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Sample records for acute thymic atrophy

  1. Acute Endotoxin-Induced Thymic Atrophy Is Characterized By Intrathymic Inflammatory and Wound Healing Responses

    PubMed Central

    Billard, Matthew J.; Gruver, Amanda L.; Sempowski, Gregory D.

    2011-01-01

    Background Productive thymopoiesis is essential for a robust and healthy immune system. Thymus unfortunately is acutely sensitive to stress resulting in involution and decreased T cell production. Thymic involution is a complication of many clinical settings, including infection, malnutrition, starvation, and irradiation or immunosuppressive therapies. Systemic rises in glucocorticoids and inflammatory cytokines are known to contribute to thymic atrophy. Little is known, however, about intrathymic mechanisms that may actively contribute to thymus atrophy or initiate thymic recovery following stress events. Methodology/Principal Findings Phenotypic, histologic and transcriptome/pathway analysis of murine thymic tissue during the early stages of endotoxemia-induced thymic involution was performed to identify putative mechanisms that drive thymic involution during stress. Thymus atrophy in this murine model was confirmed by down-regulation of genes involved in T cell development, cell activation, and cell cycle progression, correlating with observed phenotypic and histologic thymus involution. Significant gene changes support the hypothesis that multiple key intrathymic pathways are differentially activated during stress-induced thymic involution. These included direct activation of thymus tissue by LPS through TLR signaling, local expression of inflammatory cytokines, inhibition of T cell signaling, and induction of wound healing/tissue remodeling. Conclusions/Significance Taken together, these observations demonstrated that in addition to the classic systemic response, a direct intrathymic response to endotoxin challenge concurrently contributes to thymic involution during endotoxemia. These findings are a substantial advancement over current understanding of thymus response to stress and may lead to the development of novel therapeutic approaches to ameliorate immune deficiency associated with stress events. PMID:21437240

  2. Differential Expression of microRNAs in Thymic Epithelial Cells from Trypanosoma cruzi Acutely Infected Mice: Putative Role in Thymic Atrophy

    PubMed Central

    Linhares-Lacerda, Leandra; Palu, Cintia Cristina; Ribeiro-Alves, Marcelo; Paredes, Bruno Diaz; Morrot, Alexandre; Garcia-Silva, Maria Rosa; Cayota, Alfonso; Savino, Wilson

    2015-01-01

    A common feature seen in acute infections is a severe atrophy of the thymus. This occurs in the murine model of acute Chagas disease. Moreover, in thymuses from Trypanosoma cruzi acutely infected mice, thymocytes exhibit an increase in the density of fibronectin and laminin integrin-type receptors, with an increase in migratory response ex vivo. Thymic epithelial cells (TEC) play a major role in the intrathymic T cell differentiation. To date, the consequences of molecular changes promoted by parasite infection upon thymus have not been elucidated. Considering the importance of microRNA for gene expression regulation, 85 microRNAs (mRNAs) were analyzed in TEC from T. cruzi acutely infected mice. The infection significantly modulated 29 miRNAs and modulation of 9 was also dependent whether TEC sorted out from the thymus exhibited cortical or medullary phenotype. In silico analysis revealed that these miRNAs may control target mRNAs known to be responsible for chemotaxis, cell adhesion, and cell death. Considering that we sorted TEC in the initial phase of thymocyte loss, it is conceivable that changes in TEC miRNA expression profile are functionally related to thymic atrophy, providing new clues to better understanding the mechanisms of the thymic involution seen in experimental Chagas disease. PMID:26347748

  3. Thymic function is maintained during Salmonella-induced atrophy and recovery

    PubMed Central

    Ross, Ewan A.; Coughlan, Ruth E.; Flores-Langarica, Adriana; Lax, Sian; Nicholson, Julia; Desanti, Guillaume E.; Marshall, Jennifer L.; Bobat, Saeeda; Hitchcock, Jessica; White, Andrea; Jenkinson, William E.; Khan, Mahmood; Henderson, Ian R.; Lavery, Gareth G.; Buckley, Christopher D.; Anderson, Graham; Cunningham, Adam F.

    2014-01-01

    Thymic atrophy is a frequent consequence of infection with bacteria, viruses and parasites and is considered a common virulence trait between pathogens. Multiple reasons have been proposed to explain this atrophy, including premature egress of immature thymocytes, increased apoptosis or thymic shutdown to prevent tolerance to the pathogen from developing. The severe loss in thymic cell number can reflect an equally dramatic reduction in thymic output, potentially reducing peripheral T cell numbers. Here we examine the relationship between systemic Salmonella infection and thymic function. During infection, naive T cell numbers in peripheral lymphoid organs increase. Nevertheless, this occurs despite a pronounced thymic atrophy caused by viable bacteria, with a peak 50-fold reduction in thymocyte numbers. Thymic atrophy is not dependent upon homeostatic feedback from peripheral T cells or on regulation of endogenous glucocorticoids, as demonstrated by infection of genetically-altered mice. Once bacterial numbers fall, thymocyte numbers recover and this is associated with increases in the proportion and proliferation of early thymic progenitors. During atrophy, thymic T cell maturation is maintained and sjTREC analysis reveals there is only a modest fall in recent CD4+ thymic emigrants in secondary lymphoid tissues. Thus thymic atrophy does not necessarily result in a matching dysfunctional T cell output and thymic homeostasis can constantly adjust to systemic infection to ensure that naive T cell output is maintained. PMID:22993205

  4. Chagasic Thymic Atrophy Does Not Affect Negative Selection but Results in the Export of Activated CD4+CD8+ T Cells in Severe Forms of Human Disease

    PubMed Central

    Morrot, Alexandre; Terra-Granado, Eugênia; Pérez, Ana Rosa; Silva-Barbosa, Suse Dayse; Milićević, Novica M.; Farias-de-Oliveira, Désio Aurélio; Berbert, Luiz Ricardo; De Meis, Juliana; Takiya, Christina Maeda; Beloscar, Juan; Wang, Xiaoping; Kont, Vivian; Peterson, Pärt; Bottasso, Oscar; Savino, Wilson

    2011-01-01

    Extrathymic CD4+CD8+ double-positive (DP) T cells are increased in some pathophysiological conditions, including infectious diseases. In the murine model of Chagas disease, it has been shown that the protozoan parasite Trypanosoma cruzi is able to target the thymus and induce alterations of the thymic microenvironment and the lymphoid compartment. In the acute phase, this results in a severe atrophy of the organ and early release of DP cells into the periphery. To date, the effect of the changes promoted by the parasite infection on thymic central tolerance has remained elusive. Herein we show that the intrathymic key elements that are necessary to promote the negative selection of thymocytes undergoing maturation during the thymopoiesis remains functional during the acute chagasic thymic atrophy. Intrathymic expression of the autoimmune regulator factor (Aire) and tissue-restricted antigen (TRA) genes is normal. In addition, the expression of the proapoptotic Bim protein in thymocytes was not changed, revealing that the parasite infection-induced thymus atrophy has no effect on these marker genes necessary to promote clonal deletion of T cells. In a chicken egg ovalbumin (OVA)-specific T-cell receptor (TCR) transgenic system, the administration of OVA peptide into infected mice with thymic atrophy promoted OVA-specific thymocyte apoptosis, further indicating normal negative selection process during the infection. Yet, although the intrathymic checkpoints necessary for thymic negative selection are present in the acute phase of Chagas disease, we found that the DP cells released into the periphery acquire an activated phenotype similar to what is described for activated effector or memory single-positive T cells. Most interestingly, we also demonstrate that increased percentages of peripheral blood subset of DP cells exhibiting an activated HLA-DR+ phenotype are associated with severe cardiac forms of human chronic Chagas disease. These cells may contribute to the

  5. Asymptomatic cerebellar atrophy after acute enteroviral encephalitis.

    PubMed

    Vitaszil, Edina; Kamondi, Anita; Csillik, Anita; Velkey, Imre; Szirmai, Imre

    2005-07-01

    We report on a 13-year-old male who had acute enteroviral encephalitis causing cerebellar symptoms at the age of 10 years. Magnetic resonance imaging (MRI) showed no abnormalities. Clinically he appeared to be recovered completely after 6 months. Twenty-three months after the recovery, MRI was performed because he presented with slight lower-limb and truncal ataxia experienced as lack of foot coordination while playing football or riding a bicycle. MRI demonstrated severe cerebellar atrophy. Clinically he recovered completely in 10 days. Only sophisticated electrophysiological methods revealed cerebellar dysfunction. The case provides evidence for the plasticity of cerebellar regulatory structures involved in the coordination of fine movements. It seems that in childhood the slow, isolated disintegration of cerebellar systems can be compensated for by upper thalamic or telencephalic connections, in a similar way to a congenital deficit of the cerebellum. PMID:15991870

  6. Pretransplant thymic function predicts acute rejection in antithymocyte globulin-treated renal transplant recipients.

    PubMed

    Bamoulid, Jamal; Courivaud, Cécile; Crepin, Thomas; Carron, Clémence; Gaiffe, Emilie; Roubiou, Caroline; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Ducloux, Didier

    2016-05-01

    Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients. PMID:27083287

  7. Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis.

    PubMed

    Solti, Izabella; Kvell, Krisztian; Talaber, Gergely; Veto, Sara; Acs, Peter; Gallyas, Ferenc; Illes, Zsolt; Fekete, Katalin; Zalan, Petra; Szanto, Arpad; Bognar, Zita

    2015-01-01

    Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first time, how cuprizone feeding affects the thymus, the organ of T-cell maturation and selection. We found that even one week of cuprizone treatment induced significant thymic atrophy, affecting the cortex over the medulla. Fluorescent microscopy and flow-cytometric analyses of thymi from cuprizone- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged mitochondria, myelin-bodies, large lipid droplets, and large lysosomes in the thymi of cuprizone-treated mice. Some of these features were similar to those in physiological and steroid-induced accelerated aging. According to our results, apoptosis was mainly of mitochondrial origin mediated by both caspase-3- and apoptosis inducing factor-mediated mechanisms. Additionally, mitogen activated protein kinase activation and increased pro-apoptotic B cell lymphoma-2 family protein expression were the major underlying processes. Our results do not indicate a functional relationship between cuprizone-induced thymus involution and the absence of inflammatory responses or the selective demyelination observed in the cuprizone model. On the other hand, due to the reversible nature of cuprizone's deleterious effects, the cuprizone model could be valuable in studying thymus regeneration as well as remyelination processes. PMID:26053248

  8. Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model

    PubMed Central

    Luan, Tammy; Liu, Xuhui; Easley, Jeremiah T.; Ravishankar, Bharat; Puttlitz, Christian; Feeley, Brian T.

    2015-01-01

    Summary Introduction rotator cuff tears (RCTs) are the most common tendon injury seen in orthopedic patients. Muscle atrophy and fatty infiltration of the muscle are crucial factors that dictate the outcome following rotator cuff surgery. Though less studied in humans, rotator cuff muscle fibrosis has been seen in animal models as well and may influence outcomes as well. The purpose of this study was to determine if the rotator cuff would develop muscle changes even in the setting of an acute repair in a sheep model. We hypothesized that fatty infiltration and fibrosis would be present even after an acute repair six months after initial surgery. Methods twelve female adult sheep underwent an acute rotator cuff tear and immediate repair on the right shoulder. The left shoulder served as a control and did not undergo a tear or a repair. Six months following acute rotator cuff repairs, sheep muscles were harvested to study atrophy, fatty infiltration, and fibrosis by histological analysis, western blotting, and reverse transcription polymerase chain reaction (RT-PCR). Results the repair group demonstrated an increase expression of muscle atrophy, fatty infiltration, and fibrosis related genes. Significantly increased adipocytes, muscle fatty infiltration, and collagen deposition was observed in rotator cuff muscles in the tendon repair group compared to the control group. Conclusions rotator cuff muscle undergoes degradation changes including fatty infiltration and fibrosis even after the tendons are repair immediately after rupture. Level of Evidence Basic Science Study. PMID:26261789

  9. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

    PubMed Central

    Bond, Jonathan; Marchand, Tony; Touzart, Aurore; Cieslak, Agata; Trinquand, Amélie; Sutton, Laurent; Radford-Weiss, Isabelle; Lhermitte, Ludovic; Spicuglia, Salvatore; Dombret, Hervé; Macintyre, Elizabeth; Ifrah, Norbert; Hamel, Jean-François; Asnafi, Vahid

    2016-01-01

    Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently

  10. Recurrent acute-onset Cushing's syndrome 6 years after removal of a thymic neuroendocrine carcinoma: from ectopic ACTH to CRH.

    PubMed

    Schalin-Jäntti, Camilla; Asa, Sylvia L; Arola, Johanna; Sane, Timo

    2013-03-01

    We describe a rare case of ectopic Cushing's syndrome that recurred 6 years after resection of a thymic neuroendocrine carcinoma. We discuss reasons for the differing clinical presentations, management, hormone profiles, as well as immunopathology. A 41-year-old male developed acute-onset Cushing's syndrome. Clinical presentation and laboratory results were compatible with ectopic adrenocorticotropin hormone (ACTH) production. Computerized tomography (CT) showed a 3.6 cm thymic tumor which was successfully resected. Plasma ACTH (P-ACTH) normalized the first postoperative day. Histopathology demonstrated a well-differentiated neuroendocrine carcinoma with diffuse positivity for ACTH and focal corticotropin-releasing hormone (CRH) reactivity in a few scattered cells. The patient was in remission for 6 years. He then again presented with acute-onset Cushing's syndrome. Fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) PET/CT showed local uptake in the mediastinum and he underwent repeat resection. However, P-ACTH remained increased (613 ng/l) and 24-h urinary cortisol was 36,720 nmol, suggesting incomplete tumor removal or metastatic spread. Metyrapone treatment was initiated but then withdrawn because the patient spontaneously recovered and cortisol metabolism gradually normalized within 3 weeks. Histopathology demonstrated a recurrent neuroendocrine carcinoma with the same features as the previous lesion but this time CRH was strongly positive in more numerous cells. Normalization of P-ACTH after primary surgery was compatible with ectopic ACTH production. However, the delayed fall in P-ACTH and serum cortisol is compatible with ectopic CRH production and stimulation of pituitary ACTH secretion, which gradually resolved. Although ectopic CRH production is very rare, the unusual dynamics illustrated here should raise the possibility of CRH production by a neuroendocrine tumor. PMID:23233312

  11. [Thymic carcinomas].

    PubMed

    Ströbel, P; Weis, C-A; Marx, A

    2016-09-01

    Thymic carcinomas (TC) are approximately 10 times less prevalent than thymomas but of high clinical relevance because they are more aggressive, less frequently resectable than thymomas and usually refractory to classical and targeted long-term treatment approaches. Furthermore, in children and adolescents TC are more frequent than thymomas and particularly in this age group, germ cell tumors need to be a differential diagnostic consideration. In diagnostic terms pathologists face two challenges: a), the distinction between thymic carcinomas and thymomas with a similar appearance and b), the distinction between TC and histologically similar metastases and tumor extensions from other primary tumors. Overcoming these diagnostic challenges is the focus of the new WHO classification of thymic epithelial tumors. The objectives of this review are to highlight novel aspects of the WHO classification of thymic carcinomas and to address therapeutically relevant diagnostic pitfalls. PMID:27538748

  12. mTORC1 in Thymic Epithelial Cells Is Critical for Thymopoiesis, T-Cell Generation, and Temporal Control of γδT17 Development and TCRγ/δ Recombination.

    PubMed

    Wang, Hong-Xia; Shin, Jinwook; Wang, Shang; Gorentla, Balachandra; Lin, Xingguang; Gao, Jimin; Qiu, Yu-Rong; Zhong, Xiao-Ping

    2016-02-01

    Thymus is crucial for generation of a diverse repertoire of T cells essential for adaptive immunity. Although thymic epithelial cells (TECs) are crucial for thymopoiesis and T cell generation, how TEC development and function are controlled is poorly understood. We report here that mTOR complex 1 (mTORC1) in TECs plays critical roles in thymopoiesis and thymus function. Acute deletion of mTORC1 in adult mice caused severe thymic involution. TEC-specific deficiency of mTORC1 (mTORC1KO) impaired TEC maturation and function such as decreased expression of thymotropic chemokines, decreased medullary TEC to cortical TEC ratios, and altered thymic architecture, leading to severe thymic atrophy, reduced recruitment of early thymic progenitors, and impaired development of virtually all T-cell lineages. Strikingly, temporal control of IL-17-producing γδT (γδT17) cell differentiation and TCRVγ/δ recombination in fetal thymus is lost in mTORC1KO thymus, leading to elevated γδT17 differentiation and rearranging of fetal specific TCRVγ/δ in adulthood. Thus, mTORC1 is central for TEC development/function and establishment of thymic environment for proper T cell development, and modulating mTORC1 activity can be a strategy for preventing thymic involution/atrophy. PMID:26889835

  13. mTORC1 in Thymic Epithelial Cells Is Critical for Thymopoiesis, T-Cell Generation, and Temporal Control of γδT17 Development and TCRγ/δ Recombination

    PubMed Central

    Wang, Hong-Xia; Shin, Jinwook; Wang, Shang; Gorentla, Balachandra; Lin, Xingguang; Gao, Jimin; Qiu, Yu-Rong; Zhong, Xiao-Ping

    2016-01-01

    Thymus is crucial for generation of a diverse repertoire of T cells essential for adaptive immunity. Although thymic epithelial cells (TECs) are crucial for thymopoiesis and T cell generation, how TEC development and function are controlled is poorly understood. We report here that mTOR complex 1 (mTORC1) in TECs plays critical roles in thymopoiesis and thymus function. Acute deletion of mTORC1 in adult mice caused severe thymic involution. TEC-specific deficiency of mTORC1 (mTORC1KO) impaired TEC maturation and function such as decreased expression of thymotropic chemokines, decreased medullary TEC to cortical TEC ratios, and altered thymic architecture, leading to severe thymic atrophy, reduced recruitment of early thymic progenitors, and impaired development of virtually all T-cell lineages. Strikingly, temporal control of IL-17-producing γδT (γδT17) cell differentiation and TCRVγ/δ recombination in fetal thymus is lost in mTORC1KO thymus, leading to elevated γδT17 differentiation and rearranging of fetal specific TCRVγ/δ in adulthood. Thus, mTORC1 is central for TEC development/function and establishment of thymic environment for proper T cell development, and modulating mTORC1 activity can be a strategy for preventing thymic involution/atrophy. PMID:26889835

  14. Acute oxalate nephropathy due to pancreatic atrophy in newly diagnosed pancreatic carcinoma.

    PubMed

    Moinuddin, Irfan; Bala, Asif; Ali, Butool; Khan, Husna; Bracamonte, Erika; Sussman, Amy

    2016-02-01

    Acute oxalate nephropathy can occur due to primary hyperoxaluria and secondary hyperoxaluria. The primary hyperoxalurias are a group of autosomal recessive disorders of endogenous oxalate overproduction. Secondary hyperoxaluria may occur as a result of excess dietary intake, poisoning with oxalate precursors (ethylene glycol), or enteric hyperoxaluria. The differential diagnosis of enteric hyperoxaluria includes inflammatory bowel disease, short bowel syndrome, bariatric surgery (with jejunoileal bypass or Roux-en-Y gastric bypass), celiac disease, partial colectomy, and chronic pancreatitis. The common etiology in all these processes is fat malabsorption, steatorrhea, saponification of calcium, and absorption of free oxalate. Hyperoxaluria causes increased urinary oxalate excretion, urolithiasis (promoted by hypovolemia, decreased urinary pH caused by metabolic acidosis, and decreased citrate and magnesium concentrations in urine), tubulointerstitial oxalate deposits, and tubulointerstitial nephritis. We report a rare case of acute oxalate nephropathy due to pancreatic atrophy and exocrine insufficiency caused by newly diagnosed pancreatic cancer. PMID:26614399

  15. [Thymic tumors].

    PubMed

    Le Péchoux, C; Mahé, M; Bretel, J-J; Roberti, E; Ruffié, P

    2005-11-01

    Thymomas and thymic carcinomas are rare and slow-growing tumors, which develop within the anterior mediastinum. Thymomas are often associated with autoimmune disorders and most particularly myasthenia gravis. The treatment of choice remains a complete surgical resection. Postoperative radiotherapy is often combined in case of invasive thymoma invading into adjacent organs. Postoperative radiotherapy in stage II with invasion into capsule has been more controversial lately. In inoperable locally advanced, or metastatic thymic tumors, neoadjuvant cisplatin-based followed by surgery and radiotherapy has given interesting results in the past years. PMID:16168694

  16. Addition of a UL5 helicase-primase subunit point mutation eliminates bursal-thymic atrophy of Marek's disease virus ∆Meq recombinant virus but reduces vaccinal protection.

    PubMed

    Hildebrandt, Evin; Dunn, John R; Cheng, Hans H

    2015-01-01

    Marek's disease virus (MDV) is an oncogenic alphaherpesvirus and the causative agent of Marek's disease (MD), characterized by immunosuppression, paralysis, nerve enlargement and induction of T-cell lymphomas in chickens. Despite widespread usage of vaccines since the 1970s to control MD, more virulent field strains of MDV have emerged that overcome vaccinal protection, necessitating the development of new and more protective MD vaccines. The ∆Meq virus, a recombinant Md5 strain MDV lacking the viral oncogene Meq, is one candidate MD vaccine with great potential but unfortunately it also causes bursal-thymic atrophy (BTA) in maternal antibody negative chickens, raising concerns that impede commercial use as a vaccine. Previously, we identified a point mutation within UL5 that reduced in vivo replication in attenuated viruses. We proposed that introduction of the UL5 point mutation into the ∆Meq virus would reduce in vivo replication and eliminate BTA yet potentially retain high protective abilities. In birds, the ∆Meq+UL5 recombinant MDV had reduced replication compared to the original ∆Meq virus, while weights of lymphoid organs indicated that ∆Meq+UL5 did not induce BTA, supporting the hypothesis that reduction of in vivo replication would also abolish BTA. Vaccine trials of the ∆Meq+UL5 virus compared to other ∆Meq-based viruses and commercial vaccines show that, while the ∆Meq+UL5 does provide vaccinal protection, this protection was also reduced compared to the original ∆Meq virus. Therefore, it appears that a very delicate balance is required between levels of replication able to induce high vaccinal protection, yet not so high as to induce BTA. PMID:25968878

  17. The Anti-apoptotic Effect of Ghrelin on Restraint Stress-Induced Thymus Atrophy in Mice.

    PubMed

    Lee, Jun Ho; Kim, Tae-Jin; Kim, Jie Wan; Yoon, Jeong Seon; Kim, Hyuk Soon; Lee, Kyung-Mi

    2016-08-01

    Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host's ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dose-dependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis. PMID:27574503

  18. The Anti-apoptotic Effect of Ghrelin on Restraint Stress-Induced Thymus Atrophy in Mice

    PubMed Central

    Kim, Tae-Jin; Kim, Jie Wan; Yoon, Jeong Seon; Kim, Hyuk Soon

    2016-01-01

    Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host's ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dose-dependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis. PMID:27574503

  19. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy. Disuse atrophy occurs from a lack of physical activity. In most people, muscle atrophy is caused by not using the ...

  20. Muscle atrophy

    MedlinePlus

    Muscle wasting; Wasting; Atrophy of the muscles ... There are two types of muscle atrophy: disuse and neurogenic. Disuse atrophy is caused by not using the muscles enough . This type of atrophy can often be ...

  1. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model.

    PubMed

    Bindels, Laure B; Beck, Raphaël; Schakman, Olivier; Martin, Jennifer C; De Backer, Fabienne; Sohet, Florence M; Dewulf, Evelyne M; Pachikian, Barbara D; Neyrinck, Audrey M; Thissen, Jean-Paul; Verrax, Julien; Calderon, Pedro Buc; Pot, Bruno; Grangette, Corinne; Cani, Patrice D; Scott, Karen P; Delzenne, Nathalie M

    2012-01-01

    The gut microbiota has recently been proposed as a novel component in the regulation of host homeostasis and immunity. We have assessed for the first time the role of the gut microbiota in a mouse model of leukemia (transplantation of BaF3 cells containing ectopic expression of Bcr-Abl), characterized at the final stage by a loss of fat mass, muscle atrophy, anorexia and inflammation. The gut microbial 16S rDNA analysis, using PCR-Denaturating Gradient Gel Electrophoresis and quantitative PCR, reveals a dysbiosis and a selective modulation of Lactobacillus spp. (decrease of L. reuteri and L. johnsonii/gasseri in favor of L. murinus/animalis) in the BaF3 mice compared to the controls. The restoration of Lactobacillus species by oral supplementation with L. reuteri 100-23 and L. gasseri 311476 reduced the expression of atrophy markers (Atrogin-1, MuRF1, LC3, Cathepsin L) in the gastrocnemius and in the tibialis, a phenomenon correlated with a decrease of inflammatory cytokines (interleukin-6, monocyte chemoattractant protein-1, interleukin-4, granulocyte colony-stimulating factor, quantified by multiplex immuno-assay). These positive effects are strain- and/or species-specific since L. acidophilus NCFM supplementation does not impact on muscle atrophy markers and systemic inflammation. Altogether, these results suggest that the gut microbiota could constitute a novel therapeutic target in the management of leukemia-associated inflammation and related disorders in the muscle. PMID:22761662

  2. Interferons Mediate Terminal Differentiation of Human Cortical Thymic Epithelial Cells

    PubMed Central

    Vidalain, Pierre-Olivier; Laine, David; Zaffran, Yona; Azocar, Olga; Servet-Delprat, Christine; Wild, T. Fabian; Rabourdin-Combe, Chantal; Valentin, Hélène

    2002-01-01

    In the thymus, epithelial cells comprise a heterogeneous population required for the generation of functional T lymphocytes, suggesting that thymic epithelium disruption by viruses may compromise T-cell lymphopoiesis in this organ. In a previous report, we demonstrated that in vitro, measles virus induced differentiation of cortical thymic epithelial cells as characterized by (i) cell growth arrest, (ii) morphological and phenotypic changes, and (iii) apoptotis as a final step of this process. In the present report, we have analyzed the mechanisms involved. First, measles virus-induced differentiation of thymic epithelial cells is shown to be strictly dependent on beta interferon (IFN-β) secretion. In addition, transfection with double-stranded RNA, a common intermediate of replication for a broad spectrum of viruses, is reported to similarly mediate thymic epithelial cell differentiation through IFN-β induction. Finally, we demonstrated that recombinant IFN-α, IFN-β, or IFN-γ was sufficient to induce differentiation and apoptosis of uninfected thymic epithelial cells. These observations suggested that interferon secretion by either infected cells or activated leukocytes, such as plasmacytoid dendritic cells or lymphocytes, may induce thymic epithelium disruption in a pathological context. Thus, we have identified a new mechanism that may contribute to thymic atrophy and altered T-cell lymphopoiesis associated with many infections. PMID:12050353

  3. Altered metaplastic response of waved-2 EGF receptor mutant mice to acute oxyntic atrophy.

    PubMed

    Ogawa, Masako; Nomura, Sachiyo; Varro, Andrea; Wang, Timothy C; Goldenring, James R

    2006-04-01

    Metaplastic cell lineages are putative precursors for the development of gastric adenocarcinoma. The loss of parietal cells (oxyntic atrophy) is the initiating step in the evolution of gastric fundic mucosal lineage changes including metaplasia and hyperplasia. However, the intrinsic mucosal factors that promote and modulate the emergence of metaplastic phenotypes remain obscure. Over the past several years, we have studied pharmacologically induced, reversible oxyntic atrophy in rodents treated with DMP-777, a drug that acts as a parietal cell secretory membrane protonophore. DMP-777 elicits a rapid loss of parietal cells followed by the emergence of foveolar hyperplasia and spasmolytic polypeptide (SP)-expressing metaplasia (SPEM). The objective of the present study was to provide further insights into the intrinsic mucosal factors regulating the emergence of SPEM in the setting of oxyntic atrophy. We therefore studied the effects of DMP-777 administration on both SP/trefoil factor (TFF)2-deficient mice, which lack SP/TFF2, a marker of SPEM, and waved-2 mice, which harbor a point mutation in the EGF receptor that attenuates its tyrosine kinase activity. As in wild-type mice, treatment with DMP-777 for 7 days did elicit SPEM in SP/TFF2-deficient mice. These results suggest that SP/TFF2 does not impact on the development of metaplasia after the induction of parietal cell loss. In contrast, waved-2 homozygous mice displayed accelerated SPEM development by 3 days of treatment with DMP-777. These findings indicate that attenuation of EGF receptor signaling in waved-2 mice does elicit a more rapid emergence of SPEM. The results support a role for EGF receptor ligands in the regulation of gastric metaplasia. PMID:16306133

  4. Thymic involution in pregnancy: a universal finding?

    PubMed Central

    Swami, Sunil; Tong, Iris; Bilodeau, Courtney Clark; Bourjeily, Ghada

    2012-01-01

    The thymus is a lymphatic organ that plays a vital role in the development of immunity in childhood. The thymus involutes during periods of stress and may acutely decrease in size but usually recovers to its normal size. The thymus also involutes during pregnancy, a process that is possibly hormonally mediated and thought to be necessary for fetal survival. This report describes two pregnant patients with signs and symptoms suggestive of pulmonary embolism who were incidentally found to have thymic enlargement on computed tomography. Follow-up imaging postpartum in both cases demonstrates a significant reduction in thymus size, suggesting thymic hyperplasia. Both patients delivered healthy babies at term. Thymic involution does not universally occur in pregnancy, challenging the theory of its necessity to fetal survival.

  5. Giant thymic carcinoid.

    PubMed

    John, L C; Hornick, P; Lang, S; Wallis, J; Edmondson, S J

    1991-05-01

    Thymic carcinoid is a rare tumour. It may present with ectopic endocrine secretion or with symptoms of compression as a result of its size. A case is reported which presented with symptoms of compression where the size of the tumour was uniquely large such as to warrant the term giant thymic carcinoid. The typical histological features are described, together with its possible origin and its likely prognosis. PMID:1852667

  6. Cerebral Atrophy

    MedlinePlus

    ... In brain tissue, atrophy describes a loss of neurons and the connections between them. Atrophy can be ... syndrome, which interfere with the basic functions of neurons multiple sclerosis , which causes inflammation, myelin damage, and ...

  7. Transcriptional Profile of Muscle following Acute Induction of Symptoms in a Mouse Model of Kennedy's Disease/Spinobulbar Muscular Atrophy

    PubMed Central

    Halievski, Katherine; Mo, Kaiguo; Westwood, J. Timothy; Monks, Douglas A.

    2015-01-01

    Background Kennedy’s disease/Spinobulbar muscular atrophy (KD/SBMA) is a degenerative neuromuscular disease affecting males. This disease is caused by polyglutamine expansion mutations of the androgen receptor (AR) gene. Although KD/SBMA has been traditionally considered a motor neuron disease, emerging evidence points to a central etiological role of muscle. We previously reported a microarray study of genes differentially expressed in muscle of three genetically unique mouse models of KD/SBMA but were unable to detect those which are androgen-dependent or are associated with onset of symptoms. Methodology/Principal Findings In the current study we examined the time course and androgen-dependence of transcriptional changes in the HSA-AR transgenic (Tg) mouse model, in which females have a severe phenotype after acute testosterone treatment. Using microarray analysis we identified differentially expressed genes at the onset and peak of muscle weakness in testosterone-treated Tg females. We found both transient and persistent groups of differentially expressed genes and analysis of gene function indicated functional groups such as mitochondrion, ion and nucleotide binding, muscle development, and sarcomere maintenance. Conclusions/Significance By comparing the current results with those from the three previously reported models we were able to identify KD/SBMA candidate genes that are androgen dependent, and occur early in the disease process, properties which are promising for targeted therapeutics. PMID:25719894

  8. Repeated dose toxicity and relative potency of 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for induction of CYP1A1, CYP1A2 and thymic atrophy in female Harlan Sprague-Dawley rats

    PubMed Central

    Hooth, Michelle J.; Nyska, Abraham; Fomby, Laurene M.; Vasconcelos, Daphne Y.; Vallant, Molly; DeVito, Michael J.; Walker, Nigel J.

    2012-01-01

    In this study we assessed the relative toxicity and potency of the chlorinated naphthalenes 1,2,3,4,6,7-hexachloronaphthalene (PCN 66) and 1,2,3,5,6,7-hexachloronaphthalene (PCN 67) relative to that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Chemicals were administered in corn oil:acetone (99:1) by gavage to female Harlan Sprague-Dawley rats at dosages of 0 (vehicle), 500, 1500, 5000, 50000 and 500000 ng/kg (PCN 66 and PCN 67) and 1, 3, 10, 100, and 300 ng/kg (TCDD) for 2 weeks. Histopathologic changes were observed in the thymus, liver and lung of TCDD treated animals and in the liver and thymus of PCN treated animals. Significant increases in CYP1A1 and CYP1A2 associated enzyme activity were observed in all animals exposed to TCDD, PCN 66 and PCN 67. Dose response modeling of CYP1A1, CYP1A2 and thymic atrophy gave ranges of estimated relative potencies, as compared to TCDD, of 0.0015-0.0072, for PCN 66 and 0.00029-0.00067 for PCN 67. Given that PCN 66 and PCN 67 exposure resulted in biochemical and histopathologic changes similar to that seen with TCDD, this suggests that they should be included in the WHO Toxic Equivalency Factor (TEF) scheme, although the estimated relative potencies indicate that these hexachlorinated naphthalenes should not contribute greatly to the overall human body burden of dioxin-like activity. PMID:22813907

  9. Thymic function in HIV-infection.

    PubMed

    Kolte, Lilian

    2013-04-01

    This thesis is based on seven previously published articles. The work was performed during my employment at The Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, as a scholarship student from 2000-2001 and as a research assistant in the period 2004-2010. HIV-infection is characterized by CD4+ cell depletion. The differences between patients in the degree of CD4+ cell recovery upon treatment with highly active antiretroviral therapy (HAART) may in part be due to differences in the supply of naïve CD4+ cells from the thymus. The thymus atrophies with increasing age for which reason the adult thymus was previously assumed to be without function. The aim of these investigations was to examine the role of the thymus in different aspects of HIV-infection: In adult HIV-infected patients, during HIV-positive pregnancy, and in HIV-exposed uninfected (HIV-EU) children born to HIV-infected mothers. Thymic size and output were determined in 25 adult HIV-infected patients receiving HAART and in 10 controls. Larger thymic size was associated with higher CD4 counts and higher thymic output. Furthermore, patients with abundant thymic tissue seemed to have broader immunological repertoires, compared with patients with minimal thymic tissue. The study supports the mounting evidence of a contribution by the adult thymus to immune reconstitution in HIV-infection. In a follow-up study conducted till 5 years of HAART, the importance of the thymus to the rate of cellular restoration was found to primarily lie within the first two years of HAART. The effect of recombinant human growth hormone (rhGH) was then investigated in a randomized, double-blinded placebo controlled trial in 46 adult HIV-infected patients on HAART. Daily treatment with a low dose of rhGH of 0.7mg for 40 weeks stimulated thymopoiesis as expressed by thymic size, density, and output strongly supporting the assumption that rhGH possesses the potential to stimulate the ageing thymus, holding

  10. Thymic lymphosarcoma in three heifers.

    PubMed

    Hatfield, C E; Rebhun, W C; Dill, S G

    1986-12-15

    Three heifers with the thymic form of lymphosarcoma were examined. In each of the 3 cases, fever, bloat, and jugular venous distention had developed. Detectable antibody to bovine leukosis virus was not found on agar gel immunodiffusion testing in any of the cases. Thymic lymphosarcoma was confirmed by necropsy and histologic examination. Thymic lymphosarcoma must be considered in the differential diagnosis in heifers with fever, bloat, and jugular venous distention. PMID:3793601

  11. Trypanosoma cruzi Experimental Infection Impacts on the Thymic Regulatory T Cell Compartment.

    PubMed

    González, Florencia Belén; Calmon-Hamaty, Flavia; Nô Seara Cordeiro, Synara; Fernández Bussy, Rodrigo; Spinelli, Silvana Virginia; D'Attilio, Luciano; Bottasso, Oscar; Savino, Wilson; Cotta-de-Almeida, Vinícius; Villar, Silvina Raquel; Pérez, Ana Rosa

    2016-01-01

    The dynamics of regulatory T cells in the course of Trypanosoma cruzi infection is still debated. We previously demonstrated that acute murine T. cruzi infection results in an impaired peripheral CD4+Foxp3+ T cell differentiation due to the acquisition of an abnormal Th1-like phenotype and altered functional features, negatively impacting on the course of infection. Moreover, T. cruzi infection induces an intense thymic atrophy. As known, the thymus is the primary lymphoid organ in which thymic-derived regulatory T cells, known as tTregs, differentiate. Considering the lack of available data about the effect of T. cruzi infection upon tTregs, we examined tTreg dynamics during the course of disease. We confirmed that T. cruzi infection induces a marked loss of tTreg cell number associated to cell precursor exhaustion, partially avoided by glucocorticoid ablation- and IL-2 survival factor depletion. At the same time, tTregs accumulate within the CD4 single-positive compartment, exhibiting an increased Ki-67/Annexin V ratio compared to controls. Moreover, tTregs enhance after the infection the expression of signature markers (CD25, CD62L and GITR) and they also display alterations in the expression of migration-associated molecules (α chains of VLAs and chemokine receptors) such as functional fibronectin-driven migratory disturbance. Taken together, we provide data demonstrating profound alterations in tTreg compartment during acute murine T. cruzi infection, denoting that their homeostasis is significantly affected. The evident loss of tTreg cell number may compromise the composition of tTreg peripheral pool, and such sustained alteration over time may be partially related to the immune dysregulation observed in the chronic phase of the disease. PMID:26745276

  12. Thymic gallium-67 localization in pediatric patients on chemotherapy: concise communication

    SciTech Connect

    Donahue, D.M.; Leonard, J.C.; Basmadjian, G.P.; Nitschke, R.M.; Hinkle, G.H.; Ice, R.D.; Wilson, D.A.; Tunell, W.P.

    1981-12-01

    Localization of Ga-67 in the thymus has been reported to occur in children. In our control group of 87 patients, 15% of children under 5 yr and 11% of children over 5 hr demonstrated thymic localization. In contrast, in our study group of seven children with acute lymphocytic leukemia or malignant lymphoma, lymphocytic diffuse, treated on a modified non-Hodgkin's lymphoma protocol, Sloan-Kettering LSA/sub 2/-L/sub 2/, thymic localization occurred during treatment in five of the seven. We conclude that increased thymic gallium localization in children under chemotherapy for a known malignancy may reflect increased activity of thymic medullary epithelial cells and regeneration of thymic lymphocytes during recovery from involution induced by certain chemotherapeutic agents.

  13. Thymic gallium-67 localization in pediatric patients on chemotherapy: concise communication

    SciTech Connect

    Donahue, D.M.; Leonard, J.C.; Basmadjian, G.P.; Nitschke, R.M.; Hinkle, G.H.; Ice, R.D.; Wilson, D.A.; Tunell, W.P.

    1981-12-01

    Localization of 67Ga in the thymus has been reported to occur in children. In our control group of 87 patients, 15% of children under 5 yr and 11% of children over 5 yr demonstrated thymic localization. In contrast, in our study group of seven children with acute lymphocytic leukemia or malignant lymphoma, lymphocytic diffuse, treated on a modified non-Hodgkin's lymphoma protocol, Sloan-Kettering LSA2-L2, thymic localization occurred during treatment in five of the seven. We conclude that increased thymic gallium localization in children under chemotherapy for a known malignancy may reflect increased activity of thymic medullary epithelial cells and regeneration of thymic lymphocytes during recovery from involution induced by certain chemotherapeutic agents.

  14. Multiple System Atrophy

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy Information Page Condensed from Multiple System Atrophy ... Trials Organizations Publicaciones en Español What is Multiple System Atrophy? Multiple system atrophy (MSA) is a progressive ...

  15. FSP1+ fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells

    PubMed Central

    Sun, Lina; Sun, Chenming; Liang, Zhanfeng; Li, Hongran; Chen, Lin; Luo, Haiying; Zhang, Hongmei; Ding, Pengbo; Sun, Xiaoning; Qin, Zhihai; Zhao, Yong

    2015-01-01

    Thymic epithelial cells (TECs) form a 3-dimentional network supporting thymocyte development and maturation. Besides epithelium and thymocytes, heterogeneous fibroblasts are essential components in maintaining thymic microenvironments. However, thymic fibroblast characteristics, development and function remain to be determined. We herein found that thymic non-hematopoietic CD45-FSP1+ cells represent a unique Fibroblast specific protein 1 (FSP1)—fibroblast-derived cell subset. Deletion of these cells in FSP1-TK transgenic mice caused thymus atrophy due to the loss of TECs, especially mature medullary TECs (MHCIIhigh, CD80+ and Aire+). In a cyclophosphamide-induced thymus injury and regeneration model, lack of non-hematopoietic CD45-FSP1+ fibroblast subpopulation significantly delayed thymus regeneration. In fact, thymic FSP1+ fibroblasts released more IL-6, FGF7 and FSP1 in the culture medium than their FSP1- counterparts. Further experiments showed that the FSP1 protein could directly enhance the proliferation and maturation of TECs in the in vitro culture systems. FSP1 knockout mice had significantly smaller thymus size and less TECs than their control. Collectively, our studies reveal that thymic CD45-FSP1+ cells are a subpopulation of fibroblasts, which is crucial for the maintenance and regeneration of TECs especially medullary TECs through providing IL-6, FGF7 and FSP1. PMID:26445893

  16. Sudeck atrophy.

    PubMed

    Staunton, H

    2006-01-01

    This paper reviews the contribution of Sudeck to the understanding of the condition commonly referred to as 'Sudeck's atrophy' and which is commonly used as a synonym for a condition variously called reflex sympathetic dystrophy, causalgia, algodystrophy and others. Sudeck came to show in his later papers that the so-called atrophy was, in the majority of cases, a normal inflammatory process of bone change in the course of healing after an inflammatory/infective or traumatic insult. Contrary to the views of much current literature, the vast majority of such cases had a good prognosis. In those cases which became pathological and had a correspondingly poorer prognosis, the characteristic clinical picture becomes associated with radiological and pathological changes, which, uniquely, are described by Sudeck. A knowledge of such radiological and pathological substrate for clinical symptomatology is important in the analysis of pain following trauma. PMID:17274178

  17. Medullary thymic epithelial stem cells: role in thymic epithelial cell maintenance and thymic involution.

    PubMed

    Hamazaki, Yoko; Sekai, Miho; Minato, Nagahiro

    2016-05-01

    The thymus consists of two distinct anatomical regions, the cortex and the medulla; medullary thymic epithelial cells (mTECs) play a crucial role in establishing central T-cell tolerance for self-antigens. Although the understanding of mTEC development in thymic organogenesis as well as the regulation of their differentiation and maturation has improved, the mechanisms of postnatal maintenance remain poorly understood. This issue has a central importance in immune homeostasis and physiological thymic involution as well as autoimmune disorders in various clinicopathological settings. Recently, several reports have demonstrated the existence of TEC stem or progenitor cells in the postnatal thymus, which are either bipotent or unipotent. We identified stem cells specified for mTEC-lineage that are generated in the thymic ontogeny and may sustain mTEC regeneration and lifelong central T-cell self-tolerance. This finding suggested that the thymic medulla is maintained autonomously by its own stem cells. Although several issues, including the relationship with other putative TEC stem/progenitors, remain unclear, further examination of mTEC stem cells (mTECSCs) and their regulatory mechanisms may contribute to the understanding of postnatal immune homeostasis. Possible relationships between decline of mTECSC activity and early thymic involution as well as various autoimmune disorders are discussed. PMID:27088906

  18. Treatment Options for Thymoma and Thymic Carcinoma

    MedlinePlus

    ... symptoms of thymoma and thymic carcinoma include a cough and chest pain. Thymoma and thymic carcinoma may ... if you have any of the following: A cough that doesn't go away. Chest pain. Trouble ...

  19. Stages of Thymoma and Thymic Carcinoma

    MedlinePlus

    ... symptoms of thymoma and thymic carcinoma include a cough and chest pain. Thymoma and thymic carcinoma may ... if you have any of the following: A cough that doesn't go away. Chest pain. Trouble ...

  20. General Information about Thymoma and Thymic Carcinoma

    MedlinePlus

    ... and Thymic Carcinoma Treatment (PDQ®)–Patient Version General Information About Thymoma and Thymic Carcinoma Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  1. Homeostasis, thymic hormones and aging.

    PubMed

    Goya, R G; Bolognani, F

    1999-01-01

    The thymic-pituitary axis constitutes a bidirectional circuit where the ascending feedback loop is effected by thymic factors of epithelial origin. The aim of the present article is, first, to introduce the idea of an immune-neuroendocrine homeostatic network in higher animals. Next, the relevance of the thymus in this network and the possible role of this gland in the neuroendocrine imbalances associated with aging are discussed. A number of studies are next reviewed which show that the endocrine thymus produces several bioactive molecules, generally called thymic hormones, which in addition to possessing immunoregulatory properties are also active on nervous and endocrine circuits. In particular, the reported activities of thymosin fraction five, thymosin alpha 1 and thymosin beta 4 on beta-endorphin, adrenocorticotropic hormone, glucocorticoids, luteinizing hormone-releasing hormone and luteinizing hormone secretion in different animal and cell models are reviewed. The known hypophysiotropic actions of other thymic hormones like thymulin, homeostatic thymus hormone and thymus factor are also summarized, and the impact of aging on pituitary responsiveness to thymic hormones is discussed. As a conclusion, it is proposed that in addition to its central role in the regulation of the immune function, the thymus gland may extend its influence to nonimmunologic components of the body, including the neuroendocrine system. The early onset of thymus involution might, therefore, act as a triggering event which would initiate the gradual decline in homeostatic potential that characterizes the aging process. PMID:10202264

  2. Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes.

    PubMed

    Modena, B D; Kurian, S M; Gaber, L W; Waalen, J; Su, A I; Gelbart, T; Mondala, T S; Head, S R; Papp, S; Heilman, R; Friedewald, J J; Flechner, S M; Marsh, C L; Sung, R S; Shidban, H; Chan, L; Abecassis, M M; Salomon, D R

    2016-07-01

    Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation. PMID:26990570

  3. Dietary modulation of thymic enzymes.

    PubMed

    Susana, Feliu María; Paula, Perris; Slobodianik, Nora

    2014-01-01

    Malnutrition is a complex syndrome caused by an inadequate intake of energy, protein, minerals and vitamins which affects the immune system. Nutritional imbalances, present in children with energy-protein malnutrition and infections, make defining the specific effects of each of them on the thymus difficult. For this reason, it is necessary to design an experimental model in animals that could define a single variable. As the thymus atrophy described in humans is similar to that observed in murines, a rat experimental model makes the extrapolation to man possible. Some authors suggest that the activity of Adenosine Deaminase (ADA) and Purine Nucleoside Phosphorylase (PNP)--involved in purine metabolism--have an influence on T lymphocyte development and the immune system, due to intracellular accumulation of toxic levels of deoxynucleotides. Studies in our group, performed in an experimental model on Wistar growing rats, have demonstrated that protein deficiency or imbalance in the profile of essential amino acids in the diet, produce loss of thymus weight, reduction in the number of thymocytes, a diminished proportion of T cells presenting the W3/13 antigenic determinant and DNA content with concomitant increase in cell size, and the proportion of immature T cells and activity of ADA and PNP, without modifying the activity of 5´Nucleotidase in the thymus. It is important to point out that there were neither differences in energy intake between experimental groups and their controls, nor clinical symptoms of deficiency of other nutrients. The increase in these thymic enzyme activities was an alternative mechanism to avoid the accumulation of high levels of deoxynucleotides, which would be toxic for T lymphocytes. On the other hand, the administration of a recovery diet, with a high amount of high quality protein, was able to reverse the mentioned effects. The quick reply of Adenosine Deaminase to nutritional disorders and the following nutritional recovery, points

  4. Geographic Atrophy

    PubMed Central

    Bird, Alan C.; Phillips, Rachel L.; Hageman, Gregory S.

    2014-01-01

    IMPORTANCE Geographic atrophy (GA) is the major cause of blind registration in Western communities, although, with few exceptions, it is less common than choroidal neovascular disease. The variation of phenotype implies that age-related macular degeneration (AMD) does not follow the same course from one case to another and that phenotyping may be important before initiating a therapeutic trial. OBJECTIVE To document photoreceptor and retinal pigment epithelium (RPE) cell loss and other changes at the RPE-choroid interface in donated human eyes in which visual loss was deemed to be due to GA. DESIGN, SETTING, AND PARTICIPANTS Histological study of a consecutive series of eyes donated by individuals previously diagnosed clinically as having GA. Donors were chosen on the basis of available clinical records (from MidAmerica Transplant Services, St Louis, Missouri; the Iowa Lions Eye Bank, Iowa City; and the Utah Lions Eye Bank, Salt Lake City) and selected were those considered to have GA due to AMD. Tissues in the regions of atrophy were examined with light, electron, and autofluorescence microscopy. RESULTS In most of the 37 donors examined, there was marked loss of photoreceptor cells for variable distances distal from the edge of the GA. Rod loss was greater than cone loss. An inverse relationship existed between the quantity of autofluorescent inclusions in the RPE and the thickness of sub-RPE basal laminar deposit. Integrity of the choroid varied from one eye to another and was not related strictly to photoreceptor survival. In some eyes, photoreceptor loss existed in the absence of obvious morphological changes in the Bruch membrane or RPE. CONCLUSIONS AND RELEVANCE The findings support the view that photoreceptor loss occurs early in AMD in a proportion of cases and imply that photoreceptor-cell loss may contribute to the functional loss recorded in early stages of AMD at least in part. The variation of changes from one eye to another implies that patients

  5. [Clinical evaluation of thymic function].

    PubMed

    Castermans, E; Morrhaye, G; Marchand, S; Martens, H; Moutschen, M; Baron, F; Beguin, Y; Geenen, V

    2007-11-01

    The essential role of the thymus is to install an extremely diverse repertoire of T lymphocytes that are self-tolerant and competent against non-self, as well as to generate self-antigen specific regulatory T cells (Treg) able to inactivate in periphery self-reactive T cells having escaped the thymic censorship. Although indirect, techniques of medical imaging and phenotyping of peripheral T cells may help in the investigation of thymic function. Nowadays however, thymopoiesis is better evaluated through quantification by PCR of T-cell receptor excision circles (TREC) generated by intrathymic random recombination of the gene segments coding for the variable parts of the T-cell receptor for antigen (TCR). The TREC methodology is very valuable in the circumstances not associated with intense proliferation or apoptosis of peripheral T lymphocytes. PMID:18217644

  6. Studying T Cell Development in Thymic Slices.

    PubMed

    Ross, Jenny O; Melichar, Heather J; Halkias, Joanna; Robey, Ellen A

    2016-01-01

    Recently, tissue slices have been adapted to study both mouse and human T cell development. Thymic slices combine and complement the strengths of existing organotypic culture systems to study thymocyte differentiation. Specifically, the thymic slice system allows for high throughput experiments and the ability to introduce homogenous developmental intermediate populations into an environment with a well-established cortex and medulla. These qualities make thymic slices a highly versatile and technically accessible model to study thymocyte development. Here we describe methods to prepare, embed, and slice thymic lobes to study T cell development in situ. PMID:26294404

  7. Morphological imaging of thymic disorders.

    PubMed

    Camera, L; Brunetti, A; Romano, M; Larobina, M; Marano, I; Salvatore, M

    1999-10-01

    The thymus is a bilobed lymphoid organ the morphology of which varies considerably with age as a result of a process of fatty infiltration occurring after puberty. Although several diseases can arise in the thymic parenchyma, including germ cell and neuroendocrine tumours, primitive epithelial neoplasms (thymomas) are the most common neoplasms and account for almost 10% of mediastinal masses. Thymomas are usually benign but can be locally invasive. Up to 30% of patients with a thymoma have myasthenia gravis, which is more commonly associated with thymic hyperplasia. The latter results in a symmetric diffuse enlargement of the thymus. However, thymic hyperplasia can be histologically found in up to 50% of normal-sized thymuses on computed tomography (CT). CT is much more accurate in detecting thymomas than it is in detecting thymic hyperplasia, although CT findings may be unspecific. CT can be exhaustive in the case of an encapsulated thymoma (65% of all thymomas), which appear as a solid homogeneous mass with a slight contrast enhancement and a well-defined surrounding fat plane. These tumours rarely recur after surgery. CT can also accurately detect a spread through the capsule into the adjacent mediastinal fat, which characterizes invasive thymomas (35%). These, however, are best evaluated by magnetic resonance imaging (MRI). On T1-weighted MR scans the thymus is well delineated against the mediastinal fat, whereas marked inhomogeneity of the signal may appear on T2-weighted images as a result of areas of cystic degeneration in the tumour mass. The superior contrast resolution of MRI and the multiplanar images that can be produced with it are well suited for documenting the mediastinal spread of invasive thymomas. MRI depicts accurately pleural and/or pericardial implants as well as the involvement of great vessels, offering considerable aid in the planning of surgery. PMID:10574157

  8. Extended resections for thymic malignancies.

    PubMed

    Wright, Cameron D

    2010-10-01

    Almost all series reporting on the results of resection in thymic tumors indicate that the performance of a complete resection is probably the most important prognostic factor. This issue is not a factor in Masaoka stage I and II tumors that are almost always easily completely resected and have an excellent prognosis. Masaoka stage III tumors that invade the pericardium, lungs, or great vessels have relatively higher incomplete resection rates, significantly higher recurrence rates, and thus a worse prognosis. There are several small reports on the efficacy of resection of the great veins when involved by a thymic malignancy with low morbidity and meaningful long-term survival. Superior vena cava reconstruction is commonly performed by a polytetrafluroethylene, venous, or pericardial graft. These cases can usually be identified preoperatively and, thus, considered for induction therapy. Because these types of cases are almost always of marginal respectability in terms of obtaining a true en bloc resection, there is an increasing enthusiasm for offering induction therapy in an effort to enhance resectability. Preliminary results suggest increased R0 resection rates and improved survival with induction therapy for locally advanced tumors. The optimal induction treatment is unknown. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy performed for extensive pleural disease (Masaoka stage IVA). These rarely performed operations are done for IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Again these advanced patients are probably best managed by induction chemotherapy followed by resection. PMID:20859130

  9. Thymic Involution in Ontogenesis: Role in Aging Program.

    PubMed

    Shilovsky, G A; Feniouk, B A; Skulachev, V P

    2015-12-01

    In most mammals, involution of the thymus occurs with aging. In this issue of Biochemistry (Moscow) devoted to phenoptosis, A. V. Khalyavkin considered involution of a thymus as an example of the program of development and further--of proliferation control and prevention of tumor growth. However, in animals devoid of a thymus (e.g. naked mice), stimulation of carcinogenesis, but not its prevention was observed. In this report, we focus on the involution of the thymus as a manifestation of the aging program (slow phenoptosis). We also consider methods of reversal/arrest of this program at different levels of organization of life (cell, tissue, and organism) including surgical manipulations, hormonal effects, genetic techniques, as well as the use of conventional and mitochondria-targeted antioxidants. We conclude that programmed aging (at least on the model of age-dependent thymic atrophy) can be inhibited. PMID:26638690

  10. Optic nerve atrophy

    MedlinePlus

    Optic atrophy; Optic neuropathy ... There are many causes of optic atrophy. The most common is poor blood flow. This is called ischemic optic neuropathy. The problem most often affects older adults. ...

  11. Multiple system atrophy

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/000757.htm Multiple system atrophy To use the sharing features on this page, please enable JavaScript. Multiple system atrophy (MSA) is a rare condition that causes ...

  12. Thymic adenocarcinoma associated with thymic cyst: a case report and review of literature

    PubMed Central

    Wang, Leiming; Wang, Dandan; Qian, Kun; Lu, Dehong; Chen, Li; Zhao, Lan; Teng, Lianghong

    2015-01-01

    Thymic adenocarcinoma of the mediastinum is extremely rare. Only 12 cases adenocarcinoma associated with a thymic cyst have been reported in the literature. In this report, we describe a case of a thymic adenocarcinoma associated with thymic cyst. A 70-year-old man, presented with two months of chest tightness, breath shortness and chest pain. The contrast enhanced CT scan of chest revealed a round, cystic mass in right anterior mediastinum. Microscopic examination revealed that the lining consisted of flat to cuboidal and columnar epithelium and adenocarcinoma infiltrated into the thymic tissue and the soft tissue around the wall of cyst. Based on clinical history, imaging studies, pathological findings and absence of extramediastinal tumor, a diagnosis of thymic adenocarcinoma associated with thymic cyst was established. The patient was alive without any sign of recurrence 7 months after the operation. PMID:26191314

  13. Thymic involution in the suspended rat model for weightlessness - Decreased glucocorticoid receptor concentration

    NASA Technical Reports Server (NTRS)

    Steffen, J. M.; Musacchia, X. J.

    1984-01-01

    Hindlimb muscle atrophy, thymic involution and adrenal hypertrophy in rats during spaceflight can be simulated using suspension models. Skeletal muscle and thymus are sensitive to gluco-corticoids (GC), and previous studies have demonstrated that muscle atrophy in suspended rats is associated with increased GC receptor concentration. The objectives were to confirm thymic involution during suspension, and determine if involution correlated with increased GC receptor concentration. Seven days of antiorthostatic (AO) suspension of rats produced a significant (P less than 0.001) reduction in thymic wet weight not associated with an alteration of percent water content. GC receptor concentration (pmol/mg protein) decreased 20 percent (P less than 0.025) in thymus glands from 7 day AO suspended rats. Suspension, therefore, is associated with involution of the thymus, but this is not dependent upon AO positioning. Thymus GC receptor concentrations were depressed in 7-day suspended rats, in contrast with previous observations on skeletal muscle, suggesting that different mechanisms may underlie these responses.

  14. Regenerative capacity of adult cortical thymic epithelial cells.

    PubMed

    Rode, Immanuel; Boehm, Thomas

    2012-02-28

    Involution of the thymus is accompanied by a decline in the number of thymic epithelial cells (TECs) and a severely restricted peripheral repertoire of T-cell specificities. TECs are essential for T-cell differentiation; they originate from a bipotent progenitor that gives rise to cells of cortical (cTEC) and medullary (mTEC) phenotypes, via compartment-specific progenitors. Upon acute selective near-total ablation during embryogenesis, regeneration of TECs fails, suggesting that losses from the pool of TEC progenitors are not compensated. However, it is unclear whether this is also true for the compartment-specific progenitors. The decline of cTECs is a prominent feature of thymic involution. Because cTECs support early stages of T-cell development and hence determine the overall lymphopoietic capacity of the thymus, it is possible that the lack of sustained regenerative capacity of cTEC progenitor cells underlies the process of thymic involution. Here, we examine this hypothesis by cell-type-specific conditional ablation of cTECs. Expression of the human diphtheria toxin receptor (hDTR) gene under the regulatory influence of the chemokine receptor Ccx-ckr1 gene renders cTECs sensitive to the cytotoxic effects of diphtheria toxin (DT). As expected, DT treatment of preadolescent and adult mice led to a dramatic loss of cTECs, accompanied by a rapid demise of immature thymocytes. Unexpectedly, however, the cTEC compartment regenerated after cessation of treatment, accompanied by the restoration of T-cell development. These findings provide the basis for the development of targeted interventions unlocking the latent regenerative potential of cTECs to counter thymic involution. PMID:22331880

  15. mTORC2 in Thymic Epithelial Cells Controls Thymopoiesis and T Cell Development.

    PubMed

    Wang, Hong-Xia; Cheng, Joyce S; Chu, Shuai; Qiu, Yu-Rong; Zhong, Xiao-Ping

    2016-07-01

    Thymic epithelial cells (TECs) play important roles in T cell generation. Mechanisms that control TEC development and function are still not well defined. The mammalian or mechanistic target of rapamycin complex (mTORC)2 signals to regulate cell survival, nutrient uptake, and metabolism. We report in the present study that mice with TEC-specific ablation of Rictor, a critical and unique adaptor molecule in mTORC2, display thymic atrophy, which accompanies decreased TEC numbers in the medulla. Moreover, generation of multiple T cell lineages, including conventional TCRαβ T cells, regulatory T cells, invariant NKT cells, and TCRγδ T cells, was reduced in TEC-specific Rictor-deficient mice. Our data demonstrate that mTORC2 in TECs is important for normal thymopoiesis and efficient T cell generation. PMID:27233961

  16. SHP1-ing thymic selection.

    PubMed

    Gascoigne, Nicholas R J; Brzostek, Joanna; Mehta, Monika; Acuto, Oreste

    2016-09-01

    Thymocyte development and maintenance of peripheral T-cell numbers and functions are critically dependent on T-cell receptor (TCR) signal strength. SHP1 (Src homology region 2 domain-containing phosphatase-1), a tyrosine phosphatase, acts as a negative regulator of TCR signal strength. Moreover, germline SHP1 knockout mice have shown impaired thymic development. However, this has been recently questioned by an analysis of SHP1 conditional knockout mice, which reported normal thymic development of SHP1 deficient thymocytes. Using this SHP1 conditional knockout mice, in this issue of the European Journal of Immunology, Martinez et al. [Eur. J. Immunol. 2016. 46: 2103-2110] show that SHP1 indeed does have a role in the negative regulation of TCR signal strength in positively selected thymocytes, and in the final maturation of single positive thymocytes. They report that thymocyte development in such mice shows loss of mature, post-selection cells. This is due to increased TCR signal transduction in thymocytes immediately post positive-selection, and increased cell death in response to weak TCR ligands. Thus, SHP1-deficiency shows strong similarities to deficiency in the T-cell specific SHP1-associated protein Themis. PMID:27600672

  17. Chemotherapy and targeted agents for thymic malignancies.

    PubMed

    Girard, Nicolas

    2012-05-01

    Thymic malignancies are rare epithelial tumors that may be aggressive and difficult to treat. Thymomas are usually localized to the anterior mediastinum and are frequently eligible for upfront surgical resection. However, nearly 30% of patients present with locally advanced tumors at time of diagnosis, and chemotherapy is then used to reduce the tumor burden, possibly allowing subsequent surgery and/or radiotherapy. Metastatic and recurrent thymic malignancies may similarly be treated with chemotherapy. More recently, the molecular characterization of thymoma and thymic carcinoma led to the identification of potentially druggable targets, laying the foundations to implement personalized medicine for patients. PMID:22594902

  18. A unilocular thymic cyst associated with true thymic hyperplasia: a challenging diagnosis especially in a child

    PubMed Central

    Mlika, Mona; Gattoufi, Walid; Zribi, Hazem; Braham, Emna; Marghli, Adel; El Mezni, Faouzi

    2015-01-01

    We report a new case of a mediastinal mass in a 19-year-old patient corresponding microscopically to an association of unilocular thymic cyst and true thymic hyperplasia. Our aim is to highlight the absence of specificity of clinical and radiological findings and the necessity of a thorough sampling of the tumor in order to establish the diagnosis. PMID:26445562

  19. Interleukin-22 drives endogenous thymic regeneration in mice

    PubMed Central

    Dudakov, Jarrod A.; Hanash, Alan M.; Jenq, Robert R.; Young, Lauren F.; Ghosh, Arnab; Singer, Natalie V.; West, Mallory L.; Smith, Odette M.; Holland, Amanda M.; Tsai, Jennifer J.; Boyd, Richard L.; van den Brink, Marcel R.M.

    2013-01-01

    Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection or immunodepletion. The mechanisms governing this regeneration, however, remain poorly understood. Here we detail a framework of thymic regeneration centred on IL-22 and triggered by depletion of CD4+CD8+ double positive (DP) thymocytes. Intrathymic levels of IL-22 were increased following thymic insult, and thymic recovery was impaired in IL-22-deficient mice. IL-22, which signalled through thymic epithelial cells (TECs) and promoted their proliferation and survival, was upregulated by radio-resistant RORγ(t)+CCR6+NKp46− lymphoid tissue-inducer cells (LTi) after thymic injury in an IL-23 dependent manner. Importantly, administration of IL-22 enhanced thymic recovery following total body irradiation (TBI). These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence. PMID:22383805

  20. Preparation and Applications of Organotypic Thymic Slice Cultures.

    PubMed

    Sood, Aditi; Dong, Mengqi; Melichar, Heather J

    2016-01-01

    Thymic selection proceeds in a unique and highly organized thymic microenvironment resulting in the generation of a functional, self-tolerant T cell repertoire. In vitro models to study T lineage commitment and development have provided valuable insights into this process. However, these systems lack the complete three-dimensional thymic milieu necessary for T cell development and, therefore, are incomplete approximations of in vivo thymic selection. Some of the challenges related to modeling T cell development can be overcome by using in situ models that provide an intact thymic microenvironment that fully supports thymic selection of developing T cells. Thymic slice organotypic cultures complement existing in situ techniques. Thymic slices preserve the integrity of the thymic cortical and medullary regions and provide a platform to study development of overlaid thymocytes of a defined developmental stage or of endogenous T cells within a mature thymic microenvironment. Given the ability to generate ~20 slices per mouse, thymic slices present a unique advantage in terms of scalability for high throughput experiments. Further, the relative ease in generating thymic slices and potential to overlay different thymic subsets or other cell populations from diverse genetic backgrounds enhances the versatility of this method. Here we describe a protocol for the preparation of thymic slices, isolation and overlay of thymocytes, and dissociation of thymic slices for flow cytometric analysis. This system can also be adapted to study non-conventional T cell development as well as visualize thymocyte migration, thymocyte-stromal cell interactions, and TCR signals associated with thymic selection by two-photon microscopy. PMID:27585240

  1. Thymoma and thymic carcinoma: therapeutic approaches.

    PubMed

    Kurup, Anupama; Loehrer, Patrick J

    2004-07-01

    Thymomas and thymic carcinomas, which are rare epithelial tumors arising from the thymus gland, are the most common tumors of the anterior mediastinum. Thymomas are generally encapsulated, slow-growing tumors that have a "bland" histologic appearance. Thymic carcinomas possess more overtly malignant histologic features than thymomas and are more likely to present as invasive or disseminated disease. Surgery is the treatment of choice for localized thymic tumors, with complete resection being the most important prognostic factor. Complete resection also improves survival in locally invasive thymic tumors. Adjuvant postoperative radiation therapy may improve the outcome in patients with invasive disease, although the data are conflicting. Multimodal regimens, including neoadjuvant combination chemotherapy, surgery, and/or postoperative radiation therapy, are recommended for patients with advanced thymomas and thymic carcinomas. Use of octreotide plus prednisone has produced responses in thymomas, but the dosing and schedule have not been clearly defined. Prospective studies have been limited, and, as such, enrollment in clinical trials is encouraged. PMID:15310414

  2. Studies on thymus products. IV. Absence of serum `thymic activity' in adult NZB and (NZB × NZW) F1 mice

    PubMed Central

    Bach, J. -F.; Dardenne, Mireille; Salomon, J. -C.

    1973-01-01

    New Zealand Black (NZB) mice and (B/W) F1 hybrids have a normal level of serum `thymic activity' (TA) at birth but this level decreases prematurely between the third and sixth weeks of life. At 2 months, NZB and NZ (B/W) F1 mice have no significant TA, whereas TA is still at birth's level in six control mouse strains and remains at this level until the fourth to the sixth month. Six weeks after the decline of serum TA, NZB mice show disappearance of theta-positive lymph node rosette-forming cells (RFC) and 2 weeks later, progressive decrease in spleen RFC sensitivity to anti-theta serum (AΘS) and azathioprine (AZ) as in neonatally thymectomized CBA mice. Normal AZ and AΘS sensitivity of spleen and lymph node RFC is reconstituted by in vitro or in vivo treatment by thymic extracts. The early thymic abnormalities found in NZB mice are in keeping with the thymic medullar epithelium atrophy reported in newborn NZB mice. PMID:4541554

  3. Optic nerve atrophy

    MedlinePlus

    Optic nerve atrophy is damage to the optic nerve. The optic nerve carries images of what the eye sees to ... problem most often affects older adults. The optic nerve can also be damaged by shock, toxins, radiation, ...

  4. Bed Rest Muscular Atrophy

    NASA Technical Reports Server (NTRS)

    Greenleaf, John E.

    2000-01-01

    A major debilitating response from prolonged bed rest (BR) is muscle atrophy, defined as a "decrease in size of a part of tissue after full development has been attained: a wasting away of tissue as from disuse, old age, injury or disease". Part of the complicated mechanism for the dizziness, increased body instability, and exaggerated gait in patients who arise immediately after BR may be a result of not only foot pain, but also of muscular atrophy and associated reduction in lower limb strength. Also, there seems to be a close association between muscle atrophy and bone atrophy. A discussion of many facets of the total BR homeostatic syndrome has been published. The old adage that use determines form which promotes function of bone (Wolff's law) also applies to those people exposed to prolonged BR (without exercise training) in whom muscle atrophy is a consistent finding. An extreme case involved a 16-year-old boy who was ordered to bed by his mother in 1932: after 50 years in bed he had "a lily-white frame with limbs as thin as the legs of a ladder-back chair". These findings emphasize the close relationship between muscle atrophy and bone atrophy. In addition to loss of muscle mass during deconditioning, there is a significant loss of muscle strength and a decrease in protein synthesis. Because the decreases in force (strength) are proportionately greater than those in fiber size or muscle cross-sectional area, other contributory factors must be involved; muscle fiber dehydration may be important.

  5. Treatment of advanced thymoma and thymic carcinoma.

    PubMed

    Rajan, Arun; Giaccone, Giuseppe

    2008-12-01

    Although thymic epithelial tumors are rare, they are relatively common among neoplasms of the anterior superior mediastinum. They usually exhibit indolent behavior, but do have the capacity to invade surrounding structures and metastasize to distant sites. Thymic carcinomas are rare, but are highly aggressive tumors that are associated with a poor prognosis. The mainstay of therapy is complete surgical resection. Locally advanced thymoma and thymic carcinoma require a multimodality treatment approach with a combination of surgery, chemotherapy, and radiation therapy to decrease the chances of recurrence and improve survival. The risk of disease recurrence lasts for a number of years after completion of primary therapy. A majority of cases of recurrent disease present as pleural recurrences. Once again, surgical resection of recurrent disease represents the cornerstone of successful therapy and is critical to long-term survival. In recent years, a better understanding of the biologic basis of thymic epithelial tumors has led to the emergence of targeted therapy directed against this malignancy. PMID:19381821

  6. [Progresses in therapeutic strategies for thymic rejuvenation].

    PubMed

    Tan, Jian-Xin; Wang, Ya-Jun; Zhu, Xi-Ke

    2016-02-25

    The thymus is a vital primary lymphoid organ that provides unique microenvironments for the proliferation, differentiation, and maturation of T cells. With advancing age, however, the thymus gradually undergoes age-related involution and reduction in immune function, which are characterized by decreases in tissue size, cellularity, and naïve T cell output. This dynamic process leads to the reduced efficacy of the immune system with age and contributes to the increased susceptibility to infection, autoimmune disease, and cancer. In addition, bone marrow transplantation, radio-chemotherapy and virus infection also impair the thymus and give rise to the decline in immune function. Therefore, understanding the molecular mechanisms involved in age-related thymic involution and development of novel therapeutic strategies for thymic rejuvenation have gained considerable interests in recent years. This review emphasizes thymic microenvironments and thymocyte-stromal cell interactions and summarizes our current knowledge about thymic rejuvenation in terms of sex steroid, cytokines, growth factors, hormones, transcription factors, cell graft, and microRNAs. At the end of each discussion, we also highlight unanswered issues and describe possible future research directions. PMID:26915325

  7. Vanadium toxicity in the thymic development

    PubMed Central

    Cui, Hengmin

    2015-01-01

    The purpose of this study was to define the toxic effects of vanadium on thymic development in broilers fed on diets supplemented with 0, 5, 15, 30, 45 and 60 mg/kg of vanadium for 42 days. We examined the changes of relative weight, cell cycle phase, apoptotic cells, and protein expression of Bcl-2, Bax, and caspase-3 in the thymus by the methods of flow cytometry, TUNEL (terminal-deoxynucleotidyl transferase mediated nick end labeling) and immunohistochemistry. The results showed that dietary high vanadium (30mg/kg, 45mg/kg and 60mg/kg) caused the toxic effects on thymic development, which was characterized by decreasing relative weight, increasing G0/G1 phase (a prolonged nondividing state), reducing S phase (DNA replication) and proliferating index (PI), and increasing percentages of apoptotic thymocytes. Concurrently, the protein expression levels of Bax and caspase-3 were increased, and protein expression levels of Bcl-2 were decreased. The thymic development suppression caused by dietary high vanadium further leads to inhibitive effects on T lymphocyte maturity and activity, and cellular immune function. The above-mentioned results provide new evidences for further understanding the vanadium immunotoxicity. In contrast, dietary 5 mg/kg vanadium promoted the thymic development by increasing relative weight, decreasing G0/G1 phase, increasing S phase and PI, and reducing percentages of apoptotic thymocytes when compared to the control group and high vanadium groups. PMID:26416460

  8. Thymic Tumor Extension into the Heart, a Rare Finding Found by Point-of-Care Ultrasound

    PubMed Central

    Kaufman, Elizabeth; Hunter-Behrend, Michelle; Leroux, Eric; Gharahbaghian, Laleh

    2016-01-01

    We report a cardiac mass detected by point-of-care ultrasound performed within the emergency department on a 65-year-old male with thymic cancer who presented with chronic cough and fever. Results from the initial emergency workup, which included blood tests, urinalysis, and a computerized tomography with angiography scan with venous phasing of the chest, did not result in a definitive diagnosis. A point-of-care echocardiogram was performed to evaluate for possible infective endocarditis, but alternatively identified a large mass in the right atria and ventricle. The mass was later confirmed to be metastatic tumor from the patient’s known thymic cancer. This case emphasizes the vital role ultrasound can play in the acute care setting.

  9. Thymic Tumor Extension into the Heart, a Rare Finding Found by Point-of-Care Ultrasound.

    PubMed

    Kaufman, Elizabeth; Hunter-Behrend, Michelle; Leroux, Eric; Gharahbaghian, Laleh; Lobo, Viveta

    2016-01-01

    We report a cardiac mass detected by point-of-care ultrasound performed within the emergency department on a 65-year-old male with thymic cancer who presented with chronic cough and fever. Results from the initial emergency workup, which included blood tests, urinalysis, and a computerized tomography with angiography scan with venous phasing of the chest, did not result in a definitive diagnosis. A point-of-care echocardiogram was performed to evaluate for possible infective endocarditis, but alternatively identified a large mass in the right atria and ventricle. The mass was later confirmed to be metastatic tumor from the patient's known thymic cancer. This case emphasizes the vital role ultrasound can play in the acute care setting. PMID:27625910

  10. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J. (Editor); Talbot, J. M. (Editor)

    1984-01-01

    Muscle atrophy in a weightless environment is studied. Topics of investigation include physiological factors of muscle atrophy in space flight, biochemistry, countermeasures, modelling of atrophied muscle tissue, and various methods of measurement of muscle strength and endurance. A review of the current literature and suggestions for future research are included.

  11. The International Thymic Malignancy Interest Group thymic initiative: a state-of-the-art study of thymic malignancies.

    PubMed

    Detterbeck, Frank; Korst, Robert

    2014-01-01

    Thymic malignancies are relatively rare tumors. A general lack of knowledge, misconceptions about benignancy, confusion about the definition of terms, and variability in reporting of outcomes have further hampered progress in these diseases. The International Thymic Malignancy Interest Group has emerged to counter these challenges and has brought together a worldwide multidisciplinary community determined to improve outcomes for these patients. Although the organization is young (initiated in 2010), major early accomplishments have created a foundation and infrastructure for scientific research. These include consensus definitions of terms, an unprecedented global database, development of practical clinical resources and, together with the International Association for the Study of Lung Cancer, development of proposals for the first formal stage classification of these malignant tumors. Many articles have been published or are under way, and a second phase of projects building on the early success is proceeding. The greatest accomplishment of the International Thymic Malignancy Interest Group lies in the establishment of an open culture of collaboration and the engagement of a broad group of individuals united by a common mission. It is a testament to what can be achieved, despite ongoing and inherent challenges, by determination and a collective effort. PMID:25837546

  12. Graves' Patient with Thymic Expression of Thyrotropin Receptors and Dynamic Changes in Thymic Hyperplasia Proportional to Graves' Disease Activity

    PubMed Central

    Song, Young Shin; Won, Jae-Kyung; Kim, Mi Jeong; Lee, Ji Hyun; Kim, Dong-Wan; Chung, June-Key; Park, Do Joon

    2016-01-01

    Thymic hyperplasia is frequently observed in Graves' disease. However, detectable massive enlargement of the thymus is rare, and the mechanism of its formation has remained elusive. This case showed dynamic changes in thymic hyperplasia on serial computed tomography images consistent with changes in serum thyrotropin receptor (TSH-R) antibodies and thyroid hormone levels. Furthermore, the patient's thymic tissues underwent immunohistochemical staining for TSH-R, which demonstrated the presence of thymic TSH-R. The correlation between serum TSH-R antibody levels and thymic hyperplasia sizes and the presence of TSH-R in her thymus suggest that TSH-R antibodies could have a pathogenic role in thymic hyperplasia. PMID:26996584

  13. Huge cervico-thoracic thymic cyst.

    PubMed

    Sameh, Ibrahim Sersar; Ismaeil, Mohammed Fouad; Nasser, Mohammed Abdelhameed Fouda; Awadalla, Mohammed Mounir el-Saeid

    2003-09-01

    We present a case of a 6 year-old boy who presented with a huge mass in the right side of the neck and changes its size with respiration and with straining. Computed tomography of the chest and neck showed a huge mass that was thought to be cystic hygroma. It was excised by both median sternotomy and a right cervical incision. Pathology revealed a thymic cyst. PMID:17670062

  14. Ocular Myasthenia Gravis Associated With Thymic Amyloidosis.

    PubMed

    Chapman, Kristin O; Beneck, Debra M; Dinkin, Marc J

    2016-03-01

    A 45-year-old woman with ptosis and diplopia was found to have myasthenia gravis (MG) associated with amyloidosis of the thymus gland. Systemic MG is frequently associated with thymomas or thymic hyperplasia but has only once previously been reported in association with amyloidosis of the thymus. This case demonstrates that isolated ocular MG rarely may also be associated with amyloidosis of the thymus. PMID:25822660

  15. [New TNM Staging System for Thymic Malignancies].

    PubMed

    Fukui, Takayuki; Yokoi, Kohei

    2016-05-01

    In patients with malignant tumors, the TNM classification has been widely used by clinicians as a guide for estimating prognosis, and is the basis for treatment decisions. Recently, the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee and the International Thymic Malignancy Interest Group have proposed a new classification for thymic malignancies to be included in the next official staging system of the forthcoming 8th edition of the TNM classification. In this study, we reviewed 154 consecutive patients with thymic epithelial tumors who underwent complete resection at our institution, and compared their characteristics and outcomes when classified according to the proposed system with those when classified under the current Masaoka-Koga system. The proportion of patients with stage I disease increased markedly to 77.3%under the proposed system because a certain number of patients with Masaoka-Koga stages II and III diseases were downstaged to the new stage I. Regarding histology, among 69 patients with type A, AB, or B1 thymoma, 68 tumors(99%)were diagnosed as new stage I disease. When using the proposed system, the recurrence-free survival rates showed significant deterioration with increasing stage, while the overall survival rates did not. Although the new TNM classification does not serve as an effective prognostic prediction model for overall survival, it appears to offer some benefit, especially in the analysis of recurrence-free survival. PMID:27210081

  16. Thymic depletion of lymphocytes is associated with the virulence of PRRSV-1 strains.

    PubMed

    Amarilla, Shyrley Paola; Gómez-Laguna, Jaime; Carrasco, Librado; Rodríguez-Gómez, Irene M; Caridad Y Ocerín, José M; Graham, Simon P; Frossard, Jean-Pierre; Steinbach, Falko; Salguero, Francisco J

    2016-05-30

    Porcine reproductive and respiratory syndrome virus (PRRSV) exists as two distinct viruses, type 1 (PRRSV-1) and type 2 (PRRSV-2). Atrophy of the thymus in PRRSV-2 infected piglets has been associated with a loss of thymocytes. The present study aimed to evaluate the impact of PRRSV-1 strains of differing virulence on the thymus of infected piglets by analysing the histomorphometry, the presence of apoptotic cells and cells producing cytokines. Thymic samples were taken from animals experimentally infected (with LV, SU1-bel, and 215-06 strains) or mock inoculated animals at 3, 7 and 35days post-infection (dpi) and processed for histopathological and immunohistochemical analyses. PRRSV antigen was detected in the thymus from 3dpi until the end of the study in all virus-infected animals with the highest numbers of infected cells detected in SU1-bel group. The histomorphometry analysis and counts of CD3(+) thymocytes in the thymic cortex displayed significant differences between strains at different time-points (p≤0.011), with SU1-bel group showing the most severe changes at 7dpi. Cell death displayed statistically significant increase in the cortex of all infected animals, with SU1-bel group showing the highest rate at 3 and 7dpi. The number of cells immunostained against IL-1α, TNF-α and IL-10 were predominantly detected in the medulla (p≤0.01). An increase in the number of TNF-α and IL-10 positive cells was observed in LV and SU-1bel groups. Our results demonstrate that different PRRSV-1 strains induced depletion of the thymic cortex due to apoptosis of thymocytes and that the most severe depletion was associated with the highly virulent SU1-bel strain. PMID:27139029

  17. [Muscle fiber atrophy].

    PubMed

    Nonaka, Ikuya

    2012-01-01

    Muscle fibers have been classified into two major forms of red (slow twitch) and white (fast twitch) muscles. The red muscle utilizes lipid as energy source through mitochondrial metabolism and function to sustain the position against gravity (sometimes called as antigravity muscle). Under microgravity the red muscle is selectively involved. In our unloading study by hindlimb suspension experiment on rats, the one of the representative red muscle of soleus muscle underwent rapid atrophy; they reduced their weights about 50% after 2 week-unloading. In addition, myofibrils were occasionally markedly disorganized with selective thin filament loss. Mitochondria in the degenerated area were decreased in number. The white muscle fibers in the soleus muscle had mostly transformed to the red ones. It took about 1 month to recover morphologically. The satellite cell playing a major role in muscle regeneration was not activated. There still remained unsolved what are the mechanosensors to keep muscle function under normal gravity. Dr Nikawa's group proposed that one of ubiquitin ligases, Cbl-b is activated under microgravity and induces muscle fiber degeneration. There might be many factors to induce muscle atrophy and degeneration under microgravity. Further study is necessary to explore the pathomechanism of muscle atrophy in disused and under immobility conditions. PMID:23196603

  18. Thymic B Cells and Central T Cell Tolerance

    PubMed Central

    Yamano, Tomoyoshi; Steinert, Madlen; Klein, Ludger

    2015-01-01

    Central T cell tolerance is believed to be mainly induced by thymic dendritic cells and medullary thymic epithelial cells. The thymus also harbors substantial numbers of B cells. These may arise though intrathymic B lymphopoiesis or immigration from the bloodstream. Importantly, and in contrast to resting “mainstream” B cells in the periphery, thymic B cells display elevated levels of MHC class II and constitutively express CD80. Arguably, their most unexpected feature is the expression of autoimmune regulator. These unique features of thymic B cells result from a licensing process that involves cross-talk with CD4 single-positive T cells and CD40 signaling. Together, these recent findings suggest that B cells play a more prominent role as thymic APCs than previously appreciated. PMID:26257742

  19. Thymic involution: implications for self-tolerance.

    PubMed

    Hakim, Frances T; Gress, Ronald E

    2007-01-01

    The thymus contributes to the regulation of tolerance and the prevention of autoimmunity at many levels. First, auto-reactive CD4+ and CD8+ T cells are clonally deleted during negative selection in the thymus, establishing central tolerance. The unique expression of the AIRE (autoimmune regulator) gene in medullary thymic epithelial cells results in expression of a broad array of tissue-specific antigens. Thymocytes bearing T-cell receptors that bind to these tissue-specific antigens are clonally deleted. This process removes self-reactive T cells from the repertoire before T cells are exported to the periphery. Second, CD4+CD25 bright regulatory T cells (Treg) develop in parallel with CD4+ and CD8+ effector T cells in the thymus. Unlike T effector cells, Treg fail to be deleted by exposure to tissue antigens during thymic maturation. After export to the periphery, Treg cells play a critical role in the prevention of autoimmunity, suppression of inflammatory responses, and the modulation of T-cell homeostasis. Finally, productive thymopoiesis, in and of itself, may be a factor deterring autoimmunity, The thymus continuously generates stable, resting populations of naive T cells that maintain the numbers and the diversity of the T-cell repertoire. Under conditions of lymphopenia prolonged by inadequate thymopoiesis, compensatory peripheral expansion of T cells occurs to maintain stable T-cell levels. Under circumstances in which the repertoire is limited, Homeostatic proliferation may increase the opportunity for T-cells reactive with self antigens to expand, leading to autoimmune disorders. In all of these respects, the thymus maintains immunologic tolerance to self. Given the importance of the thymus in control of autoimmunity, the gradual age-dependent decline in thymic cytoarchitecture and thymopoietic productivity may, therefore, contribute to the development of auto-reactivity and loss of self-tolerance. PMID:17876107

  20. Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J; Lehmann, Manja; Schott, Jonathan M; Rabinovici, Gil D; Rossor, Martin N; Fox, Nick C

    2013-01-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management. PMID:22265212

  1. Genetics Home Reference: optic atrophy type 1

    MedlinePlus

    ... Conditions optic atrophy type 1 optic atrophy type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Optic atrophy type 1 is a condition that affects vision. Individuals with ...

  2. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells.

    PubMed

    Gray, Daniel H D; Seach, Natalie; Ueno, Tomoo; Milton, Morag K; Liston, Adrian; Lew, Andrew M; Goodnow, Christopher C; Boyd, Richard L

    2006-12-01

    Despite the importance of thymic stromal cells to T-cell development, relatively little is known about their biology. Here, we use single-cell analysis of stromal cells to analyze extensive changes in the number and composition of thymic stroma throughout life, revealing a surprisingly dynamic population. Phenotypic progression of thymic epithelial subsets was assessed at high resolution in young mice to provide a developmental framework. The cellular and molecular requirements of adult epithelium were studied, using various mutant mice to demonstrate new cross talk checkpoints dependent on RelB in the cortex and CD40 in the medulla. With the use of Ki67 and BrdU labeling, the turnover of thymic epithelium was found to be rapid, but then diminished on thymic involution. The various defects in stromal turnover and composition that accompanied involution were rapidly reversed following sex steroid ablation. Unexpectedly, mature cortical and medullary epithelium showed a potent capacity to stimulate naive T cells, comparable to that of thymic dendritic cells. Overall, these studies show that the thymic stroma is a surprisingly dynamic population and may have a more direct role in negative selection than previously thought. PMID:16896157

  3. Engineering the Human Thymic Microenvironment to Support Thymopoiesis in Vivo

    PubMed Central

    Chung, Brile; Montel-Hagen, Amélie; Ge, Shundi; Blumberg, Garrett; Kim, Kenneth; Klein, Sam; Zhu, Yuhua; Parekh, Chintan; Balamurugan, Arumugam; Yang, Otto O.; Crooks, Gay M.

    2014-01-01

    A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis, and to develop potential cell therapies for thymic insufficiency. In this report, we developed an implantable thymic microenvironment composed of two human thymic stroma populations critical for thymopoiesis; thymic epithelial cells (TECs) and thymic mesenchyme (TM). TECs and TM from postnatal human thymi were cultured in specific conditions, allowing cell expansion and manipulation of gene expression, prior to re-aggregation into a functional thymic unit. Human CD34+ hematopoietic stem and progenitor cells (HSPC) differentiated into T cells in the aggregates in vitro and in vivo following inguinal implantation of aggregates in immune deficient mice. Cord blood HSPC previously engrafted into murine bone marrow, migrated to implants and differentiated into human T cells with a broad T cell receptor repertoire. Furthermore, lentiviral-mediated expression of vascular endothelial growth factor in TM enhanced implant size and function, and significantly increased thymocyte production. These results demonstrate an in vivo system for the generation of T cells from human HSPC, and represent the first model to allow manipulation of gene expression and cell composition in the microenvironment of the human thymus. PMID:24801626

  4. Pancreatic metastasis resulting from thymic neuroendocrine carcinoma: A case report

    PubMed Central

    DU, YANG; WANG, YING; TANG, JIE; GE, JUN; QIN, QING; JIANG, LI; LIU, XIAOKE; ZHU, XIANGLAN; WANG, YONGSHENG

    2016-01-01

    Thymic neuroendocrine carcinoma (NEC) is a rare type of cancer. Unlike other thymic epithelial tumors and carcinoids originating in other locations, thymic NEC possesses a more aggressive biological behavior, including invasion to proximal structures, local recurrence and distant hematogenous metastasis. Distant metastasis is often observed in the bones, lungs, spleen, liver and adrenal glands. However, pancreatic metastasis resulting from thymic NEC is extremely uncommon, and only a few cases of patients with this disease have been reported. The current study presents the case of a patient with pancreatic metastasis resulting from thymic NEC. The patient was admitted to hospital with an anterior mediastinal neoplasm, which was identified using chest enhanced computed tomography. The patient underwent a monobloc excision of the tumor with resection of involved structures. Subsequently, a pathological diagnosis of atypical thymic carcinoid was provided, according to the morphological characteristics observed and the expression of neuroendocrine markers, as identified by immunohistochemistry. Following surgery, the patient received adjuvant chemotherapy and radiotherapy. However, ~2 years after surgery, metastasis at the pancreatic head was identified. The patient underwent a total pancreatectomy and splenectomy, and did not receive any post-operative therapies; however, the patient succumbed to the disease 9 months following surgery. Overall, the results from the present study demonstrate the clinical features of thymic NEC, which may aid with the diagnosis of this rare disease in other patients. PMID:26998098

  5. Thymic Function Is Most Severely Impaired in Chronic HIV-1 Infection, but Individuals With Faster Disease Progression During Early HIV-1 Infection Expressed Lower Levels of RTEs.

    PubMed

    He, Sijia; Zhang, Zining; Fu, Yajing; Qin, Chaolong; Li, Sha; Han, Xiaoxu; Xu, Junjie; Liu, Jing; Jiang, Yongjun; Shang, Hong

    2015-12-15

    In HIV disease course, the decline of peripheral CD4 T-cell count correlates with rapid disease progression. The supply of peripheral naive T cells by the thymus requires precursor T-cell proliferation within the thymus. In the setting of HIV-1 infection, when both naive and memory T cells are progressively depleted, the contribution of thymic dysfunction in CD4 depletion needs to be studied. Previous research has shown that thymic function may also be impaired in HIV-1 infection. However, it is inconclusive regarding whether this impairment occurred at the early time or during the chronic phase. In addition, the relationship between thymic dysfunction and disease progression remains unknown. In this study, we examined the thymic function in 65 HIV-infected individuals. Among them, 17 were in acute phase, 15 were in early chronic phase, 15 were in chronic phase with no ART (antiretroviral therapy), and 18 were on ART. We also included 11 uninfected individuals as controls. We measured the peripheral blood levels of T-cell receptor rearrangement excision circles and PTK7 and CD31 expressions for the frequency of circulating recent thymic emigrants. We observed that the 2 indicators of thymic function, sj/β-TREC and PTK7, seemed to be lower in the chronic infection group than those in the acute and early chronic groups. Both indicators returned to the normal level after ART. However, after 1-year follow-up of patients with early HIV-1 infection, rapid progressors (n = 4) had lower PTK7 and CD31 expressions than chronic progressors (n = 6). PMID:26569175

  6. [Multiple system atrophy].

    PubMed

    Damon-Perrière, Nathalie; Tison, François; Meissner, Wassilios G

    2010-09-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder of unknown etiology. It is the most frequent disorder among atypical parkinsonism with an estimated prevalence of 2 to 5 per 100 000 inhabitants. The clinical symptoms are rapidly progressing with a mean survival ranging between 6 to 9 years. The diagnosis is based on consensus criteria that have been revised in 2008. The diagnostic criteria allow defining "possible", "probable" and "definite" MSA. The latter requires post mortem confirmation of striatonigral and olivopontocerebellar degeneration with alpha-synuclein containing glial cytoplasmic inclusions. The diagnosis of "possible" and "probable" MSA is based on the variable presence and severity of parkinsonism, cerebellar dysfunction, autonomic failure and pyramidal signs. According to the revised criteria, atrophy of putamen, pons, middle cerebellar peduncle (MCP) or cerebellum on brain magnetic resonance imaging are considered to be additional features for the diagnosis of "possible" MSA. T2-weighted brain imaging may further reveal a putaminal hypointensity, a hyperintense lateral putaminal rim, the so called "hot cross bun sign" and MCP hyperintensities. Cardiovascular examination, urodynamic testing and anal sphincter electromyography may be helpful for the diagnosis of autonomic failure. Some patients may respond to levodopa, but usually to a lesser extent than those suffering from Parkinson's disease, and high doses are already required in early disease stages. No specific therapy is available for cerebellar dysfunction, while effective treatments exist for urinary and cardiovascular autonomic failure. Physical therapy may help to improve the difficulties of gait and stance, and to prevent their complications. In later disease stages, speech therapy becomes necessary for the treatment of dysarthria and dysphagia. Percutaneous gastrostomy is sometimes necessary in patients with severe dysphagia. Beyond these strategies, psychological

  7. Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function

    PubMed Central

    Garfin, Phillip M.; Nguyen, Thuyen; Sage, Julien

    2016-01-01

    The thymus is the site of T cell development and selection. In addition to lymphocytes, the thymus is composed of several types of stromal cells that are exquisitely organized to create the appropriate environment and microenvironment to support the development and selection of maturing T cells. Thymic epithelial cells (TECs) are one of the more important cell types in the thymic stroma, and they play a critical role in selecting functional T cell clones and supporting their development. In this study, we used a mouse genetics approach to investigate the consequences of deleting the Pten tumor suppressor gene in the TEC compartment of the developing thymus. We found that PTEN deficiency in TECs results in a smaller thymus with significantly disordered architecture and histology. Accordingly, loss of PTEN function also results in decreased T cells with a shift in the distribution of T cell subtypes towards CD8+ T cells. These experiments demonstrate that PTEN is critically required for the development of a functional thymic epithelium in mice. This work may help better understand the effects that certain medical conditions or clinical interventions have upon the thymus and immune function. PMID:26914657

  8. Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function.

    PubMed

    Garfin, Phillip M; Nguyen, Thuyen; Sage, Julien

    2016-01-01

    The thymus is the site of T cell development and selection. In addition to lymphocytes, the thymus is composed of several types of stromal cells that are exquisitely organized to create the appropriate environment and microenvironment to support the development and selection of maturing T cells. Thymic epithelial cells (TECs) are one of the more important cell types in the thymic stroma, and they play a critical role in selecting functional T cell clones and supporting their development. In this study, we used a mouse genetics approach to investigate the consequences of deleting the Pten tumor suppressor gene in the TEC compartment of the developing thymus. We found that PTEN deficiency in TECs results in a smaller thymus with significantly disordered architecture and histology. Accordingly, loss of PTEN function also results in decreased T cells with a shift in the distribution of T cell subtypes towards CD8+ T cells. These experiments demonstrate that PTEN is critically required for the development of a functional thymic epithelium in mice. This work may help better understand the effects that certain medical conditions or clinical interventions have upon the thymus and immune function. PMID:26914657

  9. [Thymic carcinoid associated with ectopic ACTH syndrome].

    PubMed

    Ishikawa, T; Inoue, C; Sasaki, H; Satou, K; Kimura, N

    1996-04-01

    A 63-year-old man was admitted to Sendai Red Cross Hospital complaining of chest and back pain associated with Cushing's syndrome. Based on the abnormally high levels of ACTH, cortisol, and CRH in plasma the patient was suspected of having ectopic ACTH syndrome. Histological examination of an extirpated rib and pleural tumor led to the diagnosis of atypical carcinoid tumor, with ribbon and festoon formation, immunoreactivity to ACTH, NSE, Chg-A, and argyrophilia in the tumor cells. Anti-cancer chemotherapy was not effective, and the patient died within a year after the onset of Cushing's syndrome. An autopsy revealed that the patient had an ACTH- and CRH-producing thymic carcinoid with metastases to many organs. The pituitary was atrophic with Crooke's hyaline change. There were many CRH-positive cells in the paraventricular nuclei of the hypothalamus, where no remarkable pathologic changes were seen. PMID:8691671

  10. Thymic teratoma masquerading as a thyroid lump.

    PubMed

    Cho, W S; Sahota, R; Tanweer, F; Conboy, P

    2014-05-01

    Teratomas are germ cell tumours commonly found in the sacrococcygeal region, ovary, testicle or, infrequently, the mediastinum. In very rare circumstances, these tumours are found in the neck. This case represents a thymic teratoma presenting as what appeared to be an intrathyroid lesion. This has not been described previously and demonstrates an unusual presentation of a neck lump necessitating two operations and a multidisciplinary approach for management. We would also like to highlight that while patients undergo imaging to guide surgery, the surgeon must always be prepared for the unexpected and recognise situations where the operation should be converted to an exploratory procedure instead of full resection. Often, combined surgical care is the best option for difficult congenital cases. PMID:24780013

  11. Thymic carcinoma presenting as atypical chest pain.

    PubMed

    Siddiqui, Sadiq; Connelly, Tara; Keita, Luther; Blazkova, Sylvie; Veerasingam, Dave

    2015-01-01

    A 58-year-old woman with a 2-month history of atypical chest pain was referred to the chest pain clinic by the general practitioner. Exercise stress test was positive and subsequent coronary angiogram revealed significant triple vessel disease with left ventricular impairment requiring a coronary artery bypass graft (CABG). The patient had a chest X-ray as part of the preoperative work up. Chest X-ray revealed a large anterior mediastinal mass. Subsequent thorax CT revealed a 7.2 cm anterior mediastinal mass. CT-guided biopsy of the mass revealed the diagnosis of a poorly differentiated thymic basaloid carcinoma. The patient was successfully treated with concomitant surgery involving complete resection of the mass and a CABG procedure. PMID:26607199

  12. Sonic Hedgehog regulates thymic epithelial cell differentiation

    PubMed Central

    Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L.; Ono, Masahiro; Holländer, Georg; Crompton, Tessa

    2016-01-01

    Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus. PMID

  13. Sonic Hedgehog regulates thymic epithelial cell differentiation.

    PubMed

    Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L; Ono, Masahiro; Holländer, Georg; Crompton, Tessa

    2016-04-01

    Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus. PMID

  14. Spinal muscular atrophy

    PubMed Central

    2011-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic

  15. Thymic carcinoma in myasthenia gravis developing years after thymectomy.

    PubMed

    Katzberg, Hans D; Miller, Robert G; Katz, Jonathan

    2009-07-01

    We report two patients with myasthenia gravis (MG) who underwent thymectomy but developed thymic carcinoma years after the initial surgery. In one patient, the initial thymic pathology was normal, whereas the other had an encapsulated benign thymoma that was found only on pathological assessment. These cases demonstrate that MG may occur as part of a "new" paraneoplastic syndrome even after thymectomy. The late appearance of metastatic thymoma raises questions about monitoring for these patients. PMID:19533649

  16. Research opportunities in muscle atrophy

    NASA Technical Reports Server (NTRS)

    Herbison, G. J.; Talbot, J. M.

    1984-01-01

    A trophy of skeletal muscle; muscle a trophy associated with manned space flight; the nature, causes, and mechanisms of muscle atrophy associated with space flight, selected physiological factors, biochemical aspects, and countermeasures are addressed.

  17. Dentatorubral-pallidoluysian atrophy.

    PubMed

    Tsuji, Shoji

    2012-01-01

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The most striking clinical features of DRPLA are the considerable heterogeneity in clinical presentation, depending on the age of onset, and the prominent genetic anticipation. DRPLA is caused by unstable expansion of CAG repeats coding for polyglutamine stretches located in exon 5 of the DRPLA gene. DRPLA is characterized by prominent anticipation, with paternal transmission resulting in more prominent anticipation than does maternal transmission, which is now understood based on the intergenerational stability of the CAG repeats. DRPLA protein (also called atrophin-1) is localized in the nucleus and functions as a transcription co-regulator. Recent immunohistochemical studies on autopsied tissues of patients with DRPLA have demonstrated that diffuse accumulation of mutant DRPLA protein (atrophin-1) in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), is the predominant pathologic condition and involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. Thus, age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in DRPLA. PMID:21827919

  18. Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies.

    PubMed Central

    Shen, M M; Skoda, R C; Cardiff, R D; Campos-Torres, J; Leder, P; Ornitz, D M

    1994-01-01

    Leukemia inhibitory factor (LIF) is a cytokine involved in embryonic and hematopoietic development. To investigate the effects of LIF on the lymphoid system, we generated a line of transgenic mice that expresses diffusible LIF protein specifically in T cells. These mice display two categories of phenotype that were not previously attributed to LIF overexpression. First, they display B cell hyperplasia, polyclonal hypergammaglobulinemia and mesangial proliferative glomerulonephritis, defects similar to those described for transgenic mice overexpressing the functionally related cytokine, interleukin-6. Secondly, the LIF transgenic mice display novel thymic and lymph node abnormalities. In the thymus, cortical CD4+CD8+ lymphocytes are lost, while numerous B cell follicles develop. Peripheral lymph nodes contain a vastly expanded CD4+CD8+ lymphocyte population. Furthermore, the thymic epithelium is profoundly disorganized, suggesting that disruption of stroma-lymphocyte interactions is responsible for many observed defects. Transplantation of transgenic bone marrow into wild type recipients transfers both the thymic and lymph node defects. However, transplantation of wild type marrow into transgenic recipients rescues the lymph node abnormality, but not the thymic defect, indicating the thymic epithelium is irreversibly altered. Our observations are consistent with a role for LIF in maintaining a functional thymic epithelium that will support proper T cell maturation. Images PMID:8137821

  19. Frontal Cortical Atrophy as a Predictor of Poststroke Apathy.

    PubMed

    Mihalov, Ján; Mikula, Peter; Budiš, Jaroslav; Valkovič, Peter

    2016-07-01

    The aim of the study was to identify associations between the symptoms of poststroke apathy and sociodemographic, stroke-related (severity of stroke, degree of disability, and performance in activities of daily living), and radiological correlates. We determined the degree of cortical and subcortical brain atrophy, the severity of white matter and basal ganglia lesions on baseline computed tomography (CT) scans, and the localization of acute ischemia on control CT or magnetic resonance imaging scans in subacute stages of stroke. During follow-up examinations, in addition to the assessment of apathy symptoms using the Apathy Scale, we also evaluated symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale. The study included 47 consecutive patients with acute ischemic stroke. Correlates significantly associated with apathy, determined at baseline and during follow-up, were entered into the "predictive" and "associative" multiple regression models, respectively. Frontal cortical atrophy and symptoms of depression were most strongly associated with poststroke apathy symptoms. In order to model an interrelation between both cortical atrophy and white matter lesions and aging, we supplemented 2 additional "predictive" models using interaction variables, whereby we confirmed the role of frontal cortical atrophy as a predictor of poststroke apathy also as a function of the increasing age of patients. PMID:27056065

  20. Haptoglobin Is Required to Prevent Oxidative Stress and Muscle Atrophy

    PubMed Central

    Lo Verso, Francesca; Santini, Ferruccio; Vitti, Paolo; Chisari, Carmelo; Sandri, Marco; Maffei, Margherita

    2014-01-01

    Background Oxidative stress (OS) plays a major role on tissue function. Several catabolic or stress conditions exacerbate OS, inducing organ deterioration. Haptoglobin (Hp) is a circulating acute phase protein, produced by liver and adipose tissue, and has an important anti-oxidant function. Hp is induced in pro-oxidative conditions such as systemic inflammation or obesity. The role of systemic factors that modulate oxidative stress inside muscle cells is still poorly investigated. Results We used Hp knockout mice (Hp-/-) to determine the role of this protein and therefore, of systemic OS in maintenance of muscle mass and function. Absence of Hp caused muscle atrophy and weakness due to activation of an atrophy program. When animals were stressed by acute exercise or by high fat diet (HFD), OS, muscle atrophy and force drop were exacerbated in Hp-/-. Depending from the stress condition, autophagy-lysosome and ubiquitin-proteasome systems were differently induced. Conclusions Hp is required to prevent OS and the activation of pathways leading to muscle atrophy and weakness in normal condition and upon metabolic challenges. PMID:24959824

  1. T cell-B cell thymic cross-talk: Maintenance and function of thymic B cells requires cognate CD40-CD40L interaction

    PubMed Central

    Fujihara, Chiharu; Williams, Joy A.; Watanabe, Masashi; Jeon, Hyein; Sharrow, Susan O.; Hodes, Richard J.

    2014-01-01

    Thymic development requires bidirectional interaction or cross-talk between developing T cells and thymic stromal cells, a relationship that has been best characterized for the interaction between thymocytes and thymic epithelial cells (TECs). We have characterized here the requirement for similar cross-talk in the maintenance and function of thymic B cells, another population that plays a role in selection of developing thymic T cells. We found that maintenance of thymic B cells is strongly dependent upon the presence of mature single positive (SP) thymocytes and on the interactions of these T cells with specific antigen ligand. Maintenance of thymic B cell number is strongly dependent upon B cell-autonomous expression of CD40, but not MHCII, indicating that direct engagement of CD40 on thymic B cells is necessary to support their maintenance and proliferation. Thymic B cells can mediate negative selection of superantigen-specific self-reactive SP thymocytes, and we show that CD40 expression on B cells is critical for this negative selection. Cross-talk with thymic T cells is thus required to support the thymic B cell population through a pathway that requires cell-autonomous expression of CD40, and that reciprocally functions in negative selection of autoreactive T cells. PMID:25344473

  2. Effects of muscle atrophy on motor control

    NASA Technical Reports Server (NTRS)

    Stuart, D. G.

    1985-01-01

    As a biological tissue, muscle adapts to the demands of usage. One traditional way of assessing the extent of this adaptation has been to examine the effects of an altered-activity protocol on the physiological properties of muscles. However, in order to accurately interpret the changes associated with an activity pattern, it is necessary to employ an appropriate control model. A substantial literature exists which reports altered-use effects by comparing experimental observations with those from animals raised in small laboratory cages. Some evidence suggests that small-cage-reared animals actually represent a model of reduced use. For example, laboratory animals subjected to limited physical activity have shown resistance to insulin-induced glucose uptake which can be altered by exercise training. This project concerned itself with the basic mechanisms underlying muscle atrophy. Specifically, the project addressed the issue of the appropriateness of rats raised in conventional-sized cages as experimental models to examine this phenomenon. The project hypothesis was that rats raised in small cages are inappropriate models for the study of muscle atrophy. The experimental protocol involved: 1) raising two populations of rats, one group in conventional (small)-sized cages and the other group in a much larger (133x) cage, from weanling age (21 days) through to young adulthood (125 days); 2) comparison of size- and force-related characteristics of selected test muscles in an acute terminal paradigm.

  3. Development of prelymphoma cells committed to thymic lymphomas during radiation-induced thymic lymphomagenesis in B10 mice

    SciTech Connect

    Muto, M.; Kubo, E.; Sado, T.

    1987-07-01

    Intrathymic (i.t.) as well as i.p. injection of thymus cells from B10.Thy-1.1 mice manifesting overt thymic lymphomas, 4 months after split-dose irradiation, into B10.Thy-1.2 recipient mice resulted in the development of donor-type T-cell lymphomas, indicating that they contained autonomous lymphoma cells. In contrast, injection of thymus cells from apparently nonleukemic mice 1 month after split-dose irradiation resulted in the development of donor-type tumors only when they were injected i.t., suggesting that thymus cells from these mice contained preneoplastic cells that will eventually develop into thymic lymphomas under the influence of thymic microenvironment. These thymus-dependent preneoplastic cells were termed thymic prelymphoma cells. With the use of i.t. injection assay, it was shown that these thymic prelymphoma cells were detected in 26.1% (6 of 23) of the test donor thymuses when examined at 14 days and in more than 63% (15 of 24 and 14 of 22) when examined at 21 and 31 days after irradiation. To examine the possibility that thymic prelymphoma cells might appear first in the bone marrow before they become detectable within the thymuses of the split-dose-irradiated mice, bone marrow cells from B10.Thy-1.1 donors recovered at 8, 14, 21, and 33 days after split-dose irradiation were also injected i.t. into B10.Thy-1.2-recipient mice. The results indicated that none of these recipients developed donor-type T-cell lymphomas, suggesting that bone marrow is not the first site of the appearance of thymic prelymphoma cells.

  4. The evolution of thymic lymphomas in p53 knockout mice.

    PubMed

    Dudgeon, Crissy; Chan, Chang; Kang, Wenfeng; Sun, Yvonne; Emerson, Ryan; Robins, Harlan; Levine, Arnold J

    2014-12-01

    Germline deletion of the p53 gene in mice gives rise to spontaneous thymic (T-cell) lymphomas. In this study, the p53 knockout mouse was employed as a model to study the mutational evolution of tumorigenesis. The clonality of the T-cell repertoire from p53 knockout and wild-type thymic cells was analyzed at various ages employing TCRβ sequencing. These data demonstrate that p53 knockout thymic lymphomas arose in an oligoclonal fashion, with tumors evolving dominant clones over time. Exon sequencing of tumor DNA revealed that all of the independently derived oligoclonal mouse tumors had a deletion in the Pten gene prior to the formation of the TCRβ rearrangement, produced early in development. This was followed in each independent clone of the thymic lymphoma by the amplification or overexpression of cyclin Ds and Cdk6. Alterations in the expression of Ikaros were common and blocked further development of CD-4/CD-8 T cells. While the frequency of point mutations in the genome of these lymphomas was one per megabase, there were a tremendous number of copy number variations producing the tumors' driver mutations. The initial inherited loss of p53 functions appeared to delineate an order of genetic alterations selected for during the evolution of these thymic lymphomas. PMID:25452272

  5. Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile.

    PubMed

    Patenaude, Julien; Perreault, Claude

    2016-06-01

    In order to understand the role of mesenchymal cells (MCs) in the adult thymus, we performed whole transcriptome analyses of primary thymic, bone, and skin MCs. These three MC populations shared expression of 2850 core MC genes involved in generic processes including interactions with tissue-resident macrophages. Moreover, we discovered that 2036 genes were differentially expressed, by at least 5-fold, in the three MC populations. Genes preferentially expressed in thymic MCs are instrumental in clearance of apoptotic thymocytes by macrophages, maintenance of a noninflammatory milieu, and attraction-expansion of thymocyte progenitors. Thymic and bone MCs share other sets of differentially expressed genes implicated in resolution of inflammation and expansion of hematolymphoid progenitors. Consistent with the fact that thymic and skin MCs have to support epithelial cells, they express at higher levels genes mediating epithelial cell adhesion to basement membrane and mesenchymal-epithelial cross-talk. Differentially expressed genes preferentially expressed by bone MCs are connected to formation and remodeling of bone, whereas those preferentially expressed in skin MCs are involved in skin and hair follicle homeostasis. We conclude that MCs from different organs display substantial heterogeneity and that the transcriptome of thymic MCs is exquisitely suited for interactions with epithelial and hematolymphoid cells in an environment with a high apoptosis rate. PMID:27183606

  6. Thymic neoplasm: a rare disease with a complex clinical presentation

    PubMed Central

    Rashid, Omar M.; Cassano, Anthony D.

    2013-01-01

    Thymic neoplasms constitute a broad category of rare lesions with a wide spectrum of pathologic characteristics and clinical presentations which therefore require a high index of suspicion to diagnose. The natural history of the disease is seldom predictable, anywhere from an indolent to an aggressively malignant course. Although the classification and staging of these lesions are complex and controversial, complete radical surgical resection remains the gold standard of therapy. Radiation and chemotherapy are important elements of the multimodality approach to treating these patients and it is important for thoracic surgeons to work closely with their colleagues in other disciplines in the management of and future research endeavors in thymic neoplasm. In this review, we discuss the evaluation of the patient with an anterior mediastinal mass, the classification and staging of thymic neoplasms, the role of surgery, radiation and chemotherapy in treating this disease, as well as future directions in research for novel targeted therapies. PMID:23585946

  7. Plasma thymic hormone activity in patients with chronic mucocutaneous candidiasis

    PubMed Central

    Kirkpatrick, C. H.; Greenberg, Lynn E.; Chapman, S. W.; Goldstein, G.; Lewis, Verna M.; Twomey, J. J.

    1978-01-01

    To further characterize the immunological abnormalities in patients with chronic mucocutaneous candidiasis, the thymic hormone activity in their plasma was measured. Of the sixteen patients in the study, seven had chronic diffuse candidiasis, five had candidiasis with endocrinopathies and four had candidiasis with thymoma. Only one patient, an anergic child with chronic diffuse candidiasis had severe deficiency of plasma thymic hormone activity. Two patients, a woman with candidiasis and multiple endocrinopathies and an elderly man with metastatic epithelial thymoma had supranormal values. These studies indicate that the immunological deficit in most patients with these forms of chronic mucocutaneous candidiasis is not due to deficiency of a thymic inductive activity and suggest that an intrinsic defect exists in the maturation of antigen-responsive lymphoid cells. PMID:743805

  8. Genetics Home Reference: multiple system atrophy

    MedlinePlus

    ... OPCA progressive autonomic failure with multiple system atrophy SDS Shy-Drager syndrome sporadic olivopontocerebellar atrophy Related Information ... A, Hulot JS, Morrison KE, Renton A, Sussmuth SD, Landwehrmeyer BG, Ludolph A, Agid Y, Brice A, ...

  9. Bioprocessing feasibility analysis. [thymic hormone bioassay and electrophoresis

    NASA Technical Reports Server (NTRS)

    1978-01-01

    The biology and pathophysiology of the thymus gland is discussed and a clinical procedure for thymic hormone assay is described. The separation of null lymphocytes from mice spleens and the functional characteristics of the cells after storage and transportation were investigated to develop a clinical procedure for thymic hormone assay, and to determine whether a ground-based approach will provide the desired end-product in sufficient quantities, or whether the microgravity of space should be exploited for more economical preparation of the hormone.

  10. Flow Cytometry Analysis of Thymic Epithelial Cells and Their Subpopulations.

    PubMed

    Ohigashi, Izumi; Takahama, Yousuke

    2016-01-01

    The parenchyma of the thymus is compartmentalized into the cortex and the medulla, which are constructed by cortical thymic epithelial cells (cortical TECs, cTECs) and medullary thymic epithelial cells (mTECs), respectively. cTECs and mTECs essentially and differentially regulate the development and repertoire selection of T cells. Consequently, the biology of T cell development and selection includes the study of TECs in addition to the study of developing T cells and other hematopoietic cells including dendritic cells. In this chapter, we describe the methods for flow cytometric analysis and sorting of TECs and their subpopulations, including cTECs and mTECs. PMID:26294398

  11. Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice

    PubMed Central

    Fiume, Giuseppe; Scialdone, Annarita; Albano, Francesco; Rossi, Annalisa; Maria Tuccillo, Franca; Rea, Domenica; Palmieri, Camillo; Caiazzo, Elisabetta; Cicala, Carla; Bellevicine, Claudio; Falcone, Cristina; Vecchio, Eleonora; Pisano, Antonio; Ceglia, Simona; Mimmi, Selena; Iaccino, Enrico; Laurentiis, Annamaria de; Pontoriero, Marilena; Agosti, Valter; Troncone, Giancarlo; Mignogna, Chiara; Palma, Giuseppe; Arra, Claudio; Mallardo, Massimo; Maria Buonaguro, Franco; Scala, Giuseppe; Quinto, Ileana

    2015-01-01

    Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4+ and CD8+ T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation. PMID:26343909

  12. Impairment of T cell development and acute inflammatory response in HIV-1 Tat transgenic mice.

    PubMed

    Fiume, Giuseppe; Scialdone, Annarita; Albano, Francesco; Rossi, Annalisa; Tuccillo, Franca Maria; Rea, Domenica; Palmieri, Camillo; Caiazzo, Elisabetta; Cicala, Carla; Bellevicine, Claudio; Falcone, Cristina; Vecchio, Eleonora; Pisano, Antonio; Ceglia, Simona; Mimmi, Selena; Iaccino, Enrico; de Laurentiis, Annamaria; Pontoriero, Marilena; Agosti, Valter; Troncone, Giancarlo; Mignogna, Chiara; Palma, Giuseppe; Arra, Claudio; Mallardo, Massimo; Buonaguro, Franco Maria; Scala, Giuseppe; Quinto, Ileana

    2015-01-01

    Immune activation and chronic inflammation are hallmark features of HIV infection causing T-cell depletion and cellular immune dysfunction in AIDS. Here, we addressed the issue whether HIV-1 Tat could affect T cell development and acute inflammatory response by generating a transgenic mouse expressing Tat in lymphoid tissue. Tat-Tg mice showed thymus atrophy and the maturation block from DN4 to DP thymic subpopulations, resulting in CD4(+) and CD8(+) T cells depletion in peripheral blood. In Tat-positive thymus, we observed the increased p65/NF-κB activity and deregulated expression of cytokines/chemokines and microRNA-181a-1, which are involved in T-lymphopoiesis. Upon LPS intraperitoneal injection, Tat-Tg mice developed an abnormal acute inflammatory response, which was characterized by enhanced lethality and production of inflammatory cytokines. Based on these findings, Tat-Tg mouse could represent an animal model for testing adjunctive therapies of HIV-1-associated inflammation and immune deregulation. PMID:26343909

  13. Thymic B cells promote thymus-derived regulatory T cell development and proliferation.

    PubMed

    Lu, Fang-Ting; Yang, Wei; Wang, Yin-Hu; Ma, Hong-Di; Tang, Wei; Yang, Jing-Bo; Li, Liang; Ansari, Aftab A; Lian, Zhe-Xiong

    2015-07-01

    Thymic CD4(+) FoxP3(+) regulatory T (Treg) cells are critical for the development of immunological tolerance and immune homeostasis and requires contributions of both thymic dendritic and epithelial cells. Although B cells have been reported to be present within the thymus, there has not hitherto been a definition of their role in immune cell development and, in particular, whether or how they contribute to the Treg cellular thymic compartment. Herein, using both phenotypic and functional approaches, we demonstrate that thymic B cells contribute to the maintenance of thymic Treg cells and, using an in vitro culture system, demonstrate that thymic B cells contribute to the size of the thymic Treg compartment via cell-cell MHC II contact and the involvement of two independent co-stimulatory pathways that include interactions between the CD40/CD80/CD86 co-stimulatory molecules. Our data also suggest that thymic B cells promote the generation of thymic Treg cell precursors (pre-Treg cells), but not the conversion of FoxP3(+) Treg cells from pre-Treg cells. In addition, thymic B cells directly promote the proliferation of thymic Treg cells that is MHC II contact dependent with a minimal if any role for co-stimulatory molecules including CD40/CD80/CD86. Both pathways are independent of TGFβ. In conclusion, we rigorously define the critical role of thymic B cells in the development of thymic Treg cells from non-Treg to precursor stage and in the proliferation of mature thymic Treg cells. PMID:26071985

  14. Role of chemotherapy in the management of advanced thymic tumors.

    PubMed

    Evans, Tracey L; Lynch, Thomas J

    2005-01-01

    Chemotherapy has an important role in the treatment of advanced thymic tumors. Early stage tumors are successfully treated with surgery. Locally advanced tumors (Masaoka stage III and IVA) are often treated with combined modality treatment including surgery, radiation, and chemotherapy. For patients with curable thymic tumors, the ability to attain a complete resection is a critical prognostic factor. Locally advanced tumors have a relatively high risk of recurrence and decreased rates of long-term survival. A multimodality approach including induction chemotherapy and postoperative radiation therapy can improve complete resection rates and long-term outcomes. Thymic tumors are chemoresponsive with optimal responses achieved with cisplatin-based combination chemotherapy. Chemotherapy with radiation can result in long-term progression-free survival for patients with locally advanced disease who remain inoperable following induction therapy. Patients with disseminated (stage IVB) thymic tumors can also have significant disease response and palliation of symptoms when treated with chemotherapy. Octreotide and corticosteroids also have shown efficacy. For best results, it is important that thoracic surgeons, radiation oncologists, and medical oncologists work together to obtain the best local control of tumor and optimal treatment of metastases. PMID:16104360

  15. Heterogeneity in Thymic Emigrants: Implications for Thymectomy and Immunosenescence

    PubMed Central

    Bains, Iren; Yates, Andrew J.; Callard, Robin E.

    2013-01-01

    The development of mature, antigen-inexperienced (naive) T cells begins in the thymus and continues after export into the periphery. Post-thymic maturation of naive T cells, in humans, coincides with the progressive loss of markers such as protein tyrosine kinase 7 (PTK7) and platelet endothelial cell adhesion molecule-1 (CD31). As a consequence, subpopulations of naive T cells can be recognised raising questions about the processes that give rise to the loss of these markers and their exact relationship to recent thymic emigrants (RTE). Here, we combine a mathematical survival analysis approach and data from healthy and thymectomised humans to understand the apparent persistence of populations of ‘veteran’ PTK7+T cells in thymectomised individuals. We show that a model of heterogeneity in rates of maturation, possibly linked to natural variation in TCR signalling thresholds or affinity for self-antigens, can explain the data. This model of maturation predicts that the average post-thymic age of PTK7+T cells will increase linearly with the age of the host suggesting that, despite the immature phenotype, PTK7+cells do not necessarily represent a population of RTE. Further, the model predicts an accelerated increase in the average post-thymic age of residual PTK7+T cells following thymectomy and may also explain in part the prematurely aged phenotype of the naive T cell pool in individuals thymectomised early in life. PMID:23468830

  16. Chemotherapy and prognosis in advanced thymic carcinoma patients

    PubMed Central

    Song, Zhengbo; Yu, Xinmin; Zhang, Yiping

    2015-01-01

    OBJECTIVE: The role of chemotherapy in treating advanced thymic carcinoma is unclear. The purpose of the current study was to investigate the efficacy of chemotherapy and the prognostic factors for patients with advanced thymic carcinoma. METHODS: A retrospective review of the medical records of 86 patients treated with chemotherapy for advanced thymic carcinoma was conducted between 2000 and 2012 at our institution. The clinical characteristics, chemotherapy regimens and prognostic factors were analyzed. Survival curves were plotted using the Kaplan–Meier method and the Cox proportional hazard model was used for multivariate analysis. RESULTS: Of the 86 patients, 56 were male and 30 were female. The median survival time was 24.5 months. For the first-line chemotherapy treatment, the objective response rate was 47.7% and the disease control rate was 80.2%. The median progression-free survival for all patients was 6.5 months for first-line chemotherapy. No significant differences in progression-free survival were observed among the different chemotherapy regimens. Multivariate analyses revealed that the prognostic factors for overall survival included performance status (p=0.043), histology grade (p=0.048), and liver metastasis (p=0.047). CONCLUSION: Our results suggest that there is no difference in efficacy between multiagent and doublet regimens. The prognosis of patients with advanced thymic carcinoma can be predicted based on histological grade, liver metastasis and performance status. PMID:26735216

  17. Identification of a human recent thymic emigrant phenotype

    PubMed Central

    McFarland, Richard D.; Douek, Daniel C.; Koup, Richard A.; Picker, Louis J.

    2000-01-01

    The ability to measure human thymic output would be an invaluable tool for the study of the development of the naïve T cell repertoire, as well as naïve T cell regeneration after intensive cytotoxic chemotherapy or effective antiretroviral therapy of progressive HIV infection. We and others have demonstrated previously that quantification of T cell receptor rearrangement excision circles (TREC) within peripheral T cell populations provides insight into the frequency of recent thymic emigrants (RTE) and, therefore, into thymic function. However, measurement of RTE by this approach is complicated by the fact that TREC levels also are determined by turnover within the naïve T cell compartment. Here, we report a phenotypic approach to RTE measurement. We demonstrate that αE integrin (CD103) expression is up-regulated very late in thymic development on a subset of CD8+/CD4− thymocytes and also defines a distinct subset of naïve CD8+ T cells in the periphery. The latter subset is differentiated from circulating CD103+ mucosa-associated memory T cells by its naïve T cell phenotype (CD45RO−, CD62Lbright, CD27bright, CD11adim, CD95dim) and its high concentration of TREC. Indeed, sorted CD103+ naïve CD8+ cells display higher levels of TREC than their CD103− naïve counterparts, and these cells demonstrate an age-related decline in frequency that is enhanced significantly by thymectomy. The thymic dependence of this subset and the cells' relatively evanescent presence in the periphery suggest that these cells are a population of RTE and that quantification of their frequency in peripheral blood provides an estimate of the level of ongoing thymopoiesis. PMID:10737767

  18. Thymic hormones in thymus recovery from radiation injury

    SciTech Connect

    Neta; Schwartz, G.N.; MacVittie, T.J.; Douches, S.D.

    1985-01-01

    The effect of a thymic hormone, thymosin fraction 5 (TF5), in restoring immunocompetence in the thymus of gamma-irradiated mice was examined. Three different mouse strains were used in this study, since previous work has established that the response to TF5 varies in different strains. To measure the rate of recovery of immunocompetent cells in the thymus, the responsiveness to comitogenic effect of interleukn-1 (IL-1) was used. This assay was chosen since it has been established that only more mature PNA, Lytl(+2-) medullary cells respond to this monokine. Contrary to several earlier reports that radio-resistant cells repopulating the thymus within the first 10 days after irradiation are mature, corticosteriod-resistant, immunocompetent cells, the thymic cells from irradiated mice in all strains used had greatly reduced responses to IL-1. Daily intraperitoneal injections of TF5 increased significantly the responses of thymic cells to IL-1 in 10-13 weeks old C57B1/KsJ, C3H/HeJ, and DBA/1 mice. Older mice, 5 months or more in age, of DBA/1 strain did not respond to treatment with TF5. However, C3H/HeJ mice of the same age were highly responsive. In conclusion, (a) cells repopulating the thymus within 12 days after irradiation contain lower than normal fraction of mature IL-1 responsive cells, (b) thymic hormones increase the rate of recovery of immunocompetent cells in the thymus, and (c) the effect of thymic hormones is strain and age dependent.

  19. Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution

    PubMed Central

    O’Neill, Kathy E.; Bredenkamp, Nicholas; Tischner, Christin; Vaidya, Harsh J.; Stenhouse, Frances H.; Peddie, C. Diana; Nowell, Craig S.; Gaskell, Terri; Blackburn, C. Clare

    2016-01-01

    Thymus function requires extensive cross-talk between developing T-cells and the thymic epithelium, which consists of cortical and medullary TEC. The transcription factor FOXN1 is the master regulator of TEC differentiation and function, and declining Foxn1 expression with age results in stereotypical thymic involution. Understanding of the dynamics of Foxn1 expression is, however, limited by a lack of single cell resolution data. We have generated a novel reporter of Foxn1 expression, Foxn1G, to monitor changes in Foxn1 expression during embryogenesis and involution. Our data reveal that early differentiation and maturation of cortical and medullary TEC coincides with precise sub-lineage-specific regulation of Foxn1 expression levels. We further show that initiation of thymic involution is associated with reduced cTEC functionality, and proportional expansion of FOXN1-negative TEC in both cortical and medullary sub-lineages. Cortex-specific down-regulation of Foxn1 between 1 and 3 months of age may therefore be a key driver of the early stages of age-related thymic involution. PMID:26983083

  20. Foxn1 Is Dynamically Regulated in Thymic Epithelial Cells during Embryogenesis and at the Onset of Thymic Involution.

    PubMed

    O'Neill, Kathy E; Bredenkamp, Nicholas; Tischner, Christin; Vaidya, Harsh J; Stenhouse, Frances H; Peddie, C Diana; Nowell, Craig S; Gaskell, Terri; Blackburn, C Clare

    2016-01-01

    Thymus function requires extensive cross-talk between developing T-cells and the thymic epithelium, which consists of cortical and medullary TEC. The transcription factor FOXN1 is the master regulator of TEC differentiation and function, and declining Foxn1 expression with age results in stereotypical thymic involution. Understanding of the dynamics of Foxn1 expression is, however, limited by a lack of single cell resolution data. We have generated a novel reporter of Foxn1 expression, Foxn1G, to monitor changes in Foxn1 expression during embryogenesis and involution. Our data reveal that early differentiation and maturation of cortical and medullary TEC coincides with precise sub-lineage-specific regulation of Foxn1 expression levels. We further show that initiation of thymic involution is associated with reduced cTEC functionality, and proportional expansion of FOXN1-negative TEC in both cortical and medullary sub-lineages. Cortex-specific down-regulation of Foxn1 between 1 and 3 months of age may therefore be a key driver of the early stages of age-related thymic involution. PMID:26983083

  1. Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution.

    PubMed

    Youm, Yun-Hee; Horvath, Tamas L; Mangelsdorf, David J; Kliewer, Steven A; Dixit, Vishwa Deep

    2016-01-26

    Age-related thymic degeneration is associated with loss of naïve T cells, restriction of peripheral T-cell diversity, and reduced healthspan due to lower immune competence. The mechanistic basis of age-related thymic demise is unclear, but prior evidence suggests that caloric restriction (CR) can slow thymic aging by maintaining thymic epithelial cell integrity and reducing the generation of intrathymic lipid. Here we show that the prolongevity ketogenic hormone fibroblast growth factor 21 (FGF21), a member of the endocrine FGF subfamily, is expressed in thymic stromal cells along with FGF receptors and its obligate coreceptor, βKlotho. We found that FGF21 expression in thymus declines with age and is induced by CR. Genetic gain of FGF21 function in mice protects against age-related thymic involution with an increase in earliest thymocyte progenitors and cortical thymic epithelial cells. Importantly, FGF21 overexpression reduced intrathymic lipid, increased perithymic brown adipose tissue, and elevated thymic T-cell export and naïve T-cell frequencies in old mice. Conversely, loss of FGF21 function in middle-aged mice accelerated thymic aging, increased lethality, and delayed T-cell reconstitution postirradiation and hematopoietic stem cell transplantation (HSCT). Collectively, FGF21 integrates metabolic and immune systems to prevent thymic injury and may aid in the reestablishment of a diverse T-cell repertoire in cancer patients following HSCT. PMID:26755598

  2. Oral 2.01: Proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma

    PubMed Central

    Vogel, Jennifer H.; Berman, Abigail T.; Pechet, Taine T.; William, Levin P.; Gabriel, Peter E.; Khella, Sami; Singhal, Sunil; Kucharczuk, John C.; Simone, Charles B.

    2015-01-01

    Background Radiation therapy is a critical component of treatment for thymic tumors. However, radiation-induced toxicity may reduce benefit, particularly in the adjuvant setting. Proton beam therapy (PBT), due to its characteristic Bragg peak, is ideally suited to treat the anterior mediastinum while sparing organs at risk. To date, PBT to treat thymic tumors has only been reported in three single-patient case studies. In this study, we evaluated patterns of failure and toxicity in patients treated for thymoma and thymic carcinoma using PBT and hypothesized that PBT can achieve excellent local control with limited high grade toxicity. Methods All patients with thymoma or thymic carcinoma treated with PBT between 2011–2015 were analyzed. Either double scattered proton therapy (DS-PT) or pencil beam scanning (PBS) were used. Toxicity was assessed using CTCAE v 4.2. Local control, distant control, and overall survival were analyzed by the Kaplan-Meier method from the time of PBT completion. Results Twenty-seven patients were included. Patients were a median age of 56 years, predominantly female (56%), and had thymoma (85%) or thymic carcinoma (15%). They were treated with definitive (22%) or salvage (15%) PBT or adjuvant (63%) PBT following resection with predominantly close (23%) or positive (50%) margins. Forty-one percent also received chemotherapy. Patients were treated to a median of 61.2 Gy (range 50.4–70.2 Gy) using DS-PT (85%) or PBS (15%). Median mean lung dose, volume of lung receiving ≥20 Gy (V20), and V5 were 98 cGy (1–2,050 cGy), 18% (0–38%), and 26.2% (0–55%). Median mean heart and esophagus doses were 1,065 cGy (105–3,356cGy) and 1,072cGy (0–4,655 cGy). No patient experienced grade ≥3 acute or chronic toxicity. Acute grade ≥2 toxicities included fatigue (11%), esophagitis (7%), dermatitis (37%), and pneumonitis in one patient (4%) who received 2 prior thoracic radiotherapy courses. Late grade ≥2 toxicity was limited to a single

  3. Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage III-IV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia

    ClinicalTrials.gov

    2015-10-20

    Childhood B Acute Lymphoblastic Leukemia; Childhood Burkitt Leukemia; Childhood Diffuse Large Cell Lymphoma; Mediastinal (Thymic) Large B-Cell Lymphoma; Stage III Childhood Large Cell Lymphoma; Stage IV Childhood Large Cell Lymphoma

  4. Thymic involution in the suspended rat - Adrenal hypertrophy and glucocorticoid receptor content

    NASA Technical Reports Server (NTRS)

    Steffen, J. M.; Musacchia, X. J.

    1986-01-01

    The relationship between thymic involution and adrenal hypertrophy is studied. The thymus, adrenal glands, and tissue water content are evaluated in male Sprague rats suspended in antiorthostatic (AO) or orthostatic (O) positions. A 50 percent decrease in the wet weight of the thymus and hypertrophy of the adrenal glands are observed during the seven days of AO suspension. After seven days of recovery the thymus weight is increased to control level; however, the hypertrophy of the adrenal glands remains unchanged. Thymic and renal responses in O postioned rats are similar to AO reactions. Thymic glucocorticoid (GC) receptor concentrations in the rats are analyzed; a 20 percent decrease in GC receptor site concentration, which is related to thymic involution, is detected in both AO and O rats. It is concluded that there is a temporal correlation between thymic involution and adrenal hypertrophy, which is not affected by AO positioning, and thymic involution is not associated with an increased sensitivity to GC.

  5. Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors.

    PubMed

    Papoudou-Bai, Alexandra; Barbouti, Alexandra; Galani, Vassiliki; Stefanaki, Kalliopi; Rontogianni, Dimitra; Kanavaros, Panagiotis

    2016-05-01

    The human thymus supports the production of self-tolerant T cells with competent and regulatory functions. Various cellular components of the thymic microenvironment such as thymic epithelial cells (TEC) and dendritic cells play essential roles in thymic T cell differentiation. The multiple cellular events occurring during thymic T cell and TEC differentiation involve proteins regulating cell cycle and apoptosis. Dysregulation of the cell cycle and apoptosis networks is involved in the pathogenesis of thymic epithelial tumors (TET) which are divided into two broad categories, thymomas and thymic carcinomas. The present review focuses on the usefulness of the analysis of the expression patterns of major cell cycle and apoptosis regulators in order to gain insight in the histophysiology of thymus and the histopathology, the clinical behavior and the biology of TET. PMID:25794494

  6. Vulvar Skin Atrophy Induced by Topical Glucocorticoids

    PubMed Central

    Johnson, Elisabeth; Groben, Pamela; Eanes, Alisa; Iyer, Priya; Ugoeke, Joseph; Zolnoun, Denniz

    2011-01-01

    Steroid induced skin atrophy is the most frequent and perhaps most important cutaneous side effect of topical glucocorticoid therapy. To date, it has not been described in vulvar skin. We describe a patient with significant vulvar skin atrophy following prolonged steroid application to treat vulvar dermatitis. The extensive atrophy in the perineum resulted in secondary ‘webbing’ and partial obstruction of genital hiatus and superimposed dyspareunia. Prolonged topical steroids may result in atrophic changes in vulvar skin. Therefore, further research in clinical correlates of steroid-induced atrophy in the vulvar region is warranted. PMID:22594868

  7. Intercellular Protein Transfer from Thymocytes to Thymic Epithelial Cells.

    PubMed

    Wang, Hong-Xia; Qiu, Yu-Rong; Zhong, Xiao-Ping

    2016-01-01

    Promiscuous expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is crucial for negative selection of self-reactive T cells to establish central tolerance. Intercellular transfer of self-peptide-MHC complexes from mTECs to thymic dendritic cells (DCs) allows DCs to acquire TRAs, which in turn contributes to negative selection and regulatory T cell generation. However, mTECs are unlikely to express all TRAs, such as immunoglobulins generated only in B cells after somatic recombination, hyper-mutation, or class-switches. We report here that both mTECs and cortical TECs can efficiently acquire not only cell surface but also intracellular proteins from thymocytes. This reveals a previously unappreciated intercellular sharing of molecules from thymocytes to TECs, which may broaden the TRA inventory in mTECs for establishing a full spectrum of central tolerance. PMID:27022746

  8. Ectopic thymic carcinoma presenting as an intrathoracic mass.

    PubMed

    Matsuoka, Katsunari; Murata, Yoshitake; Ueda, Mitsuhiro; Miyamoto, Yoshihiro

    2016-06-01

    An asymptomatic 83-year-old man was found to have a right intrathoracic tumor. Computed tomography demonstrated a soft-tissue density mass measuring 55 × 25 × 22 mm adjacent to the right anterior chest wall. At surgery, the tumor was found to adhere to the diaphragm and right lung, contiguous with the mediastinal fat tissue. Histology of the resected specimen demonstrated proliferation of spindle and sarcomatous cells with multinucleated giant cells. Thus the tumor was diagnosed as undifferentiated thymic carcinoma and was considered to have arisen from ectopic thymic tissue. At 2 years postoperatively, the patient had no evidence of recurrence. PMID:27072863

  9. Clinical and immunohistochemical characterization of thymic lymphosarcoma in a heifer.

    PubMed

    Alexander, A N; Constable, P D; Meier, W A; French, R A; Morin, D E; Lowry, J E; Hoffman, W E

    1996-01-01

    A 2-year-old Holstein heifer with a swollen brisket, jugular vein distention, muffled heart sounds, tachycardia, and free gas bloat was examined. Thymic lymphosarcoma was suspected based on a negative agar gel immunodiffusion test for bovine leukemia virus, presence of atypical lymphocytes in pleural fluid, and detection of a mass in the thoracic inlet. Right-sided cardiac catheterization was performed, and markedly increased jugular venous pressures (41 mm Hg) with a pressure gradient of 29 mm Hg immediately cranial to the heart indicated constriction of the cranial vena cava. Immunohistochemical staining of formalin fixed, paraffin-embedded tissue sections of the tumor using a rabbit antihuman T cell, CD3 polyclonal antibody confirmed that the neoplastic lymphocytes were of thymic origin. PMID:8819055

  10. Intercellular Protein Transfer from Thymocytes to Thymic Epithelial Cells

    PubMed Central

    Wang, Hong-Xia; Qiu, Yu-Rong; Zhong, Xiao-Ping

    2016-01-01

    Promiscuous expression of tissue restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is crucial for negative selection of self-reactive T cells to establish central tolerance. Intercellular transfer of self-peptide-MHC complexes from mTECs to thymic dendritic cells (DCs) allows DCs to acquire TRAs, which in turn contributes to negative selection and regulatory T cell generation. However, mTECs are unlikely to express all TRAs, such as immunoglobulins generated only in B cells after somatic recombination, hyper-mutation, or class-switches. We report here that both mTECs and cortical TECs can efficiently acquire not only cell surface but also intracellular proteins from thymocytes. This reveals a previously unappreciated intercellular sharing of molecules from thymocytes to TECs, which may broaden the TRA inventory in mTECs for establishing a full spectrum of central tolerance. PMID:27022746

  11. Estimation of stress in child neglect from thymic involution.

    PubMed

    Tanegashima, A; Yamamoto, H; Yada, I; Fukunaga, T

    1999-04-12

    It is difficult to evaluate the extent of stress in cases of suspected child abuse/neglect in a medico-legal autopsy. We have previously reported that stress due to abuse/neglect was found to have led to thymic involution. To elucidate the influence upon thymocytes differentiation, we compared the proportion of the thymocyte subpopulation in the thymus of a neglected child with one in an age-matched control obtained from cardiac surgery. We found that the relative number of CD4+ CD8+ double positive (DP) thymocytes decreased in the neglected child. It was presumed that the selective decrease in the number of the immature DP thymocytes with CD3- to low bcl-2low caused the thymic involution in the neglected child. It was suggested that an alteration in the proportion of thymocytes subpopulation might be used as an index of stress in cases of child abuse/neglect. PMID:10376338

  12. Chronic shoulder pain referred from thymic carcinoma: a case report and review of literature

    PubMed Central

    Dee, Shu-Wei; Kao, Mu-Jung; Hong, Chang-Zern; Chou, Li-Wei; Lew, Henry L

    2012-01-01

    We report a case of thymic carcinoma presenting as unilateral shoulder pain for 13 months. Before an accurate diagnosis was made, the patient received conservative treatment, cervical discectomies, and myofascial trigger point injection, none of which relieved his pain. When thymic carcinoma was eventually diagnosed, he received total resection of the tumor and the shoulder pain subsided completely. Thymic carcinoma is a rare carcinoma, and our review of the literature did not show shoulder pain as its initial presentation except for one case report. The purpose of this report is to document our clinical experience so that other physiatrists can include thymic carcinoma in their differential diagnosis of shoulder pain. PMID:22969299

  13. Young, proliferative thymic epithelial cells engraft and function in aging thymuses

    PubMed Central

    Kim, Mi-Jeong; Miller, Christine M.; Shadrach, Jennifer L.; Wagers, Amy J.; Serwold, Thomas

    2015-01-01

    The thymus reaches its maximum size early in life and then begins to shrink, producing fewer T cells with increasing age. This thymic decline is thought to contribute to age-related T cell lymphopenias and hinder T cell recovery following bone marrow transplantation. While several cellular and molecular processes have been implicated in age-related thymic involution, their relative contributions are not known. Using heterochronic parabiosis, we observe that young circulating factors are not sufficient to drive regeneration of the aged thymus. In contrast, we find that resupplying young, engraftable thymic epithelial cells to a middle-aged or defective thymus leads to thymic growth and increased T cell production. Intrathymic transplantation and in vitro colony forming assays reveal that the engraftment and proliferative capacities of thymic epithelial cells diminish early in life, whereas the receptivity of the thymus to thymic epithelial cell engraftment remains relatively constant with age. These results support a model in which thymic growth and subsequent involution are driven by cell intrinsic changes in the proliferative capacity of thymic epithelial cells, and further show that young thymic epithelial cells can engraft and directly drive the growth of involuted thymuses. PMID:25870244

  14. Peripubertal ovariectomy influences thymic adrenergic network plasticity in adult rats.

    PubMed

    Pilipović, Ivan; Vujnović, Ivana; Arsenović-Ranin, Nevena; Dimitrijević, Mirjana; Kosec, Duško; Stojić-Vukanić, Zorica; Leposavić, Gordana

    2016-08-15

    The study investigated the influence of peripubertal ovariectomy on the thymic noradrenaline (NA) concentration, and the thymocyte NA content and β2- and α1-adrenoceptor (AR) expression in adult 2- and 11-month-old rats. In control rats, the thymic NA concentration increased with age. This increase reflected rise in the density of catecholamine (CA)-containing fluorescent nerve fibers and cells and their CA content. Additionally, the average β2- and α1-AR thymocyte surface density changed in the opposite direction with age; the density of β2-AR decreased, whereas that of α1-AR increased. Ovariectomy diminished the thymic NA concentration in 2-month-old rats. This reflected the decrease in the density of fluorescent nerve fibers, and CA content in fluorescent nerve fibers and non-lymphoid cells, since the thymocyte NA content was increased in ovariectomized (Ox) rats. Estrogen supplementation prevented the ovariectomy-induced changes. In Ox rats, the density of CA-synthesizing nerve fibers and non-lymphoid cells diminished with age. To the contrary, NA content in thymocytes increased with age, but it did not exceed that in 11-month-old controls. Additionally, ovariectomy diminished the average thymocyte surface density of β2-ARs, but it increased that of α1-ARs in 2-month-old-rats (due to estrogen, and estrogen and progesterone deficiency, respectively). These changes, despite of the rise in circulating estrogen level post-ovariectomy, remained stable with age. This most likely reflected a decreased sensitivity to estrogen action, as a consequence of the hormone misprinting in peripubertal age. The analysis of thymocyte proliferation in culture suggested that age- and ovariectomy-induced alterations in thymocyte NA synthesis and AR expression altered NA autocrine/paracrine action on thymocytes. In conclusion, the study indicates that the ovarian hormone deficiency in peripubertal age affects ovarian steroid-dependent remodeling of thymic adrenergic

  15. Ectopic congenital thymic cyst in the right pleural cavity.

    PubMed

    Bruno, Vito D; Mariscalco, Giovanni; Franzi, Francesca; Miceli, Antonio; Piffaretti, Gabriele; Sala, Andrea

    2010-10-01

    A 37-year-old man with a huge pleural cyst, presented with symptoms of right heart compression. The mass on the right side of the chest seemed initially to be in connection with the mediastinum. Computed tomography failed to define its relationship with the pericardium, and echocardiography excluded any involvement of the mediastinal structures. The final diagnosis was a congenital thymic cyst exclusively located in the pleural cavity. PMID:20947607

  16. Thymic stromal cell subsets for T cell development.

    PubMed

    Nitta, Takeshi; Suzuki, Harumi

    2016-03-01

    The thymus provides a specialized microenvironment in which a variety of stromal cells of both hematopoietic and non-hematopoietic origin regulate development and repertoire selection of T cells. Recent studies have been unraveling the inter- and intracellular signals and transcriptional networks for spatiotemporal regulation of development of thymic stromal cells, mainly thymic epithelial cells (TECs), and the molecular mechanisms of how different TEC subsets control T cell development and selection. TECs are classified into two functionally different subsets: cortical TECs (cTECs) and medullary TECs (mTECs). cTECs induce positive selection of diverse and functionally distinct T cells by virtue of unique antigen-processing systems, while mTECs are essential for establishing T cell tolerance via ectopic expression of peripheral tissue-restricted antigens and cooperation with dendritic cells. In addition to reviewing the role of the thymic stroma in conventional T cell development, we will discuss recently discovered novel functions of TECs in the development of unconventional T cells, such as natural killer T cells and γδT cells. PMID:26825337

  17. Neuronal involvement in muscular atrophy

    PubMed Central

    Cisterna, Bruno A.; Cardozo, Christopher; Sáez, Juan C.

    2014-01-01

    The innervation of skeletal myofibers exerts a crucial influence on the maintenance of muscle tone and normal operation. Consequently, denervated myofibers manifest atrophy, which is preceded by an increase in sarcolemma permeability. Recently, de novo expression of hemichannels (HCs) formed by connexins (Cxs) and other none selective channels, including P2X7 receptors (P2X7Rs), and transient receptor potential, sub-family V, member 2 (TRPV2) channels was demonstrated in denervated fast skeletal muscles. The denervation-induced atrophy was drastically reduced in denervated muscles deficient in Cxs 43 and 45. Nonetheless, the transduction mechanism by which the nerve represses the expression of the above mentioned non-selective channels remains unknown. The paracrine action of extracellular signaling molecules including ATP, neurotrophic factors (i.e., brain-derived neurotrophic factor (BDNF)), agrin/LDL receptor-related protein 4 (Lrp4)/muscle-specific receptor kinase (MuSK) and acetylcholine (Ach) are among the possible signals for repression for connexin expression. This review discusses the possible role of relevant factors in maintaining the normal functioning of fast skeletal muscles and suppression of connexin hemichannel expression. PMID:25540609

  18. Multiple System Atrophy with Orthostatic Hypotension (Shy-Drager Syndrome)

    MedlinePlus

    ... Enhancing Diversity Find People About NINDS NINDS Multiple System Atrophy with Orthostatic Hypotension Information Page Synonym(s): Shy- ... being done? Clinical Trials Organizations What is Multiple System Atrophy with Orthostatic Hypotension? Multiple system atrophy with ...

  19. HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications

    PubMed Central

    Janik, S.; Schiefer, A. I.; Bekos, C.; Hacker, P.; Haider, T.; Moser, J.; Klepetko, W.; Müllauer, L.; Ankersmit, H. J.; Moser, B.

    2016-01-01

    Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated. PMID:27097982

  20. HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications.

    PubMed

    Janik, S; Schiefer, A I; Bekos, C; Hacker, P; Haider, T; Moser, J; Klepetko, W; Müllauer, L; Ankersmit, H J; Moser, B

    2016-01-01

    Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated. PMID:27097982

  1. Crustacean muscles: atrophy and regeneration during molting

    SciTech Connect

    Mykles, D.L.; Skinner, D.M.

    1981-01-01

    The ultrastructural basis of atrophy of claw closer muscle of the land crab and the organization of myofibrils and sacroplasmic reticulum during the hydrolysis of protein that occurs during proecdysis was examined. The changes that occur in contractile proteins during claw muscle atrophy and the involvement of Ca/sup 2 +/-dependent proteinases (CDP) in myofilament degradation were investigated. (ACR)

  2. Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans.

    PubMed

    Schulz, Axel Ronald; Mälzer, Julia Nora; Domingo, Cristina; Jürchott, Karsten; Grützkau, Andreas; Babel, Nina; Nienen, Mikalai; Jelinek, Tomas; Niedrig, Matthias; Thiel, Andreas

    2015-11-15

    Immunological competence declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. Underlying mechanisms remain largely obscure as they have been related to complex, individual systemic immune properties that are challenging to investigate. In this study, we explored age-related changes in human immunity during a primary virus infection experimentally induced by immunization with live-attenuated yellow fever (YF) vaccine. Applying detailed serology, advanced FACS analysis, and systems biology, we discovered that aged subjects developed fewer neutralizing Abs, mounted diminished YF-specific CD8(+) T cell responses, and showed quantitatively and qualitatively altered YF-specific CD4(+) T cell immunity. Among numerous immune signatures, low in vivo numbers of naive CD4(+) recent thymic emigrants and peripheral dendritic cells correlated well with reduced acute responsiveness and altered long-term persistence of human cellular immunity to YF vaccination. Hence, we reveal in this article that essential elements of immune responses such as recent thymic emigrants and dendritic cells strongly relate to productive immunity in the elderly, providing a conceivable explanation for diminished responsiveness to vaccination with neoantigens and infection with de novo pathogens in the aged population. PMID:26459351

  3. Coexisiting adenoma and granuloma involving the right inferior parathyroid gland with adjacent ectopic thymic tissue

    PubMed Central

    Gupta, Mayank; Kandasamy, Subramaniam

    2014-01-01

    Inflammatory lesions, particularly granulomas, involving adenoma of the parathyroid gland are rare. Ectopic thymic tissue is commonly associated with the thyroid and/or parathyroid gland due to their close embryonic relationship. We report a rare case of coexisting adenoma and granuloma of the parathyroid gland with adjacent ectopic thymic tissue. PMID:24957592

  4. Salvage chemotherapy with amrubicin and platinum for relapsed thymic carcinoma: experience in six cases.

    PubMed

    Koizumi, Tomonobu; Agatsuma, Toshihiko; Ichiyama, Takashi; Yokoyama, Toshiki; Ushiki, Atsuhito; Komatsu, Yoshimichi; Tanabe, Tsuyoshi; Kobayashi, Takashi; Yoshikawa, Sumiko; Yasuo, Masanori; Yamamoto, Hiroshi; Kubo, Keishi; Hachiya, Tsutomu

    2010-06-01

    It has been reported that cisplatin-based chemotherapy shows beneficial effects in certain patients with advanced thymic carcinoma. However, the usefulness of salvage therapy has not been reported. We focused on a new anthracycline agent, amrubicin, combined with platinum compounds as salvage chemotherapy in patients with thymic carcinoma. Six cases of unresectable and locally advanced thymic carcinoma relapsed from prior cisplatin-containing chemotherapy were treated with amrubicin (30-40 mg/m(2) day 1-3) plus platinum compounds (cisplatin 60 mg/m(2) day 1 or nedaplatin 70 mg/m(2) day 1) chemotherapy as salvage chemotherapy. Two patients showed a partial response. However, Grade 3/4 neutropenia and thrombocytopenia occurred in all and two of the patients, respectively. We conclude that thymic carcinoma is sensitive to platinum-based chemotherapy and that amrubicin appears to have significant activity against thymic carcinoma. The major toxicity is hematological toxicities. PMID:19415537

  5. Identifying the Spatial Relationships of Thymic Stromal and Thymocyte Subsets by Immunofluorescence Analysis.

    PubMed

    Bain, Virginia; Richie, Ellen R

    2016-01-01

    Immunofluorescence analysis of thymic tissue sections is an indispensable technique for visualizing spatial relationships among thymocyte and stromal cell subsets. The thymus is organized into distinct microenvironmental zones in which particular thymic epithelial cell (TEC) subsets support specific stages of thymocyte maturation. Conversely, thymocytes and lymphoid tissue inducer cells support functional maturation of TECs. The composition and organization of TECs change during ontogeny to generate a maximally functional organ in the young adult. Deterioration of thymic architecture and stromal organization occurs with age as the thymus undergoes involution. Such changes can be monitored by immunofluorescent staining of thymic sections obtained at different ages throughout the life-span. Here we describe methods to generate frozen or paraffin-embedded thymic tissue sections for multicolor immunofluorescence staining using antibodies to surface and/or cytoplasmic antigens. PMID:26294399

  6. Biomechanical simulation of atrophy in MR images

    NASA Astrophysics Data System (ADS)

    Castellano Smith, Andrew D.; Crum, William R.; Hill, Derek L. G.; Thacker, Neil A.; Bromiley, Paul A.

    2003-05-01

    Progressive cerebral atrophy is a physical component of the most common forms of dementia - Alzheimer's disease, vascular dementia, Lewy-Body disease and fronto-temporal dementia. We propose a phenomenological simulation of atrophy in MR images that provides gold-standard data; the origin and rate of progression of atrophy can be controlled and the resultant remodelling of brain structures is known. We simulate diffuse global atrophic change by generating global volumetric change in a physically realistic biomechanical model of the human brain. Thermal loads are applied to either single, or multiple, tissue types within the brain to drive tissue expansion or contraction. Mechanical readjustment is modelled using finite element methods (FEM). In this preliminary work we apply these techniques to the MNI brainweb phantom to produce new images exhibiting global diffuse atrophy. We compare the applied atrophy with that measured from the images using an established quantitative technique. Early results are encouraging and suggest that the model can be extended and used for validation of atrophy measurement techniques and non-rigid image registration, and for understanding the effect of atrophy on brain shape.

  7. Outcome of nonsurgical treatment for locally advanced thymic tumors

    PubMed Central

    Wang, Chang-Lu; Gao, Lan-Ting; Lv, Chang-Xing; Zhu, Lei

    2016-01-01

    Background Surgical resection remains the mainstay of treatment for patients with early-staged thymic tumors, while chemotherapy is most commonly used in stage IV cases. As for locally advanced thymic tumors, especially those unsuitable for surgery, the optimal therapy is still controversial. Thus, we conducted this retrospective study by comparing three nonsurgical treatment modalities to find some clues. Methods Three treatment modalities were used in 42 patients from October 2000 to December 2010, including radiotherapy (RT) alone, sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT). Objective response rate (ORR), overall survival (OS) and toxicity of the three regimens were compared accordingly. Results The ORR in all 42 patients was 61.9%, and 5-year OS was 46%. The ORR of RT, SCRT and CCRT were 43.8%, 50% and 87.5%, respectively (RT vs. SCRT, P=0.692; RT vs. CCRT, P=0.009; SCRT vs. CCRT, P=0.051). The 5-year OS of RT, SCRT and CCRT were 30%, 50% and 61.9%, respectively. (RT vs. SCRT, P=0.230; RT vs. CCRT, P=0.011; SCRT vs. CCRT, P=0.282). Eleven patients developed neutropenia of grade 3–4, with 7 in CCRT group and 4 in SCRT, respectively. Nine patients experienced esophagitis of grade 3 with 2 in RT, 3 in SCRT and 4 in CCRT. There were also two cases of grade 3 radiation induced pneumonitis in CCRT group. No life-threatening side effects were noted. Conclusions When used to treat locally advanced thymic tumors unsuitable for surgery, CCRT performed more favorably than RT alone or SCRT in both tumor response and long time survival, but probably with the increasing risk of pulmonary damage. CCRT may offer the best chance of disease control in the management of locally advanced disease. PMID:27114838

  8. Detection of Human Polyomavirus 7 in human thymic epithelial tumors

    PubMed Central

    Rennspiess, Dorit; Pujari, Sreedhar; Keijzers, Marlies; Abdul-Hamid, Myrurgia A.; Hochstenbag, Monique; Dingemans, Anne-Marie; Kurz, Anna Kordelia; Speel, Ernst-Jan; Haugg, Anke; Pastrana, Diana V.; Buck, Christopher B.; De Baets, Marc H.; zur Hausen, Axel

    2014-01-01

    Introduction Although the molecular genetics possibly underlying the pathogenesis of human thymoma have been extensively studied, its etiology remains poorly understood. Since murine polyomavirus consistently induces thymomas in mice, we assessed the presence of the novel human polyomavirus 7 (HPyV7) in human thymic epithelial tumors. Methods HPyV7-DNA Fluorescence in situ hybridization (FISH), DNA-PCR and immuno-histochemistry (IHC) were performed in 37 thymomas. Of these, 26 were previously diagnosed with myasthenia gravis (MG). In addition, 20 thymic hyperplasias and 20 fetal thymic tissues were tested. Results HPyV7-FISH revealed specific nuclear hybridization signals within the neoplastic epithelial cells of 23 thymomas (62.2%). With some exceptions, the HPyV7-FISH data correlated with the HPyV7-DNA PCR. By IHC large T antigen (LTAg) expression of HPyV7 was detected, and double staining confirmed its expression in the neoplastic epithelial cells. Eighteen of the 26 MG-positive and 7 of the 11 MG-negative thymomas were HPyV7-positive. 40% of the 20 hyperplastic thymi were HPyV7-positive by PCR as confirmed by FISH and IHC in the follicular lymphocytes. All 20 fetal thymi tested HPyV7-negative. Conclusions The presence of HPyV7-DNA and LTAg expression in the majority of thymomas possibly link HPyV7 to human thymomagenesis. Further investigations are needed to elucidate the possible associations of HPyV7 and MG. PMID:25526237

  9. Direct analysis of thymic function in children with Down's syndrome

    PubMed Central

    Prada, Nicole; Nasi, Milena; Troiano, Leonarda; Roat, Erika; Pinti, Marcello; Nemes, Elisa; Lugli, Enrico; Ferraresi, Roberta; Ciacci, Luigi; Bertoni, Davide; Biagioni, Ornella; Gibertoni, Milena; Cornia, Cristina; Meschiari, Liviana; Gramazio, Elisabetta; Mariotti, Mauro; Consolo, Ugo; Balli, Fiorella; Cossarizza, Andrea

    2005-01-01

    Background Down's syndrome (DS) is characterized by several immunological defects, especially regarding T cell compartment. DS is considered the best example of accelerated ageing in humans. Direct observations of the thymus have shown that in DS this organ undergoes severe histological and morphological changes. However, no data on its capacity to generate T cells are present in the literature. Here, using a new technology based upon real time PCR, we have investigated the capacity of the thymus to produce and release newly generated T lymphocytes (the so called "recent thymic emigrants", RTE) in children with DS. Methods We studied 8 children affected by DS, aged 2–7 years, compared with 8 age- and sex-matched healthy controls. Flow cytometry was used to determine different lymphocytes subsets. Real time PCR with the Taqman system was used to quantify the amount of RTE, i.e. peripheral blood lymphocytes that express the T cell receptor rearrangement excision circles (TREC). Results In comparison with control children, those with DS had a significant lower number of TREC+ peripheral blood cells. Moreover, in DS children but not in controls, a strong negative correlation between age and the levels of TREC+ cells was found. Conclusions The direct measure of thymic output indicates that the impairment of the organ results in a reduced production of newly generated T cells. This observation could suggest that cytokines able to modulate thymic function, such as interleukins, could be useful to improve the functionality of the organ and to treat the immunodeficiency present in DS subjects. PMID:15715912

  10. Chronic spinal muscular atrophy of facioscapulohumeral type.

    PubMed Central

    Furukawa, T; Toyokura, Y

    1976-01-01

    Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy. Images PMID:957378

  11. Thymic stromal lymphopoietin: master switch for allergic inflammation

    PubMed Central

    Liu, Yong-Jun

    2006-01-01

    Thymic stromal lymphopoietin (TSLP) is an interleukin (IL) 7–like cytokine that triggers dendritic cell–mediated T helper (Th)2 inflammatory responses. TSLP is highly expressed by keratinocytes in skin lesions of patients with atopic dermatitis and is associated with dendritic cell activation in situ, suggesting that TSLP might be a master switch for allergic inflammation at the epithelial cell–dendritic cell interface. New reports now establish a direct link between TSLP expression and the pathogenesis of atopic dermatitis and asthma in vivo, and begin to reveal the molecular mechanisms underlying TSLP-induced allergic inflammation. PMID:16432252

  12. Examination of Thymic Positive and Negative Selection by Flow Cytometry

    PubMed Central

    Baldwin, Troy A.

    2012-01-01

    A healthy immune system requires that T cells respond to foreign antigens while remaining tolerant to self-antigens. Random rearrangement of the T cell receptor (TCR) α and β loci generates a T cell repertoire with vast diversity in antigen specificity, both to self and foreign. Selection of the repertoire during development in the thymus is critical for generating safe and useful T cells. Defects in thymic selection contribute to the development of autoimmune and immunodeficiency disorders1-4. T cell progenitors enter the thymus as double negative (DN) thymocytes that do not express CD4 or CD8 co-receptors. Expression of the αβTCR and both co-receptors occurs at the double positive (DP) stage. Interaction of the αβTCR with self-peptide-MHC (pMHC) presented by thymic cells determines the fate of the DP thymocyte. High affinity interactions lead to negative selection and elimination of self-reactive thymocytes. Low affinity interactions result in positive selection and development of CD4 or CD8 single positive (SP) T cells capable of recognizing foreign antigens presented by self-MHC5. Positive selection can be studied in mice with a polyclonal (wildtype) TCR repertoire by observing the generation of mature T cells. However, they are not ideal for the study of negative selection, which involves deletion of small antigen-specific populations. Many model systems have been used to study negative selection but vary in their ability to recapitulate physiological events6. For example, in vitro stimulation of thymocytes lacks the thymic environment that is intimately involved in selection, while administration of exogenous antigen can lead to non-specific deletion of thymocytes7-9. Currently, the best tools for studying in vivo negative selection are mice that express a transgenic TCR specific for endogenous self-antigen. However, many classical TCR transgenic models are characterized by premature expression of the transgenic TCRα chain at the DN stage, resulting in

  13. Genetics Home Reference: spinal muscular atrophy

    MedlinePlus

    ... a loss of specialized nerve cells, called motor neurons , in the spinal cord and the part of ... spinal cord ( the brainstem ). The loss of motor neurons leads to weakness and wasting ( atrophy ) of muscles ...

  14. Infraspinatus muscle atrophy from suprascapular nerve compression.

    PubMed

    Cordova, Christopher B; Owens, Brett D

    2014-02-01

    Muscle weakness without pain may signal a nerve compression injury. Because these injuries should be identified and treated early to prevent permanent muscle weakness and atrophy, providers should consider suprascapular nerve compression in patients with shoulder muscle weakness. PMID:24463748

  15. On the estimation and correction of bias in local atrophy estimations using example atrophy simulations.

    PubMed

    Sharma, Swati; Rousseau, François; Heitz, Fabrice; Rumbach, Lucien; Armspach, Jean-Paul

    2013-01-01

    Brain atrophy is considered an important marker of disease progression in many chronic neuro-degenerative diseases such as multiple sclerosis (MS). A great deal of attention is being paid toward developing tools that manipulate magnetic resonance (MR) images for obtaining an accurate estimate of atrophy. Nevertheless, artifacts in MR images, inaccuracies of intermediate steps and inadequacies of the mathematical model representing the physical brain volume change, make it rather difficult to obtain a precise and unbiased estimate. This work revolves around the nature and magnitude of bias in atrophy estimations as well as a potential way of correcting them. First, we demonstrate that for different atrophy estimation methods, bias estimates exhibit varying relations to the expected atrophy and these bias estimates are of the order of the expected atrophies for standard algorithms, stressing the need for bias correction procedures. Next, a framework for estimating uncertainty in longitudinal brain atrophy by means of constructing confidence intervals is developed. Errors arising from MRI artifacts and bias in estimations are learned from example atrophy simulations and anatomies. Results are discussed for three popular non-rigid registration approaches with the help of simulated localized brain atrophy in real MR images. PMID:23988649

  16. Models of Multiple System Atrophy

    PubMed Central

    Fellner, Lisa; Wenning, Gregor K.; Stefanova, Nadia

    2016-01-01

    Multiple system atrophy (MSA) is a predominantly sporadic, adult-onset, fatal neurodegenerative disease of unknown etiology. MSA is characterized by autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal signs in any combination. MSA belongs to a group of neurodegenerative disorders termed α-synucleinopathies, which also include Parkinson’s disease and dementia with Lewy bodies. Their common pathological feature is the occurrence of abnormal α-synuclein positive inclusions in neurons or glial cells. In MSA, the main cell type presenting aggregates composed of α-synuclein are oligodendroglial cells. This pathological hallmark, also called glial cytoplasmic inclusions (GCIs), is associated with progressive and profound neuronal loss in various regions of the brain. The development of animal models of MSA is justified by the limited understanding of the mechanisms of neurodegeneration and GCIs formation, which is paralleled by a lack of therapeutic strategies. Two main types of rodent models have been generated to replicate different features of MSA neuropathology. On one hand, neurotoxin-based models have been produced to reproduce neuronal loss in substantia nigra pars compacta and striatum. On the other hand, transgenic mouse models with overexpression of α-synuclein in oligodendroglia have been used to reproduce GCIs-related pathology. This chapter gives an overview of the atypical Parkinson’s syndrome MSA and summarizes the currently available MSA animal models and their relevance for pre-clinical testing of disease-modifying therapies. PMID:24338664

  17. Hydrolysis of thymic humoral factor gamma 2 by neutral endopeptidase (EC 3.4.24.11).

    PubMed Central

    Indig, F E; Pecht, M; Trainin, N; Burstein, Y; Blumberg, S

    1991-01-01

    A search for the natural substrates for neutral endopeptidase (NEP; EC 3.4.24.11) in the immune system led to investigation of the enzyme's action on thymic humoral factor gamma 2 (THF). The ectoenzyme rapidly and efficiently hydrolyses the Lys6-Phe7 bond of the octapeptide. The site of cleavage was confirmed by h.p.l.c. analysis, amino acid analysis and sequence determination of the products. Phosphoramidon (3.6 microM), a potent inhibitor of the enzyme, prevents this cleavage even during prolonged incubation. The high efficiency of hydrolysis of THF by NEP is similar to that reported for [Leu5]enkephalin, and the dipeptide Phe-Leu is the C-terminal product in the hydrolysis of both peptides. The presence of NEP, reportedly identified as the common acute lymphoblastic leukaemia antigen (CALLA), in bone-marrow cells and other cells of the immune system raises the possibility that it may play a role in modulating the activity of peptides such as THF. PMID:1898375

  18. Population Distributions of Thymic Function in Adults: Variation by Sociodemographic Characteristics and Health Status.

    PubMed

    Feinstein, Lydia; Ferrando-Martínez, Sara; Leal, Manuel; Zhou, Xuan; Sempowski, Gregory D; Wildman, Derek E; Uddin, Monica; Aiello, Allison E

    2016-01-01

    The thymus is critical for mounting an effective immune response and maintaining health. However, epidemiologic studies characterizing thymic function in the population setting are lacking. Using data from 263 adults in the Detroit Neighborhood Health Study, we examined thymic function as measured by the number of signal joint T-cell receptor excision circles (sjTREC) and assessed associations with established indicators of physiological health. Overall, increasing age and male gender were significantly associated with reduced thymic function. Adjusting for covariates, individuals with elevated levels of the pro-inflammatory biomarkers C-reactive protein (β: -0.50 [95% CI: -0.82, -0.18] for moderate elevation, β: -0.29 [95% CI: -0.59, 0.00] for high elevation) and interleukin-6 (β: -0.60 [95% CI: -0.92, -0.28] for moderate elevation, β: -0.43 [95% CI: -0.77, -0.08] for severe elevation) also had lower thymic function. Compared to individuals with a BMI < 25, individuals who were overweight (β: 0.36 [95% CI: 0.07, 0.64]) or obese (β: 0.27 [95% CI: -0.03, 0.56]) had higher thymic function. Differences by self-rated health were not statistically significant. Our findings underscore demographic- and health-related gradients in thymic function among adult residents of Detroit, suggesting thymic function may be an important biomarker of health status in adults at the population level. PMID:27337555

  19. Bone marrow atrophy induced by murine cytomegalovirus infection.

    PubMed Central

    Gibbons, A E; Price, P; Shellam, G R

    1994-01-01

    Acute, sublethal infection of mice with murine cytomegalovirus (MCMV) resulted in up to 80% decreases in the number of cells recoverable from the bone marrow, and a decrease in peripheral blood leucocyte counts during the first week of infection. Depopulation of the leucopoietic areas of the marrow was evident from examination of histological sections. The severity of bone marrow atrophy in MCMV-infected mice of different strains correlated with previously described genetically determined sensitivity to MCMV disease. Although the phenomenon only occurred when mice were inoculated with infectious virus preparations, fewer than one in 10(5) marrow cells were productively infected, suggesting that atrophy was not due to lytic infection of large numbers of bone marrow cells. Interestingly, increases in serum colony-stimulating activity were observed and these were proportional to the severity of bone marrow atrophy. After MCMV infection, we observed increases in the proportions of cells expressing some B-cell and myeloid cell markers and a decrease in the proportion of cells expressing an erythroid cell marker. There was no change in the frequency of marrow cells expressing mature T-cell markers. The numbers of myeloid lineage-committed progenitor cells (GM-CFU) in the marrow decreased 10- to 20-fold in BALB/c nu/+ mice, while there was a threefold decrease in their numbers in BALB/c nu/nu mice. In addition, increases in serum colony-stimulating activity were greater in BALB/c nu/+ mice than in BALB/c nu/nu mice. Our results suggest that growth factors produced after MCMV infection may accelerate the maturation and migration of cells from the marrow to sites of virus replication and inflammation, thus accounting for the depletion in numbers of marrow cells observed soon after MCMV infection. Images Figure 3 Figure 4 PMID:7959876

  20. Investigating links between polychlorinated biphenyl (PCB) exposure and thymic involution and thymic cysts in harbour porpoises (Phocoena phocoena).

    PubMed

    Yap, Xinli; Deaville, Rob; Perkins, Matthew W; Penrose, Rod; Law, Robin J; Jepson, Paul D

    2012-10-01

    The associations between polychlorinated biphenyls (PCBs) exposure and involution of lymphoid tissue and development of epithelial-lined cysts in the thymus of UK-stranded harbour porpoises (Phocoena phocoena) (n=170) were tested. Percentage of thymic lymphoid tissue (%TLT) was histologically quantified. Multiple regression analyses (n=169) demonstrated significant positive correlation between %TLT and nutritional status (p<0.001) and significant negative association between %TLT and onset of sexual maturity (p<0.001). However, in a subgroup of porpoises with total PCB levels above a proposed threshold of toxicity (>17mg/kg lipid weight) (n=109), the negative association between %TLT (as dependent variable) and summed blubber concentrations of 25 chlorobiphenyl congeners (∑25CBs) remained significant (p<0.01) along with nutritional status (p<0.001) and onset of sexual maturity (p<0.001). These results suggest PCB-induced immuno suppression may be occurring in harbour porpoises in UK waters but only at concentrations that exceed proposed toxicity thresholds for marine mammals. In contrast, development of thymic cysts appears predominantly age-related. PMID:22917837

  1. Effect of thymic hormones on induction of experimental allergic encephalomyelitis in old mice.

    PubMed

    Endoh, M; Tabira, T

    1990-08-01

    This study was aimed at restoring decreased T-cell functions and reduced susceptibility to proteolipid apoprotein (PLP) induced-experimental allergic encephalomyelitis (EAE) in old mice with thymic hormones. Thymosin fraction 5 (TF-5) and serum thymic factor (FTS) had no significant in vitro and in vivo effect on proliferative responses to PLP and concanavalin A (Con A), and on EAE induction in young and old mice. These results suggest that decreased T-cell functions cannot be restored by these thymic hormones tested. PMID:2256103

  2. Can endoscopic atrophy predict histological atrophy? Historical study in United Kingdom and Japan

    PubMed Central

    Kono, Shin; Gotoda, Takuji; Yoshida, Shigeaki; Oda, Ichiro; Kondo, Hitoshi; Gatta, Luigi; Naylor, Greg; Dixon, Michael; Moriyasu, Fuminori; Axon, Anthony

    2015-01-01

    AIM: To assess the diagnostic concordance between endoscopic and histological atrophy in the United Kingdom and Japan. METHODS: Using published data, a total of 252 patients, 126 in the United Kingdom and 126 in Japan, aged 20 to 80 years, were evaluated. The extent of endoscopic atrophy was classified into five subgroups according to a modified Kimura-Takemoto classification system and was compared with histological findings of atrophy at five biopsy sites according to the updated Sydney system. RESULTS: The strength of agreement of the extent of atrophy between histology and visual endoscopic inspection showed good reproducibility, with a weighted kappa value of 0.76 (P < 0.001). Multivariate analysis showed that three factors were associated with decreased concordance: Japanese ethnicity [odds ratio (OR) 0.22, 95% confidence interval (CI) 0.11-0.43], older age (OR = 0.32, 95%CI: 0.16-0.66) and endoscopic atrophy (OR = 0.10, 95%CI: 0.03-0.36). The strength of agreement between endoscopic and histological atrophy, assessed by cancer risk-oriented grading, was reproducible, with a kappa value of 0.81 (95%CI: 0.75-0.87). Only nine patients (3.6%) were endoscopically underdiagnosed with antral predominant rather than extensive atrophy and were considered false negatives. CONCLUSION: Endoscopic grading can predict histological atrophy with few false negatives, indicating that precancerous conditions can be identified during screening endoscopy, particularly in patients in western countries. PMID:26673849

  3. Glucocorticoid-induced skeletal muscle atrophy.

    PubMed

    Schakman, O; Kalista, S; Barbé, C; Loumaye, A; Thissen, J P

    2013-10-01

    Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoids (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy is characterized by fast-twitch, glycolytic muscles atrophy illustrated by decreased fiber cross-sectional area and reduced myofibrillar protein content. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes ("genes involved in atrophy"), such as FOXO, Atrogin-1, and MuRF-1. The inhibitory effect of GC on muscle protein synthesis is thought to result mainly from the inhibition of the mTOR/S6 kinase 1 pathway. These changes in muscle protein turnover could be explained by changes in the muscle production of two growth factors, namely Insulin-like Growth Factor (IGF)-I, a muscle anabolic growth factor and Myostatin, a muscle catabolic growth factor. This review will discuss the recent progress made in the understanding of the mechanisms involved in GC-induced muscle atrophy and consider the implications of these advancements in the development of new therapeutic approaches for treating GC-induced myopathy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23806868

  4. LTβR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration

    PubMed Central

    Shi, Yaoyao; Wu, Weiwei; Chai, Qian; Li, Qingqing; Hou, Yu; Xia, Huan; Ren, Boyang; Xu, Hairong; Guo, Xiaohuan; Jin, Caiwei; Lv, Mengjie; Wang, Zhongnan; Fu, Yang-Xin; Zhu, Mingzhao

    2016-01-01

    Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development. However, the nature and the differentiation programme of specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here using conditional gene-deficient mice, we find that lymphotoxin beta receptor (LTβR) directly controls thymic ECs to guide HPC homing. Interestingly, T-cell deficiency or conditional ablation of T-cell-engaged LTβR signalling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTβR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTβR is required for T-cell regeneration on irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing. PMID:27493002

  5. A Rare Case of Multilocular Thymic Cyst with Follicular Lymphoid Hyperplasia: Radiologic and Histopathologic Features.

    PubMed

    Kim, Jin-Suk; Cha, Eun Jung

    2016-06-01

    Multilocular thymic cysts are rare and acquired lesions induced by an inflammatory arising within the thymus. We report a rare case of multilocular thymic cyst with follicular lymphoid hyperplasia in a 59-year-old female. Chest CT and MRI revealed a large multilocular cystic mass, which contains thick septa and nodules in the thymus. F-18 FDG PET/CT showed almost no FDG uptake of the multilocular cystic mass but moderate FDG uptake of the solid nodules. Extended total thymectomy was performed. Histopathological findings revealed follicular lymphoid hyperplasia of thymic tissue but no neoplastic lesion. Based on these findings, diagnosis of multilocular thymic cyst with follicular lymphoid hyperplasia was made. This is a rare case that preoperatively was difficult to diagnose. PMID:27275366

  6. Thymic Crosstalk Coordinates Medulla Organization and T-Cell Tolerance Induction

    PubMed Central

    Lopes, Noëlla; Sergé, Arnauld; Ferrier, Pierre; Irla, Magali

    2015-01-01

    The thymus ensures the generation of a functional and highly diverse T-cell repertoire. The thymic medulla, which is mainly composed of medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), provides a specialized microenvironment dedicated to the establishment of T-cell tolerance. mTECs play a privileged role in this pivotal process by their unique capacity to express a broad range of peripheral self-antigens that are presented to developing T cells. Reciprocally, developing T cells control mTEC differentiation and organization. These bidirectional interactions are commonly referred to as thymic crosstalk. This review focuses on the relative contributions of mTEC and DC subsets to the deletion of autoreactive T cells and the generation of natural regulatory T cells. We also summarize current knowledge regarding how hematopoietic cells conversely control the composition and complex three-dimensional organization of the thymic medulla. PMID:26257733

  7. TNF superfamily members play distinct roles in shaping the thymic stromal microenvironment.

    PubMed

    Bichele, Rudolf; Kisand, Kai; Peterson, Pärt; Laan, Martti

    2016-04-01

    The differentiation and proper function of thymic epithelial cells (TECs) depend on various tumor necrosis factor superfamily (TNFSF) signals that are needed to maintain the thymic stromal microenvironment. Nevertheless, the direct transcriptional effects of these signals on TECs remain unclear. To address this issue, we stimulated murine embryonic thymus tissue with selected TNFSF ligands and performed a gene expression profiling study. We show that Aire expression is a direct and specific effect of RANKL stimulation, whereas LTβ and TNFα are major inducers of chemokines in the thymic stroma and we propose differential NF-κB binding as one possible cause of these gene expression patterns. Our work provides further insight into the complex molecular pathways that shape the thymic microenvironment and maintain central tolerance. PMID:27011037

  8. Activation of human lymphocytes by supernatants from human thymic epithelium.

    PubMed Central

    Goust, J M; Vesole, D H; Fudenberg, H H

    1979-01-01

    Supernatants from human thymic epithelial cells (TS) were found to have a mitogenic effect on cultured human peripheral blood mononuclear cells and to potentiate their responses to lectins. This was not observed with culture supernatants from the human cell lines AV-3 and HeLa or from the murine cell line L-929. The maximum potentiating effects were observed with pokeweed mitogen (PWM) and phytohaemagglutinin (PHA), whereas the response to concanavalin A (Con A) was only slightly enhanced. TS also potentiated the mixed lymphocyte culture (MLC) response of normal T cells and thymocytes cultured with mitomycin C-treated B lymphoid cell lines. The mitogenic effect of TS was time-dependent and paralleled the appearance of lymphoid colonies in semi-solid agar. Chromatographical separation of concentrated serum-free TS on Sephadex G-100 yielded an active fraction of molecular weight 15,000--25,000 which had all the activities of unseparated TS. PMID:160851

  9. Activation of human lymphocytes by supernatants from human thymic epithelium.

    PubMed

    Goust, J M; Vesole, D H; Fudenberg, H H

    1979-11-01

    Supernatants from human thymic epithelial cells (TS) were found to have a mitogenic effect on cultured human peripheral blood mononuclear cells and to potentiate their responses to lectins. This was not observed with culture supernatants from the human cell lines AV-3 and HeLa or from the murine cell line L-929. The maximum potentiating effects were observed with pokeweed mitogen (PWM) and phytohaemagglutinin (PHA), whereas the response to concanavalin A (Con A) was only slightly enhanced. TS also potentiated the mixed lymphocyte culture (MLC) response of normal T cells and thymocytes cultured with mitomycin C-treated B lymphoid cell lines. The mitogenic effect of TS was time-dependent and paralleled the appearance of lymphoid colonies in semi-solid agar. Chromatographical separation of concentrated serum-free TS on Sephadex G-100 yielded an active fraction of molecular weight 15,000--25,000 which had all the activities of unseparated TS. PMID:160851

  10. Circulating thymic hormone activity in young cancer patients.

    PubMed Central

    Consolini, R; Cei, B; Cini, P; Bottone, E; Casarosa, L

    1986-01-01

    We measured serum levels of Facteur Thymique Sérique (FTS) in 56 young cancer patients compared to normal controls. All patients who received immunosuppressive therapy had low age-corrected titres of FTS. Low levels were also found at diagnosis and off therapy. Plasma from 22 patients contained factors capable of inhibiting biological activity of FTS in vitro. The nature of this inhibitor has not been elucidated. No zinc deficiency was found in the patients studied, suggesting that FTS is secreted in its active form. Our study points out the importance of monitoring FTS activity in young cancer patients for its implications on immunological surveillance. The practical applications of thymic hormone therapy in cancer patients are discussed. PMID:3802571

  11. Asymptomatic thymic cyst appearing in the neck on valsalva: unusual presentation of a rare disease.

    PubMed

    Hegde, Kishor V; Suneetha, P; Pradeep, P V; Kumar, Panil

    2012-01-01

    Thymic cysts are usually diagnosed accidentally during radiological evaluation of the chest for unrelated conditions. Symptoms appear late when the mass compresses on adjoining tissues. We report an unusual case of asymptomatic mediastinal thymic cyst which was seen in the neck whenever the patient was asked to perform Valsalva maneuver. This case is being reported for the unusual clinical presentation of a rare disease. The role of imaging in the diagnosis and common differential diagnoses are also discussed. PMID:22779063

  12. Natural Th17 cells are critically regulated by functional medullary thymic microenvironments

    PubMed Central

    Jenkinson, William E.; McCarthy, Nicholas I.; Dutton, Emma E.; Cowan, Jennifer E.; Parnell, Sonia M.; White, Andrea J.; Anderson, Graham

    2015-01-01

    The thymic medulla is critical for the enforcement of central tolerance. In addition to deletion of auto-reactive T-cells, the thymic medulla supports the maturation of heterogeneous natural αβT-cells linked to tolerance mechanisms. Natural IL-17-secreting CD4+αβT-cells (nTh17) represent recently described natural αβT-cells that mature and undergo functional priming intrathymically. Despite a proposed potential to impact upon either protective or pathological inflammatory responses, the intrathymic mechanisms regulating the balance of nTh17 development are unclear. Here we compare the development of distinct natural αβT-cells in the thymus. We reveal that thymic stromal MHC class II expression and RelB-dependent medullary thymic epithelial cells (mTEC), including Aire+ mTEC, are an essential requirement for nTh17 development. nTh17 demonstrate a partial, non-redundant requirement for both ICOS-ligand and CD80/86 costimulation, with a dispensable role for CD80/86 expression by thymic epithelial cells. Although mTEC constitutively expressed inducible nitric oxide synthase (iNOS), a critical negative regulator of conventional Th17 differentiation, iNOS was not essential to constrain thymic nTh17. These findings highlight the critical role of the thymic medulla in the differential regulation of novel natural αβT-cell subsets, and reveal additional layers of thymic medullary regulation of T-cell driven autoimmunity and inflammation. PMID:26143957

  13. Comparative anatomical studies on the thyroid and thymic arteries. VI. Diprotodont marsupials.

    PubMed

    Yamasaki, Masahiro

    2016-06-01

    The thyroid and thymic arteries in 44 specimens from 18 species belonging to the diprotodont marsupials were investigated. The results were compared with those of polyprotodont marsupials, suncuses, rats, rabbits, guinea pigs, and man. The superior thyroid artery was constant in three superfamily groups. The inferior thyroid artery was extremely rare. The superior thymic artery arising from the thyrocervical trunk was observed in 1 phalangeroid and 2 macropodoids, and that arising from the vertebral artery occurred in 1 macropodoid. The middle thymic artery occurred in 1 phalangeroid, but was abundant in macropodoids. The inferior thymic artery was constant in koalas and phalangeroids, but was absent in half of the macropodoids. The thyroid ima, middle thymothyroid, and the supreme thymic arteries were absent in all diprotodonts. In addition to the usual thymus, diprotodonts have the superficial cervical thymus, which is only shared with guinea pigs. The superior superficial cervical thymic artery was absent in koalas and in half of the macropodoids, but was abundant in the phalangeroids. Conversely, the inferior superficial cervical thymic artery was constant in koalas and was dominant in the macropodoids. These results show that variations in the arterial patterns for both organs were much more prevalent in macropodoids than in phalangeroids, while the arterial patterns in koalas were characteristic. As a whole, the arteries for both organs were more complex in diprotodonts than in polyprotodonts or rats, but more simple than those in rabbits or man. The superior superficial cervical thymic arteries, which showed various patterns, were compared with those in guinea pigs. PMID:26472114

  14. Phase II Study of Carboplatin and Paclitaxel in Advanced Thymoma and Thymic Carcinoma

    PubMed Central

    Lemma, Girum L.; Lee, Ju-Whei; Aisner, Seena C.; Langer, Corey J.; Tester, William J.; Johnson, David H.; Loehrer, Patrick J.

    2011-01-01

    Purpose The purpose of this study was to evaluate the impact of carboplatin and paclitaxel in patients with advanced previously untreated thymoma and thymic carcinoma. Patients and Methods We conducted a prospective multicenter study in patients with unresectable thymoma (n = 21) or thymic carcinoma (n = 23). Patients were treated with carboplatin (area under the curve, 6) plus paclitaxel (225 mg/m2) every 3 weeks for a maximum of six cycles. The primary end point of this trial was to evaluate the objective response rate. Results From February 2001 through January 2008, 46 patients were enrolled. Thirteen patients had grade 4 or greater toxicity, mostly neutropenia. Using RECIST (Response Evaluation Criteria in Solid Tumors) 1.0 criteria, three complete responses (CRs) and six partial responses (PRs; objective response rate [ORR], 42.9%; 90% CI, 24.5% to 62.8%) were observed in the thymoma cohort; 10 patients had stable disease. For patients with thymic carcinoma, no CRs and five PRs (ORR, 21.7%; 90% CI, 9.0% to 40.4%) were observed; 12 patients had stable disease. Progression-free survival (PFS) was 16.7 (95% CI, 7.2 to 19.8) and 5.0 (95% CI, 3.0 to 8.3) months for thymoma and thymic carcinoma cohorts, respectively. To date, only seven patients (33.3%) with thymoma have died, compared with 16 patients (69.6%) with thymic carcinoma. Median survival time was 20.0 months (95% CI, 5.0 to 43.6 months) for patients with thymic carcinoma, but it has not been reached for patients with thymoma. Conclusion Carboplatin plus paclitaxel has moderate clinical activity for patients with thymic malignancies, but this seems less than expected with anthracycline-based therapy. Patients with thymic carcinoma have poorer PFS and overall survival than patients with thymoma. PMID:21502559

  15. Differential sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy.

    PubMed

    de Theije, C C; Langen, R C J; Lamers, W H; Gosker, H R; Schols, A M W J; Köhler, S E

    2015-01-15

    Hypoxia as a consequence of acute and chronic respiratory disease has been associated with muscle atrophy. This study investigated the sensitivity of oxidative and glycolytic muscles to hypoxia-induced muscle atrophy. Male mice were exposed to 8% normobaric oxygen for up to 21 days. Oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles were isolated, weighed, and assayed for expression profiles of the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and glucocorticoid receptor (GR) and hypoxia-inducible factor-1α (HIF1α) signaling. Fiber-type composition and the capillary network were investigated. Hypoxia-induced muscle atrophy was more prominent in the EDL than the soleus muscle. Although increased expression of HIF1α target genes showed that both muscle types sensed hypoxia, their adaptive responses differed. Atrophy consistently involved a hypoxia-specific effect (i.e., not attributable to a hypoxia-mediated reduction of food intake) in the EDL only. Hypoxia-specific activation of the UPS and ALP and increased expression of the glucocorticoid receptor (Gr) and its target genes were also mainly observed in the EDL. In the soleus, stimulation of gene expression of those pathways could be mimicked to a large extent by food restriction alone. Hypoxia increased the number of capillary contacts per fiber cross-sectional area in both muscles. In the EDL, this was due to type II fiber atrophy, whereas in the soleus the absolute number of capillary contacts increased. These responses represent two distinct modes to improve oxygen supply to muscle fibers, but may aggravate muscle atrophy in chronic obstructive pulmonary disease patients who have a predominance of type II fibers. PMID:25429096

  16. Bioengineering Thymus Organoids to Restore Thymic Function and Induce Donor-Specific Immune Tolerance to Allografts

    PubMed Central

    Fan, Yong; Tajima, Asako; Goh, Saik Kia; Geng, Xuehui; Gualtierotti, Giulio; Grupillo, Maria; Coppola, Antonina; Bertera, Suzanne; Rudert, William A; Banerjee, Ipsita; Bottino, Rita; Trucco, Massimo

    2015-01-01

    One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering. Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses against ovalbumin on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells. Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine. PMID:25903472

  17. Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy

    PubMed Central

    Deguise, Marc-Olivier; Boyer, Justin G.; McFall, Emily R.; Yazdani, Armin; De Repentigny, Yves; Kothary, Rashmi

    2016-01-01

    Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn2B/− mice but not in the more severe Smn−/−; SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn2B/− muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn2B/− and Smn−/−; SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels. PMID:27349908

  18. Genetics Home Reference: spinal muscular atrophy with progressive myoclonic epilepsy

    MedlinePlus

    ... myoclonic epilepsy spinal muscular atrophy with progressive myoclonic epilepsy Enable Javascript to view the expand/collapse boxes. ... All Description Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a neurological condition that causes ...

  19. CD4 T Cell Tolerance to Human C-reactive Protein, an Inducible Serum Protein, Is Mediated by Medullary Thymic Epithelium

    PubMed Central

    Klein, Ludger; Klein, Thomas; Rüther, Ulrich; Kyewski, Bruno

    1998-01-01

    Inducible serum proteins whose concentrations oscillate between nontolerogenic and tolerogenic levels pose a particular challenge to the maintenance of self-tolerance. Temporal restrictions of intrathymic antigen supply should prevent continuous central tolerization of T cells, in analogy to the spatial limitation imposed by tissue-restricted antigen expression. Major acute-phase proteins such as human C-reactive protein (hCRP) are typical examples for such inducible self-antigens. The circulating concentration of hCRP, which is secreted by hepatocytes, is induced up to 1,000-fold during an acute-phase reaction. We have analyzed tolerance to hCRP expressed in transgenic mice under its autologous regulatory regions. Physiological regulation of basal levels (<10−9 M) and inducibility (>500-fold) are preserved in female transgenics, whereas male transgenics constitutively display induced levels. Surprisingly, crossing of hCRP transgenic mice to two lines of T cell receptor transgenic mice (specific for either a dominant or a subdominant epitope) showed that tolerance is mediated by intrathymic deletion of immature thymocytes, irrespective of widely differing serum levels. In the absence of induction, hCRP expressed by thymic medullary epithelial cells rather than liver-derived hCRP is necessary and sufficient to induce tolerance. Importantly, medullary epithelial cells also express two homologous mouse acute-phase proteins. These results support a physiological role of “ectopic” thymic expression in tolerance induction to acute-phase proteins and possibly other inducible self-antigens and have implications for delineating the relative contributions of central versus peripheral tolerance. PMID:9653079

  20. Redox control of skeletal muscle atrophy.

    PubMed

    Powers, Scott K; Morton, Aaron B; Ahn, Bumsoo; Smuder, Ashley J

    2016-09-01

    Skeletal muscles comprise the largest organ system in the body and play an essential role in body movement, breathing, and glucose homeostasis. Skeletal muscle is also an important endocrine organ that contributes to the health of numerous body organs. Therefore, maintaining healthy skeletal muscles is important to support overall health of the body. Prolonged periods of muscle inactivity (e.g., bed rest or limb immobilization) or chronic inflammatory diseases (i.e., cancer, kidney failure, etc.) result in skeletal muscle atrophy. An excessive loss of muscle mass is associated with a poor prognosis in several diseases and significant muscle weakness impairs the quality of life. The skeletal muscle atrophy that occurs in response to inflammatory diseases or prolonged inactivity is often associated with both oxidative and nitrosative stress. In this report, we critically review the experimental evidence that provides support for a causative link between oxidants and muscle atrophy. More specifically, this review will debate the sources of oxidant production in skeletal muscle undergoing atrophy as well as provide a detailed discussion on how reactive oxygen species and reactive nitrogen species modulate the signaling pathways that regulate both protein synthesis and protein breakdown. PMID:26912035

  1. Developing therapies for spinal muscular atrophy.

    PubMed

    Wertz, Mary H; Sahin, Mustafa

    2016-02-01

    Spinal muscular atrophy is an autosomal-recessive pediatric neurodegenerative disease characterized by loss of spinal motor neurons. It is caused by mutation in the gene survival of motor neuron 1 (SMN1), leading to loss of function of the full-length SMN protein. SMN has a number of functions in neurons, including RNA splicing and snRNP biogenesis in the nucleus, and RNA trafficking in neurites. The expression level of full-length SMN protein from the SMN2 locus modifies disease severity. Increasing full-length SMN protein by a small amount can lead to significant improvements in the neurological phenotype. Currently available interventions for spinal muscular atrophy patients are physical therapy and orthopedic, nutritional, and pulmonary interventions; these are palliative or supportive measures and do not address the etiology of the disease. In the past decade, there has been a push for developing therapeutics to improve motor phenotypes and increase life span of spinal muscular atrophy patients. These therapies are aimed primarily at restoration of full-length SMN protein levels, but other neuroprotective treatments have been investigated as well. Here, we discuss recent advances in basic and clinical studies toward finding safe and effective treatments of spinal muscular atrophy using gene therapy, antisense oligonucleotides, and other small molecule modulators of SMN expression. PMID:26173388

  2. Promoter analysis of TCDD-inducible genes in a thymic epithelial cell line indicates the potential for cell-specific transcription factor crosstalk in the AhR response

    SciTech Connect

    Frericks, Markus; Burgoon, Lyle D.; Zacharewski, Timothy R.; Esser, Charlotte

    2008-10-15

    Activation of the aryl hydrocarbon receptor (AhR{sup 1}) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elicits severe immunosuppression accompanied by thymic atrophy. Previous evidence suggests that TCDD targets both thymocytes and thymic epithelial cells. The AhR induces cell-specific changes in gene transcription via binding to the dioxin response element DRE; however, the underlying specificity-mechanisms, in particular with regard to the role of promoter element context, and possible transcription factor crosstalk remain poorly understood. Global gene expression in the cortical thymic epithelial cell line ET at 2, 4, and 6 h following 5 nM TCDD exposure resulted in differential regulation of 201 genes. JASPAR and TRANSFAC mapped the statistically over-represented promoter elements in the regulated genes to specific transcription factor binding sites, suggesting a regulatory role in AhR signaling. Over-represented elements included the xenobiotic response element XRE, NF{kappa}B-Rel, HRE, PPAR{gamma}, GR, PAX-4 and estrogen receptor binding sites. Co-treatment experiments with TCDD and CoCl{sub 2}, to induce hypoxia, or TCDD and 17-{beta}-estradiol (E2) indicated crosstalk between AhR and Hif or ER, in agreement with other experimental models. The computational identification of TFBS and the demonstration of interaction confirm their interactions with AhR signaling and suggest that the other over-represented elements may also be important in the immunosuppressive effects elicited by TCDD. In conclusion, we demonstrated the importance of promoter element cooperation in the shaping of a cell-specific AhR response. Our findings regarding the transcriptional changes in cortical epithelial cells are congruent with the well-known thymotoxic TCDD-phenotype, and useful in new hypothesis generation of the role of cortical TECs in TCDD toxicity.

  3. Progressive hemifacial atrophy. A natural history study.

    PubMed Central

    Miller, M T; Spencer, M A

    1995-01-01

    PURPOSE: To describe two very different natural history courses in 2 patients with hemifacial atrophy. Progressive hemifacial atrophy (Parry-Romberg syndrome, Romberg syndrome, PHA) is characterized by slowly progressive atrophy, frequently involving only one side of the face, primarily affecting the subcutaneous tissue and fat. The onset usually occurs during the first 2 decades of life. The cause and pathophysiology are unknown. Ophthalmic involvement is common, with progressive enophthalmos a frequent finding. Pupillary disturbances, heterochromia, uveitis, pigmentary disturbances of the ocular fundus, and restrictive strabismus have also been reported. Neurologic findings may be present, but the natural history and progression of ocular findings are often not described in the literature. METHODS: We studied the records and present findings of 2 patients with progressive hemifacial atrophy who were observed in our institution over a 10-year period. RESULTS: Both patients showed progression of ophthalmic findings, primarily on the affected side. One patient has had chronic uveitis with secondary cataract and glaucoma, in addition to retinal pigmentary changes. She also had a third-nerve paresis of the contralateral eye and mild seizure activity. The other patient had mild uveitis, some progression of unilateral retinal pigmentary changes, and a significant increase in hyperopia in the affected eye, in addition to hypotony at age 19 without a clear cause, but with secondary retinal and refractive changes. CONCLUSION: Ocular manifestations of progressive hemifacial atrophy are varied, but can progress from mild visual impairment to blindness. Images FIGURE 1 FIGURE 2 FIGURE 3A FIGURE 3B FIGURE 4 FIGURE 5 FIGURE 6 PMID:8719679

  4. Thymic Stromal Lymphopoietin Promotes Fibrosis and Activates Mitogen-Activated Protein Kinases in MRC-5 Cells

    PubMed Central

    Li, Li; Tang, Su; Tang, Xiaodong

    2016-01-01

    Background Acute lung injury (ALI) is a life-threatening hypoxemic respiratory disorder with high incidence and mortality. ALI usually manifests as widespread inflammation and lung fibrosis with the accumulation of pro-inflammatory and pro-fibrotic factors and collagen. Thymic stromal lymphopoietin (TSLP) has a significant role in regulation of inflammation but little is known about its roles in lung fibrosis or ALI. This study aimed to define the role and possible regulatory mechanism of TSLP in lung fibrosis. Material/Methods We cultured human lung fibroblast MRC-5 cells and overexpressed or inhibited TSLP by the vector or small interfering RNA transfection. Then, the pro-fibrotic factors skeletal muscle actin alpha (α-SMA) and collagen I, and the 4 mitogen-activated protein kinases (MAPKs) – MAPK7, p38, extracellular signal-regulated kinase 1 (ERK1), and c-Jun N-terminal kinase 1 (JNK1) – were detected by Western blot. Results Results showed that TSLP promoted the production of α-SMA and collagen I (P<0.001), suggesting that it can accelerate MRC-5 cell fibrosis. It also activated the expression of MAPK7, p-p38, p-ERK1, and p-JNK1, but the total MAPK7, p-38, ERK1, and JNK1 protein levels were mostly unchanged, indicating the activated MAPK pathways that might contribute to the promotion of cell fibrosis. Conclusions This study shows the pro-fibrotic role of TSLP in MRC-5 cells, suggesting TSLP is a potential therapeutic target for treating lung fibrosis in ALI. It possibly functions via activating MAPKs. These findings add to our understanding of the mechanism of fibrosis. PMID:27385084

  5. Thymic Stromal Lymphopoietin Promotes Fibrosis and Activates Mitogen-Activated Protein Kinases in MRC-5 Cells.

    PubMed

    Li, Li; Tang, Su; Tang, Xiaodong

    2016-01-01

    BACKGROUND Acute lung injury (ALI) is a life-threatening hypoxemic respiratory disorder with high incidence and mortality. ALI usually manifests as widespread inflammation and lung fibrosis with the accumulation of pro-inflammatory and pro-fibrotic factors and collagen. Thymic stromal lymphopoietin (TSLP) has a significant role in regulation of inflammation but little is known about its roles in lung fibrosis or ALI. This study aimed to define the role and possible regulatory mechanism of TSLP in lung fibrosis. MATERIAL AND METHODS We cultured human lung fibroblast MRC-5 cells and overexpressed or inhibited TSLP by the vector or small interfering RNA transfection. Then, the pro-fibrotic factors skeletal muscle actin alpha (α-SMA) and collagen I, and the 4 mitogen-activated protein kinases (MAPKs) - MAPK7, p38, extracellular signal-regulated kinase 1 (ERK1), and c-Jun N-terminal kinase 1 (JNK1) - were detected by Western blot. RESULTS Results showed that TSLP promoted the production of α-SMA and collagen I (P<0.001), suggesting that it can accelerate MRC-5 cell fibrosis. It also activated the expression of MAPK7, p-p38, p-ERK1, and p-JNK1, but the total MAPK7, p-38, ERK1, and JNK1 protein levels were mostly unchanged, indicating the activated MAPK pathways that might contribute to the promotion of cell fibrosis. CONCLUSIONS This study shows the pro-fibrotic role of TSLP in MRC-5 cells, suggesting TSLP is a potential therapeutic target for treating lung fibrosis in ALI. It possibly functions via activating MAPKs. These findings add to our understanding of the mechanism of fibrosis. PMID:27385084

  6. Loss of Periostin Results in Impaired Regeneration and Pancreatic Atrophy after Cerulein-Induced Pancreatitis.

    PubMed

    Hausmann, Simone; Regel, Ivonne; Steiger, Katja; Wagner, Nadine; Thorwirth, Manja; Schlitter, Anna M; Esposito, Irene; Michalski, Christoph W; Friess, Helmut; Kleeff, Jörg; Erkan, Mert

    2016-01-01

    The extracellular matrix molecule periostin (POSTN, encoded by POSTN), which is secreted by activated pancreatic stellate cells, has important functions in chronic pancreatitis and pancreatic cancer. However, the role of POSTN in acute pancreatitis and subsequent regeneration processes has not been addressed so far. We analyzed the function of POSTN in pancreatic exocrine regeneration after the induction of a severe acute pancreatitis. Postn-deficient mice and wild-type control animals received repetitive cerulein injections, and a detailed histologic analysis of pancreatic tissues was performed. Although there was no difference in pancreatitis severity in the acute inflammatory phase, the recovery of the exocrine pancreas was massively impaired in Postn-deficient mice. Loss of Postn expression was accompanied by strong pancreatic atrophy and acinar-to-adipocyte differentiation, which was also reflected in gene expression patterns. Our data suggest that POSTN is a crucial factor for proper exocrine lineage-specific regeneration after severe acute pancreatitis. PMID:26632158

  7. Adjuvant Therapy for Thymic Carcinoma – A Decade of Experience in a Taiwan National Teaching Hospital

    PubMed Central

    Tseng, Yen-Han; Lin, Yi-Hsuan; Tseng, Yen-Chiang; Lee, Yu-Chin; Wu, Yu-Chung; Hsu, Wen-Hu; Yen, Sang-Hue; Whang-Peng, Jacqueline; Chen, Yuh-Min

    2016-01-01

    Background Thymic carcinomas are rare tumors for which surgical resection is the first treatment of choice. The role of adjuvant treatment after surgery is unknown because of limited available data. The present study evaluated the efficacy of post-surgery adjuvant chemotherapy or radiotherapy in patients with thymic carcinoma. Methods To evaluate the role of adjuvant therapy in patients with thymic carcinoma, we retrospectively reviewed the records of patients with thymic carcinoma who were diagnosed and treated between 2004 and 2014. Results Among 78 patients with thymic carcinoma, 30 patients received surgical resection. Progression-free survival (PFS) and overall survival (OS) were significantly longer among these patients than among patients who received other treatments (PFS: 88.4 months vs 9.1 months, p<0.001; OS: 134.9 months vs 60.9 months; p = 0.003). Patients with stage III thymic carcinoma who received surgery had a longer OS than patients who did not receive surgery (70.1 months vs 23.9 months; p = 0.017, n = 11). Among 47 patients with stage IV carcinoma, 12 patients who received an extended thymothymectomy had a longer PFS than 35 patients who did not receive surgery (18.9 months vs 8.7 months; p = 0.029). Among 30 patients (with stage I- IV carcinoma) who received primary lesion surgery, 19 patients received an R0 resection and 9 patients of the 19 patients received adjuvant radiotherapy. These patients had longer PFS (50.3 months) than 2 patients who received adjuvant chemotherapy (5.9 months) or 4 patients who received concurrent chemoradiotherapy (7.5 months) after surgery (p = 0.003). Conclusions Surgical resection should be considered for patients with thymic carcinoma, even for patients with locally advanced or stage IV carcinoma. Adjuvant radiotherapy resulted in a better PFS after R0 resection. PMID:26757052

  8. Thymic involution, a co-morbidity factor in amyotrophic lateral sclerosis

    PubMed Central

    Seksenyan, Akop; Ron-Harel, Noga; Azoulay, David; Cahalon, Liora; Cardon, Michal; Rogeri, Patricia; Ko, Minhee K; Weil, Miguel; Bulvik, Shlomo; Rechavi, Gideon; Amariglio, Ninette; Konen, Eli; Koronyo-Hamaoui, Maya; Somech, Raz; Schwartz, Michal

    2010-01-01

    Abstract Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4+ T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4+ T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T-cell malfunction may develop in parallel to the motor neuron dysfunction. Here, we tested this hypothesis by assessing thymic function, which serves as a measure of peripheral T-cell availability, in an animal model of ALS (mSOD1 [superoxide dismutase] mice; G93A) and in human patients. We found a significant reduction in thymic progenitor-cell content, and abnormal thymic histology in 3–4-month-old mSOD1 mice. In ALS patients, we found a decline in thymic output, manifested in the reduction in blood levels of T-cell receptor rearrangement excision circles, a non-invasive measure of thymic function, and demonstrated a restricted T-cell repertoire. The morbidity of the peripheral immune cells was also manifested in the increase of pro-apoptotic BAX/BCXL2 expression ratio in peripheral blood mononuclear cells (PBMCs) of these patients. In addition, gene expression screening in the same PBMCs, revealed in the ALS patients a reduction in key genes known to be associated with T-cell activity, including: CD80, CD86, IFNG and IL18. In light of the reported beneficial role of T cells in animal models of ALS, the present observation of thymic dysfunction, both in human patients and in an animal model, might be a co-pathological factor in ALS, regardless of the disease aetiology. These findings may lead to the development of novel therapeutic approaches directed at overcoming the thymic defect and T-cell deficiency. PMID:19650830

  9. Increased Thymic B Cells but Maintenance of Thymic Structure, T Cell Differentiation and Negative Selection in Lymphotoxin-α and TNF Gene-Targeted Mice

    PubMed Central

    Grech, Adrian P.; Riminton, D. Sean; Gabor, Melinda J.; Hardy, Charles L.; Sedgwick, Jonathon D.

    2000-01-01

    TNF, lymphotoxin (LT) and their receptors are expressed constitutively in the thymus. It remains unclear whether these cytokines play a role in normal thymic structure or function. We have investigated thymocyte differentiation, selection and thymic organogenesis in gene targeted mice lacking LTα, TNF, or both (TNF/LTα-/-). The thymus was normal in TNF/LTα-/- mice with regard to cell yields and stromal architecture. Detailed analysis of αβ and γδ T cell-lineage thymocyte subsets revealed no abnormalities, implying that neither TNF nor LT play an essential role in T cell differentiation or positive selection. The number and distribution of thymic CD11c+ dendritic cells was also normal in the absence of both TNF and LTα. A three-fold increase in B cell numbers was observed consistently in the TNF/LTα-/- thymus. This phenotype was due entirely to the LTα deficiency and associated with changes in the hemopoietic compartment, rather than the thymic stromal compartment of LTα-/- mice. Finally, specific Vβ8+ T cell deletion within the thymus following intrathymic injection of staphylococcal enterotoxin B (SEB) was TNF/LT independent. Thus, despite the presence of these cytokines and their receptors in the normal thymus, there appears no essential role for either TNF or LT in development of organ structure or for those processes associated with T cell repertoire selection. PMID:11293812

  10. Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis

    PubMed Central

    Demehri, Shadmehr; Cunningham, Trevor J.; Manivasagam, Sindhu; Ngo, Kenneth H.; Reddy, Rasika; Meyers, Melissa A.; DeNardo, David G.; Yokoyama, Wayne M.

    2016-01-01

    Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4+ Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers. PMID:26927668

  11. Sex hormones have pervasive effects on thymic epithelial cells

    PubMed Central

    Dumont-Lagacé, Maude; St-Pierre, Charles; Perreault, Claude

    2015-01-01

    The goal of our study was to evaluate at the systems-level, the effect of sex hormones on thymic epithelial cells (TECs). To this end, we sequenced the transcriptome of cortical and medullary TECs (cTECs and mTECs) from three groups of 6 month-old mice: males, females and males castrated at four weeks of age. In parallel, we analyzed variations in the size of TEC subsets in those three groups between 1 and 12 months of age. We report that sex hormones have pervasive effects on the transcriptome of TECs. These effects were exquisitely TEC-subset specific. Sexual dimorphism was particularly conspicuous in cTECs. Male cTECs displayed low proliferation rates that correlated with low expression of Foxn1 and its main targets. Furthermore, male cTECs expressed relatively low levels of genes instrumental in thymocyte expansion (e.g., Dll4) and positive selection (Psmb11 and Ctsl). Nevertheless, cTECs were more abundant in males than females. Accumulation of cTECs in males correlated with differential expression of genes regulating cell survival in cTECs and cell differentiation in mTECs. The sexual dimorphism of TECs highlighted here may be mechanistically linked to the well-recognized sex differences in susceptibility to infections and autoimmune diseases. PMID:26250469

  12. Thymic Stromal Lymphopoietin Improves Survival and Reduces Inflammation in Sepsis.

    PubMed

    Piliponsky, Adrian M; Lahiri, Asha; Truong, Phuong; Clauson, Morgan; Shubin, Nicholas J; Han, Hongwei; Ziegler, Steven F

    2016-08-01

    The mechanisms that contribute to homeostasis of the immune system in sepsis are largely unknown. One study suggests a potential detrimental role for thymic stromal lymphopoietin (TSLP) in sepsis; however, the immune-regulatory effects of TSLP on myeloid cells within the intestinal microenvironment suggest the contrary. Our objective was to clarify TSLP's role in sepsis. Cecal ligation and puncture was performed in mice with total or myeloid-specific deficiency in the TSLP receptor (TSLPR). Survival was monitored closely, peritoneal fluids and plasma were analyzed for markers of inflammation, and myeloid cell numbers and their ability to produce inflammatory mediators was determined. The interaction of TSLP with TSLPR in myeloid cells contributed to mouse survival after septic peritonitis. Mice with TSLPR deficiency in myeloid cells displayed excessive local and systemic inflammation levels (e.g., increased inflammatory cell and cytokine levels) relative to control mice. Moreover, hepatic injury was exacerbated in mice with TSLPR deficiency in their myeloid cells. However, the enhanced inflammatory response did not affect the ability of these mice to clear bacteria. Resident neutrophils and macrophages from septic mice with TSLPR deficiency exhibited an increased ability to produce proinflammatory cytokines. Collectively, our findings suggest that the effects of TSLP on myeloid cells are crucial in reducing the multiple organ failure that is associated with systemic inflammation, which highlights the significance of this cytokine in modulating the host response to infection and in reducing the risks of sepsis development. PMID:26934097

  13. Recent thymic emigrants are tolerized in the absence of inflammation.

    PubMed

    Friesen, Travis J; Ji, Qingyong; Fink, Pamela J

    2016-05-30

    T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen. After encounter with TRAs in the absence of inflammation, RTEs exhibited defects in proliferation, diminished cytokine production, elevated expression of anergy-associated genes, and diminished diabetogenicity. These properties were mirrored in vitro by enhanced RTE susceptibility to regulatory T cell-mediated suppression. In the presence of inflammation, RTEs and mature T cells were, in contrast, equally capable of inducing diabetes, proliferating, and producing cytokines. Thus, recirculating RTEs encounter TRAs during a transitional developmental stage that facilitates tolerance induction, but inflammation converts antigen-exposed, tolerance-prone RTEs into competent effector cells. PMID:27139493

  14. [Lymphoepithelial sialadenitis (LESA)-like Thymic hyperplasia: A case report].

    PubMed

    Arndt, Börge; Gaiser, Timo; Marx, Alexander; Rieger, Christina

    2016-07-01

    A 43-year-old man was admitted to this hospital because of shortness of breath and chest pain. The patient had a history of cardiac surgery at the age of seven (due to a congenital heart defect), and of intracerebral bleeding which had occurred at the age of 23. There was no history of autoimmune disorders. Computed tomography revealed a well-circumscribed anterior mediastinal mass, measuring 4 × 3 × 3 cm with calcification and cystic components. Therefore a malignant tumor was suspected for which a thymectomy was performed. Histopathological evaluation revealed an unusual type of thymic hyperplasia strongly resembling lymphoepithelial sialadenitis (LESA) of the salivary glands. A CT scan of the neck, thorax and abdomen for staging did not display lymphadenopathy or splenomegaly. The laboratory tests revealed no abnormality. Clinical, there were no signs of lymphoma. Actually, the patient is in our aftercare. Taken together, lymphoepithelial sialadentis of the thymus is a very rare disorder and was first described in 2012. This disorder seems to be benigne and no other treatment is needed after thymectomy. PMID:27404934

  15. Rare cause of atrial fibrillation: a thymic mass.

    PubMed

    Vishwanathan, Swati; Tayshetye, Pritam; Bilimoria, Farshaad; Finley, Gene

    2016-01-01

    A 62-year-old African-American man admitted to the emergency room with chest pain and exertional dyspnoea. He was found to be in rapid atrial fibrillation with pulmonary oedema. A transoesophageal echocardiogram performed prior to cardioversion showed a depressed left ventricular function (ejection fraction 30%) and an extracardiac heterogeneous echodensity compressing the right atrium and the superior vena cava. CT of the chest confirmed an anterior mediastinal mass measuring 13.5×6.6×10.1 cm, exerting a mass effect on the right atrium with mediastinal and right hilar adenopathy. CT-guided biopsy of the mediastinal mass revealed thymic carcinoma (squamous cell subtype). The metastatic workup was negative. The mass was deemed surgically unresectable due to its proximity to the heart. Chemotherapy was initiated with carboplatin/paclitaxel every 3 weeks with plans for intensity modulated radiotherapy after one to two cycles of chemotherapy. The patient recently had a repeat CT scan of the chest showing regression of the tumour. PMID:27417995

  16. Thymic Selection of T Cells as Diffusion with Intermittent Traps

    NASA Astrophysics Data System (ADS)

    Košmrlj, Andrej

    2011-04-01

    T cells orchestrate adaptive immune responses by recognizing short peptides derived from pathogens, and by distinguishing them from self-peptides. To ensure the latter, immature T cells (thymocytes) diffuse within the thymus gland, where they encounter an ensemble of self-peptides presented on (immobile) antigen presenting cells. Potentially autoimmune T cells are eliminated if the thymocyte binds sufficiently strongly with any such antigen presenting cell. We model thymic selection of T cells as a random walker diffusing in a field of immobile traps that intermittently turn "on" and "off". The escape probability of potentially autoimmune T cells is equivalent to the survival probability of such a random walker. In this paper we describe the survival probability of a random walker on a d-dimensional cubic lattice with randomly placed immobile intermittent traps, and relate it to the result of a well-studied problem where traps are always "on". Additionally, when switching between the trap states is slow, we find a peculiar caging effect for the survival probability.

  17. Functions of thymic stromal lymphopoietin in immunity and disease.

    PubMed

    Zhang, Yanlu; Zhou, Baohua

    2012-06-01

    Thymic stromal lymphopoietin (TSLP) is an interleukin 7-like cytokine expressed mainly by epithelial cells. Current studies provide compelling evidence that TSLP is capable of activating dendritic cells to promote T helper (Th) 2 immune responses. TSLP has also been shown to directly promote Th2 differentiation of naïve CD4(+) T cell and activate natural killer T cells, basophils and other innate immune cells at the initial stage of inflammation. In addition, TSLP affects B cell maturation and activation and can also influence regulatory T (Treg) cell differentiation and development. TSLP-induced Th2 responses are associated with the pathogenesis of allergic inflammatory diseases, including atopic dermatitis, asthma, and rhinitis. Based on recent findings in humans and mouse models, TSLP might also be involved in the pathogenesis of inflammatory bowel disease and progression of cancer. In this review, we will summarize our current understanding of the biology of TSLP and highlight the important issues for future investigations. PMID:22274860

  18. Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis.

    PubMed

    Demehri, Shadmehr; Cunningham, Trevor J; Manivasagam, Sindhu; Ngo, Kenneth H; Moradi Tuchayi, Sara; Reddy, Rasika; Meyers, Melissa A; DeNardo, David G; Yokoyama, Wayne M

    2016-04-01

    Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4+ Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers. PMID:26927668

  19. Immature recent thymic emigrants are eliminated by complement1

    PubMed Central

    Hsu, Fan-Chi; Shapiro, Michael J.; Chen, Meibo W.; McWilliams, Douglas C.; Seaburg, Lauren M.; Tangen, Sarah N.; Shapiro, Virginia Smith

    2014-01-01

    Recent thymic emigrants (RTEs) must undergo phenotypic and functional maturation to become long-lived mature naïve T cells. In CD4-cre NKAP conditional knockout mice, NKAP-deficient RTEs fail to complete T cell maturation. Here, we demonstrate that NKAP-deficient immature RTEs do not undergo apoptosis, but are eliminated by complement. C3, C4 and C1q are bound to NKAP-deficient peripheral T cells, demonstrating activation of the classical arm of the complement pathway. As thymocytes mature and exit to the periphery, they increase sialic acid incorporation into cell surface glycans. This is essential to peripheral lymphocyte survival, as stripping sialic acid with neuraminidase leads to the binding of natural IgM and complement fixation. NKAP-deficient T cells have a defect in sialylation on cell surface glycans, leading to IgM recruitment. We demonstrate that the defect in sialylation is due to aberrant α2,8-linked sialylation, and the expression of three genes (ST8sia1, ST8sia4 and ST8sia6) that mediate α2,8 sialylation are down regulated in NKAP-defcient RTEs. The maturation of peripheral NKAP-deficient T cells is partially rescued in a C3-deficient environment. Thus, sialylation during T cell maturation is critical to protect immature RTEs from complement in the periphery. PMID:25367120

  20. Thymic influence on the T-lymphocyte self MHC repertoire. II. Cytotoxic T-lymphocyte precursors.

    PubMed

    Jenski, L J; Miller, B A

    1988-01-01

    We measured the frequency and specificity of thymic alloantigen-reactive cytotoxic T-lymphocyte precursors in spleens of allogeneic thymus-grafted nude mice tolerant to thymic alloantigens. Under our conditions of limiting dilution analysis we found no selective loss of cytotoxic T-lymphocyte precursors in allogeneic thymus-grafted mice. Upon analysis of individual cytotoxic T-lymphocyte clones, we found that lysis of specific and third party targets was mediated by distinct clones specific for H-2 antigens. Precursors from allogeneic thymus-grafted nudes stimulated at limiting dilutions with thymic alloantigens tended to lyse fewer targets than were lysed by normal cytotoxic T-lymphocytes or allogeneic thymus-grafted nude precursors stimulated with third party alloantigens, but the reduction in lytic activity was not statistically significant. Specific suppression was not demonstrated, but could not be ruled out unequivocally. We conclude that intrathymic deletion of thymic alloantigen-reactive pCTL is not necessary to achieve specific tolerance to thymic alloantigens. PMID:3259029

  1. Thymic influence on the T-lymphocyte self MHC repertoire. I. Helper T-lymphocyte precursors.

    PubMed

    Jenski, L J; Belloni, M L; Miller, B A

    1988-01-01

    We measured the frequencies of helper T-cell precursors in spleens of allogeneic thymus-grafted nude mice to determine whether allogeneic thymus engraftment resulted in clonal deletion of helper T-cells reactive to thymic major histocompatibility complex alloantigens, thereby producing tolerance to the thymic alloantigens. C3H thymus-grafted nudes had nearly normal numbers of C3H-reactive helper T-cell precursors, whereas C57BL/6 thymus-grafted nudes had significantly reduced numbers of C57BL/6-reactive helper T-cell precursors. Additional evidence suggested that tolerance was not due to a paucity of helper T-cell precursors: a) there was no correlation between the helper T-cell precursor frequency and the ability to mount cytotoxic responses against the thymic alloantigens, and b) exogenous helper factors did not break cytotoxic T-lymphocyte tolerance to thymic alloantigens. Thus, we conclude that immune tolerance resulting from engraftment of allogeneic thymic tissue is not necessarily due to clonal deletion of specific helper T-cell precursors. PMID:2966463

  2. Single Cell Analysis of Complex Thymus Stromal Cell Populations: Rapid Thymic Epithelia Preparation Characterizes Radiation Injury

    PubMed Central

    Williams, Kirsten M.; Mella, Heather; Lucas, Philip J.; Williams, Joy A.; Telford, William; Gress, Ronald E.

    2009-01-01

    Thymic epithelial cells (TECs) and dendritic cells are essential for the maintenance of thymopoiesis. Because these stromal elements define the progenitor niche, provide critical survival signals and growth factors, and direct positive and negative selection, detailed study of these populations is necessary to understand important elements for thymic renewal after cytotoxic injury. Study of TEC is currently hindered by lengthy enzymatic separation techniques with decreased viability. We present a new rapid separation technique that yields consistent viable TEC numbers in a quarter of the prior preparation time. Using this new procedure, we identify changes in stroma populations following total body irradiation (TBI). By flow cytometry, we show that TBI significantly depletes UEA+ medullary TEC, while sparing Ly51+ CD45− cells. Further characterization of the Ly51+ subset reveals enrichment of fibroblasts (CD45− Ly51+ MHCII−), while cortical TECs (CD45− Ly51+ MHCII+) were markedly reduced. Dendritic cells (CD11lc+ CD45+) were also decreased following TBI. These data suggest that cytotoxic preparative regimens may impair thymic renewal by reducing critical populations of cortical and medullary TEC, and that such thymic damage can be assessed by this new rapid separation technique, thereby providing a means of assessing optimal conditioning pretransplantfor enhancing thymic-dependent immune reconstitution posttranspiant. PMID:19750208

  3. In vivo administration of IL-1 induces thymic hypoplasia and increased levels of serum corticosterone

    SciTech Connect

    Morrissey, P.J.; Charrier, K.; Alpert, A.; Bressler, L.

    1988-09-01

    Administration of IL-1 alpha or IL-1 beta to normal mice induces a decrease in thymic cellularity, the magnitude of which depends on the number of injections and dose of IL-1. Twice daily injections of 200 ng of IL-1 alpha or -beta for 4 days results in a 90% decrease in thymic cellularity, which regenerated after cessation of treatment. Study of thymocyte subpopulations revealed that the number of CD4+/CD8+ thymocytes was dramatically decreased in IL-1-treated mice. Functional assessment of the CD4-/CD8- population from treated animals showed that these cells had adequate mitogenic responses in vitro and that the proportion of these cells in cycle was not different from control CD4-/CD8- cells. IL-1 treatment also prevented the regeneration of thymic cellularity after irradiation. The use of strains of mice differing genetically at the Ly 1 locus to construct radiation bone marrow chimeras demonstrated that bone marrow-derived thymocyte precursors were able to seed the thymus in the IL-1-treated animals. Again, however, the CD4+/CD8+ thymocyte population was significantly decreased. Thymic repopulation occurred upon cessation of IL-1 therapy. Finally, we determined that a single i.p. injection of IL-1 caused a three-fold increase in serum corticosterone levels, which peaked approximately 3 h after IL-1 administration. Thus, an IL-1-dependent increase in serum corticosterone levels may be responsible for the observed thymic hypoplasia.

  4. Neonatal hypoxia, hippocampal atrophy, and memory impairment: evidence of a causal sequence.

    PubMed

    Cooper, Janine M; Gadian, David G; Jentschke, Sebastian; Goldman, Allan; Munoz, Monica; Pitts, Georgia; Banks, Tina; Chong, W Kling; Hoskote, Aparna; Deanfield, John; Baldeweg, Torsten; de Haan, Michelle; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2015-06-01

    Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. PMID:24343890

  5. Neonatal Hypoxia, Hippocampal Atrophy, and Memory Impairment: Evidence of a Causal Sequence

    PubMed Central

    Cooper, Janine M.; Gadian, David G.; Jentschke, Sebastian; Goldman, Allan; Munoz, Monica; Pitts, Georgia; Banks, Tina; Chong, W. Kling; Hoskote, Aparna; Deanfield, John; Baldeweg, Torsten; de Haan, Michelle; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2015-01-01

    Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohort's HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life. PMID:24343890

  6. Brain Atrophy Correlates with Severe Enlarged Perivascular Spaces in Basal Ganglia among Lacunar Stroke Patients

    PubMed Central

    Zhang, Xiaoyu; Ding, Lingling; Yang, Lei; Qin, Wei; Yuan, Junliang; Li, Shujuan; Hu, Wenli

    2016-01-01

    Background Enlarged perivascular spaces (EPVS) correlate with cognitive impairment and incident dementia. However, etiologies for severe basal ganglia EPVS (BG-EPVS) are still unclear. Our aim was to investigate the independent risk factors for severe BG-EPVS in patients with acute lacunar stroke. Methods We prospectively identified patients with lacunar stroke (diameter on DWI ≤ 20mm) from Jan 2011 to May 2015. Patients with severe BG-EPVS were identified on T2 weighted MRI. Age (± 1 year) and sex matched controls were also recruited in the same population (two controls for one case). Vascular risk factors, clinical data, EPVS in centrum semiovale (rated 0 to 4), white matter hyperintensities (WMH) (by Fazekas scale), brain atrophy (rated 0 to 6) were compared between two groups. Logistic regression was performed to determine independent risk factors for severe BG-EPVS. Results During study period, 89 patients with severe BG-EPVS and 178 matched controls were included. Vascular risk factors did not differ between two groups. Patients with severe BG-EPVS had lower level of HbA1c and diastolic BP at admission, but presented with larger infarct size, more severe WMH (including total WMH, periventricular WMH and deep WMH) and brain atrophy. In logistic regression, brain atrophy (OR = 1.40; 95%CI 1.13, 1.73) and deep WMH (OR = 1.88; 95%CI 1.24, 2.83) were independent risk factors for severe BG-EPVS. Conclusions Brain atrophy and deep WMH are independent risk factors for severe BG-EPVS, supporting the hypothesis that brain atrophy may be associated with the development of EPVS in basal ganglia. PMID:26900696

  7. Effect of Bcl11b genotypes and {gamma}-radiation on the development of mouse thymic lymphomas

    SciTech Connect

    Yoshikai, Yoshihiro; Sato, Toshihiro; Morita, Shinichi; Kohara, Yuki; Takagi, Ritsuo; Mishima, Yukio; Kominami, Ryo

    2008-08-22

    Bcl11b is a haploinsufficient tumor suppressor gene and expressed in many tissues such as thymus, brain and skin. Irradiated Bcl11b{sup +/-} heterozygous mice mostly develop thymic lymphomas, but the preference of Bcl11b inactivation for thymic lymphomas remains to be addressed. We produced Bcl11b{sup +/-} heterozygous and Bcl11b wild-type mice of p53{sup +/-} background and compared their incidence of {gamma}-ray induced thymic lymphomas. Majority of the tumors in p53{sup +/-} mice were skin tumors, and only 5 (36%) of the 14 tumors were thymic lymphomas. In contrast, Bcl11b{sup +/-}p53{sup +/-} doubly heterozygous mice developed thymic lymphomas at the frequency of 27 (79%) of the 34 tumors developed (P = 0.008). This indicates the preference of Bcl11b impairment for thymic lymphoma development. We also analyzed loss of the wild-type alleles in the 27 lymphomas, a predicted consequence given by {gamma}-irradiation. However, the loss frequency was low, only six (22%) for Bcl11b and five (19%) for p53. The frequencies did not differ from those of spontaneously developed thymic lymphomas in the doubly heterozygous mice, though the latency of lymphoma development markedly differed between them. This suggests that the main contribution of irradiation at least in those mice is not for the tumor initiation by inducing allelic losses but probably for the promotion of thymic lymphoma development.

  8. Role of HDACs in optic nerve damage-induced nuclear atrophy of retinal ganglion cells.

    PubMed

    Schmitt, Heather M; Schlamp, Cassandra L; Nickells, Robert W

    2016-06-20

    Optic neuropathies are characterized by retinal ganglion cell (RGC) death, resulting in the loss of vision. In glaucoma, the most common optic neuropathy, RGC death is initiated by axonal damage, and can be modeled by inducing acute axonal trauma through procedures such as optic nerve crush (ONC) or optic nerve axotomy. One of the early events of RGC death is nuclear atrophy, and is comprised of RGC-specific gene silencing, histone deacetylation, heterochromatin formation, and nuclear shrinkage. These early events appear to be principally regulated by epigenetic mechanisms involving histone deacetylation. Class I histone deacetylases HDACs 1, 2, and 3 are known to play important roles in the process of early nuclear atrophy in RGCs, and studies using both inhibitors and genetic ablation of Hdacs also reveal a critical role in the cell death process. Select inhibitors, such as those being developed for cancer therapy, may also provide a viable secondary treatment option for optic neuropathies. PMID:26733303

  9. Tracheobronchial smooth muscle atrophy and separation.

    PubMed

    Mehta, Atul C; Zaki, Khawaja Salman; Banga, Amit; Singh, Jarmanjeet; Gildea, Thomas R; Arrossi, Valeria

    2015-01-01

    We report a case series involving 4 patients with chronic obstructive pulmonary disease who were on an appropriate medical regimen including a high dose of inhaled corticosteroids (ICS). During bronchoscopy, patients were found to have an excessive dynamic collapse of the posterior wall and its separation from the ends of the adjacent cartilaginous rings. This was causing a near-total occlusion of the tracheal and bronchial lumen during exhalation, thereby presenting with an obstructive pattern on the pulmonary functions. We suspect that this was caused by the atrophy of the smooth muscles of the tracheobronchial wall. We reviewed the literature to explore the mechanisms causing atrophy of the bronchial smooth muscle, focusing on the potential role of long-term ICS use. PMID:26138002

  10. [Posterior cortical atrophy with progressive visual agnosia].

    PubMed

    Zarranz, J J; Lasa, A; Fernández, M; Lezcano, E; Pérez Bas, M; Varona, L; Ruiz, J; Beristain, X

    1995-03-01

    Interest in progressive focal cerebral syndromes associated with classical degenerative diseases has increased in recent years. Descriptions of posterior cortical atrophy with progressive visual agnosia are relatively rare. We present 5 patients (2 women) ranging in age between 57 and 72 years old. In all cases symptoms began and progressed with no known etiology. All cases were sporadic. The main clinical signs are difficulty in recognizing objects, colors, persons or places; topographical disorientation and visual memory alterations; alexia, simultagnosia, loss of ocular fixing and optic ataxia. Some patients presented other disturbances of praxis or memory and 2 progressed to global dementia. Language function was preserved and behavioral disturbances did not develop. The amplitude of the P100 visual evoked potential was low but latency was normal in 4 patients and prolonged in 1. Brain images showed atrophy and hypoperfusion in the parieto-occipital area. The neuropathology status of these patients is unknown. PMID:7756009

  11. Space travel directly induces skeletal muscle atrophy

    NASA Technical Reports Server (NTRS)

    Vandenburgh, H.; Chromiak, J.; Shansky, J.; Del Tatto, M.; Lemaire, J.

    1999-01-01

    Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

  12. Diesel Exhaust Particle-Exposed Human Bronchial Epithelial Cells Induce Dendritic Cell Maturation and Polarization via Thymic Stromal Lymphopoietin

    PubMed Central

    Bleck, Bertram; Tse, Doris B.; Curotto de Lafaille, Maria A.; Zhang, Feijie

    2009-01-01

    Human exposure to air pollutants, including ambient particulate matter, has been proposed as a mechanism for the rise in allergic disorders. Diesel exhaust particles, a major component of ambient particulate matter, induce sensitization to neoallergens, but the mechanisms by which sensitization occur remain unclear. We show that diesel exhaust particles upregulate thymic stromal lymphopoietin in human bronchial epithelial cells in an oxidant-dependent manner. Thymic stromal lymphopoietin induced by diesel exhaust particles was associated with maturation of myeloid dendritic cells, which was blocked by anti-thymic stromal lymphopoietin antibodies or silencing epithelial cell-derived thymic stromal lymphopoietin. Dendritic cells exposed to diesel exhaust particle-treated human bronchial epithelial cells induced Th2 polarization in a thymic stromal lymphopoietin-dependent manner. These findings provide new insight into the mechanisms by which diesel exhaust particles modify human lung mucosal immunity. PMID:18049884

  13. Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability

    PubMed Central

    Dell'Orco, James M.; Wasserman, Aaron H.; Chopra, Ravi; Ingram, Melissa A. C.; Hu, Yuan-Shih; Singh, Vikrant; Wulff, Heike; Opal, Puneet; Orr, Harry T.

    2015-01-01

    Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated

  14. Paclitaxel and cisplatin with concurrent radiotherapy followed by surgery in locally advanced thymic carcinoma.

    PubMed

    Fukuda, Minoru; Obase, Yasushi; Miyashita, Naoyuki; Kobashi, Yoshihiro; Mohri, Keiji; Ueno, Shiro; Hayama, Makio; Shimizu, Katsuhiko; Nishimura, Hironori; Nakata, Masao; Oka, Mikio

    2007-01-01

    Thymic carcinoma is a rare neoplasm with a poor prognosis. We report the clinical course of a patient who received complete surgical resection after effective induction treatment. A 72-year-old woman with advanced thymic carcinoma (squamous cell carcinoma, stage IVb) was considered as nonresectable due to invasion of neighboring organs and mediastinal lymph node metastasis. Two cycles of chemotherapy, consisting of paclitaxel (180 mg/m2) plus cisplatin (80 mg/m2), combined with thoracic radiotherapy (total 54 Gy) were performed concurrently and complete radical resection could then be performed. She is currently alive and ambulatory and has remained disease-free for two years. This multimodal treatment may be a good treatment option for locally advanced thymic carcinoma. PMID:17595782

  15. Trimodality Therapy for an Advanced Thymic Carcinoma With Both Aorta and Vena Cava Invasion.

    PubMed

    Momozane, Tohru; Inoue, Masayoshi; Shintani, Yasushi; Funaki, Soichiro; Kawamura, Tomohiro; Minami, Masato; Shirakawa, Yukitoshi; Kuratani, Toru; Sawa, Yoshiki; Okumura, Meinoshin

    2016-08-01

    A case of locally advanced thymic carcinoma that was successfully resected with the great vessels after chemoradiation therapy is reported. A 57-year-old man with Masaoka stage III thymic carcinoma received two cycles of cisplatin/docetaxel and 60 Gy irradiation. The response was stable disease with 19% size reduction, and a radical resection with the ascending aorta and superior vena cava with the patient under circulatory arrest with the use of cardiopulmonary bypass was performed. The postoperative course was uneventful, and the patient has been free of disease for 28 months. Trimodality therapy with use of a cardiovascular surgical procedure might be a valuable option in locally advanced thymic carcinoma. PMID:27449450

  16. Concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma in an anterior mediastinal mass.

    PubMed

    Ito, Junko; Yoshida, Akihiko; Maeshima, Akiko Miyagi; Nakagawa, Kazuo; Watanabe, Shun-ichi; Kobayashi, Yukio; Fukuhara, Suguru; Tsuta, Koji

    2015-09-01

    We report a case of a 62-year-old man with concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Computed tomography revealed a 5.5-cm anterior mediastinal mass, and surgical resection was performed. Histologically, the mass showed concurrent thymoma (type AB), thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Lymphoma cells infiltrated in the left lung, pulmonary hilar lymph nodes, and involved bone marrow. The patient underwent chemotherapy for T lymphoblastic leukemia/lymphoma and achieved remission. One year after surgery, he remains free of both thymoma and thymic carcinoma, and T lymphoblastic leukemia/lymphoma remains complete remission under maintenance therapy. Thymoma and T lymphoblastic leukemia/lymphoma can combine in the same mass, although this is quite rare. At the time of the diagnosis of thymoma, additional attention should be directed toward lymphocytes in the background. PMID:26150396

  17. Histologic and immunohistochemical characterization of thymic epithelial tumours in the dog.

    PubMed

    Burgess, K E; DeRegis, C J; Brown, F S; Keating, J H

    2016-06-01

    Thymic epithelial tumour (TET) histologic subclassification has not been well described in the veterinary literature as it has in humans. The objective of this study was to identify and describe TET subtypes in dogs and to determine the utility of immunohistochemistry (IHC) in differentiating these subtypes. Samples were reviewed and classified according to a modified World Health Organization (WHO) criteria for human tumours of thymic origin. Signallment, presenting signs, treatment and survival data was collected from medical records. Histologic review confirmed the same subtypes as described in humans. Presence of high stage disease, pleomorphism, mitotic figures and capsular invasion was more common in atypical thymomas and thymic carcinomas than in thymomas. IHC was performed for GLUT-1, CD5, CD117 and CK8/18; however, this was not useful in classifying the tumours. PMID:27144380

  18. Phenotypic characterization of thymic prelymphoma cells of B10 mice treated with split-dose irradiation

    SciTech Connect

    Muto, M.; Kubo, E.; Kamisaku, H.; Sado, T. )

    1990-02-01

    Using an intrathymic injection assay on B10 Thy-1 congenic mice, it was demonstrated that thymic prelymphoma cells first developed within the thymuses from 4 to 8 days after split-dose irradiation and were detected in more than 63% of the test donor thymuses when examined at 21 and 31 days after irradiation. Moreover, some mice (25%) at 2 mo after split-dose irradiation had already developed thymic lymphomas in their thymuses. To characterize these thymic prelymphoma cells, the thymocytes from B10 Thy-1.1 mice 1 mo after irradiation were stained with anti-CD4 and anti-CD8 mAb and were sorted into four subpopulations. These fractionated cells were injected into the recipient thymuses to examine which subpopulation contained thymic prelymphoma cells. The results indicated that thymic prelymphoma cells existed mainly in CD4- CD8- and CD4- CD8+ thymocyte subpopulations and also in CD4+ CD8+ subpopulation. T cell lymphomas derived from CD4- CD8- prelymphoma cells had mainly CD4- CD8- or CD4- CD8+ phenotypes. T cell lymphomas developed from CD4- CD8+ prelymphoma cells mainly expressed CD4- CD8+ or CD4+ CD8+ phenotype. T cell lymphomas originating from CD4+ CD8+ prelymphoma cells were mainly CD4+ CD8+ but some CD4- CD8+ or CD4+ CD8- cells were also present. These thymic prelymphoma cells were further characterized phenotypically in relation to their expression of the marker defined by the mAb against J11d marker and TL-2 (thymus-leukemia) Ag, which is not expressed on normal thymocytes of B10.Thy-1.2 or B10.Thy-1.1 strain, but appears on the thymocytes of lymphomagenic irradiated mice. The results indicated that the prelymphoma cells existed in J11d+, TL-2+ cells.

  19. Adipocyte and leptin accumulation in tumor-induced thymic involution.

    PubMed

    Lamas, Alejandro; Lopez, Elena; Carrio, Roberto; Lopez, Diana M

    2016-01-01

    Cell-mediated immunity is an important defense mechanism against pathogens and developing tumor cells. The thymus is the main lymphoid organ involved in the formation of the cell-mediated immune response by the maturation and differentiation of lymphocytes that travel from the bone marrow, through the lymphatic ducts, to become T lymphocytes. Thymic involution has been associated with aging; however, other factors such as obesity, viral infection and tumor development have been shown to increase the rate of shrinkage of this organ. The heavy infiltration of adipocyte fat cells has been reported in the involuted thymuses of aged mice. In the present study, the possible accumulation of such cells in the thymus during tumorigenesis was examined by immunohistochemistry. A significant number of adipocytes around and infiltrating the thymuses of tumor-bearing mice was observed. Leptin is a pro-inflammatory adipocytokine that enhances thymopoiesis and modulates T cell immune responses. The levels of leptin and adiponectin, another adipocytokine that has anti-inflammatory properties, were examined by western blot analysis. While no changes were observed in the amounts of adiponectin present in the thymuses of the normal and tumor-bearing mice, significantly higher levels of leptin were detected in the thymocytes of the tumor-bearing mice. This correlated with an increase in the expression of certain cytokines, such as interleukin (IL)-2, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF). The co-culture of thymocytes isolated from normal mice with ex vivo isolated adipocytes from tumor-bearing mice yielded similar results. Our findings suggest that the infiltration and accumulation of adipocytes in the thymuses of tumor-bearing mice play an important role in their altered morphology and functions. PMID:26530443

  20. Coeliac disease-associated polymorphisms influence thymic gene expression.

    PubMed

    Amundsen, S S; Viken, M K; Sollid, L M; Lie, B A

    2014-09-01

    Significant associations between coeliac disease (CD) and single nucleotide polymorphisms (SNPs) distributed over 40 genetic regions have been established. The majority of these SNPs are non-coding and 20 SNPs were, by expression quantitative trait loci (eQTL) analysis, found to harbour cis regulatory potential in peripheral blood mononuclear cells (PBMC). Almost all regions contain genes with an immunological relevant function, of which many act in the same biological pathways. One such pathway is T-cell development in the thymus, a pathway previously not explored in CD pathogenesis. The aim of our study was to explore the regulatory potential of the CD-associated SNPs (n=50) by eQTL analysis in thymic tissue from 42 subjects. In total, 43 nominal significant (P<0.05) eQTLs were found within 24 CD-associated chromosomal regions, corresponding to 27 expression-altering SNPs (eSNPs) and 40 probes (eProbes) that represents 39 unique genes (eGenes). Nine significant probe-SNP pairs (corresponding to 8 eSNPs and 7 eGenes) overlapped with previous findings in PBMC (rs12727642-PARK7, rs296547-DDX59, rs917997-IL18RAP, rs842647-AHSA2, rs13003464-AHSA2, rs6974491-ELMO1, rs2074404-NSF (two independent probes) and rs2298428-UBE2L3). When compared across more tissues, we found that 14 eQTLs could represent potentially novel thymus-specific eQTLs. This implies that CD risk polymorphisms could affect gene regulation in thymus. PMID:24871462

  1. Physiology and therapeutic potential of the thymic peptide thymulin.

    PubMed

    Reggiani, Paula C; Schwerdt, Jose I; Console, Gloria M; Roggero, Eduardo A; Dardenne, Mireille; Goya, Rodolfo G

    2014-01-01

    Thymulin is a thymic hormone exclusively produced by the epithelial cells of the thymus. After its discovery and initial characterization in the '70s, it was demonstrated that the production and secretion of thymulin are strongly influenced by the neuro-endocrine system. Conversely, a growing body of evidence, to be reviewed here, suggests that thymulin is a hypophysiotropic peptide. Additionally, a substantial body of information pointing to thymulin and a synthetic analog as anti-inflammatory and analgesic peptides in the central nervous system brain and other organs will be also reviewed. In recent years, a synthetic DNA sequence encoding a biologically active analog of thymulin, metFTS, was constructed and cloned in a number of adenovectors. These include bidirectional regulatable Tet-Off vector systems that simultaneously express metFTS and green fluorescent protein and that can be down-regulated reversibly by the addition of the antibiotic doxycycline. A number of recent studies indicate that gene therapy for thymulin may be an effective therapeutic strategy to prevent some of the hormonal and reproductive abnormalities that typically appear in congenitally athymic (nude) mice, used as a suitable model of neuroendocrine and reproductive aging. Summing up, this article briefly reviews the publications on the physiology of the thymulin-neuroendocrine axis and the anti-inflammatory properties of the molecule and its analog. The availability of novel biotechnological tools should boost basic studies on the molecular biology of thymulin and should also allow an assessment of the potential of gene therapy to restore circulating thymulin levels in thymodeficient animal models and eventually, in humans. PMID:24588820

  2. Ontogeny of rat thymic macrophages. Phenotypic characterization and possible relationships between different cell subsets.

    PubMed Central

    Vicente, A; Varas, A; Moreno, J; Sacedón, R; Jiménez, E; Zapata, A G

    1995-01-01

    In the present study we combined electron microscopy, immunohistology and primary stromal cell cultures to analyse the ontogeny of rat thymic macrophages (M phi) in an attempt to clarify the relationships between the different macrophage cell subsets described in adult rat thymus. Although phagocytic cells were observed in 15-day-old fetal thymus, monoclonal antibodies (mAb) which recognize different adult macrophage types were unable to identify positive cells until the end of embryonic life. However, our in vitro results from primary thymic stromal cell cultures of 16-day-old fetal rats, and the phenotyping of enriched thymic CD2- cell suspensions, demonstrated that monocyte-like cells which strongly expressed major histocompatibility complex (MHC) class II molecules colonized the embryonic thymus early, giving rise later to distinct macrophage subsets. During the process of maturation, macrophage precursors gradually lost their MHC class II expression, acquired other surface markers (CD45, Thy-1, CD25, CD4, etc.) and increased the acid phosphatase activity. In this respect, ED1+ macrophages, which appeared for the first time in the last stages of embryonic life, consisted of a MHC class II molecule-expressing phagocytic cell population, presumably involved in the elimination of non-selected cortical thymocytes, and of non-phagocytic cells which, in the thymic cortex, might differentiate to ED2+ macrophages throughout ED1+ED2lo/med and ED1+ ED2high intermediate cell stages, observed in vitro in 16-day-old fetal thymic stromal cell cultures. At the end of embryonic life and during the postnatal period the numbers of thymic macrophages increased, particularly in the medulla and corticomedullary border (CMZ), and more slowly in the thymic cortex. This increase was presumably due to the arrival, through perivascular spaces, of new macrophage progenitors, rather than in situ proliferation of pre-existent mature macrophages. The possible function of different thymic

  3. Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy.

    PubMed

    Malavaki, C J; Sakkas, G K; Mitrou, G I; Kalyva, A; Stefanidis, I; Myburgh, K H; Karatzaferi, C

    2015-12-01

    Disuse atrophy is the loss of skeletal muscle mass due to inactivity or lower than 'normal' use. It is not only a furtive component of the 'modern' sedentary lifestyle but also a part of numerous pathologies, where muscle loss is linked to disease specific and/or other toxicity factors, eventually leading to wasting (cachexia). Whether disuse-or-disease induced, muscle loss leads to weakness and metabolic comorbidities with a high societal and financial cost. This review discusses the intricate network of interacting signalling pathways including Atrogin-1/MAFbx, IGF1-Akt, myostatin, glucocorticoids, NF-kB, MAPKs and caspases that seem to regulate disuse atrophy but also share common activation patterns in other states of muscle loss such as sarcopenia or cachexia. Reactive oxygen species are also important regulators of cell signalling pathways that can accelerate proteolysis and depress protein synthesis. Exercise is an effective countermeasure and antioxidants may show some benefit. We discuss how the experimental model used can crucially affect the outcome and hence our understanding of atrophy. Timing of sampling is crucial as some signalling mechanisms reach their peak early during the atrophy process to rapidly decline thereafter, while other present high levels even weeks and months after study initiation. The importance of such differences lays in future consideration of appropriate treatment targets. Apart from attempting to correct defective genes or negate their effects, technological advances in new rational ways should aim to regulate specific gene expression at precise time points for the treatment of muscle atrophy in therapeutic protocols depending on the origin of atrophy induction. PMID:26728748

  4. Leber's hereditary optic atrophy: further evidence for a defect of cyanide metabolism?

    PubMed Central

    Berninger, T A; von Meyer, L; Siess, E; Schon, O; Goebel, F D

    1989-01-01

    We studied one patient with Leber's optic atrophy (LOA) in the acute stage and 12 at the chronic stage of the disease, and measured the activity of rhodanese in white blood cells and the level of cyanide in whole blood. In the patient with acute disease the blood cyanide level was significantly increased at first. Treatment of this patient with cyanide antagonists reduced his cyanide level, but this was not accompanied by improvement in visual function. Rhodanese activity was normal in all patients, as were the blood cyanide levels in each of the 12 patients at the chronic stage of the disease. These findings suggest a temporary disturbance of cyanide metabolism during the acute phase of the disease in this family. The abnormal metabolic mechanism was not identified. PMID:2713312

  5. Low-frequency electrical stimulation attenuates muscle atrophy in CKD--a potential treatment strategy.

    PubMed

    Hu, Li; Klein, Janet D; Hassounah, Faten; Cai, Hui; Zhang, Cong; Xu, Ping; Wang, Xiaonan H

    2015-03-01

    Effective therapeutic strategies to treat CKD-induced muscle atrophy are urgently needed. Low-frequency electrical stimulation (LFES) may be effective in preventing muscle atrophy, because LFES is an acupuncture technique that mimics resistance exercise by inducing muscle contraction. To test this hypothesis, we treated 5/6-nephrectomized mice (CKD mice) and control mice with LFES for 15 days. LFES prevented soleus and extensor digitorum longus muscle weight loss and loss of hind-limb muscle grip in CKD mice. LFES countered the CKD-induced decline in the IGF-1 signaling pathway and led to increases in markers of protein synthesis and myogenesis and improvement in muscle protein metabolism. In control mice, we observed an acute response phase immediately after LFES, during which the expression of inflammatory cytokines (IFN-γ and IL-6) increased. Expression of the M1 macrophage marker IL-1β also increased acutely, but expression of the M2 marker arginase-1 increased 2 days after initiation of LFES, paralleling the change in IGF-1. In muscle cross-sections of LFES-treated mice, arginase-1 colocalized with IGF-1. Additionally, expression of microRNA-1 and -206, which inhibits IGF-1 translation, decreased in the acute response phase after LFES and increased at a later phase. We conclude that LFES ameliorates CKD-induced skeletal muscle atrophy by upregulation of the IGF-1 signaling pathway, which improves protein metabolism and promotes myogenesis. The upregulation of IGF-1 may be mediated by decreased expression of microRNA-1 and -206 and/or activation of M2 macrophages. PMID:25228359

  6. A Potential Mechanism of High-Dose Ticagrelor in Modulating Platelet Activity and Atherosclerosis Mediated by Thymic Stromal Lymphopoietin Receptor

    PubMed Central

    Mao, Yi; Peng, Yudong; Zeng, Qiutang; Cheng, Longxian; Wang, Boyuan; Mao, Xiaobo; Meng, Kai; Liu, Yuzhou; Lian, Yitian; Li, Dazhu

    2015-01-01

    Abnormal expression of thymic stromal lymphopoietin (TSLP) and its receptor (TSLPR) was found in patients with acute coronary syndrome. Ticagrelor, an oral platelet ADP P2Y12 receptor antagonist, is widely used in these patients. The aim of this study was to verify whether different doses of ticagrelor regulated plaque progression and platelet activity by modulating TSLP/TSLPR. Seventy-five ApoE-/- mice were randomly divided into five groups: (1) high-cholesterol diet (HCD, n = 15); (2) HCD plus ticagrelor 25 mg/kg/d (T1, n = 15); (3) HCD plus ticagrelor 50 mg/kg/d (T2, n = 15); (4) HCD plus ticagrelor 100 mg/kg/d (T3, n = 15); and (5) a normal diet group (ND, n = 15). At day 0 and at week 16, blood lipids and serum TSLP levels, expression of TSLPR, CD62, and CD63, platelet aggregation, platelet ATP release, PI3K/Akt signaling pathway, and plaque morphology were assessed. HCD increased TSLPR expression and atherosclerosis progression but high-dose ticagrelor (100 mg/kg) moderated this trend. TSLPR was positively correlated with Akt1, platelet aggregation, corrected plaque area, and vulnerability index in the T3 group (P<0.01). In conclusion, low-dose ticagrelor only inhibited platelet activity. Besides this inhibition, high-dose ticagrelor modulated platelet activity and atherosclerosis mediated by TSLPR, potentially through the PI3K/Akt signal pathway. PMID:26517374

  7. c-kit mutation-positive advanced thymic carcinoma successfully treated as a mediastinal gastrointestinal stromal tumor: A case report

    PubMed Central

    HIRAI, FUMIHIKO; EDAGAWA, MAKOTO; SHIMAMATSU, SHINICHIRO; TOYOZAWA, RYO; TOYOKAWA, GOUJI; NOSAKI, KANAME; YAMAGUCHI, MASAFUMI; SETO, TAKASHI; TWAKENOYAMA, MITSUHIRO; ICHINOSE, YUKITO

    2016-01-01

    Thymic carcinoma is an exceptionally rare tumor, which has a very poor prognosis, differing from thymoma. Although cytotoxic chemotherapy is commonly used to treat advanced thymic carcinoma, its effectiveness has not been found to be sufficient. There are several reports that thymic carcinoma also harbors an oncogenic driver mutation, similar to lung cancer. A patient with a c-kit mutation-positive thymic carcinoma received imatinib followed by sunitinib consecutively, which are both c-Kit inhibitors. Although the patient had achieved long-term disease control for 21 months, the primary lesion and pulmonary metastases had increased in size by November, 2014. Following failure of imatinib treatment, the patient received sunitinib, a multiple kinase inhibitor, initiated in December, 2014. Following administration of sunitinib, a computed tomography scan revealed a partial response and the disease was effectively controlled with continued sunitinib treatment for 6 months, up to June, 2015. The patient achieved long-term disease control (~27 months) with imatinib followed by sunitinib. The efficacy of consecutive molecular-targeted therapy for thymic carcinoma was demonstrated in this case. Therefore, thymic carcinoma with oncogenic driver mutations should be treated with molecular-targeted agents rather than with cytotoxic drugs, and it may be suitable to treat c-kit mutation-positive thymic carcinoma as a mediastinal gastrointestinal stromal tumor. PMID:27073655

  8. [Susceptibility gene in multiple system atrophy (MSA)].

    PubMed

    Tsuji, Shoji

    2014-01-01

    To elucidate molecular bases of multiple system atrophy (MSA), we first focused on recently identified MSA multiplex families. Though linkage analyses followed by whole genome resequencing, we have identified a causative gene, COQ2, for MSA. We then conducted comprehensive nucleotide sequence analysis of COQ2 of sporadic MSA cases and controls, and found that functionally deleterious COQ2 variants confer a strong risk for developing MSA. COQ2 encodes an enzyme in the biosynthetic pathway of coenzyme Q10. Decreased synthesis of coenzyme Q10 is considered to be involved in the pathogenesis of MSA through decreased electron transport in mitochondria and increased vulnerability to oxidative stress. PMID:25672683

  9. Cardiac atrophy after bed rest and spaceflight

    NASA Technical Reports Server (NTRS)

    Perhonen, M. A.; Franco, F.; Lane, L. D.; Buckey, J. C.; Blomqvist, C. G.; Zerwekh, J. E.; Peshock, R. M.; Weatherall, P. T.; Levine, B. D.

    2001-01-01

    Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity

  10. Deregulation of mTOR signaling is involved in thymic lymphoma development in Atm-/- mice

    SciTech Connect

    Kuang, Xianghong; Shen, Jianjun; Wong, Paul K.Y.; Yan, Mingshan

    2009-06-05

    Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

  11. Meis1 Is Required for the Maintenance of Postnatal Thymic Epithelial Cells

    PubMed Central

    Hirayama, Takehiro; Asano, Yusuke; Iida, Hajime; Watanabe, Takeshi; Nakamura, Takuro; Goitsuka, Ryo

    2014-01-01

    Most epithelial tissues retain stem/progenitor cells to maintain homeostasis of the adult tissues; however, the existence of a thymic epithelial cell (TEC) progenitor capable of maintaining homeostasis of the postnatal thymus remains unclear. Here, we show that a cell population expressing high levels of Meis1, a homeodomain transcription factor, is enriched in TECs with an immature cellular phenotype. These TECs selectively express genes involved in embryonic thymic organogenesis and epithelial stem cell maintenance, and also have the potential to proliferate and differentiate into mature TEC populations. Furthermore, postnatal inactivation of Meis1 in TECs caused disorganization of the thymic architecture, which ultimately leads to premature disappearance of the thymus. There was an age-associated reduction in the proportion of the TEC population expressing high levels of Meis1, which may also be related to thymic involution. These findings indicate that Meis1 is potentially involved in the maintenance of postnatal TECs with progenitor activity that is required for homeostasis of the postnatal thymus. PMID:24594519

  12. Stereotactic ablative radiotherapy with CyberKnife for advanced thymic carcinoma: a case report

    PubMed Central

    Fan, C.Y.; Huang, W.Y.; Jen, Y.M.; Lin, M.J.; Lin, K.T.

    2015-01-01

    Thymic carcinoma is a rare but lethal mediastinal cancer. The optimal treatment for advanced thymic carcinoma is not yet established. This report is the first known of stereotactic ablative radiotherapy (sabr) with CyberKnife (Accuray, Sunnyvale, CA, U.S.A.) as definitive therapy for thymic carcinoma. The patient, a 70-year-old woman with thymic carcinoma, invasion into neighboring organs, and pleural metastases—underwent CyberKnife sabr at 40 Gy in 5 fractions for two lesions, one in the thymus and one in the right paraspinal pleura. After 61 months of observation, a partial response was observed in the irradiated fields. However, disease progression in the non-irradiated pleura was noted. The patient underwent salvage CyberKnife sabr for the four initially nonirradiated pleural lesions. Computed tomography images obtained 10 months after the salvage therapy revealed a partial response. The patient is living, with progression-free irradiated lesions and no radiation-related toxicity. CyberKnife sabr is feasible for patients who are unable to undergo either surgery or conventionally fractionated radiation therapy. PMID:26628883

  13. Treatment and prognosis of Masaoka stage 3 thymic carcinoma: a retrospective study of 32 cases

    PubMed Central

    Sun, Yan; Liu, Jinshi; Yu, Xinmin

    2015-01-01

    Purpose The aim of this study was to investigate the treatment and prognostic factors in patients with Masaoka stage 3 thymic carcinoma. Methods A retrospective review was conducted of the medical records of patients with Masaoka stage 3 thymic carcinoma between 2000 and 2012 in our institution. Clinical characteristics and prognostic factors were analyzed. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis. Results Thirty-two patients with Masaoka stage 3 thymic carcinoma, operated on in Zhejiang Cancer Hospital, were identified between 2000 and 2012. Among 32 patients, 24 achieved R0 resection. The most common histological subtypes were squamous cell carcinoma (n=15, 46.8%), followed by undifferentiated carcinoma (n=12, 37.5%), and other tumors (n=5, 15.7%). The 5-year disease-free survival and overall survival rates were 56.8% and 61.5%, respectively. Patients with incomplete resection had a significantly worse disease-free survival and overall survival as compared to complete resection with univariate analyses (P-value 0.006 and 0.034, respectively). Multivariate analysis revealed that complete resection was statistically associated with disease-free survival but not overall survival (P-value 0.025 and 0.076, respectively). Conclusion Our results indicated that complete resection could impact the disease-free survival of patients with stage 3 thymic carcinoma. PMID:25897244

  14. Requirement of Stat3 Signaling in the Postnatal Development of Thymic Medullary Epithelial Cells.

    PubMed

    Satoh, Rumi; Kakugawa, Kiyokazu; Yasuda, Takuwa; Yoshida, Hisahiro; Sibilia, Maria; Katsura, Yoshimoto; Levi, Ben; Abramson, Jakub; Koseki, Yoko; Koseki, Haruhiko; van Ewijk, Willem; Hollander, Georg A; Kawamoto, Hiroshi

    2016-01-01

    Thymic medullary regions are formed in neonatal mice as islet-like structures, which increase in size over time and eventually fuse a few weeks after birth into a continuous structure. The development of medullary thymic epithelial cells (TEC) is dependent on NF-κB associated signaling though other signaling pathways may contribute. Here, we demonstrate that Stat3-mediated signals determine medullary TEC cellularity, architectural organization and hence the size of the medulla. Deleting Stat3 expression selectively in thymic epithelia precludes the postnatal enlargement of the medulla retaining a neonatal architecture of small separate medullary islets. In contrast, loss of Stat3 expression in cortical TEC neither affects the cellularity or organization of the epithelia. Activation of Stat3 is mainly positioned downstream of EGF-R as its ablation in TEC phenocopies the loss of Stat3 expression in these cells. These results indicate that Stat3 meditated signal via EGF-R is required for the postnatal development of thymic medullary regions. PMID:26789017

  15. Sporadic juvenile thymic lymphoma in a 6-month-old Holstein heifer

    PubMed Central

    2005-01-01

    Abstract A 6-month-old Holstein heifer was presented for recurrent bloat and a firm, primarily left-sided mass in the caudoventral cervical region. Surgical exploration revealed a vascularized, encapsulated mass extending from the submandibular region to the thoracic inlet. Postmortem gross and histopathologic examination and the history enabled a diagnosis of sporadic thymic lymphoma. PMID:16231655

  16. Characterization of the human thymic microenvironment: lymphoepithelial interaction in normal thymus and thymoma.

    PubMed

    Müller-Hermelink, H K; Wilisch, A; Schultz, A; Marx, A

    1997-03-01

    Recent advances in tissue culture technology and molecular biology have extended our understanding of the functional morphology of the thymus. The importance of a crosstalk between lymphoid cells and stroma has been appreciated as a prerequisite for the normal development of both. The network of direct cellular interactions and soluble factors comprising part of the microenvironment is far from being elucidated but the highly ordered thymic architecture clearly plays a pivotal role in normal thymic function. Insight into the genetic control of stroma development is only emerging while knowledge on the genetic control of the various steps in T cell development is already advanced and rapidly expanding. The present paper gives an overview on the cellular components and matrix molecules of the human thymic microenvironment and their development during ontogeny. The intrathymic cytokine network is shortly reviewed. Special emphasis is put on molecules mediating lymphoepithelial interactions that are necessary for the expansion and early selection of immature thymocytes from precursor cells and for the generation of an MHC restricted and self tolerant T cell repertoire by positive and negative selection. Considering these physiological mechanisms we summarize the molecular pathology of the microenvironment and lymphocyte/stroma interactions in thymic epithelial tumors (thymomas). Finally, a pathogenetic model for paraneoplastic myasthenia gravis is given. We suggest abnormal auto-antigen-specific positive selection of naive T cells as the essential molecular mechanism by which thymomas contribute to the autoimmunization against the acetylcholine receptor and other muscle proteins. PMID:9161686

  17. Requirement of Stat3 Signaling in the Postnatal Development of Thymic Medullary Epithelial Cells

    PubMed Central

    Satoh, Rumi; Kakugawa, Kiyokazu; Yasuda, Takuwa; Yoshida, Hisahiro; Sibilia, Maria; Katsura, Yoshimoto; Levi, Ben; Abramson, Jakub; Koseki, Yoko; Koseki, Haruhiko; van Ewijk, Willem; Hollander, Georg A.; Kawamoto, Hiroshi

    2016-01-01

    Thymic medullary regions are formed in neonatal mice as islet-like structures, which increase in size over time and eventually fuse a few weeks after birth into a continuous structure. The development of medullary thymic epithelial cells (TEC) is dependent on NF-κB associated signaling though other signaling pathways may contribute. Here, we demonstrate that Stat3-mediated signals determine medullary TEC cellularity, architectural organization and hence the size of the medulla. Deleting Stat3 expression selectively in thymic epithelia precludes the postnatal enlargement of the medulla retaining a neonatal architecture of small separate medullary islets. In contrast, loss of Stat3 expression in cortical TEC neither affects the cellularity or organization of the epithelia. Activation of Stat3 is mainly positioned downstream of EGF-R as its ablation in TEC phenocopies the loss of Stat3 expression in these cells. These results indicate that Stat3 meditated signal via EGF-R is required for the postnatal development of thymic medullary regions. PMID:26789017

  18. Sporadic juvenile thymic lymphoma in a 6-month-old Holstein heifer.

    PubMed

    Nasir, Karen S

    2005-09-01

    A 6-month-old Holstein heifer was presented for recurrent bloat and a firm, primarily left-sided mass in the caudoventral cervical region. Surgical exploration revealed a vascularized, encapsulated mass extending from the submandibular region to the thoracic inlet. Postmortem gross and histopathologic examination and the history enabled a diagnosis of sporadic thymic lymphoma. PMID:16231655

  19. A working group classification of focal prostate atrophy lesions.

    PubMed

    De Marzo, Angelo M; Platz, Elizabeth A; Epstein, Jonathan I; Ali, Tehmina; Billis, Anthanase; Chan, Teresa Y; Cheng, Liang; Datta, Milton; Egevad, Lars; Ertoy-Baydar, Dilek; Farre, Xavier; Farree, Xavier; Fine, Samson W; Iczkowski, Kenneth A; Ittmann, Michael; Knudsen, Beatrice S; Loda, Massimo; Lopez-Beltran, Antonio; Magi-Galluzzi, Cristina; Mikuz, Gregor; Montironi, Roldolfo; Pikarsky, Eli; Pizov, Galina; Rubin, Mark A; Samaratunga, Hema; Sebo, Thomas; Sesterhenn, Isabel A; Shah, Rajal B; Shah, Rajiv B; Signoretti, Sabina; Simko, Jeffery; Thomas, George; Troncoso, Patricia; Tsuzuki, Toyonori T; van Leenders, Geert J; Yang, Ximing J; Zhou, Ming; Figg, William D; Hoque, Ashraful; Hoque, Ashrafal; Lucia, M S

    2006-10-01

    Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was

  20. Brain atrophy in Alzheimer's Disease and aging.

    PubMed

    Pini, Lorenzo; Pievani, Michela; Bocchetta, Martina; Altomare, Daniele; Bosco, Paolo; Cavedo, Enrica; Galluzzi, Samantha; Marizzoni, Moira; Frisoni, Giovanni B

    2016-09-01

    Thanks to its safety and accessibility, magnetic resonance imaging (MRI) is extensively used in clinical routine and research field, largely contributing to our understanding of the pathophysiology of neurodegenerative disorders such as Alzheimer's disease (AD). This review aims to provide a comprehensive overview of the main findings in AD and normal aging over the past twenty years, focusing on the patterns of gray and white matter changes assessed in vivo using MRI. Major progresses in the field concern the segmentation of the hippocampus with novel manual and automatic segmentation approaches, which might soon enable to assess also hippocampal subfields. Advancements in quantification of hippocampal volumetry might pave the way to its broader use as outcome marker in AD clinical trials. Patterns of cortical atrophy have been shown to accurately track disease progression and seem promising in distinguishing among AD subtypes. Disease progression has also been associated with changes in white matter tracts. Recent studies have investigated two areas often overlooked in AD, such as the striatum and basal forebrain, reporting significant atrophy, although the impact of these changes on cognition is still unclear. Future integration of different MRI modalities may further advance the field by providing more powerful biomarkers of disease onset and progression. PMID:26827786

  1. [Multiple system atrophy - synuclein and neuronal degeneration].

    PubMed

    Yoshida, Mari

    2011-11-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are α-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurties. Reviewing the pathological features of 102 MSA cases, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, which suggested different phenotypic pattern of MSA might exist between races, compared to the relatively high frequency of SND-type in western countries. In early stage of MSA, NNIs, NCIs and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic cord, lower motor neurons and cortical pyramidal neurons, in additions to GCIs. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA. PMID:22277386

  2. Proximal spinal muscular atrophy: current orthopedic perspective

    PubMed Central

    Haaker, Gerrit; Fujak, Albert

    2013-01-01

    Spinal muscular atrophy (SMA) is a hereditary neuromuscular disease of lower motor neurons that is caused by a defective “survival motor neuron” (SMN) protein that is mainly associated with proximal progressive muscle weakness and atrophy. Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy. Active research for possible treatment options has become possible since the disease-causing gene defect was identified in 1995. Nevertheless, a causal therapy is not available at present, and therapeutic management of SMA remains challenging; the prolonged survival is increasing, especially orthopedic, respiratory and nutritive problems. This review focuses on orthopedic management of the disease, with discussion of key aspects that include scoliosis, muscular contractures, hip joint disorders, fractures, technical devices, and a comparative approach of conservative and surgical treatment. Also emphasized are associated complications including respiratory involvement, perioperative care and anesthesia, nutrition problems, and rehabilitation. The SMA disease course can be greatly improved with adequate therapy with established orthopedic procedures in a multidisciplinary therapeutic approach. PMID:24399883

  3. Primary polyoma virus-induced murine thymic epithelial tumors. A tumor model of thymus physiology.

    PubMed Central

    Hoot, G. P.; Kettman, J. R.

    1989-01-01

    Thymic tumors were induced in C3'/Bittner mice by neonatal inoculation with polyoma virus. The objective of this study was to identify the phenotypes of the cells within the tumors and to attempt to determine the origin of the neoplastic cell population(s). At the ultrastructural level, the neoplastic cells resembled normal thymic epithelium with tonofilaments and desmosomes. Immunoperoxidase staining demonstrated the presence of cytokeratin, Iak, -beta 2-microglobulin, -asialo-GM1, the thymic cortical epithelial marker ER-TR4, and the medullary epithelial marker ER-TR5. Islands of normal cortical thymocytes supported by residual normal cortical epithelium and acid phosphatase-positive cortical macrophages were interspersed in the tumors. Residual islands of normal medullary architecture with nonspecific esterase-positive IDCs were rarely identified in tumors. Most lymphocytes in the tumors were normal immature cortical thymocytes with the phenotype Tdt+, PNA+, Thy 1.2bright, Ly-1dull, H-2Kkdull, ThB+, J11d+, and Lyt-2+L3T4+. Lymphocytes in the tumors were steroid-sensitive like normal thymocytes. The proportions of Lyt-2+L3T4- and Lyt-2-L3T4+ cells were generally larger in the tumors than in normal thymus and reflected the higher frequency of lymphocytes in the tumors capable of proliferating in vitro in response to Con A plus IL-2. The data were consistent with the hypothesis that the neoplasia originates from thymic epithelium that is interspersed with normal, developing thymic lymphocytes. Images Figure 4 p[688]-a Figure 1 Figure 2 Figure 3 p687-a Figure 7 PMID:2552813

  4. FOXN1: A Master Regulator Gene of Thymic Epithelial Development Program

    PubMed Central

    Romano, Rosa; Palamaro, Loredana; Fusco, Anna; Giardino, Giuliana; Gallo, Vera; Del Vecchio, Luigi; Pignata, Claudio

    2013-01-01

    T cell ontogeny is a sophisticated process, which takes place within the thymus through a series of well-defined discrete stages. The process requires a proper lympho-stromal interaction. In particular, cortical and medullary thymic epithelial cells (cTECs, mTECs) drive T cell differentiation, education, and selection processes, while the thymocyte-dependent signals allow thymic epithelial cells (TECs) to maturate and provide an appropriate thymic microenvironment. Alterations in genes implicated in thymus organogenesis, including Tbx1, Pax1, Pax3, Pax9, Hoxa3, Eya1, and Six1, affect this well-orchestrated process, leading to disruption of thymic architecture. Of note, in both human and mice, the primordial TECs are yet unable to fully support T cell development and only after the transcriptional activation of the Forkhead-box n1 (FOXN1) gene in the thymic epithelium this essential function is acquired. FOXN1 is a master regulator in the TEC lineage specification in that it down-stream promotes transcription of genes, which, in turn, regulate TECs differentiation. In particular, FOXN1 mainly regulates TEC patterning in the fetal stage and TEC homeostasis in the post-natal thymus. An inborn null mutation in FOXN1 leads to Nude/severe combined immunodeficiency (SCID) phenotype in mouse, rat, and humans. In Foxn1−/− nude animals, initial formation of the primordial organ is arrested and the primordium is not colonized by hematopoietic precursors, causing a severe primary T cell immunodeficiency. In humans, the Nude/SCID phenotype is characterized by congenital alopecia of the scalp, eyebrows, and eyelashes, nail dystrophy, and a severe T cell immunodeficiency, inherited as an autosomal recessive disorder. Aim of this review is to summarize all the scientific information so far available to better characterize the pivotal role of the master regulator FOXN1 transcription factor in the TEC lineage specifications and functionality. PMID:23874334

  5. Medullary thymic epithelium expresses a ligand for CTLA4 in situ and in vitro

    SciTech Connect

    Nelson, A.J.; Hosier, S.; Farr, A.G. ); Brady, W.; Linsley, P.S. )

    1993-09-01

    A fusion protein consisting of the extracellular domain of CTLA4 and an Ig C[gamma]1 chain (CTLA4-Ig) was used to examine the distribution of the ligands for CTLA4 within the murine thymus and to characterize the nature of these ligands. Two-color immunofluorescence of thymus tissue revealed binding of the fusion protein to medullary thymic epithelial cells and dendritic cells within the corticomedullary and medullary areas of the thymus. Medullary cells binding the fusion protein also expressed MHC class II products and ICAM-1. Thymus tissue sections treated with cross-linking fixatives, such as glutaraldehyde, paraformaldehyde, or 1-ethyl-3(d dimethylaminopropyl)-carbodiimide no longer bound the CTLA4 fusion protein, indicating that binding was very sensitive to the tertiary structure of the tissue ligand. The ability of thymic tissue to bind the fusion protein was developmentally regulated. At day 14 of gestation, only scattered single cells were labeled. Clusters of labeled cells, which were detected by day 16 of gestation, increased in frequency with advancing gestational age. Consistent with the in situ labeling studies. CTLA4-lg also labeled several thymic epithelial cell lines previously shown to have a medullary phenotype. Polymerase chain reaction analysis of mRNA extracted from these cells indicated they contained mRNA for B7, a known counter receptor for CTLA4 and CD28. Immunoprecipitation of [sup 125]I-labeled thymic epithelial cells with the CTLA4-Ig detected a M[sub r] 65,000 to 70,000 species under reducing conditions, consistent with previous studies of B7. These data suggest that the ligand for CTLA4 expressed by thymic epithelial cells in vitro is B7 and that the expression of this ligand in situ is largely restricted to the medullary compartment and is associated with epithelial cells and dendritic cells.

  6. Cerebellar atrophy and prognosis after temporal lobe resection.

    PubMed Central

    Specht, U; May, T; Schulz, R; Rohde, M; Ebner, A; Schmidt, R C; Schütz, M; Wolf, P

    1997-01-01

    OBJECTIVE: Experimental data indicate inhibitory effects of the cerebellum on seizure activity. Structural damage such as cerebellar atrophy, which is a common finding in patients with chronic epilepsy, may reduce these effects. METHODS: Outcome after temporal lobectomy was studied in 78 consecutive patients, with or without cerebellar atrophy diagnosed by MRI. RESULTS: Thirty five patients (45%) showed cerebellar atrophy. At a mean follow up of 14.6 (range, 6-40) months, 50 patients (64%) had no postoperative seizures. In these patients, the frequency of cerebellar atrophy was significantly lower (34%) than in patients who relapsed (64%, p < 0.01). Occurrence of generalised tonic-clonic seizures (GTCS) within two years before surgery, occurrence of GTCS at any time preoperatively, long duration of epilepsy, and older age at surgery were also associated with recurrence of seizures. Multiple logistic regression analysis suggested occurrence of GTCS within two years before surgery and cerebellar atrophy as the main predictive indicators. When both factors were present, the percentage of patients remaining seizure free since surgery fell to 30%, compared with 60% when only GTCS were present, 78.6% when only cerebellar atrophy was present, and 87.5% when both factors were absent. CONCLUSIONS: Cerebellar atrophy shown by MRI was a frequent finding in surgically treated patients with temporal lobe epilepsy. The presence of cerebellar atrophy seems to worsen the prognosis after temporal lobe resection. Images PMID:9153610

  7. Molecular events in skeletal muscle during disuse atrophy

    NASA Technical Reports Server (NTRS)

    Kandarian, Susan C.; Stevenson, Eric J.

    2002-01-01

    This review summarizes the current knowledge of the molecular processes underlying skeletal muscle atrophy due to disuse. Because the processes involved with muscle wasting due to illness are similar to disuse, this literature is used for comparison. Areas that are ripe for further study and that will advance our understanding of muscle atrophy are suggested.

  8. Simulation of tissue atrophy using a topology preserving transformation model.

    PubMed

    Karaçali, Bilge; Davatzikos, Christos

    2006-05-01

    We propose a method to simulate atrophy and other similar volumetric change effects on medical images. Given a desired level of atrophy, we find a dense warping deformation that produces the corresponding levels of volumetric loss on the labeled tissue using an energy minimization strategy. Simulated results on a real brain image indicate that the method generates realistic images of tissue loss. The method does not make assumptions regarding the mechanics of tissue deformation, and provides a framework where a pre-specified pattern of atrophy can readily be simulated. Furthermore, it provides exact correspondences between images prior and posterior to the atrophy that can be used to evaluate provisional image registration and atrophy quantification algorithms. PMID:16689268

  9. Bone and muscle atrophy with suspension of the rat

    NASA Technical Reports Server (NTRS)

    Leblanc, A.; Marsh, C.; Evans, H.; Johnson, P.; Schneider, V.; Jhingran, S.

    1985-01-01

    In order to identify a suitable model for the study of muscle atrophy due to suspension in space, a modified version of the Morey tail suspension model was used to measure the atrophic responses of rat bone and muscle to 14-30 days of unloading of the hindlimbs. The progress of atrophy was measured by increases in methylene diphosphonate (MDP) uptake. It is found that bone uptake of methylene diphosphonate followed a phasic pattern similar to changes in the bone formation rate of immobilized dogs and cats. Increased MDP uptake after a period of 60 days indicated an accelerated bone metabolism. Maximum muscle atrophy in the suspended rats was distinctly different from immobilization atrophy. On the basis of the experimental results, it is concluded that the tail suspension model is an adequate simulation of bone atrophy due to suspension.

  10. Indices of Regional Brain Atrophy: Formulae and Nomenclature

    PubMed Central

    Arias-Carrión, Oscar

    2015-01-01

    The pattern of brain atrophy helps to discriminate normal age-related changes from neurodegenerative diseases. Albeit indices of regional brain atrophy have proven to be a parameter useful in the early diagnosis and differential diagnosis of some neurodegenerative diseases, indices of absolute regional atrophy still have some important limitations. We propose using indices of relative atrophy for representing how the volume of a given region of interest (ROI) changes over time in comparison to changes in global brain measures over the same time. A second problem in morphometric studies is terminology. There is a lack of systematization naming indices and the same measure can be named with different terms by different research groups or imaging softwares. This limits the understanding and discussion of studies. In this technological report, we provide a general description on how to compute indices of absolute and relative regional brain atrophy and propose a standardized nomenclature. PMID:26261753

  11. [Optic neuropathy in acute poisoning with methanol].

    PubMed

    Sekkat, A; Maillard, P; Dupeyron, G; Bensouda, J; Arne, J L; Bec, P

    1982-01-01

    The authors report four cases of methanol poisoning, two of which suffering acute bilateral optic neuropathy which secondarily leads to optic atrophy. The report the main clinical features of such a poisoning and the actual basis of its physiopathology and treatment. According to the four cases reported, they underline the importance of early diagnosis and specific treatment. PMID:7169508

  12. Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output

    NASA Astrophysics Data System (ADS)

    Emre, Yalin; Irla, Magali; Dunand-Sauthier, Isabelle; Ballet, Romain; Meguenani, Mehdi; Jemelin, Stephane; Vesin, Christian; Reith, Walter; Imhof, Beat A.

    2013-11-01

    Thymic epithelial cells (TEC) are heterogeneous stromal cells that generate microenvironments required for the formation of T cells within the thymus. Defects in TEC lead to immunodeficiency or autoimmunity. Here we identify TEC as the major source of cysteine-rich protein 61 (CYR61), a matricellular protein implicated in cell proliferation and migration. Binding of CYR61 to LFA-1, ICAM-1 and integrin α6 supports the adhesion of TEC and thymocytes as well as their interaction. Treatment of thymic lobes with recombinant CYR61 expands the stromal compartment by inducing the proliferation of TEC and activates Akt signalling. Engraftment of CYR61-overexpressing thymic lobes into athymic nude mice drastically boosts the yield of thymic output via expansion of TEC. This increases the space for the recruitment of circulating hematopoietic progenitors and the development of T cells. Our discovery paves the way for therapeutic interventions designed to restore thymus stroma and T-cell generation.

  13. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge.

    PubMed

    Cash, David M; Frost, Chris; Iheme, Leonardo O; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B; Pennec, Xavier; Pierson, Ronald K; Gunter, Jeffrey L; Senjem, Matthew L; Jack, Clifford R; Guizard, Nicolas; Fonov, Vladimir S; Collins, D Louis; Modat, Marc; Cardoso, M Jorge; Leung, Kelvin K; Wang, Hongzhi; Das, Sandhitsu R; Yushkevich, Paul A; Malone, Ian B; Fox, Nick C; Schott, Jonathan M; Ourselin, Sebastien

    2015-12-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated "direct" measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  14. Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge

    PubMed Central

    Cash, David M.; Frost, Chris; Iheme, Leonardo O.; Ünay, Devrim; Kandemir, Melek; Fripp, Jurgen; Salvado, Olivier; Bourgeat, Pierrick; Reuter, Martin; Fischl, Bruce; Lorenzi, Marco; Frisoni, Giovanni B.; Pennec, Xavier; Pierson, Ronald K.; Gunter, Jeffrey L.; Senjem, Matthew L.; Jack, Clifford R.; Guizard, Nicolas; Fonov, Vladimir S.; Collins, D. Louis; Modat, Marc; Cardoso, M. Jorge; Leung, Kelvin K.; Wang, Hongzhi; Das, Sandhitsu R.; Yushkevich, Paul A.; Malone, Ian B.; Fox, Nick C.; Schott, Jonathan M.; Ourselin, Sebastien

    2015-01-01

    Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated “direct” measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the

  15. The neuropsychiatric profile of posterior cortical atrophy.

    PubMed

    Isella, Valeria; Villa, Giulia; Mapelli, Cristina; Ferri, Francesca; Appollonio, Ildebrando Marco; Ferrarese, Carlo

    2015-06-01

    We analyzed scores obtained at the Neuropsychiatric Inventory (NPI) by 20 patients with posterior cortical atrophy (PCA) and contrasted it with 20 patients having Alzheimer disease (AD). Patients with hallucinations and delusions were not included due to the high probability of a diagnosis of Lewy body disease. Prevalence of behavioral and psychological symptoms (BPSD) was 95% in the PCA group, the most frequent being apathy and anxiety. Cluster analysis on NPI subscales highlighted a behavioral subsyndrome characterized by agitated temper and irritability. Depression, anxiety, and apathy did not cluster with any other BPSD nor with each other. The PCA group showed a significantly higher proportion of anxious patients and worse anxiety score than patients with AD. No correlation was found between NPI data and demographic, clinical, or neuropsychological features nor were there significant differences for the same variables between anxious and nonanxious cases with PCA. In agreement with anecdotal reports, anxiety seems particularly relevant in PCA. PMID:25330926

  16. Cardiac atrophy in women following bed rest.

    PubMed

    Dorfman, Todd A; Levine, Benjamin D; Tillery, Tommy; Peshock, Ronald M; Hastings, Jeff L; Schneider, Suzanne M; Macias, Brandon R; Biolo, Gianni; Hargens, Alan R

    2007-07-01

    Both chronic microgravity exposure and long-duration bed rest induce cardiac atrophy, which leads to reduced standing stroke volume and orthostatic intolerance. However, despite the fact that women appear to be more susceptible to postspaceflight presyncope and orthostatic hypotension than male astronauts, most previous high-resolution studies of cardiac morphology following microgravity have been performed only in men. Because female athletes have less physiological hypertrophy than male athletes, we reasoned that they also might have altered physiological cardiac atrophy after bed rest. Magnetic resonance imaging was performed in 24 healthy young women (32.1 +/- 4 yr) to measure left ventricular (LV) and right ventricular (RV) mass, volumes, and morphology accurately before and after 60 days of 6 degrees head-down tilt (HDT) bed rest. Subjects were matched and then randomly assigned to sedentary bed rest (controls, n = 8) or two treatment groups consisting of 1) exercise training using supine treadmill running within lower body negative pressure plus resistive training (n = 8), or 2) protein (0.45 g x kg(-1) x day(-1) increase) plus branched-chain amino acid (BCAA) (7.2 g/day) supplementation (n = 8). After sedentary bed rest without nutritional supplementation, there were significant reductions in LV (96 +/- 26 to 77 +/- 25 ml; P = 0.03) and RV volumes (104 +/- 33 to 86 +/- 25 ml; P = 0.02), LV (2.2 +/- 0.2 to 2.0 +/- 0.2 g/kg; P = 0.003) and RV masses (0.8 +/- 0.1 to 0.6 +/- 0.1 g/kg; P < 0.001), and the length of the major axis of the LV (90 +/- 6 to 84 +/- 7 mm. P < 0.001), similar to what has been observed previously in men (8.0%; Perhonen MA, Franco F, Lane LD, Buckey JC, Blomqvist Zerwekh JE, Peshock RM, Weatherall PT, Levine BD. J Appl Physiol 91: 645-653, 2001). In contrast, there were no significant reductions in LV or RV volumes in the exercise-trained group, and the length of the major axis was preserved. Moreover, there were significant increases in

  17. Infantile spinal muscular atrophy (SMA) and multiple congenital bone fractures in sibs: a lethal new syndrome.

    PubMed Central

    Borochowitz, Z; Glick, B; Blazer, S

    1991-01-01

    Acute infantile spinal muscular atrophy (SMA type I, Werdnig-Hoffmann disease) has generally been accepted as an autosomal recessive disorder. However, several investigators have noted a slightly increased male to female ratio. We describe here a family with two affected male sibs who had a form of acute infantile SMA with congenital bone fractures, whose parents were first cousins. Pedigree analysis strongly suggested autosomal recessive inheritance, but X linked recessive inheritance could not be ruled out. In view of the heterogeneity of the SMAs, and the distinct clinical features found in our patients, we suggest that their infantile SMA might well be a distinct entity. We suggest that SMA I with congenital contractures and bone fractures appears to be a recognisable disorder that can be distinguished from the more common classic form of SMA I. PMID:1865475

  18. Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma.

    PubMed

    Moser, Bernhard; Schiefer, Ana Iris; Janik, Stefan; Marx, Alexander; Prosch, Helmut; Pohl, Wolfgang; Neudert, Barbara; Scharrer, Anke; Klepetko, Walter; Müllauer, Leonhard

    2015-04-01

    We report 2 cases of primary thymic adenocarcinoma with enteric differentiation. One carcinoma occurred in a 41-year-old man as a 7-cm-diameter cystic tumor and the other one in a 39-year-old woman as a 6-cm-diameter solid mass. Both tumors were located in the anterior mediastinum. Clinical staging did not reveal any extrathymic tumor. Histologically, the tumors were classified as adenocarcinoma, not otherwise specified, and a mucinous (colloid) carcinoma, respectively. Immunohistochemically, both tumors were positive for cytokeratin 20 (CK20), CDX2, and carcinoembryonic antigen, reflecting enteric differentiation. A review of the literature on 43 other cases of primary thymic adenocarcinomas suggested 11 further cases with enteric differentiation, as assessed by CK20 and/or CDX2 expression. We propose that thymic adenocarcinoma with enteric differentiation represents a novel subtype of thymic carcinoma. It is mostly of mucinous morphology and frequently associated with thymic cysts. The clinical outcome is variable. Recognition of primary thymic adenocarcinoma with enteric differentiation is helpful for the differentiation from metastatic disease, mainly from the gastrointestinal tract. PMID:25517960

  19. Transcriptional profile of a myotube starvation model of atrophy

    NASA Technical Reports Server (NTRS)

    Stevenson, Eric J.; Koncarevic, Alan; Giresi, Paul G.; Jackman, Robert W.; Kandarian, Susan C.

    2005-01-01

    Skeletal muscle wasting is a pervasive phenomenon that can result from a wide range of pathological conditions as well as from habitual muscular inactivity. The present work describes a cell-culture condition that induces significant atrophy in skeletal muscle C2C12 myotubes. The failure to replenish differentiation media in mature myotubes leads to rapid atrophy (53% in diameter), which is referred to here as starvation. Affymetrix microarrays were used to develop a transcriptional profile of control (fed) vs. atrophied (nonfed) myotubes. Myotube starvation was characterized by an upregulation of genes involved in translational inhibition, amino acid biosynthesis and transport, and cell cycle arrest/apoptosis, among others. Downregulated genes included several structural and regulatory elements of the extracellular matrix as well as several elements of Wnt/frizzled and TGF-beta signaling pathways. Interestingly, the characteristic transcriptional upregulation of the ubiquitin-proteasome system, calpains, and cathepsins known to occur in multiple in vivo models of atrophy were not seen during myotube starvation. With the exception of the downregulation of extracellular matrix genes, serine protease inhibitor genes, and the upregulation of the translation initiation factor PHAS-I, this model of atrophy in cell culture has a transcriptional profile quite distinct from any study published to date with atrophy in whole muscle. These data show that, although the gross morphology of atrophied muscle fibers may be similar in whole muscle vs. myotube culture, the processes by which this phenotype is achieved differ markedly.

  20. Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect.

    PubMed

    Durand, Paul D; Couto, Rafael A; Isakov, Raymond; Yoo, Donald B; Azizzadeh, Babak; Guyuron, Bahman; Zins, James E

    2016-04-01

    While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter. PMID:26780946

  1. Bioengineering mini functional thymic units with EAK16-II/EAKIIH6 self-assembling hydrogel.

    PubMed

    Tajima, Asako; Liu, Wen; Pradhan, Isha; Bertera, Suzanne; Bagia, Christina; Trucco, Massimo; Meng, Wilson S; Fan, Yong

    2015-09-01

    Herein, we highlight the technical feasibility of generating a functional mini thymus with a novel hydrogel system, based on a peptide-based self-assembly platform that can induce the formation of 3-D thymic epithelial cell (TEC) clusters. Amphiphilic peptide EAK16-II co-assembled with its histidinylated analogue EAKIIH6 into beta-sheet fibrils. When adaptor complexes (recombinant protein A/G molecules loaded with both anti-His and anti-EpCAM IgGs) were added to the mix, TECs were tethered to the hydrogel and formed 3-D mini clusters. TECs bound to the hydrogel composites retained their molecular properties; and when transplanted into athymic nude mice, they supported the development of functional T-cells. These mini thymic units of TECs can be useful in clinical applications to reconstitute T-cell adaptive immunity. PMID:25805654

  2. Apoptosis-promoted tumorigenesis: gamma-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death.

    PubMed

    Michalak, Ewa M; Vandenberg, Cassandra J; Delbridge, Alex R D; Wu, Li; Scott, Clare L; Adams, Jerry M; Strasser, Andreas

    2010-08-01

    Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in gamma-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from gamma-irradiation-induced death, because their glucocorticoid-mediated decimation in Puma-deficient mice activated cycling of stem/progenitor cells and restored thymic lymphomagenesis. Our demonstration that cycles of cell attrition and repopulation by stem/progenitor cells can drive tumorigenesis has parallels in human cancers, such as therapy-induced malignancies. PMID:20679396

  3. Genetic background influences loss of heterozygosity patterns in radiation-induced mouse thymic lymphoma

    PubMed Central

    Hang, Michael; Huang, Yurong; Snijders, Antoine M.; Mao, Jian-Hua

    2015-01-01

    Previous studies have revealed that p53 heterozygous (p53+/−) mice are extremely susceptible to radiation-induced tumorigenesis. To investigate whether genetic background influences radiation induced tumor susceptibility, we crossed p53+/− 129/Sv mice with genetically diverse strains to generate p53+/− F1 hybrids. The results showed that genetic background had a profound impact on tumor latency after exposure to gamma radiation, while the tumor spectrum did not change. We further characterized the thymic lymphomas that arose in the p53+/− mice by genome-wide loss of heterozygosity (LOH) analyses and found that genetic background strongly influenced the frequency of LOH and the loss of which parental allele on different chromosomes. Further research is needed to identify which genetic variations control the LOH patterns in radiation-induced thymic lymphomas and to evaluate its relevance to human cancers. PMID:25932465

  4. Thymic carcinoma diagnosed by using endoscopic ultrasound with fine-needle aspiration.

    PubMed

    Patel, Pragnesh; Guider, Julie; Rahimi, Erik; Guha, Sushovan; Zhang, Songlin; Thosani, Nirav

    2016-01-01

    There is a paucity of literature on the use of endoscopic ultrasound (EUS) for evaluating superior mediastinal structures, especially the thymus gland. We report a case of thymic carcinoma diagnosed by using EUS elastography with strain ratio and fine-needle aspiration (FNA). A 64-year-old woman presented with altered mental status and was diagnosed with autoimmune encephalitis. Further work-up suggested a superior mediastinal mass, for which she underwent EUS. A hypoechoic mass was found in the superior mediastinum at the level of the aortic arch. Real-time EUS elastography showed a predominantly blue hue to the mass concerning for malignancy. FNA of the mass was performed, which revealed numerous large neoplastic cells under a background of a small lymphoid infiltrate. Immunohistochemistry was strongly positive for PAX8, pancytokeratin, and CAM5.2. The pathologic and immunohistochemical stains were consistent with thymic carcinoma. PMID:27386480

  5. Available evidence and new biological perspectives on medical treatment of advanced thymic epithelial tumors.

    PubMed

    Serpico, D; Trama, A; Haspinger, E R; Agustoni, F; Botta, L; Berardi, R; Palmieri, G; Zucali, P; Gallucci, R; Broggini, M; Gatta, G; Pastorino, U; Pelosi, G; de Braud, F; Garassino, M C

    2015-05-01

    Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here, we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments. Epidermal growth factor receptor (EGFR), stem-cell factor receptor, insulin-like growth factor-1 receptor (IGF1R), and vascular endothelial growth factors (VEGF-A, VEGF-B, and VEGF-2) are overexpressed in TETs. EGFR overexpression in TETs is associated with higher stage, and IGF1R overexpression has poor prognostic value. Data indicate that anti-IGF1R monoclonal antibodies, and inhibitors of angiogenesis, somatostatin receptors, histone deacetylase, mammalian target of rapamycin, and cyclin-dependent kinases may be active against TETs. Continued investigations in this field could lead to advancement of targeted and biological therapies for TETs. PMID:25411417

  6. Thymic carcinoma diagnosed by using endoscopic ultrasound with fine-needle aspiration

    PubMed Central

    Patel, Pragnesh; Guider, Julie; Rahimi, Erik; Guha, Sushovan; Zhang, Songlin; Thosani, Nirav

    2016-01-01

    There is a paucity of literature on the use of endoscopic ultrasound (EUS) for evaluating superior mediastinal structures, especially the thymus gland. We report a case of thymic carcinoma diagnosed by using EUS elastography with strain ratio and fine-needle aspiration (FNA). A 64-year-old woman presented with altered mental status and was diagnosed with autoimmune encephalitis. Further work-up suggested a superior mediastinal mass, for which she underwent EUS. A hypoechoic mass was found in the superior mediastinum at the level of the aortic arch. Real-time EUS elastography showed a predominantly blue hue to the mass concerning for malignancy. FNA of the mass was performed, which revealed numerous large neoplastic cells under a background of a small lymphoid infiltrate. Immunohistochemistry was strongly positive for PAX8, pancytokeratin, and CAM5.2. The pathologic and immunohistochemical stains were consistent with thymic carcinoma. PMID:27386480

  7. Brief Report: Role of Thymic Reconstitution in the Outcome of AIDS-Related PML.

    PubMed

    Chalkias, Spyridon G; Gheuens, Sarah; Bord, Evelyn; Batson, Stephanie; Koralnik, Igor J

    2015-12-01

    Implications of thymopoiesis in AIDS-related opportunistic infections remain unexplored. We used progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), as an opportunistic infection model, and we simultaneously investigated thymic output and T-cell responses against JCV in 22 patients with PML treated with combined antiretroviral therapy. Thymic output was significantly associated with JCV-specific CD4⁺ and CD8⁺ T-cell responses and improved survival. Our data suggest that patients with AIDS-related PML and impaired thymopoiesis are less likely to develop a robust JCV-specific cellular immune response and consequently are at an increased risk for a poor clinical outcome. PMID:26181821

  8. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact.

    PubMed

    Rojas, Juan Ignacio; Patrucco, Liliana; Miguez, Jimena; Cristiano, Edgardo

    2016-03-01

    Multiple sclerosis (MS) was always considered as a white matter inflammatory disease. Today, there is an important body of evidence that supports the hypothesis that gray matter involvement and the neurodegenerative mechanism are at least partially independent from inflammation. Gray matter atrophy develops faster than white matter atrophy, and predominates in the initial stages of the disease. The neurodegenerative mechanism creates permanent damage and correlates with physical and cognitive disability. In this review we describe the current available evidence regarding brain atrophy and its consequence in MS patients. PMID:27050854

  9. Potential Role of Adjuvant Radiation Therapy in Cervical Thymic Neoplasm Involving Thyroid Gland or Neck

    PubMed Central

    Noh, Jae Myoung; Ha, Sang Yun; Ahn, Yong Chan; Oh, Dongryul; Seol, Seung Won; Oh, Young Lyun; Han, Joungho

    2015-01-01

    Purpose The purpose of this study is to assess the clinicopathologic features, treatment outcomes, and role of adjuvant radiation therapy (RT) in cervical thymic neoplasm involving the thyroid gland or neck. Materials and Methods The medical and pathologic records of eight patients with cervical thymic neoplasm were reviewed retrospectively. All patients underwent surgical resection, including thyroidectomy or mass excision. Adjuvant RT was added in five patients with adverse clinicopathologic features. The radiation doses ranged from 54 Gy/27 fractions to 66 Gy/30 fractions delivered to the primary tumor bed and pathologically involved regional lymphatics using a 3-dimensional conformal technique. Results Eight cases of cervical thymic neoplasm included three patients with carcinoma showing thymus-like differentiation (CASTLE) and five with ectopic cervical thymoma. The histologic subtypes of ectopic cervical thymoma patients were World Health Organization (WHO) type B3 thymoma in one, WHO type B1 thymoma in two, WHO type AB thymoma in one, and metaplastic thymoma in one, respectively. The median age was 57 years (range, 40 to 76 years). Five patients received adjuvant RT: three with CASTLE; one with WHO type B3; and one with WHO type AB with local invasiveness. After a median follow-up period of 49 months (range, 11 to 203 months), no recurrence had been observed, regardless of adjuvant RT. Conclusion Adjuvant RT after surgical resection might be worthwhile in patients with CASTLE and ectopic cervical thymoma with WHO type B2-C and/or extraparenchymal extension, as similarly indicated for primary thymic epithelial tumors. A longer follow-up period may be needed in order to validate this strategy. PMID:25648096

  10. Clinical Characteristics and Outcomes for Patients with Thymic Carcinoma: Evaluation of Masaoka Staging

    PubMed Central

    Litvak, Anya M.; Woo, Kaitlin; Hayes, Sara; Huang, James; Rimner, Andreas; Sima, Camelia S.; Moreira, Andre L.; Tsukazan, Maria; Riely, Gregory J.

    2015-01-01

    Background Thymic carcinomas are rare cancers with limited data regarding outcomes, particularly for those patients with advanced disease. Methods We identified patients with thymic carcinomas diagnosed between 1993 and 2012. Patient characteristics, recurrence free survival (RFS), and overall survival (OS) were analyzed. Results One hundred twenty-one patients with thymic carcinomas were identified. Higher Masaoka stage was associated with worse OS and RFS (5-yr OS of 100%, 81%, 51%, 24%, and 17% for stage I, II, III, IVa and IVb respectively, p<0.001 and 5-yr RFS of 80%, 28%, and 7% for stage I/II, III, and IV respectively, p<0.001). Patients with stage IVb lymph node (LN) only disease had a better 5-year OS as compared to patients with distant metastasis (24% vs. 7%, p=0.025). Of the 61 patients with stage IVb disease, 22/29 patients (76%) with LN-only disease underwent curative intent resection vs. 3/32 patients (9%) with distant metastasis. Twenty-two patients with LN involvement were treated with multi-modality therapy. Three (14%) remain free of disease with long-term follow-up (range: 3.4+ years to 6.8+ years). Conclusions We describe the clinical features of a large series of patients with thymic carcinoma in North America. The Masaoka staging system effectively prognosticated OS and RFS. Patients with stage IVb LN-only disease had significantly better OS as compared to patients with distant metastasis with a subset of patients sustaining long term RFS with multi-modality therapy. If validated, these data would support a revised staging system with sub-classification of stage IVb disease into two groups. PMID:25393794

  11. Spinal Metastasis of Thymic Carcinoma as a Rare Manifestation: A Summary of 7 Consecutive Cases

    PubMed Central

    Jee, Tae Keun; Lee, Sun-Ho; Kim, Eun-Sang; Eoh, Whan

    2014-01-01

    Backgrounds Thymic carcinomas are very rare tumors that are often associated with extrathoracic metastasis to other organs. However, it is well known that thymic carcinomas rarely metastasize to the spine, and the prognosis, treatment, and natural course of this disease are not yet standardized. Methods We describe seven thymic carcinoma patients with spinal metastasis who were diagnosed and treated in our institute from January 2006 to December 2011. We performed surgical treatment and adjuvant chemotherapy and/or radiation therapy, in consideration of each individual disease's course, and we regularly followed up the patients. Results Of the seven patients, five were male and two were female. Six had metastases in the thoracic spine, and one had metastases in the lumbar spine. An extradural lesion was found in five patients, and two patients had both extradural and intradural lesions. The period from the primary diagnosis to spinal metastases varied widely (range, 1.23-14 years). After surgery, all patients showed an improvement of back pain and radicular pain. Two patients were lost to follow-up, but the other five maintained ambulatory function until their final follow-up. Four patients died because of pulmonary complications accompanied with the disease's progression. One patient died from uncontrolled brain metastases. After surgery, the median survival was 204±111.43 days. Conclusion Because metastasis to the spine from thymic carcinoma is very rare, there are no treatment guidelines. Nevertheless, we suggest that appropriate surgical management of the metastatic lesion is necessary for the preservation of the patient's quality of life during survival. PMID:25346762

  12. Unusual diagnosis of a solitary thyroid nodule in the paediatric population: cervical thymic cyst.

    PubMed

    Sadacharan, Dhalapathy; Sathya, Anjali; Ravikumar, Divya; Nallapa, Deepakala

    2015-01-01

    We present a case of an 8-year-old girl with a painless swelling in her neck. An ultrasonogram revealed a cystic nodule with internal echoes, lying posterior to right lobe of thyroid, and MRI confirmed it. Thyroid scintigraphy did not show any uptake in the swelling. Intraoperatively, the lesion was densely adherent to the thyroid gland, hence a hemithyroidectomy was performed. Histopathology showed it to be an ectopic cervical thymic cyst with parathyroid tissue. PMID:26420701

  13. P12: Somatostatin analogs as maintenance therapy in heavily pretreated thymic epithelial tumors

    PubMed Central

    Palmieri, Giovannella; Ottaviano, Margaret; Nappi, Lucia; Rescigno, Pasquale; Tucci, Irene; Marino, Mirella; von Arx, Claudia; Palumbo, Giuliano; Del Vecchio, Silvana; Damiano, Vincenzo

    2015-01-01

    Background Thymic epithelial tumors (TETs) are rare neoplasms with a particular biological behavior, treated with a combination of therapeutic strategies such as surgery, chemotherapy, radiotherapy and target agents. No continuation maintenance therapy exists for these rare tumors. A high uptake of indium-labeled octreotide (111In-DTPA-D-Phe1-octreotide) and curative application of somatostatin analogs in thymic tumors have been widely demonstrated. Methods Eighteen patients (nine women and nine men, median age 54.5 years; range, 32–78 years) with advanced thymic tumors (seven patients with stage III; seven with IVa; four with IVb according to the Masaoka-Koga staging system), histotype sec. WHO revised by central review (three AB, two B1, three B2, five B3, three B2/B3, two thymic carcinoma) with a partial response or stable disease to conventional chemotherapeutic regimens platinum or not platinum-based, after performed OctreoScan, were enrolled in this monocentric referral center study. The schedule includes administration of long-acting analog octreotide (30 mg/every 28 days intramuscularly), until progression of disease was documented. Median time to progression and toxicity were evaluated. Results Median follow-up was of 43 months with a median time to progression of 14.5 months (range, 2–77 months). Treatment was generally well tolerated with acceptable toxicity: grade 1 diarrhea (five patients), grade 2 hyperglycemia (four patients). No patients interrupted treatment because of toxicity. Conclusions The current study indicates that single-agent somatostatin analogs maintenance therapy is a potential treatment strategy for advanced TETs OctreoScan positive which respond to previous conventional chemotherapy. In particular, somatostatin analogs may provide effective maintenance treatment duration regardless of histotype and stage of disease with an acceptable toxicity and an improved patients’ compliance.

  14. Reversal of Age-related Thymic Involution by an LHRH Agonist in Miniature Swine

    PubMed Central

    Hirakata, Atsushi; Okumi, Masayoshi; Griesemer, Adam D.; Shimizu, Akira; Nobori, Shuji; Tena, Aseda; Moran, Shannon; Arn, Scott; Boyd, Richard L; Sachs, David H; Yamada, Kazuhiko

    2010-01-01

    Background and aims of study We have previously demonstrated a requirement for the presence of a juvenile thymus for the induction of transplantation tolerance to renal allografts by a short-course of calcineurin inhibition in miniature swine. We have also shown that aged, involuted thymi can be rejuvenated when transplanted as vascularized thymic lobes into juvenile swine recipients. The present studies were aimed at elucidating the extrinsic factors facilitating this restoration of function in the aged thymus. In particular, we tested the impact of sex steroid blockade by Luteinizing Hormone-Releasing Hormone (LHRH). Materials and Methods 30 naive animals (25 males and 5 females) were used for measurement of serum testosterone levels. 3 mature male pigs (aged at 22, 22 and 29 months old) were used to test the effects of Lupron (LHRH analog) injection at 45 mg (per 70–80kg body weight) as a 3-month depot on testosterone levels and thymic rejuvenation. Thymic rejuvenation was assessed by histology, flow cytometric analysis, morphometric analysis and TREC assays. Results Hormonal alterations were induced by Lupron and resulted in macroscopic and histologic regeneration of the thymus of aged animals within 2 months, as evidenced by restoration of juvenile thymus architecture and increased cellularity. Two animals that were evaluated for TREC both showed increased levels in the periphery following Lupron treatment. Conclusion Treatment of aged animals with Lupron leads to thymic rejuventaion in adult miniature swine. This result could expanding the applicability of thymus-dependent tolerance-inducing regimens to adult recipients. PMID:20692342

  15. Expression of early activation antigen (CD69) during human thymic development.

    PubMed Central

    Jung, L K; Haynes, B F; Nakamura, S; Pahwa, S; Fu, S M

    1990-01-01

    The novel early activation antigen, EA1, has been shown to be induced by mitogens, antigens and the tumour promoter, phorbol myristate acetate (PMA), on human lymphocytes. This antigen has been designated to be CD69. EA1 has also been shown to be expressed on thymocytes without exogenous activation stimuli. In order to characterize further the expression of EA1 on thymocytes, the ontogeny of its expression was studied. EA1 appeared between 7 and 9.5 weeks of gestation, after colonization of the thymic rudiment with CD7+ T cell precursors, but before the onset of compartmentalization of the thymus into cortical and medullary zones. After cortico-medullary differentiation, the majority of medullary thymocytes expressed EA1 while only a fraction of the cortical thymocytes expressed this antigen. In the fetal and post-natal cortex, EA1 expression appeared to cluster in the subcapsular cortex. EA1+ cells were also scattered throughout the inner cortex. By two-colour fluorocytometric analysis of post-natal thymocytes, it was shown that EA1 was expressed on 30 to 65% of thymocytes. EA1 was expressed on CD4+ CD8+ as well as on the more immature CD4- CD8- thymocytes. In contrast to circulating T cells, thymocytes were much less responsive to PMA stimulation for the expression of EA1. Molecular characterization showed that EA1 on thymocytes had the same structure as that of activated peripheral T cells. In addition, thymic EA1 was constitutively phosphorylated. Thus, EA1 expression is acquired early during thymic development after colonization of the thymic rudiment by CD7+ T cell precursors. However, the specific role that EA1 may play in the activation and function of developing thymocytes remains to be determined. Images Fig. 7 Fig. 8 PMID:2204504

  16. Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

    PubMed Central

    Iyer, Chitra C.; McGovern, Vicki L.; Wise, Dawnne O.; Glass, David J.; Burghes, Arthur H. M.

    2014-01-01

    Spinal Muscular Atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx−/−–SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. PMID:24656734

  17. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress

    PubMed Central

    Malcolm, Tim I. M.; Villarese, Patrick; Fairbairn, Camilla J.; Lamant, Laurence; Trinquand, Amélie; Hook, C. Elizabeth; Burke, G. A. Amos; Brugières, Laurence; Hughes, Katherine; Payet, Dominique; Merkel, Olaf; Schiefer, Ana-Iris; Ashankyty, Ibraheem; Mian, Shahid; Wasik, Mariusz; Turner, Martin; Kenner, Lukas; Asnafi, Vahid; Macintyre, Elizabeth; Turner, Suzanne D.

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM–ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy. PMID:26753883

  18. Evaluation of bovine thymic function by measurement of signal joint T-cell receptor excision circles.

    PubMed

    Hisazumi, Rinnosuke; Kayumi, Miya; Zhang, Weidong; Kikukawa, Ryuji; Nasu, Tetuo; Yasuda, Masahiro

    2016-01-01

    A signal joint T-cell receptor excision circle (sjTREC) is a circular DNA produced by T-cell receptor α gene rearrangement in the thymus. Measurements of sjTREC values have been used to evaluate thymic function. We recently established a quantitative PCR (QPCR) assay of bovine sjTREC. In the present study, we used this QPCR assay to measure the sjTREC value in bovine peripheral blood mononuclear cells and we then evaluated the relationships between sjTREC values and peripheral blood T-cell number, growth stage, gender, and meteorological season. The sjTREC value was highest at the neonatal stage, and its value subsequently decreased with age. On the other hand, the peripheral T-cell number increased with age. The sjTREC value in calves up to 50-days old was significantly higher for males than for females, suggesting that thymic function might differ by gender. In addition, the sjTREC value and the peripheral T-cell number were significantly higher in calves in the summer season than in calves in the winter season. These data suggest that bovine thymic function is highly variable and varies according to the growth stage, gender, and environmental factors such as air temperature or the UV index. PMID:26827842

  19. Thymic Indoleamine 2,3-Dioxygenase-Positive Eosinophils in Young Children

    PubMed Central

    Tulic, Meri K.; Sly, Peter D.; Andrews, David; Crook, Maxine; Davoine, Francis; Odemuyiwa, Solomon O.; Charles, Adrian; Hodder, Megan L.; Prescott, Susan L.; Holt, Patrick G.; Moqbel, Redwan

    2009-01-01

    Eosinophils expressing indoleamine 2, 3-dioxygenase (IDO) may contribute to T-helper cell (Th)2 predominance. To characterize human thymus IDO+ eosinophil ontogeny relative to Th2 regulatory gene expression, we processed surgically obtained thymi from 22 children (age: 7 days to 12 years) for immunohistochemistry and molecular analysis, and measured cytokine and kynurenine levels in tissue homogenates. Luna+ eosinophils (∼2% of total thymic cells) decreased in number with age (P = 0.02) and were IDO+. Thymic IDO immunoreactivity (P = 0.01) and kynurenine concentration (P = 0.01) decreased with age as well. In addition, constitutively-expressed interleukin (IL)-5 and IL-13 in thymus supernatants was highest in youngest children. Eosinophil numbers correlated positively with expression of the Th2 cytokines IL-5, IL-13 (r = 0.44, P = 0.002), and IL-4 (r = 0.46, P = 0.005), transcription factor signal transducer and activator of transcription-6 (r = 0.68, P = 0.001), and the chemokine receptor, CCR3 (r = 0.17, P = 0.04), but negatively with IL-17 mRNA (r = −0.57, P = 0.02) and toll-like receptor 4 expression (r = −0.74, P = 0.002). Taken together, these results suggest that functional thymic IDO+ eosinophils during human infant life may have an immunomodulatory role in Th2 immune responses. PMID:19815714

  20. Generation of Functional Thymic Epithelium from Human Embryonic Stem Cells that Supports Host T Cell Development

    PubMed Central

    Parent, Audrey V.; Russ, Holger A.; Khan, Imran S.; LaFlam, Taylor N.; Metzger, Todd C.; Anderson, Mark S.; Hebrok, Matthias

    2013-01-01

    SUMMARY Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGFβ, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age-and stress-related thymic decline. PMID:23684540

  1. Anaplastic large cell lymphoma arises in thymocytes and requires transient TCR expression for thymic egress.

    PubMed

    Malcolm, Tim I M; Villarese, Patrick; Fairbairn, Camilla J; Lamant, Laurence; Trinquand, Amélie; Hook, C Elizabeth; Burke, G A Amos; Brugières, Laurence; Hughes, Katherine; Payet, Dominique; Merkel, Olaf; Schiefer, Ana-Iris; Ashankyty, Ibraheem; Mian, Shahid; Wasik, Mariusz; Turner, Martin; Kenner, Lukas; Asnafi, Vahid; Macintyre, Elizabeth; Turner, Suzanne D

    2016-01-01

    Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma presenting mostly in children and young adults. The natural progression of this disease is largely unknown as is the identity of its true cell of origin. Here we present a model of peripheral ALCL pathogenesis where the malignancy is initiated in early thymocytes, before T-cell receptor (TCR) β-rearrangement, which is bypassed in CD4/NPM-ALK transgenic mice following Notch1 expression. However, we find that a TCR is required for thymic egress and development of peripheral murine tumours, yet this TCR must be downregulated for T-cell lymphomagenesis. In keeping with this, clonal TCR rearrangements in human ALCL are predominantly in-frame, but often aberrant, with clonal TCRα but no comparable clonal TCRβ rearrangement, yielding events that would not normally be permissive for survival during thymic development. Children affected by ALCL may thus harbour thymic lymphoma-initiating cells capable of seeding relapse after chemotherapy. PMID:26753883

  2. CCX-CKR deficiency alters thymic stroma impairing thymocyte development and promoting autoimmunity.

    PubMed

    Bunting, Mark D; Comerford, Iain; Seach, Natalie; Hammett, Maree V; Asquith, Darren L; Körner, Heinrich; Boyd, Richard L; Nibbs, Robert J B; McColl, Shaun R

    2013-01-01

    The atypical chemokine receptor CCX-CKR regulates bioavailability of CCL19, CCL21, and CCL25, homeostatic chemokines that play crucial roles in thymic lymphopoiesis. Deletion of CCX-CKR results in accelerated experimental autoimmunity induced by immunization. Here we show that CCX-CKR deletion also increases incidence of a spontaneous Sjögren's syndrome-like pathology, characterized by lymphocytic infiltrates in salivary glands and liver of CCX-CKR(-/-) mice, suggestive of a defect in self-tolerance when CCX-CKR is deleted. This prompted detailed examination of the thymus in CCX-CKR(-/-) mice. Negatively selected mature SP cells were less abundant in CCX-CKR(-/-) thymi, yet expansion of both DP and immature SP cells was apparent. Deletion of CCX-CKR also profoundly reduced proportions of DN3 thymocyte precursors and caused DN2 cells to accumulate within the medulla. These effects are likely driven by alterations in thymic stroma as CCX-CKR(-/-) mice have fewer cTECs per thymocyte, and cTECs express the highest level of CCX-CKR in the thymus. A profound decrease in CCL25 within the thymic cortex was observed in CCX-CKR(-/-) thymi, likely accounting for their defects in thymocyte distribution and frequency. These findings identify a novel role for CCX-CKR in regulating cTEC biology, which promotes optimal thymocyte development and selection important for self-tolerant adaptive immunity. PMID:23152546

  3. Novel primary thymic defect with T lymphocytes expressing gamma delta T cell receptor.

    PubMed

    Geisler, C; Pallesen, G; Platz, P; Odum, N; Dickmeiss, E; Ryder, L P; Svejgaard, A; Plesner, T; Larsen, J K; Koch, C

    1989-07-01

    Flow cytometric analysis of the peripheral blood mononuclear cells in a six year old girl with a primary cellular immune deficiency showed a normal fraction of CD3 positive T cells. Most (70%) of the CD3 positive cells, however, expressed the gamma delta and not the alpha beta T cell receptor. Immunoprecipitation and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) showed that most of the gamma delta T cell receptors existed as disulphide-linked heterodimers. Proliferative responses to mitogens were severely reduced, but specific antibody responses after vaccination could be detected. A thymic biopsy specimen showed severe abnormalities of both the thymic lymphoid and epithelial component with abortive medullary differentiation and almost an entire lack of Hassall's corpuscles. This patient represents a case of primary immune deficiency syndrome not previously described. Thymic deficiency associated with a high proportion of T cells expressing the gamma delta T cell receptor has been described in nude mice, and it is suggested that the immune deficiency of this patient may represent a human analogue. PMID:2527256

  4. Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors.

    PubMed

    Wölfler, Albert; Danen-van Oorschot, Astrid A; Haanstra, Jurgen R; Valkhof, Marijke; Bodner, Claudia; Vroegindeweij, Eric; van Strien, Paulette; Novak, Alexandra; Cupedo, Tom; Touw, Ivo P

    2010-11-18

    Hematopoiesis is tightly controlled by transcription regulatory networks, but how and when specific transcription factors control lineage commitment are still largely unknown. Within the hematopoietic stem cell (Lin(-)Sca-1(+)c-Kit(+)) compartment these lineage-specific transcription factors are expressed at low levels but are up-regulated with the process of lineage specification. CCAAT/enhancer binding protein α (C/EBPα) represents one of these factors and is involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor cells, which express C/EBPα, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and a conditional EYFP allele. We show that Cebpa/EYFP(+) cells represent a significant subset of multipotent hematopoietic progenitors, which predominantly give rise to myeloid cells in steady-state hematopoiesis. C/EBPα induced a strong myeloid gene expression signature and down-regulated E2A-induced regulators of early lymphoid development. In addition, Cebpa/EYFP(+) cells compose a fraction of early thymic progenitors with robust myeloid potential. However, Cebpa/EYFP(+) multipotent hematopoietic progenitors and early thymic progenitors retained the ability to develop into erythroid and T-lymphoid lineages, respectively. These findings support an instructive but argue against a lineage-restrictive role of C/EBPα in multipotent hematopoietic and thymic progenitors. PMID:20807890

  5. Expression of the TrkB neurotrophin receptor by thymic macrophages.

    PubMed Central

    García-Suárez, O; Hannestad, J; Esteban, I; Sainz, R; Naves, F J; Vega, J A

    1998-01-01

    Increasing evidence suggests that some members of the neurotrophic factor family of neurotrophins could be implicated in the regulation of immune responses. Neurotrophins, as well as their tyrosine kinase signal-transducing receptors (the so-called Trk neurotrophin receptors), have been detected in different lymphoid tissues, although their cellular localization is not well known. In this study we used single and double immunohistochemistry to localize TrkB in situ in the rat thymus (in animals from 0 days to 2 years of age), in cytospin preparations of rat thymic cells, and in two mouse monocyte-macrophage cell lines (RAW 264.7 and J774A.1). We found TrkB protein expression in a subpopulation of cells in the corticomedullary junction, which simultaneously expressed the rat macrophage marker ED1. The density of TrkB-expressing cells increased with age, reaching maximal values at 2 years. Conversely, no evidence of TrkB protein expression could be found in dendritic cells, epithelial cells or thymocytes. Thymic macrophages in cytospin preparations, as well as in the mouse monocyte macrophage cell lines, also expressed TrkB protein. Although the possible function of TrkB in the thymic macrophage remains to be clarified, present findings add further evidence to the proposed role of neurotrophins in the immune system. Images Figure 1 Figure 2 Figure 3 Figures 4 and 5 PMID:9741346

  6. Mechanisms of cisplatin-induced muscle atrophy

    SciTech Connect

    Sakai, Hiroyasu; Sagara, Atsunobu; Arakawa, Kazuhiko; Sugiyama, Ryoto; Hirosaki, Akiko; Takase, Kazuhide; Jo, Ara; Sato, Ken; Chiba, Yoshihiko; Yamazaki, Mitsuaki; Matoba, Motohiro; Narita, Minoru

    2014-07-15

    Fatigue is the most common side effect of chemotherapy. However, the mechanisms of “muscle fatigue” induced by anti-cancer drugs are not fully understood. We therefore investigated the muscle-atrophic effect of cisplatin, a platinum-based anti-cancer drug, in mice. C57BL/6J mice were treated with cisplatin (3 mg/kg, i.p.) or saline for 4 consecutive days. On Day 5, hindlimb and quadriceps muscles were isolated from mice. The loss of body weight and food intake under the administration of cisplatin was the same as those in a dietary restriction (DR) group. Under the present conditions, the administration of cisplatin significantly decreased not only the muscle mass of the hindlimb and quadriceps but also the myofiber diameter, compared to those in the DR group. The mRNA expression levels of muscle atrophy F-box (MAFbx), muscle RING finger-1 (MuRF1) and forkhead box O3 (FOXO3) were significantly and further increased by cisplatin treated group, compared to DR. Furthermore, the mRNA levels of myostatin and p21 were significantly upregulated by the administration of cisplatin, compared to DR. On the other hand, the phosphorylation of Akt and FOXO3a, which leads to the blockade of the upregulation of MuRF1 and MAFbx, was significantly and dramatically decreased by cisplatin. These findings suggest that the administration of cisplatin increases atrophic gene expression, and may lead to an imbalance between protein synthesis and protein degradation pathways, which would lead to muscle atrophy. This phenomenon could, at least in part, explain the mechanism of cisplatin-induced muscle fatigue. - Highlights: • Cisplatin decreased mass and myofiber diameter in quadriceps muscle. • The mRNA of MAFbx, MuRF1 and FOXO3 were increased by the cisplatin. • The mRNA of myostatin and p21 were upregulated by cisplatin. • The phosphorylation of Akt and FOXO3a was decreased by cisplatin.

  7. Abnormalities of fundus autofluorescence in pigmented paravenous chorioretinal atrophy.

    PubMed

    Hashimoto, Yuki; Kase, Satoru; Saito, Wataru; Ishida, Susumu

    2012-01-01

    The aim of this study is to investigate fundus autofluorescence (FAF) as well as fluorescein angiography (FA), indocyanine green angiography (IA), and optical coherence tomography (OCT) in a patient with pigmented paravenous chorioretinal atrophy (PPCRA). A funduscopic examination revealed chorioretinal atrophy along the paravenous area in both eyes. A marked bone spicule pigment clumping together with the atrophy was noted left eye. FA and IA showed a window defect and hypofluorescence, respectively, which exclusively corresponds to the atrophic area along the retinal vein area and the optic disc both eyes. FAF revealed geographic hypofluorescence along the paravenous and supranasal retinal areas. Hyperfluorescence was noted, which comparatively surrounded the hypofluorescence in the peripheral paravenous distribution. Hypofluorescence detected by FAF corresponded to the areas of retinal thinning and atrophy detected by OCT and FA. FAF is a useful examination in PPCRA, which can noninvasively demonstrate the distribution of deficit and dysfunction of retinal pigment epithelium. PMID:23264840

  8. Biochemical adaptations of antigravity muscle fibers to disuse atrophy

    NASA Technical Reports Server (NTRS)

    Booth, F. W.

    1978-01-01

    Studies are presented in four parts of this report. The four parts include; (1) studies to gain information on the molecular basis of atrophy by antigravity muscle; (2) studies on the work capacity of antigravity muscles during atrophy and during recovery from atrophy; (3) studies on recovery of degenerated antigravity fibers after removal of hind-limb casts; and (4) studies on the atrophy and recovery of bone. The philosophy of these studies was to identify the time sequence of events in the soleus muscle of the rat following immobilization of the hind limbs, so that the length of the soleus muscle within the fixed limb is less than its resting length. In two separate studies, no decline in the weight of the soleus muscle could be detected during the first 72 hours of limb immobilization.

  9. Circulating micrornas as potential biomarkers of muscle atrophy

    NASA Astrophysics Data System (ADS)

    Wang, Fei

    2016-07-01

    Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for muscle atrophy patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the medium levels of six muscle-specific miRNAs (miR-1/23a/206/133/499/208b, also known as myomiRs) were all elevated in the medium of starved C2C12 cell (P < 0.01). And, the level of miR-1 and miR-23a were all elevated in the serum of hindlimb unloaded mice (P < 0.01). miR-23a levels were negatively correlated with both muscle mass and muscle fiber cross section area in muscle atrophy patients, indicating that they might represent the degree of muscle atrophy. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for muscle atrophy.

  10. Calculation of brain atrophy using computed tomography and a new atrophy measurement tool

    NASA Astrophysics Data System (ADS)

    Bin Zahid, Abdullah; Mikheev, Artem; Yang, Andrew Il; Samadani, Uzma; Rusinek, Henry

    2015-03-01

    Purpose: To determine if brain atrophy can be calculated by performing volumetric analysis on conventional computed tomography (CT) scans in spite of relatively low contrast for this modality. Materials & Method: CTs for 73 patients from the local Veteran Affairs database were selected. Exclusion criteria: AD, NPH, tumor, and alcohol abuse. Protocol: conventional clinical acquisition (Toshiba; helical, 120 kVp, X-ray tube current 300mA, slice thickness 3-5mm). Locally developed, automatic algorithm was used to segment intracranial cavity (ICC) using (a) white matter seed (b) constrained growth, limited by inner skull layer and (c) topological connectivity. ICC was further segmented into CSF and brain parenchyma using a threshold of 16 Hu. Results: Age distribution: 25-95yrs; (Mean 67+/-17.5yrs.). Significant correlation was found between age and CSF/ICC(r=0.695, p<0.01 2-tailed). A quadratic model (y=0.06-0.001x+2.56x10-5x2 ; where y=CSF/ICC and x=age) was a better fit to data (r=0.716, p < 0.01). This is in agreement with MRI literature. For example, Smith et al. found annual CSF/ICC increase in 58 - 94.5 y.o. individuals to be 0.2%/year, whereas our data, restricted to the same age group yield 0.3%/year(0.2-0.4%/yrs. 95%C.I.). Slightly increased atrophy among elderly VA patients is attributable to the presence of other comorbidities. Conclusion: Brain atrophy can be reliably calculated using automated software and conventional CT. Compared to MRI, CT is more widely available, cheaper, and less affected by head motion due to ~100 times shorter scan time. Work is in progress to improve the precision of the measurements, possibly leading to assessment of longitudinal changes within the patient.

  11. Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy.

    PubMed

    Shakespeare, Timothy J; Kaski, Diego; Yong, Keir X X; Paterson, Ross W; Slattery, Catherine F; Ryan, Natalie S; Schott, Jonathan M; Crutch, Sebastian J

    2015-07-01

    The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal 'visual dementia' and most common atypical Alzheimer's disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients' (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer's disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer's disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer's disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with 'sticky fixation'. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer's disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions

  12. Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy

    PubMed Central

    Kaski, Diego; Yong, Keir X. X.; Paterson, Ross W.; Slattery, Catherine F.; Ryan, Natalie S.; Schott, Jonathan M.; Crutch, Sebastian J.

    2015-01-01

    The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal ‘visual dementia’ and most common atypical Alzheimer’s disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients’ (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer’s disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer’s disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer’s disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with ‘sticky fixation’. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer’s disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large

  13. Novel therapeutic approaches in multiple system atrophy.

    PubMed

    Palma, Jose-Alberto; Kaufmann, Horacio

    2015-02-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  14. Spinal Muscular Atrophy: Current Therapeutic Strategies

    NASA Astrophysics Data System (ADS)

    Kiselyov, Alex S.; Gurney, Mark E.

    Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord. SMA is caused by deletion and/or mutation of the survival motor neuron gene (SMN1) on chromosome 5q13. There are variable numbers of copies of a second, related gene named SMN2 located in the proximity to SMN1. Both genes encode the same protein (Smn). Loss of SMN1 and incorrect splicing of SMN2 affect cellular levels of Smn triggering death of motor neurons. The severity of SMA is directly related to the normal number of copies of SMN2 carried by the patient. A considerable effort has been dedicated to identifying modalities including both biological and small molecule agents that increase SMN2 promoter activity to upregulate gene transcription and produce increased quantities of full-length Smn protein. This review summarizes recent progress in the area and suggests potential target product profile for an SMA therapeutic.

  15. Prenatal prediction of spinal muscular atrophy.

    PubMed Central

    Daniels, R J; Suthers, G K; Morrison, K E; Thomas, N H; Francis, M J; Mathew, C G; Loughlin, S; Heiberg, A; Wood, D; Dubowitz, V

    1992-01-01

    Spinal muscular atrophy (SMA) is a common cause of inherited morbidity and mortality in childhood. The wide range of phenotypes in SMA, uncertainty regarding its mode of inheritance, and the suggestion of linkage heterogeneity have complicated the genetic counselling of parents of affected children. The locus responsible for autosomal recessive SMA has been mapped to 5q11.2-q13.3. The most likely order of loci is cen-D5S6-(SMA,D5S125)-(JK53CA1/2,D5S112)-D5S3 9-qter, with highly polymorphic loci being identified at JK53CA1/2 and D5S39. We describe linkage studies with another highly polymorphic locus, D5S127, that is closely linked to D5S39. This genetic map can be used as the basis for genetic counselling in families with autosomal recessive SMA. Appropriate allowance can be made for sporadic cases owing to non-inherited causes and for linkage heterogeneity or misdiagnoses. Images PMID:1348091

  16. Facilitating text reading in posterior cortical atrophy

    PubMed Central

    Rajdev, Kishan; Shakespeare, Timothy J.; Leff, Alexander P.; Crutch, Sebastian J.

    2015-01-01

    Objective: We report (1) the quantitative investigation of text reading in posterior cortical atrophy (PCA), and (2) the effects of 2 novel software-based reading aids that result in dramatic improvements in the reading ability of patients with PCA. Methods: Reading performance, eye movements, and fixations were assessed in patients with PCA and typical Alzheimer disease and in healthy controls (experiment 1). Two reading aids (single- and double-word) were evaluated based on the notion that reducing the spatial and oculomotor demands of text reading might support reading in PCA (experiment 2). Results: Mean reading accuracy in patients with PCA was significantly worse (57%) compared with both patients with typical Alzheimer disease (98%) and healthy controls (99%); spatial aspects of passages were the primary determinants of text reading ability in PCA. Both aids led to considerable gains in reading accuracy (PCA mean reading accuracy: single-word reading aid = 96%; individual patient improvement range: 6%–270%) and self-rated measures of reading. Data suggest a greater efficiency of fixations and eye movements under the single-word reading aid in patients with PCA. Conclusions: These findings demonstrate how neurologic characterization of a neurodegenerative syndrome (PCA) and detailed cognitive analysis of an important everyday skill (reading) can combine to yield aids capable of supporting important everyday functional abilities. Classification of evidence: This study provides Class III evidence that for patients with PCA, 2 software-based reading aids (single-word and double-word) improve reading accuracy. PMID:26138948

  17. Meibomian gland dysfunction: hyperkeratinization or atrophy?

    PubMed

    Jester, James V; Parfitt, Geraint J; Brown, Donald J

    2015-01-01

    Meibomian gland dysfunction (MGD) is the major cause of evaporative dry eye disease (EDED) and dysfunction is widely thought to mechanistically involve ductal hyperkeratinization, plugging and obstruction. This review re-evaluates the role of hyperkeratinization in MGD based on more recent findings from mouse models. In these studies, eyelids from normal young and old mice or mice exposed to desiccating stress were evaluated by immunofluorescent tomography and 3-dimensional reconstruction to evaluate gland volume, expression of hyperkeratinization markers and cell proliferation or stimulated Raman scattering (SRS) microscopy to assess lipid quality. Results indicate that aging mice show dropout of meibomian glands with loss of gland volume and a forward migration of the mucocutaneous junction anterior to the gland orifice; similar age-related changes that are detected in human subjects. Atrophic glands also showed evidence of epithelial plugging of the orifice without the presence of hyperkeratinization. Mice exposed to desiccating stress showed hyperproliferation of the meibomian gland and ductal dilation suggesting a marked increase in lipid synthesis. Lipid quality was also affected in EDED mice with an increase in the protein content of lipid within the duct of the gland. Overall, age-related changes in the mouse show similar structural and functional correlates with that observed in clinical MGD without evidence of hyperkeratinization suggesting that gland atrophy may be a major cause of EDED. The response of the meibomian gland to desiccating stress also suggest that environmental conditions may accelerate or potentiate age-related changes. PMID:26817690

  18. Preventable Sternocleidomastoid Muscular Atrophy after Neck Dissection

    PubMed Central

    Yamamoto, Nao; Sawai, Natsuko Yoshimura; Ishimoto, Shunsuke; Ogura, Hide; Aikawa, Tomonao; Kogo, Mikihiko

    2015-01-01

    Background: Modified radical neck dissection (mRND) [preserving the sternocleidomastoid muscle (SCM) and the spinal accessory nerve] and supraomohyoid neck dissection have become common surgical procedures for treating head and neck cancer. Postoperative severe asymmetry of the neck and severe atrophy of the SCM, however, have been demonstrated. Methods: Using computed tomographic images, cross-sectional areas of the SCMs were measured in 99 patients with carcinoma of the oral cavity who underwent unilateral mRND or supraomohyoid neck dissection. An asymmetry index was used. Results: Innervation to the SCM was preserved in 91 patients. The spinal accessory nerve and the innervation were sacrificed in 3 patients; the innervation was repaired in 5 patients. Sacrifice of innervation to the SCM resulted in extremely severe asymmetry. Repair of the innervation prevented severe asymmetry in 40%. Preservation of the innervation prevented severe asymmetry in 75% at the middle portion of the neck and in 56% at the lower portion after mRND. Conclusion: Preserving innervation to the SCM and gentle handling of the nerve during neck dissection could prevent severe asymmetry after neck dissection. PMID:26495217

  19. Multiple system atrophy: pathogenic mechanisms and biomarkers.

    PubMed

    Jellinger, Kurt A; Wenning, Gregor K

    2016-06-01

    Multiple system atrophy (MSA) is a unique proteinopathy that differs from other α-synucleinopathies since the pathological process resulting from accumulation of aberrant α-synuclein (αSyn) involves the oligodendroglia rather than neurons, although both pathologies affect multiple parts of the brain, spinal cord, autonomic and peripheral nervous system. Both the etiology and pathogenesis of MSA are unknown, although animal models have provided insight into the basic molecular changes of this disorder. Accumulation of aberrant αSyn in oligodendroglial cells and preceded by relocation of p25α protein from myelin to oligodendroglia results in the formation of insoluble glial cytoplasmic inclusions that cause cell dysfunction and demise. These changes are associated with proteasomal, mitochondrial and lipid transport dysfunction, oxidative stress, reduced trophic transport, neuroinflammation and other noxious factors. Their complex interaction induces dysfunction of the oligodendroglial-myelin-axon-neuron complex, resulting in the system-specific pattern of neurodegeneration characterizing MSA as a synucleinopathy with oligodendroglio-neuronopathy. Propagation of modified toxic αSyn species from neurons to oligodendroglia by "prion-like" transfer and its spreading associated with neuronal pathways result in a multi-system involvement. No reliable biomarkers are currently available for the clinical diagnosis and prognosis of MSA. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable diagnostic biomarkers and to deliver targets for effective treatment of this hitherto incurable disorder is urgently needed. PMID:27098666

  20. Novel Therapeutic Approaches in Multiple System Atrophy

    PubMed Central

    Palma, Jose-Alberto; Kaufmann, Horacio

    2014-01-01

    Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly, progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein–containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprise cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflamatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchimal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review. PMID:24928797

  1. Towards translational therapies for multiple system atrophy

    PubMed Central

    Kuzdas-Wood, Daniela; Stefanova, Nadia; Jellinger, Kurt A.; Seppi, Klaus; Schlossmacher, Michael G.; Poewe, Werner; Wenning, Gregor K.

    2014-01-01

    Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiopathogenesis manifesting with autonomic failure, parkinsonism, and ataxia in any combination. The underlying neuropathology affects central autonomic, striatonigral and olivopontocerebellar pathways and it is associated with distinctive glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) that contain aggregates of α-synuclein. Current treatment options are very limited and mainly focused on symptomatic relief, whereas disease modifying options are lacking. Despite extensive testing, no neuroprotective drug treatment has been identified up to now; however, a neurorestorative approach utilizing autologous mesenchymal stem cells has shown remarkable beneficial effects in the cerebellar variant of MSA. Here, we review the progress made over the last decade in defining pathogenic targets in MSA and summarize insights gained from candidate disease-modifying interventions that have utilized a variety of well-established preclinical MSA models. We also discuss the current limitations that our field faces and suggest solutions for possible approaches in cause-directed therapies of MSA. PMID:24598411

  2. P08: Somatostatin analogs plus prednisone in aggressive histotype and advanced stage of thymic epithelial tumors

    PubMed Central

    Ottaviano, Margaret; Damiano, Vincenzo; Nappi, Lucia; Rescigno, Pasquale; Marino, Mirella; Del Vecchio, Silvana; Tucci, Irene; von Arx, Claudia; Palumbo, Giuliano; Palmieri, Giovannella

    2015-01-01

    Background Thymic epithelial tumors (TETs) are rare neoplasms characterized by histological variability and different expression at the molecular level. Several biological agents have been evaluated in TETs in small phase II trials. Efficacy of octreotide/lanreotide with or without prednisone in TETs OctreoScan positive has been widely demonstrated in thymoma, but no clearly in thymic carcinoma. Methods Twelve patients (five men, seven women; median age 47 years; range, 27–70 years) with advanced stage disease according to the Masaoka-Koga staging system (seven with IVa stage; five with IVb stage), and aggressive histotype according to WHO classification, revised by central review (two B2/B3; five B3; one B3/thymic carcinoma; four thymic carcinoma) were enrolled in this monocentric referral study. All the patients showed a progressive disease according to RECIST 1.1 criteria to previous conventional chemotherapeutic regimens platinum or not platinum-based. All the patients performed OctreoScan. The schedule includes administration of long-acting analog octreotide (30 mg/every 28 days intramuscularly) plus prednisone 0.2 mg/kg/day until progression of disease was documented. Overall response rate and toxicity were evaluated. Results The median time to progression was 6 months (range, 3–24 months), the overall response rate was 74.9%, particularly three patients (25%) obtained stable disease; four patients (33.3%) partial response; two patients (16.6%) complete response; three patients (25%) progression disease. One patient with Good Syndrome interrupted treatment after 6 months for infection disease. One patient has been lost to follow-up after 24 months of treatment. One patient died after progression disease for PRCA. Treatment was generally well tolerated with acceptable toxicity: no symptomatic cholelithiasis (one patient), grade 1 diarrhea (two patients) hyperglycemia (one patient). One patient with thymic carcinoma and IVB stage had PS improvement from 2

  3. Pancreatic atrophy and diabetes mellitus following blunt abdominal trauma.

    PubMed

    Edwards, Mary J; Crudo, David F; Carlson, Terri L; Pedersen, Anita M; Keller, Laura

    2013-02-01

    Following pancreatic trauma, loss of uninjured parenchyma as a result of surgical management is expected, and atrophy of parenchyma following nonoperative management has been described. While endocrine insufficiency as a sequela of pancreatic trauma has been reported in adults, it is not a described entity in children. We report a case of pancreatic atrophy following blunt injury in an 8 year old boy who presented 3 years later with diabetes mellitus. Further analysis revealed significant genetic predisposition to diabetes. PMID:23414880

  4. Network structure of brain atrophy in de novo Parkinson's disease

    PubMed Central

    Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

    2015-01-01

    We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation. DOI: http://dx.doi.org/10.7554/eLife.08440.001 PMID:26344547

  5. Rapamycin delays salivary gland atrophy following ductal ligation

    PubMed Central

    Bozorgi, S S; Proctor, G B; Carpenter, G H

    2014-01-01

    Salivary gland atrophy is a frequent consequence of head and neck cancer irradiation therapy but can potentially be regulated through the mammalian target of rapamycin (mTOR). Excretory duct ligation of the mouse submandibular gland provokes severe glandular atrophy causing activation of mTOR. This study aims to discover the effects of blocking mTOR signaling in ligation-induced atrophic salivary glands. Following 1 week of unilateral submandibular excretory duct ligation: gland weights were significantly reduced, 4E-BP1 and S6rp were activated, and tissue morphology revealed typical signs of atrophy. However, 3 days following ligation with rapamycin treatment, a selective mTOR inhibitor, gland weights were maintained, 4E-BP1 and S6rp phosphorylation was inhibited, and there were morphological signs of recovery from atrophy. However, following 5 and 7 days of ligation and rapamycin treatment, glands expressed active mTOR and showed signs of considerable atrophy. This evidence suggests that inhibition of mTOR by rapamycin delays ligation-induced atrophy of salivary glands. PMID:24675464

  6. FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension

    PubMed Central

    Eash, John; Olsen, Aaron; Breur, Gert; Gerrard, Dave; Hannon, Kevin

    2007-01-01

    Background Skeletal muscle atrophy can occur under many different conditions, including prolonged disuse or immobilization, cachexia, cushingoid conditions, secondary to surgery, or with advanced age. The mechanisms by which unloading of muscle is sensed and translated into signals controlling tissue reduction remains a major question in the field of musculoskeletal research. While the fibroblast growth factors (FGFs) and their receptors are synthesized by, and intimately involved in, embryonic skeletal muscle growth and repair, their role maintaining adult muscle status has not been examined. Methods We examined the effects of ectopic expression of FGFR1 during disuse-mediated skeletal muscle atrophy, utilizing hindlimb suspension and DNA electroporation in mice. Results We found skeletal muscle FGF4 and FGFR1 mRNA expression to be modified by hind limb suspension,. In addition, we found FGFR1 protein localized in muscle fibers within atrophying mouse muscle which appeared to be resistant to atrophy. Electroporation and ectopic expression of FGFR1 significantly inhibited the decrease in muscle fiber area within skeletal muscles of mice undergoing suspension induced muscle atrophy. Ectopic FGFR1 expression in muscle also significantly stimulated protein synthesis in muscle fibers, and increased protein degradation in weight bearing muscle fibers. Conclusion These results support the theory that FGF signaling can play a role in regulation of postnatal skeletal muscle maintenance, and could offer potentially novel and efficient therapeutic options for attenuating muscle atrophy during aging, illness and spaceflight. PMID:17425786

  7. Association of murine lupus and thymic full-length endogenous retroviral expression maps to a bone marrow stem cell

    SciTech Connect

    Krieg, A.M.; Gourley, M.F.; Steinberg, A.D. )

    1991-05-01

    Recent studies of thymic gene expression in murine lupus have demonstrated 8.4-kb (full-length size) modified polytropic (Mpmv) endogenous retroviral RNA. In contrast, normal control mouse strains do not produce detectable amounts of such RNA in their thymuses. Prior studies have attributed a defect in experimental tolerance in murine lupus to a bone marrow stem cell rather than to the thymic epithelium; in contrast, infectious retroviral expression has been associated with the thymic epithelium, rather than with the bone marrow stem cell. The present study was designed to determine whether the abnormal Mpmv expression associated with murine lupus mapped to thymic epithelium or to a marrow precursor. Lethally irradiated control and lupus-prone mice were reconstituted with T cell depleted bone marrow; one month later their thymuses were studied for endogenous retroviral RNA and protein expression. Recipients of bone marrow from nonautoimmune donors expressed neither 8.4-kb Mpmv RNA nor surface MCF gp70 in their thymuses. In contrast, recipients of bone marrow from autoimmune NZB or BXSB donors expressed thymic 8.4-kb Mpmv RNA and mink cell focus-forming gp70. These studies demonstrate that lupus-associated 8.4-kb Mpmv endogenous retroviral expression is determined by bone marrow stem cells.

  8. Abnormalities of Thymic Stroma may Contribute to Immune Dysregulation in Murine Models of Leaky Severe Combined Immunodeficiency

    PubMed Central

    Rucci, Francesca; Poliani, Pietro Luigi; Caraffi, Stefano; Paganini, Tiziana; Fontana, Elena; Giliani, Silvia; Alt, Frederick W.; Notarangelo, Luigi Daniele

    2011-01-01

    Lymphostromal cross-talk in the thymus is essential to allow generation of a diversified repertoire of T lymphocytes and to prevent autoimmunity by self-reactive T cells. Hypomorphic mutations in genes that control T cell development have been associated with immunodeficiency and immune dysregulation both in humans and in mice. We have studied T cell development and thymic stroma architecture and maturation in two mouse models of leaky severe combined immune deficiency, carrying hypomorphic mutations in rag1 and lig4 genes. Defective T cell development was associated with abnormalities of thymic architecture that predominantly affect the thymic medulla, with reduction of the pool of mature medullary thymic epithelial cells (mTECs). While the ability of mTECs to express autoimmune regulator (Aire) is preserved in mutant mice, the frequency of mature mTECs expressing Aire and tissue-specific antigens is severely reduced. Similarly, the ability of CD4+ T cells to differentiate into Foxp3+ natural regulatory T cells is preserved in rag1 and lig4 mutant mice, but their number is greatly reduced. These data indicate that hypomorphic defects in T cell development may cause defective lymphostromal cross-talk and impinge on thymic stromal cells maturation, and thus favor immune dysregulation. PMID:21822418

  9. Quantitative approach to lectin-based glycoprofiling of thymic tissues in the control- and the dexamethasone-treated mice.

    PubMed

    Balcan, Erdal

    2016-06-01

    Dexamethasone (DEX) is the most commonly used synthetic glucocorticoid in treatment of various inflammatory conditions. Here we focused on evaluating the effect of DEX on apoptosis and glycan profile in the mouse thymic tissues. Histological examinations revealed that the DEX treatment cause severe alterations in thymus, such as disruption of thymic capsule, impaired epithelial cell-thymocyte contacts, cellular loss and increased apoptosis. The identification of thymic glycans in the control- and the DEX-treated mice was carried out by using a panel of five plant lectins, Maackia amurensis agglutinin (MAA), peanut agglutinin (PNA), Sambucus nigra agglutinin (SNA), Concanavalin A (ConA) and wheat germ agglutinin (WGA). Lectin histochemistry results showed that glycosylation pattern of thymus changes upon DEX treatment. For further detailed quantitative analyses of the binding intensities for each lectin, histochemical data were scored as high positive (HP), mild positive (MP) and low positive (LP) and differences among signaling densities were investigated. The staining patterns of thymic regions observed with lectin histochemistry suggest that DEX can affect the thymic glycan profile as well as thymocyte apoptosis. These results are consistent with the opinion that not only sialic acid, but also other sugar motifs may be responsible for thymocyte development. PMID:27067421

  10. Quantitative analysis of cultured thymic reticulo-epithelial cells labelled by different antibodies: a flow cytometric study.

    PubMed Central

    Fabien, N; Auger, C; Bonnard, M; Andreoni, C; Rigal, D; Monier, J C

    1989-01-01

    Quantitative measurements of cultured human and murine thymic, and human thymoma reticuloepithelial cells (REC), immunolabeled by different antibodies (Ab) (TE3, TE4, anti-HTLV p19(p19), lu5, K11 and Aks) and by thymic hormones (thymulin and thymosin alpha 1 (Ta1)) within these cells, were performed using a flow cytometric technique. The anti-keratin polyclonal Ab labeled nearly the whole human or murine population. The p19 monoclonal Ab (MoAb), specific for the subcortical/medullary thymic regions, labelled 37-77% of the human REC. The TE3 MoAb, specific for the cortical region, labelled 54-83% of the REC. These percentages suggest that the cultured thymic REC (TREC) had markers of both regions together and therefore that these markers are not absolutely specific to determine their subcortical/medullary or cortical thymic origin. For the three populations there were more cells containing Ta1 than thymulin. The overlap of the percentage of labelled cells suggests that the same cell could synthesize the two hormones and that these hormones could be localized within the TE3 positive cells. PMID:2649289

  11. The language profile of Posterior Cortical Atrophy

    PubMed Central

    Crutch, Sebastian J.; Lehmann, Manja; Warren, Jason D.; Rohrer, Jonathan D.

    2015-01-01

    Background Posterior Cortical Atrophy (PCA) is typically considered to be a visual syndrome, primarily characterised by progressive impairment of visuoperceptual and visuospatial skills. However patients commonly describe early difficulties with word retrieval. This paper details the first systematic analysis of linguistic function in PCA. Characterising and quantifying the aphasia associated with PCA is important for clarifying diagnostic and selection criteria for clinical and research studies. Methods Fifteen patients with PCA, 7 patients with logopenic/phonological aphasia (LPA) and 18 age-matched healthy participants completed a detailed battery of linguistic tests evaluating auditory input processing, repetition and working memory, lexical and grammatical comprehension, single word retrieval and fluency, and spontaneous speech. Results Relative to healthy controls, PCA patients exhibited language impairments across all the domains examined, but with anomia, reduced phonemic fluency and slowed speech rate the most prominent deficits. PCA performance most closely resembled that of LPA patients on tests of auditory input processing, repetition and digit span, but was relatively stronger on tasks of comprehension and spontaneous speech. Conclusions The study demonstrates that in addition to the well-reported degradation of vision, literacy and numeracy, PCA is characterised by a progressive oral language dysfunction with prominent word retrieval difficulties. Overlap in the linguistic profiles of PCA and LPA, which are both most commonly caused by Alzheimer’s disease, further emphasises the notion of a phenotypic continuum between typical and atypical manifestations of the disease. Clarifying the boundaries between AD phenotypes has important implications for diagnosis, clinical trial recruitment and investigations into biological factors driving phenotypic heterogeneity in AD. Rehabilitation strategies to ameliorate the phonological deficit in PCA are required

  12. A Mechanism of Rapidly Reversible Cerebral Ventricular Enlargement Independent of Tissue Atrophy

    PubMed Central

    Zahr, Natalie M; Mayer, Dirk; Rohlfing, Torsten; Orduna, Juan; Luong, Richard; Sullivan, Edith V; Pfefferbaum, Adolf

    2013-01-01

    Ventricular enlargement, a common in vivo marker of aging, disease, and insult, is presumed to reflect atrophy of surrounding brain regions. Pathological mechanisms underlying ventricular enlargement, however, are likely specific to the condition under investigation. Here, multimodal imaging, incorporating structural magnetic resonance imaging (MRI), MR spectroscopy (MRS), and diffusion weighted imaging (DWI), was used in rats exposed to binge ethanol (EtOH) to provide insight into a mechanism of reversible ventricular enlargement. During intoxication, MRI revealed expansion of ventricles, but volume changes in dorsal or ventral hippocampi, caudate-putamen, or thalamus were not detectible. MRS of whole-brain parenchyma showed decreases in N-acetylasparate (NAA) and tissue water T2, and increases in choline-containing compounds (Cho). DWI showed decreased diffusivity selective to the thalamus. All MR parameters returned to baseline with 7 days of recovery. Rapid recovery of ventricular volume and the absence of detectable tissue volume reductions in brain regions adjacent to ventricles argue against atrophy as a mechanism of ventricular expansion. Decreased tissue water T2 and decreased thalamic diffusivity suggest lower tissue water content and a role for both NAA and Cho, as osmolytes is proposed. Together, these data support a model of fluid redistribution during acute EtOH intoxication and recovery to account for rapid ventricular volume changes. PMID:23306181

  13. Linkage disequilibrium and haplotype analysis among Polish families with spinal muscular atrophy

    SciTech Connect

    Brzustowicz, L.M.; Wang, C.H.; Matseoane, D.; Kleyn, P.W.; Vitale, E.; Das, K.; Penchaszadeh, G.K.; Gilliam, T.C.; Munsat, T.L.; Hausmanowa-Petrusewicz, I.

    1995-01-01

    Spinal muscular atrophy (SMA) is an inherited degenerative disorder of anterior horn cells that results in progressive muscle weakness and atrophy. The autosomal recessive forms of childhood-onset SMA have been mapped to chromosome 5q11.2-13.3, in a number of studies examining different populations. A total of 9 simple sequence repeat markers were genotyped against 32 Polish families with SMA. The markers span an {approximately}0.7 cM region defined by the SMA flanking markers D5S435 and MAP1B. Significant linkage disequilibrium (corrected P<0.5) was detected at four of these markers, with D/D{sub max} values of {le}.89. Extended haplotype analysis revealed a predominant haplotype associated with SMA. The apparently high mutation rate of some of the markers has resulted in a number of haplotypes that vary slightly from this predominant haplotype. The predominant haplotype and these closely related patterns represent 25% of the disease chromosomes and none of the nontransmitted parental chromosomes. This predominant haplotype is present both in patients with acute (type I) and in chronic (types II and III) forms of SMA and occurs twice in a homozygous state, both times in children with chronic SMA. 34 refs., 2 figs., 2 tabs.

  14. Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: Potential model for thymic education

    SciTech Connect

    Godfrey, V.L.; Rinchik, E.M.; Russell, L.B. ); Wilkinson, J.E. )

    1991-07-01

    Characteristic lesions in mice hemi- or homozygous for the X-linked mutation scurfy (sf) include lymphohistiocytic proliferation in the skin and lymphoid organs, Coombs' test-positive anemia, hypergammaglobulinemia, and death by 24 days of age. The role of the thymus in the development of fatal lymphoreticular disease in the scurfy mouse was investigated. Neonatal thymectomy doubles the life span of scurfy mice, moderates the histologic lesions, and prevents anemia, despite the continued presence of high levels of serum IgG. Animals bred to be nude and scurfy (nu/nu;sf/Y) are viable, fertile, and free of scurfy lesions. Bone marrow from scurfy mice can reconstitute lethally irradiated, H-2-compatible animals but does not transmit scurfy disease. The authors conclude, from these data, that scurfy lesions are mediated by T lymphocytes that mature in an abnormal (sf) thymic environment.

  15. Diagnostic Utility of PET CT in Thymic Tumours with Emphasis on 68Ga-DOTATATE PET CT in Thymic Neuroendocrine Tumour - Experience at a Tertiary Level Hospital in India

    PubMed Central

    Shanthly, Nylla; Oommen, Regi

    2014-01-01

    Introduction:18 Fluorine-fluoro-2-deoxyglucose positron emis–sion tomography/computed tomography (18F- FDG-PET/CT) is of importance in assessing high-risk thymoma and thymic carcinomas. Detection of advanced thymoma versus thymic carcinoma by routine cross sectional anatomical imaging such as computed tomography (CT), magnetic resonance imaging (MRI) often poses a diagnostic dilemma. In this case series we observed the utility of FDG uptake to predict advanced thymoma and distinguish thymoma from thymic cancer. Materials and Methods: We reviewed 18F- FDG-PET/CT scans of 12 patients (8 males, 4 females); age 24-60yrs with thymic epithelial malignancy from January 2011 to May 2013. FDG activity in lesions was quantified using maximum standardised uptake value (SUVmax) and correlated with Masaoka staging and WHO classification. All patients fasted 4 hr prior to 18F-FDG PET/CT. Images from vertex to mid-thigh were acquired 60min post injection of 3.7 -4.7 MBq/kg (Mega Becquerel)/kilogram of18F-FDG and SUV max of each tumour was measured. One patient underwent DOTATATE scan, received 138MBq of 68Gallium (68Ga)-DOTATATE injection IV and imaging was done after 60 min. Results: Higher FDG uptake of SUVmax 7.35 was seen in type B3 thymoma. FDG uptake was higher in thymic carcinoma (20.45 in primary and 17.46 in the node) or neuroendocrine differentiation (NED) than in patients with thymomas (ranged 7.35 - 3.02). No significant association was observed between higher focal FDG uptake and advanced-stage disease in thymoma. In NED 68Ga - DOTATATE imaging identified more lesions than in FDG. Conclusion: PET CT is a valuable diagnostic tool in evaluation of thymic tumours, to assess in initial workup, for treatment response and for prognostication. 68Ga-DOTATATE PET/CT is beneficial in assessing neuroendocrine thymic tumours. Focal FDG uptake cannot predict advanced thymoma but is helpful in distinguishing thymoma from thymic carcinoma, or the more aggressive thymoma B3. PMID

  16. Response to nab-paclitaxel and nedaplatin in a heavily-metastatic thymic carcinoma: A case report

    PubMed Central

    ZHAN, PING; XIE, HAIYAN; YU, LI-KE

    2015-01-01

    Metastatic thymic carcinoma is an aggressive cancer that usually responds poorly to multimodal therapies. Although surgical resection is the preferred treatment for patients with advanced or metastatic disease, the clinical prognosis is typically poor. The present study describes a 63-year-old patient with thymic carcinoma who underwent a range of antitumor treatments, including surgical resection, post-operative radiotherapy and post-operative chemotherapy with several drugs, but ultimately responded to treatment with nab-paclitaxel (nab-P) and nedaplatin. Subsequent to six cycles of nab-P and nedaplatin, the lung and peritoneal metastases decreased in size and the pleural effusion was reduced. To the best of our knowledge, this is the first study to describe the response of an advanced thymic carcinoma to nab-P chemotherapy. PMID:25789028

  17. A thymic neuroendocrine tumour in a young female: a rare cause of relapsing and remitting Cushing’s syndrome

    PubMed Central

    Farah, G; Stokes, V J; Wang, L M; Grossman, A B

    2016-01-01

    Summary We present a case of a young female patient with a rare cause of relapsing and remitting Cushing’s syndrome due to ectopic ACTH secretion from a thymic neuroendocrine tumour. A 34-year-old female presented with a constellation of symptoms of Cushing’s syndrome, including facial swelling, muscle weakness and cognitive impairment. We use the terms ‘relapsing and remitting’ in this case report, given the unpredictable time course of symptoms, which led to a delay of 2 years before the correct diagnosis of hypercortisolaemia. Diagnostic workup confirmed ectopic ACTH secretion, and a thymic mass was seen on mediastinal imaging. The patient subsequently underwent thymectomy with complete resolution of her symptoms. Several case series have documented the association of Cushing’s syndrome with thymic neuroendocrine tumours (NETs), although to our knowledge there are a few published cases of patients with relapsing and remitting symptoms. This case is also notable for the absence of features of the MEN-1 syndrome, along with the female gender of our patient and her history of non-smoking. Learning points Ectopic corticotrophin (ACTH) secretion should always be considered in the diagnostic workup of young patients with Cushing’s syndrome There is a small but growing body of literature describing the correlation between ectopic ACTH secretion and thymic neuroendocrine tumours (NETs) The possibility of a MEN-1 syndrome should be considered in all patients with thymic NETs, and we note the observational association with male gender and cigarette smoking in this cohort An exception to these associations is the finding of relatively high incidence of thymic NETs among female non-smoking MEN-1 patients in the Japanese compared with Western populations The relapsing and remitting course of our patient’s symptoms is noteworthy, given the paucity of this finding among other published cases PMID:27252866

  18. Long-Term Follow-Up and Prognostic Factors for Advanced Thymic Carcinoma

    PubMed Central

    Wu, Jun-xin; Chen, Hui-qin; Shao, Ling-dong; Qiu, Su-fang; Ni, Qian-yu; Zheng, Bu-hong; Wang, Jie-zhong; Pan, Jian-ji; Li, Jin-luan

    2014-01-01

    Abstract The aim of this study was to evaluate the long-term survival outcomes in patients with advanced thymic carcinoma and identify prognostic factors influencing the survival. We retrospectively analyzed 90 consecutive patients with pathologically confirmed advanced thymic carcinoma (Masaoka III and IV) in our institute, from December 2000 to 2012. Age, sex, clinical characteristics, laboratory findings, Masaoka and tumor node metastasis staging, pathologic grade, and treatment modalities were analyzed to identify prognostic factors associated with the progress-free survival (PFS) and the overall survival (OS) rates. Statistical analysis was conducted using SPSS, version 19.0 (SPSS, Inc, Chicago, IL). A total of 73 (81.1%) male and 17 (18.9%) female patients participated in the study. The median follow-up time was 75 months (range, 20–158 months). The 5-year PFS and OS rates were 23.6% (95% confidence interval [CI], 14.6%–33.8%) and 35.7% (95% CI, 25.1%–46.4%), respectively. The multivariate Cox regression model analysis showed that factors improving the PFS were the normal lactate dehydrogenase (LDH) level (P < 0.001), Masaoka III stage (P = 0.028), and radiotherapy (RT) (P < 0.001). The LDH (P < 0.001), T stage (P < 0.001), and the pathologic grade (P = 0.047) were independently prognostic of OS. Long-term follow-up of the advanced thymic carcinoma showed poor outcomes of PFS and OS. LDH, Masaoka stage, and RT affected the PFS, and LDH, T stage, and pathologic grade seemed to affect the OS. Establishing a better staging system for predicting outcomes would be warranted. PMID:25526488

  19. Elevated proportions of recent thymic emigrants in children and adolescents with type 1 diabetes.

    PubMed

    Hofer, Johannes; Hofer, Sabine; Zlamy, Manuela; Jeller, Verena; Koppelstaetter, Christian; Brandstätter, Anita; Kern, Hannelore; Köhle, Julia; Zimmerhackl, Lothar Bernd; Prelog, Martina

    2009-10-01

    It is unclear, whether pediatric patients with type 1 diabetes (T1DM) show immunological alterations typically found in autoimmune conditions resembling immune dysfunction of the thymus, such as decrease of naïve T cells, lower T cell receptor excision circle (TREC) numbers, telomeric erosion, and diminished interleukin-7 (IL-7) levels. Furthermore, it is unknown, whether long-term therapy with insulin, a thymic growth factor, interferes with these changes. Therefore, the aim of this study was to analyze the quantity of the naïve T cell subset and its TREC content, relative telomere length (RTL) of naïve T cells, and peripheral IL-7 levels in patients with recent-onset T1DM (n = 5), long-standing T1DM (n = 33), and age-matched healthy donors (HD) (n = 37). In long-standing T1DM, TREC numbers/CD8+CD45RA+ T cells were enhanced (p < 0.01) compared to HD and correlated with disease duration (p < 0.02), an independent factor for increased thymic output (p < 0.01), and insulin dosage at blood withdrawal (p < 0.05). IL-7 serum levels were elevated in long-standing T1DM (p < 0.001) and positively correlated with TREC numbers (p < 0.01) and disease duration (p < 0.0001). RTLs in CD8+CD45RA+ T cells were significantly increased compared to HD (p < 0.02). Our data suggest that longterm insulin therapy may serve as a driving factor for thymic function and rejuvenation of the naïve T cell compartment. The ability of the immune system to reconstitute the naïve T cell compartment under well-adjusted insulin therapy may be of major importance for recognition of new antigens, response to vaccinations, and defense of infectious complications. PMID:19725773

  20. Large thymic carcinoma presenting with right ventricular failure: a case report.

    PubMed

    Saleem, T; Fatimi, S H; Khalid, U

    2011-01-01

    Thymic carcinoma is an overall rare tumour with variable clinical manifestations. Right ventricular failure remains an uncommon occurrence and has not been reported in literature so far. A 40-year-old lady presented with the complaints of progressively worsening retrosternal chest pain, shortness of breath, easy fatigability and cough since 1 year. Computed tomography scan of the thorax revealed a mass measuring 12 x 10 cm in the anterior mediastinum. This mass appeared to be adherent to both lungs and pericardium and was impinging on the right atrium and right ventricle. It appeared to be infiltrating the ascending aorta, pulmonary arteries and superior vena cava. Ultrasound of the abdomen showed hepatomegaly and moderate ascites. Echocardiography showed evidence of right ventricular dysfunction as well as elevated right ventricular systolic pressures secondary to extrinsic compression. Percutaneous biopsy of the thymus was performed showing a malignant thymoma. Radical thymectomy with resection of pericardium was planned. Intra-operatively, the tumour was separated from the right and left lungs, pulmonary artery and aortic arch. Morphologically, immunochemically and clinically, the features were consistent with those seen in Masoka stage III thymic carcinoma. She also received six cycles of chemotherapy (PAC regimen) including cisplatin (50 mg/m2), doxorubicin (50 mg/m2) and cyclophosphamide (500 mg/m2). Radiation therapy in the adjuvant setting was planned but the patient was lost to follow-up after 4 months. Although right ventricular failure is a very rare presentation of thymic carcinoma, clinicians should be aware of this presentation to appreciate the complete clinical spectrum of presentation of this neoplasm. PMID:21938989

  1. Expression of acetylcholine receptor genes in human thymic epithelial cells: implications for myasthenia gravis.

    PubMed

    Wakkach, A; Guyon, T; Bruand, C; Tzartos, S; Cohen-Kaminsky, S; Berrih-Aknin, S

    1996-10-15

    The intrathymic presence of the muscle acetylcholine receptor (AChR) is controversial, and the nature of the cell(s) expressing it is unclear. We thus analyzed the molecular expression of muscle AChR in human thymi. mRNA studies indicated that the two isoforms (P3A+ and P3A-) of the alpha-subunit were present in thymic extracts and in cultured thymic epithelial cells (TEC), while expression in thymocytes was low and not consistently detectable. The amount of mRNA coding for the alpha-subunit, evaluated by means of quantitative PCR, was about 20 times less in TEC than in muscle, and was similar in TEC from normal subjects and from patients with myasthenia gravis (MG). The beta- and epsilon-subunits present in adult AChR were also expressed in TEC (but not in thymocytes), while the embryonic subunit (gamma) was absent. In TEC cultures, the AChR alpha- and epsilon-subunit mRNA levels were down-regulated by forskolin, as also observed in the TE671 rhabdomyosarcoma cell line, suggesting similar regulation of AChR subunits in thymus and muscle. Protein expression was evidenced on TEC (but not on thymocytes), by Western blotting as well as by immunofluorescence, thus demonstrating AChR expression on human thymic epithelial cells. There was no difference in the expression of AChR between TEC from MG patients and controls, meaning that the expression of AChR subunits alone is not sufficient to explain the onset of MG. PMID:8871679

  2. Functional Domains of Autoimmune Regulator (AIRE) Modulate INS-VNTR Transcription in Human Thymic Epithelial Cells.

    PubMed

    Sparks, Avis E; Chen, Chiachen; Breslin, Mary B; Lan, Michael S

    2016-05-20

    INS-VNTR (insulin-variable number of tandem repeats) and AIRE (autoimmune regulator) have been associated with the modulation of insulin gene expression in thymus, which is essential to induce either insulin tolerance or the development of insulin autoimmunity and type 1 diabetes. We sought to analyze whether each functional domain of AIRE is critical for the activation of INS-VNTR in human thymic epithelial cells. Twelve missense or nonsense mutations in AIRE and two chimeric AIRE constructs were generated. A luciferase reporter assay and a pulldown assay using biotinylated INS-class I VNTR probe were performed to examine the transactivation and binding activities of WT, mutant, and chimeric AIREs on the INS-VNTR promoter. Confocal microscopy analysis was performed for WT or mutant AIRE cellular localization. We found that all of the AIRE mutations resulted in loss of transcriptional activation of INS-VNTR except mutant P252L. Using WT/mutant AIRE heterozygous forms to modulate the INS-VNTR target revealed five mutations (R257X, G228W, C311fsX376, L397fsX478, and R433fsX502) that functioned in a dominant negative fashion. The LXXLL-3 motif is identified for the first time to be essential for DNA binding to INS-VNTR, whereas the intact PHD1, PHD2, LXXLL-3, and LXXLL-4 motifs were important for successful transcriptional activation. AIRE nuclear localization in the human thymic epithelial cell line was disrupted by mutations in the homogenously staining region domain and the R257X mutation in the PHD1 domain. This study supports the notion that AIRE mutation could specifically affect human insulin gene expression in thymic epithelial cells through INS-VNTR and subsequently induce either insulin tolerance or autoimmunity. PMID:27048654

  3. Early and Degressive Putamen Atrophy in Multiple Sclerosis

    PubMed Central

    Krämer, Julia; Meuth, Sven G.; Tenberge, Jan-Gerd; Schiffler, Patrick; Wiendl, Heinz; Deppe, Michael

    2015-01-01

    Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the time point of atrophy onset in patients with relapsing-remitting MS (RRMS). 68 patients with RRMS and 26 healthy controls (HC) were admitted to 3T MRI in a cross-sectional study. We quantitatively analyzed the putamen volume of individual patients in relation to disease duration by correcting for age and intracranial volume (ICV). Patient’s relative putamen volume (RPV), expressed in percent of ICV, was significantly reduced compared to HC. Based on the correlation between RPV and age, we computed the age-corrected RPV deviation (ΔRPV) from HC. Patients showed significantly negative ΔRPV. Interestingly, the age-corrected ΔRPV depended logarithmically on disease duration: Directly after first symptom manifestation, patients already showed a reduced RPV followed by a further degressive volumetric decline. This means that atrophy progression was stronger in the first than in later years of disease. Putamen atrophy starts directly after initial symptom manifestation or even years before, and progresses in a degressive manner. Due to its important role in neurological functions, early detection of putamen atrophy seems necessary. High-resolution structural MRI allows monitoring of disease course. PMID:26404239

  4. Intrathecal Injections in Children With Spinal Muscular Atrophy

    PubMed Central

    Swoboda, Kathryn J.; Sethna, Navil; Farrow-Gillespie, Alan; Khandji, Alexander; Xia, Shuting; Bishop, Kathie M.

    2016-01-01

    Nusinersen (ISIS-SMNRx or ISIS 396443) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy. We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension. During the studies, 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy. No complications occurred in 50 (68%) lumbar punctures; in 23 (32%) procedures, adverse events were attributed to lumbar puncture. Most common adverse events were headache (n = 9), back pain (n = 9), and post–lumbar puncture syndrome (n = 8). In a subgroup analysis, adverse events were more frequent in older children, children with type 3 spinal muscular atrophy, and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller. Lumbar punctures were successfully performed in children with spinal muscular atrophy; lumbar puncture–related adverse event frequency was similar to that previously reported in children. PMID:26823478

  5. Astaxanthin intake attenuates muscle atrophy caused by immobilization in rats.

    PubMed

    Shibaguchi, Tsubasa; Yamaguchi, Yusuke; Miyaji, Nobuyuki; Yoshihara, Toshinori; Naito, Hisashi; Goto, Katsumasa; Ohmori, Daijiro; Yoshioka, Toshitada; Sugiura, Takao

    2016-08-01

    Astaxanthin is a carotenoid pigment and has been shown to be an effective inhibitor of oxidative damage. We tested the hypothesis that astaxanthin intake would attenuate immobilization-induced muscle atrophy in rats. Male Wistar rats (14-week old) were fed for 24 days with either astaxanthin or placebo diet. After 14 days of each experimental diet intake, the hindlimb muscles of one leg were immobilized in plantar flexion position using a plaster cast. Following 10 days of immobilization, both the atrophic and the contralateral plantaris muscles were removed and analyzed to determine the level of muscle atrophy along with measurement of the protein levels of CuZn-superoxide dismutase (CuZn-SOD) and selected proteases. Compared with placebo diet animals, the degree of muscle atrophy in response to immobilization was significantly reduced in astaxanthin diet animals. Further, astaxanthin supplementation significantly prevented the immobilization-induced increase in the expression of CuZn-SOD, cathepsin L, calpain, and ubiquitin in the atrophied muscle. These results support the postulate that dietary astaxanthin intake attenuates the rate of disuse muscle atrophy by inhibiting oxidative stress and proteolysis via three major proteolytic pathways. PMID:27482075

  6. Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations.

    PubMed

    Iwama, Kazuhiro; Sasaki, Masayuki; Hirabayashi, Shinichi; Ohba, Chihiro; Iwabuchi, Emi; Miyatake, Satoko; Nakashima, Mitsuko; Miyake, Noriko; Ito, Shuichi; Saitsu, Hirotomo; Matsumoto, Naomichi

    2016-06-01

    Cerebellar atrophy is recognized in various types of childhood neurological disorders with clinical and genetic heterogeneity. Genetic analyses such as whole exome sequencing are useful for elucidating the genetic basis of these conditions. Pathological recessive mutations in Sep (O-phosphoserine) tRNA:Sec (selenocysteine) tRNA synthase (SEPSECS) have been reported in a total of 11 patients with pontocerebellar hypoplasia type 2, progressive cerebellocerebral atrophy or progressive encephalopathy, yet detailed clinical features are limited to only four patients. We identified two new families with progressive cerebellar atrophy, and by whole exome sequencing detected biallelic SEPSECS mutations: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26Profs*42) in family 1, and c.356A>G (p.Asn119Ser) and c.467G>A (p.Arg156Gln) in family 2. Their development was slightly delayed regardless of normal brain magnetic resonance imaging (MRI) in infancy. The progression of clinical symptoms in these families is evidently slower than in previously reported cases, and the cerebellar atrophy milder by brain MRI, indicating that SEPSECS mutations are also involved in milder late-onset cerebellar atrophy. PMID:26888482

  7. Predictive modeling of neuroanatomic structures for brain atrophy detection

    NASA Astrophysics Data System (ADS)

    Hu, Xintao; Guo, Lei; Nie, Jingxin; Li, Kaiming; Liu, Tianming

    2010-03-01

    In this paper, we present an approach of predictive modeling of neuroanatomic structures for the detection of brain atrophy based on cross-sectional MRI image. The underlying premise of applying predictive modeling for atrophy detection is that brain atrophy is defined as significant deviation of part of the anatomy from what the remaining normal anatomy predicts for that part. The steps of predictive modeling are as follows. The central cortical surface under consideration is reconstructed from brain tissue map and Regions of Interests (ROI) on it are predicted from other reliable anatomies. The vertex pair-wise distance between the predicted vertex and the true one within the abnormal region is expected to be larger than that of the vertex in normal brain region. Change of white matter/gray matter ratio within a spherical region is used to identify the direction of vertex displacement. In this way, the severity of brain atrophy can be defined quantitatively by the displacements of those vertices. The proposed predictive modeling method has been evaluated by using both simulated atrophies and MRI images of Alzheimer's disease.

  8. Whole-Brain Atrophy Rate in Idiopathic Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy

    PubMed Central

    Guevara, C.; Bulatova, K.; Barker, G. J.; Gonzalez, G.; Crossley, N.; Kempton, M. J.

    2016-01-01

    In multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), the absence of surrogate endpoints makes clinical trials long and expensive. We aim to determine annualized whole-brain atrophy rates (a-WBAR) in idiopathic Parkinson's disease (IPD), MSA, and PSP. Ten healthy controls, 20 IPD, 12 PSP, and 8 MSA patients were studied using a volumetric MRI technique (SIENA). In controls, the a-WBAR was 0.37% ± 0.28 (CI 95% 0.17–0.57), while in IPD a-WBAR was 0.54% ± 0.38 (CI 95% 0.32–0.68). The IPD patients did not differ from the controls. In PSP, the a-WBAR was 1.26% ± 0.51 (CI 95%: 0.95–1.58). In MSA, a-WBAR was 1.65% ± 1.12 (CI 95%: 0.71–2.59). MSA did not differ from PSP. The a-WBAR in PSP and MSA were significantly higher than in the IPD group (p = 0.004 and p < 0.001, resp.). In PSP, the use of a-WBAR required one-half of the patients needed for clinical scales to detect a 50% reduction in their progression. In MSA, one-quarter of the patients would be needed to detect the same effect. a-WBAR is a reasonable candidate to consider as a surrogate endpoint in short clinical trials using smaller sample sizes. The confidence intervals for a-WBAR may add a potential retrospective application for a-WBAR to improve the diagnostic accuracy of MSA and PSP versus IPD. PMID:27190673

  9. Argyrophilic ubiquitinated cytoplasmic inclusions of Leu-7-positive glial cells in olivopontocerebellar atrophy (multiple system atrophy).

    PubMed

    Kato, S; Nakamura, H; Hirano, A; Ito, H; Llena, J F; Yen, S H

    1991-01-01

    We described cytoplasmic inclusions in glial cells in 18 patients with olivopontocerebellar atrophy (OPCA) (multiple system atrophy, MSA). These glial inclusions showed intense argyrophilia with modified Bielschowsky's and Bodian's silver impregnation techniques, and were observed in the pons, cerebellar white matter, midbrain, medulla oblongata and basal ganglia, as well as cerebral white matter and spinal cord. None of the 54 control cases had glial argyrophilic inclusions. Immunohistochemically, these inclusions were intensely labeled by anti-ubiquitin antibody. Some of them reacted with an antibody to Rosenthal fiber (RF) protein. The cytoplasm of ubiquitinated inclusion-bearing glial cells was immunostained by anti-Leu-7 antibody, but not by anti-GFAP antibody. Ultrastructurally, the glial inclusions were composed primarily of approximately 24- to 40-nm fibrils, which were coated with osmiophilic granular material along their length in longitudinal section. These fibrils appeared as annuli in cross section. Often, a central granule approximately 5 nm in diameter was seen in the lucent lumen of a cross-sectioned fibril. The granule-coated fibrils were not seen in the glial filament-containing astrocytes. Electron microscopic examination of silver-impregnated specimens revealed that the granule-coated fibrils had strong affinity for silver. Immunoelectron microscopy using the indirect immunoperoxidase techniques with antibodies to ubiquitin and RF protein revealed that the electron-dense reaction products respective to both were located on constituents of glial inclusions. Our observation that Leu-7-positive glial cells, mainly oligodendroglial cells, had argyrophilic ubiquitinated inclusions may be of significance for the evaluation of the pathology of OPCA(MSA). PMID:1723828

  10. The application of postoperative chemotherapy in thymic tumors and its prognostic effect

    PubMed Central

    Ma, Ke; Gu, Zhitao; Fu, Jianhua; Shen, Yi; Wei, Yucheng; Tan, Lijie; Zhang, Peng; Chen, Chun; Zhang, Renquan; Li, Yin; Chen, Keneng; Chen, Hezhong; Liu, Yongyu; Cui, Youbing; Wang, Yun; Pang, Liewen; Yu, Zhentao; Zhou, Xinming; Liu, Yangchun; Liu, Yuan

    2016-01-01

    Background To study the role of postoperative chemotherapy and its prognostic effect in Masaoka-Koga stage III and IV thymic tumors. Methods Between 1994 and 2012, 1,700 patients with thymic tumors who underwent surgery without neoadjuvant therapy were enrolled for the study. Among them, 665 patients in Masaoka-Koga stage III and IV were further analyzed to evaluate the clinical value of postoperative chemotherapy. The Kaplan-Meier method was used to obtain the survival curve of the patients divided into different subgroups, and the Cox regression analysis was used to make multivariate analysis on the factors affecting prognosis. A Propensity-Matched Study was used to evaluate the clinical value of chemotherapy. Results Two-hundred and twenty-one patients were treated with postoperative chemotherapy, while the rest 444 cases were not. The two groups showed significant differences (P<0.05) regarding the incidence of myasthenia gravis, World Health Organization (WHO) histological subtypes, pathological staging, resection status and the use of postoperative radiotherapy. WHO type C tumors, incomplete resection, and postoperative radiotherapy were significantly related to increased recurrence and worse survival (P<0.05). Five-year and 10-year disease free survivals (DFS) and recurrence rates in patients who underwent surgery followed by postoperative chemotherapy were 51% and 30%, 46% and 68%, comparing with 73% and 58%, 26% and 40% in patients who had no adjuvant chemotherapy after surgery (P=0.001, P=0.001, respectively). In propensity-matched study, 158 pairs of patients with or without postoperative chemotherapy (316 patients in total) were selected and compared accordingly. Similar 5-year survival rates were detected between the two groups (P=0.332). Conclusions Pathologically higher grade histology, incomplete resection, and postoperative radiotherapy were found to be associated with worse outcomes in advanced stage thymic tumors. At present, there is no evidence

  11. Thymic stromal lymphopoietin as a novel mediator amplifying immunopathology in rheumatic disease.

    PubMed

    Hillen, Maarten R; Radstake, Timothy R D J; Hack, Cornelis E; van Roon, Joel A G

    2015-10-01

    Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis. PMID:26163286

  12. Morvan Syndrome Secondary to Thymic Carcinoma in a Patient with Systemic Lupus Erythematosus

    PubMed Central

    Koussa, Salam

    2016-01-01

    Morvan syndrome (MoS) is a rare paraneoplastic autoimmune disorder characterized by peripheral nerve hyperexcitability, autonomic dysfunction, and sleep disorders. Systemic lupus erythmatosus (SLE) cooccurs in 6–10% of patients with thymoma. It may occur before, concurrently with, or after thymoma diagnosis. This paper reports the first case of cooccurrence of SLE, thymic carcinoma, and MoS. The cooccurrence of SLE, thymoma, and MoS delineates the generalized autoimmunity process. Symptoms of both MoS and SLE abated upon tumor resection. PMID:27247812

  13. Thymic fat pad flap to cover the left internal thoracic artery graft.

    PubMed

    Jelenc, Matija; Kneževič, Ivan

    2013-11-01

    With a skeletonized harvesting technique of the left internal thoracic artery (LITA), opening of the pleural space during dissection can usually be avoided. However, due to the bulging of the ventilated lungs, the LITA graft comes to lie immediately below the sternum at the end of the procedure, which makes it vulnerable to injury in case of a reoperation. The authors present a simple technique to move the skeletonized LITA graft away from the undersurface of the sternum, by using a thymic fat pad flap (TFP). PMID:23837883

  14. Thymic and mammary lymphosarcoma in a three-year-old heifer.

    PubMed

    Matthews, H K; Hunt, E; Duncan, D E

    1992-03-01

    Ventral edema, dyspnea, fever, tachycardia, bloat and muffled heart sounds were identified in a 3-year-old heifer. Attempts to relieve the bloat by passing an orogastric tube were unsuccessful. The heifer was bovine leukemia virus-negative by the agar gel immunodiffusion test, and had normocytic, normochromic anemia, mature neutrophilia, and hyperproteinemia. Pleural effusion was identified by thoracic ultrasonography. Cytologic examination of pleural fluid revealed an increased number of atypical lymphocytes. The heifer died, and at necropsy, thymic and metastatic mammary lymphosarcoma was confirmed. PMID:1568914

  15. The enlightenments from ITMIG Consensus on WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting

    PubMed Central

    Wu, Jie; Fang, Wentao

    2016-01-01

    The World Health Organization (WHO) histological classification of the thymoma and thymic carcinoma (TC) has been criticized for poor interobserver reproducibility or inconsistencies in the routine pathological diagnosis. The International Thymic Malignancy Interest Group (ITMIG) panel achieved an agreement to maintain the widely accepted WHO framework but to refine historic definitions and histological criteria, and further introduce some new terms with the aim to improve interobserver reproducibility. This review addresses the enlightenments we can get from the ITMIG consensus on the WHO histological classification of the thymoma and TC, which may be helpful for most pathologists. PMID:27114842

  16. Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial

    PubMed Central

    Thomas, Anish; Rajan, Arun; Berman, Arlene; Tomita, Yusuke; Brzezniak, Christina; Lee, Min-Jung; Lee, Sunmin; Ling, Alexander; Spittler, Aaron J; Carter, Corey A; Guha, Udayan; Wang, Yisong; Szabo, Eva; Meltzer, Paul; Steinberg, Seth M; Trepel, Jane B; Loehrer, Patrick J; Giaccone, Giuseppe

    2015-01-01

    Summary Background No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor. Methods Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov, number NCT01621568. Findings 41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14·0–18·4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12·1–45·3, 95% CI 10·2–48·4) had partial responses, 15 (65%, 95% CI 42·7–83·6) achieved stable disease, and two (9%, 1·1–28·0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0·2–30·2) had a partial response, 12 (75%, 47·6–92·7) had stable disease, and three (19%, 4·1–45·7) had progressive disease

  17. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia

    PubMed Central

    Schmidt, Wolfgang M.; Rutledge, S. Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Züchner, Stephan; Boltshauser, Eugen; Bittner, Reginald E.

    2015-01-01

    Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID:26581903

  18. Molecular detection of chicken parvovirus in broilers with enteric disorders presenting curving of duodenal loop, pancreatic atrophy, and mesenteritis.

    PubMed

    Nuñez, L F N; Sá, L R M; Parra, S H S; Astolfi-Ferreira, C S; Carranza, C; Ferreira, A J P

    2016-04-01

    Enteric disorders are an important cause of economic losses in broiler chickens worldwide. Several agents have been associated with enteric problems, such as viruses, bacteria, and parasites. In this study, broiler chickens showing signs of enteric disorders were subjected to molecular diagnosis for several viral agents and also for pathological examination for elucidating this problem. Thus, the chickens were screened for avian nephritis virus (ANV), chicken astrovirus (CAstV), avian rotavirus (ArtV), avian reovirus (AReoV), infectious bronchitis virus (IBV), fowl adenovirus group I (FAdV-1), and chicken parvovirus (ChPV). Postmortem examinations revealed a curving of the duodenal loop (J-like appearance) and intestines filled with liquid and gaseous content. Histopathological analysis of the duodenal loop showed pancreatic atrophy, acute mesenteritis, and enteritis. PCR results showed that ChPV was the sole viral agent detected in samples with lesions such as the curved duodenal loop and pancreatic atrophy. Molecular characterization of the nucleotide and deduced amino acid sequences revealed a high similarity with other strains of ChPV from Brazil, Canada, United States, Europe, and Asia. These findings suggest an association between ChPV and the development of enteritis, pancreatitis, and pancreatic atrophy, which may lead to curling of the duodenal loop. Together, these alterations may disrupt the normal functioning of the digestive system, diminishing digestion and the absorption of dietary nutrients and consequently leading to reduced weight gain, flock impairment, dwarfism, and an elevated feed conversion rate. PMID:26908891

  19. Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia.

    PubMed

    Schmidt, Wolfgang M; Rutledge, S Lane; Schüle, Rebecca; Mayerhofer, Benjamin; Züchner, Stephan; Boltshauser, Eugen; Bittner, Reginald E

    2015-12-01

    Hereditary ataxias comprise a group of genetically heterogeneous disorders characterized by clinically variable cerebellar dysfunction and accompanied by involvement of other organ systems. The molecular underpinnings for many of these diseases are widely unknown. Previously, we discovered the disruption of Scyl1 as the molecular basis of the mouse mutant mdf, which is affected by neurogenic muscular atrophy, progressive gait ataxia with tremor, cerebellar vermis atrophy, and optic-nerve thinning. Here, we report on three human individuals, from two unrelated families, who presented with recurrent episodes of acute liver failure in early infancy and are affected by cerebellar vermis atrophy, ataxia, and peripheral neuropathy. By whole-exome sequencing, compound-heterozygous mutations within SCYL1 were identified in all affected individuals. We further show that in SCYL1-deficient human fibroblasts, the Golgi apparatus is massively enlarged, which is in line with the concept that SCYL1 regulates Golgi integrity. Thus, our findings define SCYL1 mutations as the genetic cause of a human hepatocerebellar neuropathy syndrome. PMID:26581903

  20. Tongue atrophy and fasciculations in transthyretin familial amyloid neuropathy

    PubMed Central

    Mozaffar, Tahseen

    2015-01-01

    Objective: Macroglossia is a well-known feature of amyloidosis; however, tongue atrophy and fasciculations are rarely seen and can lead to the misdiagnosis of amyotrophic lateral sclerosis (ALS). Methods: We identified 2 unrelated patients with atypical features of tongue atrophy and fasciculations in the setting of a severe neuropathy. Results: Both patients were confirmed to have transthyretin-related familial amyloid polyneuropathy (TTR-FAP) by genetic testing. Conclusions: TTR-FAP should be considered as a possible mimicker of ALS when tongue atrophy and fasciculations are seen in the setting of a severely progressive polyneuropathy. Other atypical mimickers of ALS include polyglucosan body disease, hexosaminidase A deficiency, multisystem proteinopathy, and Allgrove syndrome. PMID:27066555

  1. Pathomechanisms of atrophy in insular cortex in Alzheimer's disease.

    PubMed

    Moon, Yeonsil; Moon, Won-Jin; Han, Seol-Heui

    2015-08-01

    The insular cortex is associated with neuropsychiatric symptoms, changes in cardiovascular and autonomic control, and mortality in Alzheimer's dementia. However, the insular cortex does not provide information on the contribution of the other cortices to cognitive decline. We hypothesized that the factors that affect to atrophy in insular cortex are different from other cortical regions. A total of 42 patients with probable Alzheimer's dementia were included in the analyses. The manual drawing of regions of interest was used to detect insular cortex located in the deep gray matter and to avoid coatrophy. Covariates, which could affect to the atrophy of the cerebral cortex, were selected based on previous studies. Any of the demographic factors, vascular risk factors, and the severity scales of dementia was not associated with any insular volume ratio. We suggest that the pathomechanisms of atrophy in insular cortex are different from those of other cortex regions in Alzheimer's disease. PMID:25596207

  2. Progressive Hemifacial Atrophy With Contralateral Uveitis: A Case Report

    PubMed Central

    Ayyildiz, Onder; Ayyildiz, Simel; Durukan, Ali Hakan; Sobaci, Gungor

    2015-01-01

    Introduction: Progressive hemifacial atrophy, known as Parry-Romberg syndrome (PRS), was first described by Parry in 1825. There is a progressive atrophy of facial tissues including skin, bones and muscles. Ophthalmic disorders are common and include keratitis, uveitis, cataract, ipsilateral enophthalmos, optic neuritis, retinal vasculitis and scleral melting. Case Presentation: We describe a patient with progressive hemifacial atrophy at right facial side who developed granulomatous uveitis and periferic retinal vasculitis in his left eye. We started topical and systemic steroid therapy. Uveitic reaction had regressed almost entirely after a 3-month steroid treatment. Conclusions: The individuals should have multidisciplinary approach for the variety of disorders to maintain the appropriate treatment for a better appearance of the patients. PMID:26473067

  3. Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis.

    PubMed

    MacKenzie-Graham, Allan J; Rinek, Gilda A; Avedisian, Andrea; Morales, Laurie B; Umeda, Elizabeth; Boulat, Benoit; Jacobs, Russell E; Toga, Arthur W; Voskuhl, Rhonda R

    2012-07-01

    Gray matter atrophy is an important correlate to clinical disability in multiple sclerosis (MS), and many treatment trials include atrophy as an outcome measure. Atrophy has been shown to occur in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The clinical severity of EAE is reduced in estrogen-reated mice, but it remains unknown whether estrogen treatment can reduce gray matter atrophy in EAE. In this study, mice with EAE were treated with either estrogen receptor (ER)-α ligand or ER-β ligand, and diffusion tensor images (DTI) were collected and neuropathology was performed. DTI showed atrophy in the cerebellar gray matter of vehicle-treated EAE mice compared with healthy controls but not in ER-α or ER-β ligand-treated EAE mice. Neuropathology demonstrated that Purkinje cell numbers were decreased in vehicle-treated EAE mice, whereas neither ER ligand-treated EAE groups showed a decrease. This is the first report of a neuroprotective therapy in EAE that unambiguously prevents gray matter atrophy while sparing a major neuronal cell type. Fractional anisotropy (FA) in the cerebellar white matter was decreased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Inflammatory cell infiltration was increased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Myelin staining was decreased in vehicle-treated EAE mice and was spared in both ER ligand-treated groups. This is consistent with decreased FA as a potential biomarker for inflammation rather than myelination or axonal damage in the cerebellum in EAE. PMID:22411609

  4. Muscle ring finger 1 mediates cardiac atrophy in vivo.

    PubMed

    Willis, Monte S; Rojas, Mauricio; Li, Luge; Selzman, Craig H; Tang, Ru-Hang; Stansfield, William E; Rodriguez, Jessica E; Glass, David J; Patterson, Cam

    2009-04-01

    Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1(-/-) mice decreased approximately 70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by beta-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1(-/-) and wild-type hearts after TAC release. In the second model, MuRF1(-/-) mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic

  5. Olivopontocerebellar atrophy of neonatal onset and disialotransferrin developmental deficiency syndrome.

    PubMed Central

    Horslen, S P; Clayton, P T; Harding, B N; Hall, N A; Keir, G; Winchester, B

    1991-01-01

    Two brothers presented with olivopontocerebellar atrophy of neonatal onset. The clinical features (failure to thrive, hypotonia, liver disease, effusions, and visual inattention) were similar to those of the four cases already reported, as were the necropsy findings of olivopontocerebellar atrophy, hepatic steatosis and fibrosis, and microcystic renal changes. The clinical similarities between this and the disialotransferrin developmental deficiency syndrome were noted. The characteristic abnormality of serum transferrin found in the latter syndrome was also found in the two cases reported here. We suggest that both syndromes are caused by the same, or related, defects in glycoprotein metabolism. Images Figure 2 p1028-b Figure 3 p1029-b Figure 4 PMID:1929507

  6. [A Case of Musicophilia with Right Predominant Temporal Lobe Atrophy].

    PubMed

    Shinagawa, Shunichiro; Nakayama, Kazuhiko

    2015-11-01

    A 68-year-old woman exhibiting musicophilia with right predominant temporal lobe atrophy happened to visit our clinic. She had no musical background, but beginning two years ago, she acquired a strong preference for especially popular music and sometimes sang at home. She did not exhibit obvious semantic aphasia or facial agnosia, and showed only mild behavioral changes including apathy. Her musicophilia can be explained as an instance of stereotypical behavior. Her right temporal lobe atrophy may have caused changes in her emotional and reward systems, resulting in her music specific behaviors. PMID:26560960

  7. Respiratory management of spinal muscular atrophy type 2.

    PubMed

    Gormley, Maurade C

    2014-12-01

    Respiratory insufficiency is the primary cause of morbidity and mortality among patients with spinal muscular atrophy type 2. The primary complications include ineffective cough with decreased airway clearance, nocturnal hypoventilation, diminished lung and chest wall development, and increased risk for pulmonary infection. Respiratory devices including mechanical insufflator-exsufflator and bilevel positive airway pressure are the primary devices of respiratory maintenance and treatment and are associated with decreased morbidity and fewer hospital admissions. This article discusses the primary respiratory complications of spinal muscular atrophy type 2 and the role of respiratory interventions to promote growth and development, improve cough efficacy, reverse nocturnal hypoventilation, and prevent and treat pulmonary infection. PMID:25365058

  8. Late onset GM2 gangliosidosis mimicking spinal muscular atrophy.

    PubMed

    Jamrozik, Z; Lugowska, A; Gołębiowski, M; Królicki, L; Mączewska, J; Kuźma-Kozakiewicz, M

    2013-09-25

    A case of late onset GM2 gangliosidodis with spinal muscular atrophy phenotype followed by cerebellar and extrapyramidal symptoms is presented. Genetic analysis revealed compound heterozygous mutation in exon 10 of the HEXA gene. Patient has normal intelligence and emotional reactivity. Neuroimaging tests of the brain showed only cerebellar atrophy consistent with MR spectroscopy (MRS) abnormalities. (18)F-fluorodeoxyglucose positron emission tomography (18)F-FDG PET/CT of the brain revealed glucose hypometabolism in cerebellum and in temporal and occipital lobes bilaterally. PMID:23820084

  9. Vulvar and Vaginal Atrophy: Physiology, Clinical Presentation, and Treatment Considerations.

    PubMed

    Lev-Sagie, Ahinoam

    2015-09-01

    Vulvovaginal atrophy is a common condition associated with decreased estrogenization of the vaginal tissue. Symptoms include vaginal dryness, irritation, itching, soreness, burning, dyspareunia, discharge, urinary frequency, and urgency. It can occur at any time in a woman's life cycle, although more commonly in the postmenopausal phase, during which the prevalence is approximately 50%. Despite the high prevalence and the substantial effect on quality of life, vulvovaginal atrophy often remains underreported and undertreated. This article aims to review the physiology, clinical presentation, assessment, and current recommendations for treatment, including aspects of effectiveness and safety of local vaginal estrogen therapies. PMID:26125962

  10. Lactic acidosis associated with cerebellar vermal atrophy and cardiomyopathy.

    PubMed

    Challa, V R; Markesbery, W R; Baumann, R J; Noonan, J A

    1978-08-01

    The association of fluctuating neurological signs and congestive cardiomyopathy with chronic lactic acidosis is described in a 5 1/2 year-old-boy who ultimately succumbed to congestive heart failure. The autopsy findings included severe atrophy of the anterior cerebellar vermis and a hypertrophied heart with left sided endocardial fibroelastosis. Skeletal and cardial muscle calcification was prominent and probably due to the effect of intracellular metabolic alterations associated with lactic acidosis. A review of the literature shows that the combination of cardiomyopathy, isolated atrophy of cerebellar vermis and muscle fiber calcification have not been reported in association with idiopathic lactic acidosis previously. PMID:152418

  11. Thymic tuberculosis preoperatively evaluated with thallium-201 SPECT: two resected cases.

    PubMed

    Iwata, Takashi; Inoue, Kiyotoshi; Mizuguchi, Shinjiro; Tsukioka, Takuma; Morita, Ryuhei; Suehiro, Shigefumi

    2007-02-01

    We present 2 resected cases of thymic tuberculosis, which had been preoperatively diagnosed as invasive thymoma, using a thallium-201 ((201)Tl) single photon emission computed tomography ((201)Tl SPECT). [Patient 1] A 74-old-male with a 32-year history of steroid therapy for rheumatic arthritis was diagnosed with an anterior mediastinal tumor by routine chest CT scans after onset of myocardial infarction. [Patient 2] A 56-old-female with a 28-year history of diabetes mellitus presented with a dry cough. A chest CT demonstrated an anterior mediastinal tumor. Neither patient showed pulmonary infiltrations on chest x-ray. (201)Tl SPECT was undertaken for each patient. Abnormal findings could not be detected on a planar image of the scintigraphy; however, on SPECT images accumulations of (201)Tl were clearly detected in the anterior mediastinal mass and a thymoma was thus suspected in each case. Total thymectomy was carried out in each case and the mass then diagnosed as caseous granuloma in the thymus. Both patients are well without recurrence after operation. In patients with a (201)Tl SPECT positive anterior mediastinal tumor associated with an immunologically deficient status, and with negative findings in planar images on thallium scintigraphy, the possibility of thymic tuberculosis should be considered. PMID:17392671

  12. Human thymocytes bind to autologous and allogeneic thymic epithelial cells in vitro.

    PubMed Central

    Singer, K H; Wolf, L S; Lobach, D F; Denning, S M; Tuck, D T; Robertson, A L; Haynes, B F

    1986-01-01

    The thymus plays a critical role in the generation of immunocompetent T lymphocytes. In the thymus, lymphocytes are in close contact with epithelial cells, and this contact is necessary for T-cell maturation. Using cultured human thymic epithelial (TE) cells, we have found that human thymocytes bind to human TE cells in vitro. Thymocytes bound to both allogeneic and autologous TE cells and to the epidermoid carcinoma cell line A431 but did not bind to epidermal keratinocytes or to thymic fibroblasts. Thymocyte binding to TE cells was trypsin- and cytochalasin B-sensitive. Indirect immunofluorescence assays showed that both mature (T6-, T3+) and immature (T6+, T3-) thymocytes bound TE cells. In our system, TE-thymocyte binding was not inhibited by antibodies to class I or class II major histocompatibility antigens. In vitro binding of thymocytes to TE cells may represent a correlate of in vivo TE-thymocyte interactions and provides a model system for the study of human intrathymic T-lymphocyte maturation and activation. Images PMID:3092215

  13. Thymic epithelium determines a spontaneous chronic neuritis in Icam1(tm1Jcgr)NOD mice.

    PubMed

    Meyer zu Horste, Gerd; Mausberg, Anne K; Cordes, Steffen; El-Haddad, Houda; Partke, Hans-Joachim; Leussink, Verena I; Roden, Michael; Martin, Stephan; Steinman, Lawrence; Hartung, Hans-Peter; Kieseier, Bernd C

    2014-09-15

    The NOD mouse strain spontaneously develops autoimmune diabetes. A deficiency in costimulatory molecules, such as B7-2, on the NOD genetic background prevents diabetes but instead triggers an inflammatory peripheral neuropathy. This constitutes a shift in the target of autoimmunity, but the underlying mechanism remains unknown. In this study, we demonstrate that NOD mice deficient for isoforms of ICAM-1, which comediate costimulatory functions, spontaneously develop a chronic autoimmune peripheral neuritis instead of diabetes. The disease is transferred by CD4(+) T cells, which infiltrate peripheral nerves together with macrophages and B cells and are autoreactive against peripheral myelin protein zero. These Icam1(tm1Jcgr)NOD mice exhibit unaltered numbers of regulatory T cells, but increased IL-17-producing T cells, which determine the severity, but not the target specificity, of autoimmunity. Ab-mediated ICAM-1 blockade triggers neuritis only in young NOD mice. Thymic epithelium from Icam1(tm1Jcgr)NOD mice features an altered expression of costimulatory molecules and induces neuritis and myelin autoreactivity after transplantation into nude mice in vivo. Icam1(tm1Jcgr)NOD mice exhibit a specifically altered TCR repertoire. Our findings introduce a novel animal model of chronic inflammatory neuropathies and indicate that altered expression of ICAM-1 on thymic epithelium shifts autoimmunity specifically toward peripheral nerves. This improves our understanding of autoimmunity in the peripheral nervous system with potential relevance for human diseases. PMID:25108020

  14. Inhibins Tune the Thymocyte Selection Process by Regulating Thymic Stromal Cell Differentiation

    PubMed Central

    Carbajal-Franco, Ebzadrel; de la Fuente-Granada, Marisol; Alemán-Muench, Germán R.; García-Zepeda, Eduardo A.; Soldevila, Gloria

    2015-01-01

    Inhibins and Activins are members of the TGF-β superfamily that regulate the differentiation of several cell types. These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system. We have previously demonstrated that Inhibins are the main Activin ligands expressed in the murine thymus and that they regulate thymocyte differentiation, promoting the DN3-DN4 transition and the selection of SP thymocytes. As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function. Here, we demonstrate that, in the absence of Inhibins, thymic conventional dendritic cells display reduced levels of MHC Class II (MHCII) and CD86. In addition, the ratio between cTECs and mTECs was affected, indicating that mTEC differentiation was favoured and cTEC diminished in the absence of Inhibins. These changes appeared to impact thymocyte selection leading to a decreased selection of CD4SP thymocytes and increased generation of natural regulatory T cells. These findings demonstrate that Inhibins tune the T cell selection process by regulating both thymocyte and stromal cell differentiation. PMID:25973437

  15. Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator.

    PubMed

    Akiyama, Nobuko; Takizawa, Nobukazu; Miyauchi, Maki; Yanai, Hiromi; Tateishi, Ryosuke; Shinzawa, Miho; Yoshinaga, Riko; Kurihara, Masaaki; Demizu, Yosuke; Yasuda, Hisataka; Yagi, Shintaro; Wu, Guoying; Matsumoto, Mitsuru; Sakamoto, Reiko; Yoshida, Nobuaki; Penninger, Josef M; Kobayashi, Yasuhiro; Inoue, Jun-Ichiro; Akiyama, Taishin

    2016-07-25

    Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire(+) mTECs) is unclear. Here, we describe novel embryonic precursors of Aire(+) mTECs. We found the candidate precursors of Aire(+) mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire(+) mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire(+) mTECs and efficiently suppressed the onset of autoimmunity induced by Aire(+) mTEC deficiency. Mechanistically, pMECs differentiated into Aire(+) mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire(+) mTECs. PMID:27401343

  16. Thymic localization of gallium-67 in pediatric patients with lymphoid and nonlymphoid tumors

    SciTech Connect

    Hibi, S.; Todo, S.; Imashuku, S.

    1987-03-01

    To determine the significance of /sup 67/Ga localization in the thymus of children, 142 /sup 67/Ga photoscans from 45 children with various tumors were studied. Sixty-nine photoscans were taken for 17 cases of lymphoma, 73 photoscans were made for 28 cases of nonlymphoid tumors. Thymic localization of /sup 67/Ga was positive in 16 (36%) of the 45 patients and in 30 (21%) of the 142 photoscans. Positive thymus scans were seen in five (29%) of the 17 cases of lymphoma and 11 (39%) of the 28 solid tumors. The positive incidence was highest (90%) in ages 1-2 yr old. Of the eight grade 2 (strong positive) patients, the thymus in one case of Hodgkin's disease was diagnosed as malignant and the other seven solid tumor cases were nonmalignant. Most of the latter seven cases became positive after beginning of treatment (surgery and/or chemotherapy). Although the precise mechanism is not well understood, thymic localization of /sup 67/Ga may represent immunologic response to tumors, especially in infants with nonlymphoid neoplasms.

  17. TNF receptor family signaling in the development and functions of medullary thymic epithelial cells

    PubMed Central

    Akiyama, Taishin; Shinzawa, Miho; Akiyama, Nobuko

    2012-01-01

    Thymic epithelial cells (TECs) provide the microenvironment required for the development of T cells in the thymus. A unique property of medullary thymic epithelial cells (mTECs) is their expression of a wide range of tissue-restricted self-antigens, critically regulated by the nuclear protein AIRE, which contributes to the selection of the self-tolerant T cell repertoire, thereby suppressing the onset of autoimmune diseases. The TNF receptor family (TNFRF) protein receptor activator of NF-κB (RANK), CD40 and lymphotoxin β receptor (LtβR) regulate the development and functions of mTECs. The engagement of these receptors with their specific ligands results in the activation of the NF-κB family of transcription factors. Two NF-κB activation pathways, the classical and non-classical pathways, promote the development of mature mTECs induced by these receptors. Consistently, TNF receptor-associated factor (TRAF6), the signal transducer of the classical pathway, and NF-κB inducing kinase (NIK), the signal transducer of the non-classical pathway, are essential for the development of mature mTECs. This review summarizes the current understanding of how the signaling by the TNF receptor family controls the development and functions of mTEC. PMID:22969770

  18. Thyroid Carcinoma Showing Thymic-Like Differentiation Causing Fracture of the Trachea

    PubMed Central

    Marini, Aikaterini; Kanakis, Meletios; Valakis, Konstantinos; Laschos, Nikolaos; Chorti, Maria; Lioulias, Achilleas

    2016-01-01

    Thyroid carcinoma showing thymic-like differentiation (CASTLE) comprises a rare neoplasm of the thyroid gland which arises from ectopic thymic tissue or remnants of brachial pouches. CASTLE is regarded as an indolent neoplasm with a favorable prognosis, irrespective of its metastatic potential. Diagnosis is difficult as clinicopathological features have not been yet well-defined. Radiological findings are not specific and only immunohistochemical positivity for CD5 and CD117 staining is highly suggestive of CASTLE. Despite lack of universally accepted treatment recommendations, the mainstay treatment includes thyroidectomy and systematic lymph node dissection. We report a case of CASTLE tumour with very uncommon characteristics developed in a 76-year-old man, who presented with rapidly deteriorating dyspnea and severe cough, resulting in respiratory failure. At surgery, a suspicious looking tumour arising from the upper pole of the right lobe of the thyroid gland, surrounding the trachea and displacing the right common carotid artery, was identified. The patient underwent en bloc resection of the tumour with the thyroid gland and regional lymph node dissection. This is the first reported case of CASTLE causing tracheal ring fracture. PMID:27110248

  19. Thymic abnormalities: antigen or antibody? Response to thymectomy in myasthenia gravis.

    PubMed

    Penn, A S; Jaretzki, A; Wolff, M; Chang, H W; Tennyson, V

    1981-01-01

    The therapeutic value of thymectomy for myasthenia is still questioned although it retains an important place among management modalities that strive for sustained remission. Questions derive from uncertainty as to appropriate timing, variable extent of resection and quantitation of response. Forty-seven patients, followed one to seven years, underwent an extended transsternal or combined transcervical-transsternal procedure with anterior mediastinal exenteration. Sixteen have been in complete remission from six months to six years, four are asymptomatic on occasional pyridostigmine and eight are significantly improved. Evaluation of thymic pathology (hyperplasic, involuted areas, and thymoma) included a search for thymic myoid cells by fluorescence cytochemistry. Antibodies to acetylcholine receptor present in 38 of 43, decreased post-operatively to normal in four, by 50% to 80% in 14, by 20 to 50% in three and were unchanged in 14. Most remissions occurred in young women with noninvoluted hyperplastic glands and variably high anti-AChR titers which dropped toward normal in seven of 15. These results encourage us to utilize this procedure routinely. PMID:6951500

  20. Doxycycline enhances the Ras-MAPK signaling and proliferation of mouse thymic epithelial cells.

    PubMed

    Chen, Xun; Xia, Sheng; Li, Rong; Liu, Hui; Huang, Ying; Qian, Xiaoping; Xiao, Xueyuan; Xu, Xun; Lin, Xin; Tian, Yuxiang; Zong, Yangyong; He, Dacheng; Chen, Weifeng; Zhang, Yu; Shao, Qixiang

    2009-06-01

    Depletion of T-cell-dependent immunity is a major consideration for patients suffering from infections of human immunodeficiency virus (HIV), those undergoing organ transplantation, and those receiving anti-cancer chemotherapy and/or radiotherapy. In general, T-cell regeneration occurs in the thymus through thymopoiesis. We have found that doxycycline (Dox), a tetracycline derivative, enhances the proliferation of mouse thymic epithelial cells, which are unique in their capacity to support positive selection and are essential throughout the development of thymocytes. Cell cycle analysis indicates that the increased cell proliferation is due to a shortened G(0)/G(1) phase. To reveal the underlying mechanisms, we examined the expression of an array of molecules that regulate the cell cycle. The results show that in mouse thymic medullary-type epithelial cell line 1 (MTEC1) Dox leads to elevated levels of H-Ras, phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), cyclin E, cyclin dependent kinase 4/2 (CDK4/CDK2), E2F3, and c-myc. These data, and the observation that the proliferation-enhancing effect is largely abolished following treatment with an ERK inhibitor support an active role of the Ras-ERK/mitogen-activated protein kinase (MAPK) signaling pathway. In conclusion, the present study reveals a new activity of an old family of antibiotics. The in vivo effect of Dox on immune reconstitution warrants further exploration. PMID:19330805

  1. Thymic Epithelial Cells Are a Nonredundant Source of Wnt Ligands for Thymus Development.

    PubMed

    Brunk, Fabian; Augustin, Iris; Meister, Michael; Boutros, Michael; Kyewski, Bruno

    2015-12-01

    Wnt signaling has been implicated in T cell development. However, it remained unclear which cell type is the major source of Wnt ligands and to what extent thymic epithelial cell (TEC) development is dependent on Wnt signaling. In this study, we analyzed the role of Wnt ligands provided by TECs for the development of T cells and TECs without manipulating the intracellular Wnt signaling machinery in either cell type. To this end, we used conditional knockout mice (FoxN1-Gpr177) in which TECs are unable to secrete Wnt ligands. Gpr177 (Evi/Wls) is a Wnt-specific cargo receptor that is required for the secretion of Wnt ligands. We found that TECs are the main source of Wnt ligands in the thymus, which serves a nonredundant role, and lack of TEC-provided Wnt ligands led to thymic hypotrophy, as well as a reduced peripheral T cell pool. Despite being reduced in numbers, T cells that developed in the absence of TEC-secreted Wnt ligands were functionally competent, and the subset composition of the peripheral T cell pool was not affected. Thus, our data suggest that T cell development is not directly dependent on TEC-provided Wnt ligands. Rather, TEC-secreted Wnt ligands are essential for normal thymus development and normal peripheral T cell frequencies but are dispensable for T cell function in the periphery. PMID:26512137

  2. RET/GFRα Signals Are Dispensable for Thymic T Cell Development In Vivo

    PubMed Central

    Almeida, Afonso Rocha Martins; Arroz-Madeira, Sílvia; Fonseca-Pereira, Diogo; Ribeiro, Hélder; Lasrado, Reena; Pachnis, Vassilis; Veiga-Fernandes, Henrique

    2012-01-01

    Identification of thymocyte regulators is a central issue in T cell biology. Interestingly, growing evidence indicates that common key molecules control neuronal and immune cell functions. The neurotrophic factor receptor RET mediates critical functions in foetal hematopoietic subsets, thus raising the possibility that RET-related molecules may also control T cell development. We show that Ret, Gfra1 and Gfra2 are abundantly expressed by foetal and adult immature DN thymocytes. Despite the developmentally regulated expression of these genes, analysis of foetal thymi from Gfra1, Gfra2 or Ret deficient embryos revealed that these molecules are dispensable for foetal T cell development. Furthermore, analysis of RET gain of function and Ret conditional knockout mice showed that RET is also unnecessary for adult thymopoiesis. Finally, competitive thymic reconstitution assays indicated that Ret deficient thymocytes maintained their differentiation fitness even in stringent developmental conditions. Thus, our data demonstrate that RET/GFRα signals are dispensable for thymic T cell development in vivo, indicating that pharmacological targeting of RET signalling in tumours is not likely to result in T cell production failure. PMID:23300832

  3. Intrathymic radioresistant stem cells follow an IL-2/IL-2R pathway during thymic regeneration after sublethal irradiation

    SciTech Connect

    Zuniga-Pfluecker, J.C.K.; Kruisbeek, A.M. )

    1990-05-15

    Sublethally irradiated mice undergo thymic regeneration which follows a phenotypic pattern of events similar to that observed during normal fetal development. Thymic regeneration after irradiation is the product of a limited pool of intrathymic radioresistant stem cells undergoing simultaneous differentiation. We show that in this model of T cell development, thymic regeneration follows a pathway in which the IL-2R is transiently expressed on CD4-/CD8- cells. IL-2R expression occurred during the exponential growth period of thymic regeneration, and IL-2R blocking prevented this explosive growth. Flow cytometry analysis revealed that the IL-2R blockade affected primarily the development of the immature CD3-/CD4-/CD8- (triple negative) cells and their ability to generate CD3+/CD4+/CD8+ or CD3+/CD4+/CD8- and CD3+/CD4-/CD8+ thymocytes. Thus, our findings demonstrate that blocking of the IL-2R resulted in an arrest in proliferation and differentiation by intrathymic radioresistant stem cells, indicating that the IL-2/IL-2R pathway is necessary for the expansion of immature triple negative T cells.

  4. Evidence of enhanced recombinant interleukin-2 sensitivity in thymic lymphocytes from patients with myasthenia gravis: possible role in autoimmune pathogenesis.

    PubMed

    Cohen-Kaminsky, S; Levasseur, P; Binet, J P; Berrih-Aknin, S

    1989-09-01

    We evaluated the activation state of thymic lymphocytes in patients with myasthenia gravis (MG) by cytofluorographic analysis of CD25 expression and by testing their sensitivity to recombinant interleukin-2 (rIL-2) in the absence of any known previous stimulation. We detected no phenotypic signs of activation in fresh MG thymic lymphocyte suspensions, while functional signs of activation were reflected in a significantly higher sensitivity to rIL-2 in MG patients than in controls. The responses to rIL-2 were time- and dose-dependent, were inhibited by a blocking anti-IL-2 receptor antibody, and were associated with an increase in CD25+ T cells in both patients and controls. The T cells with functional signs of previous activation may represent autoreactive cells involved in the autoimmune process and confirm thymus gland hyperactivity in MG. These cells could result from primary autosensitization against the thymic acetylcholine receptor (AChR)-like molecule or from altered migration of peripheral activated cells into an abnormal thymic environment. Our results also provide a clue for understanding the effect of thymectomy in myasthenia gravis. PMID:2808688

  5. A highly conserved NF-κB-responsive enhancer is critical for thymic expression of Aire in mice.

    PubMed

    Haljasorg, Uku; Bichele, Rudolf; Saare, Mario; Guha, Mithu; Maslovskaja, Julia; Kõnd, Karin; Remm, Anu; Pihlap, Maire; Tomson, Laura; Kisand, Kai; Laan, Martti; Peterson, Pärt

    2015-12-01

    Autoimmune regulator (Aire) has a unique expression pattern in thymic medullary epithelial cells (mTECs), in which it plays a critical role in the activation of tissue-specific antigens. The expression of Aire in mTECs is activated by receptor activator of nuclear factor κB (RANK) signaling; however, the molecular mechanism behind this activation is unknown. Here, we characterize a conserved noncoding sequence 1 (CNS1) containing two NF-κB binding sites upstream of the Aire coding region. We show that CNS1-deficient mice lack thymic expression of Aire and share several features of Aire-knockout mice, including downregulation of Aire-dependent genes, impaired terminal differentiation of the mTEC population, and reduced production of thymic Treg cells. In addition, we show that CNS1 is indispensable for RANK-induced Aire expression and that CNS1 is activated by NF-κB pathway complexes containing RelA. Together, our results indicate that CNS1 is a critical link between RANK signaling, NF-κB activation, and thymic expression of Aire. PMID:26364592

  6. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghreli...

  7. Episodic Memory and Regional Atrophy in Frontotemporal Lobar Degeneration

    PubMed Central

    Söderlund, Hedvig; Black, Sandra E.; Miller, Bruce L.; Freedman, Morris; Levine, Brian

    2008-01-01

    It has been unclear to what extent memory is affected in frontotemporal lobar degeneration (FTLD). Since patients usually have atrophy in regions implicated in memory function, the frontal and/or temporal lobes, one would expect some memory impairment, and that the degree of atrophy in these regions would be inversely related to memory function. The purposes of this study were 1) to assess episodic memory function in FTLD, and more specifically patients' ability to episodically re-experience an event, and determine its source; 2) to examine whether memory performance is related to quantified regional brain atrophy. FTLD patients (n=18) and healthy comparison subjects (n=14) were assessed with cued recall, recognition, “remember/know” (self-reported re-experiencing) and source recall, at 30 min and 24 hr after encoding. Regional gray matter volumes were assessed with high resolution structural MRI concurrently to testing. Patients performed worse than comparison subjects on all memory measures. Gray matter volume in the left medial temporal lobe was positively correlated with recognition, re-experiencing, and source recall. Gray matter volume in the left posterior temporal lobe correlated significantly with recognition, at 30 min and 24 hr, and with source recall at 30 min. Estimated familiarity at 30 min was positively correlated with gray matter volume in the left inferior parietal lobe. In summary, episodic memory deficits in FTLD may be more common than previously thought, particularly in patients with left medial and posterior temporal atrophy. PMID:17888461

  8. Posterior Cortical Atrophy Presenting with Superior Arcuate Field Defect

    PubMed Central

    Wan, Sue Ling; Bukowska, Danuta M.; Ford, Stephen; Chen, Fred K.

    2015-01-01

    An 80-year-old female with reading difficulty presented with progressive arcuate field defect despite low intraocular pressure. Over a 5-year period, the field defect evolved into an incongruous homonymous hemianopia and the repeated neuroimaging revealed progressive posterior cortical atrophy. Further neuropsychiatric assessment demonstrated symptoms and signs consistent with Benson's syndrome. PMID:26417467

  9. Intravaginally applied oxytocin improves post-menopausal vaginal atrophy

    PubMed Central

    Uvnäs-Moberg, Kerstin; Jonasson, Aino F

    2015-01-01

    Objective To explore the efficacy of local oxytocin for the treatment of post-menopausal vaginal atrophy. Design Double-blinded randomised controlled trial. Setting Healthy post-menopausal women in Stockholm, Sweden. Participants Sixty four post-menopausal women between February and June 2012 at the Karolinska University Hospital Huddinge/Sweden. Main outcome measures The efficacy of oxytocin for treatment of vaginal atrophy after seven weeks and cytological evaluation. Results The percentage of superficial cells in the vaginal smears and the maturation values were significantly increased after seven weeks of treatment with vagitocin 400 IU (p = 0.0288 and p = 0.0002, respectively). The vaginal pH decreased significantly after seven weeks of treatment with vagitocin 100 IU (p = 0.02). The scores of vaginal atrophy, according to the histological evaluation, were significantly reduced after administration of vagitocin 100 IU (p = 0.03). The thickness of the endometrium did not differ between the treatment and placebo groups after seven weeks of treatment. The symptom experienced as the most bothersome was significantly reduced after seven weeks of treatment in the women receiving vagitocin 400 IU compared to women in the placebo group (p = 0.0089). Conclusions Treatment with intravaginally applied oxytocin could be an alternative to local estrogen treatment in women with post-menopausal vaginal atrophy. PMID:25995333

  10. Atrophy of the Parietal Lobe in Preclinical Dementia

    ERIC Educational Resources Information Center

    Jacobs, Heidi I. L.; Van Boxtel, Martin P. J.; Uylings, Harry B. M.; Gronenschild, Ed H. B. M.; Verhey, Frans R.; Jolles, Jelle

    2011-01-01

    Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults…

  11. Benefits of Laser Therapy in Postmenopausal Vaginal Atrophy

    NASA Astrophysics Data System (ADS)

    Brînzan, Daniela; Pǎiuşan, Lucian; Daşcǎu, Voicu; Furǎu, Gheorghe

    2011-08-01

    Maybe the worst aspect of menopause is the decline of the quality of the sexual life. The aim of the study is to demonstrate the beneficial effects of laser therapy in comparison with topical application of estrogen preparations, for the treatment of vaginal atrophy and sexual dysfunctions induced by menopause. A total of 50 menopausal patients were examined during a one year period. The methods used for objectifying vaginal atrophy and sexual dysfunctions were history taking, local clinical exam and PAP smear. From this group, 40 patients had vaginal atrophy with sexual dysfunctions. They have been treated differently, being included in four groups: patients treated with local estrogens, patients treated with intravaginal laser therapy, patients treated with both laser therapy and estrogens, patients treated with estrogens and placebo laser therapy. Therapeutic benefit, improvement of vaginal atrophy and quality of sexual life, were objectified by anamnesis (questionnaire), local and general clinical examination and PAP smear. The best results have been obtained, by far, in the 3rd group, followed by the women treated only with laser. In conclusion, we can say that laser therapy is the best way for solving the sexual inconveniences of menopause.

  12. Characterization of disuse skeletal muscle atrophy and the efficacy of a novel muscle atrophy countermeasure during spaceflight and simulated microgravity

    NASA Astrophysics Data System (ADS)

    Hanson, Andrea Marie

    Humans are an integral part of the engineered systems that will enable return to the Moon and eventually travel to Mars. Major advancements in countermeasure development addressing deleterious effects of microgravity and reduced gravity on the musculoskeletal system need to be made to ensure mission safety and success. The primary objectives of this dissertation are to advance the knowledge and understanding of skeletal muscle atrophy, and support development of novel countermeasures for disuse atrophy to enable healthy long-duration human spaceflight. Models simulating microgravity and actual spaceflight were used to examine the musculoskeletal adaptations during periods of unloading. Myostatin inhibition, a novel anti-atrophy drug therapy, and exercise were examined as a means of preventing and recovering from disuse atrophy. A combination of assays was used to quantify adaptation responses to unloading and examine efficacy of the countermeasures. Body and muscle masses were collected to analyze systemic changes due to treatments. Hindlimb strength and individual muscle forces were measured to demonstrate functional adaptations to treatments. Muscle fiber morphology and myosin heavy chain (MHC) expression was examined to identify adaptations at the cellular level. Protein synthesis signals insulin-like growth factor-1 (IGF-1), Akt, and p70s6 kinase; and the degradation signals Atrogin-1 and MuRF-1 were examined to identify adaptations at the molecular level that ultimately lead to muscle hypertrophy and atrophy. A time course study provided a thorough characterization of the adaptation of skeletal muscle during unloading in C57BL/6 mice, and baseline data for comparison to and evaluation of subsequent studies. Time points defining the on-set and endpoints of disuse muscle atrophy were identified to enable characterization of rapid vs. long-term responses of skeletal muscle to hindlimb suspension. Unloading-induced atrophy primarily resulted from increased protein

  13. Is the Supraspinatus Muscle Atrophy Truly Irreversible after Surgical Repair of Rotator Cuff Tears?

    PubMed Central

    Chung, Seok Won; Kim, Sae Hoon; Tae, Suk-Kee; Yoon, Jong Pil; Choi, Jung-Ah

    2013-01-01

    Background Atrophy of rotator cuff muscles has been considered an irreversible phenomenon. The purpose of this study is to evaluate whether atrophy is truly irreversible after rotator cuff repair. Methods We measured supraspinatus muscle atrophy of 191 patients with full-thickness rotator cuff tears on preoperative magnetic resonance imaging and postoperative multidetector computed tomography images, taken at least 1 year after operation. The occupation ratio was calculated using Photoshop CS3 software. We compared the change between pre- and postoperative occupation ratios after modifying the preoperative occupation ratio. In addition, possible relationship between various clinical factors and the change of atrophy, and between the change of atrophy and cuff integrity after surgical repair were evaluated. Results The mean occupation ratio was significantly increased postoperatively from 0.44 ± 0.17 to 0.52 ± 0.17 (p < 0.001). Among 191 patients, 81 (42.4%) showed improvement of atrophy (more than a 10% increase in occupation ratio) and 33 (17.3%) worsening (more than a 10% decrease). Various clinical factors such as age tear size, or initial degree of atrophy did not affect the change of atrophy. However, the change of atrophy was related to repair integrity: cuff healing failure rate of 48.5% (16 of 33) in worsened atrophy; and 22.2% (18 of 81) in improved atrophy (p = 0.007). Conclusions The supraspinatus muscle atrophy as measured by occupation ratio could be improved postoperatively in case of successful cuff repair. PMID:23467404

  14. [Liver Atrophy and Failure Associated with Paclitaxel and Bevacizumab Combination Therapy for Metastatic Breast Cancer].

    PubMed

    Yamamoto, Mari; Ikeda, Masahiko; Kubo, Shinichiro; Tsukioki, Takahiro; Nakamoto, Shougo

    2016-07-01

    We managed 6 cases of severe liver atrophy and failure associated with paclitaxel and bevacizumab combination therapy (PB therapy)for HER2-negative metastatic breast cancer. In this case-controlstudy, we examined the records of these 6 patients to investigate past treatment, medication history, and degree of atrophy, and compared their data with that of 67 patients without liver atrophy. The degree of the liver atrophy used SYNAPSE VINCENT®of the image analysis software. The results showed that patients with liver atrophy had a longer pretreatment period than those without liver atrophy(33.5 months vs 15.5 months), and they also experienced a longer median time to treatment failure with PB therapy than other patients(11 months vs 6 months). The ratio of individuals presenting with diffuse liver metastasis among patients with liver metastasis was 80% with liver atrophy, compared to 8% without liver atrophy. The degree of liver atrophy was an average of 67%in terms of volume ratio before/after PB therapy(57-82%). The individualwith the greatest extent of liver atrophy died of liver failure, not as a result of breast cancer progression. The direct causal link between bevacizumab and liver atrophy and failure is unclear, but the individuals in this study had a long previous history of treatment, and diffuse liver metastases may develop in patients undergoing long periods of PB therapy, which may also cause liver atrophy; therefore, the possibility of liver failure should be considered in such cases. PMID:27431631

  15. Potential predictors of hippocampal atrophy in Alzheimer's disease.

    PubMed

    Dhikav, Vikas; Anand, Kuljeet

    2011-01-01

    The hippocampus is a vulnerable and plastic brain structure that is damaged by a variety of stimuli, e.g. hypoxia, hypoperfusion, hypoglycaemia, stress and seizures. Alzheimer's disease is a common and important disorder in which hippocampal atrophy is reported. Indeed, the available evidence suggests that hippocampal atrophy is the starting point of the pathogenesis of Alzheimer's disease and a significant number of patients with hippocampal atrophy will develop Alzheimer's disease. Studies indicate that hippocampal atrophy has functional consequences, e.g. cognitive impairment. Deposition of tau protein, formation of neurofibrillary tangles and accumulation of β-amyloid (Aβ) contributes to hippocampal atrophy together with damage caused by several other factors. Some of the factors associated with the development of hippocampal atrophy in Alzheimer's disease have been identified, e.g. hypertension, diabetes mellitus, hyperlipidaemia, seizures, affective disturbances and stress, and more is being learnt about other factors. Hypertension can potentially damage the hippocampus through ischaemia caused by atherosclerosis and cerebral amyloid angiopathy. Diabetes can produce hippocampal lesions via both vascular and non-vascular pathologies and can reduce the threshold for hippocampal damage. Carriers of the apolipoprotein E (ApoE)-ε4 genotype have been shown to have greater mesial temporal atrophy and poorer memory functions than non-carriers. In addition to giving rise to abnormal lipid metabolism, the ApoE-ε4 allele can affect the course of Alzheimer's disease via both Aβ-dependent and -independent pathways. Repetitive seizures can increase Aβ-peptide production and cause neurotransmission dysfunction and cytoskeletal abnormalities or a combination of these. Affective disturbances and stress are proposed to increase corticosteroid-induced hippocampal damage in many different ways. In the absence of any specific markers for predicting Alzheimer's disease

  16. Clinical Outcomes of Myasthenia Gravis with Thymoma and Thymic Hyperplasia Undergoing Extended Transsternal Thymectomy: A Single-Center Experience

    PubMed Central

    Nazarbaghi, Surena; Amiri-Nikpour, Mohammad Reza; Mahmodlou, Rahim; Arjmand, Nasim; Rezaei, Yousef

    2015-01-01

    Background: Despite the widespread use of thymectomy in myasthenia gravis (MG) patients, it has remained controversial as to whether this procedure is of a similar efficacy and clinical outcome among MG patients with thymoma and thymic hyperplasia. Aim: We sought to determine the long-term clinical outcomes of MG patients who received extended transsternal thymectomy associated with pyridostigmine and prednisolone postoperatively. Materials and Methods: In a retrospective study from January 1999 to December 2013, MG patients who underwent thymectomy were followed up. Out of 41 MG patients admitted in our center, 25 patients had undergone thymectomy adjunctive to pyridostigmine and prednisolone therapy postoperatively. The primary endpoints included improvement in individual diplopia, ptosis, dysphagia, dysarthria, dyspnea, and limb weakness. In addition, according to the MG Foundation of America (MGFA) criteria, response to therapy was defined as complete stable remission (CSR), pharmacologic remission (PR), and minimal manifestation (MM) as secondary endpoints. Results: Majority of the patients were male (60%) and the mean age of the patients was 32.2 ± 13.9 years. Fifteen (60%) and 10 patients (40%) had thymoma and thymic hyperplasia, respectively. All the patients were followed up during a mean period of of 86.9 ± 50.3 months (minimum 10 months and maximum 168 months). The rates of CSR, PR, and MM were comparable between the thymoma and thymic hyperplasia groups (P = 0.584). Based on the Kaplan Meier analysis, the probabilities of CSR, PR, and MM were not significantly different between patients with thymoma and thymic hyperplasia. Conclusion: The extended transsternal thymectomy, along with the postoperative regimen of pyridostigmine and prednisolone was associated with a high rate of clinical improvement among MG patients with thymoma or thymic hyperplasia. PMID:26713298

  17. AND-34, a novel p130Cas-binding thymic stromal cell protein regulated by adhesion and inflammatory cytokines.

    PubMed

    Cai, D; Clayton, L K; Smolyar, A; Lerner, A

    1999-08-15

    We have characterized a novel cDNA whose steady state mRNA levels rise in the thymus 2 to 6 h following the induction of CD4+CD8+ thymocyte apoptosis by in vivo cross-linking of CD3 epsilon. This cDNA, AND-34-1, contains an open reading frame (ORF) encoding a protein with an amino-terminal Src homology 2 (SH2) domain and a carboxyl-terminal domain homologous to GDP-exchange factors (GEFs). Northern analysis demonstrates widespread expression of the AND-34 gene. Anti-CD3 epsilon treatment induces up-regulation of the AND-34 mRNA levels in total thymic RNA but not in RNA from purified thymocytes, suggesting that this transcript is derived from a thymic stromal cell population. IL-1 and TNF increase AND-34 transcript levels in thymic cortical reticular, thymic nurse, and fibroblast cell lines. In the thymic cortical reticular cell line, IL-1 and TNF induce a protein of the predicted 93-kDa size reactive with anti-AND-34 peptide antisera. Fifteen minutes of serum stimulation of vanadate-pretreated AND-34-1-transfected NIH3T3 fibroblasts induces tyrosine phosphorylation of AND-34 as well as coprecipitating 95-, 125-, and 130-kDa proteins. One of these tyrosine phosphorylated proteins is identified as p130Cas (Crk-associated substrate), a signaling molecule previously known to bind to a GDP-exchange factor (C3G) and inducibly associate with the focal adhesion complex. Consistent with such an association, AND-34 tyrosine phosphorylation is induced following adherence of trypsinized fibroblasts to fibronectin or poly-L -lysine-coated surfaces. PMID:10438950

  18. Analysis of APC types involved in CD4 tolerance and regulatory T cell generation using reaggregated thymic organ cultures.

    PubMed

    Guerri, Lucia; Peguillet, Isabelle; Geraldo, Yvette; Nabti, Sabrina; Premel, Virginie; Lantz, Olivier

    2013-03-01

    Tolerance to self-Ags is generated in the thymus. Both epithelial and hematopoietic thymic stromal cells play an active and essential role in this process. However, the role of each of the various stromal cell types remains unresolved. To our knowledge, we describe the first comparative analysis of several types of thymic hematopoietic stromal cells (THSCs) for their ability to induce CD4 tolerance to self, in parallel with the thymic epithelium. The THSCs--two types of conventional dendritic cells (cDCs), plasmacytoid dendritic cells, macrophages (MΦs), B lymphocytes, and eosinophils--were first characterized and quantified in adult mouse thymus. They were then examined in reaggregated thymic organ cultures containing mixtures of monoclonal and polyclonal thymocytes. This thymocyte mixture allows for the analysis of Ag-specific events while avoiding the extreme skewing frequently seen in purely monoclonal systems. Our data indicate that thymic epithelium alone is capable of promoting self-tolerance by eliminating autoreactive CD4 single-positive thymocytes and by supporting regulatory T cell (Treg) development. We also show that both non-Treg CD4 single-positive thymocytes and Tregs are efficiently deleted by the two populations of cDCs present in the thymus, as well as to a lesser extent by MΦs. Plasmacytoid dendritic cells, B lymphocytes, and eosinophils were not able to do so. Finally, cDCs were also the most efficient THSCs at supporting Treg development in the thymus, suggesting that although they may share some characteristics required for negative selection with MΦs, they do not share those required for the support of Treg development, making cDCs a unique cell subset in the thymus. PMID:23365074

  19. Renal Atrophy Secondary to Chemoradiotherapy of Abdominal Malignancies

    SciTech Connect

    Yang, Gary Y.; May, Kilian Salerno; Iyer, Renuka V.; Chandrasekhar, Rameela M.A.; Wilding, Gregory E.; McCloskey, Susan A.; Khushalani, Nikhil I.; Yendamuri, Saikrishna S.; Gibbs, John F.; Fakih, Marwan; Thomas, Charles R.

    2010-10-01

    Purpose: To identify factors predictive of renal atrophy after chemoradiotherapy of gastrointestinal malignancies. Methods and Materials: Patients who received chemotherapy and abdominal radiotherapy (RT) between 2002 and 2008 were identified for this study evaluating change in kidney size and function after RT. Imaging and biochemical data were obtained before and after RT in 6-month intervals. Kidney size was defined by craniocaudal measurement on CT images. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Receiver operating characteristic (ROC) curves were generated to predict risk for renal atrophy. Results: Of 130 patients, median age was 64 years, and 51.5% were male. Most primary disease sites were pancreas and periampullary tumors (77.7%). Median follow-up was 9.4 months. Creatinine clearance declined 20.89%, and size of the PK decreased 4.67% 1 year after completion of chemoradiation. Compensatory hypertrophy of the non-PK was not seen. Percentage volumes of the PK receiving {>=}10 Gy (V{sub 10}), 15 Gy (V{sub 15}), and 20 Gy (V{sub 20}) were significantly associated with renal atrophy 1 year after RT (p = 0.0030, 0.0029, and 0.0028, respectively). Areas under the ROC curves for V{sub 10}, V{sub 15}, and V{sub 20} to predict >5% decrease in PK size were 0.760, 0.760, and 0.762, respectively. Conclusions: Significant detriments in PK size and renal function were seen after abdominal RT. The V{sub 10}, V{sub 15}, and V{sub 20} were predictive of risk for PK atrophy 1 year after RT. Analyses suggest the association of lower-dose renal irradiation with subsequent development of renal atrophy.

  20. DNA methylation profile of Aire-deficient mouse medullary thymic epithelial cells

    PubMed Central

    2012-01-01

    Background Medullary thymic epithelial cells (mTECs) are characterized by ectopic expression of self-antigens during the establishment of central tolerance. The autoimmune regulator (Aire), which is specifically expressed in mTECs, is responsible for the expression of a large repertoire of tissue-restricted antigens (TRAs) and plays a role in the development of mTECs. However, Aire-deficient mTECs still express TRAs. Moreover, a subset of mTECs, which are considered to be at a stage of terminal differentiation, exists in the Aire-deficient thymus. The phenotype of a specific cell type in a multicellular organism is governed by the epigenetic regulation system. DNA methylation modification is an important component of this system. Every cell or tissue type displays a DNA methylation profile, consisting of tissue-dependent and differentially methylated regions (T-DMRs), and this profile is involved in cell-type-specific genome usage. The aim of this study was to examine the DNA methylation profile of mTECs by using Aire-deficient mTECs as a model. Results We identified the T-DMRs of mTECs (mTEC-T-DMRs) via genome-wide DNA methylation analysis of Aire−/− mTECs by comparison with the liver, brain, thymus, and embryonic stem cells. The hypomethylated mTEC-T-DMRs in Aire−/− mTECs were associated with mTEC-specific genes, including Aire, CD80, and Trp63, as well as other genes involved in the RANK signaling pathway. While these mTEC-T-DMRs were also hypomethylated in Aire+/+ mTECs, they were hypermethylated in control thymic stromal cells. We compared the pattern of DNA methylation levels at a total of 55 mTEC-T-DMRs and adjacent regions and found that the DNA methylation status was similar for Aire+/+ and Aire−/− mTECs but distinct from that of athymic cells and tissues. Conclusions These results indicate a unique DNA methylation profile that is independent of Aire in mTECs. This profile is distinct from other cell types in the thymic microenvironment and is

  1. Pretreatment biopsy for histological diagnosis and induction therapy in thymic tumors

    PubMed Central

    Yue, Jie; Gu, Zhitao; Zhang, Hongdian; Ma, Zhao; Liu, Yuan

    2016-01-01

    Background This study was to investigate the value of pretreatment biopsy for histological diagnosis and induction therapies in the management of locally advanced thymic malignancies. Methods The clinical pathological data of patients with thymic tumors in the Chinese Alliance for Research in Thymomas (ChART) who underwent biopsy before treatment from 1994 to December 2012 were retrospectively reviewed. The application trend of preoperative histological diagnosis and its influence on treatment outcome were analyzed. Results Of 1,902 cases of thymic tumors, 336 (17.1%) had undergone biopsy for histological diagnosis before therapeutic decision was decided. In recent years, percentage of pretreatment histological diagnosis significantly increased in the later ten years than the former during the study period (P=0.008). There was also a significant increase in thoracoscopy/mediastinoscopy/E-BUS biopsy as compared to open biopsy (P=0.029). Survival in Patients with preoperative biopsy for histology had significantly higher stage lesions (P=0.000) and higher grade malignancy (P=0.000), thus a significantly lower complete resection rate (P=0.000) and therefore a significantly worse survival than those without preoperative biopsy (P=0.000). In the biopsied 336 patients, those who received upfront surgery had significantly better survival than those received surgery after induction therapy (P=0.000). In stage III and IVa diseases, the R0 resection rate after induction therapies increased significantly as compared to the surgery upfront cases (65.5% vs. 46.2%, P=0.025). Tumors downstaged after induction had similar outcomes as those having upfront surgery (92.3% vs. 84.2%, P=0.51). However, tumors not downstaged by induction had significantly worse prognosis than those downstaged (P=0.004), and fared even worse than those having definitive chemoradiation without surgery (37.2% vs. 62.4%, P=0.216). Conclusions It is crucial to get histological diagnosis for thymoma before

  2. Induction of epithelial to mesenchymal transition (EMT) and inhibition on adipogenesis: Two different sides of the same coin? Feasible roles and mechanisms of transforming growth factor β1 (TGF-β1) in age-related thymic involution.

    PubMed

    Tan, Jianxin; Wang, Yajun; Zhang, Nannan; Zhu, Xike

    2016-08-01

    Age-related thymic involution is characterized by a loss of thymic epithelial cells (TECs) and a concomitant increase in adipocytes, but the mechanisms involved in thymic adipogenesis are still not clear. Transforming growth factor β1 (TGF-β1) is a pleiotropic cytokine that has been reported to be up-regulated with age in thymic stromal cells in both human and mouse. However, the exact role of TGF-β1 in age-related thymic involution remains to be further elucidated. On the basis of previous findings, we propose a novel hypothesis that TGF-β1 functions a dual role in age-related thymic involution. On one hand, up-regulation of TGF-β1 promotes epithelial to mesenchymal transition (EMT) process in TECs via activating forkhead box protein C2 (FoxC2). On the other hand, TGF-β1 inhibits the transdifferentiation of EMT-derived mesenchymal cells to adipocytes in the thymus. If confirmed, our hypothesis will not only provide further evidence supporting that the transdifferentiation of TECs into pre-adipocytes represents a source of thymic adiposity during age-related thymic involution, but also uncover a unique role of TGF-β1 in the transdifferentiation of TECs into pre-adipocytes. Collectively, the inhibition of TGF-β1 may serve as a strategy to hinder age-related thymic involution or even to restore thymic function in the elderly. PMID:27189906

  3. Factors Associated with Changes in Brain Atrophy during a Three-Year Observation in Elderly Diabetic Patients: Effect of Renal Impairment on Hippocampal Atrophy

    PubMed Central

    Kawamura, Takahiko; Umemura, Toshitaka; Umegaki, Hiroyuki; Imamine, Rui; Kawano, Naoko; Mase, Hajime; Mizoguchi, Asako; Minatoguchi, Makiko; Kusama, Minoru; Kouchi, Yu; Watarai, Atsuko; Kanai, Akio; Nakashima, Eitaro; Hotta, Nigishi

    2016-01-01

    Background/Aims We conducted a 3-year longitudinal study concerning factors associated with changes in brain atrophy in elderly diabetic patients. Methods We evaluated hippocampal and global brain atrophy using automatic voxel-based morphometry of structural magnetic resonance images, 4 cognitive function tests, and cerebral small vessel disease (SVD) in 66 diabetic patients. Results During the 3-year follow-up, hippocampal and global brain atrophy advanced, and cognitive functions worsened. For changes in hippocampal atrophy, changes in estimated glomerular filtration rate (eGFR), albuminuria, and being an ApoE ε4 carrier were independent factors; change in the number of silent brain infarctions was an independent factor for changes in global brain atrophy. A significant association of changes in eGFR and albuminuria with hippocampal atrophy remained after adjusting for confounders including SVD. Both types of brain atrophy at baseline were significantly correlated with cognitive impairment at baseline and especially associated with changes in delayed word recall during the follow-up after adjusting for confounders. Conclusion Changes in eGFR and albuminuria during follow-up were independent risk factors for hippocampal atrophy, which was associated with decline in delayed word recall, suggesting that management of chronic kidney disease may prevent the progression of hippocampal atrophy. PMID:27293417

  4. A case of successful preoperative chemotherapy with cisplatin and irinotecan followed by curative-intent surgery for locally advanced thymic carcinoma.

    PubMed

    Suzuki, Shigeki; Horio, Hirotoshi; Hato, Tai; Harada, Masahiko; Okuma, Yusuke; Hishima, Tsunekazu

    2013-03-01

    The optimal chemotherapy for thymic carcinoma has yet to be determined based on clinical evidence because of the rarity of this pathological entity. We report the case of a patient with locally advanced thymic carcinoma in whom radical excision was achieved with intensive preoperative chemotherapy followed by curative-intent surgery. A 59-year-old woman was diagnosed with Masaoka-Koga stage III thymic cancer showing squamous cell carcinoma histology. Invasion to the ascending aorta and left brachiocephalic vein was suspected from imaging, so preoperative chemotherapy with three cycles of cisplatin and irinotecan was administered. Partial response to chemotherapy was achieved and the residual tumor was completely resected with subsequent surgery. Histopathological examination of the resected specimen demonstrated stage II thymic carcinoma. The patient has shown no evidence of recurrence or surgical complications as of 46 months after completing preoperative chemotherapy. PMID:22760255

  5. Effects of steroids on the secretion of immunoregulatory factors by thymic epithelial cell cultures.

    PubMed Central

    Stimson, W H; Crilly, P J

    1981-01-01

    Rat thymic epithelial cells were cultured for 39 days in the presence of various concentrations of oestradiol, testosterone, progesterone and corticosterone and the supernatants assessed for effects on the stimulation of cells from the thymus, bone marrow, lymph nodes and spleen, with several agents. All the steroids, except progesterone, were found to significantly regulate the secretion of immunoregulatory factors by the epithelial cells at physiological levels but the effects were dose dependent. Fractionation of active supernatants indicated that the capacity to enhance or depress cellular proliferation was mainly associated with substances having molecular weights greater than 30,000 or less than 1000, respectively. This study supports the idea that certain steroids can influence the immune response indirectly through the thymus. PMID:7298074

  6. Aire controls gene expression in the thymic epithelium with ordered stochasticity

    PubMed Central

    Meredith, Matthew; Zemmour, David; Mathis, Diane; Benoist, Christophe

    2015-01-01

    Aire controls immunologic tolerance by inducing the ectopic thymic expression of many tissue-specific genes, acting broadly by removing stops on the transcriptional machinery. To better understand Aire’s specificity, we performed single-cell RNAseq and DNA methylation analysis in Aire-sufficient and -deficient medullary epithelial cells (mTECs). Each of Aire’s target genes was induced in only a minority of mTECs, independently of DNA methylation patterns, as small inter-chromosomal gene clusters activated in concert in a proportion of mTECs. These microclusters differed between individual mice, and thus suggest an organization of the DNA or of the epigenome that results from stochastic determinism, but is bookmarked and stable through mTEC divisions, ensuring more effective presentation of self-antigens, and favoring diversity of self-tolerance between individuals. PMID:26237550

  7. Single-cell transcriptome analysis reveals coordinated ectopic gene expression patterns in medullary thymic epithelial cells

    PubMed Central

    Brennecke, Philip; Reyes, Alejandro; Pinto, Sheena; Rattay, Kristin; Nguyen, Michelle; Küchler, Rita; Huber, Wolfgang; Kyewski, Bruno; Steinmetz, Lars M.

    2015-01-01

    Expression of tissue-restricted self-antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for self-tolerance induction and prevents autoimmunity, with each TRA being expressed in only a few mTECs. How this process is regulated in single mTECs and coordinated at the population level, such that the varied single-cell patterns add up to faithfully represent TRAs, is poorly understood. Here we used single-cell RNA-sequencing and provide evidence for numerous recurring TRA co-expression patterns, each present in only a subset of mTECs. Co-expressed genes clustered in the genome and showed enhanced chromatin accessibility. Our findings characterize TRA expression in mTECs as a coordinated process, which might involve local re-modeling of chromatin and thus ensures a comprehensive representation of the immunological self. PMID:26237553

  8. Pharmacological Inhibitors of the Proteosome in Atrophying Muscles

    NASA Technical Reports Server (NTRS)

    Goldberg, Alfred

    1999-01-01

    It is now clear that the marked loss of muscle mass that occurs with disuse, denervation or in many systemic diseases (cancer cachexia, sepsis, acidosis, various endocrine disorders) is due primarily to accelerated degradation of muscle proteins, especially myofibrillar components. Recent work primarily in Dr. Goldberg's laboratory had suggested that in these diverse conditions, the enhancement of muscle proteolysis results mainly from activation of the Ub-proteasome degradative pathway. In various experimental models of atrophy, rat muscles show a common series of changes indicative of activation of this pathway, including increases in MRNA for Ub and proteasome subunits, content of ubiquitinated proteins, and sensitivity to inhibitors of the proteasome. In order to understand the muscle atrophy seen in weightlessness, Dr. Goldberg's laboratory is collaborating with Dr. Baldwin in studies to define the changes in these parameters upon hind-limb suspension. Related experiments will explore the effects on this degradative system of exercise regimens and also of glucocorticoids, which are known to rise in space personnel and to promote muscle, especially in inactive muscles. The main goals will be: (A) to define the enzymatic changes leading to enhanced activity of the Ub-proteasome pathway in inactive muscles upon hind-limb suspension, and the effects on this system of exposure to glucocorticoids or exercise; and (B) to learn whether inhibitors of the Ub-proteasome pathway may be useful in retarding the excessive proteolysis in atrophying muscles. Using muscle extracts, Dr. Goldberg's group hopes to define the rate-limiting, enzymatic changes that lead to the accelerated Ub-conjugation and protein degradation. They have recently developed cell-free preparations from atrophying rat muscles, in which Ub-conjugation to muscle proteins is increased above control levels. Because these new preparations seem to reproduce the changes occurring in vivo, they will analyze in

  9. Expanding the spectrum of neuronal pathology in multiple system atrophy

    PubMed Central

    Cykowski, Matthew D.; Coon, Elizabeth A.; Powell, Suzanne Z.; Jenkins, Sarah M.; Benarroch, Eduardo E.; Low, Phillip A.; Schmeichel, Ann M.

    2015-01-01

    Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients

  10. Dynamic Foot Pressure as a Countermeasure to Muscle Atrophy

    NASA Astrophysics Data System (ADS)

    Kyparos, A.; Layne, C. S.; Martinez, D. A.; Clarke, M. S. F.; Feeback, D. L.

    2002-01-01

    Mechanical unloading of skeletal muscle (SKM) as a consequence of space flight or ground-based analogues, such as human bedrest and rodent hindlimb suspension (HLS) models, induces SKM atrophy particularly affecting the anti-gravity musculature of the lower limbs. In the context of manned space flight, the subsequent loss of muscle strength and functionality will pose operational implications jeopardizing mission success. Exercise, currently the primary muscle degradation countermeasure, has not proven completely effective in preventing muscle atrophy. It is therefore imperative that some other forms of in- flight countermeasure be also developed to supplement the prescribed exercise regimen the astronauts follow during spaceflight. Previous work in both humans and rats has shown that mechanical stimulation of the soles of the feet increases neuromuscular activation in the lower limb musculature and that such stimulation results in the limited prevention of atrophy in the soleus muscle of unloaded rats. This study was designed to investigate the effect of cutaneous mechanoreceptor stimulation on hindlimb unloading- induced SKM atrophy in rats. It was hypothesized that mechanical stimulation of the plantar surface of the rat foot during hindlimb suspension (HLS), utilizing a novel stimulation paradigm known as Dynamic Foot Pressure (DFP), would attenuate unloading-induced SKM atrophy. Mature adult male Wistar rats were randomly assigned to four groups of 10 rats each as follows: sedentary controls (Ctrl), hindlimb suspended only (HLS), hindlimb suspended wearing an inflatable boot (HLS-IFL) and hindlimb suspended rats wearing a non-inflatable boot (HLS-NIFL). The stimulation of mechanoreceptors was achieved by applying pressure to the plantar surface of the foot during the 10-day period of HLS using a custom-built boot. The anti-atrophic effects of DFP application was quantified directly by morphological (muscle wet weight, myofiber cross-sectional area

  11. Thymic neoplasms.

    PubMed

    Komaki, R; Putnam, J B; Shin, D M; Cox, J D

    1997-03-01

    Thymomas are infrequent and relatively indolent mediastinal tumors. They are usually encapsulated and readily removed. Invasive tumors, even if completely resected, require additional therapy. Although efforts have been made to relate histopathologic characteristics to outcome, the most important prognostic factors are stage and ability to achieve complete resection. The responsiveness of these tumors to chemotherapy and radiation therapy has led to combining all three modalities in a consistent sequence to derive maximal benefit from each to outcome in patients with locally advanced stage tumors. PMID:9161794

  12. NMR study of thymulin, a lymphocyte differentiating thymic nonapeptide. Conformational states of free peptide in solution.

    PubMed

    Laussac, J P; Cung, M T; Pasdeloup, M; Haran, R; Marraud, M; Lefrancier, P; Dardenne, M; Bach, J F

    1986-06-15

    The nonapeptide less than Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asn (formerly called serum thymic factor) is a factor produced by the thymic epithelium, which needs a zinc ion to express its immunoregulatory properties. We report here on 1H and 13C NMR investigation of the conformational properties of the free peptide in aqueous medium and in dimethyl sulfoxide-d6 solution by a combination of homo- and heteronuclear one- and two-dimensional experiments. The various resonances have been assigned in a straightforward manner on the basis of 1H,1H COSY spectroscopy for the recognition of the proton spin systems; two-dimensional NOESY spectra with the correlation peaks across amide bonds and for the amino acid sequence assignment; amide bonds and for the amino acid sequence assignment; 13C,1H COSY experiments using selective polarization transfer from 1H- to 13C-nucleus via the 13C,1H long-range couplings for the attribution of the carboxyl and carbonyl groups; and 13C,1H COSY experiments with selective polarization transfer via the 13C,1H direct couplings for the assignment of all the aliphatic carbons. Other experiments such as pH-dependent chemical shifts, combined use of multiple and selective proton-decoupled 1H and 13C NMR spectra, the temperature and the concentration dependence of the proton shifts of the amide resonances, the solvent dependences of peptide carbonyl carbon resonances, and comparison of the spectra with three different analogues were performed. In aqueous solution, the data are compatible with the assumption of a highly mobile dynamic equilibrium among different conformations, whereas in dimethyl sulfoxide-d6, a more rigid structure is found involving three internal hydrogen bonds. These observations provide an insight into the conformational tendencies of this peptidic hormone in two different media. PMID:3711109

  13. Thymic education curtailed: defective immune responses in nude rats reconstituted with immature thymocyte subsets.

    PubMed

    Yang, C P; Bell, E B

    1994-04-01

    We have studied the ability of thymocyte subsets from allotype marked donors to populate athymic nude rats with T cells and to restore immune responsiveness. Following adoptive transfer, CD4-CD8- double-negative (DN) thymocytes (lymphoid precursor cells) or the CD4+CD8+ double-positive (DP) subset (intermediate thymocytes) or CD4+CD8- single-positive (CD4 SP) cells (mature thymocytes) each generated a permanent population of CD4+ progeny in syngeneic nude recipients. DN and DP thymocytes also produced small numbers of CD8+ cells; there was no evidence of a CD4-CD8- or CD4+CD8+ donor cell population. CD4 SP thymocytes conferred T cell functions [graft-versus-host (GVH) responses, allograft rejection and thymus-dependent antibody responses] on nude rats that were almost indistinguishable from those conferred by mature peripheral recirculating CD4 T cells. Transfer of DP thymocytes extended the life-span of the immunoincompetent nudes and produced CD4+ progeny with near normal GVH responsiveness. However, DP-derived CD4+ cells were deficient at inducing allograft rejection and provided little or no help for antibody synthesis. The CD4+ progeny of DN thymocytes did not prolong the survival of nude recipients, gave reduced GVH reactivity, showed almost no capacity to initiate skin allograft rejection and failed to help B cells produce antibody. The results suggest that intrathymic development proceeds stepwise; each stage is accompanied by acquisition of additional properties that are reflected by T cell responses in the periphery. Thymic education does not become complete until the SP stage is reached when thymocytes become fully independent of the thymic microenvironment. PMID:8018597

  14. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells.

    PubMed

    Depreter, Marianne G L; Blair, Natalie F; Gaskell, Terri L; Nowell, Craig S; Davern, Kathleen; Pagliocca, Adelina; Stenhouse, Frances H; Farley, Alison M; Fraser, Adrian; Vrana, Jan; Robertson, Kevin; Morahan, Grant; Tomlinson, Simon R; Blackburn, C Clare

    2008-01-22

    The thymus is essential for a functional immune system, because the thymic stroma uniquely supports T lymphocyte development. We have previously identified the epithelial progenitor population from which the thymus arises and demonstrated its ability to generate an organized functional thymus upon transplantation. These thymic epithelial progenitor cells (TEPC) are defined by surface determinants recognized by the mAbs MTS20 and MTS24, which were also recently shown to identify keratinocyte progenitor cells in the skin. However, the biochemical nature of the MTS20 and MTS24 determinants has remained unknown. Here we show, via expression profiling of fetal mouse TEPC and their differentiated progeny and subsequent analyses, that both MTS20 and MTS24 specifically bind an orphan protein of unknown function, Placenta-expressed transcript (Plet)-1. In the postgastrulation embryo, Plet-1 expression is highly restricted to the developing pharyngeal endoderm and mesonephros until day 11.5 of embryogenesis, consistent with the MTS20 and MTS24 staining pattern; both MTS20 and MTS24 specifically bind cell lines transfected with Plet-1; and antibodies to Plet-1 recapitulate MTS20/24 staining. In adult tissues, we demonstrate expression in a number of sites, including mammary and prostate epithelia and in the pancreas, where Plet-1 is specifically expressed by the major duct epithelium, providing a specific cell surface marker for this putative reservoir of pancreatic progenitor/stem cells. Plet-1 will thus provide an invaluable tool for genetic analysis of the lineage relationships and molecular mechanisms operating in the development, homeostasis, and injury in several organ/tissue systems. PMID:18195351

  15. Influence of age on the proliferation and peripheralization of thymic T cells

    SciTech Connect

    Hirokawa, K.; Utsuyama, M.; Katsura, Y.; Sado, T.

    1988-01-01

    Bone marrow cells obtained from B10.Thy-1.1 mice (H-2b, Thy-1.1) were injected directly into the thymus of C57BL/6 mice (H-2b,Thy 1.2) of various ages. Thymocyte precursors in the injected donor-bone marrow cells could proliferate in the thymic microenvironment in the following manner: first, preferentially proliferating into the subcapsular cortex; and second, spreading to the whole layer of the cortex, a portion of them gradually moving into the medulla. The proliferation of donor-type thymocytes was most pronounced when intrathymic injection of bone marrow cells (ITB) was performed in newborn mice and especially prominent in week-old mice; it took approximately ten weeks for donor-type thymocytes to finish the whole course of proliferation, differentiation, and emigration to the periphery. When ITB was performed in mice 4 weeks of age and older, the proliferation of donor-type thymocytes was retarded at onset, less pronounced in magnitude, and disappeared earlier. Emigration of donor-type T cells from the thymus to the peripheral lymphoid tissues occurred most rapidly when ITB was performed in newborn mice, and these T cells continued to reside thereafter in the peripheral lymphoid tissues. However, when ITB was performed in mice 4 weeks of age and older, the number of emigrated T cells in the spleen decreased (about a tenth of that in newborn mice) and, moreover, these T cells resided only transiently in the spleen. It was suggested that T cells emigrating from the thymus of mice from newborn to 2 weeks of age are long-lived, whereas those from the thymus in mice 4 weeks of age and older are short-lived. However, when 4-week-old young adult mice were treated by irradiation or hydrocortisone, the thymic capacity was enhanced in terms of proliferation and peripheralization of thymocytes, and emigrated T cells became long-lived.

  16. Cholinergic chemosensory cells of the thymic medulla express the bitter receptor Tas2r131.

    PubMed

    Soultanova, Aichurek; Voigt, Anja; Chubanov, Vladimir; Gudermann, Thomas; Meyerhof, Wolfgang; Boehm, Ulrich; Kummer, Wolfgang

    2015-11-01

    The thymus is the site of T cell maturation which includes positive selection in the cortex and negative selection in the medulla. Acetylcholine is locally produced in the thymus and cholinergic signaling influences the T cell development. We recently described a distinct subset of medullary epithelial cells in the murine thymus which express the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT) and components of the canonical taste transduction cascade, i.e. transient receptor potential melastatin-like subtype 5 channel (TRPM5), phospholipase Cβ(2), and Gα-gustducin. Such a chemical phenotype is characteristic for chemosensory cells of mucosal surfaces which utilize bitter receptors for detection of potentially hazardous compounds and cholinergic signaling to initiate avoidance reflexes. We here demonstrate mRNA expression of bitter receptors Tas2r105, Tas2r108, and Tas2r131 in the murine thymus. Using a Tas2r131-tauGFP reporter mouse we localized the expression of this receptor to cholinergic cells expressing the downstream elements of the taste transduction pathway. These cells are distinct from the medullary thymic epithelial cells which promiscuously express tissue-restricted self-antigens during the process of negative selection, since double-labeling immunofluorescence showed no colocalization of autoimmune regulator (AIRE), the key mediator of negative selection, and TRPM5. These data demonstrate the presence of bitter taste-sensing signaling in cholinergic epithelial cells in the thymic medulla and opens a discussion as to what is the physiological role of this pathway. PMID:26102274

  17. A signal integration model of thymic selection and natural regulatory T cell commitment.

    PubMed

    Khailaie, Sahamoddin; Robert, Philippe A; Toker, Aras; Huehn, Jochen; Meyer-Hermann, Michael

    2014-12-15

    The extent of TCR self-reactivity is the basis for selection of a functional and self-tolerant T cell repertoire and is quantified by repeated engagement of TCRs with a diverse pool of self-peptides complexed with self-MHC molecules. The strength of a TCR signal depends on the binding properties of a TCR to the peptide and the MHC, but it is not clear how the specificity to both components drives fate decisions. In this study, we propose a TCR signal-integration model of thymic selection that describes how thymocytes decide among distinct fates, not only based on a single TCR-ligand interaction, but taking into account the TCR stimulation history. These fates are separated based on sustained accumulated signals for positive selection and transient peak signals for negative selection. This spans up the cells into a two-dimensional space where they are either neglected, positively selected, negatively selected, or selected as natural regulatory T cells (nTregs). We show that the dynamics of the integrated signal can serve as a successful basis for extracting specificity of thymocytes to MHC and detecting the existence of cognate self-peptide-MHC. It allows to select a self-MHC-biased and self-peptide-tolerant T cell repertoire. Furthermore, nTregs in the model are enriched with MHC-specific TCRs. This allows nTregs to be more sensitive to activation and more cross-reactive than conventional T cells. This study provides a mechanistic model showing that time integration of TCR-mediated signals, as opposed to single-cell interaction events, is needed to gain a full view on the properties emerging from thymic selection. PMID:25392533

  18. IL-33 and thymic stromal lymphopoietin mediate immune pathology in response to chronic airborne allergen exposure.

    PubMed

    Iijima, Koji; Kobayashi, Takao; Hara, Kenichiro; Kephart, Gail M; Ziegler, Steven F; McKenzie, Andrew N; Kita, Hirohito

    2014-08-15

    Humans are frequently exposed to various airborne allergens in the atmospheric environment. These allergens may trigger a complex network of immune responses in the airways, resulting in asthma and other chronic airway diseases. In this study, we investigated the immunological mechanisms involved in the pathological changes induced by chronic exposure to multiple airborne allergens. Naive mice were exposed intranasally to a combination of common airborne allergens, including the house dust mite, Alternaria, and Aspergillus, for up to 8 wk. These allergens acted synergistically and induced robust eosinophilic airway inflammation, specific IgE Ab production, type 2 cytokine response, and airway hyperresponsiveness in 4 wk, followed by airway remodeling in 8 wk. Increased lung infiltration of T cells, B cells, and type 2 innate lymphoid cells was observed. CD4(+) T cells and type 2 innate lymphoid cells contributed to the sources of IL-5 and IL-13, suggesting involvement of both innate and adaptive immunity in this model. The lung levels of IL-33 increased quickly within several hours after allergen exposure and continued to rise throughout the chronic phase of inflammation. Mice deficient in IL-33R (Il1rl1(-/-)) and thymic stromal lymphopoietin receptor (Tslpr(-/-)) showed significant reduction in airway inflammation, IgE Ab levels, and airway hyperresponsiveness. In contrast, mice deficient in IL-25R or IL-1R showed minimal differences as compared with wild-type animals. Thus, chronic exposure to natural airborne allergens triggers a network of innate and adaptive type 2 immune responses and airway pathology, and IL-33 and thymic stromal lymphopoietin most likely play key roles in this process. PMID:25015831

  19. Acute Bronchitis

    MedlinePlus

    ... or though physical contact (for example, on unwashed hands). Being exposed to tobacco smoke, air pollution, dusts, vapors, and fumes can also cause acute bronchitis. Less often, bacteria can also cause acute bronchitis. To diagnose acute ...

  20. Cystitis - acute

    MedlinePlus

    Uncomplicated urinary tract infection; UTI - acute; Acute bladder infection; Acute bacterial cystitis ... control. Menopause also increases the risk for a urinary tract infection. The following also increase your chances of having ...

  1. Acute Werdnig-Hoffmann disease

    PubMed Central

    Pearn, J. H.; Wilson, J.

    1973-01-01

    76 cases of acute Werdnig-Hoffmann disease (acute infantile spinal muscular atrophy) have been reviewed. The cases comprise an unselected consecutive series in which rigid diagnostic criteria have been applied. The natural history of the disease has been investigated. In at least one-third of cases the disease is manifest before or at delivery. All cases have shown delayed milestones by 5 months of age: 95% are dead by 18 months. Cumulative frequency curves for age at onset and age at death figures are presented for use both as prognostic guidelines and as aids in the management of sibs of index cases. Diagnosis, management, and genetic implications are discussed. ImagesFIG. 1 PMID:4712772

  2. Cognitive planning deficit in patients with cerebellar atrophy.

    PubMed

    Grafman, J; Litvan, I; Massaquoi, S; Stewart, M; Sirigu, A; Hallett, M

    1992-08-01

    We compared the performance of 12 patients with cerebellar atrophy (CA) and 12 normal controls matched for age and education on the Tower of Hanoi, a nine-problem task that requires cognitive planning. CA patients performed significantly worse than controls on this task despite no difference in planning and between-move pause times. A reanalysis of the data using just the subgroup of patients with pure cerebellar cortical atrophy (CCA) (N = 9) replicated the above results and also showed that CCA patients had significantly increased planning times compared with controls. Neither age, sex, education level, severity of dementia, word fluency, response time, memory, nor visuomotor procedural learning predicted CA or CCA performance. This deficit in cognitive planning suggests a functional link between the cerebellum, basal ganglia, and the frontal lobe concerning specific cognitive processes. However, the exact role of the cerebellum in cognitive planning remains undetermined. PMID:1641142

  3. Crustaceans as a model for microgravity-induced muscle atrophy

    NASA Astrophysics Data System (ADS)

    Mykles, D. L.

    Atrophy of skeletal muscles is a serious problem in a microgravity environment. It is hypothesized that the unloading of postural muscles, which no longer must resist gravity force, causes an accelerated breakdown of contractile proteins, resulting in a reduction in muscle mass and strength. A crustacean model using the land crab, Gecarcinus lateralis, to assess the effects of spaceflight on protein metabolism is presented. The model is compared to a developmentally-regulated atrophy in which a premolt reduction in muscle mass allows the withdrawal of the large claws at molt. The biochemical mechanisms underlying protein breakdown involves both Ca^2+-dependent and multicatalytic proteolytic enzymes. Crustacean claw muscle can be used to determine the interactions between shortening and unloading at the molecular level.

  4. Crustaceans as a model for microgravity-induced muscle atrophy

    NASA Technical Reports Server (NTRS)

    Mykles, D. L.

    1996-01-01

    Atrophy of skeletal muscles is a serious problem in a microgravity environment. It is hypothesized that the unloading of postural muscles, which no longer must resist gravity force, causes an accelerated breakdown of contractile proteins, resulting in reduction in muscle mass and strength. A crustacean model using the land crab, Gecarcinus lateralis, to assess the effects of spaceflight on protein meatabolism is presented. The model is compared to a developmentally-regulated atrophy in which a premolt reduction in muscle mass allows the withdrawal of the large claws at molt. The biochemical mechanisms underlying protein breakdown involves both Ca2(+) -dependent and multicatalytic proteolytic enzymes. Crustacean claw muscle can be used to determine the interactions between shortening and unloading at the molecular level.

  5. A Case of Solitary Kidney Atrophy Due to Primary Hyperparathyroidism

    PubMed Central

    Lin, Yu-Ting; Jiang, Jiunn-Song; Fang, Yu-Wei; Tsai, Ming-Hsien

    2016-01-01

    Abstract Although primary hyperparathyroidism (PHPT) is asymptomatic in most patients, its main clinical manifestation is nephrolithiasis. In general, hypercalcemia would lead to unilateral renal stones, which may become bilateral over time. We present a rare case of a large unilateral asymptomatic ureteral stone in a patient with hypercalcemia secondary to PHPT, which eventually led to renal atrophy. The diagnosis of PHPT should be considered in patients with hypercalcemia and renal stones, as asymptomatic PHPT may result in a devastating renal outcome. PMID:26765435

  6. Neonatal lupus erythematosus associated with unilateral pectoralis major atrophy.

    PubMed

    Mondal, Rakesh; Nandi, Madhumita; Sarkar, Sumantra; Mukherjee, Krishnendu

    2011-11-01

    Neonatal lupus erythematosus (NLE), in most cases, presents with cardiac and dermatological manifestation due to transferred IgG auto antibodies (anti Ro/SSA and anti La/SSB) from the mother. Some unusual associations with myelopathy, vasculopathy, transient myasthenia gravis, congenital nephrotic syndrome, chondrodysplasia punctata etc. are also reported. Here, the authors present a case of NLE with isolated left sided pectoralis major muscle atrophy, which has not been reported earlier. PMID:21553209

  7. Potential role of lampalizumab for treatment of geographic atrophy

    PubMed Central

    Rhoades, William; Dickson, Drew; Do, Diana V

    2015-01-01

    The purpose of this article is to review the pathways underlying age-related macular degeneration and potential therapeutic targets, focusing on the complement pathway and the recent MAHALO Phase II trial of the investigational drug lampalizumab. This trial was the first to have shown positive results for the treatment of geographic atrophy in age-related macular degeneration. It has potential as a future treatment, and is currently undergoing a Phase III trial. PMID:26089637

  8. Masticatory muscles of mouse do not undergo atrophy in space

    PubMed Central

    Philippou, Anastassios; Minozzo, Fabio C.; Spinazzola, Janelle M.; Smith, Lucas R.; Lei, Hanqin; Rassier, Dilson E.; Barton, Elisabeth R.

    2015-01-01

    Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 ± 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12-fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P-Akt, and 50–90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle.—Philippou, A., Minozzo, F. C., Spinazzola, J. M., Smith, L. R., Lei, H., Rassier, D. E., Barton, E. R. Masticatory muscles of mouse do not undergo atrophy in space. PMID:25795455

  9. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

    PubMed

    Fukawa, Tomoya; Yan-Jiang, Benjamin Chua; Min-Wen, Jason Chua; Jun-Hao, Elwin Tan; Huang, Dan; Qian, Chao-Nan; Ong, Pauline; Li, Zhimei; Chen, Shuwen; Mak, Shi Ya; Lim, Wan Jun; Kanayama, Hiro-Omi; Mohan, Rosmin Elsa; Wang, Ruiqi Rachel; Lai, Jiunn Herng; Chua, Clarinda; Ong, Hock Soo; Tan, Ker-Kan; Ho, Ying Swan; Tan, Iain Beehuat; Teh, Bin Tean; Shyh-Chang, Ng

    2016-06-01

    Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia. PMID:27135739

  10. Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance

    PubMed Central

    Troncoso, Rodrigo; Paredes, Felipe; Parra, Valentina; Gatica, Damián; Vásquez-Trincado, César; Quiroga, Clara; Bravo-Sagua, Roberto; López-Crisosto, Camila; Rodriguez, Andrea E; Oyarzún, Alejandra P; Kroemer, Guido; Lavandero, Sergio

    2014-01-01

    Glucocorticoids, such as dexamethasone, enhance protein breakdown via ubiquitin–proteasome system. However, the role of autophagy in organelle and protein turnover in the glucocorticoid-dependent atrophy program remains unknown. Here, we show that dexamethasone stimulates an early activation of autophagy in L6 myotubes depending on protein kinase, AMPK, and glucocorticoid receptor activity. Dexamethasone increases expression of several autophagy genes, including ATG5, LC3, BECN1, and SQSTM1 and triggers AMPK-dependent mitochondrial fragmentation associated with increased DNM1L protein levels. This process is required for mitophagy induced by dexamethasone. Inhibition of mitochondrial fragmentation by Mdivi-1 results in disrupted dexamethasone-induced autophagy/mitophagy. Furthermore, Mdivi-1 increases the expression of genes associated with the atrophy program, suggesting that mitophagy may serve as part of the quality control process in dexamethasone-treated L6 myotubes. Collectively, these data suggest a novel role for dexamethasone-induced autophagy/mitophagy in the regulation of the muscle atrophy program. PMID:24897381

  11. Counteracting Muscle Atrophy using Galvanic Stimulation of the Vestibular System

    NASA Technical Reports Server (NTRS)

    Fox, Robert A.; Polyakov, Igor

    1999-01-01

    The unloading of weight bearing from antigravity muscles during space flight produces significant muscle atrophy and is one of the most serious health problems facing the space program. Various exercise regimens have been developed and used either alone or in combination with pharmacological techniques to ameliorate this atrophy, but no effective countermeasure exists for this problem. The research in this project was conducted to evaluate the potential use of vestibular galvanic stimulation (VGS) to prevent muscle atrophy resulting from unloading of weight bearing from antigravity muscles. This approach was developed based on two concepts related to the process of maintaining the status of the anti-gravity neuromuscular system. These two premises are: (1) The "tone," or bias on spinal motorneurons is affected by vestibular projections that contribute importantly to maintaining muscle health and status. (2) VGS can be used to modify the excitability, or 'tone' of motorneuron of antigravity muscles. Thus, the strategy is to use VGS to modify the gain of vestibular projections to antigravity muscles and thereby change the general status of these muscles.

  12. A family with optic atrophy and congenital hearing loss.

    PubMed

    Amemiya, T; Honda, A

    1994-06-01

    A 37-year-old woman had optic atrophy in both eyes and low-tone hearing disturbance of both ears noted after 34 years of age. Her visual acuity was 0.5 in the right eye and 0.6 in the left. The visual fields of both eyes showed slight progressive concentric narrowing. Hearing loss was gradually progressive. Her 13-year-old daughter also had optic atrophy in both eyes and low-tone hearing loss in both ears after 11 years of age. Her visual acuity was 0.8 in the right eye and 1.0 in the left. Her visual fields showed slight concentric narrowing. She had enlarged blind spots in both eyes. The mother and her daughter had deuteranomaly. Family history showed that the father, one brother and three sisters of the mother had congenital hearing loss. No other cause for the optic nerve atrophy and hearing disturbance could be found except heredity. PMID:7850273

  13. Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy

    PubMed Central

    Calvani, Riccardo; Joseph, Anna-Maria; Adhihetty, Peter J.; Miccheli, Alfredo; Bossola, Maurizio; Leeuwenburgh, Christiaan; Bernabei, Roberto; Marzetti, Emanuele

    2014-01-01

    Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions. PMID:23154422

  14. Masticatory muscles of mouse do not undergo atrophy in space.

    PubMed

    Philippou, Anastassios; Minozzo, Fabio C; Spinazzola, Janelle M; Smith, Lucas R; Lei, Hanqin; Rassier, Dilson E; Barton, Elisabeth R

    2015-07-01

    Muscle loading is important for maintaining muscle mass; when load is removed, atrophy is inevitable. However, in clinical situations such as critical care myopathy, masticatory muscles do not lose mass. Thus, their properties may be harnessed to preserve mass. We compared masticatory and appendicular muscles responses to microgravity, using mice aboard the space shuttle Space Transportation System-135. Age- and sex-matched controls remained on the ground. After 13 days of space flight, 1 masseter (MA) and tibialis anterior (TA) were frozen rapidly for biochemical and functional measurements, and the contralateral MA was processed for morphologic measurements. Flight TA muscles exhibited 20 ± 3% decreased muscle mass, 2-fold decreased phosphorylated (P)-Akt, and 4- to 12-fold increased atrogene expression. In contrast, MAs had no significant change in mass but a 3-fold increase in P-focal adhesion kinase, 1.5-fold increase in P-Akt, and 50-90% lower atrogene expression compared with limb muscles, which were unaltered in microgravity. Myofibril force measurements revealed that microgravity caused a 3-fold decrease in specific force and maximal shortening velocity in TA muscles. It is surprising that myofibril-specific force from both control and flight MAs were similar to flight TA muscles, yet power was compromised by 40% following flight. Continued loading in microgravity prevents atrophy, but masticatory muscles have a different set point that mimics disuse atrophy in the appendicular muscle. PMID:25795455

  15. Atrophy of the parietal lobe in preclinical dementia.

    PubMed

    Jacobs, Heidi I L; Van Boxtel, Martin P J; Uylings, Harry B M; Gronenschild, Ed H B M; Verhey, Frans R; Jolles, Jelle

    2011-03-01

    Cortical grey matter atrophy patterns have been reported in healthy ageing and Alzheimer disease (AD), but less consistently in the parietal regions of the brain. We investigated cortical grey matter volume patterns in parietal areas. The grey matter of the somatosensory cortex, superior and inferior parietal lobule was measured in 75 older adults (38 cognitively stable and 37 individuals with cognitive decline after 3 years). Dementia screening 6 years after scanning resulted in nine AD cases from the cognitively stable (n=3) and cognitive decline group (n=6), who were assigned to a third group, the preclinical AD group. When regional differences in cortical volume in the parietal lobe areas were compared between groups, significant differences were found between either the cognitive decline or stable group on the one hand and preclinical AD individuals on the other hand in the inferior parietal lobule. Group membership was best predicted by the grey matter volume of the inferior parietal lobule, compared to the other parietal lobe areas. The parietal lobe was characterised by a differential atrophy pattern based on cognitive status, which is in agreement with the 'last-developed-first-atrophied' principle. Future studies should investigate the surplus value of the inferior parietal lobe as a potential marker for the diagnosis of AD compared to other brain regions, such as the medial temporal lobe and the prefrontal lobe. PMID:21130554

  16. Motor features in posterior cortical atrophy and their imaging correlates.

    PubMed

    Ryan, Natalie S; Shakespeare, Timothy J; Lehmann, Manja; Keihaninejad, Shiva; Nicholas, Jennifer M; Leung, Kelvin K; Fox, Nick C; Crutch, Sebastian J

    2014-12-01

    Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by impaired higher visual processing skills; however, motor features more commonly associated with corticobasal syndrome may also occur. We investigated the frequency and clinical characteristics of motor features in 44 PCA patients and, with 30 controls, conducted voxel-based morphometry, cortical thickness, and subcortical volumetric analyses of their magnetic resonance imaging. Prominent limb rigidity was used to define a PCA-motor subgroup. A total of 30% (13) had PCA-motor; all demonstrating asymmetrical left upper limb rigidity. Limb apraxia was more frequent and asymmetrical in PCA-motor, as was myoclonus. Tremor and alien limb phenomena only occurred in this subgroup. The subgroups did not differ in neuropsychological test performance or apolipoprotein E4 allele frequency. Greater asymmetry of atrophy occurred in PCA-motor, particularly involving right frontoparietal and peri-rolandic cortices, putamen, and thalamus. The 9 patients (including 4 PCA-motor) with pathology or cerebrospinal fluid all showed evidence of Alzheimer's disease. Our data suggest that PCA patients with motor features have greater atrophy of contralateral sensorimotor areas but are still likely to have underlying Alzheimer's disease. PMID:25086839

  17. The pathogenesis and treatment of cardiac atrophy in cancer cachexia.

    PubMed

    Murphy, Kate T

    2016-02-15

    Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass associated with significant functional impairment. In addition to a loss of skeletal muscle mass and function, many patients with cancer cachexia also experience cardiac atrophy, remodeling, and dysfunction, which in the field of cancer cachexia is described as cardiac cachexia. The cardiac alterations may be due to underlying heart disease, the cancer itself, or problems initiated by the cancer treatment and, unfortunately, remains largely underappreciated by clinicians and basic scientists. Despite recent major advances in the treatment of cancer, little progress has been made in the treatment of cardiac cachexia in cancer, and much of this is due to lack of information regarding the mechanisms. This review focuses on the cardiac atrophy associated with cancer cachexia, describing some of the known mechanisms and discussing the current and future therapeutic strategies to treat this condition. Above all else, improved awareness of the condition and an increased focus on identification of mechanisms and therapeutic targets will facilitate the eventual development of an effective treatment for cardiac atrophy in cancer cachexia. PMID:26718971

  18. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. III. Growth conditions of human thymic epithelial cells and immunomodulatory activities in their culture supernatant.

    PubMed Central

    Schreiber, L; Eshel, I; Meilin, A; Sharabi, Y; Shoham, J

    1991-01-01

    We report here on a new approach to the cultivation of human thymic epithelial (HTE) cells, which apparently allows more faithful preservation of cell function. This approach, previously developed by us for mouse thymic epithelial (MTE) cells, is based on the use of culture plates coated with extracellular matrix (ECM), and on the use of serum-free, growth factor-supplemented medium. The nutritional requirements of HTE and MTE are somewhat different. Although both are critically dependent on ECM and insulin, they differ in their dependency on other growth factors: selenium and transferrin are much more important for HTE cells, whereas epidermal growth factor and hydrocortisone play a more essential role in MTE cultures. The epithelial nature of the cultured cells is indicated by positive staining with anti-keratin antibodies and by the presence of desmosomes and tonofilaments. The ultrastructural appearance of the cells further suggests high metabolic and secretory activities, not usually found in corresponding cell lines. The culture supernatant (CS) of HTE cells exhibited a strong enhancing effect on thymocyte response to Con A stimulation, as measured by cell proliferation and lymphokine production. The effect was observed on both human and mouse thymocytes, but was much stronger in the homologous combination. Thymic factors tested in parallel did not have such a differential effect. The dose-effect relationships were in the form of a bell-shaped curve, with fivefold enhancement of response at the peak and a measurable effect even with 1:1000 dilution, when human thymocytes were used. The responding thymocytes were those which do not bind peanut agglutinin and are resistant to hydrocortisone. The culture system described here may have advantages for the in vitro study of thymic stromal cell function. Images Figure 1 Figure 3 Figure 4 PMID:1783421

  19. Osseous oligometastases from thymic carcinoma: a case report suggesting the effectiveness of palliative-intent radiotherapy treatment

    PubMed Central

    Kashima, Jumpei; Horio, Hirotoshi; Okuma, Yusuke; Hosomi, Yukio; Hishima, Tsunekazu

    2016-01-01

    Background Oligometastasis, a recently proposed concept, is defined as an intermediate state of cancer, between localized and systemic disease, that may be well controlled by local ablative treatment. Thymic carcinoma is a rare cancer with a poor prognosis. A definitive management approach has yet to be confirmed by a high level of evidence. Case presentation We present the case of a 41-year-old female who underwent curative-intent surgery for a stage III squamous cell carcinoma of the thymus. Bone metastases were detected 1 year later by magnetic resonance imaging. These were treated with palliative-intent radiotherapy. Disease progression has not been observed in more than 15 years since the achievement of complete radiological remission. Conclusion The treatment outcomes in this and other reported cases suggest that some patients with oligometastatic thymic carcinoma may achieve prolonged survival or even cure with low-dose radiotherapy delivered to the metastases. PMID:27013896

  20. The Autoimmunity-Associated Gene CLEC16A Modulates Thymic Epithelial Cell Autophagy and Alters T Cell Selection.

    PubMed

    Schuster, Cornelia; Gerold, Kay D; Schober, Kilian; Probst, Lilli; Boerner, Kevin; Kim, Mi-Jeong; Ruckdeschel, Anna; Serwold, Thomas; Kissler, Stephan

    2015-05-19

    CLEC16A variation has been associated with multiple immune-mediated diseases, including type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, celiac disease, Crohn's disease, Addison's disease, primary biliary cirrhosis, rheumatoid arthritis, juvenile idiopathic arthritis, and alopecia areata. Despite strong genetic evidence implicating CLEC16A in autoimmunity, this gene's broad association with disease remains unexplained. We generated Clec16a knock-down (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes and found that Clec16a silencing protected against autoimmunity. Disease protection was attributable to T cell hyporeactivity, which was secondary to changes in thymic epithelial cell (TEC) stimuli that drive thymocyte selection. Our data indicate that T cell selection and reactivity were impacted by Clec16a variation in thymic epithelium owing to Clec16a's role in TEC autophagy. These findings provide a functional link between human CLEC16A variation and the immune dysregulation that underlies the risk of autoimmunity. PMID:25979422

  1. The thymic cortical epithelium determines the TCR repertoire of IL-17-producing γδT cells

    PubMed Central

    Nitta, Takeshi; Muro, Ryunosuke; Shimizu, Yukiko; Nitta, Sachiko; Oda, Hiroyo; Ohte, Yuki; Goto, Motohito; Yanobu-Takanashi, Rieko; Narita, Tomoya; Takayanagi, Hiroshi; Yasuda, Hisataka; Okamura, Tadashi; Murata, Shigeo; Suzuki, Harumi

    2015-01-01

    The thymus provides a specialized microenvironment in which distinct subsets of thymic epithelial cells (TECs) support T-cell development. Here, we describe the significance of cortical TECs (cTECs) in T-cell development, using a newly established mouse model of cTEC deficiency. The deficiency of mature cTECs caused a massive loss of thymic cellularity and impaired the development of αβT cells and invariant natural killer T cells. Unexpectedly, the differentiation of certain γδT-cell subpopulations—interleukin-17-producing Vγ4 and Vγ6 cells—was strongly dysregulated, resulting in the perturbation of γδT-mediated inflammatory responses in peripheral tissues. These findings show that cTECs contribute to the shaping of the TCR repertoire, not only of “conventional” αβT cells but also of inflammatory “innate” γδT cells. PMID:25770130

  2. Treatment Modalities and Outcomes in Patients with Advanced Invasive Thymoma or Thymic Carcinoma: A Retrospective Multicenter Study

    PubMed Central

    Modh, Ankit; Rimner, Andreas; Allen, Pamela K.; Greenfield, Brad; Marom, Edith M.; Rice, David; Huang, James; Rosenzweig, Kenneth E.; Komaki, Ritsuko; Gomez, Daniel R.

    2016-01-01

    Introduction We investigated relationships between treatment characteristics and long-term outcomes in patients with locally advanced thymoma or thymic carcinoma. Methods We retrospectively reviewed 146 patients treated in 1980–2011 at two tertiary cancer care centers, 110 with Masaoka-Koga stage III–IVa invasive thymoma and 36 with stage I–IVa thymic carcinoma. Survival probabilities were estimated with the Kaplan-Meier method. Risk factors related to survival were identified by univariate and multivariate competing risk analysis, with overall survival (OS) as the competing risk. Cox regression analysis was used to identify risk factors for OS. Results Median follow-up time for all patients was 64 months. At 5/10 years, rates of OS and freedom from recurrence (FFR) were 81/58% and 81/65%, respectively. Of patients who underwent surgery, trimodality treatment produced better survival compared to less aggressive treatment among patients with stage III disease (p=0.03). Among patients who underwent trimodality treatment, patients with stage III disease had better OS (p=0.03) and FFR (p<0.001) than those with stage IVA disease. On Cox regression analysis, decreased OS was associated with thymic carcinoma (hazard ratio [HR]=7.36, 95% CI=2.38–22.77, p=0.001), R2/unresectable disease (HR=8.45, 95% CI=1.44–49.42, p=0.02) and an Eastern Cooperative Oncology Group performance score of 1 (HR=8.14, 95% CI=1.55–42.75, p=0.01) or 2–3 (HR=29.60, 95% CI=4.0–218.98, p=0.001) versus 0. Conclusion Aggressive treatment with chemotherapy, surgical resection, and postoperative radiation therapy can produce long-term survival for patients with invasive thymic malignanices. PMID:24390276

  3. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.

    PubMed

    Glass, David J

    2010-01-01

    Activation of the PI3 kinase pathway can induce skeletal muscle hypertrophy, defined as an increase in skeletal muscle mass. In mammals, skeletal muscle hypertrophy occurs as a result of an increase in the size, as opposed to the number, of pre-existing skeletal muscle fibers. This pathway's effects on skeletal muscle have been implicated most prominently downstream of Insulin-like growth factor 1 signaling. IGF-1's pro-hypertrophy activity comes predominantly through its ability to activate the Phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Akt is a serine-threonine protein kinase that can induce protein synthesis and block the transcriptional upregulation of key mediators of skeletal muscle atrophy, the E3 ubiquitin ligases MuRF1 and MAFbx (also called Atrogin-1), by phosphorylating and thereby inhibiting the nuclear translocation of the FOXO (also called "forkhead") family of transcription factors. Once phosphorylated by Akt, the FOXOs are excluded from the nucleus, and upregulation of MuRF1 and MAFbx is blocked. MuRF1 and MAFbx mediate atrophy by ubiquitinating particular protein substrates, causing them to undergo degradation by the proteasome. MuRF1's substrates include several components of the sarcomeric thick filament, including Myosin Heavy Chain (MyHC). Thus, by blocking MuRF1 activation, IGF-1 helps prevent the breakdown of the thick filament under atrophy conditions.IGF1/PI3K/Akt signaling also can dominantly inhibit the effects of a secreted protein called "myostatin," which is a member of the TGFβ family of proteins. Deletion or inhibition of myostatin causes an increase in skeletal muscle size, because myostatin acts both to inhibit myoblast differentiation and to block the Akt pathway. Thus by blocking myostatin, PI3K/Akt activation stimulates differentiation and protein synthesis by this distinct mechanism. Myostatin induces the phosphorylation and activation of the transcription factors of Smad2 and Smad3, downstream of the Act

  4. Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats

    NASA Technical Reports Server (NTRS)

    Dodd, D. E.; Stuart, B. O.; Rothenberg, S. J.; Kershaw, M.; Mann, P. C.; James, J. T.; Lam, C. W.

    1994-01-01

    . Microscopic lesions included degeneration of the seminiferous tubular cells, pyknosis or absence of germ cells, and hypospermia in the epididymis. Rats of the 600 ppm group had a slight decrease in thymic weight and a transient decrease in body weight. Results of the acute, 2-wk, and 13-wk inhalation studies indicate DMES concentrations of 1000 ppm and higher produce narcosis that rapidly disappears following exposure. Repeated exposure of rats to DMES at either 3000 ppm for 2 wk or 2000 ppm for 13 wk caused testicular atrophy and hypospermia in male rats. Female rats exposed to 2000 ppm for 13 wk had delayed estrous cycles. Toxicological effects in rats of the 600 ppm group were minimal and equivocal. The 160 ppm concentration was a no-observable-effect level (NOEL) for 13 wk of exposure to DMES.

  5. Development of combined thymic carcinoma and thymoma in an extrathymic lesion during long follow-up for recurrent thymoma

    PubMed Central

    OHUE, YASUHIRO; MATSUOKA, SHUNICHIRO; KUMEDA, HIROTAKA; AGATSUMA, HIROYUKI; HYOUGOTANI, AKIRA; TOISHI, MASAYUKI; SHIINA, TAKAYUKI; YOSHIDA, KAZUO; SHINGU, KUNIHIKO; FUKUSHIMA, TOSHIROU; KOIZUMI, TOMONOBU

    2016-01-01

    The present study reported a rare case of combined thymic squamous cell carcinoma and thymoma exhibiting a mass on the left chest wall. The patient underwent thoracotomy for invasive thymoma 15 years previously, however, suffered a relapse in the left intrathoracic space. Radiotherapy, chemotherapy and partial resection, as secondary surgery for the intrathoracic mass, were performed. The histological findings in the resected specimens revealed type B3 thymoma. As the patient developed a left chest wall mass and pain in 2013, the mass was resected. The histological findings indicated two separate components composed of type B3 thymoma and squamous cell carcinoma. Immunohistological findings revealed that the thymoma cells were positive for CD5, while the thymic carcinoma cells were negative for CD5. Several reports have demonstrated the coexistence of thymic carcinoma and thymoma in the primary thymus, however, the development of a combined tumor in an extrathymic lesion is extremely rare. The present case had a long follow-up for recurrent thymoma. The present case indicated that the development and/or coexistence of malignant components in the thymoma must be taken into consideration for the treatment and/or management of patients with thymoma and that a pre-existence of CD5 expression in thymoma and the lost change may be associated with the process of malignant transformation. PMID:26893849

  6. Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras

    PubMed Central

    Win, Chan M.; Parrott, Roberta E.; Cooney, Myriah; Moser, Barry K.; Roberts, Joseph L.; Sempowski, Gregory D.; Buckley, Rebecca H.

    2009-01-01

    Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen–identical or rigorously T cell–depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term. PMID:19433858

  7. Activity of neutral endopeptidase and aminopeptidase N in mouse thymic stromal cells which bind double-positive thymocytes.

    PubMed

    Small, M; Kaiser, M; Tse, W; Heimfeld, S; Blumberg, S

    1996-04-01

    The activity of two peptidases was determined in immortalized lines of thymic stromal cells. A line of total stromal cells (T-TG-St) was grown from transgenic mouse expressing temperature-sensitive SV40 T antigen under the control of the regulatory elements of the mouse major histocompatibility complex class I gene. From these cells we isolated a subset (DP-TG-St) that binds thymocytes which are mainly CD4+8+. We also assayed a clone of fetal thymic epithelial cells (BA/10) that binds CD4+8+ thymocytes. Both lines of double -positive cell-binding stroma exhibited strong activity of two peptidases, neutral endopeptidase (NEP; EC 3.4.24.11) and aminopeptidase N (APN; EC 3.4.11.2). In contrast, the activity of both enzymes was very low in the total thymic stromal line. Use of the specific inhibitors confirmed that these two enzymes were responsible for the activity observed but also suggested the presence of additional unidentified aminopeptidase(s) in the same stromal cells. The high activity of the two peptidases on stromal cells that bind thymocytes at the double-positive stage raises the possibility that they might contribute to the microenvironment of the developing thymocytes. PMID:8625997

  8. MicroRNA-375 regulation of thymic stromal lymphopoietin by diesel exhaust particles and ambient particulate matter in human bronchial epithelial cells§

    PubMed Central

    Bleck, Bertram; Grunig, Gabriele; Chiu, Amanda; Liu, Mengling; Gordon, Terry; Kazeros, Angeliki; Reibman, Joan

    2013-01-01

    Air pollution contributes to acute exacerbations of asthma and the development of asthma in children and adults. Airway epithelial cells interface innate and adaptive immune responses and have been proposed to regulate much of the response to pollutants. Thymic stromal lymphopoietin (TSLP) is a pivotal cytokine linking innate and Th2 adaptive immune disorders and is upregulated by environmental pollutants, including ambient particulate matter (PM) and diesel exhaust particles (DEP). We now show that DEP and ambient fine PM upregulate TSLP mRNA and hsa-miR-375 in primary human bronchial epithelial cells (pHBEC). Moreover, transfection of pHBEC with anti-hsa-miR-375 reduced TSLP mRNA in DEP but not TNF-α treated cells. In silico pathway evaluation suggested the aryl hydrocarbon receptor (AhR) as one possible target of miR-375. DEP and ambient fine PM (3 μg/cm2), down regulated AhR mRNA. Transfection of mimic-hsa-miR-375 resulted in a small downregulation of AhR mRNA compared to resting AhR mRNA. AhR mRNA was increased in pHBEC treated with DEP after transfection with anti-hsa-miR-375. Our data show that two pollutants, DEP and ambient PM, upregulate TSLP in human bronchial epithelial cells by a mechanism that includes hsa-miR-375 with complex regulatory effects on AhR mRNA. The absence of this pathway in TNF-α-treated cells suggests multiple regulatory pathways for TSLP expression in these cells. PMID:23455502

  9. Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy.

    PubMed

    Dyle, Michael C; Ebert, Scott M; Cook, Daniel P; Kunkel, Steven D; Fox, Daniel K; Bongers, Kale S; Bullard, Steven A; Dierdorff, Jason M; Adams, Christopher M

    2014-05-23

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy. PMID:24719321

  10. Cerebral blood flow and brain atrophy correlated by xenon contrast CT scanning

    SciTech Connect

    Kitagawa, Y.; Meyer, J.S.; Tanahashi, N.; Rogers, R.L.; Tachibana, H.; Kandula, P.; Dowell, R.E.; Mortel, K.F.

    1985-11-01

    Correlations between cerebral blood flow (CBF) measured during stable xenon contrast CT scanning and standard CT indices of brain atrophy were investigated in the patients with senile dementia of Alzheimer type, multi-infarct dementia and idiopathic Parkinson's disease. Compared to age-matched normal volunteers, significant correlations were found in patients with idiopathic Parkinson's disease between cortical and subcortical gray matter blood flow and brain atrophy estimated by the ventricular body ratio, and mild to moderate brain atrophy were correlated with stepwise CBF reductions. However, in patients with senile dementia of Alzheimer type and multi-infarct dementia, brain atrophy was not associated with stepwise CBF reductions. Overall correlations between brain atrophy and reduced CBF were weak. Mild degrees of brain atrophy are not always associated with reduced CBF.

  11. RNA interference-mediated knockdown of CD49e (α5 integrin chain) in human thymic epithelial cells modulates the expression of multiple genes and decreases thymocyte adhesion

    PubMed Central

    2010-01-01

    Background The thymus is a central lymphoid organ, in which bone marrow-derived T cell precursors undergo a complex process of maturation. Developing thymocytes interact with thymic microenvironment in a defined spatial order. A component of thymic microenvironment, the thymic epithelial cells, is crucial for the maturation of T-lymphocytes through cell-cell contact, cell matrix interactions and secretory of cytokines/chemokines. There is evidence that extracellular matrix molecules play a fundamental role in guiding differentiating thymocytes in both cortical and medullary regions of the thymic lobules. The interaction between the integrin α5β1 (CD49e/CD29; VLA-5) and fibronectin is relevant for thymocyte adhesion and migration within the thymic tissue. Our previous results have shown that adhesion of thymocytes to cultured TEC line is enhanced in the presence of fibronectin, and can be blocked with anti-VLA-5 antibody. Results Herein, we studied the role of CD49e expressed by the human thymic epithelium. For this purpose we knocked down the CD49e by means of RNA interference. This procedure resulted in the modulation of more than 100 genes, some of them coding for other proteins also involved in adhesion of thymocytes; others related to signaling pathways triggered after integrin activation, or even involved in the control of F-actin stress fiber formation. Functionally, we demonstrated that disruption of VLA-5 in human TEC by CD49e-siRNA-induced gene knockdown decreased the ability of TEC to promote thymocyte adhesion. Such a decrease comprised all CD4/CD8-defined thymocyte subsets. Conclusion Conceptually, our findings unravel the complexity of gene regulation, as regards key genes involved in the heterocellular cell adhesion between developing thymocytes and the major component of the thymic microenvironment, an interaction that is a mandatory event for proper intrathymic T cell differentiation. PMID:21210968

  12. Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors

    PubMed Central

    Padda, Sukhmani K.; Riess, Jonathan W.; Schwartz, Erich J.; Lu, Tian; Kohrt, Holbrook E.; Neal, Joel W.; West, Robert B.; Wakelee, Heather A.

    2016-01-01

    Introduction Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA). Methods The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15, Sino Biological) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0=none, 1=equivocal/uninterpretable, 2=weak, and 3=intermediate-strong. Those cases with all cores scoring 3 in the epithelial component were categorized as PD-L1high and the remaining as PD-L1low. Results PD-L1high scores were more frequent in TETs than controls (68.1% vs. 17.6%, p=0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in WHO B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/gender), PD-L1high TETs had a significantly worse overall survival (HR 5.40, 95% CI 1.13-25.89, p=0.035) and a trend for worse event-free survival (HR 2.94, 95% CI 0.94-9.24, p=0.064). Conclusions PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than controls, and PD-L1high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD1/PD-L1 therapy in this rare tumor type. PMID:25402569

  13. Extracoporeal photopheresis treatment of acute graft-versus-host disease following allogeneic haematopoietic stem cell transplantation

    PubMed Central

    Flinn, Aisling M.; Gennery, Andrew R.

    2016-01-01

    Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery. PMID:27408705

  14. Multiple system atrophy: alpha-synuclein and neuronal degeneration.

    PubMed

    Yoshida, Mari

    2007-10-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmark is the formation of alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) in oligodendroglia. alpha-synuclein aggregation is also found in glial nuclear inclusions, neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. We evaluated the pathological features of 102 MSA cases, and presented the pathological spectrum of MSA and initial features of alpha-synuclein accumulation. We found that 39% of the 102 cases showed equivalent SND and OPCA pathologies, 33% showed OPCA- and 22% showed SND-predominant pathology, whereas 6% showed extremely mild changes. Our pathological analysis indicated that OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases, compared to the relatively high frequency of SND-type in Western countries, suggesting that different phenotypic patterns of MSA may exist between races. In the early stage, in addition to GCIs, NNIs and diffuse homogenous alpha-synuclein staining in neuronal nuclei and cytoplasm were observed in lesions in the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of thoracic spinal cord, lower motor neurons and cortical pyramidal neurons. A subgroup of MSA cases with severe temporal atrophy showed numerous NCIs, particularly in the limbic system. These findings suggest that primary non-fibrillar and fibrillar alpha-synuclein aggregation also occur in neurons. The oligo-myelin-axon-neuron complex mechanism, along with the direct involvement of neurons themselves, may synergistically accelerate the degenerative process of MSA. PMID:18018485

  15. Dominant spinal muscular atrophy with lower extremity predominance

    PubMed Central

    Harms, M.B.; Allred, P.; Gardner, R.; Fernandes Filho, J.A.; Florence, J.; Pestronk, A.; Al-Lozi, M.; Baloh, R.H.

    2010-01-01

    Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA. Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed. Results: Ten affected individuals (ages 7–58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 (θ = 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,765–106,368,585. No segregating copy number variations were found within the disease interval. Conclusions: We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy–lower extremity, dominant. GLOSSARY lod = logarithm of the odds; SMA = spinal muscular atrophy; SMA-LED = spinal muscular atrophy–lower extremity, dominant; SNP = single-nucleotide polymorphism. PMID:20697106

  16. Abdominal Obesity and Brain Atrophy in Type 2 Diabetes Mellitus

    PubMed Central

    Callisaya, Michele; Blizzard, Leigh; Sharman, James E.; Venn, Alison; Phan, Thanh G.; Beare, Richard; Forbes, Josephine; Blackburn, Nicholas B.; Srikanth, Velandai

    2015-01-01

    Aim Type 2 diabetes mellitus (T2D) is associated with gray matter atrophy. Adiposity and physical inactivity are risk factors for T2D and brain atrophy. We studied whether the associations of T2D with total gray matter volume (GMV) and hippocampal volume (HV) are dependent on obesity and physical activity. Materials and Methods In this cross-sectional study, we measured waist-hip ratio (WHR), body mass index (BMI), mean steps/day and brain volumes in a community dwelling cohort of people with and without T2D. Using multivariable linear regression, we examined whether WHR, BMI and physical activity mediated or modified the association between T2D, GMV and HV. Results There were 258 participants with (mean age 67±7 years) and 302 without (mean age 72±7 years) T2D. Adjusting for age, sex and intracranial volume, T2D was independently associated with lower total GMV (p = 0.001) and HV (p<0.001), greater WHR (p<0.001) and BMI (p<0.001), and lower mean steps/day (p = 0.002). After adjusting for covariates, the inclusion of BMI and mean steps/day did not significantly affect the T2D-GMV association, but WHR attenuated it by 32% while remaining independently associated with lower GMV (p<0.01). The T2D-HV association was minimally changed by the addition of BMI, steps/day or WHR in the model. No statistical interactions were observed between T2D and measures of obesity and physical activity in explaining brain volumes. Conclusions Abdominal obesity or its downstream effects may partially mediate the adverse effect of T2D on brain atrophy. This requires confirmation in longitudinal studies. PMID:26560876

  17. Fibrosis, adipogenesis, and muscle atrophy in congenital muscular torticollis.

    PubMed

    Chen, Huan-Xiong; Tang, Sheng-Ping; Gao, Fu-Tang; Xu, Jiang-Long; Jiang, Xian-Ping; Cao, Juan; Fu, Gui-Bing; Sun, Ke; Liu, Shi-Zhe; Shi, Wei

    2014-11-01

    In the traditional view, muscle atrophy and interstitial fibrosis were regarded as the basic pathological features of congenital muscular torticollis (CMT). But in the ultrastructure study, the mesenchyme-like cells, myoblasts, myofibroblasts, and fibroblasts were found in the proliferation of interstitium of CMT. To investigate the characteristics of pathological features and the mechanisms of muscle atrophy in CMT, we retrospectively reviewed the medical records of 185 CMT patients from July 2009 to July 2011 in Shenzhen Children's Hospital in China and performed pathological studies. According to age, the 185 CMT patients were divided into 4 groups. All resected surgical specimens were processed for hematoxylin and eosin staining and Masson trichromic staining. Sudan III staining was used for frozen sections, whereas immunohistochemical staining for S-100, calpain-1, ubiquitin, and 20S proteasome was carried out on 40 CMT specimens. Eight adductor muscle specimens from 8 patients with development dysplasia of the hip were taken as control group in the immunohistochemical staining. By Masson trichromic staining, the differences in the percent area of fibrous tissue in each CMT groups were significant. In Sudan III staining and immunostaining for S-100, adipocyte hyperplasia was the pathological feature of CMT. Moreover, compared with controls, most atrophic muscle fibers in CMT specimens were found to show strong immunoreactivity for calpain-1, ubiquitin, and 20S proteasome. With increasing age, fibrosis peaked at both sides and it was low in middle age group. Adipocytes increased with age. The characteristics of pathological features in CMT are changeable with age. The calpain and the ubiquitin-proteasome system may play a role in muscle atrophy of CMT. In the CMT, adipogenesis, fibrogenesis, and myogenesis may be the results of mesenchyme-like cells in SCM (sternocleidomastoid muscle). In conclusion, the present study furthermore supports maldevelopment of the

  18. Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy.

    PubMed

    Tando, Toshimi; Hirayama, Akiyoshi; Furukawa, Mitsuru; Sato, Yuiko; Kobayashi, Tami; Funayama, Atsushi; Kanaji, Arihiko; Hao, Wu; Watanabe, Ryuichi; Morita, Mayu; Oike, Takatsugu; Miyamoto, Kana; Soga, Tomoyoshi; Nomura, Masatoshi; Yoshimura, Akihiko; Tomita, Masaru; Matsumoto, Morio; Nakamura, Masaya; Toyama, Yoshiaki; Miyamoto, Takeshi

    2016-06-01

    Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes. PMID:27129272

  19. Mitochondrial Dysfunction Launches Dexamethasone-Induced Skeletal Muscle Atrophy via AMPK/FOXO3 Signaling.

    PubMed

    Liu, Jing; Peng, Yunhua; Wang, Xun; Fan, Yingying; Qin, Chuan; Shi, Le; Tang, Ying; Cao, Ke; Li, Hua; Long, Jiangang; Liu, Jiankang

    2016-01-01

    Muscle atrophy occurs in several pathologic conditions such as diabetes and chronic obstructive pulmonary disease (COPD), as well as after long-term clinical administration of synthesized glucocorticoid, where increased circulating glucocorticoid accounts for the pathogenesis of muscle atrophy. Others and we previously reported mitochondrial dysfunction in muscle atrophy-related conditions and that mitochondria-targeting nutrients efficiently prevent kinds of muscle atrophy. However, whether and how mitochondrial dysfunction involves glucocorticoid-induced muscle atrophy remains unclear. Therefore, in the present study, we measured mitochondrial function in dexamethasone-induced muscle atrophy in vivo and in vitro, and we found that mitochondrial respiration was compromised on the 3rd day following after dexamethasone administration, earlier than the increases of MuRF1 and Fbx32, and dexamethasone-induced loss of mitochondrial components and key mitochondrial dynamics proteins. Furthermore, dexamethasone treatment caused intracellular ATP deprivation and robust AMPK activation, which further activated the FOXO3/Atrogenes pathway. By directly impairing mitochondrial respiration, FCCP leads to similar readouts in C2C12 myotubes as dexamethasone does. On the contrary, resveratrol, a mitochondrial nutrient, efficiently reversed dexamethasone-induced mitochondrial dysfunction and muscle atrophy in both C2C12 myotubes and mice, by improving mitochondrial function and blocking AMPK/FOXO3 signaling. These results indicate that mitochondrial dysfunction acts as a central role in dexamethasone-induced skeletal muscle atrophy and that nutrients or drugs targeting mitochondria might be beneficial in preventing or curing muscle atrophy. PMID:26592738

  20. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy.

    PubMed

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  1. Effect of Oenothera odorata Root Extract on Microgravity and Disuse-Induced Muscle Atrophy

    PubMed Central

    Lee, Yong-Hyeon; Seo, Dong-Hyun; Park, Ji-Hyung; Kabayama, Kazuya; Opitz, Joerg; Lee, Kwang Ho; Kim, Han-Sung; Kim, Tack-Joong

    2015-01-01

    Muscle atrophy, a reduction of muscle mass, strength, and volume, results from reduced muscle use and plays a key role in various muscular diseases. In the microgravity environment of space especially, muscle atrophy is induced by muscle inactivity. Exposure to microgravity induces muscle atrophy through several biological effects, including associations with reactive oxygen species (ROS). This study used 3D-clinostat to investigate muscle atrophy caused by oxidative stress in vitro, and sciatic denervation was used to investigate muscle atrophy in vivo. We assessed the effect of Oenothera odorata root extract (EVP) on muscle atrophy. EVP helped recover cell viability in C2C12 myoblasts exposed to microgravity for 24 h and delayed muscle atrophy in sciatic denervated mice. However, the expressions of HSP70, SOD1, and ceramide in microgravity-exposed C2C12 myoblasts and in sciatic denervated mice were either decreased or completely inhibited. These results suggested that EVP can be expected to have a positive effect on muscle atrophy by disuse and microgravity. In addition, EVP helped characterize the antioxidant function in muscle atrophy. PMID:25945103

  2. A randomized clinical trial of lithium in multiple system atrophy.

    PubMed

    Saccà, Francesco; Marsili, Angela; Quarantelli, Mario; Brescia Morra, Vincenzo; Brunetti, Arturo; Carbone, Rosa; Pane, Chiara; Puorro, Giorgia; Russo, Cinzia Valeria; Salvatore, Elena; Tucci, Tecla; De Michele, Giuseppe; Filla, Alessandro

    2013-02-01

    The aim of our study was to test the safety and tolerability of lithium in multiple system atrophy (MSA). The study was randomized, placebo-controlled, and double-blind. The primary endpoint of the study was safety and tolerability. An interim analysis, performed 1 year after the first patient was randomized, showed a higher proportion of trial abandon (P < 0.01) and a higher number of adverse events (P < 0.02) in the lithium group. The trial was stopped by the Data Monitoring Committee. Overall, lithium was not well tolerated, and we do not encourage future studies with lithium in MSA patients. PMID:22932748

  3. Cerebellar atrophy in a patient with velocardiofacial syndrome.

    PubMed Central

    Lynch, D R; McDonald-McGinn, D M; Zackai, E H; Emanuel, B S; Driscoll, D A; Whitaker, L A; Fischbeck, K H

    1995-01-01

    Velocardiofacial syndrome and DiGeorge syndrome have not previously been associated with central nervous system degeneration. We report a 34 year old man who presented for neurological evaluation with cerebellar atrophy of unknown aetiology. On historical review, he had neonatal hypocalcaemia, an atrial septal defect, and a corrected cleft palate. His physical examination showed the characteristic facies of velocardiofacial syndrome as well as dysmetria and dysdiadocho-kinesia consistent with cerebellar degeneration. Molecular cytogenetic studies showed a deletion of 22q11.2. This man is the first reported patient with the association of a neurodegenerative disorder and 22q11.2 deletion syndrome. Images PMID:7562973

  4. Muscle spasms associated with Sudeck's atrophy after injury.

    PubMed Central

    Marsden, C D; Obeso, J A; Traub, M M; Rothwell, J C; Kranz, H; La Cruz, F

    1984-01-01

    Four patients developed abnormal involuntary movements of a limb after injury. All subsequently developed sympathetic algodystrophy with Sudeck's atrophy and then abnormal muscle spasms or jerks of the affected limb, lasting years. Sympathetic block in three patients did not relieve the abnormal movements. Two patients obtained partial recovery spontaneously, but the other two required surgery for relief. The pathophysiology of this condition remains to be determined but the evidence suggests that it is a distinct, disabling clinical syndrome. Images FIG 1 FIG 3 PMID:6198018

  5. Spinal cord atrophy in neuromyelitis optica spectrum disorders.

    PubMed

    Wang, Yanqiang; Wang, Yuge; Tan, Sa; Lu, Zhengqi

    2016-07-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is an immune mediated inflammatory disease of the central nervous system (CNS) and often displays a monophasic or relapsing-remitting course. Spinal cord lesions is one of the predominant characteristics in NMOSD. Assessment of spinal cord atrophy (SCA) is of growing interest in monitoring disease progression in multiple sclerosis (MS), and correlates closely with the neurological disability. However, the studies of the SCA in NMOSD are still scarce. In this review, we describe the recent progress about the SCA in NMOSD, mainly the NMOSD with spinal cord lesions. PMID:27456868

  6. Evaluation of the endogenous glucocorticoid hypothesis of denervation atrophy

    NASA Technical Reports Server (NTRS)

    Konagaya, Masaaki; Konagaya, Yoko; Max, Stephen R.

    1988-01-01

    The effects are studied of the oral administration of RU38486, a potent selective glucocorticoid antagonist, on muscle weight, non-collagen protein content, and selected enzyme activities (choline acetyltransferase, glucose 6-phosphate dehydrogenase, and glutamine synthetase) following denervation of rat skeletal muscle. Neither decreases in muscle weight, protein content, and choline acetyltransferase activity, nor increases in the activities of glucose 6-phosphate dehydrogernase and glutamine synthetase were affected by RU38486. These data do not support the hypothesis that denervation atrophy results from enhanced sensitivity of muscle to endogenous glucocorticoids.

  7. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy

    PubMed Central

    Mohseni, Jafar; Zabidi-Hussin, Z.A.M.H.; Sasongko, Teguh Haryo

    2013-01-01

    Histone acetylation plays an important role in regulation of transcription in eukaryotic cells by promoting a more relaxed chromatin structure necessary for transcriptional activation. Histone deacetylases (HDACs) remove acetyl groups and suppress gene expression. HDAC inhibitors (HDACIs) are a group of small molecules that promote gene transcription by chromatin remodeling and have been extensively studied as potential drugs for treating of spinal muscular atrophy. Various drugs in this class have been studied with regard to their efficacy in increasing the expression of survival of motor neuron (SMN) protein. In this review, we discuss the current literature on this topic and summarize the findings of the main studies in this field. PMID:24130434

  8. Protective variant for hippocampal atrophy identified by whole exome sequencing.

    PubMed

    Nho, Kwangsik; Kim, Sungeun; Risacher, Shannon L; Shen, Li; Corneveaux, Jason J; Swaminathan, Shanker; Lin, Hai; Ramanan, Vijay K; Liu, Yunlong; Foroud, Tatiana M; Inlow, Mark H; Siniard, Ashley L; Reiman, Rebecca A; Aisen, Paul S; Petersen, Ronald C; Green, Robert C; Jack, Clifford R; Weiner, Michael W; Baldwin, Clinton T; Lunetta, Kathryn L; Farrer, Lindsay A; Furney, Simon J; Lovestone, Simon; Simmons, Andrew; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; McDonald, Brenna C; Farlow, Martin R; Ghetti, Bernardino; Huentelman, Matthew J; Saykin, Andrew J

    2015-03-01

    We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. PMID:25559091

  9. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy

    PubMed Central

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term “minipolyfasciculations” may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  10. Fasciculations masquerading as minipolymyoclonus in bulbospinal muscular atrophy.

    PubMed

    Bhat, Sushanth; Ma, Wei; Kozochonok, Elena; Chokroverty, Sudhansu

    2015-01-01

    Minipolymyoclonus has been described in both anterior horn cell disorders and central nervous system degenerative conditions. While its etiology remains unclear and speculative, a central generator has been previously proposed. We describe a case of bulbospinal muscular atrophy (Kennedy's disease), where minipolymyoclonus-like movements corresponded to fasciculations in neurophysiological studies. Our novel finding suggests that the etiologies of minipolymyoclonus in central and peripheral nervous system disorders are distinct, despite outward clinical similarity. The term "minipolyfasciculations" may be more reflective of the underlying process causing minipolymyoclonus-like movements in lower motor neuron disorders. PMID:26019432

  11. IPSCs, a Promising Tool to Restore Muscle Atrophy.

    PubMed

    Pareja-Galeano, Helios; Sanchis-Gomar, Fabian; Emanuele, Enzo; Gallardo, María Esther; Lucia, Alejandro

    2016-02-01

    Induced pluripotent stem cells (iPSCs) are a promising tool for regenerative medicine in chronic conditions associated with muscle atrophy since iPSCs are easier to obtain, pose less ethical limitations and can better capture human genetic diversity compared with human embryonic stem cells. We highlight the potentiality of iPSCs for treating muscle-affecting conditions for which no effective cure is yet available, notably aging sarcopenia and inherited neurometabolic conditions. J. Cell. Physiol. 231: 259-260, 2016. © 2015 Wiley Periodicals, Inc. PMID:26224204

  12. Clinical and Genetic Study of Algerian Patients with Spinal Muscular Atrophy.

    PubMed

    Sifi, Y; Sifi, K; Boulefkhad, A; Abadi, N; Bouderda, Z; Cheriet, R; Magen, M; Bonnefont, J P; Munnich, A; Benlatreche, C; Hamri, A

    2013-01-01

    Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder. It is divided into the acute Werdnig-Hoffmann disease (type I), the intermediate form (type II), the Kugelberg-Welander disease (type III), and the adult form (type IV). The gene involved in all four forms of SMA, the so-called survival motor neuron (SMN) gene, is duplicated, with a telomeric (tel SMN or SMN1) and a centromeric copy (cent SMN or SMN2). SMN1 is homozygously deleted in over 95% of SMA patients. Another candidate gene in SMA is the neuronal apoptosis inhibitory protein (NAIP) gene; it shows homozygous deletions in 45-67% of type I and 20-42% of type II/type III patients. Here we studied the SMN and NAIP genes in 92 Algerian SMA patients (20 type I, 16 type II, 53 type III, and 3 type IV) from 57 unrelated families, using a semiquantitative PCR approach. Homozygous deletions of SMN1 exons 7 and/or 8 were found in 75% of the families. Deletions of exon 4 and/or 5 of the NAIP gene were found in around 25%. Conversely, the quantitative analysis of SMN2 copies showed a significant correlation between SMN2 copy number and the type of SMA. PMID:26317002

  13. HDAC4-Myogenin Axis As an Important Marker of HD-Related Skeletal Muscle Atrophy

    PubMed Central

    Smeets, Cleo J. L. M.; Franklin, Sophie A.; Bondulich, Marie K.; Jolinon, Nelly; Muller, Thomas; Ahmed, Mhoriam; Dick, James R. T.; Piotrowska, Izabela; Greensmith, Linda; Smolenski, Ryszard T.; Bates, Gillian P.

    2015-01-01

    Skeletal muscle remodelling and contractile dysfunction occur through both acute and chronic disease processes. These include the accumulation of insoluble aggregates of misfolded amyloid proteins that is a pathological feature of Huntington’s disease (HD). While HD has been described primarily as a neurological disease, HD patients’ exhibit pronounced skeletal muscle atrophy. Given that huntingtin is a ubiquitously expressed protein, skeletal muscle fibres may be at risk of a cell autonomous HD-related dysfunction. However the mechanism leading to skeletal muscle abnormalities in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that symptomatic animals developed a progressive impairment of the contractile characteristics of the hind limb muscles tibialis anterior (TA) and extensor digitorum longus (EDL), accompanied by a significant loss of motor units in the EDL. In symptomatic animals, these pronounced functional changes were accompanied by an aberrant deregulation of contractile protein transcripts and their up-stream transcriptional regulators. In addition, HD mouse models develop a significant reduction in muscle force, possibly as a result of a deterioration in energy metabolism and decreased oxidation that is accompanied by the re-expression of the HDAC4-DACH2-myogenin axis. These results show that muscle dysfunction is a key pathological feature of HD. PMID:25748626

  14. [An autopsy case of progressive generalized muscle atrophy over 14 years due to post-polio syndrome].

    PubMed

    Oki, Ryosuke; Uchino, Akiko; Izumi, Yuishin; Ogawa, Hirohisa; Murayama, Shigeo; Kaji, Ryuji

    2016-01-01

    We report the case of a 72-year-old man who had contracted acute paralytic poliomyelitis in his childhood. Thereafter, he had suffered from paresis involving the left lower limb, with no relapse or progression of the disease. He began noticing slowly progressive muscle weakness and atrophy in the upper and lower extremities in his 60s. At the age of 72, muscle weakness developed rapidly, and he demonstrated dyspnea on exertion and dysphagia. He died after about 14 years from the onset of muscle weakness symptoms. Autopsy findings demonstrated motoneuron loss and glial scars not only in the plaque-like lesions in the anterior horns, which were sequelae of old poliomyelitis, but also throughout the spine. No Bunina bodies, TDP-43, and ubiquitin inclusions were found. Post-polio syndrome is rarely fatal due to rapid progressive dyspnea and dysphagia. Thus, the pathological findings in the patient are considered to be related to the development of muscle weakness. PMID:26616485

  15. [Obese woman presenting as vocal cord abductor paralysis and floppy arytenoid associated with early signs of multiple system atrophy].

    PubMed

    Sakuta, Hideki; Miyamoto, Masayuki; Suzuki, Keisuke; Miyamoto, Tomoyuki; Nakajima, Itsuo; Nakamura, Toshiki; Hirata, Koichi

    2012-01-01

    In multiple system atrophy (MSA), sleep-related breathing disorders are commonly observed, including vocal cord abductor paralysis (VCAP), which can cause sudden death. In its early stage, VCAP occurs only during sleep, but as the disease progresses, it appears when both awake and asleep. We encountered a 59-year-old obese woman who had been under continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea syndrome (OSAS) for approximately one year but later developed acute respiratory failure because of VCAP. VCAP was the predominant finding that led to the diagnosis of MSA in our patient. On laryngoscopic examination, the movement of the patient's larynx was normal during wakefulness, but VCAP, paradoxical movements of the vocal cord and a floppy arytenoid were observed during drug-induced sleep. We suggest that detection of VCAP and laryngopharyngeal abnormalities such as floppy arytenoid in the early stage of MSA is important for determining treatment options. PMID:22790804

  16. Sunitinib in metastatic thymic carcinomas: Laboratory findings and initial clinical experience

    PubMed Central

    Ströbel, P; Bargou, R; Wolff, A; Spitzer, D; Manegold, C; Dimitrakopoulou-Strauss, A; Strauss, L; Sauer, C; Mayer, F; Hohenberger, P; Marx, A

    2010-01-01

    Background: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. Methods: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. Results: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-β and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18+ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40+ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. Conclusions: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection. PMID:20571495

  17. TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets.

    PubMed

    Muñoz-Ruiz, Miguel; Ribot, Julie C; Grosso, Ana R; Gonçalves-Sousa, Natacha; Pamplona, Ana; Pennington, Daniel J; Regueiro, José R; Fernández-Malavé, Edgar; Silva-Santos, Bruno

    2016-06-01

    The mouse thymus produces discrete γδ T cell subsets that make either interferon-γ (IFN-γ) or interleukin 17 (IL-17), but the role of the T cell antigen receptor (TCR) in this developmental process remains controversial. Here we show that Cd3g(+/-) Cd3d(+/-) (CD3 double-haploinsufficient (CD3DH)) mice have reduced TCR expression and signaling strength on γδ T cells. CD3DH mice had normal numbers and phenotypes of αβ thymocyte subsets, but impaired differentiation of fetal Vγ6(+) (but not Vγ4(+)) IL-17-producing γδ T cells and a marked depletion of IFN-γ-producing CD122(+) NK1.1(+) γδ T cells throughout ontogeny. Adult CD3DH mice showed reduced peripheral IFN-γ(+) γδ T cells and were resistant to experimental cerebral malaria. Thus, TCR signal strength within specific thymic developmental windows is a major determinant of the generation of proinflammatory γδ T cell subsets and their impact on pathophysiology. PMID:27043412

  18. Hyperoside regulates the level of thymic stromal lymphopoietin through intracellular calcium signalling.

    PubMed

    Han, Na-Ra; Go, Ji-Hyun; Kim, Hyung-Min; Jeong, Hyun-Ja

    2014-07-01

    Hyperoside (HYP) is the principle active component of Crataegus pinnatifida. Thymic stromal lymphopoietin (TSLP) plays a vital role in the pathogenesis of allergic reactions. Here, we investigated how HYP regulates the levels of TSLP in a human mast cell line, HMC-1 cells. We analyzed the levels of TSLP by treatment with HYP in phorbol myristate acetate plus calcium ionophore A23187-stimulated HMC-1 cells with ELISA and a polymerase chain reaction analysis. We also analyzed the pathway that HYP regulates TSLP by measuring the level of fluorescent intracellular calcium and using a Western blot analysis. HYP decreased the level of intracellular calcium in stimulated HMC-1 cells. It also significantly decreased the production and mRNA expression of TSLP in stimulated HMC-1 cells. It significantly decreased the levels of receptor-interacting protein 2 and active caspase-1 in stimulated HMC-1 cells. HYP significantly decreased the translocation of NF-κB into the nucleus and degradation of IκBα in the cytoplasm in stimulated HMC-1 cells. Furthermore, it significantly decreased the production and mRNA expression of interleukin-1β and interleukin-6 in stimulated HMC-1 cells. Taken together, our findings establish HYP as a potential agent for the treatment of allergic reactions. PMID:24338918

  19. Stat3 Signaling Promotes Survival And Maintenance Of Medullary Thymic Epithelial Cells

    PubMed Central

    Bolner, Michelle; Reeh, Kaitlin A. G.; Kang, Rhea; Reddy, Madhava C.; DiGiovanni, John; Richie, Ellen R.

    2016-01-01

    Medullary thymic epithelial cells (mTECs) are essential for establishing central tolerance by expressing a diverse array of self-peptides that delete autoreactive thymocytes and/or divert thymocytes into the regulatory T cell lineage. Activation of the NFκB signaling pathway in mTEC precursors is indispensable for mTEC maturation and proliferation resulting in proper medullary region formation. Here we show that the Stat3-mediated signaling pathway also plays a key role in mTEC development and homeostasis. Expression of a constitutively active Stat3 transgene targeted to the mTEC compartment increases mTEC cellularity and bypasses the requirement for signals from positively selected thymocytes to drive medullary region formation. Conversely, conditional deletion of Stat3 disrupts medullary region architecture and reduces the number of mTECs. Stat3 signaling does not affect mTEC proliferation, but rather promotes survival of immature MHCIIloCD80lo mTEC precursors. In contrast to striking alterations in the mTEC compartment, neither enforced expression nor deletion of Stat3 affects cTEC cellularity or organization. These results demonstrate that in addition to the NFkB pathway, Stat3-mediated signals play an essential role in regulating mTEC cellularity and medullary region homeostasis. PMID:26789196

  20. Fezf2 Orchestrates a Thymic Program of Self-Antigen Expression for Immune Tolerance.

    PubMed

    Takaba, Hiroyuki; Morishita, Yasuyuki; Tomofuji, Yoshihiko; Danks, Lynett; Nitta, Takeshi; Komatsu, Noriko; Kodama, Tatsuhiko; Takayanagi, Hiroshi

    2015-11-01

    Self-tolerance to immune reactions is established via promiscuous expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), leading to the elimination of T cells that respond to self-antigens. The transcriptional regulator Aire has been thought to be sufficient for the induction of TRAs, despite some indications that other factors may promote TRA expression in the thymus. Here, we show that the transcription factor Fezf2 directly regulates various TRA genes in mTECs independently of Aire. Mice lacking Fezf2 in mTECs displayed severe autoimmune symptoms, including the production of autoantibodies and inflammatory cell infiltration targeted to peripheral organs. These responses differed from those detected in Aire-deficient mice. Furthermore, Fezf2 expression and Aire expression are regulated by distinct signaling pathways and promote the expression of different classes of proteins. Thus, two independent factors, Fezf2 and Aire, permit the expression of TRAs in the thymus to ensure immune tolerance. PMID:26544942

  1. Risk of extrathyroid tumors following radiation treatment in infancy for thymic enlargement

    SciTech Connect

    Hildreth, N.G.; Shore, R.E.; Hempelmann, L.M.; Rosenstein, M.

    1985-06-01

    Two thousand eight hundred and fifty-six individuals who received X-ray treatments in infancy for an enlarged thymus gland and their 5053 nonirradiated siblings have been followed prospectively since 1953 to evaluate the risk of radiation-induced neoplastic disease. Based on the cumulative experience of five surveys of this cohort, the irradiated group has a statistically significant increased risk for both benign and malignant extrathyroid tumors, the age-adjusted relative risks being 2.0 and 2.2, respectively. Benign tumors of the bone, nervous system, salivary gland, skin, and breast (females only) and malignant tumors of the skin and breast (females only) account for the excess incidence of extrathyroid tumors among the thymic-irradiated individuals. Although a radiation-induced excess of extrathyroid tumors was suggested in an earlier survey of this cohort, small numbers restricted attribution of this excess to specific sites. The implications of these findings are discussed. Thyroid tumors are addressed in a separate paper.

  2. Stat3 Signaling Promotes Survival And Maintenance Of Medullary Thymic Epithelial Cells.

    PubMed

    Lomada, Dakshayani; Jain, Manju; Bolner, Michelle; Reeh, Kaitlin A G; Kang, Rhea; Reddy, Madhava C; DiGiovanni, John; Richie, Ellen R

    2016-01-01

    Medullary thymic epithelial cells (mTECs) are essential for establishing central tolerance by expressing a diverse array of self-peptides that delete autoreactive thymocytes and/or divert thymocytes into the regulatory T cell lineage. Activation of the NFκB signaling pathway in mTEC precursors is indispensable for mTEC maturation and proliferation resulting in proper medullary region formation. Here we show that the Stat3-mediated signaling pathway also plays a key role in mTEC development and homeostasis. Expression of a constitutively active Stat3 transgene targeted to the mTEC compartment increases mTEC cellularity and bypasses the requirement for signals from positively selected thymocytes to drive medullary region formation. Conversely, conditional deletion of Stat3 disrupts medullary region architecture and reduces the number of mTECs. Stat3 signaling does not affect mTEC proliferation, but rather promotes survival of immature MHCIIloCD80lo mTEC precursors. In contrast to striking alterations in the mTEC compartment, neither enforced expression nor deletion of Stat3 affects cTEC cellularity or organization. These results demonstrate that in addition to the NFkB pathway, Stat3-mediated signals play an essential role in regulating mTEC cellularity and medullary region homeostasis. PMID:26789196

  3. Ca(2+)-activated K+ channels in rat thymic lymphocytes: activation by concanavalin A.

    PubMed

    Mahaut-Smith, M P; Mason, M J

    1991-08-01

    1. The role of ion channels in the mitogenic response of rat thymic lymphocytes to concanavalin A (ConA) was studied using single-channel patch-clamp recordings and measurements of membrane potential with the fluorescent probe bis-oxonol. 2. ConA (20 micrograms ml-1) evoked a rapid membrane hyperpolarization; Indo-1 measurements indicated a concurrent increase in [Ca2+]i. The hyperpolarization was blocked by cytoplasmic loading with the Ca2+ buffer BAPTA (bis(O-amino-phenoxy)ethane-N,N,N',N'-tetraacetic acid), or charybdotoxin, a component of scorpion venom known to block K+ channels in lymphocytes. 3. Cell-attached patch-clamp recordings showed that both ConA and the Ca2+ ionophore ionomycin activated channels with high selectivity for K+. Two conductance levels were observed -6-7 pS and 17-18 pS-measured as inward chord conductance at 60 mV from reversal potential (Erev) with 140 mM-KCl in the pipette. The current-voltage relationship for the larger channel displayed inward rectification and channel open probability was weakly dependent upon membrane potential. 4. These experiments provide the first direct evidence for mitogen-activated Ca(2+)-gated K+ channels (IK(Ca)) in lymphocytes. This conductance is relatively inactive in unstimulated rat thymocytes but following the intracellular Ca2+ rises induced by ConA, IK(Ca) channels are activated and produce a significant hyperpolarization of the cell potential. PMID:1716678

  4. Thymic repopulation following intrathymic injection of mouse bone marrow cells in MHC matched and mismatched recipients

    SciTech Connect

    Chervenak, R.

    1986-03-01

    T cell precursors (pre-T cells) have traditionally been detected by their ability to repopulate the thymus of heavily irradiated mice following intravenous injection. Recently, Goldschneider et. al. developed an assay system which involves the direct injection of pre-T cells into the thymus. The authors used this technique to evaluate the ability of bone marrow cells to repopulate thymuses in various donor-host strain combinations. Sub-lethally irradiated (600R) mice were injected intrathymically with 2 x 10/sup 6/ bone marrow cells which differed from the recipient with respect to their Thy 1 allotype. The percentage of thymus cells expressing either the donor or recipient type Thy 1 marker was determined 14 to 21 days after injection. These experiments showed that in MHC matched donor-host combinations (AKR/cum ..-->.. AKR/J and CBA/J ..-->.. AKR/J), cells derived from the donor inoculum accounted for 40% to 75% of the total thymus population. MHC mismatched donor-host combinations (C57BL/6J ..-->.. AKR/J and Balb/c ..-->.. AKR/J) resulted in significantly less donor-type repopulation of the thymus. In these cases, donor repopulation typically ranged from 0% to 4%. The ability of the pre-T cells detected by intrathymic injection to proliferate in the thymic environment, therefore, appears to be influenced by the MHC. This may reflect commitment of pre-T cells to MHC haplotype recognition prior to their migration to the thymus.

  5. Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP).

    PubMed

    Bjerkan, Louise; Sonesson, Andreas; Schenck, Karl

    2016-01-01

    Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine, hitherto mostly known to be involved in inflammatory responses and immunoregulation. The human tslp gene gives rise to two transcription and translation variants: a long form (lfTSLP) that is induced by inflammation, and a short, constitutively-expressed form (sfTSLP), that appears to be downregulated by inflammation. The TSLP forms can be produced by a number of cell types, including epithelial and dendritic cells (DCs). lfTSLP can activate mast cells, DCs, and T cells through binding to the lfTSLP receptor (TSLPR) and has a pro-inflammatory function. In contrast, sfTSLP inhibits cytokine secretion of DCs, but the receptor mediating this effect is unknown. Our recent studies have demonstrated that both forms of TSLP display potent antimicrobial activity, exceeding that of many other known antimicrobial peptides (AMPs), with sfTSLP having the strongest effect. The AMP activity is primarily mediated by the C-terminal region of the protein and is localized within a 34-mer peptide (MKK34) that spans the C-terminal α-helical region in TSLP. Fluorescent studies of peptide-treated bacteria, electron microscopy, and liposome leakage models showed that MKK34 exerted membrane-disrupting effects comparable to those of LL-37. Expression of TSLP in skin, oral mucosa, salivary glands, and intestine is part of the defense barrier that aids in the control of both commensal and pathogenic microbes. PMID:27399723

  6. Dramatic Response of S-1 Administration to Chemorefractory Advanced Thymic Cancer.

    PubMed

    Kaira, Kyoichi; Naruse, Ichiro; Imai, Hisao; Sunaga, Noriaki; Hisada, Takeshi; Motegi, Masahiko; Asao, Takayuki; Yamada, Masanobu

    2014-01-01

    Thymic cancer (TC) is a rare malignancy in thoracic tumors, and there has been no standard therapeutics for advanced or relapsed patients. The clinical significance of second-line or beyond chemotherapy for platinum refractory advanced TC remains unclear. Here, we present the experience of a patient with TC showing a complete response to S-1 as third-line chemotherapy. A 54-year-old female with TC was treated with carboplatin plus paclitaxel and thoracic radiotherapy as first-line chemoradiotherapy and amrubicin as second-line chemotherapy. After 3 cycles of amrubicin administration, the metastatic hepatic lesions revealed a markedly progressive disease. A single agent of S-1 was administered as sequencing chemotherapy. After 2 cycles of S-1, the patient achieved a complete remission of multiple metastatic sites. There was evidence of immunohistochemical staining of a low thymidylate synthase (TS) expression. The expression of TS may be closely associated with the efficacy of S-1 in patients with TC. PMID:26389778

  7. IL-13 induces skin fibrosis in atopic dermatitis by thymic stromal lymphopoietin.

    PubMed

    Oh, Min-Hee; Oh, Sun Young; Yu, Jinho; Myers, Allen C; Leonard, Warren J; Liu, Yong Jun; Zhu, Zhou; Zheng, Tao

    2011-06-15

    Skin fibrotic remodeling is a major feature in human atopic dermatitis (AD). Inflammation and tissue fibrosis are common consequences of Th2 responses. Elevated IL-13 and thymic stromal lymphopoietin (TSLP) have been found in the AD skin lesions. Fibrocytes can be recruited to inflamed tissues to promote wound healing and fibrosis. Dermal transgenic expression of IL-13 causes an AD-like phenotype with fibrosis and increased TSLP. However, the role of TSLP in fibrotic remodeling is unknown. In this study, we investigated the role of TSLP and fibrocytes in the generation of IL-13-induced skin fibrosis. In AD lesion, cessation of IL-13 transgene expression resulted in reduced skin inflammation but with no effect on further progression of fibrosis. This was accompanied by markedly increased CD34(+)/procollagen 1(+) fibrocytes. Furthermore, fibrocytes express TSLP receptor (TSLPR), and TSLP directly promotes PBMC-derived fibrocytes to produce collagen. Neutralization of TSLP or genetic deletion of TSLPR in IL-13 transgenic mice resulted in a significant reduction in fibrocytes and in skin fibrosis. Furthermore, reduction of fibrosis by depletion of TSLP was independent of IL-13. Interestingly, the number of fibrocytes was highly increased in the skin samples of AD patients. These data indicate that the progression of skin fibrosis in IL-13-induced AD occurs via TSLP/TSLPR-dependent but IL-13-independent novel mechanisms by promoting fibrocyte functions. PMID:21576506

  8. Thymic stromal lymphopoietin (TSLP) inhibits human colon tumor growth by promoting apoptosis of tumor cells

    PubMed Central

    Yang, Xuguang; Li, Bingji; Liu, Jie; He, Rui

    2016-01-01

    Thymic stromal lymphopoietin (TSLP) has recently been suggested in several epithelial cancers, either pro-tumor or anti-tumor. However, the role of TSLP in colon cancer remains unknown. We here found significantly decreased TSLP levels in tumor tissues compared with tumor-surrounding tissues of patients with colon cancer and TSLP levels negatively correlated with the clinical staging score of colon cancer. TSLPR, the receptor of TSLP, was expressed in all three colon cancer cell lines investigated and colon tumor tissues. The addition of TSLP significantly enhanced apoptosis of colon cancer cells in a TSLPR-dependent manner. Interestingly, TSLP selectively induced the apoptosis of colon cancer cells, but not normal colonic epithelial cells. Furthermore, we demonstrated that TSLP induced JNK and p38 activation and initiated apoptosis mainly through the extrinsic pathway, as caspase-8 inhibitor significantly reversed the apoptosis-promoting effect of TSLP. Finally, using a xenograft mouse model, we demonstrated that peritumoral administration of TSLP greatly reduced tumor growth accompanied with extensive tumor apoptotic response, which was abolished by tumor cell-specific knockdown of TSLPR. Collectively, our study reveals a novel anti-tumor effect of TSLP via direct promotion of the apoptosis of colon cancer cells, and suggests that TSLP could be of value in treating colon cancer. PMID:26919238

  9. Aire Expression Is Inherent to Most Medullary Thymic Epithelial Cells during Their Differentiation Program.

    PubMed

    Kawano, Hiroshi; Nishijima, Hitoshi; Morimoto, Junko; Hirota, Fumiko; Morita, Ryoko; Mouri, Yasuhiro; Nishioka, Yasuhiko; Matsumoto, Mitsuru

    2015-12-01

    Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire(+) mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor-knockin mice in which long-term ablation of Aire(+) mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs. PMID:26503950

  10. Feasibility of the Medial Temporal lobe Atrophy index (MTAi) and derived methods for measuring atrophy of the medial temporal lobe

    PubMed Central

    Conejo Bayón, Francisco; Maese, Jesús; Fernandez Oliveira, Aníbal; Mesas, Tamara; Herrera de la Llave, Estibaliz; Álvarez Avellón, Tania; Menéndez-González, Manuel

    2014-01-01

    Introduction: The Medial Temporal-lobe Atrophy index (MTAi), 2D-Medial Temporal Atrophy (2D-MTA), yearly rate of MTA (yrRMTA) and yearly rate of relative MTA (yrRMTA) are simple protocols for measuring the relative extent of atrophy in the medial temporal lobe (MTL) in relation to the global brain atrophy. Albeit preliminary studies showed interest of these methods in the diagnosis of Alzheimer’s disease (AD), frontotemporal lobe degeneration (FTLD) and correlation with cognitive impairment in Parkinson’s disease (PD), formal feasibility and validity studies remained pending. As a first step, we aimed to assess the feasibility. Mainly, we aimed to assess the reproducibility of measuring the areas needed to compute these indices. We also aimed to assess the efforts needed to start using these methods correctly. Methods: A series of 290 1.5T-MRI studies from 230 subjects ranging 65–85 years old who had been studied for cognitive impairment were used in this study. Six inexperienced tracers (IT) plus one experienced tracer (ET) traced the three areas needed to compute the indices. Finally, tracers underwent a short survey on their experience learning to compute the MTAi and experience of usage, including items relative to training time needed to understand and apply the MTAi, time to perform a study after training and overall satisfaction. Results: Learning to trace the areas needed to compute the MTAi and derived methods is quick and easy. Results indicate very good intrarater Intraclass Correlation Coefficient (ICC) for the MTAi, good intrarater ICC for the 2D-MTA, yrMTA and yrRMTA and also good interrater ICC for the MTAi, 2D-MTA, yrMTA and yrRMTA. Conclusion: Our data support that MTAi and derived methods (2D-MTA, yrMTA and yrRTMA) have good to very good intrarater and interrater reproducibility and may be easily implemented in clinical practice even if new users have no experience tracing the area of regions of interest. PMID:25414666

  11. Genetic inhibition of JNK3 ameliorates spinal muscular atrophy.

    PubMed

    Genabai, Naresh K; Ahmad, Saif; Zhang, Zhanying; Jiang, Xiaoting; Gabaldon, Cynthia A; Gangwani, Laxman

    2015-12-15

    Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA. PMID:26423457

  12. Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype.

    PubMed

    Johnson, W G; Wigger, H J; Karp, H R; Glaubiger, L M; Rowland, L P

    1982-01-01

    A 24-year-old Ashkenazi Jewish man was evaluated for a nine-year history of progressive leg weakness with fasciculations. Electromyography, nerve conduction velocities, muscle biopsy, and serum creatine kinase were consistent with anterior horn cell disease. On rectal biopsy, ganglion cells were filled with membranous cytoplasmic bodies and an unusual submucosal layer of periodic acid-Schiff positive histiocytes filled with granules was seen. Hexosaminidase A in serum and leukocytes was severely decreased in the patient and partially decreased in parents and a brother. A paternal relative had classic infantile Tay-Sachs disease. Juvenile spinal muscular atrophy in this patient, closely resembling the Kugelberg-Welander phenotype, resulted from an alpha-locus hexosaminidase deficiency disorder, possibly a genetic compound of HEX alpha 2 and a milder hexosaminidase alpha-locus allele. Other cases of hexosaminidase deficiency have included anterior horn cell disease as part of a more complex disorder, but this is the first case, to our knowledge, of a hexosaminidase deficiency disorder presenting as spinal muscular atrophy. PMID:6460466

  13. Neuropsychiatric Symptoms in Posterior Cortical Atrophy and Alzheimer Disease

    PubMed Central

    Crutch, Sebastian J.; Franco-Macías, Emilio; Gil-Néciga, Eulogio

    2016-01-01

    Background: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by early progressive visual dysfunction in the context of relative preservation of memory and a pattern of atrophy mainly involving the posterior cortex. The aim of the present study is to characterize the neuropsychiatric profile of PCA. Methods: The Neuropsychiatric Inventory was used to assess 12 neuropsychiatric symptoms (NPS) in 28 patients with PCA and 34 patients with typical Alzheimer disease (AD) matched by age, disease duration, and illness severity. Results: The most commonly reported NPS in both groups were depression, anxiety, apathy, and irritability. However, aside from a trend toward lower rates of apathy in patients with PCA, there were no differences in the percentage of NPS presented in each group. All those patients presenting visual hallucinations in the PCA group also met diagnostic criteria for dementia with Lewy bodies (DLB). Auditory hallucinations were only present in patients meeting diagnosis criteria for DLB. Conclusion: Prevalence of the 12 NPS examined was similar between patients with PCA and AD. Hallucinations in PCA may be helpful in the differential diagnosis between PCA-AD and PCA-DLB. PMID:26404166

  14. Spinal muscular atrophy with respiratory distress type 1 (SMARD1)

    PubMed Central

    San Millan, Beatriz; Fernandez, Jose M.; Navarro, Carmen; Reparaz, Alfredo; Teijeira, Susana

    2016-01-01

    Background: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a clinically and genetically distinct and uncommon variant of SMA that results from irreversible degeneration of α-motor neurons in the anterior horns of the spinal cord and in ganglion cells on the spinal root ganglia. Aims: To describe the clinical, electrophysiological, neuropathological, and genetic findings, at different stages from birth to death, of a Spanish child diagnosed with SMARD1. Patient and methods: We report the case of a 3-month-old girl with severe respiratory insufficiency and, later, intense hypotonia. Paraclinical tests included biochemistry, chest X-ray, and electrophysiological studies, among others. Muscle and nerve biopsies were performed at 5 and 10 months and studied under light and electron microscopy. Post-mortem examination and genetic investigations were performed. Results: Pre- and post-mortem histopathological findings demonstrated the disease progression over time. Muscle biopsy at 5 months of age was normal, however a marked neurogenic atrophy was present in post-mortem samples. Peripheral motor and sensory nerves were severely involved likely due to a primary axonal disorder. Automatic sequencing of IGHMBP2 revealed a compound heterozygous mutation. Conclusions: The diagnosis of SMARD1 should be considered in children with early respiratory insufficiency or in cases of atypical SMA. Direct sequencing of the IGHMBP2 gene should be performed. PMID:26709713

  15. Clinical features of spinal and bulbar muscular atrophy

    PubMed Central

    Rhodes, Lindsay E.; Freeman, Brandi K.; Auh, Sungyoung; Kokkinis, Angela D.; La Pean, Alison; Chen, Cheunju; Lehky, Tanya J.; Shrader, Joseph A.; Levy, Ellen W.; Harris-Love, Michael; Di Prospero, Nicholas A.

    2009-01-01

    Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models. PMID:19846582

  16. [Mechanism of neuronal degeneration of multiple system atrophy].

    PubMed

    Yoshida, Mari; Sone, Mie

    2009-09-01

    Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder that encompasses olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND) and Shy-Drager syndrome (SDS). The histopathological hallmarks are alpha-synuclein (AS) positive glial cytoplasmic inclusions (GCIs) in oligodendroglias. AS aggregation is also found in glial nuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs), neuronal nuclear inclusions (NNIs) and dystrophic neurites. Reviewing the pathological features in 102 MSA cases revealed that the, OPCA-type was relatively more frequent and SND-type was less frequent in Japanese MSA cases. The frequency of the SND-type is relatively high in Western countries. This different in the dominant type suggests that the phenotypic patterns of MSA may vary with the race. In early stages of MSA, in addition to GCIs, NNIs, NCIs, and diffuse homogenous stain of AS in neuronal nuclei and cytoplasm were observed in various vulnerable lesions including the pontine nuclei, putamen, substantia nigra, locus ceruleus, inferior olivary nucleus, intermediolateral column of the thoracic cord, lower motor neurons, and cortical pyramidal neurons. These findings indicated that the primary nonfibrillar and fibrillar AS aggregation also occurred in neurons. Therefore, both the direct involvement of neurons themselves and the oligodendroglia-myelin-axon mechanism may synergistically accelerate the degenerative process of MSA. PMID:19803404

  17. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy

    PubMed Central

    Tisdale, Sarah

    2015-01-01

    Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID:26063904

  18. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    PubMed Central

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  19. Nuclear Factor-kappa B Signaling in Skeletal Muscle Atrophy

    PubMed Central

    Li, Hong; Malhotra, Shweta; Kumar, Ashok

    2008-01-01

    Skeletal muscle atrophy/wasting is a serious complication of a wide range of diseases and conditions such as aging, disuse, AIDS, chronic obstructive pulmonary disease, space travel, muscular dystrophy, chronic heart failure, sepsis, and cancer. Emerging evidence suggests that nuclear factor-kappa B (NF-κB) is one of most important signaling pathways linked to the loss of skeletal muscle mass in various physiological and pathophysiological conditions. Activation of NF-κB in skeletal muscle leads to degradation of specific muscle proteins, induces inflammation and fibrosis, and blocks the regeneration of myofibers after injury/atrophy. Recent studies employing genetic mouse models have provided strong evidence that NF-κB can serve as an important molecular target for the prevention of skeletal muscle loss. In this article, we have outlined the current understanding regarding the role of NF-κB in skeletal muscle with particular reference to different models of muscle-wasting and the development of novel therapy. PMID:18574572

  20. Active immunization therapies for Parkinson's disease and multiple system atrophy.

    PubMed

    Schneeberger, Achim; Tierney, Lanay; Mandler, Markus

    2016-02-01

    Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs. PMID:26260853

  1. The evolution of alexia and simultanagnosia in posterior cortical atrophy.

    PubMed

    Mendez, M F; Cherrier, M M

    1998-04-01

    Early alexia and higher visual impairments characterize Posterior cortical atrophy (PCA), a progressive dementing syndrome most often caused by Alzheimer disease. Posterior cortical atrophy is rare, and the nature of the visual impairments in PCA are unclear. The authors observed two patients who had an insidiously progressive reading difficulty characterized by letter-by-letter reading and otherwise intact cognitive functions. Over time, these patients developed "ventral simultanagnosia" with preserved detection of multiple stimuli but inability to interpret whole scenes. Subsequently, they progressed to Balint syndrome with "dorsal simultanagnosia," optic ataxia, and oculomotor apraxia. Structural imaging was normal, but functional imaging revealed posterior cortical dysfunction. On a letter reading task, both patients had a word superiority effect, and on a whole word reading task, they could not read most words with missing or crosshatched letters. An inability to assess whole scenes progressed to an inability to detect more than one stimulus in an array. These findings suggest an evolution of PCA with progressive difficulty in visual integration beginning with letters, progressing to whole scenes, and culminating in Balint syndrome. These changes may reflect an extension of the pathophysiology of PCA from the extrastriate visual cortex to its occipitotemporal and occipitoparietal connections. PMID:9652488

  2. Acute Bronchitis

    MedlinePlus

    Bronchitis is an inflammation of the bronchial tubes, the airways that carry air to your lungs. It ... chest tightness. There are two main types of bronchitis: acute and chronic. Most cases of acute bronchitis ...

  3. Autophagy-Associated Atrophy and Metabolic Remodeling of the Mouse Diaphragm after Short-Term Intermittent Hypoxia

    PubMed Central

    Giordano, Christian; Lemaire, Christian; Li, Tong; Kimoff, R. John; Petrof, Basil J.

    2015-01-01

    Background Short-term intermittent hypoxia (IH) is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm. Methods We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%), and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways), markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC) expression, and in vitro contractile properties. Results After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size) together with increased LC3B-II protein (2.4-fold) and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3), whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1) were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold) after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro. Conclusions Short-term IH induces preferential atrophy

  4. Multiple system atrophy presenting as parkinsonism: clinical features and diagnostic criteria.

    PubMed Central

    Albanese, A; Colosimo, C; Bentivoglio, A R; Fenici, R; Melillo, G; Colosimo, C; Tonali, P

    1995-01-01

    To evaluate the possibility that parkinsonian signs may be the only presenting feature of multiple system atrophy (MSA), parkinsonian patients were studied who had no atypical clinical signs and had no symptoms of autonomic dysfunction, but who reported that they had not experienced the anticipated good response to dopaminergic treatment. These stringent criteria identified 20 patients from a series of 298 consecutive parkinsonian outpatients. The following clinical pointers were analysed: (a) rate of disease progression; (b) symmetry of parkinsonian symptoms and signs; (c) occurrence of resting tremor during the first three years from onset. In addition, all patients underwent (d) acute and chronic challenge with dopaminergic drugs; (e) cardiovascular reflex autonomic function tests; (f) high field MRI. Rapid progression of disease was seen in 45% of patients, onset was symmetric in 25%, tremor was absent at onset in 70%, response to dopaminergic drug challenges was inadequate in 40%, abnormal cardiovascular reflexes occurred in 50%, and some abnormal MRI finding occurred in 35% of cases. Each of these features was equally weighted by giving to each patient a 0 to 6 point score corresponding to the number of abnormal findings. Fifteen patients scoring higher than 1 were considered at risk for having MSA: five of them were classified as clinically possible (score 2), six as clinically probable (score 3-4), and four patients were classified as clinically definite multiple system atrophy (score 5). The six pointers considered were variably combined in each patient, none of them being universally abnormal in patients with high scores. The patients were followed up for a mean 2.1 (SEM 0.65) years. All but one of the 10 patients prospectively classified as probable or definite MSA developed unequivocal clinical signs of fully symptomatic MSA. A receiver operator characteristic cure was plotted for the prospective score based on follow up diagnosis. The best compromise

  5. Multimodal treatment of metastatic thymic carcinoma including high-dose chemotherapy with autologous stem cell transplantation: report of a case with more than 4-year disease-free survival.

    PubMed

    Geffen, D B; Benharroch, D; Yellin, A; Ariad, S; Or, R; Cohen, Y

    2001-12-01

    Thymic carcinoma is a rare epithelial malignancy differentiated from thymoma by the presence of cytologically malignant cells. There are few reports of the treatment of locally advanced or metastatic thymic carcinoma. We describe a patient who sought treatment for thymic carcinoma metastatic to pleura, pericardium, retroperitoneum, and neck nodes. He was treated with neoadjuvant etoposide, ifosfamide, and cisplatin, and underwent resection. We then administered high-dose chemotherapy with autologous stem cell support, followed by radiation therapy. The patient remains in complete remission more than 4 years after diagnosis. To our knowledge, this is the first report of metastatic thymic carcinoma treated with neoadjuvant therapy and postoperative high-dose chemotherapy. Metastatic thymic carcinoma may be curable by aggressive combined therapies. PMID:11801755

  6. Thymic regulatory T cell niche size is dictated by limiting interleukin 2 from antigen-bearing dendritic cells and feedback competition

    PubMed Central

    Weist, Brian M.; Kurd, Nadia; Boussier, Jeremy; Chan, Shiao Wei; Robey, Ellen A.

    2015-01-01

    Thymic regulatory T (Treg) cell production requires interleukin 2 (IL-2) and agonist TCR ligands, and is controlled by competition for a limited developmental niche, but the thymic sources of IL-2 and the factors that limit access to the niche are poorly understood. Here we show that IL-2 produced by antigen-bearing dendritic cells plays a key role in Treg cell development, and that existing Treg cells limit new Treg cell development by competing for IL-2. . Our data suggest that antigen-presenting cells that can provide both IL-2 and a TCR ligand comprise the thymic niche, and that competition by existing Treg cells for a limited supply of IL-2 provides negative feedback for new Treg cell production. PMID:25939026

  7. DIGESTIVE TUBULE ATROPHY IN EASTERN OYSTERS, CRASSOSTREA VIRGINICA (GMELI, 1791), EXPOSED TO SALINITY AND STARVATION STRESS

    EPA Science Inventory

    Oysters sampled in February 1992, from a low salinity site (3 ppt) in Apalachicola Bay, Florida, showed digestive tubule atrophy when salinity site (18 ppt) 16 kilometers away. xperiments designed to induce tubule atrophy in the and two salinity stress tests. o quantify tubule co...

  8. The relationship of pineal calcification to cerebral atrophy on CT scan in multiple sclerosis.

    PubMed

    Sandyk, R; Awerbuch, G I

    1994-05-01

    Calcification is a known morphological feature of the pineal gland. The mechanisms underlying the development of pineal calcification (PC) are elusive although there is experimental evidence that calcification may be a marker of the past secretory activity of the gland and/or of degeneration. The increased incidence of PC with aging suggests that it may reflect cerebral degenerative changes as well. In a recent Editorial in this Journal it was proposed that the pineal gland is implicated in the pathogenesis of multiple sclerosis (MS). Cerebral atrophy, which can be demonstrated on CT scan, is a common feature of MS resulting from demyelination and gliosis. If PC is a marker of a cerebral degenerative process, then one would expect a higher incidence of calcification of the gland in patients with cerebral atrophy compared to those without cerebral atrophy. To test this hypothesis, we studied the incidence of PC on CT scan in a cohort of 48 MS patients, 21 of whom had cerebral atrophy. For the purpose of comparison, we also assessed the incidence of choroid plexus calcification (CPC) in relation to cerebral atrophy. PC was found in 42 patients (87.5%) and its incidence in patients with cerebral atrophy was significantly higher compared to the incidence in patients without cerebral atrophy (100% vs. 77.7%; p < .025). In contrast, CPC was unrelated to cerebral atrophy or to PC thus supporting the notion of a specific association between the pineal gland and the pathogenesis of MS.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7960471

  9. [The hemodynamic disorders in Sudeck's atrophy and the effect on them of interference therapy].

    PubMed

    Nikolova, L

    1992-01-01

    Interferential currents applied to the forearm fracture region of 80 patients with Sudeck atrophy eliminated hemodynamic changes in the affected limb as shown by capillaroscopy, rheovasography. The effect of the treatment is attributed to recovery of normal blood flow and microcirculation in the region of bone atrophy as well as analgetic action of pulse current. PMID:1384234

  10. Relating Cortical Atrophy in Temporal Lobe Epilepsy with Graph Diffusion-Based Network Models

    PubMed Central

    Abdelnour, Farras; Mueller, Susanne; Raj, Ashish

    2015-01-01

    Mesial temporal lobe epilepsy (TLE) is characterized by stereotyped origination and spread pattern of epileptogenic activity, which is reflected in stereotyped topographic distribution of neuronal atrophy on magnetic resonance imaging (MRI). Both epileptogenic activity and atrophy spread appear to follow white matter connections. We model the networked spread of activity and atrophy in TLE from first principles via two simple first order network diffusion models. Atrophy distribution is modeled as a simple consequence of the propagation of epileptogenic activity in one model, and as a progressive degenerative process in the other. We show that the network models closely reproduce the regional volumetric gray matter atrophy distribution of two epilepsy cohorts: 29 TLE subjects with medial temporal sclerosis (TLE-MTS), and 50 TLE subjects with normal appearance on MRI (TLE-no). Statistical validation at the group level suggests high correlation with measured atrophy (R = 0.586 for TLE-MTS, R = 0.283 for TLE-no). We conclude that atrophy spread model out-performs the hyperactivity spread model. These results pave the way for future clinical application of the proposed model on individual patients, including estimating future spread of atrophy, identification of seizure onset zones and surgical planning. PMID:26513579

  11. Maintenance electroconvulsive therapy in a patient with multiple system atrophy and bipolar disorder.

    PubMed

    Obiora, Onwuameze; McCormick, Laurie May; Karim, Yasser; Gonzales, Pedro; Beeghly, James

    2012-06-01

    Multiple system atrophy is a rapidly progressive neurodegenerative disorder with no known cure. It is a clinical diagnosis with no confirmation available other than brain biopsy after death. We report the successful treatment of multiple system atrophy co-occurring with bipolar disorder in a 62-year-old man using electroconvulsive therapy. PMID:22622294

  12. Parapapillary atrophy and optic disc region assessment (PANDORA): retinal imaging tool for assessment of the optic disc and parapapillary atrophy

    NASA Astrophysics Data System (ADS)

    Lu, Cheng-Kai; Tang, Tong Boon; Laude, Augustinus; Dhillon, Baljean; Murray, Alan F.

    2012-10-01

    We describe a computer-aided measuring tool, named parapapillary atrophy and optic disc region assessment (PANDORA), for automated detection and quantification of both the parapapillary atrophy (PPA) and the optic disc (OD) regions in two-dimensional color retinal fundus images. The OD region is segmented using a combination of edge detection and ellipse fitting methods. The PPA region is identified by the presence of bright pixels in the temporal zone of the OD, and it is segmented using a sequence of techniques, including a modified Chan-Vese approach, thresholding, scanning filter, and multiseed region growing. PANDORA has been tested with 133 color retinal images (82 with PPA; 51 without PPA) drawn randomly from the Lothian Birth Cohort (LBC) database, together with a "ground truth" estimate from an ophthalmologist. The PPA detection rate is 89.47% with a sensitivity of 0.83 and a specificity of 1. The mean accuracy in defining the OD region is 81.31% (SD=10.45) when PPA is present and 95.32% (SD=4.36) when PPA is absent. The mean accuracy in defining the PPA region is 73.57% (SD=11.62). PANDORA demonstrates for the first time how to quantify the OD and PPA regions using two-dimensional fundus images, enabling ophthalmologists to study ocular diseases related to PPA using a standard fundus camera.

  13. Dietary zinc deficiency lowers the proportions of splenic CD90+ (Thy-1+) B-cells and late thymic emigrant T-cells in growing rats.

    PubMed

    Hosea, Heather J; Rector, Edward S; Taylor, Carla G

    2007-12-01

    Zn-deficient (ZD) rats have a lower proportion of splenic CD90+T-cells which could be due to fewer new T-cells exiting the thymus, defective post-thymic maturation or increased cell death. Post-thymic maturation of splenic lymphocytes and their viability were determined by flow cytometry in weanling rats assigned to ZD ( < 1 mg Zn/kg; ad libitum), diet-restricted (DR; 30 mg Zn/kg; limited to the amount of feed as consumed by ZD rats), marginally Zn-deficient (MZD; 10 mg Zn/kg; ad libitum) or control (30 mg Zn/kg; ad libitum) groups for 3 weeks. ZD rats had a 29 % lower percentage of splenic CD90+T-cells and both ZD and DR rats had a 30 % lower proportion of splenic CD90+B-cells compared with control rats. When the splenic CD90+T-cells were characterised further, there was no difference among the groups in the first two stages of post-thymic development; however, ZD, DR and MZD rats had a 42 % lower proportion of late thymic emigrants (TCRalphabeta+CD90+CD45RC+RT6.1+) compared with control rats. There was no difference among groups in the proportion of splenic CD90+T-cells in the non-viable region; however, ZD rats had a higher proportion of CD90+B-cells in the non-viable region compared with MZD and control animals, suggesting that this phenotype was more susceptible to cell death during deficiency. The lower proportion of splenic CD90+T-cells in ZD rats does not appear to be due to a defect in thymic production or increased cell death in the spleen. Future studies should determine if late thymic emigrants have homed to other peripheral organs. PMID:18309546

  14. Clinical Features, Treatments, and Outcomes of Patients with Thymic Carcinoids and Multiple Endocrine Neoplasia Type 1 Syndrome at MD Anderson Cancer Center.

    PubMed

    Christakis, Ioannis; Qiu, Wei; Silva Figueroa, Angelica M; Hyde, Samuel; Cote, Gilbert J; Busaidy, Naifa L; Williams, Michelle; Grubbs, Elizabeth; Lee, Jeffrey E; Perrier, Nancy D

    2016-08-01

    Thymic carcinoids are rare neuroendocrine tumors that occur in 1-5 % of patients with multiple endocrine neoplasia type 1 (MEN1) and are a major cause of morbidity and mortality. The few published reports associate these tumors with male sex and smoking. Our objective was to describe cases of these tumors treated at our institution. We performed a retrospective chart review of all patients diagnosed with MEN1 at our tertiary referral center from 1980 to 2014. Patients with a histopathologic, fine-needle aspiration, or clinical diagnosis of a thymic carcinoid were included. Two hundred ninety-one patients fulfilled the criteria for a diagnosis of MEN1. Clinicopathologic characteristics, MEN1 genetic testing results, treatments, and survival rates were analyzed. Nine patients had a thymic carcinoid, six men (67 %) and three women (33 %). Six patients were non-smokers (67 %). Two patients had synchronous (22 %) and eight patients (89 %) had metachronous distant metastasis. The 10-year overall survival rate was 45 % (lower 95 % upper 95 % CI 20-100 %). The 10-year disease-free survival rate was 42 % (lower 95 % upper 95 % CI 15-100 %). Five patients had MEN1 genetic testing, and the genotypes of affected individuals were p.W341X, c.275_286delGCTTCACCGCCC, p.R98X, c.1350+(1_11)del11, and partial duplication of exons 9 and 10. A higher percentage of MEN1-related thymic carcinoids can occur in women and in non-smokers than previously reported. Both novel and known mutations were present in our cohort. Eighty nine percent of patients developed a metachronous metastasis from the thymic carcinoid. Patients with MEN1 and thymic carcinoids should be followed closely. PMID:27311764

  15. Two subpopulations of human triple-negative thymic cells are susceptible to infection by human immunodeficiency virus type 1 in vitro.

    PubMed Central

    Valentin, H; Nugeyre, M T; Vuillier, F; Boumsell, L; Schmid, M; Barré-Sinoussi, F; Pereira, R A

    1994-01-01

    Some infants infected with human immunodeficiency virus type 1 (HIV-1) rapidly develop a fatal disease characterized by a severe lymphopenia. To explain the immune dysfunction, we proposed a mechanism by which a nongeneration of CD4+ T cells is caused by HIV-1 infection of thymic cells. To examine this hypothesis, we infected primary triple-negative (TN; phenotypically CD3- CD4- CD8-), CD1a- TN, or CD1a+ TN thymic cell subsets. Our data indicate that by flow cytometry, TN, CD1a- TN, and CD1a+ TN cells remain CD4 negative throughout the culture period. We demonstrated that TN and CD1a+ TN thymic cell subsets are susceptible to HIV-1 as is the entire thymic cell population, whereas CD1a- TN cells are not. A limited number of infected TN cells are expressing HIV-1 but the level of transcription is very high in permissive cells, as detected by in situ hybridization. We then performed blocking experiments on TN cells to examine the mechanism of HIV-1 entry into these cells. CD4 (OKT4a) monoclonal antibody blocks their infection. Finally, infection experiments on two subpopulations of TN cells (CD2+ CD7+ and CD2- CD7-) indicate that infected TN cells may correspond to both immature thymocytes and thymic dendritic cells. These data are of particular interest since infection of thymic stromal cells might result in an impairment of T-cell differentiation, which may explain a nongeneration of functional CD4+ T-cell population in the thymus. This phenomenon may play a role in AIDS pathogenesis, in particular in infants born from seropositive mothers. Images PMID:7512158

  16. Thymic Stromal Lymphopoietin-Activated Plasmacytoid Dendritic Cells Induce the Generation of FOXP3+ Regulatory T Cells in Human Thymus

    PubMed Central

    Hanabuchi, Shino; Ito, Tomoki; Park, Woon-Ryon; Watanabe, Norihiko; Shaw, Joanne L.; Roman, Eulogia; Arima, Kazuhiko; Wang, Yui-Hsi; Voo, Kui Shin; Cao, Wei; Liu, Yong-Jun

    2012-01-01

    Human thymus contains major dendritic cell (DC) subsets, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). We previously showed that mDCs, educated by thymic stromal lymphopoietin (TSLP) produced by the epithelial cells of the Hassall’s corpuscles, induced differentiation of CD4+CD25− thymocytes into Forkhead Box P3+ (FOXP3+) regulatory T cells (TR) within the medulla of human thymus. In this study, we show that pDCs expressed the TSLP receptor and IL-7 receptor a complexes upon activation and became responsive to TSLP. TSLP-activated human pDCs secrete macrophage-derived chemokine CCL-22 and thymus- and activation-regulated chemokine CCL-17 but not Th1- or Th2-polarizing cytokines. TSLP-activated pDCs induced the generation of FOXP3+ TR from CD4+CD8−CD25− thymocytes, which could be strongly inhibited by Th1-polarizing cytokine IL-12 or Th2-polarizing cytokine IL-4. Interestingly, the FOXP3+ TR induced by the TSLP-pDCs expressed more IL-10 but less TGF-b than that induced by the TSLP-mDCs. These data suggest that TSLP expressed by thymic epithelial cells can activate mDCs and pDCs to positively select the FOXP3+ TR with different cytokine production potential in human thymus. The inability of TSLP to induce DC maturation without producing Th1- or Th2-polarizing cytokines may provide a thymic niche for TR development. PMID:20173030

  17. Ectopic Aire Expression in the Thymic Cortex Reveals Inherent Properties of Aire as a Tolerogenic Factor within the Medulla.

    PubMed

    Nishijima, Hitoshi; Kitano, Satsuki; Miyachi, Hitoshi; Morimoto, Junko; Kawano, Hiroshi; Hirota, Fumiko; Morita, Ryoko; Mouri, Yasuhiro; Masuda, Kiyoshi; Imoto, Issei; Ikuta, Koichi; Matsumoto, Mitsuru

    2015-11-15

    Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) play essential roles in the positive and negative selection of developing thymocytes, respectively. Aire in mTECs plays an essential role in the latter process through expression of broad arrays of tissue-restricted Ags. To determine whether the location of Aire within the medulla is absolutely essential or whether Aire could also function within the cortex for establishment of self-tolerance, we used bacterial artificial chromosome technology to establish a semiknockin strain of NOD-background (β5t/Aire-transgenic) mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein in β5t/Aire-Tg mice, cTECs expressing Aire ectopically did not confer transcriptional expression of either Aire-dependent or Aire-independent tissue-restricted Ag genes. We then crossed β5t/Aire-Tg mice with Aire-deficient NOD mice, generating a strain in which Aire expression was confined to cTECs. Despite the presence of Aire(+) cTECs, these mice succumbed to autoimmunity, as did Aire-deficient NOD mice. The thymic microenvironment harboring Aire(+) cTECs, within which many Aire-activated genes were present, also showed no obvious alteration of positive selection, suggesting that Aire's unique property of generating a self-tolerant T cell repertoire is functional only in mTECs. PMID:26453754

  18. 3D Organotypic Co-culture Model Supporting Medullary Thymic Epithelial Cell Proliferation, Differentiation and Promiscuous Gene Expression.

    PubMed

    Pinto, Sheena; Stark, Hans-Jürgen; Martin, Iris; Boukamp, Petra; Kyewski, Bruno

    2015-01-01

    Intra-thymic T cell development requires an intricate three-dimensional meshwork composed of various stromal cells, i.e., non-T cells. Thymocytes traverse this scaffold in a highly coordinated temporal and spatial order while sequentially passing obligatory check points, i.e., T cell lineage commitment, followed by T cell receptor repertoire generation and selection prior to their export into the periphery. The two major resident cell types forming this scaffold are cortical (cTECs) and medullary thymic epithelial cells (mTECs). A key feature of mTECs is the so-called promiscuous expression of numerous tissue-restricted antigens. These tissue-restricted antigens are presented to immature thymocytes directly or indirectly by mTECs or thymic dendritic cells, respectively resulting in self-tolerance. Suitable in vitro models emulating the developmental pathways and functions of cTECs and mTECs are currently lacking. This lack of adequate experimental models has for instance hampered the analysis of promiscuous gene expression, which is still poorly understood at the cellular and molecular level. We adapted a 3D organotypic co-culture model to culture ex vivo isolated mTECs. This model was originally devised to cultivate keratinocytes in such a way as to generate a skin equivalent in vitro. The 3D model preserved key functional features of mTEC biology: (i) proliferation and terminal differentiation of CD80(lo), Aire-negative into CD80(hi), Aire-positive mTECs, (ii) responsiveness to RANKL, and (iii) sustained expression of FoxN1, Aire and tissue-restricted genes in CD80(hi) mTECs. PMID:26275017

  19. Gelatinase B (MMP-9), but not its inhibitor (TIMP-1), dictates the growth rate of experimental thymic lymphoma.

    PubMed

    Aoudjit, F; Masure, S; Opdenakker, G; Potworowski, E F; St-Pierre, Y

    1999-08-27

    Dysregulation of metalloproteinase production at tumor sites contributes to the modification of local stromal tissue necessary for tumor development. Gelatinase B (matrix metalloproteinase-9, MMP-9) is one of the key enzymes that have been associated with the progression of several tumors. Paradoxically, MMP-9 expression by tumor cells, most notably by lymphoma cells, is concomitant with the expression of its physiological inhibitor, TIMP-1. Not only are both genes often co-expressed in the most aggressive forms of lymphomas but also both are up-regulated upon contact with stromal cells. Since TIMP-1 is known to regulate growth in several cell types and some aggressive lymphoma cells express TIMP-1 constitutively without MMP-9, it is unclear whether the over-expression of MMP-9 is counterbalanced by TIMP-1 and whether TIMP-1 expression alone could favor the development of lymphoma. To gain further insight into the respective roles of MMP-9 and TIMP-1 in lymphoma, we generated lymphoma cell lines expressing constitutively high levels of MMP-9 or TIMP-1 and compared these cells for the ability to form thymic lymphoma in vivo. Moreover, we generated lymphoma cell lines expressing constitutively high levels of both MMP-9 and TIMP-1 to reproduce the net physiological balance resulting from the expression of both genes simultaneously and to determine which gene overrides the other. Our results show that mice injected with lymphoma cells expressing MMP-9 constitutively developed thymic lymphoma more rapidly than those injected with control lymphoma cells. Over-expression of TIMP-1 alone did not significantly influence tumor progression of lymphoma nor did it delay the capacity of MMP-9 to accelerate the development of thymic lymphoma. PMID:10417774

  20. Eph/ephrin-B-mediated cell-to-cell interactions govern MTS20(+) thymic epithelial cell development.

    PubMed

    Montero-Herradón, Sara; García-Ceca, Javier; Sánchez Del Collado, Beatriz; Alfaro, David; Zapata, Agustín G

    2016-08-01

    Thymus development is a complex process in which cell-to-cell interactions between thymocytes and thymic epithelial cells (TECs) are essential to allow a proper maturation of both thymic cell components. Although signals that control thymocyte development are well known, mechanisms governing TEC maturation are poorly understood, especially those that regulate the maturation of immature TEC populations during early fetal thymus development. In this study, we show that EphB2-deficient, EphB2LacZ and EphB3-deficient fetal thymuses present a lower number of cells and delayed maturation of DN cell subsets compared to WT values. Moreover, deficits in the production of chemokines, known to be involved in the lymphoid seeding into the thymus, contribute in decreased proportions of intrathymic T cell progenitors (PIRA/B(+)) in the mutant thymuses from early stages of development. These features correlate with increased proportions of MTS20(+) cells but fewer MTS20(-) cells from E13.5 onward in the deficient thymuses, suggesting a delayed development of the first epithelial cells. In addition, in vitro the lack of thymocytes or the blockade of Eph/ephrin-B-mediated cell-to-cell interactions between either thymocytes-TECs or TECs-TECs in E13.5 fetal thymic lobes coursed with increased proportions of MTS20(+) TECs. This confirms, for the first time, that the presence of CD45(+) cells, corresponding at these stages to DN1 and DN2 cells, and Eph/ephrin-B-mediated heterotypic or homotypic cell interactions between thymocytes and TECs, or between TECs and themselves, contribute to the early maturation of MTS20(+) TECs. PMID:27060907