Induction of Osmolyte Pathways in Skeletal Muscle Inflammation: Novel Biomarkers for Myositis

We recently identified osmolyte accumulators as novel biomarkers for chronic skeletal muscle inflammation and weakness, but their precise involvement in inflammatory myopathies remains elusive. In the current study, we demonstrate in vitro that, in myoblasts and myotubes exposed to pro-inflammatory cytokines or increased salt concentration, mRNA levels of the osmolyte carriers SLC5A3, SLC6A6, SLC6A12, and AKR1B1 enzyme can be upregulated. Induction of SLC6A12 and AKR1B1 was confirmed at the protein level using immunofluorescence and Western blotting. Gene silencing by specific siRNAs revealed that these factors were vital for muscle cells under hyperosmotic conditions. Pro-inflammatory cytokines activated mitogen-activated protein kinases, nuclear factor κB as well as nuclear factor of activated T-cells 5 mRNA expression. In muscle biopsies from patients with polymyositis or sporadic inclusion body myositis, osmolyte pathway activation was observed in regenerating muscle fibers. In addition, the osmolyte carriers SLC5A3 and SLC6A12 localized to subsets of immune cells, most notably to the endomysial macrophages and T-cells. Collectively, this study unveiled that muscle cells respond to osmotic and inflammatory stress by osmolyte pathway activation, likely orchestrating general protection of the tissue. Moreover, pro-inflammatory properties are attributed to SLC5A3 and SLC6A12 in auto-aggressive macrophages and T-cells in inflamed skeletal muscle

Timektomija kod bolesnika oboljelih od miastenije gravis

Svrha ovog preglednog rada je prikaz timektomije kao oblika liječenja u osoba oboljelih od miastenije gravis. Miastenija gravis je kronična, autoimuna, neuromuskularna bolest karakterizirana slabošću i zamaranjem skeletnih , poprečnoprugastih, mišića. U 80% oboljelih od miastenije gravis nalazi se abnormalnost timusa od čega 10-20% ima timom, a preostali dio hiperplaziju timusa. Timus je parenhimatozni organ sivocrvenkaste boje smješten u prednjem gornjem dijelu medijastinuma, iza prsne kosti. To je središnji organ limfatičnog sustava čija je glavna uloga prethodna obrada limfocita T. Poremećaji u obradi limfocita T imaju ulogu u patogenezi miastenije gravis. Liječenje miastenije gravis je simptomatsko, a cilj liječenja je potpuni nestanak simptoma. Timektomija, uz farmakološko liječenje, predstavlja oblik terapije za oboljele od miastenije gravis. Timektomijom se želi postići značajno poboljšanje simptoma kod bolesnika, prvenstveno smanjiti slabost mišića, zatim u najvećoj mogućoj mjeri reducirati farmakološku terapiju te u idealnom slučaju postići potpunu remisiju bolesti. Više različitih čimbenika, kao što su dob i spol bolesnika, težina simptoma, prisutnost timoma, prisutnost protutijela na AChR ili MuSK receptore, oblik bolesti, pa čak i trudnoća utječu na odluku o tome da li će osoba biti podvrgnuta timektomiji ili ne.Razlikujemo nekoliko glavnih kirurških pristupa: transcervikalnu, transsternalnu i VATS timektomiju. Nije potvrđeno da VATS timektomija ima veću učinkovitost u remisiji bolesti od transsternalne timektomije, ali minimalno invazivni postupci imaju niže stope morbiditeta i mortaliteta, manji broj komplikacija te je kraće vrijeme oporavka bolesnika.The purpose of this thesis is to present timectomy as a form of treatment in people suffering from myasthenia gravis. Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by weakness and fatigue of skeletal muscles. In 80% of patients with myasthenia gravis there is an abnormality of thymus, of which 10-20% has a thymoma, and the rest of them the thymus hyperplasia. Timus is a parenchymal organ of reddish-brown color placed in the front upper part of the mediastinum behind the chest bone. It is the central organ of the lymphatic system whose main role is the prior processing of lymphocytes T. Thymus plays a role in the pathogenesis of myasthenia gravis. The treatment of myasthenia gravis is symptomatic, and the goal of treatment is complete disappearance of symptoms. Timectomy, along with pharmacological treatment, is a form of therapy for people suffering from myasthenia gravis. Timectomy seeks to significantly improve clinical symptoms of the patient, primarily to reduce the muscle weakness, then to reduce the pharmacological therapy and ideally achieve complete remission of the disease. Multiple factors, such as age and sex, symptom weight, thymoma presence, presence of antibodies to AChR or MuSK receptors, the form of the disease, and even the pregnancy, influence the decision whether or not the subject will be operated. Major surgical approaches are: transcervical, transcernal, and VATS timectomy. It has not been shown that VATS timectomy has greater efficacy in remission of myasthenia gravis, but minimal invasive procedures have lower rates of morbidity and mortality, fewer complications, and shorter recovery time of the patient

Timektomija kod bolesnika oboljelih od miastenije gravis

Svrha ovog preglednog rada je prikaz timektomije kao oblika liječenja u osoba oboljelih od miastenije gravis. Miastenija gravis je kronična, autoimuna, neuromuskularna bolest karakterizirana slabošću i zamaranjem skeletnih , poprečnoprugastih, mišića. U 80% oboljelih od miastenije gravis nalazi se abnormalnost timusa od čega 10-20% ima timom, a preostali dio hiperplaziju timusa. Timus je parenhimatozni organ sivocrvenkaste boje smješten u prednjem gornjem dijelu medijastinuma, iza prsne kosti. To je središnji organ limfatičnog sustava čija je glavna uloga prethodna obrada limfocita T. Poremećaji u obradi limfocita T imaju ulogu u patogenezi miastenije gravis. Liječenje miastenije gravis je simptomatsko, a cilj liječenja je potpuni nestanak simptoma. Timektomija, uz farmakološko liječenje, predstavlja oblik terapije za oboljele od miastenije gravis. Timektomijom se želi postići značajno poboljšanje simptoma kod bolesnika, prvenstveno smanjiti slabost mišića, zatim u najvećoj mogućoj mjeri reducirati farmakološku terapiju te u idealnom slučaju postići potpunu remisiju bolesti. Više različitih čimbenika, kao što su dob i spol bolesnika, težina simptoma, prisutnost timoma, prisutnost protutijela na AChR ili MuSK receptore, oblik bolesti, pa čak i trudnoća utječu na odluku o tome da li će osoba biti podvrgnuta timektomiji ili ne.Razlikujemo nekoliko glavnih kirurških pristupa: transcervikalnu, transsternalnu i VATS timektomiju. Nije potvrđeno da VATS timektomija ima veću učinkovitost u remisiji bolesti od transsternalne timektomije, ali minimalno invazivni postupci imaju niže stope morbiditeta i mortaliteta, manji broj komplikacija te je kraće vrijeme oporavka bolesnika.The purpose of this thesis is to present timectomy as a form of treatment in people suffering from myasthenia gravis. Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by weakness and fatigue of skeletal muscles. In 80% of patients with myasthenia gravis there is an abnormality of thymus, of which 10-20% has a thymoma, and the rest of them the thymus hyperplasia. Timus is a parenchymal organ of reddish-brown color placed in the front upper part of the mediastinum behind the chest bone. It is the central organ of the lymphatic system whose main role is the prior processing of lymphocytes T. Thymus plays a role in the pathogenesis of myasthenia gravis. The treatment of myasthenia gravis is symptomatic, and the goal of treatment is complete disappearance of symptoms. Timectomy, along with pharmacological treatment, is a form of therapy for people suffering from myasthenia gravis. Timectomy seeks to significantly improve clinical symptoms of the patient, primarily to reduce the muscle weakness, then to reduce the pharmacological therapy and ideally achieve complete remission of the disease. Multiple factors, such as age and sex, symptom weight, thymoma presence, presence of antibodies to AChR or MuSK receptors, the form of the disease, and even the pregnancy, influence the decision whether or not the subject will be operated. Major surgical approaches are: transcervical, transcernal, and VATS timectomy. It has not been shown that VATS timectomy has greater efficacy in remission of myasthenia gravis, but minimal invasive procedures have lower rates of morbidity and mortality, fewer complications, and shorter recovery time of the patient

Timektomija kod bolesnika oboljelih od miastenije gravis

Svrha ovog preglednog rada je prikaz timektomije kao oblika liječenja u osoba oboljelih od miastenije gravis. Miastenija gravis je kronična, autoimuna, neuromuskularna bolest karakterizirana slabošću i zamaranjem skeletnih , poprečnoprugastih, mišića. U 80% oboljelih od miastenije gravis nalazi se abnormalnost timusa od čega 10-20% ima timom, a preostali dio hiperplaziju timusa. Timus je parenhimatozni organ sivocrvenkaste boje smješten u prednjem gornjem dijelu medijastinuma, iza prsne kosti. To je središnji organ limfatičnog sustava čija je glavna uloga prethodna obrada limfocita T. Poremećaji u obradi limfocita T imaju ulogu u patogenezi miastenije gravis. Liječenje miastenije gravis je simptomatsko, a cilj liječenja je potpuni nestanak simptoma. Timektomija, uz farmakološko liječenje, predstavlja oblik terapije za oboljele od miastenije gravis. Timektomijom se želi postići značajno poboljšanje simptoma kod bolesnika, prvenstveno smanjiti slabost mišića, zatim u najvećoj mogućoj mjeri reducirati farmakološku terapiju te u idealnom slučaju postići potpunu remisiju bolesti. Više različitih čimbenika, kao što su dob i spol bolesnika, težina simptoma, prisutnost timoma, prisutnost protutijela na AChR ili MuSK receptore, oblik bolesti, pa čak i trudnoća utječu na odluku o tome da li će osoba biti podvrgnuta timektomiji ili ne.Razlikujemo nekoliko glavnih kirurških pristupa: transcervikalnu, transsternalnu i VATS timektomiju. Nije potvrđeno da VATS timektomija ima veću učinkovitost u remisiji bolesti od transsternalne timektomije, ali minimalno invazivni postupci imaju niže stope morbiditeta i mortaliteta, manji broj komplikacija te je kraće vrijeme oporavka bolesnika.The purpose of this thesis is to present timectomy as a form of treatment in people suffering from myasthenia gravis. Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by weakness and fatigue of skeletal muscles. In 80% of patients with myasthenia gravis there is an abnormality of thymus, of which 10-20% has a thymoma, and the rest of them the thymus hyperplasia. Timus is a parenchymal organ of reddish-brown color placed in the front upper part of the mediastinum behind the chest bone. It is the central organ of the lymphatic system whose main role is the prior processing of lymphocytes T. Thymus plays a role in the pathogenesis of myasthenia gravis. The treatment of myasthenia gravis is symptomatic, and the goal of treatment is complete disappearance of symptoms. Timectomy, along with pharmacological treatment, is a form of therapy for people suffering from myasthenia gravis. Timectomy seeks to significantly improve clinical symptoms of the patient, primarily to reduce the muscle weakness, then to reduce the pharmacological therapy and ideally achieve complete remission of the disease. Multiple factors, such as age and sex, symptom weight, thymoma presence, presence of antibodies to AChR or MuSK receptors, the form of the disease, and even the pregnancy, influence the decision whether or not the subject will be operated. Major surgical approaches are: transcervical, transcernal, and VATS timectomy. It has not been shown that VATS timectomy has greater efficacy in remission of myasthenia gravis, but minimal invasive procedures have lower rates of morbidity and mortality, fewer complications, and shorter recovery time of the patient