THE THYMUS GLAND (THYMUS) ASPECTS IN CHILDREN (PART VI). ASPECTS OF TREATMENT AND PREVENTION OF "THYMUS-MEDIATED" (to a certain extent) PATHOLOGICAL CONDITIONS
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Abstract
Studies of drugs that affect the T-cell link of immunity, which began in the middle of the 20th century, continue without losing relevance even now. There have been many attempts in the medical community to create drugs from thymus extracts that have a peptide base. Some of which – «thymalin», «thymosin», «tactivin», are used at the present time, though with a narrower range of indications. Gone is the era of the use of these drugs, for example, in immunosuppression of hematopoiesis, in primary immunodeficiency states, in the treatment of acute septic and purulent-inflammatory pathologies, in frequently and long-term ill children (with combined thymomegaly), etc.
This was facilitated by the development of new diagnostic technologies that prove the multicomponent nature of the regulatory structures of the immune system, which cannot be fully squeezed into the Procrustean bed of the action of only thymic peptides. But in recent years, positive results have been obtained using these drugs in patients with COVID-19, and with acquired immunodeficiency syndrome (AIDS), as well as in the treatment of lymphocytopenia in an infant.
In addition to thymus peptides, the use of growth hormone (GH) is proposed, which acts as a stimulator of thymus stromal cells. In different countries of the world, research is being conducted aimed at preventing thymus involution, ways to restore the thymus gland are being considered: from the use of Korean red ginseng to progenitor cell transplantation. In addition, active work is underway in an attempt to create an artificial thymus based on thymus cells embedded in nanofibers.
Currently, hundreds of types of primary immunodeficiencies (PID) have been identified, new diagnostic methods and markers have been improved and discovered, which has made it possible to overestimate the role of thymomegaly and microthymus in the origin of immunodeficiency in children, although the facts of increased morbidity (often viral etiology) in young children with data bipolar states of the thymus are difficult to dispute, especially when the subsequent long-term follow-up of these children was not seriously subjected to scientific analysis.
And if we take into account the position that the clinical manifestation of a primary immunodeficiency state is possible at any age, then the presence of critical thymomegaly or microthymus (even transient) at an early age can be the “first signs” of this syndrome, which will clinically manifest itself much later, then, when the processes of age-related involution of the VJ are added to this. In any case, this category of children requires further study and close attention of scientists in order to develop modern methods of diagnosis and treatment.
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Author Biographies
Юрий Иванович Ровда, Kemerovo State Medical University
Rovda Yuryi Ivanovich
MD, PhD, professor
He is the Honoured Doctor of the Russian Federation, the Head of the Department of Pediatrics and Neonatology. He graduated from the Pediatric Faculty of Kemerovo Medical Institute in 1973. On his initiative the Regional Pediatric Cardiac Center was organized. His researches concerning the metabolic syndrome, purinosis, hypertension in children are priorities in the Russian Federation.
He is an expert of the Russian Task Group of Federal Service on Surveillance in Healthcare, dealing with mentioned diseases.
He was the first who developed and implemented method of diagnostics of visceral fat deposition in children with echocardiography and a number of different new scientific-practical methods (the prevention of purine metaboliс imbalance, prenosological diagnostics and prevention of arterial hypertension and metabolic syndrome in children and adolescents, alternative methods of prevention and treatment of metabolic syndrome, allergodermia in children – ozone therapy, etc.).Наталья Николаевна Миняйлова, Kemerovo State Medical University
doctor of medical sciences, professor, professor of the department of pediatrics and neonatologyАлена Владимировна Ведерникова, Kemerovo State Medical University
assistant, department of pediatrics and neonatologyИван Константинович Халивопуло, Research Institute of Complex Problems of Cardiovascular Diseases, Kemerovo
head of the department of cardiac surgeryАндрей Владимирович Шабалдин, Kemerovo State Medical University; Research Institute of Complex Problems of Cardiovascular Diseases, Kemerovo
doctor of medical sciences, docent, professor of the department of polyclinic pediatrics, propaedeutics of childhood diseases and postgraduate training; leading researcherАнна Андреевна Лобыкина, Kemerovo State Medical University
resident in pediatricsОльга Валерьевна Шмакова, Kemerovo State Medical University
candidate of medical sciences, docent, head of the department of prediatry and neonatologyСергей Фадеевич Зинчук, Kemerovo State Medical University
candidate of medical sciences, docent, head of the department of morphology and forensic medicineНаталья Степановна Черных, Kemerovo State Medical University
candidate of medical sciences, docent, docent of the department of polyclinic pediatrics, propaedeutics of childhood diseases and postgraduate trainingВладислав Викторович Сохарев, Kemerovo State Medical University
student of the faculty of pediatricsЯна Вячеславовна Юнкина, Kuzbass Clinical Hospital named after S.V. Belyaev, Kemerovo
candidate of medical sciences, head of the pediatric specialized departmentReferences
Tishevskaya NV, Gevorkyan NM, Kozlova NI. The role of T-lymphocytes in hormonal regulation of morphogenetic processes. Advances in modern biology. 2015; 135(2): 189-202. Russian (Тишевская Н.В., Геворкян Н.М., Козлова Н.И. Роль T-лимфоцитов в гормональной регуляции морфогенетических процессов //Успехи современной биологии. 2015. Т. 135, № 2. С. 189-202)
Clinical pharmacology of thymogen /ed. VS Smirnov, SPb., 2004. 104 p. Russian (Клиническая фармакология тимогена /под ред. В.С. Смирнова. СПб., 2004. 104 с.)
Arion VYa, Zimina IV, Moskvina SN, Bystrova OV. T-activin is a natural immunocorrector. Clinical application. Immunopathology, allergology, infectology. 2007; 4: 11-26. Russian (Арион В.Я., Зимина И.В., Москвина С.Н., Быстрова О.В. Т-активин – природный иммунокорректор. Клиническое применение //Иммунопатология, аллергология, инфектология. 2007. № 4. С. 11-26)
Arion VYa, Ivanushkin EF. Principles of immunocorrective therapy with thymus preparation T-activin: A.s. 1673122 SSSR, MKI 5A61K35/26; Krasnoyarsk med. in-t. No. 4452382/12; Appl. 05/31/88; Published 30.98.91, Bull. No. 32. Russian (Арион В.Я., Иванушкин Е.Ф. Принципы иммунокоррегирующей терапии препаратом тимуса Т-активин: А.с. 1673122 СССР, МКИ 5А61К35/26; Красноярский мед. ин-т. № 4452382/12; Заявл. 31.05.88; Опубл. 30.98.91, Бюл. № 32)
Vaganov PD, Martynova MI, Arion VYa. Clinical and immunological characteristics of children with enlarged thymus syndrome and their correction. Russian Bulletin of Perinatology and Pediatrics. 2001; 46(3): 59-60. Russian (Ваганов П.Д., Мартынова М.И., Арион В.Я. Клинико-иммунологическая характеристика детей с синдромом увеличенной вилочковой железы и их коррекция //Российский вестник перинатологии и педиатрии. 2001. Т. 46, № 3. С. 59-60)
Arion VIa, Karaulov AV, Khromenkov IuI, Sanina IV, Tagirova AK. Change in immunological and biochemical parameters in germ-free animals in response to T-activin. Bulletin of experimental biology and medicine. 1987; 104(9): 332-334. Russian (Арион В.Я., Караулов Ю.В., Хроменков Ю.И., Санина И.В., Тагирова А.К. Изменения некоторых иммунологических и биохимических параметров Т-активина у безмикробных животных //Бюллетень экспериментальной биологии и медицины. 1987. Т. 104, № 9. C. 332-334)
Kuzmenko LG. Conceptual view on the genesis of congenital thymomegaly. Pediatria n.a. G.N. Speransky. 2012; 3: 38-43. Russian (Кузьменко Л.Г. Концептуальный взгляд на генез врожденной тимомегалии //Педиатрия. 2012. № 3. С. 38-43)
Lastovka I.N., Matveev V.A. Features of the course of acute respiratory viral infections in young children with enlarged thymus syndrome. Topical issues of infectious pathology and vaccination: Proceedings of the IX Congress of children's infectious disease specialists in Russia. 2010. S. 54-55. Russian (Ластовка И.Н., Матвеев В.А. Особенности течения острых респираторных вирусных инфекций у детей раннего возраста с синдромом увеличенной вилочковой железы //Актуальные вопросы инфекционной патологии и вакцинопрофилактики: Материалы IX конгресса детских инфекционистов России. 2010. С. 54-55)
Kuzmenko LG, Kiseleva NM. Contemporary opinion on the role of thymus in living organisms and its participation in the vaccinal process in children of young age. Clinical pathophysiology. 2016; 22(3): 104-114. Russian (Кузьменко Л.Г., Киселева Н.М. Современный взгляд на роль тимуса в живом организме и его участие в вакцинальном процессе у детей раннего возраста //Клиническая патофизиология. 2016. Т. 22, № 3. С. 104-114)
Diagtyareva EA, Kuzmenko LG, Tyurin NA. Immunotropic drugs in pediatric cardiology. Journal of Arrhythmology. 2000; 18: 20-21. Russian (Дягтярева Е.А., Кузьменко Л.Г., Тюрин Н.А. Иммунотропные средства в детской кардиологии //Вестник аритмологии. 2000. № 18. С.20-21)
Matkovskaya TV. To the pathogenesis of thymomegaly in children. Problems of endocrinology. 1988; 2: 34-38. Russian (Матковская Т.В. К патогенезу тимомегалии у детей //Проблемы эндокринологии. 1988. № 2. С. 34-38)
Vaganov PD, Martynov MI, Mikheeva IG, Vaganova LP, Romanova LF, Kuznetsova LF. Hormonal disorders in children with thymus enlargement syndrome and their possible correction. Russian Bulletin of Perinatology and Pediatrics. 2000; 45(4): 32. Russian (Ваганов П.Д., Мартынов М.И., Михеева И.Г., Ваганова Л.П., Романова Л.Ф., Кузнецова Л.Ф. Гормональные нарушения у детей с синдромом увеличения вилочковой железы и возможная их коррекция //Российский вестник перинатологии и педиатрии. 2000. Т. 45, № 4. С. 32)
Heavy AV. Thymomegaly in children (clinical and immunological characteristics and therapeutic and preventive measures): abstr. dis. … dr. med. sci. Kyiv, 1986. 43 p. Russian (Тяжкая А.В. Тимомегалия у детей (клинико-иммунологическая характеристика и лечебно-профилактические мероприятия): автореф. дис. ... д-ра мед. наук. Киев, 1986. 43 с.)
Ivanovskaya TE, Katasonova LP. Thymus structure, immune status and pathological process. Arkhive Pathologii. 1986; 48(1): 9. Russian (Ивановская Т.Е., Катасонова Л.П. Структура тимуса, иммунный статус и патологический процесс //Архив патологии. 1986. Т. 48, № 1. C. 9)
Pishchalnikov AYu. Thymomegaly syndrome in young children as a marker of a slow immune start: abstr. dis. … cand. med. sci. Chelyabinsk, 1992. 21 p. Russian (Пищальников А.Ю. Синдром тимомегалии у детей раннего возраста как маркер медленного иммунного старта: автореф. дис. … канд. мед. наук. Челябинск, 1992. 21 с.)
Kuzmenko LG, Andzhel AE, Neizhko LY. Case of successful correction of severe lymphocytopenia by polypeptides of thymus in an infant. Pediatria n.a. G.N. Speransky. 2017; 96(5): 201-205. Russian (Кузьменко Л.Г., Анджель А.Е., НеижкоЛ.Ю. Случай успешной коррекции полипептидами тимуса тяжелой лимфоцитопении у ребенка грудного возраста //Педиатрия. Журнал им. Г.Н. Сперанского. 2017. Т. 96, № 5. С. 201-205)
Vaganov PD, Donetskova AD, Nikonova MF, Yanovskaya EYu, Petryaikina EE, Pugacheva IA, et al. The effect of tactivin therapy on T-lymphopoiesis under thymomegalia in children of early age with acute obstructive bronchitis. Medical Journal of the Russian Federation. 2015; 21(4): 18-20. Russian (Ваганов П.Д., Донецкова А.Д., Никонова М.Ф., Яновская Э.Ю., Петряйкина Е.Е., Пугачева И.А., и др. Влияние терапии тактивином на Т-лимфопоэз при тимомегалии у детей раннего возраста с острым обструктивным бронхитом //Российский медицинский журнал. 2015. Т. 21, № 4. С. 18-20)
Petrov RV. Synthetic immunomodulators. M.: Nauka, 1991. 197 p. Russian (Петров Р.В. Синтетические иммуномодуляторы. М.: Наука, 1991. 197 с.)
Kuzmenko LG, Smyslova ZV, Kiseleva NM, Bystrova OV, Agarval RK. To the question of the thymus, associated terminology, and health status of childrens with a large thymus. Journal of scientific articles health and education in the XXI century. 2015; 17(4): 97-107. Russian (Кузьменко Л.Г., Смыслова З.В., Киселева Н.М., Быстрова О.В., Агарвал Р.К. К вопросу о тимусе, связанной с ним терминологии и состоянии здоровья детей с большим тимусом //Журнал научных статей здоровье и образование в XXI веке. 2015. Т. 17, № 4. С. 97-107)
Kuzmenko LG, Neizhko LYu, Smyislova ZV, Byistrova OV, Esmurzieva ZI, Vahrusheva SI, et al. Pediatria n.a. G.N. Speransky. 2014; 93(3). Russian (Кузьменко Л.Г., Неижко Л.Ю., Смыслова З.В., Быстрова О.В., Эсмурзиева З.И., Вахрушева С.И., и др. Оценка массы тимуса у детей раннего возраста по данным ультразвукового сканирования //Педиатрия им. Г.Н. Сперанского. 2014. Т. 93, № 3)
Protocol for clinical approbation of the method «Using modern methods and technologies to detect complications and evaluate the effectiveness of personalized rehabilitation of children with primary immunodeficiencies» /Dmitry Rogachev Ministry of Health of Russia. 2019. 37 p. Russian (Протокол клинической апробации метода «Использование современных методов и технологий для выявления осложнений и оценка эффективности персонализированной реабилитации детей с первичными иммунодефицитами /ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева Минздава России. 2019. 37 с.)
Rumyantsev AG. Prospects for the development of clinical immunology. Pediatric Hematology/Oncology and Immunopathology. 2020; 19(S4): 14-17. Russian (Румянцев А.Г. Перспективы развития клинической иммунологии //Вопросы гематологии/онкологии иммунопатологии в педиатрии. 2020. Т. 19, № S4. С. 14-17)
Shcherbina AYu. Immunodeficiency states in real clinical practice (Lecture). Russian (Щербина А.Ю. Иммунодефицитные состояния в реальной клинической практике (Лекция).) https://www.youtube.com/watch?v=8Zw4zwGE07I)
Schaad UB. OM-85 BV, an immunostimulant in pediatric recurrent respiratory tract infections: a systematic review. World J Pediatr. 2010; 6(1): 5-12. DOI: 10.1007/s12519- 010-0001-x
Acute respiratory viral infection in children (ARVI): clinical guidelines. M., 2018. 33 p. Russian (Острая респираторная вирусная инфекция у детей (ОРВИ): клинические рекомендации. М., 2018. 33 с.)
A.A. Baranov (red.). Rukovodstvo po ambulatorno-klinicheskoy pediatrii. M. Geotar-Media. 2-ye izd. 2009. Russian (А.А. Баранов (ред.). Руководство по амбулаторно-клинической педиатрии. М. Гэотар-Медиа. 2-еизд. 2009) (in Russian)
Danzi GB, Loffi M, Galeazzi G, Gherbesi E. A cute pulmonary embolism and COVID-19 pneumonia: a random association. Eur Heart J. 2020; 41: 1858
Tolstova EM, Zaitseva OV. Thymus physiology and pathology in childhood. Pediatria n.a. G.N. Speransky. 2018; 97(6): 166-172. Russian (Толстова Е.М., Зайцева О.В. Физиология и патология тимуса в детском возрасте //Педиатрия им. Г.Н. Сперанского. 2018. Т. 97, № 6. С. 166-172)
Liu Yu, Pan Yu, Hu Z, Wu M, Wang C, Feng Z, et al. Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells. Clin Infect Dis. 2020; 71(16): 2150-2157. DOI: 10.1093/cid/ciaa630
Khavinson VK, Kuznik BI, Trofimova SV, Volchkov VA, Rukavishnikova SA, Titova ON, et al. Results and Prospects of Using Activator of Hematopoietic Stem Cell Differentiation in Complex Therapy for Patients with COVID-19. Stem Cell Rev Rep. 2021; 17: 285-290 (). DOI: 10.1007/s12015-020-10087-6
Liu X, Liu Y, Wang L, Hu L, Liu D, Li J. Analysis of the prophylactic effect of thymosin drugs on COVID-19 for 435 medical staff: A hospital-based retrospective study. J Med Virol. 2021; 93(3): 1573-1580. DOI: 10.1002/jmv.26492
Wang W, Thomas R, Oh J, Su DM. Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly. Cells. 2021; 10(3): 628. DOI: 10.3390/cells10030628
Matteucci C, Grelli S, Balestrieri E, et al. Thymosin alpha 1 and HIV-1: recent advances and future perspectives. Future Microbiol. 2017; 12(2): 141-155
Henson SM, Snelgrove R, Hussell T, Wells DJ, Aspinall R. An IL-7 Fusion Protein That Shows Increased Thymopoietic Ability. J Immunol. 2005; 175: 4112-4118
Laterre PF, François B, Collienne C, Hantson P, Jeannet R, Remy KE, Hotchkiss RS. Association of Interleukin 7 Immunotherapy with Lymphocyte Counts Among Patients with Severe Coronavirus Disease 2019 (COVID-19). JAMA Netw Open. 2020; 3: e2016485
Monneret G, De Marignan D, Coudereau R, Bernet C, Ader F, Frobert E, et al. Immune monitoring of interleukin-7 compassionate use in a critically ill COVID-19 patient. Cell Mol Immunol. 2020; 17: 1001-1003
Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C. Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway. Aging Cell. 2010; 9: 785-798
Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, et al. mTOR regulates memory CD8 T-cell differentiation. Nat Cell Biol. 2009; 460: 108-112
Mannick JB, Morris M, Hockey H-UP, Roma G, Beibel M, Kulmatycki K, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018; 10: eaaq1564
Kennedy RB, Ovsyannikova IG, Haralambieva IH, Oberg AL, Zimmermann MT, Grill DE, Poland GA. Immunosenescence-Related Transcriptomic and Immunologic Changes in Older Individuals Following Influenza Vaccination. Front Immunol. 2016; 7: 450
Maciolek J, Pasternak JA, Wilson HL. Metabolism of activated T lymphocytes. Curr Opin Immunol. 2014; 27: 60-74
Elahi A, Sabui S, Narasappa NN, Agrawal S, Lambrecht NW, Agrawal A, Said HM. Biotin Deficiency Induces Th1- and Th17-Mediated Proinflammatory Responses in Human CD4+ T Lymphocytes via Activation of the mTOR Signaling Pathway. J Immunol. 2018; 200: 2563-2570
Zhang F, Liu G, Li D, Wei C, Hao J. DDIT4 and Associated lncDDIT4 Modulate Th17 Differentiation through the DDIT4/TSC/mTOR Pathway. J Immunol. 2018; 200: 1618-1626
Tang L, Yin Z, Hu Y, Mei H. Controlling Cytokine Storm Is Vital in COVID-19. Front Immunol. 2020; 11: 570993
Kempuraj D, Selvakumar GP, Ahmed ME, Raikwar SP, Thangavel R, Khan A, et al. COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist. 2020; 26: 402-414
Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. High TNF-α levels in resting B cells negatively correlate with their response. Exp Gerontol. 2014; 54: 116-122
Khan SI, Shihata WA, Andrews KL, Lee MKS, Moore X-L, Jefferis A-M, et al. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat. FASEB J. 2018; 33: 1510-1521
Alexia C, Cren M, Louis-Plence P, et al. Polyoxidonium® activates cytotoxic lymphocyte responses through dendritic cell maturation: Clinical effects in breast cancer. Front Immunol. 2019; 10: 2693. DOI: 10.3389/fimmu.2019. 02693
Talayev VYu, Matveichev AV, Zaichenko IYe, et al. Vaktsinnyy ad"yuvant Polioksidoniy® usilivayet immunnyy otvet na nizkuyu dozu antigenov grippa. Nauchnoye obespecheniye protivoepidemicheskoy zashchity naseleniya: aktual'nyye problem i resheniya: collection of scientific papers. N. Novgorod: Remedium Privolzh'ye, 2019. P. 363-365. Russian (Талаев В.Ю., Матвеичев А.В., Заиченко И.Е. и др. Вакцинный адъювант Полиоксидоний® усиливает иммунный ответ на низкую дозу антигенов гриппа //Научное обеспечение противоэпидемической защиты населения: актуальные проблемы и решения: сб. науч. трудов. Н. Новгород: Ремедиум Приволжье, 2019. С. 363-365)
Kostinov MP, Markelova EV, Svitich OA, Polishchuk VB. Immune mechanisms of SARS-COV-2 and potential drugs in the prevention and treatment of COVID-19. Pulmonologiya. 2020; 5: 700-708. Russian (Костинов М.П., Маркелова Е.В., Свитич О.А., Полищук В.Б. Иммунные механизмы SARS-CoV-2 и потенциальные препараты для профилактики и лечения COVID-19 //Пульмонология. 2020. № 5. С. 700-708)
Shin KK, Yi Y-S, Kim JK, Kim H, Hossain MA, Kim J-H, Cho JY. Korean red ginseng plays an anti-aging role by modulating expression of aging-related genes and immune cell subsets. Molecules. 2020; 25(7): 1492. DOI: 10.3390/molecules25071492
Pouzolles M, Machado A, Guilbaud M, Irla M, Gailhac S, Barennes P, Zimmermann VS. Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells. Allergy Clin Immunol. 2020; 145(2): 679-697.e5. DOI: 10.1016/j.jaci.2019.08.029
Shichkin VP, Antica M. Thymus Regeneration and Future Challenges. Stem Cell Revand Rep. 2020; 16(2): 239-250. DOI: 10.1007/s12015-020-09955-y
Zeng Y, Liu C, Gong Y, Bai Z, Hou S, He J, et al. Single-Cell RNA Sequencing Resolves Spatiotemporal Development of Pre-thymic Lymphoid Progenitors and Thymus Organogenesis in Human Embryos. Immunity. 2019; 51(5): 930-948. DOI: 10.1016/j.immuni.2019.09.008
Abusarah J, Khodayarian F, Cui Y, El-Kadiry AE-H, Rafei M. Thymic Rejuvenation: Are We There Yet? From the ed. volume Gerontology /Ed. by D’Onofrio G, Greco A, Sancarlo D. 2018. DOI: 10.5772/intechopen.74048
Hora J. Češivy robili prvníumělý brzlík, pacient ůmpo operacimů žeposílitimunitu. iDNES. 2018, 3 května
Cowan JE, Takahama Y, Bhandoola A, Ohigashi I. Postnatal Involution and Counter-Involution of the Thymus. Front Immunol. 2020; 11: 897. DOI: 10.3389/fimmu.2020.00897
Sikandar А. Shahzaib and Naeem Ullah. Microarchitecture of the Thymus Gland; Its Age and Disease-Associated Morphological Alterations, and Possible Means to Prolong Its Physiological Activity. January 2020. DOI: 10.5772/intechopen.88480
Ansari AR, Liu H. Acute Thymic Involution and Mechanisms for Recovery. Arch Immunol Ther Exp. 2017; 65(5): 401-420. DOI: 10.1007/s00005-017-0462-x