},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L I Astafyeva, P L Kalinin, Y Y Trunin, G L Kobyakov, Y G Sidneva
{"title":"[Efficacy of standard methods in the treatment of prolactin-secreting pituitary carcinoma].","authors":"L I Astafyeva, P L Kalinin, Y Y Trunin, G L Kobyakov, Y G Sidneva","doi":"10.14341/probl13401","DOIUrl":"https://doi.org/10.14341/probl13401","url":null,"abstract":"<p><p>Pituitary carcinoma (metastatic neuroendocrine tumor of the pituitary gland) is the pituitary tumor with confirmed craniospinal and/or systemic metastases. These tumors are extremely rare accounting for only 0.1% to 0.5% of all pituitary tumours and are characterized by high mortality. In the presented case, pituitary carcinoma with intracranial metastasis was diagnosed in a young patient 25 years after manifestation of an aggressive recurrent prolactin-secreting pituitary tumor. Standard therapy (removal of metastasis, radiation therapy, cabergoline therapy) resulted in a long-term remission of the disease.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"40-45"},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"[Meta-analysis of experimental studies of the effect of melatonin monotherapy on the levels of thyroid hormones and glucocorticoids in rats kept under standard condition].","authors":"N V Kuzmenko, V A Tsyrlin, M G Pliss","doi":"10.14341/probl13396","DOIUrl":"10.14341/probl13396","url":null,"abstract":"<p><strong>Background: </strong>Melatonin is known to modulate circadian and seasonal rhythms in metabolism, reproduction, and behavior. However, the effect of exogenous melatonin supplementation on the functioning of the thyroid and adrenal glands in species without a clear seasonality in reproduction is still unclear.</p><p><strong>Aim: </strong>Using a meta-analysis of publications, to investigate the effect of melatonin monotherapy on the concentrations of pituitary thyroid-stimulating hormone, thyroid hormones (TG), pituitary adrenocorticotropic hormone and corticosterone (CS) in rats kept under standard laboratory conditions.</p><p><strong>Materials and methods: </strong>In our work, using the Review Manager 5.3 program, we conducted a meta-analysis of publications examining the effect of melatonin monotherapy on the functioning of the thyroid gland (22 papers) and adrenal glands (20 papers) in rats kept under standard conditions.</p><p><strong>Results: </strong>According to the results of our meta-analysis, the effects of melatonin on the levels of TG and CS depend on the dose and duration of therapy. A decrease in TG and CS was associated with therapy lasting no more than 4-5 weeks and with high doses of melatonin. An increase in CS and a trend toward increased TG levels were observed with longer therapy. However, a few studies have observed a decrease in TG with very long-term melatonin therapy (≥32 weeks). Among all TGs, total thyroxine (T4) showed maximum sensitivity to exogenous melatonin, which indicates the influence of melatonin on the secretory function of the thyroid gland. In addition, melatonin increased the relative weight of the adrenal glands. There was no convincing evidence that the effects of melatonin were influenced by the route and timing of administration, or the timing of blood sampling.</p><p><strong>Conclusion: </strong>As a result, exogenous melatonin can modulate TG and CS levels, even in species without a clear seasonality in reproductive function.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"91-105"},"PeriodicalIF":0.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"[The use of TruCare III insulin pump in patients with type 1 diabetes mellitus].","authors":"I A Barsukov, A A Demina","doi":"10.14341/probl13516","DOIUrl":"https://doi.org/10.14341/probl13516","url":null,"abstract":"<p><p>The development of devices for continuous subcutaneous insulin infusion (CSII or insulin pumps) dramatically improved medical care for patients with diabetes mellitus. Insulin pump production widens annually resulting in number of new models entering the market, that differs in price but are similar in technical features. The entering of such new models to the Russian market can cause practical issues both in patient and in health care provider, so their estimation is of great importance. Insulin pump TruCare III (Apex Medical Co., Ltd, China) was registered in Russian Federation in September 15, 2023. The clinical experience of the TruCare III use in patients with type 1 diabetes mellitus is presented with the focus on glycemic parameters and custom features.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"70-75"},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G N Nurullina, I N Pushkarev, E G Przhiyalkovskaya
{"title":"[Cephalgic syndrome in patients with acromegaly].","authors":"G N Nurullina, I N Pushkarev, E G Przhiyalkovskaya","doi":"10.14341/probl13423","DOIUrl":"https://doi.org/10.14341/probl13423","url":null,"abstract":"<p><p>The aim of this review is to summarize the data available in the literature on the causes of headache in patients with acromegaly, as well as on the effect of various methods of acromegaly treatment on headache. Publications were searched in the PubMed database using the keywords «Headache in patients with acromegaly», «Headache in patients with pituitary adenomas», «Tension-type headache», «Migraine». Headache in patients with pituitary adenomas secreting somatotropic hormone (STH) is not uncommon: according to various authors, cephalgic syndrome occurs in 30-70% of patients with acromegaly and can worsen their quality of life, along with other factors, up to disability. By the nature of development, headache with acromegaly is classified into primary (migraine, tension headache, trigeminal autonomic cephalgia, for example, SUNCT syndrome and cluster headaches), and can also be caused by various causes directly related to the tumor. All this requires differential diagnosis. The factors causing headaches in somatotropinomas have not yet been well studied and require further research. These include the mass effect of the tumor, hormonal hypersecretion, pathology of the temporomandibular joint, sodium and fluid retention in the body, psychological factors, etc. The authors evaluated the effect on headache of various methods of acromegaly treatment: transnasal transsphenoidal adenomectomy, radiation therapy and drug therapy with somatostatin analogues, dopamine agonists and growth hormone receptor antagonist. However, even when normal levels of STH and insulin-like growth factor 1 (IGF-1) are reached, cephalgic syndrome may persist, therefore patients should be warned about this in advance and referred to a cephalgologist to select adequate headache therapy.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"14-22"},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S A Gronskaia, N V Rusyaeva, Zh E Belaya, G A Melnichenko
{"title":"[Non-classical hormones from the fibroblast growth factor family].","authors":"S A Gronskaia, N V Rusyaeva, Zh E Belaya, G A Melnichenko","doi":"10.14341/probl13441","DOIUrl":"https://doi.org/10.14341/probl13441","url":null,"abstract":"<p><p>Fibroblast growth factors (FGFs) are a group of signaling molecules named for their ability to promote the growth and proliferation of fibroblasts and various other cell types. Typically, FGFs exert their effects locally by binding to receptors within the tissues where they are synthesized. However, certain members of this family, such as FGF 19, FGF 21, and FGF 23, diverge from this pattern. Following synthesis, these FGFs enter the bloodstream and act on distant organs and tissues by binding to their receptors and associated cofactors, thereby classified as non-classical hormones within the FGF family.The biological functions of FGFs are diverse and contingent upon the specific receptors and cofactors involved in their signaling pathways. For instance, FGF 19 and FGF 21 play crucial roles in regulating glucose and lipid metabolism, whereas FGF 23 primarily influences phosphorus metabolism. Given their varied roles, FGFs present promising targets for therapeutic interventions and drug development.This review aims to consolidate current understanding of FGF family hormones, elucidating their biological impacts and exploring their potential applications as therapeutic targets.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"23-33"},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A S Nazarova, S S Prikazchikova, V Y Kalashnikov, G A Melnichenko, N G Mokrysheva
{"title":"[Analysis of the provision of medical care using telemedicine technologies at the endocrinology research centre].","authors":"A S Nazarova, S S Prikazchikova, V Y Kalashnikov, G A Melnichenko, N G Mokrysheva","doi":"10.14341/probl13500","DOIUrl":"10.14341/probl13500","url":null,"abstract":"<p><strong>Background: </strong>In the first months after the pandemic of the COVID-19, the provision of medical care through telemedicine technologies took a leading position, in particular regarding endocrine nosologies. Meanwhile, at present, comprehensive information on telecommunications interaction between doctors of various medical organizations of the regions of the Russian Federation and employees of federal centers is insufficient, which determines the relevance of studying this topic.</p><p><strong>Aim: </strong>Analysis of the provision of medical care in remote interaction of medical workers using telemedicine technologies («doctor-doctor») between the Endocrinology Research Centre and the regions of the Russian Federation in 2019-2023.</p><p><strong>Materials and methods: </strong>A single-center, observational, single-sample study was conducted, including completed planned and urgent telemedicine consultations in the format of «doctor-doctor « in the fields of «endocrinology» and «pedia-tric endocrinology», conducted through a telemedicine system for remote consultations at federal and regional levels between 2019 and 2023. Data on the referral rate of medical personnel from the regions of the Russian Federation to the Endocrinology Research Centre for telemedicine consultations were analyzed, including annual dynamics of treatment, frequency of referrals from each region, nosological structure of referrals, and number of patients admitted to the center based on the results of these consultations. Analysis of interdepartmental cooperation between the Endocrinology Research Centre and other federal centers was also performed.</p><p><strong>Results: </strong>In the period from 2019-2023, 14,475 telemedicine consultations «doctor-doctor» were conducted. In 2019, medical workers from 78 regions of the Russian Federation applied to the Endocrinology Research Centre. By 2023, this figure has increased to 88 (including newly annexed territories). The Yamalo-Nenets Autonomous Okrug, Tambov Region and Astrakhan Region were the leading regions in terms of the circulation of medicines at the Endocrinology Research Centre. In the nosological structure, the largest number of consultations in adult patients were conducted for acromegaly and primary hyperparathyroidism, in children for stunting and type 1 diabetes mellitus. In the period from 2019-2023, the Endocrinology Research Centre sent a total of 300 «outgoing» requests to 17 medical organizations.</p><p><strong>Conclusion: </strong>Consulting with the use of telemedicine technologies has become a convenient and multifunctional way of providing medical care. Further analysis of the place of telemedicine in practical healthcare will expand its capabilities, including considering the introduction of financing by the territorial fund of compulsory medical insurance for this area of medical activity.</p>","PeriodicalId":101419,"journal":{"name":"Problemy endokrinologii","volume":"70 5","pages":"4-13"},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}