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Sample records for medullary thymic epithelium

  1. Thymic medullary epithelium and thymocyte self tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways

    PubMed Central

    Williams, Joy A.; Zhang, Jingjing; Jeon, Hyein; Nitta, Takeshi; Ohigashi, Izumi; Klug, David; Kruhlak, Michael J.; Choudhury, Baishakhi; Sharrow, Susan O.; Granger, Larry; Adams, Anthony; Eckhaus, Michael A.; Jenkinson, S. Rhiannon; Richie, Ellen R.; Gress, Ronald E.; Takahama, Yousuke; Hodes, Richard J.

    2014-01-01

    A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC) and mTEC development in turn requires signals from mature single positive (SP) thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTα, LTβ and RANK in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of SP thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 KO mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development. PMID:24337745

  2. 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

  3. A Common Stem Cell for Murine Cortical and Medullary Thymic Epithelial Cells?

    PubMed Central

    Van Soest, Peter; Platenburg, Peter Paul; Van Ewijk, Willem

    1995-01-01

    We have addressed the question whether the epithelial stroma in the thymus is derived from a common stem cell or whether cortical and medullary epithelial cells are derived from different embryonic stem cells emerging, for example, from endoderm and ectoderm. By the use of rapidly expanding cultures of thymic epithelial cells (TEC) from 14 to 16 day-old murine fetuses and by specific antibodies against cortical and medullary epithelium, respectively, we were able to demonstrate a small subpopulation of double-labeled TEC in the cultures. These cells were not present in TEC cultures initiated from thymuses of neonatal mice. Double-labeled TEC were also found in tissue sections from fetal thymuses. These findings may indicate that TEC populations of the cortex and the medulla are derived from a common stem cell, with potential for differentiation toward both cortical and medullary TEC. PMID:9700364

  4. Ontogeny of Rat Thymic Epithelium Defined by Monoclonal Anticytokeratin Antibodies

    PubMed Central

    Jovanović, Suzana; Vasiljevski, Milijana; Dujić, Aleksandar

    1990-01-01

    Ontogenetic study on the expression of cytokeratin (CK) polypeptides within particular subsets of rat thymic epithelial cells (TEC) has been performed by a large panel of anti-CK monoclonal antibodies (mAbs) using the streptavidin-biotin immunoperoxidase method. Simultaneous presence of two or more CK subunits in the same TEC has been demonstrated by double immunoflouorescence labeling. The obtained results showed that the expression of CK polypeptides in fetal and neonatal thymus differed from the adult patterns. The main difference was observed in expression of CK10, 18, and 19 polypeptides. During fetal ontogeny, CK10 and 18 are markers for most medullary TEC or a subset of medullary TEC, respectively, whereas CK19 is mainly a pan-TEC marker. In the adult animals, they are localized in the cortical and a subset of medullary TEC (CK18), subcapsular/perivascular and some medullary TEC (CK19), or in a subset of medullary TEC and Hasall’s corpuscles (HC) (CK10). The switch in their expression in the cortex was observed during the first two weeks of postnatal life. PMID:1726554

  5. Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells

    SciTech Connect

    Adkins, B.; Gandour, D.; Strober, S.; Weissman, I.

    1988-05-15

    Mice given multiple doses of sublethal irradiation to both the thymus and the peripheral lymphoid tissues showed major transient, and some persistent disruptions in general thymic architecture and in thymic stromal components. At 2 wk after total lymphoid irradiation (TLI), the thymus lacked identifiable medullary regions by immunohistochemical analyses. Medullary stromal cells expression MHC Ag or a medullary epithelial cell Ag, as well as medullary macrophages, were undetectable. Instead, the processes of cortical epithelial cells were observed throughout the entire thymus. Strikingly, thymocyte subsets with mature phenotypes (CD4+CD8- and CD4-CD8+) were present in the apparent absence of a medulla. This early, gross effect was rapidly reversed such that by 1 to 2 mo after TLI, medullary areas with MHC Ag-positive cells were evident. However, abnormalities in a subset of medullary stromal cells appeared to be more persistent. Medullary epithelial cells, identified by the MD1 mAb, were greatly reduced in number and abnormally organized for at least 4 mo after TLI. In addition, macrophages containing endogenous peroxidase activity, normally abundant in medullary regions, were undetectable at all times examined after TLI. Therefore, this irradiation regimen induced both transient and long term effects in the thymus, primarily in medullary regions. These results suggest that TLI may be used as an experimental tool for studying the impact of selective depletion of medullary stromal cells on the development of specific T cell functions.

  6. 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.

  7. 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

  8. Thymic Medullary Epithelial Cell Differentiation, Thymocyte Emigration, and the Control of Autoimmunity Require Lympho–Epithelial Cross Talk via LTβR

    PubMed Central

    Boehm, Thomas; Scheu, Stefanie; Pfeffer, Klaus; Bleul, Conrad C.

    2003-01-01

    Thymocytes depend on the interaction with thymic epithelial cells for the generation of a diverse, nonautoreactive T cell repertoire. In turn, thymic epithelial cells acquire their three-dimensional cellular organization via instructive signals from developing thymocytes. The nature of these signals has been elusive so far. We show that thymocytes and medullary epithelial cells (MECs) communicate via the lymphotoxin β receptor (LTβR) signaling axis. Normal differentiation of thymic MECs requires LTβR ligand on thymocytes and LTβR together with nuclear factor–κB-inducing kinase (Nik) in thymic epithelial cells. Impaired lympho–epithelial cross talk in the absence of the LTβR causes aberrant differentiation and reduced numbers of thymic MECs, leads to the retention of mature T lymphocytes, and is associated with autoimmune phenomena, suggesting an unexpected role for LTβR signaling in central tolerance induction. PMID:12953095

  9. 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

  10. NF-κB2 is required for the control of autoimmunity by regulating the development of medullary thymic epithelial cells*

    PubMed Central

    Zhang, Baochun; Wang, Zhe; Ding, Jane; Peterson, Pärt; Gunning, William T.; Ding, Han-Fei

    2007-01-01

    Medullary thymic epithelial cells function as antigen-presenting cells in negative selection of self-reactive T cell clones, a process essential for the establishment of central self-tolerance. These cells mirror peripheral tissues through promiscuous expression of a diverse set of tissue-restricted self-antigens. The genes and signaling pathways that regulate the development of medullary thymic epithelial cells are not fully understood. Here we show that mice deficient in NF-κB2, a member of the NF-κB family, display a marked reduction in the number of mature medullary thymic epithelial cells that express CD80 and bind the lectin Ulex europaeus agglutinin-1, leading to a significant decrease in the extent of promiscuous gene expression in the thymus of NF-κB2−/− mice. Moreover, NF-κB2−/− mice manifest autoimmunity characterized by multiorgan infiltration of activated T cells and high levels of autoantibodies to multiple organs. A subpopulation of the mice also develops immune-complex glomerulonephritis. These findings identify a physiological function of NF-κB2 in the development of medullary thymic epithelial cells and, thus, the control of self-tolerance induction. PMID:17046818

  11. Epithelial LTβR signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice

    PubMed Central

    Wu, Weiwei; Shi, Yaoyao; Xia, Huan; Chai, Qian; Jin, Caiwei; Ren, Boyang; Zhu, Mingzhao

    2017-01-01

    The establishment of T cell central tolerance critically relies on the development and maintenance of the medullary thymic epithelial cells (mTECs). Disrupted signaling of lymphotoxin beta receptor (LTβR) results in dramatically reduced mTEC population. However, whether LTβR directly or indirectly control mTECs remains undetermined; how LTβR controls this process also remain unclear. In this study, by utilizing K14-Cre × Ltbrfl/fl conditional knockout (cKO) mice, we show that epithelial intrinsic LTβR was essential for the mTEC development postnatally. Mechanistically, LTβR did not directly impact the proliferation or survival of mTECs; the maturation of mTECs from MHC-IIlo to MHC-IIhi stage was also unaltered in the absence of LTβR; interestingly, the number of mTEC progenitors (Cld3,4hiSSEA-1+) was found significantly reduced in LTβR cKO mice at the neonatal stage, but not at E18.5. Consequently, epithelial deficiency of LTβR resulted in significant defect of thymic negative selection as demonstrated using OT-I and RIP-OVA transgenic mouse system. In summary, our study clarifies the epithelial intrinsic role of LTβR on mTEC development and function; more importantly, it reveals a previously unrecognized function of LTβR on the control of the size of mTEC progenitor population. PMID:28290551

  12. Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus.

    PubMed

    Ribeiro, Ana R; Meireles, Catarina; Rodrigues, Pedro M; Alves, Nuno L

    2014-10-01

    Cortical and medullary thymic epithelial cells (cTECs and mTECs, respectively) provide inductive microenvironments for T-cell development and selection. The differentiation pathway of cTEC/mTEC lineages downstream of common bipotent progenitors at discrete stages of development remains unresolved. Using IL-7/CCRL1 dual reporter mice that identify specialized TEC subsets, we show that the stepwise acquisition of chemokine (C-C motif) receptor-like 1 (CCRL1) is a late determinant of cTEC differentiation. Although cTECs expressing high CCRL1 levels (CCRL1(hi) ) develop normally in immunocompetent and Rag2(-/-) thymi, their differentiation is partially blocked in Rag2(-/-) Il2rg(-/-) counterparts. These results unravel a novel checkpoint in cTEC maturation that is regulated by the cross-talk between TECs and immature thymocytes. Additionally, we identify new Ulex europaeus agglutinin 1 (UEA)(+) mTEC subtypes expressing intermediate CCRL1 levels (CCRL1(int) ) that conspicuously emerge in the postnatal thymus and differentially express Tnfrsf11a, Ccl21, and Aire. While rare in fetal and in Rag2(-/-) thymi, CCRL1(int) mTECs are restored in Rag2(-/-) Marilyn TCR-Tg mice, indicating that the appearance of postnatal-restricted mTECs is closely linked with T-cell selection. Our findings suggest that alternative temporally restricted routes of new mTEC differentiation contribute to the establishment of the medullary niche in the postnatal thymus.

  13. UEA-I-binding to thymic medullary epithelial cells selectively reduces numbers of cortical TCRalphabeta+ thymocytes in FTOCs.

    PubMed

    Graziano, M; St-Pierre, Y; Potworowski, E F

    2001-07-02

    Thymic medullary epithelial cells (TMECs) constitute a major stromal cell type, the function of which is incompletely understood. Some TMECs express L-fucose-glycosylated proteins on their plasma membrane; these have been shown to specifically bind the lectin UEA-I. We exploited this observation to investigate the consequences of in situ blockage of TMECs in FTOCs by UEA-I. In UEA-I-treated FTOCs, we noted a decreased cellularity among TCRalphabeta+ but not TCRgammadelta+ cells. In fact, CD3- and CD3lo cortical cells were markedly depleted, while CD3hi cells were unaffected. Since the affected cell subsets are in a different compartment from that where UEA-I binding occurs, it is likely that the effect is mediated through a soluble factor. Two possible mechanisms are proposed: a reduced activation of either TMECs or of medullary thymocytes which normally bind to them, results in lowered production of soluble factors responsible for cortical thymocyte proliferation. Alternately, the binding of UEA-I to TMECs could activate the latter to produce signals inhibitory to cortical thymocytes.

  14. Positive and Negative Regulatory Mechanisms for Fine-Tuning Cellularity and Functions of Medullary Thymic Epithelial Cells

    PubMed Central

    Akiyama, Taishin; Tateishi, Ryosuke; Akiyama, Nobuko; Yoshinaga, Riko; Kobayashi, Tetsuya J.

    2015-01-01

    Self-tolerant T cells and regulatory T cells develop in the thymus. A wide variety of cell–cell interactions in the thymus is required for the differentiation, proliferation, and repertoire selection of T cells. Various secreted and cell surface molecules expressed in thymic epithelial cells (TECs) mediate these processes. Moreover, cytokines expressed by cells of hematopoietic origin regulate the cellularity of TECs. Tumor necrosis factor (TNF) family RANK ligand, lymphotoxin, and CD40 ligand, expressed in T cells and innate lymphoid cells (ILCs), promote the differentiation and proliferation of medullary TECs (mTECs) that play critical roles in the induction of immune tolerance. A recent study suggests that interleukin-22 (IL-22) produced by ILCs promotes regeneration of TECs after irradiation. Intriguingly, tumor growth factor-β and osteoprotegerin limit cellularity of mTECs, thereby attenuating regulatory T cell generation. We will review recent insights into the molecular basis for cell–cell interactions regulating differentiation and proliferation of mTECs and also discuss about a perspective on use of mathematical models for understanding this complicated system. PMID:26441966

  15. Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells

    PubMed Central

    Oliveira, Ernna H.; Macedo, Claudia; Collares, Cristhianna V.; Freitas, Ana Carolina; Donate, Paula Barbim; Sakamoto-Hojo, Elza T.; Donadi, Eduardo A.; Passos, Geraldo A.

    2016-01-01

    Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA–mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA–mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3′ UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA–mRNA network controlling PTAs in mTEC cells. PMID:27933063

  16. Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction.

    PubMed

    Pezzi, Nicole; Assis, Amanda Freire; Cotrim-Sousa, Larissa Cotrim; Lopes, Gabriel Sarti; Mosella, Maritza Salas; Lima, Djalma Sousa; Bombonato-Prado, Karina F; Passos, Geraldo Aleixo

    2016-09-01

    We demonstrate that even a partial reduction of Aire mRNA levels by siRNA-induced Aire knockdown (Aire KD) has important consequences to medullary thymic epithelial cells (mTECs). Aire knockdown is sufficient to reduce Aire protein levels, impair its nuclear location, and cause an imbalance in large-scale gene expression, including genes that encode cell adhesion molecules. These genes drew our attention because adhesion molecules are implicated in the process of mTEC-thymocyte adhesion, which is critical for T cell development and the establishment of central self-tolerance. Accordingly, we consider the following: 1) mTECs contribute to the elimination of self-reactive thymocytes through adhesion; 2) Adhesion molecules play a crucial role during physical contact between these cells; and 3) Aire is an important transcriptional regulator in mTECs. However, its role in controlling mTEC-thymocyte adhesion remains unclear. Because Aire controls adhesion molecule genes, we hypothesized that the disruption of its expression could influence mTEC-thymocyte interaction. To test this hypothesis, we used a murine Aire(+) mTEC cell line as a model system to reproduce mTEC-thymocyte adhesion in vitro. Transcriptome analysis of the mTEC cell line revealed that Aire KD led to the down-modulation of more than 800 genes, including those encoding for proteins involved in cell adhesion, i.e., the extracellular matrix constituent Lama1, the CAM family adhesion molecules Vcam1 and Icam4, and those that encode peripheral tissue antigens. Thymocytes co-cultured with Aire KD mTECs had a significantly reduced capacity to adhere to these cells. This finding is the first direct evidence that Aire also plays a role in controlling mTEC-thymocyte adhesion.

  17. Hypergravity Provokes a Temporary Reduction in CD4+CD8+ Thymocyte Number and a Persistent Decrease in Medullary Thymic Epithelial Cell Frequency in Mice

    PubMed Central

    Miyauchi, Maki; Yoshinaga, Riko; Sasanuma, Hiroki; Kudo, Takashi; Shimbo, Miki; Shinohara, Masahiro; Obata, Koji; Inoue, Jun-ichiro; Shirakawa, Masaki; Shiba, Dai; Asahara, Hiroshi; Yoshida, Nobuaki; Takahashi, Satoru; Morita, Hironobu; Akiyama, Taishin

    2015-01-01

    Gravity change affects many immunological systems. We investigated the effects of hypergravity (2G) on murine thymic cells. Exposure of mice to 2G for three days reduced the frequency of CD4+CD8+ thymocytes (DP) and mature medullary thymic epithelial cells (mTECs), accompanied by an increment of keratin-5 and keratin-8 double-positive (K5+K8+) TECs that reportedly contain TEC progenitors. Whereas the reduction of DP was recovered by a 14-day exposure to 2G, the reduction of mature mTECs and the increment of K5+K8+ TEC persisted. Interestingly, a surgical lesion of the inner ear’s vestibular apparatus inhibited these hypergravity effects. Quantitative PCR analysis revealed that the gene expression of Aire and RANK that are critical for mTEC function and development were up-regulated by the 3-day exposure and subsequently down-regulated by the 14-day exposure to 2G. Unexpectedly, this dynamic change in mTEC gene expression was independent of the vestibular apparatus. Overall, data suggest that 2G causes a temporary reduction of DP and a persistent reduction of mature mTECs in a vestibular system-dependent manner, and also dysregulates mTEC gene expression without involving the vestibular system. These data might provide insight on the impact of gravity change on thymic functions during spaceflight and living. PMID:26513242

  18. Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

    PubMed Central

    Alexandropoulos, Konstantina; Bonito, Anthony J.; Weinstein, Erica G.; Herbin, Olivier

    2015-01-01

    Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease. PMID:25603179

  19. Feedback inhibition of thymic secretory activity in mice treated by the thymic extract TP-1 (thymostimulin).

    PubMed Central

    Shoham, J; Ben-David, E; Sandbank, U

    1982-01-01

    The ultrastructural changes occurring in the medullary epithelium of the thymus of young mice, as a result of repeated injections of thymic extract, TP-1 (thymostimulin) was investigated. After daily injection of TP-1 for 3 weeks, no changes in thymus architecture could be observed by light microscopy. However, by electron microscopy, specific changes were noticed in the epithelial cells. The secretory granules became dilated and engorged; diameter of granules in normal control thymus was approximately 200-250 nm, but reached 1000 nm in treated mice. Degenerative changes appeared in some of these granules, including myelin bodies, distorted configuration and fat droplets. Signs of involution of whole cells and presence of cellular debri within macrophages were observed. Acid phosphatase staining disclosed many lysosomes containing ingested granules. No such findings were observed in control untreated mice, or in mice treated by a heart extract similarly prepared to TP-1. All these findings can be taken as ultrastructural evidence for feedback inhibition of thymic secretory activity, in analogy to the changes occurring other feedback inhibited, peptide hormone secreting glands. The data indicate that (i) the thymus respond to feedback inhibitory stimuli, as other endocrine glands do; (ii)TP-1, the thymic extract under study, contains a physiologically significant thymic hormone, which, when introduced in high doses can exert specific feedback inhibition. This can be taken as an additional, new criterion for the definition of thymic hormones. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:7056566

  20. Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection.

    PubMed

    Liu, Haiyin; Jain, Reema; Guan, Jing; Vuong, Vivian; Ishido, Satoshi; La Gruta, Nicole L; Gray, Daniel H; Villadangos, Jose A; Mintern, Justine D

    2016-08-22

    Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8(-/-) mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)(-) medullary TECs (mTECs), but not AIRE(+) mTECs. Despite this, thymic and splenic CD4(+) T cell numbers and repertoires remained unaltered in March8(-/-) mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83(anu/anu) mice) have impaired CD4(+) T cell selection, but deleting March8 in Cd83(anu/anu) mice restored CD4(+) T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4(+) T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.

  1. Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection

    PubMed Central

    Guan, Jing; La Gruta, Nicole L.; Gray, Daniel H.

    2016-01-01

    Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type–specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8−/− mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)− medullary TECs (mTECs), but not AIRE+ mTECs. Despite this, thymic and splenic CD4+ T cell numbers and repertoires remained unaltered in March8−/− mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/anu mice restored CD4+ T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4+ T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation. PMID:27503069

  2. Epithelium

    MedlinePlus

    The term "epithelium" refers to layers of cells that line hollow organs and glands. It is also those cells that make ... Epithelium. In: Kierszenbaum AL, Tres LL. Histology and Cell Biology - An Introduction to Pathology , 3rd ed. Philadelphia, ...

  3. Improved method for freeze-fracture radioautography of tissues and cells, as applied to duodenal epithelium and thymic lymphocytes

    SciTech Connect

    Kan, F.W.; Kopriwa, B.M.; Leblond, C.P.

    1984-01-01

    An improved method has been devised for the localization of radioactive substances to either one of the leaflets of cellular membranes. After tissue specimens are freeze-fractured and covered with a platinum-carbon replica, they are freeze-dried to allow coating with radioautographic emulsion at room temperature. After exposure at 4 degrees C and development, the emulsion is protected by layers of carbon and grease before the tissue underlying the replica is dissolved in sodium hypochlorite. The grease is removed in Freon 14 and the replica with its emulsion cover is mounted on a specimen grid for electron microscopic examination. The accuracy of radioactivity localization was demonstrated using /sup 3/H-thymidine-labeled liver by finding silver grains over the same sites after freeze-fracture as after thin section radioautography. Tests with /sup 3/H-methacrylate revealed that the interposition of a platinum-carbon replica decreased the radioautographic reaction by over 80%; hence, the need for long exposure. Only 67% of the silver grains came from radiation sources located beyond the upper 0.05 micron of the specimen and, therefore, the emulsion could be affected by radiation sources located not only within membrane leaflets but also in nearby cytoplasm. Thus, when /sup 3/H-fucose was injected into rats to locate newly formed glycoproteins within intestinal epithelium membranes, some of the silver grains found over E and P faces might be produced by radiation coming from the adjacent cytoplasm. To localize label within membrane leaflets in the absence of radiation sources in the cytoplasm, lymphocyte suspensions were incubated with /sup 3/H-concanavalin A at 0 degrees C. The plasmalemma radioactivity was then restricted to the two membrane leaflets, with 87-93% of the silver grains on the E leaflet and 7-13% on the P leaflet.

  4. Thymic crosstalk restrains the pool of cortical thymic epithelial cells with progenitor properties.

    PubMed

    Meireles, Catarina; Ribeiro, Ana R; Pinto, Rute D; Leitão, Catarina; Rodrigues, Pedro M; Alves, Nuno L

    2017-03-20

    Cortical (cTEC) and medullary (mTEC) thymic epithelial cells establish key microenvironments for T-cell differentiation and arise from thymic epithelial cell progenitors (TEP). However, the nature of TEPs and the mechanism controlling their stemness in the postnatal thymus remain poorly defined. Using TEC clonogenic assays as a surrogate to survey TEP activity, we found that a fraction of cTECs generates specialized clonal-derived colonies, which contain cells with sustained colony-forming capacity (ClonoTECs). These ClonoTECs are EpCAM+MHCII-Foxn1lo cells that lack traits of mature cTECs or mTECs but co-express stem-cell markers, including CD24 and Sca-1. Supportive of their progenitor identity, ClonoTECs reintegrate within native thymic microenvironments and generate cTECs or mTECs in vivo. Strikingly, the frequency of cTECs with the potential to generate ClonoTECs wanes between the postnatal and young adult immunocompetent thymus, but it is sustained in alymphoid Rag2-/-Il2rg-/- counterparts. Conversely, transplantation of wild-type bone marrow hematopoietic progenitors into Rag2-/-Il2rg-/- mice and consequent restoration of thymocyte-mediated TEC differentiation diminishes the frequency of colony-forming units within cTECs. Our findings provide evidence that the cortical epithelium contains a reservoir of epithelial progenitors whose abundance is dynamically controlled by continual interactions with developing thymocytes across lifespan. This article is protected by copyright. All rights reserved.

  5. 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

  6. 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.

  7. Intestinal lymphangiectasia and thymic hypoplasia.

    PubMed Central

    Sorensen, R U; Halpin, T C; Abramowsky, C R; Hornick, D L; Miller, K M; Naylor, P; Incefy, G S

    1985-01-01

    We have evaluated the immunological abnormalities present in a 6 year old patient with primary intestinal and generalized lymphangiectasia confirmed by intestinal, lung and lymph node biopsies. Lymphocyte loss through the gut was confirmed by the detection of lymphocytes in her stool. An increased enteric protein loss was suggested by hypoproteinaemia, peripheral oedema, and a very short half-life for i.v. immune serum globulin (3 days). Lymphocyte subpopulation analysis revealed a selective loss of T lymphocytes, with a proportionally increased loss of the OKT4 positive helper/inducer subpopulation. Functionally, there was a decrease in proliferative responses to some mitogens and to allogeneic cells, and a lack of T cell help for in vitro B lymphocyte differentiation into immunoglobulin secreting cells. Natural killer function was normal. In this patient, a concomitant thymic deficiency was documented by failure to identify thymic tissue on a thymus biopsy and by an absence or decrease of the serum thymic factor (thymulin) and thymosin alpha 1. No compensatory lymphopoiesis was detected in the bone marrow. In an attempt to increase T lymphocyte development, the patient was treated with thymosin fraction 5. Daily treatment with this preparation resulted in a transient clinical improvement which could not be sustained on a weekly thymosin treatment schedule. However, lymphocyte numbers did not increase during this treatment. The findings in this patient support the notion that T lymphocytes are needed to stimulate thymic epithelium. In situations of excessive loss of long lived T lymphocytes a secondary thymic atrophy may occur and further contribute to the development of a deficiency in cell-mediated immunity. Images Fig. 1 Fig. 2 PMID:3971596

  8. Bilateral Thyroid and Ultimobranchial Medullary Carcinoma.

    PubMed

    Patey, Martine; Flament, Jean Bernard; Caron, Jean; Delisle, Marie Joelle; Delemer, Brigitte; Pluot, Michel

    1996-01-01

    The ultimobranchial bodies in human embryos develop from the fourth and fifth branchial pouch complexes along with thymic and parathyroid tissue. They become incorporated within the lateral thyroid lobes and are believed to be involved in the development of C-cells. We report a case of an unusual bilateral thyroid and neck prelaryngeal medullary carcinoma in a 23-year-old male patient who belongs to a multiple endocrine neoplasia type 2a (MEN type 2a) family with thyroid tumors and pheochromocytomas. The medullary carcinoma was located in an abnormal cystic structure that seems to be a remnant of the ultimobranchial body (UBB) in the neck. Within the contralateral thyroid lobe, the medullary carcinoma was associated with C-cell hyperplasia.

  9. Thyroid cancer - medullary carcinoma

    MedlinePlus

    Thyroid - medullary carcinoma; Cancer - thyroid (medullary carcinoma); MTC; Thyroid nodule - medullary ... in children and adults. Unlike other types of thyroid cancer, MTC is less likely to be caused by ...

  10. Expression of nerve growth factor is upregulated in the rat thymic epithelial cells during thymus regeneration following acute thymic involution.

    PubMed

    Lee, Hee-Woo; Kim, Sung-Min; Shim, Na-Ri; Bae, Soo-Kyung; Jung, Il-Gun; Kwak, Jong-Young; Kim, Bong-Seon; Kim, Jae-Bong; Moon, Jeon-Ok; Chung, Joo-Seop; Yoon, Sik

    2007-06-07

    Neuroimmune networks in the thymic microenvironment are thought to be involved in the regulation of T cell development. Nerve growth factor (NGF) is increasingly recognized as a potent immunomodulator, promoting "cross-talk" between various types of immune system cells. The present study describes the expression of NGF during thymus regeneration following acute involution induced by cyclophosphamide in the rat. Immunohistochemical stain demonstrated not only the presence of NGF but also its upregulated expression mainly in the subcapsular, paraseptal, and perivascular epithelial cells, and medullary epithelial cells including Hassall's corpuscles in both the normal and regenerating thymus. Biochemical data obtained using Western blot and RT-PCR supported these results and showed that thymic extracts contain NGF protein and mRNA, at higher levels during thymus regeneration. Thus, our results suggest that NGF expressed in these thymic epithelial cells plays a role in the T lymphopoiesis associated with thymus regeneration during recovery from acute thymic involution.

  11. Stabilized beta-catenin in thymic epithelial cells blocks thymus development and function.

    PubMed

    Zuklys, Saulius; Gill, Jason; Keller, Marcel P; Hauri-Hohl, Mathias; Zhanybekova, Saule; Balciunaite, Gina; Na, Kyung-Jae; Jeker, Lukas T; Hafen, Katrin; Tsukamoto, Noriyuki; Amagai, Takashi; Taketo, Makoto M; Krenger, Werner; Holländer, Georg A

    2009-03-01

    Thymic T cell development is dependent on a specialized epithelial microenvironment mainly composed of cortical and medullary thymic epithelial cells (TECs). The molecular programs governing the differentiation and maintenance of TECs remain largely unknown. Wnt signaling is central to the development and maintenance of several organ systems but a specific role of this pathway for thymus organogenesis has not yet been ascertained. In this report, we demonstrate that activation of the canonical Wnt signaling pathway by a stabilizing mutation of beta-catenin targeted exclusively to TECs changes the initial commitment of endodermal epithelia to a thymic cell fate. Consequently, the formation of a correctly composed and organized thymic microenvironment is prevented, thymic immigration of hematopoietic precursors is restricted, and intrathymic T cell differentiation is arrested at a very early developmental stage causing severe immunodeficiency. These results suggest that a precise regulation of canonical Wnt signaling in thymic epithelia is essential for normal thymus development and function.

  12. Thymic epithelial cell development and its dysfunction in human diseases.

    PubMed

    Sun, Lina; Li, Hongran; Luo, Haiying; Zhao, Yong

    2014-01-01

    Thymic epithelial cells (TECs) are the key components in thymic microenvironment for T cells development. TECs, composed of cortical and medullary TECs, are derived from a common bipotent progenitor and undergo a stepwise development controlled by multiple levels of signals to be functionally mature for supporting thymocyte development. Tumor necrosis factor receptor (TNFR) family members including the receptor activator for NF κ B (RANK), CD40, and lymphotoxin β receptor (LT β R) cooperatively control the thymic medullary microenvironment and self-tolerance establishment. In addition, fibroblast growth factors (FGFs), Wnt, and Notch signals are essential for establishment of functional thymic microenvironment. Transcription factors Foxn1 and autoimmune regulator (Aire) are powerful modulators of TEC development, differentiation, and self-tolerance. Dysfunction in thymic microenvironment including defects of TEC and thymocyte development would cause physiological disorders such as tumor, infectious diseases, and autoimmune diseases. In the present review, we will summarize our current understanding on TEC development and the underlying molecular signals pathways and the involvement of thymus dysfunction in human diseases.

  13. Thymic immunopathology and progression of SIVsm infection in cynomolgus monkeys.

    PubMed

    Li, S L; Kaaya, E E; Ordónez, C; Ekman, M; Feichtinger, H; Putkonen, P; Böttiger, D; Biberfeld, G; Biberfeld, P

    1995-05-01

    Thymuses from 22 cynomolgus monkeys infected with simian immunodeficiency virus (SIVsm) developed characteristic cortical and medullary changes including formation of B-cell follicles (8/21) and accumulation of virus immune complexes. Advanced thymic histopathology was correlated with more pronounced immunodeficiency. SIVsm provirus was detected by polymerase chain reaction (PCR) in most (16/18) thymuses and spliced viral env mRNA in 3 (3/7) thymuses with advanced histopathologic changes indicative of thymic SIVsm replication. By combined in situ hybridization (ISH) and immunohistochemistry, viral RNA was localized mainly to the follicular dendritic network, macrophages, multinucleated giant cells, and lymphocytes of the medullary regions. Latent infection by an Epstein-Barr-related herpesvirus (HVMF1) was also found by PCR and by ISH in medullary regions of three (3 of 8) thymuses with B-cell follicles, suggestive of an inductive role for B-cell proliferation in these thymuses. In a control group of HIV-2-infected nonimmunosuppressed monkeys, no comparable thymic changes were observed. Our results indicate that SIV, and probably by analogy HIV, can have direct and diverse pathogenic effects on the thymus that are important in the development of simian (human) AIDS.

  14. 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.

  15. 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.

  16. Is There an Interspecific Diversity of the Thymic Microenvironment?

    PubMed Central

    de Souza, Lucia Renata Meireles; Trajano, Valeria

    1993-01-01

    Thymic epithelial cells (TEC) heterogeneity suggests the existence of functional subsets. Anti-cytokeratin (Anti-CK) monoclonal antibodies (MAb), markers of epithelial differentiation, have been used to detect TEC subsets in rodents and humans. These MAb revealed a different topography of CK-defined TEC subsets in mice and humans, leading us to carry out a comparative study of mammalian thymuses. Our study showed that the distribution pattern of cytokeratins in the thymic epithelium is complex and unique, with coexpression of CK typical of simple and stratified epithelia. Moreover, we demonstrated an interspecific diversity of CK expression within the thymic lobules. Interestingly, such diversity was not a general phenomenon for the expression of any thymic microenvironmental proteins, because the location of extracellular matrix components was essentially similar in the mammalian species studied. PMID:7507744

  17. Functional anatomy of the thymic microenvironment.

    PubMed Central

    Kendall, M D

    1991-01-01

    This paper presents a review of our current understanding of the nature of the thymic microenvironment, after briefly considering the major role of the gland. The epithelial cells and their products are of fundamental importance, and other cells of the macrophage series are implicated in most functional events. The embryological origin of the epithelium is still not clear, although disease conditions would suggest a single origin. Immigration and emigration of thymocytes is considered, and also the passage of antigens into the gland. The events within the thymus are under the control of the CNS acting through the innervation or via hormonal pathways. Both of these areas are considered in detail, especially thymic hormone origins, functions and interactions. Images Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 11 PMID:1769884

  18. The contribution of thymic stromal abnormalities to autoimmune disease.

    PubMed

    Fletcher, Anne L; Calder, Adrienne; Hince, Melanie N; Boyd, Richard L; Chidgey, Ann P

    2011-01-01

    In essence, normal thymus function involves the production of a broad repertoire of αβT cells capable of responding to foreign antigens with low risk of autoreactivity. Thymic epithelial cells are an essential component of the thymic stromal microenvironment, promoting the growth and export of self-tolerant thymocytes. Autoimmune disease, resulting from a loss of self-tolerance, is clinically and genetically complex, and accordingly has many potential etiological origins. However, it is commonly linked to defects in the thymic epithelial microenvironment. The study of autoimmune-linked thymic stromal dysfunction has indisputably advanced our understanding of T cell tolerance; notably, a field-wide paradigm shift occurred when autoimmune regulator (Aire) was found to drive expression of a multitude of peripheral tissue-restricted antigens in medullary thymic epithelial cells. Many other associations with polygenically controlled autoimmune diseases have been reported but are more difficult to definitively dissect. Paradoxically, immunodeficiency and age-related immunosenescence are also linked with increased autoimmunity. Here we discuss the theoretical basis and the evidence gathered thus far to support these associations.

  19. Selection of antibodies to cell surface determinants on mouse thymic epithelial cells using a phage display library.

    PubMed Central

    Palmer, D B; George, A J; Ritter, M A

    1997-01-01

    The network of thymic epithelium contributes significantly to the thymic stromal cell environment, which plays a vital role in the generation and maturation of thymocytes. Monoclonal antibodies (mAb) have revealed considerable heterogeneity within this epithelial component of the mouse thymic microenvironment, but many of these antibodies recognize epitopes that are located inside the cell and so cannot be used in functional studies. As an alternative approach to isolate antibodies specific to thymic epithelium, we used a phage display library expressing single chain Fv antibodies. For selection, a thymic cell suspension was incubated with the phage display library, and major histocompatibility complex class II positive cells, the majority of which are epithelial, were then specifically selected. Phage bound to these cells were eluted and the selection procedure was repeated for a further five rounds. Immunohistochemical analysis revealed that these phage antibodies show differential staining of thymic epithelial subsets. Flow cytometric analysis of a thymic epithelial cell line using a panel of these antibodies demonstrated that they recognize epitopes on the cell surface. Furthermore, some of these antibodies also labelled human thymic epithelium, suggesting that the epitopes recognized by these antibodies are conserved between human and rodent thymus. Our approach therefore provides a rapid method to select antibodies specific for thymic epithelial cell surface determinants in their native configuration. Images Figure 2 Figure 3 PMID:9301539

  20. Established thymic epithelial progenitor/stem cell-like cell lines differentiate into mature thymic epithelial cells and support T cell development.

    PubMed

    Chen, Pengfei; Zhang, Jun; Zhan, Yu; Su, Juanjuan; Du, Yarui; Xu, Guoliang; Shi, Yufang; Siebenlist, Ulrich; Zhang, Xiaoren

    2013-01-01

    Common thymic epithelial progenitor/stem cells (TEPCs) differentiate into cortical and medullary thymic epithelial cells (TECs), which are required for the development and selection of thymocytes. Mature TEC lines have been widely established. However, the establishment of TEPC lines is rarely reported. Here we describe the establishment of thymic epithelial stomal cell lines, named TSCs, from fetal thymus. TSCs express some of the markers present on tissue progenitor/stem cells such as Sca-1. Gene expression profiling verifies the thymic identity of TSCs. RANK stimulation of these cells induces expression of autoimmune regulator (Aire) and Aire-dependent tissue-restricted antigens (TRAs) in TSCs in vitro. TSCs could be differentiated into medullary thymic epithelial cell-like cells with exogenously expressed NF-κB subunits RelB and p52. Importantly, upon transplantation under the kidney capsules of nude mice, TSCs are able to differentiate into mature TEC-like cells that can support some limited development of T cells in vivo. These findings suggest that the TSC lines we established bear some characteristics of TEPC cells and are able to differentiate into functional TEC-like cells in vitro and in vivo. The cloned TEPC-like cell lines may provide useful tools to study the differentiation of mature TEC cells from precursors.

  1. Human thymic epithelial primary cells produce exosomes carrying tissue-restricted antigens

    PubMed Central

    Skogberg, Gabriel; Lundberg, Vanja; Berglund, Martin; Gudmundsdottir, Judith; Telemo, Esbjörn; Lindgren, Susanne; Ekwall, Olov

    2015-01-01

    Exosomes are nano-sized vesicles released by cells into the extracellular space and have been shown to be present in thymic tissue both in mice and in humans. The source of thymic exosomes is however still an enigma and hence it is not known whether thymic epithelial cells (TECs) are able to produce exosomes. In this work, we have cultured human TECs and isolated exosomes. These exosomes carry tissue-restricted antigens (TRAs), for example, myelin basic protein and desmoglein 3. The presence of TRAs indicates a possible role for thymic epithelium-derived exosomes in the selection process of thymocytes. The key contribution of these exosomes could be to disseminate self-antigens from the thymic epithelia, thus making them more accessible to the pool of maturing thymocytes. This would increase the coverage of TRAs within the thymus, and facilitate the process of positive and negative selection. PMID:25776846

  2. Thymic hormone-containing cells. Characterization and localization of serum thymic factor in young mouse thymus studied by monoclonal antibodies

    PubMed Central

    1982-01-01

    The characterization and distribution of cells containing the serum thymic factor (FTS) in the thymus of young mice was studied by immunofluorescence using monoclonal anti-FTS antibodies. FTS+ cells were distributed throughout the thymic parenchyma but were more frequent in the medullary region than in the cortex. FTS-containing cells presented a stellate or globular aspect, and some of them exhibited fluorescent cytoplasmic granules. The epithelial nature of FTS+ cells was confirmed by double-labeling experiments using an anti- keratin antiserum (as an epithelial cell marker). Nevertheless, only a minority of keratin-positive epithelial reticular cells contained FTS. All controls, including the incubation of sections from nonthymic tissues with the anti-FTS antibodies, were negative. Taken together, these results confirm the exclusive localization of FTS-containing cells within the mouse thymus. PMID:7047671

  3. S1P lyase in thymic perivascular spaces promotes egress of mature thymocytes via up-regulation of S1P receptor 1.

    PubMed

    Maeda, Yasuhiro; Yagi, Hideki; Takemoto, Kana; Utsumi, Hiroyuki; Fukunari, Atsushi; Sugahara, Kunio; Masuko, Takashi; Chiba, Kenji

    2014-05-01

    Sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P1) play an important role in the egress of mature CD4 or CD8 single-positive (SP) thymocytes from the thymus. Fingolimod hydrochloride (FTY720), an S1P1 functional antagonist, induced significant accumulation of CD62L(high)CD69(low) mature SP thymocytes in the thymic medulla. Immunohistochemical staining using anti-S1P1 antibody revealed that S1P1 is predominantly expressed on thymocytes in the thymic medulla and is strongly down-regulated even at 3h after FTY720 administration. 2-Acetyl-4-tetrahydroxybutylimidazole (THI), an S1P lyase inhibitor, also induced accumulation of mature SP thymocytes in the thymic medulla with an enlargement of the perivascular spaces (PVS). At 6h after THI administration, S1P1-expressing thymocytes reduced partially as if to form clusters and hardly existed in the proximity of CD31-expressing blood vessels in the thymic medulla, suggesting S1P lyase expression in the cells constructing thymic medullary PVS. To determine the cells expressing S1P lyase in the thymus, we newly established a mAb (YK19-2) specific for mouse S1P lyase. Immunohistochemical staining with YK19-2 revealed that S1P lyase is predominantly expressed in non-lymphoid thymic stromal cells in the thymic medulla. In the thymic medullary PVS, S1P lyase was expressed in ER-TR7-positive cells (reticular fibroblasts and pericytes) and CD31-positive vascular endothelial cells. Our findings suggest that S1P lyase expressed in the thymic medullary PVS keeps the tissue S1P concentration low around the vessels and promotes thymic egress via up-regulation of S1P1.

  4. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. I. Growth conditions and morphology of murine thymic epithelial and mesenchymal cells.

    PubMed

    Eshel, I; Savion, N; Shoham, J

    1990-03-01

    We report here the successful selective cultivation of murine thymic mesenchymal reticular cells (MTMC) and murine thymic epithelial cells (MTEC) grown on extracellular matrix in the presence of defined medium. The selective growth of these two cell types was based on 1) conditions of tissue disruption and 2) differential growth requirements. Both cell types were dependent on transferrin, high density lipoproteins, insulin, hydrocortisone, and epidermal growth factor, whereas MTMC was dependent also on selenium and 3,5,3'-triiodothyronine. The elimination of single factors or extracellular matrix resulted in specific and different changes in the growth pattern of each cell subpopulation. Cells of both types exhibited the ultrastructural features of high metabolic activity. The epithelial nature of MTEC cultures was defined by bundles of tonofilaments and desmosomes and by positive staining to keratins and negative to vimentin. In addition MTEC were positively stained with mAb to thymic medullary epithelial cells and by Ulex europeus agglutinin, and were able to form Hassall's corpuscles, suggesting their medullary origin. MTEC were also H-2 and Ia positive. In contrast MTMC were positive for vimentin and periodic acid-Schiff, low positive for H-2, and negative for keratin and Ia. Both cells did not contain nonspecific esterase, nor did they phagocytize latex beads. With the use of all these criteria we classified MTEC as epithelial cells from the medullary compartment of the thymus and MTMC as reticular cells of mesenchymal origin.

  5. Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

    PubMed

    Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

    2014-01-01

    Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

  6. Expression of RAGE and HMGB1 in Thymic Epithelial Tumors, Thymic Hyperplasia and Regular Thymic Morphology

    PubMed Central

    Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

    2014-01-01

    Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (p<0.001). HMGB1 nuclear staining was strongest in A and AB, and gradually less in B1 = B2>B3>thymic carcinoma (p<0.001). Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none), B1 (strong), B2 (moderate), B3 and thymic carcinoma (weak); (p<0.001). Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer. PMID:24705787

  7. Conus medullaris stroke

    PubMed Central

    Alanazy, Mohammed H.

    2016-01-01

    Absent F wave in the stage of spinal shock has been described in cases of traumatic spinal cord injury. The role of F wave in predicting prognosis after conus medullaris infarct has not been described. We describe herein a middle aged-man with a conus medullaris infarct. Both tibial and peroneal F waves were absent on day 4. The left tibial F wave reappeared in the following study on day 18. All F waves reappeared on day 56 at which time the patient was still wheelchair bound. He regained walking on day 105. We hypothesize that reappearance of initially absent F waves post conus medullaris infarct is a good prognostic sign for the return of ambulation. The applicability of this observation requires further research. We also discuss clinical and diagnostic caveats in this case. PMID:27356660

  8. Renal Medullary Interstitial Cells

    NASA Astrophysics Data System (ADS)

    Rao, Reena; Hao, Chuan-Ming; Breyer, Matthew D.

    2007-04-01

    Renal medullary interstitial cells (RMICs) are specialized fibroblast-like cells that reside in the renal medulla among the vasa recta, the thin limbs of Henle's loop, and medullary collecting ducts. These cells are characterized by abundant lipid droplets in the cytoplasm. The lipid droplets are composed of triglycerides, cholesterol esters and free long-chain fatty acids, including arachidonic acid. RMICs are also a major site of cyclooxygenase2 (COX-2) expression, and thus a major site of COX-2 derived prostanoid biosynthesis. RMICs are also a potential target of hormones such as angiotensin II and endothelin. The RMIC COX-2 expression and the abundance of lipid droplets change with salt and water intake. These properties of RMICs are consistent with an important role of these cells in modulating physiologic and pathologic processes of the kidney.

  9. Renal medullary carcinomas: histopathologic phenotype associated with diverse genotypes.

    PubMed

    Gatalica, Zoran; Lilleberg, Stan L; Monzon, Federico A; Koul, Manika Sapru; Bridge, Julia A; Knezetic, Joseph; Legendre, Ben; Sharma, Poonam; McCue, Peter A

    2011-12-01

    Chromosomal abnormalities and gene mutations have become major determinants in the classification of kidney carcinomas. Most renal medullary carcinomas develop in patients with hereditary sickle cell disease, but sporadic cases unassociated with sickle cell disease have also been described, for which underlying genetic abnormality is unknown. We evaluated 3 patients with renal medullary carcinoma (1 patient with sickle cell disease and 2 patients without sickle cell disease) for germ line and somatic mutations in genes commonly involved in pathogenesis of renal carcinomas using denaturing high-performance liquid chromatography and direct sequencing. Chromosomal abnormalities were studied by the conventional cytogenetic and SNP arrays analysis. Expression of hypoxia-inducible factor 1α was examined using immunohistochemistry. Two new mutations in the gene for fumarate hydratase were identified in 1 case of medullary renal carcinoma without sickle cell disease: a germ line mutation in exon 6 (R233H) and an acquired (somatic) mutation in exon 8 (P374S). No fumarate hydratase mutations were identified in the other 2 patients. The second sporadic case of renal medullary carcinoma harbored double somatic mutations in von Hippel-Lindau gene, and renal medullary carcinoma in the patient with sickle cell disease showed von Hippel-Lindau gene promoter methylation (epigenetic silencing). No consistent pattern of chromosomal abnormalities was found between 2 cases tested. All 3 cases showed increased hypoxia-inducible factor 1α expression. Medullary renal carcinomas from patients with or without sickle cell disease show involvement of genes important in hypoxia-induced signaling pathways. Generalized cellular hypoxia (in sickle cell disease) or pseudohypoxia (in tumors with fumarate hydratase and von Hippel-Lindau mutations or epigenetic silencing) may act alone or in concert at the level of medullary tubular epithelium to promote development of this rare type of renal

  10. General Information about 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 ...

  11. Treatment Options for Thymoma and Thymic Carcinoma

    MedlinePlus

    ... Thymoma & Thymic Carcinoma Treatment Thymoma and Thymic Carcinoma Treatment (PDQ®)–Patient Version General Information About Thymoma and ... Certain factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment ...

  12. The Role of Thymic Stromal Lymphopoietin (TSLP) in Allergic Disorders

    PubMed Central

    Ziegler, Steven F.

    2010-01-01

    Summary The importance of the epithelium in initiating and controlling immune responses is becoming more appreciated. For example, allergens contact first occurs at mucosal sites in exposed to the external environment such as the skin, airways and gastrointestinal tract. This exposure leads to the production of a variety of cytokines and chemokines that are involved in driving allergic inflammatory responses. One such product is thymic stromal lymphopoietin (TSLP). Recent studies, in both humans and mouse models, have implicated TSLP in the development and progression of atopy and atopic diseases. This review will discuss this work and place TSLP in the inflammatory cascade that leads to allergic disease. PMID:21109412

  13. Thymic deficiency in Down's syndrome.

    PubMed

    Levin, S; Schlesinger, M; Handzel, Z; Hahn, T; Altman, Y; Czernobilsky, B; Boss, J

    1979-01-01

    Children with Down's syndrome (DS) often have small and abnormal thymuses, with lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation--a picture resembling thymic involution. Besides this, they have markedly enlarged Hassall's corpuscles, some surrounded by a sheath of lymphocytes. Patients with DS are known to have increased numbers of respiratory infections; they also have a higher incidence of lymphatic leukemia than do individuals who do not have DS. Studies of cell-mediated (thymic-dependent) immunity demonstrate that children with DS have both diminished numbers of T cells as well as functional deficiency of these cells.

  14. 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.

  15. TSCOT+ thymic epithelial cell-mediated sensitive CD4 tolerance by direct presentation.

    PubMed

    Ahn, Sejin; Lee, Gwanghee; Yang, Soo Jung; Lee, Deokjae; Lee, Seunghyuk; Shin, Hyo Sun; Kim, Min Cheol; Lee, Kee Nyung; Palmer, Douglas C; Theoret, Marc R; Jenkinson, Eric J; Anderson, Graham; Restifo, Nicholas P; Kim, Moon Gyo

    2008-08-05

    Although much effort has been directed at dissecting the mechanisms of central tolerance, the role of thymic stromal cells remains elusive. In order to further characterize this event, we developed a mouse model restricting LacZ to thymic stromal cotransporter (TSCOT)-expressing thymic stromal cells (TDLacZ). The thymus of this mouse contains approximately 4,300 TSCOT+ cells, each expressing several thousand molecules of the LacZ antigen. TSCOT+ cells express the cortical marker CDR1, CD40, CD80, CD54, and major histocompatibility complex class II (MHCII). When examining endogenous responses directed against LacZ, we observed significant tolerance. This was evidenced in a diverse T cell repertoire as measured by both a CD4 T cell proliferation assay and an antigen-specific antibody isotype analysis. This tolerance process was at least partially independent of Autoimmune Regulatory Element gene expression. When TDLacZ mice were crossed to a novel CD4 T cell receptor (TCR) transgenic reactive against LacZ (BgII), there was a complete deletion of double-positive thymocytes. Fetal thymic reaggregate culture of CD45- and UEA-depleted thymic stromal cells from TDLacZ and sorted TCR-bearing thymocytes excluded the possibility of cross presentation by thymic dendritic cells and medullary epithelial cells for the deletion. Overall, these results demonstrate that the introduction of a neoantigen into TSCOT-expressing cells can efficiently establish complete tolerance and suggest a possible application for the deletion of antigen-specific T cells by antigen introduction into TSCOT+ cells.

  16. Alterations of Thymic Epithelial Cells in Lipopolysaccharide-induced Neonatal Thymus Involution

    PubMed Central

    Zhou, Yong-Jie; Peng, Hua; Chen, Yan; Liu, Ya-Lan

    2016-01-01

    Background: Vascular endothelial growth factor (VEGF) in the thymus was mainly produced by the thymic epithelial cells (TECs), the predominant component of the thymic microenvironment. The progression of TECs and the roles of VEGF in the neonatal thymus during sepsis have not been reported. This study aimed to explore the alterations of TECs and VEGF level in the neonatal thymus involution and to explore the possible mechanisms at the cellular level. Methods: By establishing a model of clinical sepsis, the changes of TECs were measured by hematoxylin-eosin staining, confocal microscopy, and flow cytometry. Moreover, the levels of VEGF in serum and thymus were assessed based on enzyme-linked immunosorbent assay and Western blotting. Results: The number of thymocytes and TECs was significantly decreased 24 h after lipopolysaccharide (LPS) challenge, (2.40 ± 0.46)×107 vs. (3.93 ± 0.66)×107 and (1.16 ± 0.14)×105 vs. (2.20 ± 0.19)×105, P < 0.05, respectively. Cortical TECs and medullary TECs in the LPS-treated mice were decreased 1.5-fold and 3.9-fold, P < 0.05, respectively, lower than those in the controls. The number of thymic epithelial progenitors was also decreased. VEGF expression in TECs was down-regulated in a time-dependent manner. Conclusion: VEGF in thymic cells subsets might contribute to the development of TECs in neonatal sepsis. PMID:26712434

  17. Medullary thyroid carcinoma.

    PubMed

    Leboulleux, Sophie; Baudin, Eric; Travagli, Jean-Paul; Schlumberger, Martin

    2004-09-01

    Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells that produce calcitonin (CT), and accounts for 5-10% of all thyroid cancers. MTC is hereditary in about 25% of cases. The discovery of a MTC in a patient has several implications: disease extent should be evaluated, phaeochromocytoma and hyperparathyroidism should be screened for and whether the MTC is sporadic or hereditary should be determined by a direct analysis of the RET proto-oncogene. In this review, pathological characteristics, tumour markers and genetic abnormalities in MTC are discussed. The diagnostic and therapeutic modalities applied to patients with clinical MTC and those identified with preclinical disease through familial screening are also described. Progresses concerning genetics, initial treatment, follow-up, screening and treatment of pheochromocytoma have permitted an improvement in the long-term outcome. However, there is no effective treatment for distant metastases, and new therapeutic modalities are urgently needed.

  18. Renal Medullary Carcinoma; A Rare Entity

    PubMed Central

    Çalışkan, Selahattin; Gökçe, Ali Murat; Gümrükçü, Gülistan; Önenerk, Mine

    2017-01-01

    Renal medullary carcinoma (RMC) is an uncommon aggressive neoplasm of the kidney. RMC is biologically aggressive with a very poor prognosis, and metastasis is seen in up to 95% of the patients at diagnosis or shortly thereafter. The common sites of metastasis are respectively lymph nodes, lungs, livers, and adrenal glands in order of frequency. The presence of poorly differentiated eosinophilic cells in a characteristic fibro-inflammatory stroma is seen in histological examination. The origin and pathogenesis of RMC are unclear. The radiographical and pathological findings suggest that RMC probably originates in the calyceal epithelium in or near the renal papillae, which could be the result of chronic ischemic damage in the renal papillae epithelium by sickled erythrocytes. Positivity of VEGF and HIF-1α supports the chronic hypoxia that may be caused in the pathogenesis of RMC. Other factors such as genetic or environmental factors are important. Although hemoglobinopathy is very common, RMC is very rare. An understanding of the molecular and genetic factors of this rare disease is important for its prevention and treatment. We herein describe an adult Turkish patient, who presented with hematuria. The diagnosis was RMC after pathological examination. PMID:28360450

  19. Thymic Nurse Cells Exhibit Epithelial Progenitor Phenotype and Create Unique Extra-Cytoplasmic Membrane Space for Thymocyte Selection

    PubMed Central

    Hendrix, Tonya M.; Chilukuri, Rajendra V.E.; Martinez, Marcia; Olushoga, Zachariah; Blake, Andrew; Brohi, Moazzam; Walker, Christopher; Samms, Michael; Guyden, Jerry C.

    2010-01-01

    Thymic nurse cells (TNCs) are epithelial cells in the thymic cortex that contain as many as fifty thymocytes within specialized cytoplasmic vacuoles. The function of this cell-in-cell interaction has created controversy since their discovery in 1980. Further, some skepticism exists about the idea that apoptotic thymocytes within the TNC complex result from negative selection, a process believed to occur exclusively within the medulla. In this report, we have microscopic evidence that defines a unique membranous environment wherein lipid raft aggregates around the αβTCR expressed on captured thymocytes and class II MHC molecules expressed on TNCs. Further, immunohistological examination of thymic sections show TNCs located within the cortico-medullary junction to express cytokeratins five and eight (K5 and K8), and the transcription factor Trp-63, the phenotype defined elsewhere as the thymic epithelial progenitor subset. Our results suggest that the microenvironment provided by TNCs plays an important role in thymocyte selection as well as the potential for TNCs to be involved in the maintenance of thymic epithelia. PMID:20035931

  20. 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

  1. Thymic involution and immune reconstitution

    PubMed Central

    Lynch, Heather E.; Goldberg, Gabrielle L.; Chidgey, Ann; Van den Brink, Marcel R.M.; Boyd, Richard; Sempowski, Gregory D.

    2009-01-01

    Chronic thymus involution associated with aging results in less efficient T-cell development and decreased emigration of naïve T cells to the periphery. Thymic decline in the aged is linked to increased morbidity and mortality in a wide range of clinical settings. Negative consequences of these effects on global health make it of paramount importance to understand the mechanisms driving thymic involution and homeostatic processes across the lifespan. There is growing evidence that thymus tissue is plastic and that the involution process might be therapeutically halted or reversed. We present here progress on the exploitation of thymosuppressive and thymostimulatory pathways using factors such as keratinocyte growth factor, interleukin 7 or sex steroid ablation for therapeutic thymus restoration and peripheral immune reconstitution in adults. PMID:19540807

  2. Thymic epithelial cells of human patients affected by myasthenia gravis overexpress IGF-I immunoreactivity.

    PubMed

    Marinova, Tsvetana T; Kuerten, Stefanie; Petrov, Danail B; Angelov, Doychin N

    2008-01-01

    Accumulating evidence shows that several kinds of thymic cells express insulin-like growth factor-I (IGF-I), which is known to play an important role in T cell ontogeny under both physiological and pathological conditions. Still, little is known about the mechanisms of IGF-I involvement in the pathological transformation of the thymocyte microenvironment. The present study focuses on a comparative analysis of the IGF-I immunoreactivity of thymic epithelial cells (EC) from human patients with hyperplasia-associated myasthenia gravis (MG) versus physiological thymic tissue from healthy controls using immunohistochemistry and immunoelectron microscopy. We show that myasthenic EC overexpress IGF-I in comparison to EC from control subjects. The IGF-I immunoreactivity in the medullary and cortical EC from MG patients was stronger than in the normal gland. The increased expression of IGF-I and more frequent distribution of IGF-I and IGF-I-receptor (IGF-IR) immunopositive EC correlated with modulation in the immunoreactivity of double (IGF-I/IGF-IR) positive EC. Our data provide new immunocytochemial evidence for alterations of IGF-I and IGF-IR immunoreactivity in EC from pathological thymi. The persisting expression of IGF-I and IGF-IR most likely indicates that the myasthenic thymus is still capable of governing IGF-I signaling pathways, which are involved in the local regulation of T cell development and plasticity.

  3. Heterogeneity of thymic epithelial cells in promoting T-lymphocyte differentiation in vivo.

    PubMed Central

    Gutierrez, J C; Palacios, R

    1991-01-01

    To study in vivo the contribution of different thymic epithelial cells to T-lymphocyte differentiation, we have established several nontransformed thymic epithelial cell lines and developed an in vivo assay, not involving exposure to drugs or radiation, that permitted us to study the capacity of these epithelial lines to support T-cell differentiation. We found that cell lines EA2 and ET, which express markers of cortical epithelial cells, produce interleukin 7 mRNA and after being injected into the spleens of young athymic nude mice support in vivo generation of CD4+CD8- T-cell receptor alpha beta+ T lymphocytes (ET line) or both CD4+CD8- and CD4-CD8+ T-cell receptor alpha beta+ T cells (EA2 line). Both cell lines also supported generation of T-cell receptor gamma delta+ T cells but appear not to support development of double-positive (CD4+CD8+) cells. One cell line, EB3, which expresses markers of medullary epithelial cells, produces interleukin 1 alpha RNA transcripts but does not support T-lymphocyte differentiation. The results provide direct evidence for functional heterogeneity of thymic epithelial cells in vivo and show the involvement of different cortical epithelial cells in the differentiation of T-cell progenitors into distinct thymocyte subsets. Images PMID:1988959

  4. Effects of hypophyseal or thymic allograft on thymus development in partially decerebrate chicken embryos: expression of PCNA and CD3 markers.

    PubMed

    Aita, M; Benedetti, F; Carafelli, E; Caccia, E; Romano, N

    2010-08-30

    Changes in chicken embryo thymus after partial decerebration (including the hypophysis) and after hypophyseal or thymic allograft were investigated. Chicken embryos were partially decerebrated at 36-40 hr of incubation and on day 12 received a hypophysis or a thymus allograft from 18-day-old donor embryos. The thymuses of normal, sham-operated and partially decerebrate embryos were collected on day 12 and 18. The thymuses of the grafted embryos were collected on day 18. The samples were examined with histological method and tested for the anti-PCNA and anti-CD3 immune-reactions. After partial decerebration, the thymic cortical and medullary compartments diminished markedly in size. Anti-PCNA and anti-CD3 revealed a reduced immune-reaction, verified also by statistical analysis. In hypophyseal or grafted embryos, the thymic morphological compartments improved, the anti-PCNA and anti-CD3 immune-reactions recovered much better after the thymic graft, probably due to the thymic growth factors and also by an emigration of thymocytes from the same grafted thymus.

  5. Images in pediatrics: the thymic sail sign and thymic wave sign.

    PubMed

    Alves, Nuno D; Sousa, Marta

    2013-01-01

    The authors present a radiographic image portraying the "thymic sail sign" and the "thymic wave sign," both normal findings in infant radiographs and present a short description of these signs. These are distinguished from pathologic findings such as the "spinnaker-sail sign" in pneumomediastinum.

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

    PubMed

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

    2016-05-01

    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.

  7. B cell infiltration of the thymic medulla in New Zealand black, New Zealand white, and (New Zealand black x New Zealand white)F1 mice. Effect of total lymphoid irradiation

    SciTech Connect

    Farinas, M.C.; Adkins, B.; Stall, A.M.; Weissman, I.; Strober, S. )

    1990-05-01

    Thymuses from female (New Zealand black x New Zealand white)F1 (( NZB x NZW)F1), New Zealand black, and New Zealand white mice of different ages were examined by immunohistochemical and flow cytometric analysis. Two-and-a-half-month-old (NZB x NZW)F1 mice showed infiltration of the thymus with B cells, and by 6-8 months of age, showed a disruption of the entire medullary area. More than 80% of the thymic B cells had the phenotypic characteristics of conventional B cells (IgM+, IgD+, Ly-1-). Total lymphoid irradiation induced a marked depletion of medullary B cells and a restoration of the thymic architecture.

  8. BDNF and its receptors in human myasthenic thymus: implications for cell fate in thymic pathology.

    PubMed

    Berzi, Angela; Ayata, C Korcan; Cavalcante, Paola; Falcone, Chiara; Candiago, Elisabetta; Motta, Teresio; Bernasconi, Pia; Hohlfeld, Reinhard; Mantegazza, Renato; Meinl, Edgar; Farina, Cinthia

    2008-07-15

    Here we show that in myasthenic thymus several cell types, including thymic epithelial cells (TEC) and immune cells, were the source and the target of the neurotrophic factor brain-derived growth factor (BDNF). Interestingly, many actively proliferating medullary thymocytes expressed the receptor TrkB in vivo in involuted thymus, while this population was lost in hyperplastic or neoplastic thymuses. Furthermore, in hyperplastic thymuses the robust coordinated expression of BDNF in the germinal centers together with the receptor p75NTR on all proliferating B cells strongly suggests that this factor regulates germinal center reaction. Finally, all TEC dying of apoptosis expressed BDNF receptors, indicating that this neurotrophin is involved in TEC turnover. In thymomas both BDNF production and receptor expression in TEC were strongly hindered. This may represent an attempt of tumour escape from cell death.

  9. Medullary sponge kidney in childhood

    SciTech Connect

    Patriquin, H.B.; O'Regan, S.

    1985-08-01

    Medullary sponge kidney is reported in six children aged 2-18 years. One child was asymptomatic; the others had hematuria or a urine-concentrating defect. Renal function and size were otherwise normal, as was liver function. The diagnosis was made at excretory urography according to criteria established in adults. Sonography revealed hyperechogenic pyramids, at first at the periphery, later generalized. Computed tomography is very sensitive to the pyramidal nephrocalcinosis that complicates this disease and explains the frequent presenting symptom of hematuria in these children.

  10. Imaging of Renal Medullary Carcinoma

    PubMed Central

    Faiella, Eliodoro; Santucci, Domiziana; Mallio, Carlo Augusto; Nezzo, Marco; Quattrocchi, Carlo Cosimo; Beomonte Zobel, Bruno; Grasso, Rosario Francesco

    2017-01-01

    Renal medullary carcinoma (RMC) is a rare, highly aggressive tumor recognized as an independent pathological entity. African-descent adolescents and young adults with sickle cell hemoglobinopathy are the most affected groups. This rare subtype of renal cell carcinoma has its own morphogenetic and pathological characteristics. The major clinical manifestations include gross hematuria, abdominal or flank pain, and weight loss. The prognosis is very poor, with 95% of cases diagnosed at an advanced stage of the disease. In this review, we summarize the morphologic and dynamic characteristics of RMC under various imaging modalities such as ultrasound, computed tomography, and magnetic resonance. Differential diagnosis and management strategies are also discussed.

  11. Medullary sponge kidney associated with congenital hemihypertrophy.

    PubMed

    Indridason, O S; Thomas, L; Berkoben, M

    1996-08-01

    Medullary sponge kidney is a developmental disorder characterized by ectatic and cystic malformation of the collecting ducts and tubules. Clinical manifestations include urinary tract infections, renal stones, and hematuria. It can be associated with other developmental disorders. A case of medullary sponge kidney associated with congenital hemihypertrophy, complicated by nephrocalcinosis and nephrolithiasis, is reported here.

  12. Hashimoto's Thyroiditis and Medullary Carcinoma of Thyroid.

    PubMed

    Dasgupta, S; Chakrabarti, S; Mandal, P K; Das, S

    2014-01-01

    Hashimoto's thyroiditis (HT) has been found to be associated with lymphoma, papillary carcinoma and Hürthle cell neoplasms of thyroid. In contrast, there are only a few reports of co-existence of HT with medullary carcinoma of thyroid. An overall prevalence of medullary carcinoma of only 0.35% has been reported in HT patients. Such a rare combination is being presented here. A 33 year old female presented with history of goiter for one year. Fine needle aspiration cytology (FNAC) of the swelling revealed cytological features suggestive of medullary carcinoma of thyroid. Histopathological examination of total thyroidectomy specimen revealed Hashimoto's thyroiditis along with medullary carcinoma of thyroid. Although Hashimoto's thyroiditis can uncommonly co-exist with thyroid neoplasm, its association with medullary carcinoma is extremely rare and hence being presented.

  13. Neuropeptides Exert Direct Effects on Rat Thymic Epithelial Cells in Culture

    PubMed Central

    Head, Gail M.; Mentlein, R.; Patay, Birte Von; Downing, J. E.G.

    1998-01-01

    To determine if major thymic neuropeptides and neurotransmitters can directly influence the functional activity of cultured rat thymic epithelium, neuropeptides and neurotransmitters were applied, and intercellular communication, proliferation, and thymulin secretion assessed. After injections of a mixture of lucifer yellow dextran (too large to pass gap junctions) and cascade blue (which does) into single cells, some neuropeptides decrease dye coupling: 0.1 mM GABA (P < 0.0001), 100 nM NPY (P < 0.0001), 100 nM VIP (P < 0.001), 100 nM CGRP (P < 0.001), 100 nM SP (P < 0.01), and 0.1 mM histamine (P < 0.01), whereas 0.1 mM 5-HT, mM acetylcholine, and 1 μM isoproterenol (β-adrenergic agonist) had no effect. Proliferation (incorporation of tritiated thymidine) was increased by CGRP (P = 0.004) and histamine (P < 0.02), but decreased by isoproterenol (P = 0.002), 5-HT (P = 0.003), and acetylcholine (P < 0.05). The percentage of multinucleate cells was decreased after isoproterenol (2.5%), and increased after 5-HT (21.3%), GABA (15%), and histamine (15.1%). Compared to controls, thymulin in the supernatant was decreased after challenge with acetylcholine (52%), isoproterenol (71%), 5-HT (73%), and histamine (84%). This study demonstrates direct effects of neuropeptides and neurotransmitters on functional aspects of cultured thymic epithelial cells. PMID:9716910

  14. Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator

    PubMed Central

    Takizawa, Nobukazu; Miyauchi, Maki; Yanai, Hiromi; Tateishi, Ryosuke; Shinzawa, Miho; Yoshinaga, Riko; Kurihara, Masaaki; Yasuda, Hisataka; Sakamoto, Reiko; Yoshida, Nobuaki

    2016-01-01

    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

  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.

  16. [Thymic abnormalities in patients with myasthenia gravis].

    PubMed

    Utsugisawa, Kimiaki; Nagane, Yuriko

    2011-07-01

    Thymic abnormalities were first noticed at autopsies of patients with myasthenia gravis (MG) more than 100 years ago. The thymus is believed to play an important role in the pathogenesis of MG, an autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) of skeletal muscles. Production of these antibodies in B cells is T cell dependent. T cells potentially specific for AChR are probably generated in the thymus via nontolerogenic thymopoiesis by an aberrant function of thymic epithelial cells. However, generation of these AChR-specific T cells is not the cause of MG, because these cells are also found in healthy individuals. The pathogenetic step in MG involves the activation of these potentially AChR-specific T cells; this activation is the trigger to develop the disease and a therapeutic target. The intra-thymic activation of AChR-specific T cells is probably limited to particular types of MG patients: those with early-onset MG in whom the thymus exhibits lymphofollicular hyperplasia (TLFH) and a few patients in whom MG is associated with a thymoma. The majority of thymomas and atrophic thymuses of patients with late-onset MG, an increasingly common condition, do not exhibit this T cell-activation process. In this paper, we review the available literature on thymic changes (TLFH, thymoma, and atrophic thymus) and the relationship of these changes to the pathogenesis of MG.

  17. 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

  18. Thymic emigration: conveyor belts or lucky dips?

    PubMed

    Scollay, R; Godfrey, D I

    1995-06-01

    The thymic medulla has always seemed a rather uncomplicated compartment, simply storing mature thymocytes until they are exported to the peripheral lymphoid organs. However, as discussed here by Roland Scollay and Dale Godfrey, a careful look at recent data suggests that events in the medulla may be more complex and protracted than previously thought.

  19. 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

  20. Medullary cystic disease: a family study.

    PubMed

    Chen, H C; Chang, J M; Tsai, J H; Lai, Y H

    1998-03-01

    Medullary cystic disease of the kidney is characterized by progressive tubulointerstitial disease with medullary cyst formation and secondary glomerular sclerosis. We treated a patient with chronic renal failure and investigated the family history of renal disease. The patient, an 18-year-old woman, was admitted due to poor appetite and fatigue for several months. Findings on physical examination were normal except for a pale conjunctiva. Urinalysis revealed only mild proteinuria with clear sediment. The hemogram showed normocytic normochromic anemia with hemoglobin 86 g/L. The patient was azotemic and her creatinine clearance rate was 10.7 mL/min. Renal sonography showed contraction of both kidneys with a marked increase in cortical echogenicity. One small cyst was found in the medullary area. Computed tomography (CT) and magnetic resonance imaging revealed several medullary cysts. Percutaneous renal biopsy showed focal and periglomerular sclerosis, marked tubular atrophy, and interstitial fibrosis. Ten of her family members were examined for renal function, and by sonography and CT. Five had medullary cysts, and three of the five showed abnormal renal function. Medullary cystic disease should be considered in the differential diagnosis of patients with renal disease and a positive family history.

  1. Imaging of thymus in myasthenia gravis: from thymic hyperplasia to thymic tumor.

    PubMed

    Priola, A M; Priola, S M

    2014-05-01

    Myasthenia gravis (MG) is an autoimmune disorder often associated with thymic abnormalities. At onset, thymic lymphoid hyperplasia (TLH) and thymoma can be found in up to 65% and 15% of patients, respectively. Diagnostic imaging is crucial in this setting in order to detect the presence and type of the thymic abnormality and in the preoperative planning, when indicated. Chest radiography has a minor role due to its low accuracy. Computed tomography is the imaging modality of choice, although the differentiation between a small thymoma and TLH that appears as a focal soft-tissue mass may be not possible. Magnetic resonance imaging (MRI) is not usually employed, but it is useful in equivocal cases, especially in differentiating focal TLH from thymoma by using chemical-shift sequences for defining the proper management. In addition, diffusion-weighted (DW)-MRI can differentiate lipid-poor normal/hyperplastic thymus from thymoma and could be useful in differentiating non-advanced from advanced thymomas. Positron emission tomography (PET)-CT is not helpful in distinguishing early from advanced thymoma but can be used to differentiate thymic carcinoma from thymoma. Hereby, we discuss the imaging features of thymic abnormalities in MG, even focusing on novel aspects of chemical-shift and DW-MRI.

  2. Diagnosis and Management of Cervical Thymic Cysts in Children

    PubMed Central

    Dedhia, Kavita; Chi, David H

    2017-01-01

    We present the case of a 10-year-old boy with the sudden onset of a large, painless left neck mass. Findings on magnetic resonance imaging (MRI) and fine needle aspiration (FNA) biopsy suggest a cystic lesion, most likely of thymic origin. Cervical thymic cysts are a rare form of cervical mass, which are easily overlooked in the differential diagnosis of children presenting with painless neck masses. A combination of CT and MRI investigations can be helpful in differentiating thymic cysts from other congenital and neoplastic masses, but the definitive diagnosis of thymic cyst requires histopathological documentation of thymic tissue. Surgical excision is considered the management of choice for thymic cysts, and no cases of postoperative recurrence have been reported. PMID:28191377

  3. Adrenal cortical and medullary imaging.

    PubMed

    Freitas, J E

    1995-07-01

    Adrenal disease can be manifested by endocrine dysfunction or anatomic abnormalities detected by cross-sectional imaging modalities. With the advent of newer and more reliable in vitro assays and a better understanding of the spectrum of adrenal pathology, the physician can now adopt a more accurate and cost-effective approach to the diagnosis of adrenal disease. Both functional and anatomic imaging modalities can play an important role in the evaluation of the incidental adrenal mass, the early detection of adrenal metastases, differentiation of the various causes of Cushings's syndrome, selection of patients for potentially curative surgery in primary aldosteronism and adrenal hyperandrogenism, and localization of pheochromocytomas and neuroblastomas. The usefulness of the adrenal cortical radiopharmaceutical, 131I-6-beta-iodomethylnorcholesterol (NP-59), and the adrenal medullary radiopharmaceuticals, 131I and 123I-metaiodobenzylguanidine (MIBG), is detailed for these various clinical settings and the role of NP-59 and MIBG is contrasted to that of the cross-sectional modalities, computed tomography and magnetic resonance imaging (MRI). Incidental adrenal masses are common, but malignancies are few. Imaging studies select those patients who require a further evaluation by biopsy examination or adrenalectomy. In the hyperfunctioning endocrine states, such as Cushing's syndrome, primary aldosteronism, adrenal androgenism, and pheochromocytoma, correlation of biochemical findings with both functional and anatomic imaging is necessary to avoid inappropriate and ineffective surgical intervention, yet not miss an opportunity for curative resection. Lastly, MIBG and MRI are complementary in the detection and staging of neuroblastoma.

  4. The ureteric bud epithelium: morphogenesis and roles in metanephric kidney patterning.

    PubMed

    Nagalakshmi, Vidya K; Yu, Jing

    2015-03-01

    The mammalian metanephric kidney is composed of two epithelial components, the collecting duct system and the nephron epithelium, that differentiate from two different tissues -the ureteric bud epithelium and the nephron progenitors, respectively-of intermediate mesoderm origin. The collecting duct system is generated through reiterative ureteric bud branching morphogenesis, whereas the nephron epithelium is formed in a process termed nephrogenesis, which is initiated with the mesenchymal-epithelial transition of the nephron progenitors. Ureteric bud branching morphogenesis is regulated by nephron progenitors, and in return, the ureteric bud epithelium regulates nephrogenesis. The metanephric kidney is physiologically divided along the corticomedullary axis into subcompartments that are enriched with specific segments of these two epithelial structures. Here, we provide an overview of the major molecular and cellular processes underlying the morphogenesis and patterning of the ureteric bud epithelium and its roles in the cortico-medullary patterning of the metanephric kidney.

  5. Morphometric analysis of peritumoral lymph nodes in patients operated on for uterine cancer, locally treated with a thymic extract.

    PubMed

    Corradi, G; Cappellari, A; Pomari, R; Cappello, F

    1989-01-01

    By means of a morphometric analysis, the authors have evaluated the structure and dimensions of the lymph node functional areas (cortical, medullary, paracortical, histiocytosis of the sinuses, germinal centres) in regional nodes of women with carcinoma of the uterus in the 1st and 2nd stages. Twenty patients were treated 8 days before surgery with a dose of 1.5 mg kg-1 body weight of thymic hormone directly into the uterine portio. Ten patients, on the other hand, were injected with physiological saline solution. The quantitative and qualitative results show that in peritumoral lymph nodes of women treated with thymostimolin there is a marked increase, statistically significant (P less than 0.001), of the paracortical zone and of the number of germinal centres.

  6. Thymic Langerhans cell histiocytosis mimicking lymphoma.

    PubMed

    Yağci, Begül; Varan, Ali; Uner, Aysegül; Akyüz, Canan; Büyükpamukçu, Münevver

    2008-12-01

    Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal expansion of antigen presenting Langerhans cells. Different clinical features can be seen according to the involved organs and systems. Multisystem disease with organ dysfunction is more common in infants, whereas single system disease is usually observed in older children. The disease can affect any system or organ throughout the body. Thymus is a rarely involvement site reported in LCH and usually is accompanied by skin, bone or lung disease. Here we report a 12-year-old male with thymic involvement by LCH clinically mimicking lymphoma.

  7. Occasional detection of thymic epithelial tumor 4 years after diagnosis of adult onset Still disease

    PubMed Central

    Lococo, Filippo; Bajocchi, Gianluigi; Caruso, Andrea; Valli, Riccardo; Ricchetti, Tommaso; Sgarbi, Giorgio; Salvarani, Carlo

    2016-01-01

    Abstract Background: Thymoma is a T cell neoplasm arising from the thymic epithelium that due to its immunological role, frequently undercover derangements of immunity such a tumors and autoimmune diseases. Methods: Herein, we report, to the best of our knowledge, the first description of an association between thymoma and adult onset Still disease (AOSD) in a 47-year-old man. The first one was occasionally detected 4 years later the diagnosis of AOSD, and surgically removed via right lateral thoracotomy. Histology confirmed an encapsulated thymic tumor (type AB sec. WHO-classification). Results: The AOSD was particularly resistant to the therapy, requiring a combination of immunosuppressant followed by anti-IL1R, that was the only steroids-sparing treatment capable to induce and maintain the remission. The differential diagnosis was particularly challenging because of the severe myasthenic-like symptoms that, with normal laboratory tests, were initially misinterpreted as fibromyalgia. The pathogenic link of this association could be a thymus escape of autoreactive T lymphocytes causing autoimmunity. Conclusion: Clinicians should be always include the possibility of a thymoma in the differential diagnosis of an unusual new onset of weakness and normal laboratories data, in particular once autoimmune disease is present in the medical history. PMID:27603335

  8. Immuno- and Enzyme-histochemistry of HRP for Demonstration of Blood Vessel Permeability in Mouse Thymic Tissues by "In Vivo Cryotechnique".

    PubMed

    Wu, Bao; Ohno, Nobuhiko; Saitoh, Yurika; Bai, Yuqin; Huang, Zheng; Terada, Nobuo; Ohno, Shinichi

    2014-01-01

    It is difficult to understand the in vivo permeability of thymic blood vessels, but "in vivo cryotechnique" (IVCT) is useful to capture dynamic blood flow conditions. We injected various concentrations of horseradish peroxidase (HRP) with or without quantum dots into anesthetized mice via left ventricles to examine architectures of thymic blood vessels and their permeability at different time intervals. At 30 sec after HRP (100 mg/ml) injection, enzyme reaction products were weakly detected in interstitium around some thick blood vessels of corticomedullary boundary areas, but within capillaries of cortical areas. At 1 and 3 min, they were more widely detected in interstitium around all thick blood vessels of the boundary areas. At 10 min, they were diffusely detected throughout interstitium of cortical areas, and more densely seen in medullary areas. At 15 min, however, they were uniformly detected throughout interstitium outside blood vessels. At 30 min, phagocytosis of HRP by macrophages was scattered throughout the interstitium, which was accompanied by decrease of HRP reaction intensity in interstitial matrices. Thus, time-dependent HRP distributions in living mice indicate that molecular permeability and diffusion depend on different areas of thymic tissues, resulting from topographic variations of local interstitial flow starting from corticomedullary areas.

  9. Immuno- and Enzyme-histochemistry of HRP for Demonstration of Blood Vessel Permeability in Mouse Thymic Tissues by “In Vivo Cryotechnique”

    PubMed Central

    Wu, Bao; Ohno, Nobuhiko; Saitoh, Yurika; Bai, Yuqin; Huang, Zheng; Terada, Nobuo; Ohno, Shinichi

    2014-01-01

    It is difficult to understand the in vivo permeability of thymic blood vessels, but “in vivo cryotechnique” (IVCT) is useful to capture dynamic blood flow conditions. We injected various concentrations of horseradish peroxidase (HRP) with or without quantum dots into anesthetized mice via left ventricles to examine architectures of thymic blood vessels and their permeability at different time intervals. At 30 sec after HRP (100 mg/ml) injection, enzyme reaction products were weakly detected in interstitium around some thick blood vessels of corticomedullary boundary areas, but within capillaries of cortical areas. At 1 and 3 min, they were more widely detected in interstitium around all thick blood vessels of the boundary areas. At 10 min, they were diffusely detected throughout interstitium of cortical areas, and more densely seen in medullary areas. At 15 min, however, they were uniformly detected throughout interstitium outside blood vessels. At 30 min, phagocytosis of HRP by macrophages was scattered throughout the interstitium, which was accompanied by decrease of HRP reaction intensity in interstitial matrices. Thus, time-dependent HRP distributions in living mice indicate that molecular permeability and diffusion depend on different areas of thymic tissues, resulting from topographic variations of local interstitial flow starting from corticomedullary areas. PMID:25859061

  10. Thymic remodeling associated with hyperplasia in myasthenia gravis.

    PubMed

    Le Panse, Rozen; Bismuth, Jacky; Cizeron-Clairac, Géraldine; Weiss, Julia Miriam; Cufi, Perrine; Dartevelle, Philippe; De Rosbo, Nicole Kerlero; Berrih-Aknin, Sonia

    2010-08-01

    Acquired myasthenia gravis (MG), a neurological autoimmune disease, is caused by autoantibodies against components of the neuromuscular junction that lead to disabling muscle fatigability. The thymus is clearly involved in the pathogenesis of early-onset MG with anti-acetylcholine receptor antibodies, and thymic hyperplasia of lympho-proliferative origin is a hallmark of the disease. In this review, we describe the structural and cellular changes associated with thymic hyperplasia, its main characteristics being the development of ectopic germinal centers (GCs) associated with active neoangiogenic processes, such as development of high endothelial venules and lymphangiogenesis. What triggers such thymic abnormalities in MG is not yet clear. A thymic transcriptome analysis has demonstrated a strong inflammatory signature in MG that could orchestrate the development of thymic hyperplasia. In this context, thymic epithelial cells (TECs) seem to play a central role, either by contributing or responding to the inflammatory environment and up-regulating the autoimmune response. In particular, MG TECs clearly overexpress various cytokines, among which chemokines play a crucial role in the recruitment of peripheral lymphocytes to the thymus via the newly expanded vessel network, thereby leading to the development of ectopic GCs. Clearly, a better understanding of major events that lead to thymic hyperplasia will help optimize strategies toward more specific therapy for MG.

  11. A Quantitative Trait Locus on chr.4 Regulates Thymic Involution

    PubMed Central

    Kumar, Ritu; Avagyan, Serine

    2010-01-01

    The mechanisms underlying age-associated thymic involution are unknown. In mice, thymic involution shows mouse strain–dependent genetic variation. Identification of the underlying genes would provide mechanistic insight into this elusive process. We previously showed that responsiveness of hematopoietic stem and progenitor cells (HSPCs) to transforming growth factor-beta 2, a positive regulator of HSPC proliferation, is regulated by a quantitative trait locus (QTL) on chr. 4, Tb2r1. Interestingly, Tgfb2+/− mice have delayed thymic involution. Therefore, we tested the hypothesis that a QTL on chr. 4 might regulate thymic involution. Aged, but not young, B6.D2-chr.4 congenic mice, where the telomeric region of chr. 4 was introgressed from DBA/2 to C57BL/6 mice, had larger thymi, and better maintenance of early thymic precursors than C57BL/6 control mice. These observations unequivocally demonstrate that the telomeric region of chr. 4 contains a QTL, Ti1 (thymic involution 1) that regulates thymic involution, and suggest the possibility that Ti1 may be identical to Tb2r1. PMID:20371546

  12. Ephrin-B-dependent thymic epithelial cell-thymocyte interactions are necessary for correct T cell differentiation and thymus histology organization: relevance for thymic cortex development.

    PubMed

    Cejalvo, Teresa; Munoz, Juan J; Tobajas, Esther; Fanlo, Lucía; Alfaro, David; García-Ceca, Javier; Zapata, Agustín

    2013-03-15

    Previous analysis on the thymus of erythropoietin-producing hepatocyte kinases (Eph) B knockout mice and chimeras revealed that Eph-Eph receptor-interacting proteins (ephrins) are expressed both on T cells and thymic epithelial cells (TECs) and play a role in defining the thymus microenvironments. In the current study, we have used the Cre-LoxP system to selectively delete ephrin-B1 and/or ephrin-B2 in either thymocytes (EfnB1(thy/thy), EfnB2(thy/thy), and EfnB1(thy/thy)EfnB2(thy/thy) mice) or TECs (EfnB1(tec/tec), EfnB2(tec/tec), and EfnB1(tec/tec)EfnB2(tec/tec) mice) and determine the relevance of these Eph ligands in T cell differentiation and thymus histology. Our results indicate that ephrin-B1 and ephrin-B2 expressed on thymocytes play an autonomous role in T cell development and, expressed on TECs, their nonautonomous roles are partially overlapping. The effects of the lack of ephrin-B1 and/or ephrin-B2 on either thymocytes or TECs are more severe and specific on thymic epithelium, contribute to the cell intermingling necessary for thymus organization, and affect cortical TEC subpopulation phenotype and location. Moreover, ephrin-B1 and ephrin-B2 seem to be involved in the temporal appearance of distinct cortical TECs subsets defined by different Ly51 levels of expression on the ontogeny.

  13. Evaluation of thymic volume by postmortem computed tomography.

    PubMed

    Abe, Shuntaro; Hasegawa, Iwao; Vogel, Hermann; Heinemann, Axel; Suzuki, Koichi; Püschel, Klaus

    2015-07-01

    The thymus is exceedingly sensitive to stress and undergoes abrupt involution as a result of exposure to strong stress in early childhood. Therefore, thymic involution is often utilized to assess the presence of a stressful environment, such as an environment involving child abuse, in forensic medicine. In recent years, computed tomography (CT) has been commonly used in the daily practice of forensic medicine. We have focused on the thymic volume in postmortem CT images to evaluate the presence of a stressful antemortem environment. We calculated the thymus volume from postmortem CT images of children under six years old and demonstrated that the volume showed a positive correlation with the real weight obtained from an autopsy. The evaluation of thymic volume by CT may make it possible for us to identify child maltreatment. The most useful feature of this application of CT is to be able to demonstrate thymic involution less invasively in a surviving victim.

  14. Schwannosis induced medullary compression in VACTERL syndrome.

    PubMed

    Treacy, A; Redmond, M; Lynch, B; Ryan, S; Farrell, M; Devaney, D

    2009-01-01

    A 7-year-old boy with a history of VACTERL syndrome was found collapsed in bed. MRI had shown basilar invagination of the skull base and narrowing of the foramen magnum. Angulation, swelling and abnormal high signal at the cervicomedullary junction were felt to be secondary to compression of the medulla. Neuropathologic examination showed bilateral replacement of the medullary tegmentum by an irregularly circumscribed cellular lesion which was composed of elongated GFAP/S 100-positive cells with spindled nuclei and minimal atypia. The pathologic findings were interpreted as intramedullary schwannosis with mass effect. Schwannosis, is observed in traumatized spinal cords where its presence may represent attempted, albeit aberrant, repair by inwardly migrating Schwann cells ofperipheral origin. In our view the compressive effect of the basilar invagination on this boy's medulla was of sufficient magnitude to have caused tumoral medullary schwannosis with resultant intermittent respiratory compromise leading to reflex anoxic seizures.

  15. Medullary carcinoma in a lingual thyroid.

    PubMed

    Yaday, S; Singh, I; Singh, J; Aggarwal, N

    2008-03-01

    Total ectopia of thyroid is a rare phenomenon and malignant change in an ectopic thyroid is even rarer. We report a case of medullary carcinoma in a total ectopic lingual thyroid occurring in a 45-year-old woman who presented with dysphagia, plummy voice and a round sessile mass at the base of the tongue. The mass was extirpated using Trotter's midline approach. Upon examination, it was found to be medullary carcinoma in an ectopic thyroid. Permanent substitution therapy with thyroxine secured the euthyroid status of the patient. The embrylogical basis and a review of literature regarding carcinomatous change in an ectopic thyroid are also discussed. There is a need to investigate for an ectopic thyroid, or even total ectopia, in the case of any smooth mass found at the base of the tongue.

  16. Bradshaw lecture, 1976. Thyroid medullary carcinoma.

    PubMed Central

    Taylor, S.

    1977-01-01

    The main characteristics of medullary carcinoma of the thyroid are its non-follicular histological appearance, resulting from its origin from the parafollicular C cells, its secretion of calcitonin, providing a relatively simple diagnostic test, and its equal sex incidence, in contrast to all other diseases of the thyroid. Sporadic cases are seen and it occurs in familial groups, with autosomal dominant inheritance, when it is associated with phaeochromocytoma and parathyroid hyperplasia to form the second type of multiple endocrine adenomatosis (MEA2). These last features make it necessary in every case of medullary carcinoma of the thyroid to examine other members of the family and to investigate the possibility of concomitant adrenal and parathyroid disease. The priorities of treatment when these are present and the indications for total thyroidectomy are discussed. Images Fig. 1 PMID:20027

  17. Medial medullary infarction: abnormal ocular motor findings.

    PubMed

    Kim, J Soo; Choi, K-D; Oh, S-Y; Park, S-H; Han, M-K; Yoon, B-W; Roh, J-K

    2005-10-25

    In 20 consecutive patients with isolated medial medullary infarction, abnormal ocular motor findings included nystagmus (n = 8), ocular contrapulsion (n = 5), and contralesional ocular tilt reaction (n = 2). The nystagmus was ipsilesional (n = 4), gaze-evoked (n = 5), upbeating (n = 4), and hemiseesaw (n = 1). The ocular motor abnormalities may be explained by involvements of the nucleus prepositus hypoglossi, medial longitudinal fasciculus or efferent fibers from the vestibular nuclei, climbing fibers, and cells of the paramedian tracts.

  18. Normal conus medullaris: CT criteria for recognition

    SciTech Connect

    Grogan, J.P.; Daniels, D.L.; Williams, I.L.; Rauschning, W.; Haughton, V.M.

    1984-06-01

    The normal CT configuration and dimension of the conus medullaris and adjacent spinal cord were determined in 30 patients who had no clinical evidence of conus compression. CT studies were also correlated with anatomic sections in cadavers. The normal conus on CT has a distinctive oval configuration, an arterior sulcus, and a posterior promontory. The anteroposterior diameter ranged from 5 to 8 mm; the transverse diameter from 8 to 11 mm. Intramedullary processes altered both the dimensions and configuration of the conus.

  19. Thymic exosomes promote the final maturation of thymocytes

    PubMed Central

    Lundberg, Vanja; Berglund, Martin; Skogberg, Gabriel; Lindgren, Susanne; Lundqvist, Christina; Gudmundsdottir, Judith; Thörn, Karolina; Telemo, Esbjörn; Ekwall, Olov

    2016-01-01

    Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4+CD25− cells into mature thymocytes with S1P1+Qa2+ and CCR7+Qa2+ phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4+CD25+FoxP3+ thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC’s is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus. PMID:27824109

  20. Thymoma versus thymic carcinoma: differences in biology impacting treatment.

    PubMed

    Kelly, Ronan J

    2013-05-01

    A better understanding of the biology of both thymomas and thymic carcinomas has occurred in recent years thanks to advanced technologies such as comparative genomic hybridization, expression array analysis, and next-generation sequencing. Gene expression profiling and genomic clustering studies have shown that thymic tumors as classified by the 2004 WHO system do have different molecular features. Because of the rarity of these tumors, there is a paucity of high-quality clinical research data, and treatment decisions are often guided by the small amount of prospective trial data, retrospective series, and individual case reports. The literature does report on several advanced thymic tumors that have responded to new targeted agents, indicating that across the spectrum of thymic malignancies there may be clinically relevant molecular subsets. Genomic profiling distinguishes type B3 thymoma and thymic carcinoma from type A and B2 thymomas. Furthermore, type B2 thymomas can be separated from other subgroups in that it has a more distinctly lymphocytic component than the other groups in which epithelial cells predominate. The presence of KIT mutations in thymic carcinomas rather than in thymomas further adds to a growing body of evidence showing that underlying tumor biology may in the future lead to molecular classifications, which may enhance therapies for these rare tumors.

  1. Quantitation of the prominent medullary pyramid: a reappraisal.

    PubMed

    Paling, M R; Black, W C

    1986-06-01

    We propose a revised objective measurement of the size of the renal medullary pyramid in the assessment of the prominent renal pyramid: the medullary-renal ratio (MRR). (Formula: see text). This is a more accurate assessment of the size of the renal pyramid relative to the size of the kidney than the previously proposed medullary pyramid index, which fails to take into account the varying morphology of otherwise normal kidneys.

  2. MerTK regulates thymic selection of autoreactive T cells.

    PubMed

    Wallet, Mark A; Flores, Rafael R; Wang, Yaming; Yi, Zuoan; Kroger, Charles J; Mathews, Clayton E; Earp, H Shelton; Matsushima, Glenn; Wang, Bo; Tisch, Roland

    2009-03-24

    T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) are believed to be the result in part of inefficient negative selection of self-specific thymocytes. However, the events regulating thymic negative selection are not fully understood. In the current study, we demonstrate that nonobese diabetic (NOD) mice lacking expression of the Mer tyrosine kinase (MerTK) have reduced inflammation of the pancreatic islets and fail to develop diabetes. Furthermore, NOD mice deficient in MerTK expression (Mer(-/-)) exhibit a reduced frequency of beta cell-specific T cells independent of immunoregulatory effectors. The establishment of bone marrow chimeric mice demonstrated that the block in beta cell autoimmunity required hematopoietic-derived cells lacking MerTK expression. Notably, fetal thymic organ cultures and self-peptide administration showed increased thymic negative selection in Mer(-/-) mice. Finally, thymic dendritic cells (DC) prepared from Mer(-/-) mice exhibited an increased capacity to induce thymocyte apoptosis in a peptide-specific manner in vitro. These findings provide evidence for a unique mechanism involving MerTK-mediated regulation of thymocyte negative selection and thymic DC, and suggest a role for MerTK in contributing to beta cell autoimmunity.

  3. The evolution of thymic lymphomas in p53 knockout mice

    PubMed Central

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

    2014-01-01

    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

  4. Medullary trichomalacia in 6 German shepherd dogs.

    PubMed

    Tieghi, Chiara; Miller, William H; Scott, Danny W; Pasquinelli, Gianandrea

    2003-02-01

    Medullary trichomalacia is the name proposed for a hair shaft abnormality that was recognized in 6 German shepherd dogs. Affected dogs had multifocal areas of broken hairs, especially on the dorsolateral trunk. Microscopic examination of hair shafts revealed focal areas of loss of architecture, swelling, and apparent softening of the medulla, followed by longitudinal (length-wise) splitting and breakage of the hair shaft. No cause could be found. Affected dogs were otherwise healthy, and apparent spontaneous recovery was the usual outcome. Relapses may occur.

  5. Intramedullary bronchogenic cyst of the conus medullaris.

    PubMed

    Yilmaz, Cem; Gulsen, Salih; Sonmez, Erkin; Ozger, Ozkan; Unlukaplan, Muge; Caner, Hakan

    2009-10-01

    Spinal bronchogenic cysts are rare congenital lesions. The authors describe their experience in the treatment of a 17-year-old boy who presented with back pain and paresthesia in both lower extremities. Lumbar MR imaging revealed the presence of an intramedullary cystic lesion at the conus medullaris and histopathological analysis revealed a bronchogenic cyst. To the best of the authors' knowledge, this is the first report of an intramedullary spinal bronchogenic cyst arising at the conus; all previously reported spinal bronchogenic cysts were either intradural extramedullary or not located at the conus.

  6. Central pontine myelinolysis and medullary myelinolysis.

    PubMed

    Bhagavan, B S; Wagner, J A; Juanteguy, J

    1976-05-01

    Central pontine myelinolysis (CPM) is a rare, acute, and uniformly fatal demyelinative process that involves the pons almost exclusively. Three cases diagnosed at autopsy illustrate the characteristic clinical course and pathologic features of CPM. A unique extrapontine location of a similar process is noted in the medulla of a 6-year-old girl. The term "medullary myelinolysis" is a descriptive designation for demyelination that occurs predominantly in this area. The clinical and pathologic features of CPM are reviewed in detail, together with a brief review of theories of metabolic, nutritional, vascular, and endogenous and exogenous toxic factors that act either singly or in concert in the cause and pathogenesis of CPM.

  7. Invasive atypical thymic carcinoid: three case reports and literature review

    PubMed Central

    Zhu, Shan; Wang, Zhong-Tang; Liu, Wen-Zhi; Zong, Shi-Xiang; Li, Bao-Sheng

    2016-01-01

    Atypical thymic carcinoid is an extremely rare thymic neuroendocrine tumor derived from the neuroendocrine system. The aims of this paper were to investigate the clinical features of atypical thymic carcinoid and collate information and experience to improve the diagnosis and treatment of this disease. We describe three cases of atypical carcinoid of the thymus; clinical features, pathological data, treatment modalities, and short-term patient outcomes were summarized and analyzed. The initial clinical symptoms and signs of all three patients were nonspecific and an anterior mediastinal mass was found in each patient on chest computed tomography scan. All three patients underwent surgical resection (total thymectomy and complete excision of the tumor), followed by postoperative radiotherapy, with or without chemotherapy. The diagnoses of three patients were confirmed by pathological and immunohistochemical evaluation. We also present a review of the literature to collate as much information as possible and provide a reference for proper diagnosis and treatment of atypical thyroid carcinoid. PMID:27785065

  8. The pathology of preclinical medullary thyroid carcinoma.

    PubMed

    Ashworth, Michael

    2004-01-01

    Medullary carcinoma of the thyroid (MTC) occurs sporadically, or in familial forms in familial medullary thyroid carcinoma and multiple endocrine neoplasia types 2A and 2B. In the familial forms it is associated with well-characterized, germline mutations in the RET protooncogene. The mutation sites differ in MEN2A and MEN2B, and MTC develops at an earlier age and is more aggressive in MEN2B. Screening of relatives of affected individuals for such mutations can identify those at risk of developing MTC and total thyroidectomy can be carried out in the first decade of life before the development of clinical disease. Analysis of such removed thyroid glands shows abnormalities of the parafollicular C-cells in almost all cases. The abnormalities range from C-cell hyperplasia, either diffuse or nodular, to microcarcinoma and occasionally frank MTC. The abnormalities are bilateral and affect the upper two thirds of the thyroid lobes. Microcarcinomas may be visible with the naked eye, but often they are identified only on microscopy. Histopathological examination of the entire gland is essential.

  9. Myf5 and Myogenin in the development of thymic myoid cells - Implications for a murine in vivo model of myasthenia gravis.

    PubMed

    Hu, Bo; Simon-Keller, Katja; Küffer, Stefan; Ströbel, Philipp; Braun, Thomas; Marx, Alexander; Porubsky, Stefan

    2016-03-01

    Myasthenia gravis (MG) is caused by autoantibodies against the neuromuscular junction of striated muscle. Most MG patients have autoreactive T- and B-cells directed to the acetylcholine receptor (AChR). To achieve immunologic tolerance, developing thymocytes are normally eliminated after recognition of self-antigen-derived peptides. Presentation of muscle-specific antigens is likely achieved through two pathways: on medullary thymic epithelial cells and on medullary dendritic cells cross-presenting peptides derived from a unique population of thymic myoid cells (TMC). Decades ago, it has been hypothesized that TMC play a key role in the induction of immunological tolerance towards skeletal muscle antigens. However, an experimental model to address this postulate has not been available. To generate such a model, we tested the hypothesis that the development of TMC depends on myogenic regulatory factors. To this end, we utilized Myf5-deficient mice, which lack the first wave of muscle cells but form normal skeletal muscles later during development, and Myogenin-deficient mice, which fail to form differentiated myofibers. We demonstrate for the first time that Myf5- and Myogenin-deficient mice showed a partial or complete, respectively, loss of TMC in an otherwise regularly structured thymus. To overcome early postnatal lethality of muscle-deficient, Myogenin-knockout mice we transplanted Myogenin-deficient fetal thymuses into Foxn1(nu/nu) mice that lack their own thymus anlage. We found that the transplants are functional but lack TMC. In combination with established immunization strategies (utilizing AChR or Titin), this model should enable us in the future testing the hypothesis that TMC play an indispensable role in the development of central tolerance towards striated muscle antigens.

  10. Fine needle aspiration cytology of thymic carcinoid tumor.

    PubMed

    Wang, D Y; Kuo, S H; Chang, D B; Yang, P C; Lee, Y C; Hsu, H C; Luh, K T

    1995-01-01

    Carcinoid tumors of the thymus are very rare, and their cytologic findings have not been reported previously in English. Retrospective study of fine needle aspiration (FNA) cytologic features in four histopathologically verified thymic carcinoid tumors are described here in detail. The FNA cytology of thymic carcinoids is characterized by predominantly single and some loose clusters of small, round to oval cells with scanty cytoplasm, interspersed with some larger cells with moderate to abundant, granular cytoplasm. The differential diagnosis of the cytologic features between carcinoid tumor and other mediastinal tumors is also discussed.

  11. Thymus organogenesis and development of the thymic stroma.

    PubMed

    Nowell, Craig S; Farley, Alison M; Blackburn, C Clare

    2007-01-01

    T-cell development occurs principally in the thymus. Here, immature progenitor cells are guided through the differentiation and selection steps required to generate a complex T-cell repertoire that is both self-tolerant and has propensity to bind self major histocompatibility complex. These processes depend on an array of functionally distinct epithelial cell types within the thymic stroma, which have a common developmental origin in the pharyngeal endoderm. Here, we describe the structural and phenotypic attributes of the thymic stroma, and review current cellular and molecular understanding of thymus organogenesis.

  12. 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.

  13. C-cell hyperplasia and medullary thyroid microcarcinoma.

    PubMed

    Albores-Saavedra, J A; Krueger, J E

    2001-01-01

    Since the discovery of the thyroid C-cell, considerable progress has been made regarding its origin, function, and pathology. In this article an attempt is made to summarize and update our knowledge about physiologic or reactive C-cell hyperplasia, neoplastic C-cell hyperplasia (medullary carcinoma in situ), and medullary microcarcinoma. Seldom recognized preoperatively, physiologic C-cell hyperplasia is associated with inflammatory, metabolic, and neoplastic thyroid disorders as well as with hypercalcemia. However, the pathogenesis is still unclear. Although physiologic C-cell hyperplasia may progress to medullary carcinoma, the full malignant potential is unknown. Problems related to the definition of physiologic C-cell hyperplasia are discussed. Immunohistochemistry and quantitative analysis are required for the diagnosis. By contrast, C-cell hyperplasia associated with MEN II syndromes or familial medullary carcinoma can be diagnosed preoperatively in asymptomatic children or adolescents by the detection of germline mutations of the RET protooncogene. Morphologic and genetic abnormalities support the idea that C-cells in the familial form of C-cell hyperplasia are neoplastic and can be recognized with conventional stains. Therefore, the number of C-cells is irrelevant for the diagnosis. Medullary microcarcinoma is a neoplasm that measures < 1 cm. The sporadic variant is usually an incidental microscopic finding, whereas the familial form can be diagnosed by genetic testing. Its morphologic features and biologic behavior differ from those of larger medullary carcinomas. The frequency of medullary microcarcinoma will probably increase with the use of genetic testing.

  14. Age- and sex-dependent thymic abnormalities in NZB × SJL F1 hybrid mice

    PubMed Central

    Dumont, F.; Robert, F.

    1980-01-01

    The cellular organization of the thymus was investigated in 3- and 12-month-old NZB × SJL F1 hybrid (NS) mice. Age-dependent alterations were demonstrated which differed strikingly according to the sex of the animals. In female mice, marked abnormalities of the thymus developed during ageing. They consisted of a more or less pronounced hypertrophy accompanied by histological changes and modifications in the nature of the lymphocyte populations. Three types of qualitative changes were found at 12 months of age: (1) depletion of cortical thymocytes as evidenced by histology, by the evaluation of peanut-agglutinin (PNA) binding and by cell electrophoresis; (2) hyperplasia of the medullary lymphoid tissue, probably reflecting the expansion of a population of mature T lymphocytes. This was further suggested by a rise (up to 60%) in the frequency of lymphocytes lacking both PNA receptor and B cell markers, by an increased proportion (57%) of high electrophoretic mobility (EPM) lymphocytes and by an augmentation of in vitro reactivities to phytohaemagglutinin (PHA) and, although to a lesser extent, to concanavalin A (Con A). (3) The appearance of significant numbers of B lymphocytes (up to 20%) as assessed by surface immunoglobulin (sIg) and complement receptor (CR) detection which was accompanied by a vigorous responsiveness of thymus cells to lipopolysaccharide (LPS). None of these abnormalities was seen in the male mice. Instead, the thymus of NS males displayed a nearly normal age-related involution without major change in the proportions of its lymphocyte subpopulations. NS mice thus provide an interesting model of thymic disease influenced by sex-linked factors. ImagesFig. 3 PMID:7438550

  15. [Dysphagia with lateral medullary infarction (Wallenberg's syndrome)].

    PubMed

    Oshima, Fumiko

    2011-11-01

    Dysphagia after lateral medullary infarction (LMI) is common. The dysphagia of LMI is dynamically characterized by a failure in triggering of the pharyngeal-phase swallowing movements, reduced output, and lack of coordination (swallowing pattern abnormality). Based on accurate evaluation, we can select suitable rehabilitative approaches for individual patients, including respiratory therapy, food modification, postural changes, and oral care. We focused on the absence of upper esophageal sphincter (UES) opening of the unaffected side of the medullae. The movement pattern was defined as failure of bolus passage through the intact side of the UES, occurring at least once during the videofluorographic evaluation of each individual. Three abnormal patterns of UES opening were classified. The passage pattern abnormality shows the failure of the stereotyped motor sequence. For severe cases, it is necessary to consider long-term treatment, including botulinum toxin injection or surgery to prevent aspiration and adequate nutritional management.

  16. 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.

  17. Establishment of a Human Thymic Myoid Cell Line

    PubMed Central

    Wakkach, Abdel; Poea, Sandrine; Chastre, Eric; Gespach, Christian; Lecerf, Florence; De la Porte, Sabine; Tzartos, Socrates; Coulombe, Alain; Berrih-Aknin, Sonia

    1999-01-01

    The subset of myoid cells is a normal component of the thymic stroma. To characterize these cells, we immortalized stromal cells from human thymus by using a plasmid vector encoding the SV40 T oncogene. Among the eight cell lines obtained, one had myoid characteristics including desmin and troponin antigens. This new line was designated MITC (myoid immortalized thymic cells). These cells expressed both the fetal and adult forms of muscle acetylcholine receptor (AChR) at the mRNA level, as well as the myogenic transcription factor MyoD1. α-Subunit AChR protein expression was detected by flow cytometry and the AChR was functional in patch-clamp studies. In addition, AChR expression was down-modulated by myasthenia gravis sera or by monoclonal antibody anti-AChR on MITC line similarly to TE671 rhabdomyosarcoma cells, making the MITC line an interesting tool for AChR antigenic modulation experiments. Finally, the MITC line expressed LFA-3, produced several cytokines able to act on T cells, and protected total thymocytes from spontaneous apoptosis in vitro. These results are compatible with a role of thymic myoid cells in some steps of thymocyte development. Therefore MITC line appears to be a useful tool to investigate the physiological role of thymic myoid cells. PMID:10514405

  18. Mouse thymic necrosis virus: a novel murine lymphotropic agent.

    PubMed

    Morse, S S

    1987-12-01

    Mouse thymic necrosis virus (TA), one of two naturally occurring herpesviruses in laboratory mice, was first described in 1961. TA has received relatively little attention even though the virus has been isolated independently from various mouse colonies. This neglect is probably due, at least in part, to the lack of suitable cell culture systems. This review summarizes current knowledge concerning thymic necrosis virus, including new results from the author's laboratory. In vivo, TA causes massive thymic necrosis in newborn mice, with temporary ablation of thymocyte precursors for most T lymphocyte classes except T suppressor cells. All strains of laboratory mice appear susceptible. Severe immunosuppression has been demonstrated in acutely infected mice. Most infected animals survive and shed TA chronically from salivary glands and possibly other glandular tissues. In adult mice, primary infection results in persistent salivary gland infection without overt thymic lesions. Infection appears lifelong, with few clinical signs, but possible effects of chronic TA infection on immune function have been studied little. Recent evidence from the author's laboratory suggests that chronic infection may involve T lymphocytes. The name mouse T lymphotropic virus (abbreviation MTLV) is proposed.

  19. 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.

  20. Oral complications associated with idiopathic medullary aplasia: case report.

    PubMed

    Clercq, Marcel; Gagné-Tremblay, Mélanie

    2008-05-01

    This article describes a patient who experienced serious oral sequelae after severe oral hemorrhage associated with medullary aplasia. These complications required medical, surgical and prosthetic treatments necessitating dental expertise in the hospital setting.

  1. [Study of Medullary Thyroid Carcinoma from a proband].

    PubMed

    Morlán Herrador, Laura; de Arriba, Antonio; Miguel, Gloria; Ferrera, Marta; Labarta, José I

    2016-12-01

    Thyroid cancer is an uncommon type of cancer, accounting less than 1% of all cancers in adults, and 0.5-3% of all cancers in children. There are four different types: papillary carcinoma (80-90% of cases), follicular (5-10%), medullary (5%) and anaplastic cell (2-3%). Eighty per cent of cases of medullary thyroid cancer are sporadic, but 20% are associated with an inherited syndrome that is divided into three groups: multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. The inherited forms are caused by a disruption in the RET oncogene, which is located in the long arm of chromosome 10. A hereditary case of medullary thyroid carcinoma is presented. It was detected because of a familial genetic study. The purpose of the paper is emphasize the importance of the early diagnosis and the intervention of multidisciplinary teams of experts.

  2. Hypercalcitoninemia is not Pathognomonic of Medullary Thyroid Carcinoma

    PubMed Central

    Toledo, Sergio PA; Lourenço, Delmar M; Santos, Marcelo Augusto; Tavares, Marcos R; Toledo, Rodrigo A; de Menezes Correia-Deur, Joya Emilie

    2009-01-01

    Hypercalcitoninemia has frequently been reported as a marker for medullary thyroid carcinoma. Currently, calcitonin measurements are mostly useful in the evaluation of tumor size and progression, and as an index of biochemical improvement of medullary thyroid carcinomas. Although measurement of calcitonin is a highly sensitive method for the detection of medullary thyroid carcinoma, it presents a low specificity for this tumor. Several physiologic and pathologic conditions other than medullary thyroid carcinoma have been associated with increased levels of calcitonin. Several cases of thyroid nodules associated with increased values of calcitonin are not medullary thyroid carcinomas, but rather are related to other conditions, such as hypercalcemias, hypergastrinemias, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, and goiter. Furthermore, prolonged treatment with omeprazole (> 2–4 months), beta-blockers, glucocorticoids and potential secretagogues, have been associated with hypercalcitoninemia. An association between calcitonin levels and chronic auto-immune thyroiditis remains controversial. Patients with calcitonin levels >100 pg/mL have a high risk for medullary thyroid carcinoma (~90%–100%), whereas patients with values from 10 to 100 pg/mL (normal values: <8.5 pg/mL for men, < 5.0 pg/mL for women; immunochemiluminometric assay) have a <25% risk for medullary thyroid carcinoma. In multiple endocrine neoplasia type 2 (MEN2), RET mutation analysis is the gold-standard for the recommendation of total preventive thyroidectomy to relatives at risk of harboring a germline RET mutation (50%). False-positive calcitonin results within MEN2 families have led to incorrect indications of preventive total thyroidectomy to RET mutation negative relatives. In this review, we focus on the differential diagnosis of hypercalcitoninemia, underlining its importance for the avoidance of misdiagnosis of medullary thyroid carcinoma and

  3. Multiple medullary venous malformations decreasing cerebral blood flow: Case report

    SciTech Connect

    Tomura, N.; Inugami, A.; Uemura, K.; Hadeishi, H.; Yasui, N. )

    1991-02-01

    A rare case of multiple medullary venous malformations in the right cerebral hemisphere is reported. The literature review yielded only one case of multiple medullary venous malformations. Computed tomography scan showed multiple calcified lesions with linear contrast enhancement representing abnormal dilated vessels and mild atrophic change of the right cerebral hemisphere. Single-photon emission computed tomography using N-isopropyl-p-({sup 123}I) iodoamphetamine demonstrated decreased cerebral blood flow in the right cerebral hemisphere.

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

    PubMed Central

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

    2016-01-01

    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

  5. Thymic hyperplasia after chemotherapy in adults with mature B cell lymphoma and its influence on thymic output and CD4+ T cells repopulation

    PubMed Central

    Sun, Dao-Ping; Jin, Hui; Ding, Chong-Yang; Liang, Jin-Hua; Wang, Li; Fan, Lei; Wu, Yu-Jie; Xu, Wei; Li, Jian-Yong

    2016-01-01

    ABSTRACT To investigate the thymic regenerative potential in adults accepting chemotherapy for lymphoma. The dynamics of thymic activity in 54 adults from baseline to 12 mo post-chemotherapy was analyzed by assessing thymic structural changes with serial computed tomography (CT) scans, and correlating these with measurements of thymic output by concurrent analysis of single-joint (sj) T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. Furthermore, the consequence of thymic renewal on peripheral CD4+ T cell recovery after chemotherapy was evaluated. Time-dependent changes of thymic size and thymic output assessed by both sjTREC levels and CD31+ RTE counts in peripheral blood were observed during and after chemotherapy. Enlargement of thymus over baseline following chemotherapy regarded as rebound thymic hyperplasia (TH) was identified in 20 patients aged 18−53 y (median 33 y). By general linear models repeated measure analysis, it was found that, patients with TH (n = 20) had a faster recovery of sjTREC levels and CD31+ RTE counts after chemotherapy than patients with comparable age, gender, diagnosis, disease stage, thymic volume and output function at baseline but without TH (n = 18) (p = 0.035, 0.047); besides, patients with TH had a faster repopulation of both naïve CD4+ T cell and natural regulatory CD4+ T cell subsets than those without TH (p = 0.042, 0.038). These data suggested that adult thymus retains the capacity of regeneration after chemotherapy, especially in young adults. The presence of TH could contribute to the renewal of thymopoiesis and the replenishment of peripheral CD4+ T cell pool following chemotherapy in adults. PMID:27467956

  6. Medical Management of Metastatic Medullary Thyroid Cancer

    PubMed Central

    Maxwell, Jessica E.; Sherman, Scott K.; O’Dorisio, Thomas M.; Howe, James R.

    2014-01-01

    Medullary thyroid cancer (MTC) is an aggressive form of thyroid cancer, which occurs in both heritable and sporadic forms. Discovery that mutations in the RET protooncogene predispose to familial cases of this disease has allowed for presymptomatic identification of gene carriers and prophylactic surgery to improve the prognosis of these patients. A significant number of patients with the sporadic type of MTC and even with familial disease, still present with nodal or distant metastases, making surgical cure difficult. Over the past several decades, many different types of therapy for metastatic disease have been attempted, with limited success. Improved understanding of the molecular defects and pathways involved in both familial and sporadic MTC has resulted in new hope for these patients with the development of drugs targeting the specific alterations responsible. This new era of targeted therapy with kinase inhibitors represents a significant step forward from previous trials of chemotherapy, radiotherapy, and hormonal therapy. Although much progress has been made, additional agents and strategies are needed to achieve durable, long-term responses in patients with metastatic MTC. This article reviews the history and results of medical management for metastatic MTC from the early 1970s up until the present day. PMID:24942936

  7. Diagnosis and treatment of medullary thyroid cancer.

    PubMed

    Modigliani, E; Franc, B; Niccoli-sire, P

    2000-12-01

    Medullary carcinoma of the thyroid (MTC) is a rare tumour derived from thyroid C cells with serum calcitonin as a specific and sensitive marker. MTC is inherited in 25% of cases, with an autosomal dominant transmission, age-related penetrance and variable expressivity. MTC is an obligatory component of multiple endocrine neoplasia type 2 (MEN2), which comprises three well defined syndromes: MEN2A, which may be associated with pheochromocytoma and/or hyperparathyroidism; the much rarer MEN2B, which occurs early and is accompanied by developmental abnormalities; while in contrast, familial MTC (FMTC) is not associated with any endocrinopathy. The RET proto-oncogene is the causative gene of the MEN2 syndromes and mutations in this gene are found in >90% of inherited cases, allowing easier and more reliable family screening than pentagastrin stimulation tests. Nevertheless, the correlation between the genotype and the different clinical phenotypes is not perfect. The prognosis of MTC depends on its staging at presentation, and the early appearance of cervical lymph node metastases emphasizes the need for extensive surgery, although many patients still do not normalize calcitonin levels post-operatively, and they remain a challenge for the further management.

  8. Medullary sponge kidney: state of the art.

    PubMed

    Fabris, Antonia; Anglani, Franca; Lupo, Antonio; Gambaro, Giovanni

    2013-05-01

    Medullary sponge kidney (MSK) is a kidney malformation that generally manifests with nephrocalcinosis and recurrent renal stones; other signs may be renal acidification and concentration defects, and pre-calyceal duct ectasias. MSK is generally considered a sporadic disorder, but an apparently autosomal dominant inheritance has also been observed. As MSK reveals abnormalities in both the lower and the upper nephron and is often associated with urinary tract developmental anomalies, its pathogenesis should probably be sought in one of the numerous steps characterizing renal morphogenesis. Given the key role of the GDNF-RET interaction in kidney and urinary tract development and nephrogenesis, anomalies in these molecules are reasonable candidates for explaining a disorder such as MSK. As a matter of fact, we detected two, hitherto unknown, rare variants of the GDNF gene in MSK patients. We surmise that a defective distal acidification has a central role in MSK and is followed by a chain of events including defective bone mineralization, hypercalciuria, hypocitraturia and stone formation.

  9. 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.

  10. Thymic Carcinoma Treated by CyberKnife Stereotactic Body Radiotherapy

    PubMed Central

    Miyazaki, Shinichiro

    2017-01-01

    The standard treatment for advanced thymic carcinoma has not yet been established. Most patients have no symptoms until the advanced stage. Radiation therapy has been used for advanced stage cancer, usually in combination with surgery or chemotherapy; however, the survival rates are 30%-50%. We performed hypofractionated stereotactic radiotherapy with CyberKnife (Accuray, Sunnyvale, CA, USA) for 10 cases of advanced thymic cancer. All cases reached at least partial remission (PR) in two months with progression-free irradiated lesions and minimal radiation-related toxicity. It took only seven to 12 days for each therapy that did not require admission. CyberKnife is beneficial for patients even at the terminal stage. PMID:28367393

  11. Thymic carcinoids in multiple endocrine neoplasia type 1.

    PubMed Central

    Teh, B T; Zedenius, J; Kytölä, S; Skogseid, B; Trotter, J; Choplin, H; Twigg, S; Farnebo, F; Giraud, S; Cameron, D; Robinson, B; Calender, A; Larsson, C; Salmela, P

    1998-01-01

    OBJECTIVE: To study the clinical, pathologic, and genetic features of thymic carcinoids in the setting of multiple endocrine neoplasia type 1 (MEN1) and to study means for detection and prevention of this tumor in patients with MEN1. SUMMARY BACKGROUND DATA: Thymic carcinoid is a rare malignancy, with approximately 150 cases reported to date. It may be associated with MEN1 and carries a poor prognosis, with no effective treatment. Its underlying etiology is unknown. METHODS: Ten patients with MEN1 from eight families with anterior mediastinal tumors were included in a case series study at tertiary referring hospitals. Clinicopathologic studies were done on these patients, with a review of the literature. Mutation analysis was performed on the MEN1 gene in families with clusterings of the tumor to look for genotype-phenotype correlation. Loss of heterozygosity was studied in seven cases to look for genetic abnormalities. RESULTS: Histologic studies of all tumors were consistent with the diagnosis of thymic carcinoid. Clustering of this tumor was found in some of the families-three pairs of brothers and three families with first- or second-degree relatives who had thymic carcinoid. All patients described here were men, with a mean age at detection of 44 years (range 31 to 66). Most of the patients had chest pain or were asymptomatic; none had Cushing's or carcinoid syndrome. All tumors were detected by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. The results of octreoscans performed in three patients were all positive. Histopathologic studies were consistent with the diagnosis of thymic carcinoid and did not stain for ACTH. Mutation analysis of the families with clustering revealed mutations in different exons/introns of the MEN1 gene. Loss of heterozygosity (LOH) studies of seven tumors did not show LOH in the MEN1 region, but two tumors showed LOH in the 1p region. CONCLUSIONS: MEN1-related thymic carcinoids constitute approximately 25

  12. [Impact of thymic function in age-related immune deterioration].

    PubMed

    Ferrando-Martínez, Sara; de la Fuente, Mónica; Guerrero, Juan Miguel; Leal, Manuel; Muñoz-Fernández, M Ángeles

    2013-01-01

    Age-related biological deterioration also includes immune system deterioration and, in consequence, a rise in the incidence and prevalence of infections and cancers, as well as low responses to vaccination strategies. Out of all immune cell subsets, T-lymphocytes seem to be involved in most of the age-related defects. Since T-lymphocytes mature during their passage through the thymus, and the thymus shows an age-related process of atrophy, thymic regression has been proposed as the triggering event of this immune deterioration in elderly people. Historically, it has been accepted that the young thymus sets the T-lymphocyte repertoire during the childhood, whereupon atrophy begins until the elderly thymus is a non-functional evolutionary trace. However, a rising body of knowledge points toward the thymus functioning during adulthood. In the elderly, higher thymic function is associated with a younger immune system, while thymic function failure is associated with all-cause mortality. Therefore, any new strategy focused on the improvement of the elderly quality of life, especially those trying to influence the immune system, should take into account, together with peripheral homeostasis, thymus function as a key element in slowing down age-related decline.

  13. HLA-DR and ß2 microglobulin expression in medullary and atypical medullary carcinoma of the breast: histopathologically similar but biologically distinct entities

    PubMed Central

    Feinmesser, M.; Sulkes, A.; Morgenstern, S.; Sulkes, J.; Stern, S.; Okon, E.

    2000-01-01

    Aims—To examine the expression of HLA-DR and ß2 microglobulin in medullary carcinoma and atypical medullary carcinoma of the breast to determine if the effective presentation of tumour antigens to the immune system can differentiate between these two histopathologically similar entities. Methods—Expression of HLA-DR and ß2 microglobulin was examined by immunohistochemical methods in five samples of medullary carcinoma of the breast, which has a relatively favourable prognosis, six samples of atypical medullary carcinoma of the breast, which has a prognosis closer to that of regular invasive duct carcinoma, and 20 samples of invasive duct carcinomas, 10 with an accompanying lymphocytic infiltrate. Results—A positive and significant correlation was found between tumour type and both HLA-DR and ß2 microglobulin expression. Expression was most prominent in medullary carcinoma, followed by atypical medullary carcinoma and invasive duct carcinoma with and without lymphocytic infiltrates. The mean intensity and percentage of HLA-DR tumour immunostaining were significantly higher in medullary carcinoma than in the other three tumour groups, as was the mean intensity of ß2 microglobulin immunostaining. Mean percentage of ß2 microglobulin immunostaining was significantly higher in medullary carcinoma than in invasive duct carcinoma without lymphocytic infiltrates, and showed a trend to increase from invasive duct carcinoma with lymphocytic infiltrates to atypical medullary carcinoma and medullary carcinoma. Conclusions—Medullary carcinoma and atypical medullary carcinoma of the breast differ in their expression of HLA-DR and ß2 microglobulin. The relatively favourable prognosis of medullary carcinoma of the breast may be related to effective tumour antigen presentation to the immune system through MHC-I and MHC-II expression. Immunotherapy aimed at MHC-I and MHC-II induction might have a beneficial effect in breast cancer. Key Words: medullary carcinoma of the

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

    PubMed

    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.

  15. Sporadic Medullary Thyroid Carcinoma: Clinical Data From A University Hospital

    PubMed Central

    Correia-Deur, Joya Emilie M.; Toledo, Rodrigo A.; Imazawa, Alice T.; Lourenço, Delmar M.; Ezabella, Marilza C. L.; Tavares, Marcos R.; Toledo, Sergio P. A.

    2009-01-01

    INTRODUCTION: Medullary thyroid carcinoma may occur in a sporadic (s-medullary thyroid carcinoma, 75%) or in a multiple endocrine neoplasia type 2 form (MEN2, 25%). These clinical forms differ in many ways, as s-medullary thyroid carcinoma cases are RET-negative in the germline and are typically diagnosed later than medullary thyroid carcinoma in MEN2 patients. In this study, a set of cases with s-medullary thyroid carcinoma are documented and explored. PURPOSE: To document the phenotypes observed in s-medullary thyroid carcinoma cases from a university group and to attempt to improve earlier diagnosis of s-medullary thyroid carcinoma. Some procedures for diagnostics are also recommended. METHOD: Patients (n=26) with apparent s-medullary thyroid carcinoma were studied. Their clinical data were reviewed and peripheral blood was collected and screened for RET germline mutations. RESULTS: The average age at diagnosis was 43.9 years (± 10.82 SD) and did not differ between males and females. Calcitonin levels were increased in all cases. Three patients presented values that were 100-fold greater than the normal upper limit. Most (61.54%) had values that were 20-fold below this limit. Carcinoembryonic antigen levels were high in 70.6% of cases. There was no significant association between age at diagnosis, basal calcitonin levels or time of disease onset with thyroid tumor size (0.6–15 cm). Routine thyroid cytology yielded disappointing diagnostic accuracy (46.7%) in this set of cases. After total thyroidectomy associated with extensive cervical lymph node resection, calcitonin values remained lower than 5 pg/mL for at least 12 months in eight of the cases (30.8%). Immunocyto- and histochemistry for calcitonin were positive in all analyzed cases. None of the 26 cases presented germline mutations in the classical hotspots of the RET proto-oncogene. CONCLUSION: Our cases were identified late. The basal calcitonin measurements and immunostaining for calcitonin were

  16. 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

  17. 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

    2016-04-21

    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.

  18. An Association of Chronic Hyperaldosteronism with Medullary Nephrocalcinosis

    PubMed Central

    Mittal, Kartik; Anandpara, Karan; Dey, Amit K.; Sharma, Rajaram; Thakkar, Hemangini; Hira, Priya; Deshmukh, Hemant

    2015-01-01

    Summary Background An association between chronic hyperaldosteronism and medullary nephrocalcinosis has rarely been made, with only a handful of cases described in literature. Case Report We describe five cases of hyperaldosteronism with a long- standing history in whom associated medullary nephrocalcinosis was established. Conclusions We infer that a chronic hyperaldosteronic status, whether primary or secondary, is a causal factor in the etiopathogenesis of medullary nephrocalcinosis. This article illustrates and summarizes various postulated theories that support our proposed association between hyperaldosteronism and nephrocalcinosis. We conclude that chronic hyperaldosteronism should be included as one of the causes of nephrocalcinosis and that our case series emphasizes the need of a well-organized retrospective study to prove it further. PMID:26413177

  19. Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia.

    PubMed Central

    Robles, A I; Larcher, F; Whalin, R B; Murillas, R; Richie, E; Gimenez-Conti, I B; Jorcano, J L; Conti, C J

    1996-01-01

    To study the involvement of cyclin D1 in epithelial growth and differentiation and its putative role as an oncogene in skin, transgenic mice were developed carrying the human cyclin D1 gene driven by a bovine keratin 5 promoter. As expected, all squamous epithelia including skin, oral mucosa, trachea, vaginal epithelium, and the epithelial compartment of the thymus expressed aberrant levels of cyclin D1. The rate of epidermal proliferation increased dramatically in transgenic mice, which also showed basal cell hyperplasia. However, epidermal differentiation was unaffected, as shown by normal growth arrest of newborn primary keratinocytes in response to high extracellular calcium. Moreover, an unexpected phenotype was observed in the thymus. Transgenic mice developed a severe thymic hyperplasia that caused premature death due to cardio-respiratory failure within 4 months of age. By 14 weeks, the thymi of transgenic mice increased in weight up to 40-fold, representing 10% of total body weight. The hyperplastic thymi had normal histology revealing a well-differentiated cortex and medulla, which supported an apparently normal T-cell developmental program based on the distribution of thymocyte subsets. These results suggest that proliferation and differentiation of epithelial cells are under independent genetic controls in these organs and that cyclin D1 can modulate epithelial proliferation without altering the initiation of differentiation programs. No spontaneous development of epithelial tumors or thymic lymphomas was perceived in transgenic mice during their first 8 months of life, although they continue under observation. This model provides in vivo evidence of the action of cyclin D1 as a pure mediator of proliferation in epithelial cells. Images Fig. 1 Fig. 2 Fig. 3 PMID:8755527

  20. Mixed medullary and follicular carcinoma of the thyroid.

    PubMed

    Pfaltz, M; Hedinger, C E; Mühlethaler, J P

    1983-01-01

    We report a case of medullary carcinoma of the thyroid which on light microscopy showed not only the well known arrangement of cells in sheets and nests but also unequivocal follicular structures. These follicular structures are present both in the primary tumor and in lymph node metastases. Immunohistochemical investigations revealed that the cells lining the follicles produce thyroglobulin, whereas the remaining tumor tissue is positive for calcitonin and carcinoembrionic antigen. This case represents a medullary carcinoma of the thyroid with an atypical pattern consisting of both thyroglobulin and calcitonin producing cells.

  1. [Medullary thyroid carcinoma and other rare types of thyroid carcinoma].

    PubMed

    Obara, Takao

    2007-11-01

    Among 4 major traditional groups of thyroid carcinoma, papillary and follicular carcinomas are most common, and other forms, anaplastic and medullary carcinomas, are relatively rare. The 2003 WHO histological classification of thyroid tumor separated 7 other malignant thyroid tumors into distinct pathological entities, such as poorly differentiated, squamous cell, mucinous carcinomas, carcinoma showing thymus-like differentiation (CASTLE), etc. Although they are also extremely rare, recognition of their clinicopathologic features are very important. In this review, not only diagnostic and therapeutic strategies for the rare forms of thyroid carcinomas, specifically focussed on medullary carcinoma and CASTLE, but also their histogenetic abnormalities were discussed.

  2. 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.

  3. Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells

    PubMed Central

    1991-01-01

    To assess the role of different types of antigen-presenting cells (APC) in the induction of tolerance, we isolated B cells, macrophages, and dendritic cells from thymus and spleen, and injected these into neonatal BALB/c mice across an Mls-1 antigenic barrier. One week after injection of APC from Mls-1-incompatible mice or from control syngeneic mice, we measured the number of thymic, Mls-1a-reactive, V beta 6+ T cells and the capacity of thymocytes to induce a graft-vs.-host (GVH) reaction in popliteal lymph nodes of Mls-1a mice. Injection of thymic but not spleen B cells deleted thymic, Mls-1a-reactive V beta 6+ T cells and induced tolerance in the GVH assay. The thymic B cells were primarily of the CD5+ type, and fluorescence-activated cell sorter- purified CD5+ thymic B cells were active. Injection of dendritic cells from spleen or thymus also induced tolerance, but the V beta 6 cells were anergized rather than deleted. Macrophages from thymus did not induce tolerance. Dendritic cells and thymic B cells were also effective in inducing tolerance even when injected into Mls-, major histocompatibility complex-incompatible, I-E- mice, but only thymic B cells depleted V beta 6-expressing T cells. Therefore, different types of bone marrow-derived APC have different capacities for inducing tolerance, and the active cell types (dendritic cells and CD5+ thymic B cells) can act by distinct mechanisms. PMID:1900075

  4. 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

  5. Apoptosis and the Airway Epithelium

    PubMed Central

    White, Steven R.

    2011-01-01

    The airway epithelium functions as a barrier and front line of host defense in the lung. Apoptosis or programmed cell death can be elicited in the epithelium as a response to viral infection, exposure to allergen or to environmental toxins, or to drugs. While apoptosis can be induced via activation of death receptors on the cell surface or by disruption of mitochondrial polarity, epithelial cells compared to inflammatory cells are more resistant to apoptotic stimuli. This paper focuses on the response of airway epithelium to apoptosis in the normal state, apoptosis as a potential regulator of the number and types of epithelial cells in the airway, and the contribution of epithelial cell apoptosis in important airways diseases. PMID:22203854

  6. Interleukin-1 stimulates zinc uptake by human thymic epithelial cells

    SciTech Connect

    Coto, J.A.; Hadden, J.W. )

    1991-03-15

    Thymic epithelial cells (TEC) are known to secrete peptides which influence the differentiation and maturation of T-lymphocytes. These peptides include the thymic hormones thymulin, thymosin-{alpha}1, and thymopoietin. The biological activity of thymulin is dependent on the presence of zinc in an equimolar ratio. The authors have shown that both interleukin-1{alpha}(IL-1{alpha}) and interleukin-1{beta}(IL-1{beta}), which stimulate proliferation of TEC, stimulate the uptake of Zn-65 in-vitro independent of this proliferation. Mitomycin-C was used to inhibit the proliferation of TEC. Two other stimulators of proliferation of TEC, bovine pituitary extract (BPE) and epidermal growth factor (EGF), did not stimulate zinc uptake by the TEC independent of proliferation. They have also shown, utilizing in-situ hybridization, that IL-1 and zinc induce metallothionein(MT) mRNA expression in human thymic epithelial cells. The exact role of metallothionein is not clear, but it is thought to be involved in regulation of trace metal metabolism, especially in maintenance of zinc homeostasis. Their current hypothesis is that IL-1 stimulates uptake of zinc into the TEC, followed by its complexing with metallothionein. Zinc is then thought to be transferred from metallothionein to thymulin. Immunostaining, utilizing an antithymulin antibody and a fluoresceinated goat anti-rabbit second antibody, confirms the presence of thymulin in TEC and its dependence on zinc. Upon stimulation, thymulin is then secreted. Known stimulants for thymulin include progesterone, dexamethasone, estradiol, testosterone, and prolactin. None of these secretagogues increase zinc uptake, suggesting the priming of the zinc-thymulin complex is unrelated to the regulation of its secretion.

  7. 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

  8. Prognostic value of preoperative serum lactate dehydrogenase in thymic carcinoma

    PubMed Central

    Yuan, Zu-Yang; Gao, Shu-Geng; Mu, Ju-Wei; Xue, Qi; Mao, You-Sheng; Wang, Da-Li; Zhao, Jun; Gao, Yu-Shun; Huang, Jin-Feng

    2016-01-01

    Background The prognostic value of serum lactate dehydrogenase (LDH) has been demonstrated in various solid tumors. We attempted to determine whether serum LDH was predictive of survival in thymic carcinoma after surgical resection. Methods Ninety-five patients with thymic carcinoma treated in our hospital between January 2005 and December 2015 were retrospectively enrolled. Serum LDH was measured before surgery and categorized as low or high relative to the upper limit of normal (ULN) (225 U/L). The relationships of serum LDH level and other clinical variables with survival were estimated by Cox regression and Kaplan-Meier survival analysis. Results Serum LDH levels were found to be significantly associated with overall survival (OS) and progression-free survival (PFS) of these patients. The 1-, 3-, and 5-year PFS were 76%, 51%, and 38%, and the 1-, 3- and 5-year OS were 97%, 75%, and 46%, respectively. Univariate analysis found that high serum LDH (>225 U/L) was associated with both lower OS [hazard ratio (HR) =2.710; 95% confidence interval (CI): 1.363–1.5.391; P=0.004] and PFS (HR =3.365; 95% CI: 1.776–6.374; P<0.001). Multivariate analysis found that high serum LDH was associated with lower PFS (HR =2.122; 95% CI: 1.056–4.267; P=0.035). Moreover, high LDH was significantly associated with advanced Masaoka stage (P=0.001). Conclusions High serum LDH (>225 U/L) was an independent predictor of decreased PFS in thymic carcinoma patients. It was also significantly associated with reduced OS, but was not an independent predictor of death in those patients. PMID:27746998

  9. Reassessing the role of growth hormone and sex steroids in thymic involution.

    PubMed

    Min, Hyeyoung; Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth

    2006-01-01

    The concomitant decline in growth hormone (GH) and increase in sex steroid production with age is thought to be responsible for thymic involution. If changes in the production of these hormones trigger or sustain thymic involution, that process should be accelerated in little mice, which have a genetic deficiency resulting in reduced production of thymopoietic GH, and delayed in the hypogonadal strain, which fails to produce thymocytotoxic sex steroids. The results indicated that thymic involution in both strains progressed in a manner similar to their normal littermates. That blocking sex steroid production did not delay thymic involution was surprising since castration reportedly increases thymus cellularity. Re-examination of that phenomenon revealed that, while gonadectomy results in increased thymus size, its effects are transient, and the thymus ultimately undergoes involution. Taken together, these data suggest that age-related changes in the endocrine system do not underlie thymic involution.

  10. Thymic cysts following radiation therapy for Hodgkin disease

    SciTech Connect

    Baron, R.L.; Sagel, S.S.; Baglan, R.J.

    1981-12-01

    In 3 patients, benign thymic cycsts developed following radiation therapy for Hodgkin disease. Autopsy or surgical specimens provided a diagnosis in all 3 cases; computed tomographic (CT) scans obtained in two of the patients provided a preoperative diagnosis. The etiology of these cysts is uncertain; they may arise following successful radiation treatment of Hodgkin disease involving the thymus. When an anterior mediastinal mass develops in a patient with Hodgkin disease following radiation therapy, careful evaluation to exclude a benign process is indicated prior to initiating additional therapy.

  11. Medullary serotonin neurons are CO2 sensitive in situ

    PubMed Central

    Richerson, George B.; Harris, Michael B.

    2013-01-01

    Brainstem central chemoreceptors are critical to the hypercapnic ventilatory response, but their location and identity are poorly understood. When studied in vitro, serotonin-synthesizing (5-HT) neurons within the rat medullary raphé are intrinsically stimulated by CO2/acidosis. The contributions of these neurons to central chemosensitivity in vivo, however, are controversial. Lacking is documentation of CO2-sensitive 5-HT neurons in intact experimental preparations and understanding of their spatial and proportional distribution. Here we test the hypothesis that 5-HT neurons in the rat medullary raphé are sensitive to arterial hypercapnia. We use extracellular recording and hypercapnic challenge of spontaneously active medullary raphé neurons in the unanesthetized in situ perfused decerebrate brainstem preparation to assess chemosensitivity of individual cells. Juxtacellular labeling of a subset of recorded neurons and subsequent immunohistochemistry for the 5-HT-synthesizing enzyme tryptophan hydroxylase (TPH) identify or exclude this neurotransmitter phenotype in electrophysiologically characterized chemosensitive and insensitive cells. We show that the medullary raphé houses a heterogeneous population, including chemosensitive and insensitive 5-HT neurons. Of 124 recorded cells, 16 cells were juxtacellularly filled, visualized, and immunohistochemically identified as 5-HT synthesizing, based on TPH-immunoreactivity. Forty-four percent of 5-HT cells were CO2 stimulated (increased firing rate with hypercapnia), while 56% were unstimulated. Our results demonstrate that medullary raphé neurons are heterogeneous and clearly include a subset of 5-HT neurons that are excited by arterial hypercapnia. Together with data identifying intrinsically CO2-sensitive 5-HT neurons in vitro, these results support a role for such cells as central chemoreceptors in the intact system. PMID:24047906

  12. Temporal increase in thymocyte negative selection parallels enhanced thymic SIRPα(+) DC function.

    PubMed

    Kroger, Charles J; Wang, Bo; Tisch, Roland

    2016-10-01

    Dysregulation of negative selection contributes to T-cell-mediated autoimmunity, such as type 1 diabetes. The events regulating thymic negative selection, however, are ill defined. Work by our group and others suggest that negative selection is inefficient early in ontogeny and increases with age. This study examines temporal changes in negative selection and the thymic DC compartment. Peptide-induced thymocyte deletion in vivo was reduced in newborn versus 4-week-old NOD mice, despite a similar sensitivity of the respective thymocytes to apoptosis induction. The temporal increase in negative selection corresponded with an elevated capacity of thymic antigen-presenting cells to stimulate T cells, along with altered subset composition and function of resident DC. The frequency of signal regulatory protein α(+) (SIRPα(+) ) and plasmacytoid DCs was increased concomitant with a decrease in CD8α(+) DC in 4-week-old NOD thymi. Importantly, 4-week-old versus newborn thymic SIRPα(+) DC exhibited increased antigen processing and presentation via the MHC class II but not class I pathway, coupled with an enhanced T-cell stimulatory capacity not seen in thymic plasmacytoid DC and CD8α(+) DC. These findings indicate that the efficiency of thymic DC-mediated negative selection is limited early after birth, and increases with age paralleling expansion of functionally superior thymic SIRPα(+) DC.

  13. Histologic characteristics of thymic adenocarcinomas: Clinicopathologic study of a nine-case series and a review of the literature.

    PubMed

    Kwon, Ah-Young; Han, Joungho; Chu, Jinah; Choi, Yong Soo; Jeong, Byeong-Ho; Ahn, Myung-Ju; Ahn, Yong Chan

    2017-02-01

    Primary thymic adenocarcinoma is an extraordinarily rare malignancy; only 49 cases have been reported in the medical literature to date. Because of its rarity, clinical and pathologic characteristics of thymic adenocarcinoma are unclear. We present nine cases of primary thymic adenocarcinoma and discuss clinicopathologic findings in the context of the existing literature. Two-hundred twenty-six thymic carcinoma cases were diagnosed at Samsung Medical Center in Korea, from January, 2001 to July, 2016. Nine of these 226 cases were primary thymic adenocarcinomas. The mean age of primary thymic adenocarcinoma patients was 53.6 years, slightly younger than the mean age of patients with thymic squamous cell carcinomas. The male to female ratio was 2:1. Symptoms, if present, were usually due to compression by the tumor. Tumors showed an extra- or intra-cellular mucin and tubular growth pattern, with CK20- and CDX2-immunoreactivity, similar to adenocarcinomas of the lower intestinal tract. Twenty-five previously reported cases, classified as mucinous adenocarcinoma and adenocarcinoma, not otherwise specified, also had similar characteristics to enteric-type adenocarcinoma and generally expressed CK20, CDX2, CEA, and/or MUC2. Some of these cases had a thymic cyst. These characteristics are different from those of papillary thymic carcinomas, which are morphologically similar to papillary thyroid carcinomas, express CK7 but not CK20, and are often associated with thymoma. The prognosis of thymic adenocarcinoma, enteric type appeared to be worse than the prognosis of papillary thymic carcinoma or carcinoma with adenoid cystic carcinoma-like features. In summary, we demonstrated that common primary thymic adenocarcinomas show enteric-type differentiation with mucin. This tumor type has distinct clinical, pathological, immunohistochemical and prognostic characteristics and is different from other subtypes of thymic adenocarcinoma, papillary thymic carcinoma, and carcinoma with

  14. Thymic emigration patterns in patients with type 2 diabetes treated with metformin

    PubMed Central

    Dworacki, Grzegorz; Urazayev, Olzhas; Bekmukhambetov, Yerbol; Iskakova, Saule; Frycz, Bartosz A; Jagodziński, Paweł P; Dworacka, Marzena

    2015-01-01

    Recent data suggest that thymic output, which provides the naive T cells necessary for the normal functioning of T-cell-dependent immunosurveillance cellular immunity including anti-cancer protection, can be disturbed in the course of type 2 diabetes. Metformin, an anti-diabetic drug commonly confirmed as an agent with many potential anti-cancer activities, might be helpful in this immune correction. The profile of thymic output was evaluated in the current study on the basis of the signal-joint T-cell receptor excision circle (sjTREC) concentration in peripheral blood polymorphonuclear cells and thymic emigrant content in peripheral blood evaluated from CD127 and/or CD132 antigen expression. It was revealed that recent thymic emigrants and more differentiated CD127+ CD132+ cell populations were decreased among naive T cells and CD8+ T cells, whereas RTE count was increased in CD4+ T cells, and the CD127+ CD132+ cell population was less numerous than in non-diabetic participants. Terminally differentiated thymic emigrants, i.e. CD127− CD132+ cells, were increased in naive T cells and in CD8+ T cells. Metformin affects mainly the early phases of thymic export, increasing CD127+ CD132− and CD127+ CD132+ cell populations in naive T cells and the CD127+ CD132− population in CD4+ T lymphocytes. It could be concluded that type 2 diabetes deteriorates thymic immunostasis. The decreased thymic output could be compensated by metformin, especially with regard to CD4+ naive T cells. It is the first time that therapy with metformin has been documented by us as particularly useful in the control and normalization of thymus function, regarding correction of early populations of thymic emigrants. PMID:26271466

  15. Microsurgical anatomy of the arterial basket of the conus medullaris.

    PubMed

    Martirosyan, Nikolay L; Kalani, M Yashar S; Lemole, G Michael; Spetzler, Robert F; Preul, Mark C; Theodore, Nicholas

    2015-06-01

    OBJECT The arterial basket of the conus medullaris (ABCM) consists of 1 or 2 arteries arising from the anterior spinal artery (ASA) and circumferentially connecting the ASA and the posterior spinal arteries (PSAs). The arterial basket can be involved in arteriovenous fistulas and arteriovenous malformations of the conus. In this article, the authors describe the microsurgical anatomy of the ABCM with emphasis on its morphometric parameters and important role in the intrinsic blood supply of the conus medullaris. METHODS The authors performed microsurgical dissections on 16 formalin-fixed human spinal cords harvested within 24 hours of death. The course, diameter, and branching angles of the arteries comprising the ABCM were then identified and measured. In addition, histological sections were obtained to identify perforating vessels arising from the ABCM. RESULTS The ASA tapers as it nears the conus medullaris (mean preconus diameter 0.7 ± 0.12 mm vs mean conus diameter 0.38 ± 0.08 mm). The ASA forms an anastomotic basket with the posterior spinal artery (PSA) via anastomotic branches. In most of the specimens (n= 13, 81.3%), bilateral arteries formed connections between the ASA and PSA. However, in the remaining specimens (n= 3, 18.7%), a unilateral right-sided anastomotic artery was identified. The mean diameter of the right ABCM branch was 0.49 ± 0.13 mm, and the mean diameter of the left branch was 0.53 ± 0.14 mm. The mean branching angles of the arteries forming the anastomotic basket were 95.9° ± 36.6° and 90° ± 34.3° for the right- and left-sided arteries, respectively. In cases of bilateral arterial anastomoses between the ASA and PSA, the mean distance between the origins of the arteries was 4.5 ± 3.3 mm. Histological analysis revealed numerous perforating vessels supplying tissue of the conus medullaris. CONCLUSIONS The ABCM is a critical anastomotic connection between the ASA and PSA, which play an important role in the intrinsic blood supply

  16. Russell-Silver syndrome associated with low conus medullaris.

    PubMed

    Gabor, Larisa; Canaz, Huseyin; Canaz, Gokhan; Kara, Nursu; Alatas, Ibrahim; Bozkus, Hakan

    2016-01-01

    Russell-Silver syndrome is a rare heterogeneous disorder mainly characterized by intrauterine and postnatal growth retardation, craniofacial disproportion, clinodactyly, variation in urogenital development, and skeletal asymmetry. It is rare to come across tethered cord-associated Russell-Silver syndrome. We report a rare case of Russell-Silver syndrome associated with low conus medullaris in a 2-year-old patient with demonstrative phenotype. Magnetic resonance imaging indicated a low conus medullaris at the inferior border of the L3 vertebral body. Urodynamic study revealed detrusor-sphincter dyssynergia and detrusor overactivity. A decision to follow-up the patient was made because of the suspicion of tethered cord syndrome. Even though tethered cord syndrome is not a common finding in Russell-Silver syndrome, it is important to consider tethered cord syndrome to avoid scoliosis and other long-term complications.

  17. Effect of Space Flight on Adrenal Medullary Function

    NASA Technical Reports Server (NTRS)

    Lelkes, Peter I.

    1999-01-01

    We hypothesize that microgravity conditions during space flight alter the expression and specific activities of the adrenal medullary CA synthesizing enzymes (CASE). Previously, we examined adrenals from six rats flown for six days aboard STS 54 and reported that microgravity induced a decrease in the expression and specific activity of rat adrenal medullary tyrosine hydroxylase, the rate limiting enzyme of CA synthesis, without affecting the expression of other CASE. In the past, we analyzed some of the > 300 adrenals from two previous Space Shuttle missions (PARE 03 and SLS 2). The preliminary results (a) attest to the good state of tissue preservation, thus proving the feasibility of subsequent large-scale evaluation, and (b) confirm and extend our previous findings. With this grant we will be able to expeditiously analyze all our specimens and to complete our studies in a timely fashion.

  18. Russell–Silver syndrome associated with low conus medullaris

    PubMed Central

    Gabor, Larisa; Canaz, Huseyin; Canaz, Gokhan; Kara, Nursu; Alatas, Ibrahim; Bozkus, Hakan

    2016-01-01

    Russell–Silver syndrome is a rare heterogeneous disorder mainly characterized by intrauterine and postnatal growth retardation, craniofacial disproportion, clinodactyly, variation in urogenital development, and skeletal asymmetry. It is rare to come across tethered cord-associated Russell–Silver syndrome. We report a rare case of Russell–Silver syndrome associated with low conus medullaris in a 2-year-old patient with demonstrative phenotype. Magnetic resonance imaging indicated a low conus medullaris at the inferior border of the L3 vertebral body. Urodynamic study revealed detrusor-sphincter dyssynergia and detrusor overactivity. A decision to follow-up the patient was made because of the suspicion of tethered cord syndrome. Even though tethered cord syndrome is not a common finding in Russell–Silver syndrome, it is important to consider tethered cord syndrome to avoid scoliosis and other long-term complications. PMID:28217167

  19. Medullary sponge kidney and testicular dysgenesis syndrome: a rare association.

    PubMed

    Masciovecchio, Stefano; Saldutto, Pietro; Paradiso Galatioto, Giuseppe; Vicentini, Carlo

    2014-01-01

    The medullary sponge kidney is also known as Lenarduzzi's kidney or Cacchi and Ricci's disease from the first Italian authors who described its main features. A review of the scientific literature underlines particular rarity of the association of MSK with developmental abnormalities of the lower urinary tract and genital tract such as hypospadias and bilateral cryptorchidism. The work presented is the only one in the scientific literature that shows the association between the medullary sponge kidney and the testicular dysgenesis syndrome. A question still remains unanswered: are the MSK and TDS completely independent malformation syndromes occurring, in this case, simultaneously for a rare event or are they different phenotypic expressions of a common malformative mechanism? In the future we hope that these questions will be clarified.

  20. Medullary Sponge Kidney and Testicular Dysgenesis Syndrome: A Rare Association

    PubMed Central

    Masciovecchio, Stefano; Saldutto, Pietro; Paradiso Galatioto, Giuseppe; Vicentini, Carlo

    2014-01-01

    The medullary sponge kidney is also known as Lenarduzzi's kidney or Cacchi and Ricci's disease from the first Italian authors who described its main features. A review of the scientific literature underlines particular rarity of the association of MSK with developmental abnormalities of the lower urinary tract and genital tract such as hypospadias and bilateral cryptorchidism. The work presented is the only one in the scientific literature that shows the association between the medullary sponge kidney and the testicular dysgenesis syndrome. A question still remains unanswered: are the MSK and TDS completely independent malformation syndromes occurring, in this case, simultaneously for a rare event or are they different phenotypic expressions of a common malformative mechanism? In the future we hope that these questions will be clarified. PMID:24716085

  1. Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus

    PubMed Central

    Hayashida, Jun-Nosuke; Maehara, Takashi; Ishiguro, Noriko; Kubota, Keigo; Furukawa, Sachiko; Ohta, Miho; Sakamoto, Mizuki; Tanaka, Akihiko; Nakamura, Seiji

    2017-01-01

    Oral lichen planus (OLP) is a chronic inflammatory disease characterized by subepithelial T-cell infiltration. Recent studies reported that specific T helper (Th) subsets, especially Th2 cells, are involved in the pathogenesis of OLP. Thymic stromal lymphopoietin (TSLP) is mainly secreted by epithelial cells and potently activates myeloid dendritic cells (mDCs) to induce Th2-mediated inflammation. Here, we investigated the expression of TSLP and related molecules in OLP. Buccal mucosa specimens from patients with OLP, hyperkeratosis, and ulcer were analyzed by immunohistochemistry for expression of TSLP, its receptor (TSLPR), and inflammatory cells. TSLP was detected in/around the epithelium of patients with OLP and hyperkeratosis, whereas TSLPR, CD11c (mDC), and GATA3 (Th2) were strongly expressed in the subepithelial layer only in OLP patients. Double immunofluorescence staining showed that TSLPR expression mainly co-localized with CD11c. Moreover, the number of CD11c- and GATA-3 positive cells was correlated in OLP patients. In lesions selectively extracted by laser microdissection, the mRNA expression of Th2 (IL-4, MDC, TARC, GATA3)- and Th17 (IL-17, RORγt)-related molecules in OLP patients was significantly higher than in other groups. These results suggest that CD11c+ mDCs expressing TSLPR contribute to aberrant Th2 immune responses and the pathogenesis of OLP via TSLP stimulation. PMID:28278185

  2. Medullary carcinoma of the colon: can the undifferentiated be differentiated?

    PubMed

    Fiehn, Anne-Marie Kanstrup; Grauslund, Morten; Glenthøj, Anders; Melchior, Linea Cecilie; Vainer, Ben; Willemoe, Gro Linno

    2015-01-01

    Medullary carcinoma of the colon is a rare variant of colorectal cancer claimed to have a more favorable prognosis than conventional adenocarcinomas. The histopathologic appearance may be difficult to distinguish from poorly differentiated adenocarcinoma. The study aimed to evaluate the diagnostic interobserver agreement and to characterize the immunohistochemical and molecular differences between these two subgroups. Fifteen cases initially classified as medullary carcinoma and 30 cases of poorly differentiated adenocarcinomas were included. Two pathologists reviewed the slides independently without knowledge of the original diagnosis and subgrouped the tumors into the two entities. Agreement was reached in 31 of 45 cases (69 %) with kappa = 0.32. An extensive immunohistochemical panel was performed, and KRAS, NRAS, and BRAF mutational status was assessed. Of the 31 cases with diagnostic agreement, the expression of only MLH-1 along with corresponding expression of PMS-2 differed significantly (p = 0.04). A high rate of BRAF mutations was detected in both subgroups without significant differences. Expression of MLH-1 was superior in dividing the tumors into two separate entities with significant differences in CK20 (p = 0.005) expression and in the rate of BRAF mutations (p = 0.0035). In conclusion, medullary carcinomas of the colon are difficult to discriminate from poorly differentiated adenocarcinoma even with the help of immunohistochemical and molecular analyses. This raises the question whether these morphological subtypes should be maintained or whether an alternative classification of poorly differentiated colorectal adenocarcinomas based on MLH-1 status rather than morphology should be suggested.

  3. Effect of chronic renal medullary nitric oxide inhibition on blood pressure.

    PubMed

    Mattson, D L; Lu, S; Nakanishi, K; Papanek, P E; Cowley, A W

    1994-05-01

    The effects of chronic nitric oxide inhibition in the renal medulla on renal cortical and medullary blood flow, sodium balance, and blood pressure were evaluated in conscious uninephrectomized Sprague-Dawley rats. During a 5-day renal medullary interstitial infusion of the nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 120 micrograms/h) in saline (0.5 ml/min), renal medullary blood flow was selectively decreased by 30% after 2 h and was maintained at that level for the entire infusion. The decrease in medullary blood flow was associated with sodium retention and increased blood pressure. After the cessation of L-NAME infusion, medullary blood flow returned to control, and the sodium balance became negative as blood pressure returned to baseline. These data indicate that renal medullary nitric oxide plays an important role in the regulation of renal blood flow, sodium excretion, and blood pressure.

  4. A Rare Tumor with a Very Rare Initial Presentation: Thymic Carcinoma as Bone Marrow Metastasis

    PubMed Central

    Dawson, Leelavathi

    2017-01-01

    Tumors of thymus gland are rare and account for 0.2% to 1.5% of all the neoplasms. They constitute a heterogeneous group that has an unknown etiology and a complex as well as varied biology. This has led to difficulty in their histological classification and in predicting their prognostic and survival markers. Among them, thymic carcinoma is the most aggressive thymic epithelial tumor exhibiting cytological malignant features and a diversity of clinicopathological characteristics that can cause diagnostic dilemmas, misdiagnosis, and therapeutic challenge. We herein describe a case of a 60-year-old man who while undergoing evaluation for the cause of pancytopenia was discovered having bone marrow metastasis from an asymptomatic thymic carcinoma. Bone marrow metastasis is an extremely rare initial presentation of thymic carcinoma with only few cases reported in the literature. PMID:28116199

  5. Thymic neuroblastoma with the syndrome of inappropriate secretion of antidiuretic hormone.

    PubMed

    Ogawa, Fumihiro; Amano, Hideki; Iyoda, Akira; Satoh, Yukitoshi

    2009-11-01

    We describe a rare case of thymic neuroblastoma with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). A 60-year-old male patient was admitted to our hospital for further examination and treatment of anterior mediastinal tumor found at a regular health check-up. On examination there was hyponatremia, decrease in plasma osmolarity and elevation of plasma antidiuretic hormone (ADH) level. Thus, he underwent total thymectomy under the diagnosis of thymoma with SIADH. The tumor was located in the right lobe of the thymus and the final diagnosis was thymic neuroblastoma. To our knowledge, this is the first reported case of thymic neuroblastoma in which production of ADH by tumor cells is demonstrated immunohistochemically. This case highlights the need to consider functional activity of thymic neuroblastoma and complete resection of the tumor is warranted for treatment.

  6. Investigating Factors Associated with Thymic Regeneration after Chemotherapy in Patients with Lymphoma

    PubMed Central

    Sun, Dao-Ping; Wang, Li; Ding, Chong-Yang; Liang, Jin-Hua; Zhu, Hua-Yuan; Wu, Yu-Jie; Fan, Lei; Li, Jian-Yong; Xu, Wei

    2016-01-01

    The factors involved in thymus regeneration after chemotherapy has not been sufficiently explored. This study was aimed to identify the clinical characteristics and single-nucleotide polymorphisms in the gene (IL7R) encoding IL-7Rα associated with thymus renewal after chemotherapy in Chinese Han individuals with lymphoma. The dynamics of thymic activity in 134 adults with Hodgkin lymphoma (HL) and B cell lymphoma from baseline to 12 months post-chemotherapy were analyzed by assessing thymic structural changes using serial computed tomography scans and correlating these with measurements of thymic output by concurrent analysis of single-joint T-cell receptor excision circles (sjTREC) and CD31+ recent thymic emigrants (RTE) in peripheral blood. The association of clinical variables and IL7R polymorphisms with the occurrence of rebound thymic hyperplasia (TH) and the recovery of thymic output following chemotherapy were evaluated. Thymic regeneration was observed, with the evidence that TH occurred in 38/134 (28.4%) cases, and thymic output, assessed by CD31+ RTE numbers and sjTREC content, recovered to baseline levels within 1 year after the end of therapy. The frequencies of the T allele and TT + GT genotype of rs7718919 located in the promoter of IL7R were significantly higher in patients with TH compared with those without TH (P = 0.031 and 0.027, respectively). In contrast, no significant difference was found between two groups with respect to the distribution of allele and genotype frequencies of rs6897932. By general linear models repeated-measure analysis, rs7718919 and rs6897932 were determined to exert no significant effects on the recovery of thymic output after therapy. Univariate analysis revealed host age under 30, the diagnosis of HL, baseline thymic index and CD31+ RTE counts, and rs7718919 genotype as potential predictors for TH after chemotherapy (P < 0.05); after multivariate adjustment, only host age was independently associated

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

    PubMed

    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

    2015-07-01

    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.

  8. Nature of nontargeted radiation effects observed during fractionated irradiation-induced thymic lymphomagenesis in mice.

    PubMed

    Tsuji, Hideo; Ishii-Ohba, Hiroko; Shiomi, Tadahiro; Shiomi, Naoko; Katsube, Takanori; Mori, Masahiko; Nenoi, Mitsuru; Ohno, Mizuki; Yoshimura, Daisuke; Oka, Sugako; Nakabeppu, Yusaku; Tatsumi, Kouichi; Muto, Masahiro; Sado, Toshihiko

    2013-05-01

    Changes in the thymic microenvironment lead to radiation-induced thymic lymphomagenesis, but the phenomena are not fully understood. Here we show that radiation-induced chromosomal instability and bystander effects occur in thymocytes and are involved in lymphomagenesis in C57BL/6 mice that have been irradiated four times with 1.8-Gy γ-rays. Reactive oxygen species (ROS) were generated in descendants of irradiated thymocytes during recovery from radiation-induced thymic atrophy. Concomitantly, descendants of irradiated thymocytes manifested DNA lesions as revealed by γ-H2AX foci, chromosomal instability, aneuploidy with trisomy 15 and bystander effects on chromosomal aberration induction in co-cultured ROS-sensitive mutant cells, suggesting that the delayed generation of ROS is a primary cause of these phenomena. Abolishing the bystander effect of post-irradiation thymocytes by superoxide dismutase and catalase supports ROS involvement. Chromosomal instability in thymocytes resulted in the generation of abnormal cell clones bearing trisomy 15 and aberrant karyotypes in the thymus. The emergence of thymic lymphomas from the thymocyte population containing abnormal cell clones indicated that clones with trisomy 15 and altered karyotypes were prelymphoma cells with the potential to develop into thymic lymphomas. The oncogene Notch1 was rearranged after the prelymphoma cells were established. Thus, delayed nontargeted radiation effects drive thymic lymphomagenesis through the induction of characteristic changes in intrathymic immature T cells and the generation of prelymphoma cells.

  9. Thymic involution perturbs negative selection leading to autoreactive T cells that induce chronic inflammation.

    PubMed

    Coder, Brandon D; Wang, Hongjun; Ruan, Linhui; Su, Dong-Ming

    2015-06-15

    Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level proinflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a Foxn1 conditional knockout mouse model that induces accelerated thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype consisting of cellular infiltration into non-lymphoid tissues, increased TNF-α production, and elevated serum IL-6. Autoreactive T cell clones were detected in the periphery of Foxn1 conditional knockout mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related regulatory T cell accumulation in naturally aged mice, but not inflammatory infiltration. Taken together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a contributing source of chronic inflammation (inflammaging).

  10. 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

  11. Critical role of SP thymocyte motility in regulation of thymic output in neonatal Aire−/− mice

    PubMed Central

    Jin, Rong; Aili, Abudureyimujiang; Wang, Yuqing; Wu, Jia; Sun, Xiuyuan; Zhang, Yu; Ge, Qing

    2017-01-01

    Autoimmune regulator (Aire) is essential in the perinatal period to prevent the multiorgan autoimmunity. Here we show that Aire-regulated single positive thymocyte trafficking in neonatal period is critical for thymic egress. Reduced thymic emigration was found in Aire−/− mice during neonatal period, leading to enhanced homeostatic expansion of peripheral T cells as early as 2 weeks of age. In neonatal Aire−/− mice, thymic expression of CCR7 ligands were dramatically reduced, resulting in decreased thymocyte motility and thymocyte emigration. This reduction of thymic egress in Aire−/− mice was alleviated beyond 3 weeks of age by an early upregulation of S1P1 signaling. As the numbers and quality of thymic emigrants are essential for the establishment and maintenance of peripheral tolerance, the reduced thymic emigration during neonatal period may deteriorate autoimmunity caused by the emigration of autoreactive T cells. PMID:27965471

  12. Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE)

    PubMed Central

    Chandramouleeswaran, Prasanna M.; Shen, Dawen; Lee, Anna J.; Benitez, Alain; Dods, Kara; Gambanga, Fiona; Wilkins, Benjamin J.; Merves, Jamie; Noah, Yuliana; Toltzis, Sarit; Yearley, Jennifer H.; Spergel, Jonathan M.; Nakagawa, Hiroshi; Malefyt, Rene deWaal; Muir, Amanda B.; Wang, Mei-Lun

    2016-01-01

    Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface

  13. Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE).

    PubMed

    Chandramouleeswaran, Prasanna M; Shen, Dawen; Lee, Anna J; Benitez, Alain; Dods, Kara; Gambanga, Fiona; Wilkins, Benjamin J; Merves, Jamie; Noah, Yuliana; Toltzis, Sarit; Yearley, Jennifer H; Spergel, Jonathan M; Nakagawa, Hiroshi; Malefyt, Rene deWaal; Muir, Amanda B; Wang, Mei-Lun

    2016-01-01

    Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface

  14. Airway responses towards allergens - from the airway epithelium to T cells.

    PubMed

    Papazian, D; Hansen, S; Würtzen, P A

    2015-08-01

    The prevalence of allergic diseases such as allergic rhinitis is increasing, affecting up to 30% of the human population worldwide. Allergic sensitization arises from complex interactions between environmental exposures and genetic susceptibility, resulting in inflammatory T helper 2 (Th2) cell-derived immune responses towards environmental allergens. Emerging evidence now suggests that an epithelial dysfunction, coupled with inherent properties of environmental allergens, can be responsible for the inflammatory responses towards allergens. Several epithelial-derived cytokines, such as thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, influence tissue-resident dendritic cells (DCs) as well as Th2 effector cells. Exposure to environmental allergens does not elicit Th2 inflammatory responses or any clinical symptoms in nonatopic individuals, and recent findings suggest that a nondamaged, healthy epithelium lowers the DCs' ability to induce inflammatory T-cell responses towards allergens. The purpose of this review was to summarize the current knowledge on which signals from the airway epithelium, from first contact with inhaled allergens all the way to the ensuing Th2-cell responses, influence the pathology of allergic diseases.

  15. Involvement of medullary serotonergic groups in multiple system atrophy.

    PubMed

    Benarroch, Eduardo E; Schmeichel, Ann M; Low, Phillip A; Parisi, Joseph E

    2004-03-01

    We sought to determine whether medullary serotonergic neurons were affected in multiple system atrophy (MSA). Immunostaining for tryptophan hydroxylase was performed on serial 50 microm sections of the medulla of brains obtained at autopsy from six control subjects, eight subjects with clinical diagnosis of MSA, and four with Parkinson's disease. There was a severe depletion of serotonergic neurons in the nucleus raphe magnus, raphe obscurus, raphe pallidus, and ventrolateral medulla in MSA. Depletion of serotonergic neurons may contribute to impaired control of sympathetic outflow and other abnormalities in MSA.

  16. Ependymoma of conus medullaris presenting as subarachnoid haemorrhage.

    PubMed

    Ulrich, C T; Beck, J; Seifert, V; Marquardt, G

    2008-02-01

    Subarachnoid haemorrhage (SAH) due to spinal ependymoma is very rare. We report a 37 year old man who presented with typical clinical signs of SAH. Lumbar puncture confirmed SAH but cerebral angiography was negative, and further diagnostic work-up revealed an ependymoma of the conus medullaris as the source of the haemorrhage. A comprehensive review of the literature was conducted. Only 17 patients with spontaneous SAH due to a spinal ependymoma have been reported since 1958. However, in cases of SAH and negative diagnostic findings for cerebral aneurysms or malformations, this aetiology should be considered and work-up of the spinal axis completed.

  17. 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.

  18. Surgical Approaches for Stage IVA Thymic Epithelial Tumors.

    PubMed

    Shapiro, Mark; Korst, Robert J

    2014-01-14

    Thymic epithelial tumors (TET) are rare mediastinal neoplasms that can metastasize to the pleural space (stage IVA). Complete surgical resection remains the backbone of therapy for patients with early stage TET, however, the role of surgery in the management of patients with stage IVA disease is not fully defined. Published reports in this regard are mainly small, retrospective, and uncontrolled, with unclear inclusion criteria. Surgical options to manage pleural disease include metastasectomy, extrapleural pneumonectomy, and metastasectomy/pleurectomy combined with heated intrapleural chemotherapy. The choice of the most appropriate surgical strategy needs to be individualized according to the quantity and location of disease, the patient's overall condition, as well as operator and institutional expertise. In the majority of cases, metastasectomy of pleural implants will be sufficient to achieve a complete resection. The available literature suggests that in selected patients with stage IVA TET, delivery of neoadjuvant chemotherapy followed by complete resection is a viable treatment option that can be associated with long-term survival.

  19. Cell-surface marker analysis of rat thymic dendritic cells.

    PubMed Central

    Bañuls, M P; Alvarez, A; Ferrero, I; Zapata, A; Ardavin, C

    1993-01-01

    Rat thymic dendritic cells have been isolated by collagenase digestion, separation of the low-density cell fraction by centrifugation on metrizamide, and differential adherence. The resulting dendritic cell preparation had a purity of > 90%, and has been analysed by flow cytometry (FCM) using a large panel of monoclonal antibodies (mAb). Dendritic cells expressed major histocompatibility (MHC) class I and class II molecules, the leucocyte common antigen CD45, the rat leucocyte antigen OX44, the rat macrophage marker ED1, and the adhesion molecules Mac-1, LFA-1 and ICAM-1. They were negative for the T- and B-cell-specific forms of CD45, CD45R and B220, and the B-cell marker OX12. Concerning T-cell marker expression, they were negative for T-cell receptor (TcR) and OX40, but they expressed CD2, CD4 and CD8, and interestingly, 50% of DC were CD5+, 50% expressed the alpha-chain of interleukin-2 receptor (IL-2R), and 80% were positive for the T-cell activation antigen recognized by the mAb OX48. Moreover, 60% of DC expressed high levels of Thy-1, whereas 40% displayed intermediate levels of this T-cell marker. PMID:8102122

  20. Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. II. Cytokine activities in murine thymic epithelial and mesenchymal cell culture supernatants.

    PubMed

    Eshel, I; Savion, N; Shoham, J

    1990-03-01

    Two morphologically distinct primary cultures of murine thymic stroma were established and found to be of epithelial (MTEC) and mesenchymal (MTMC) origin. These cultures were generated by selective conditions of tissue disruption and were maintained on extracellular matrix in defined medium. Culture supernatants (CS) from these cultures (EC-CS and MC-CS respectively), were tested for cytokine production and for effects on thymocyte maturation. Both supernatants displayed the activities of IL-3 and of granulocyte/macrophage-CSF and not of IL-1, -2, -4, or IFN. In addition they were found to be mitogenic to murine thymocytes in a "spontaneous" [3H]TdR incorporation assay. The two supernatants differed, however, in their effect on Con A stimulation. EC-CS had a strong enhancing effect, both when used for preincubation (18 h) before Con A stimulation or when present simultaneously with it. MC-CS had a small inconsistent effect under these conditions. Also EC-CS enhanced IL-2 and IL-3 production by thymocytes. The responsive thymocyte subpopulation was the one that does not bind peanut agglutinin. CS of an established thymic epithelial cell line displayed only part of these activities at a considerably lower level. CS from primary kidney cell culture was completely devoid of activity. The results suggest that primary thymic stromal cell cultures, cultivated under the defined conditions described here, may better preserve physiologic secretory activities, and probably also other cell functions, compared with established cell lines. Furthermore, the results are compatible with the hypothesis that the soluble factors, secreted by thymic stromal cells, are active on either very early or late stages of thymic differentiation, whereas the main intrathymic stages of differentiation are conceivable dependent primarily on direct contact with stromal cells.

  1. Ductal barriers in mammary epithelium

    PubMed Central

    Owens, Mark B; Hill, Arnold DK; Hopkins, Ann M

    2013-01-01

    Tissue barriers play an integral role in the biology and pathobiology of mammary ductal epithelium. In normal breast physiology, tight and adherens junctions undergo dynamic changes in permeability in response to hormonal and other stimuli, while several of their proteins are directly involved in mammary tumorigenesis. This review describes first the structure of mammary ductal epithelial barriers and their role in normal mammary development, examining the cyclical changes in response to puberty, pregnancy, lactation and involution. It then examines the role of adherens and tight junctions and the participation of their constituent proteins in mammary tumorigenic functions such as migration, invasion and metastasis. Finally, it discusses the potential of these adhesion proteins as both prognostic biomarkers and potential therapeutic targets in breast cancer. PMID:24665412

  2. Protective effect of angiotensin II-induced increase in nitric oxide in the renal medullary circulation.

    PubMed

    Zou, A P; Wu, F; Cowley, A W

    1998-01-01

    This study examined the effect of intravenous infusion of subpressor doses of angiotensin (Ang II) on renal medullary blood flow (MBF), medullary partial oxygen pressure (PO2), and nitric oxide (NO) concentration under normal conditions and during reduction of the medullary nitric oxide synthase (NOS) activity in anesthetized rats. With laser Doppler flowmetry and polarographic measurement of PO2 with microelectrodes, Ang II (5 ng/kg per minute) did not alter renal cortical and medullary blood flows or medullary PO2. N(omega)-nitro-L-arginine methyl ester (L-NAME) was infused into the renal medullary interstitial space at a dose of 1.4 microg/kg per minute, a dose that did not significantly alter basal levels of MBF or PO2. Intravenous infusion of Ang II at the same dose in the presence of L-NAME decreased MBF by 23% and medullary PO2 by 28%, but it had no effect on cortical blood flow or arterial blood pressure. An in vivo microdialysis-oxyhemoglobin NO trapping technique was used in other rats to determine tissue NO concentrations using the same protocol. Ang II infusion increased tissue NO concentrations by 85% in the renal cortex and 150% in the renal medulla. Renal medullary interstitial infusion of L-NAME (1.4 microg/kg per minute) reduced medullary NO concentrations and substantially blocked Ang II-induced increases in NO concentrations in the renal medulla, but not in the renal cortex. Tissue slices of the renal cortex and medulla were studied to determine the effects of Ang II and L-NAME on the nitrite/nitrate production. Ang II stimulated the nitrite/nitrate production predominately in the renal medulla, which was significantly attenuated by L-NAME. We conclude that small elevations of circulating Ang II levels increase medullary NO production and concentrations, which plays an important role in buffering the vasoconstrictor effects of this peptide and in maintaining a constancy of MBF.

  3. [Thymic epithelial neoplasms: updates on diagnosis, staging, biology and management in France].

    PubMed

    Hadoux, Julien; Girard, Nicolas; Besse, Benjamin

    2012-11-01

    Thymic epithelial neoplasms are rare malignancies with about 250 new incident cases in France every year. The WHO histologic classification distinguishes thymoma and thymic carcinoma which are tumors with different biological and clinical behaviors and outcomes. The Masaoka-Koga staging system is considered as a reference and is also of prognosis value. Diagnosis, multimodal treatment and follow-up of thymic epithelial neoplasms require a multidisciplinary approach where surgery is the cornerstone treatment. A national expert center coordinates thymic epithelial neoplasms management with 12 other regional expert centers through the French organization named RYTHMIC (www.rythmic.org). Patient's files have to be discussed at regional or national multidisciplinary staff. A group of expert pathologists will centrally review tumors when the diagnosis or classification is a matter of controversy. Among its objectives, RYHTMIC has to promote medical education, patient's information and research. This review focuses on RYTHMIC guidelines and data regarding multimodal management and targeted therapies in epithelial thymic neoplasms.

  4. 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.

  5. 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.

  6. Neuromodulatory loop mediated by nerve growth factor and interleukin 6 in thymic stromal cell cultures.

    PubMed Central

    Screpanti, I; Meco, D; Scarpa, S; Morrone, S; Frati, L; Gulino, A; Modesti, A

    1992-01-01

    Neural crest cell derivatives have been suggested to be involved in thymus development. We established nonlymphoid thymic stromal cell cultures capable of supporting T-cell differentiation. In these nonlymphoid cell cultures, we identified cells with phenotypic and biochemical markers specific for neuronal cells. Neurofilament mRNA and 68- and 160-kDa neurofilament proteins, as well as 74-kDa synapsin I isoform, were expressed in many of the cultured cells. For example, neurofilament immunoreactivity was detected in 20-30% of the cells. To see whether thymic neuronal-like cells were involved in a neural differentiation pathway, we investigated the effect of nerve growth factor (NGF) and interleukin 6 (IL-6), two known neurotrophic factors. The expression of the above-described neural markers was enhanced by NGF and IL-6, which we report to be produced in an autocrine way by thymic stromal cell cultures. Finally, we found that IL-6 gene expression in these cell cultures was enhanced by NGF. Evidence is thus offered of a neuromodulatory loop within the thymic stromal cell population supported by local production of NGF and IL-6 and involving neural cell elements. Interestingly, IL-6, which is known to be implicated in thymocyte differentiation, also displays a neuromodulatory activity on thymic stromal cells, suggesting a multivalent role for this cytokine within the thymus. Images PMID:1373490

  7. Increased P16 DNA Methylation in Mouse Thymic Lymphoma Induced by Irradiation

    PubMed Central

    Song, Wengang; Liu, Yongzhe; Liu, Ying; Zhang, Cong; Yuan, Bao; Zhang, Lianbo; Sun, Shilong

    2014-01-01

    DNA methylation is an important part of epigenetics. In this study, we examined the methylation state of two CpG islands in the promoter of the p16 gene in radiation-induced thymic lymphoma samples. The mRNA and protein levels of P16 were significantly reduced in radiation-induced thymic lymphoma tissue samples. Twenty-three CpG sites of the CpG islands in the p16 promoter region were detected, and the methylation percentages of −71, −63, −239, −29, −38, −40, −23, 46 CpG sites were significantly higher in radiation-induced thymic lymphoma tissue samples than those in matched non-irradiated thymus tissue samples. This study provides new evidence for the methylation state of p16 in the radiation-induced thymic lymphoma samples, which suggests that the methylation of these CpG sites in the p16 promoter may reduce its expression in the thymic lymphoma after irradiation. PMID:24747802

  8. Medullary infarcts may cause ipsilateral masseter reflex abnormalities.

    PubMed

    Thömke, Frank; Marx, Jürgen J; Cruccu, Giorgio; Stoeter, Peter; Hopf, Hanns C

    2007-10-01

    There is a suprasegmental influence on the masseter reflex (MassR) in animals, which is mediated via the fifth nerve spinal nucleus (5SpN). Corresponding data in humans are lacking. Out of 268 prospectively recruited patients with clinical signs of acute brainstem infarctions, we identified 38 with magnetic resonance imaging (MRI)-documented unilateral infarcts caudal to the levels of the fifth nerve motor and main sensory nuclei. All had biplanar T2- and echo planar diffusion-weighted MRI and MassR testing. Five patients (13%) had ipsilateral MassR abnormalities. In all, the infarcts involved the region of the 5SpN. Patients with medullary infarcts involving the region of the 5SpN may thus have ipsilateral MassR abnormalities. This possibly represents an interruption of an excitatory projection mediated via the 5SpN to masseter motoneurons in the fifth nerve motor nucleus. MassR abnormalities with medullary lesions restrict the topodiagnostic value of the MassR.

  9. Cytological aspects of melanotic variant of medullary thyroid carcinoma.

    PubMed

    de Lima, M A; Dias Medeiros, J; Rodrigues Da Cunha, L; de Cássia Caldas Pessôa, R; Silveira Tavares, F; de Fátima Borges, M; Marinho, E O

    2001-03-01

    We had the opportunity to examine a case of fine-needle aspiration (FNA) of a melanotic variant of medullary thyroid carcinoma (MTC) in a 20-yr-old man. The patient presented a single node, hardened and mobile upon deglutition, in the right lobe of the thyroid, for 9 mo, without symptoms of glandular dysfunction. Calcitonin (138 pg/ml), urinary calcium (177 mg/dl), and the carcinoembryonic antigen (341 ng/ml) were increased. The nodular aspirate, drawn by FNA, was represented by pleomorphic cells, with frequent intranuclear cytoplasmic inclusions, sometimes bi- or multinucleated, with abundant, finely granular cytoplasm, sometimes containing a brown pigment resembling melanin. An immunohistochemical study using monoclonal antibodies (Dako Corp., Carpinteria, CA) showed that the neoplastic cells were intensely and diffusely positive for calcitonin and chromogranin, and focally positive for HMB45. In view of these findings, the case was characterized as a melanotic variant of medullary carcinoma, a rare type of neoplasia, but having a prognosis similar to the classical variant of MTC.

  10. Secretion of Parathyroid Hormone in Patients with Medullary Thyroid Carcinoma

    PubMed Central

    Deftos, Leonard J.; Parthemore, Jacqueline G.

    1974-01-01

    The secretion of parathyroid hormone (PTH) and calcitonin (CT) was studied in 30 patients with medullary thyroid carcinoma. Most patients with elevated levels of CT were normocalcemic and also had normal basal levels of PTH. Five of six patients with associated hyperparathyroidism were hypercalcemic and had elevated basal PTH levels. Hormone secretion was also studied during infusions with standard and low doses of calcium. PTH unexpectedly increased during 12 of 18 calcium infusions. Such a paradoxical increase in PTH was seen in those patients with the greatest increase in CT and the least increase in calcium during the calcium infusion. Accordingly, increases in PTH concentration during the calcium infusions could be correlated directly with increases in CT and correlated inversely with increases in calcium. These observations suggest that, in some patients with medullary thyroid carcinoma, a further increase in the abnormally elevated CT levels may stimulate PTH secretion. Therefore, at least in acute studies, there may be a functional, as well as a genetic, relationship between the secretion of these two hormones in patients with this thyroid tumor. PMID:4847251

  11. Role of renal medullary adenosine in the control of blood flow and sodium excretion.

    PubMed

    Zou, A P; Nithipatikom, K; Li, P L; Cowley, A W

    1999-03-01

    This study determined the levels of adenosine in the renal medullary interstitium using microdialysis and fluorescence HPLC techniques and examined the role of endogenous adenosine in the control of medullary blood flow and sodium excretion by infusing the specific adenosine receptor antagonists or agonists into the renal medulla of anesthetized Sprague-Dawley rats. Renal cortical and medullary blood flows were measured using laser-Doppler flowmetry. Analysis of microdialyzed samples showed that the adenosine concentration in the renal medullary interstitial dialysate averaged 212 +/- 5.2 nM, which was significantly higher than 55.6 +/- 5.3 nM in the renal cortex (n = 9). Renal medullary interstitial infusion of a selective A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 300 pmol. kg-1. min-1, n = 8), did not alter renal blood flows, but increased urine flow by 37% and sodium excretion by 42%. In contrast, renal medullary infusion of the selective A2 receptor blocker 3, 7-dimethyl-1-propargylxanthine (DMPX; 150 pmol. kg-1. min-1, n = 9) decreased outer medullary blood flow (OMBF) by 28%, inner medullary blood flows (IMBF) by 21%, and sodium excretion by 35%. Renal medullary interstitial infusion of adenosine produced a dose-dependent increase in OMBF, IMBF, urine flow, and sodium excretion at doses from 3 to 300 pmol. kg-1. min-1 (n = 7). These effects of adenosine were markedly attenuated by the pretreatment of DMPX, but unaltered by DPCPX. Infusion of a selective A3 receptor agonist, N6-benzyl-5'-(N-ethylcarbonxamido)adenosine (300 pmol. kg-1. min-1, n = 6) into the renal medulla had no effect on medullary blood flows or renal function. Glomerular filtration rate and arterial pressure were not changed by medullary infusion of any drugs. Our results indicate that endogenous medullary adenosine at physiological concentrations serves to dilate medullary vessels via A2 receptors, resulting in a natriuretic response that overrides the tubular A1 receptor

  12. Correlation between acetylcholine receptor antibody levels and thymic pathology in myasthenia gravis: a review.

    PubMed

    Huang, G Z; Lo, Y L

    2013-06-01

    Myasthenia gravis is the most common chronic autoimmune neuromuscular disease. Anti-acetylcholine receptor (AChR) antibodies are found in at least 80% of patients with generalized myasthenia and have been implicated in disease pathogenesis. Thymic abnormalities are frequently found in seropositive patients, and the thymus is thought to be involved in generation of autoimmunity. This article reviews existing literature on the role of AChR antibodies in the pathogenesis of myasthenia gravis, and the correlation between AChR antibody titers and thymic pathology. Most studies found that highest titers are seen in thymic hyperplasia, followed by intermediate titers in thymoma, and lowest titers in atrophic or normal thymus. One publication found no difference between titers in thymoma and normal thymus.

  13. Thymic hyperplasia associated with primary Sjogren’s syndrome cured by thymectomy

    PubMed Central

    Xin, Yanzhong; Cai, Hongfei; Li, Yang

    2017-01-01

    Thymus hyperplasia associated with Sjogren’s syndrome is a rare morbid state. The present study described a 55-year-old woman who presented with a dryness of the oral cavity, and itchy eyes. Chest computed tomography identified a mass, measuring 4×2.5×2.5 cm, located at the anterior mediastinum. The mass was suspected as thymoma, thymic cyst, or teratoma, and resected by thymectomy. The postoperative pathological diagnosis was thymic lymphoid hyperplasia. After 1-year follow-up period, her sicca syndrome has been resolved. The present study records a successful case for thymectomy to treat the patients with thymic hyperplasia associated with primary Sjogren’s syndrome (pSS). PMID:28275496

  14. Effect of dDAVP on basolateral cell surface water permeability in the outer medullary collecting duct.

    PubMed

    Solenov, E I; Nesterov, V V; Baturina, G S; Khodus, G R; Ivanova, L N

    2003-11-01

    We report a novel approach for assessing the volume of living cells which allows quantitative, high-resolution characterization of dynamic changes in cell volume while retaining the cell functionality. The aim of this study was to evaluate the short-term effect of vasopressin on basolateral cell surface water permeability in the outer medullary collecting duct (OMCD). The permeability of the basolateral cell membrane was determined in the tubules where the apical membrane was blocked with oil injected into the lumen. The apparent coefficient of water permeability (Pf) was evaluated by measuring the cell swelling after the step from hypertonic to isotonic medium (600 mosm to 300 mosm). Desmopressin (dDAVP) induced an increase of the basolateral Pf from 113.7+/-8.5 microm/s in control cells to 186.6+/-11.4 mum/s in micro-dissected fragments of the OMCD incubated in vitro (10(-7) M dDAVP, 30 min at 37 degrees C) (P<0.05). Mercury caused pronounced inhibition of basolateral water permeability (26.0+/-6.9 microm/s; P<0.05). The effect of mercury (1.0 mM HgCl2) was reversible: after washing the fragments with PBS for 20 min, Pf values were restored to the control levels (125.0+/-9.5 microm/s). The results of the study indicate the existence of a mechanism controlling the osmotic water permeability of the basolateral cell membrane in the OMCD epithelium.

  15. Isolation and identification of a new thymic peptide from calf thymus.

    PubMed

    Qin, Xi-Ming; Duan, Ming-Xing; Deng, Bin; Liu, Xi-Cheng; Zhang, Qiang-Zhe; Liu, Zheng; He, Hong-Xuan

    2004-08-01

    Various thymic peptides (including thymulin, thymic humoral factor, thymopoietin, etc.) play important roles in the process of T cell maturation and development. We isolated a new peptide from calf thymus and named it thymus activity factor II (TAF-II). A yield of 0.92 mg of TAF-II was purified from 500 g calf thymus. Analysis by LC/MSD-Trap showed the amino acid sequence of this hexapeptide to be Glu-Ala-Lys-Ser-Gln-Gly-OH with molecular weight 618.5 daltons. We have also begun to investigate the influence of TAF-II.

  16. [Thymic ectopia and parathyroid tissue in the pangolin (Manis tricuspis Rafinesque)].

    PubMed

    Bureau, J P; Senelar, R; Serrou, B; Kreher, P

    1975-09-01

    Thymic ectopies are under study in 45 Pangolin's thyroids (Manis tricuspis Rafinesque). Their frequency seems to be independent of the sex of the animal but this frequency also appears to be in relation to the age of the animal. The topographic and morphological studies suggest a close relationship between these inclusions made out of thymic tissue and the presence of parathyroid islets included into the thyroid capsule. Some pictures, showing a connection between parathyroid cells and thymis parenchym elements, plead in favour of a functional interelation between these different structures as the Mc Manus experiments suggest it.

  17. A pediatric case of life-threatening airway obstruction caused by a cervicomediastinal thymic cyst.

    PubMed

    Komura, Makoto; Kanamori, Yutaka; Sugiyama, Masahiko; Fukushima, Noriyoshi; Iwanaka, Tadashi

    2010-09-01

    Most patients with thymic cysts complain of a slowly enlarging, asymptomatic cervical mass. Only 6-10% suffer dysphagia, dyspnoea, stridor, cervical pain or vocal paralysis. In some rare cases sudden onset of severe dyspnoea or asphyxia is the first symptom, especially in neonates and small infants. We report a unique case of a 20-month-old child, who required emergency tracheal intubation due to asphyxia. Cervicomediastinal thymic cyst might need to be included in causes of life-threatening airway obstruction in young children.

  18. A 9 years boy with MEN-2B variant of medullary thyroid carcinoma.

    PubMed

    Sattar, M A; Hadi, H I; Ekramuddoula, F M; Hasanuzzaman, S M

    2013-04-01

    To highlight a rare disease like multiple endocrine neoplasia (MEN)-2B variant of medullary thyroid carcinoma and to optimize the management option in such cases, we present a nine year old boy with thyroid swelling, cervical lymphadenopathy and thick lips. His calcitonin level was raised. Investigation's results of the boy were as following fine needle aspiration cytology (FNAC) was medullary carcinoma of thyroid, preoperative calcitonin was >2000pg/ml, post operative histopathological report was medullary carcinoma. Total thyroidectomy with aggressive initial neck surgery may reduce the recurrence and increase better prognosis and survival rate. Calcitonin is used as diagnostic and follow-up marker.

  19. Genetic Alterations in Medullary Thyroid Cancer: Diagnostic and Prognostic Markers

    PubMed Central

    A, Taccaliti; F, Silvetti; G, Palmonella; M, Boscaro

    2011-01-01

    Medullary thyroid carcinoma (MTC) is a rare calcitonin producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, with consequently essential roles in cell survival, differentiation and proliferation. Somatic or germline mutations of the RET gene play an important role in this neoplasm in development of sporadic and familial forms, respectively. Genetic diagnosis has an important role in differentiating sporadic from familiar MTC. Furthermore, depending on the location of the mutation, patients can be classified into risk classes. Therefore, genetic screening of the RET gene plays a critical role not only in diagnosis but also in assessing the prognosis and course of MTC. PMID:22654561

  20. 2012 European Thyroid Association Guidelines for Metastatic Medullary Thyroid Cancer

    PubMed Central

    Schlumberger, M.; Bastholt, L.; Dralle, H.; Jarzab, B.; Pacini, F.; Smit, J.W.A.

    2012-01-01

    Distant metastases are the main cause of death in patients with medullary thyroid cancer (MTC). These 21 recommendations focus on MTC patients with distant metastases and a detailed follow-up protocol of patients with biochemical or imaging evidence of disease, selection criteria for treatment, and treatment modalities, including local and systemic treatments based on the results of recent trials. Asymptomatic patients with low tumor burden and stable disease may benefit from local treatment modalities and can be followed up at regular intervals of time. Imaging is usually performed every 6–12 months, or at longer intervals of time depending on the doubling times of serum calcitonin and carcinoembryonic antigen levels. Patients with symptoms, large tumor burden and progression on imaging should receive systemic treatment. Indeed, major progress has recently been achieved with novel targeted therapies using kinase inhibitors directed against RET and VEGFR, but further research is needed to improve the outcome of these patients. PMID:24782992

  1. Medullary thyroid carcinoma with ectopic adrenocorticotropic hormone syndrome.

    PubMed

    Choi, Hong Seok; Kim, Min Joo; Moon, Chae Ho; Yoon, Jong Ho; Ku, Ha Ra; Kang, Geon Wook; Na, Im Il; Lee, Seung-Sook; Lee, Byung-Chul; Park, Young Joo; Kim, Hong Il; Ku, Yun Hyi

    2014-03-01

    Ectopic adrenocorticotropic hormone (ACTH) syndrome is caused most frequently by a bronchial carcinoid tumor or by small cell lung cancer. Medullary thyroid carcinoma (MTC) is a rare etiology of ectopic ACTH syndrome. We describe a case of Cushing syndrome due to ectopic ACTH production from MTC in a 48-year-old male. He was diagnosed with MTC 14 years ago and underwent total thyroidectomy, cervical lymph node dissection and a series of metastasectomies. MTC was confirmed by the pathological examination of the thyroid and metastatic mediastinal lymph node tissues. Two years after his last surgery, he developed Cushingoid features, such as moon face and central obesity, accompanied by uncontrolled hypertension and new-onset diabetes. The laboratory results were compatible with ectopic ACTH syndrome. A bilateral adrenalectomy improved the clinical and laboratory findings that were associated with Cushing syndrome. This is the first confirmed case of ectopic ACTH syndrome caused by MTC in Korea.

  2. Treating medullary thyroid cancer in the age of targeted therapy

    PubMed Central

    Cabanillas, Maria E; Hu, Mimi I; Jimenez, Camilo; Grubbs, Elizabeth G; Cote, Gilbert J

    2015-01-01

    Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor deriving from the thyroid parafollicular cell. Thyroidectomy continues to serve as the primary initial treatment for this cancer. Because standard cytotoxic chemotherapy has proven ineffective, reoperation and external beam radiation therapy had been the only tools to treat recurrences or distant disease. The discovery that aberrant activation of RET, a receptor tyrosine kinase, is a primary driver of MTC tumorigenesis led to clinical trials using RET-targeting tyrosine kinase inhibitors. The successes of those trials led to the approval of vandetanib and cabozantinib for treating patients with progressive or symptomatic MTC. The availability of these drugs, along with additional targeted therapies in development, requires a thoughtful reconsideration of the approach to treating patients with unresectable locally advanced and/or metastatic progressive MTC. PMID:25908961

  3. Medullary Sponge Kidney and Urinary Calculi Aeromedical Concerns

    NASA Technical Reports Server (NTRS)

    Jones, Jeffrey A.; Cherian, Sebastian F.; Barr, Yael R.; Stocco, Amber

    2008-01-01

    Medullary Sponge Kidney (MSK) is a benign disorder associated with renal stones in 60% of patients. Patients frequently have episodic painless hematuria but are otherwise asymptomatic unless renal calculi or infections complicate the disease. Nephrolithiasis is a relative, but frequently enforced, contraindication to space or other high performance flight. Two case reports of asymptomatic NASA flight crew with MSK and three cases of military aviators diagnosed with MSK are reviewed, all cases resulted in waiver and return to flight status after treatment and a vigorous follow up and prophylaxis protocol. MSK in aviation and space flight necessitates a highly case-by-case dependent evaluation and treatment process to rule out other potential confounding factors that might also contribute to stone formation and in order to re-qualify the aviator for flight duties.

  4. Pain and neuroma formation in Wallenberg's lateral medullary syndrome.

    PubMed

    Moffie, D; Hamburger, H L

    1986-01-01

    We report a patient with a Wallenberg's lateral medullary syndrome in which pain was a prominent feature. This led to substitution of the original and correct diagnosis by that of a thalamic syndrome for which a prefrontal leucotomy was performed. The patient died some years later from a myocardial infarction and autopsy was performed. In the dorsolateral part of the medulla oblongata a cavity was found in which aberrant nerve fibres with neuroma-like formations could be seen. These fibres coursed along blood vessels, and penetrated from the surface of the medulla oblongata. On the base of the clinico-pathological correlations, it is conjectured that destruction of the lateral reticular formation cannot be the sole cause of the severe pain.

  5. [Biomechanical analysis of the medullary bone nail and its locking].

    PubMed

    Teubner, E

    1985-07-01

    By mechanical definition an intramedullary nail is not a nail but rather a bendable feather, subject to longitudinal tension and to a lesser degree to transverse pressure. Reaming the medullary canal is necessary for centralization of the nail as well as to increase the area of contact with the bone. However, this procedure is detrimental to the bone metabolism and reduces its elasticity against torsional forces. The dynamic locking nail-system is more biologic than conventional nailing and it reduces rotatory instability with the help of additional components, such as transverse screws. Only static locking allows true static weight bearing with crutches, but not dynamic mobilisation. Nails with conventional strength and in leaf of trefoil formation are superior to other designs. However, an improved angle in the proximal locking is suggested, as this would allow for a three to four times greater weight bearing.

  6. Lateral medullary stroke in patient with granulomatous polyangiitis.

    PubMed

    Taraschenko, Olga D; Amory, Colum F; Waldman, Jonathan; Hanspal, Era K; Bernardini, Gary L

    2014-01-01

    Granulomatous polyangiitis (GPA), also known as Wegener granulomatosis, is a systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis that infrequently affects the central nervous system. We report a 41-year-old man with lateral medullary infarction who developed rapidly progressive renal failure. He was diagnosed with GPA based on positive serum c-ANCA and antiproteinase 3 antibodies and demonstration of pauci-immune crescentic glomerulonephritis on kidney biopsy. He was treated with Coumadin, pulse steroids, cyclophosphamide, and plasmapheresis. He had resolution of his neurologic deficits and improvement in renal function. This case report highlights the importance to consider GPA vasculitis in the differential diagnosis of stroke in patients with development of acute kidney injury.

  7. The junctional epithelium originates from the odontogenic epithelium of an erupted tooth.

    PubMed

    Yajima-Himuro, Sara; Oshima, Masamitsu; Yamamoto, Gou; Ogawa, Miho; Furuya, Madoka; Tanaka, Junichi; Nishii, Kousuke; Mishima, Kenji; Tachikawa, Tetsuhiko; Tsuji, Takashi; Yamamoto, Matsuo

    2014-05-02

    The junctional epithelium (JE) is an epithelial component that is directly attached to the tooth surface and has a protective function against periodontal diseases. In this study, we determined the origin of the JE using a bioengineered tooth technique. We transplanted the bioengineered tooth germ into the alveolar bone with an epithelial component that expressed green fluorescence protein. The reduced enamel epithelium from the bioengineered tooth fused with the oral epithelium, and the JE was apparently formed around the bioengineered tooth 50 days after transplantation. Importantly, the JE exhibited green fluorescence for at least 140 days after transplantation, suggesting that the JE was not replaced by oral epithelium. Therefore, our results demonstrated that the origin of the JE was the odontogenic epithelium, and odontogenic epithelium-derived JE was maintained for a relatively long period.

  8. Comparative cytokeratin distribution patterns in cholesteatoma epithelium.

    PubMed

    Olszewska, E; Sudhoff, H

    2007-01-01

    Cytokeratins (CKs) are known as the intermediate filament proteins of epithelial origin. Their distribution in human epithelia is different according to the type of epithelium, state of growth and differentiation. We used monoclonal mouse antibodies against cytokeratins to study CK expression in the following human tissues: cholesteatoma, middle ear mucosa, glandular epithelium, and meatal ear canal epithelium. Immunohistochemical processing was performed using the labeled steptavidin peroxidase method to demonstrate the presence of CKs in cells of human epidermis. Positive reaction was obtained for CK4, CK34betaE12, CK10, CK14 in skin and cholesteatoma epithelium. However, a more extensive positive reaction with those CKs was observed in cholesteatoma epithelium. Positive immunoreactivity was seen with anti- CK19 in the glandular epithelium. Middle ear mucosa specimens revealed positive immunoreactivity with the antibodies against CK4. The expression of CK4 was definitely positive within the basal layers of the epidermis. The glandular epithelium showed no positive reaction with anti- CK4, anti- CK34betaE12, anti- CK14 and anti-CK10. Immunohistochemistry for CK18 showed no reaction in all examined tissues. Cholesteatoma is known as a proliferative disease in the middle ear which pathogenesis is not completely understood. Keratinocytes express hyperproliferation- associated CKs and after reaching the suprabasal layers they finally undergo apoptosis creating keratinous debris. Cytokeratin expression observed in the epithelium explains proliferative behavior of cholesteatoma which is associated with increased keratinocyte migration. Cytokeratins can be used as potential proliferative markers. It can also allow for searching the usefulness of inhibiting regulators in the treatment of hyperproliferative diseases.

  9. Osmotic regulation of airway reactivity by epithelium.

    PubMed

    Fedan, J S; Yuan, L X; Chang, V C; Viola, J O; Cutler, D; Pettit, L L

    1999-05-01

    Inhalation of nonisotonic solutions can elicit pulmonary obstruction in asthmatic airways. We evaluated the hypothesis that the respiratory epithelium is involved in responses of the airways to nonisotonic solutions using the guinea pig isolated, perfused trachea preparation to restrict applied agents to the mucosal (intraluminal) or serosal (extraluminal) surface of the airway. In methacholine-contracted tracheae, intraluminally applied NaCl or KCl equipotently caused relaxation that was unaffected by the cyclo-oxygenase inhibitor, indomethacin, but was attenuated by removal of the epithelium and Na+ and Cl- channel blockers. Na+-K+-2Cl- cotransporter and nitric oxide synthase blockers caused a slight inhibition of relaxation, whereas Na+,K+-pump inhibition produced a small potentiation. Intraluminal hyperosmolar KCl and NaCl inhibited contractions in response to intra- or extraluminally applied methacholine, as well as neurogenic cholinergic contractions elicited with electric field stimulation (+/- indomethacin). Extraluminally applied NaCl and KCl elicited epithelium-dependent relaxation (which for KCl was followed by contraction). In contrast to the effects of hyperosmolarity, intraluminal hypo-osmolarity caused papaverine-inhibitable contractions (+/- epithelium). These findings suggest that the epithelium is an osmotic sensor which, through the release of epithelium-derived relaxing factor, can regulate airway diameter by modulating smooth muscle responsiveness and excitatory neurotransmission.

  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. C-Phycocyanin: an effective protective agent against thymic atrophy by tributyltin.

    PubMed

    Gupta, Monika; Dwivedi, Upendra Nath; Khandelwal, Shashi

    2011-07-04

    Spirulina platensis, used worldwide as a food supplement, is a natural source of protein, vitamins, carbohydrates and polyunsaturated fatty acids. C-Phycocyanin (C-Pc), its major biliprotein, is known to possess anti-oxidant, anti-inflammatory and radical scavenging properties. Our present study showed that treatment with C-Pc protects the rats from Tributyltin (TBT) induced thymic atrophy. The results reveal TBT-induced oxidative stress mediated apoptosis in rat thymocytes in vivo and its attenuation by C-Pc. This ameliorative effect could be attributed to antioxidant activity of the biliprotein. C-Pc also increased TBTC reduced thymic weight and cellularity as well. TBTC-induced ROS generation and lowered GSH levels were restored by C-Pc, suggesting its radical scavenging properties. The various apoptotic determinants such as mitochondrial membrane potential, Bax/Bcl-2 ratio, caspase-3 activity and apoptotic cell population were effectively modulated by C-Pc treatment. We make this first observation to illustrate the effectiveness of C-Pc in reducing TBTC-induced thymic atrophy. The morphology of thymic tissue was restored to near normal by this biliprotein. The present study, therefore, suggests that C-Pc could serve as an effective natural antioxidant for efficient management of TBTC induced oxidative damage.

  12. Appraisal of experimental and commercial Marek's disease vaccines to induce bursal and thymic atrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recently, several experimental Marek’s disease (MD) vaccines were developed that appear to protect equally or better than the best commercial vaccines. However, some of the experimental vaccines were reported to induce transient bursal and thymic atrophies. We will report on two promising experiment...

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

    PubMed

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

    2015-10-01

    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.

  14. Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

    PubMed Central

    Guntermann, Christine; Piaia, Alessandro; Hamel, Marie-Laure; Theil, Diethilde; Rubic-Schneider, Tina; del Rio-Espinola, Alberto; Dong, Linda; Billich, Andreas; Kaupmann, Klemens; Dawson, Janet; Hoegenauer, Klemens; Orain, David; Hintermann, Samuel; Stringer, Rowan; Patel, Dhavalkumar D.; Doelemeyer, Arno; Deurinck, Mark

    2017-01-01

    Retinoic-acid-orphan-receptor-C (RORC) is a master regulator of Th17 cells, which are pathogenic in several autoimmune diseases. Genetic Rorc deficiency in mice, while preventing autoimmunity, causes early lethality due to metastatic thymic T cell lymphomas. We sought to determine whether pharmacological RORC inhibition could be an effective and safe therapy for autoimmune diseases by evaluating its effects on Th17 cell functions and intrathymic T cell development. RORC inhibitors effectively inhibited Th17 differentiation and IL-17A production, and delayed-type hypersensitivity reactions. In vitro, RORC inhibitors induced apoptosis, as well as Bcl2l1 and BCL2L1 mRNA downregulation, in mouse and nonhuman primate thymocytes, respectively. Chronic, 13-week RORC inhibitor treatment in rats caused progressive thymic alterations in all analyzed rats similar to those in Rorc-deficient mice prior to T cell lymphoma development. One rat developed thymic cortical hyperplasia with neoplastic features, including increased mitosis and reduced IKAROS expression, albeit without skewed T cell clonality. In summary, pharmacological inhibition of RORC not only blocks Th17 cell development and related cytokine production, but also recapitulates thymic aberrations seen in Rorc-deficient mice. While RORC inhibition may offer an effective therapeutic principle for Th17-mediated diseases, T cell lymphoma with chronic therapy remains an apparent risk. PMID:28289717

  15. The medullary pyramid index: an objective assessment of prominence in renal transplant rejection.

    PubMed

    Fried, A M; Woodring, J H; Loh, F K; Lucas, B A; Kryscio, R J

    1983-12-01

    Prominence of the medullary pyramids at sonography has been considered a sign of renal transplant rejection. A search of the literature reveals no previously published objective assessment of this phenomenon. Medullary pyramids of 67 normal kidneys, 53 nonrejecting transplanted kidneys, and 71 transplanted kidneys in rejection were measured. The area of the pyramid was related to the thickness of the overlying renal cortex by a "medullary pyramid index" (MPI): MPI (formula; see text) The median MPI was 4.17 for normal kidneys, 6.0 for nonrejecting transplanted kidneys, and 7.50 for transplanted kidneys in rejection. The results are significantly different (P = 0.0001) for all possible pairs. Overlap between rejection and nonrejection distributions is, however, considerable, rendering the discriminatory value of an individual observation quite low (0.69). Prominence of the medullary pyramids is therefore of very limited predictive value in the determination of transplant rejection in an individual patient.

  16. Kidney Involvement in Systemic Calcitonin Amyloidosis Associated With Medullary Thyroid Carcinoma.

    PubMed

    Koopman, Timco; Niedlich-den Herder, Cindy; Stegeman, Coen A; Links, Thera P; Bijzet, Johan; Hazenberg, Bouke P C; Diepstra, Arjan

    2017-04-01

    A 52-year-old woman with widely disseminated medullary thyroid carcinoma developed nephrotic syndrome and slowly decreasing kidney function. A kidney biopsy was performed to differentiate between malignancy-associated membranous glomerulopathy and tyrosine kinase inhibitor-induced focal segmental glomerulosclerosis. Surprisingly, the biopsy specimen revealed diffuse glomerular deposition of amyloid that was proved to be derived from the calcitonin hormone (Acal), produced by the medullary thyroid carcinoma. This amyloid was also present in an abdominal fat pad biopsy. Although local ACal deposition is a characteristic feature of medullary thyroid carcinoma, the systemic amyloidosis involving the kidney that is presented in this case report has not to our knowledge been described previously and may be the result of long-term high plasma calcitonin levels. Our case illustrates that systemic calcitonin amyloidosis should be considered in the differential diagnosis of proteinuria in patients with medullary thyroid carcinoma.

  17. Fenestration of the superior medullary velum as treatment for a trapped fourth ventricle: a feasibility study.

    PubMed

    Tubbs, R Shane; Wellons, John C; Salter, George; Oakes, W Jerry

    2004-03-01

    We developed a novel approach for fenestration of the trapped fourth ventricle utilizing the superior medullary velum (valve of Vieussens). Trapped fourth ventricles, which are seen often in the pediatric hydrocephalic population, are troublesome entities surgically. A right burr hole was carried out in 10 adult cadavers with no gross intracranial pathology and the superior medullary velum was fenestrated to the quadrigeminal cistern with the aid of an endoscope. This technique was carried out easily in all cadaveric specimens. With endoscopy, no vascular insult was appreciated either before or after fenestration of the superior medullary velum. These preliminary findings demonstrate that fenestration of the superior medullary velum may provide a good alternative to the present therapy of shunting trapped fourth ventricles, a therapy wrought with complications.

  18. Thymic Germinal Centers and Corticosteroids in Myasthenia Gravis: an Immunopathological Study in 1035 Cases and a Critical Review.

    PubMed

    Truffault, Frédérique; de Montpreville, Vincent; Eymard, Bruno; Sharshar, Tarek; Le Panse, Rozen; Berrih-Aknin, Sonia

    2017-02-01

    The most common form of Myasthenia gravis (MG) is due to anti-acetylcholine receptor (AChR) antibodies and is frequently associated with thymic pathology. In this review, we discuss the immunopathological characteristics and molecular mechanisms of thymic follicular hyperplasia, the effects of corticosteroids on this thymic pathology, and the role of thymic epithelial cells (TEC), a key player in the inflammatory thymic mechanisms. This review is based not only on the literature data but also on thymic transcriptome results and analyses of pathological and immunological correlations in a vast cohort of 1035 MG patients without thymoma. We show that among patients presenting a thymic hyperplasia with germinal centers (GC), 80 % are females, indicating that thymic follicular hyperplasia is mainly a disease of women. The presence of anti-AChR antibodies is correlated with the degree of follicular hyperplasia, suggesting that the thymus is a source of anti-AChR antibodies. The degree of hyperplasia is not dependent upon the time from the onset, implying that either the antigen is chronically expressed and/or that the mechanisms of the resolution of the GC are not efficiently controlled. Glucocorticoids, a conventional therapy in MG, induce a significant reduction in the GC number, together with changes in the expression of chemokines and angiogenesis. These changes are likely related to the acetylation molecular process, overrepresented in corticosteroid-treated patients, and essential for gene regulation. Altogether, based on the pathological and molecular thymic abnormalities found in MG patients, this review provides some explanations for the benefit of thymectomy in early-onset MG patients.

  19. Medullary thyroid carcinoma metastatic to the pituitary gland: an unusual site of metastasis.

    PubMed

    Williams, Michelle D; Asa, Sylvia L; Fuller, Gregory N

    2008-06-01

    We present a case of metastatic medullary thyroid carcinoma involving the pituitary gland of a 23-year-old woman with multiple endocrine neoplasia type 2b who presented with diabetes insipidus and visual loss. The diagnostic features, including cytomorphology and immunohistochemistry, used to differentiate pituitary adenoma from metastatic medullary carcinoma are discussed. Pituitary metastases and tumor-to-tumor metastases in this region are also highlighted.

  20. Failure of pentagastrin-stimulated calcitonin testing in early manifestation of familial medullary thyroid cancer.

    PubMed

    Pirich, Christian; Rendl, Gundula; Hauser-Kronberger, Cornelia; Häusler, Ingrid

    2012-10-01

    This case report describes three generations of a family with familial medullary thyroid cancer (RET gene mutation L790F). One of the three siblings-all of them carrier of the respective mutation-exhibited the absence of pathological basal and pentagastrin-stimulated calcitonin levels in spite of multifocal medullary thyroid microcancer. This case illustrates the challenge to consider the biological diversity of RET gene mutations in the clinical management of affected gene carriers.

  1. Utility of Electrocardiography (ECG)-Gated Computed Tomography (CT) for Preoperative Evaluations of Thymic Epithelial Tumors

    PubMed Central

    Ozawa, Yoshiyuki; Hara, Masaki; Nakagawa, Motoo; Shibamoto, Yuta

    2016-01-01

    Summary Background Preoperative evaluation of invasion to the adjacent organs is important for the thymic epithelial tumors on CT. The purpose of our study was to evaluate the utility of electrocardiography (ECG)-gated CT for assessing thymic epithelial tumors with regard to the motion artifacts produced and the preoperative diagnostic accuracy of the technique. Material/Methods Forty thymic epithelial tumors (36 thymomas and 4 thymic carcinomas) were examined with ECG-gated contrast-enhanced CT using a dual source scanner. The scan delay after the contrast media injection was 30 s for the non-ECG-gated CT and 100 s for the ECG-gated CT. Two radiologists blindly evaluated both the non-ECG-gated and ECG-gated CT images for motion artifacts and determined whether the tumors had invaded adjacent structures (mediastinal fat, superior vena cava, brachiocephalic veins, aorta, pulmonary artery, pericardium, or lungs) on each image. Motion artifacts were evaluated using a 3-grade scale. Surgical and pathological findings were used as a reference standard for tumor invasion. Results Motion artifacts were significantly reduced for all structures by ECG gating (p=0.0089 for the lungs and p<0.0001 for the other structures). Non-ECG-gated CT and ECG-gated CT demonstrated 79% and 95% accuracy, respectively, during assessments of pericardial invasion (p=0.03). Conclusions ECG-gated CT reduced the severity of motion artifacts and might be useful for preoperative assessment whether thymic epithelial tumors have invaded adjacent structures. PMID:27920842

  2. Decreased GABAA receptor binding in the medullary serotonergic system in the sudden infant death syndrome.

    PubMed

    Broadbelt, Kevin G; Paterson, David S; Belliveau, Richard A; Trachtenberg, Felicia L; Haas, Elisabeth A; Stanley, Christina; Krous, Henry F; Kinney, Hannah C

    2011-09-01

    γ-Aminobutyric acid (GABA) neurons in the medulla oblongata help regulate homeostasis, in part through interactions with the medullary serotonergic (5-HT) system. Previously, we reported abnormalities in multiple 5-HT markers in the medullary 5-HT system of infants dying from sudden infant death syndrome (SIDS), suggesting that 5-HT dysfunction is involved in its pathogenesis. Here, we tested the hypothesis that markers of GABAA receptors are decreased in the medullary 5-HT system in SIDS cases compared with controls. Using tissue receptor autoradiography with the radioligand H-GABA, we found 25% to 52% reductions in GABAA receptor binding density in 7 of 10 key nuclei sampled of the medullary 5-HT system in the SIDS cases (postconceptional age [PCA] = 51.7 ± 8.3, n = 28) versus age-adjusted controls (PCA = 55.3 ± 13.5, n = 8) (p ≤ 0.04). By Western blotting, there was 46.2% reduction in GABAAα3 subunit levels in the gigantocellularis (component of the medullary 5-HT system) of SIDS cases (PCA = 53.9 ± 8.4, n = 24) versus controls (PCA = 55.3 ± 8.3, n = 8) (56.8% standard in SIDS cases vs 99.35% in controls; p = 0.026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems.

  3. Do egg-laying crocodilian (Alligator mississippiensis) archosaurs form medullary bone?

    PubMed

    Schweitzer, M H; Elsey, R M; Dacke, C G; Horner, J R; Lamm, E-T

    2007-04-01

    It is beyond question that Mesozoic dinosaurs, like Aves and Crocodylia, are archosaurs. However, within the archosaurian clade, the origin and distribution of some major features are less clear, particularly with respect to reproductive physiology. Medullary bone, a highly mineralized, bony reproductive tissue present in the endosteal cavities of all extant egg-laying birds thus far examined, has recently been reported in Tyrannosaurus rex. Its presence or absence in extant crocodilians, therefore, may shed light on the timing of its evolutionary appearance. If medullary bone is present in all three taxa, it arose before the three lineages diverged. However, if medullary bone arose after this divergence, it may be present in both extinct dinosaurs and birds, or in birds only. If present in extinct dinosaurs and birds, but not crocodilians, it would indicate that it arose in the common ancestor of this clade, thus adding support to the closer phylogenetic relationship of dinosaurs and birds relative to crocodilians. Thus, the question of whether the crocodilian Alligator mississippiensis forms medullary bone during the production of eggs has important evolutionary significance. Our examination of long bones from several alligators (two alligators with eggs in the oviducts, one that had produced eggs in the past but was not currently in reproductive phase, an immature female and an adult male) shows no differences on the endosteal surfaces of the long bones, and no evidence of medullary bone, supporting the hypothesis that medullary bone first evolved in the dinosaur-bird line, after the divergence of crocodilians from this lineage.

  4. Two-dimensional Fourier analysis of the spongy medullary keratin of structurally coloured feather barbs

    PubMed Central

    Prum, R. O.; Torres, R.; Williamson, S.; Dyck, J.

    1999-01-01

    We conducted two-dimensional (2D) discrete Fourier analyses of the spatial variation in refractive index of the spongy medullary keratin from four different colours of structurally coloured feather barbs from three species of bird: the rose-faced lovebird, Agapornis roseicollis (Psittacidae), the budgerigar, Melopsittacus undulatus (Psittacidae), and the Gouldian finch, Poephila guttata (Estrildidae). These results indicate that the spongy medullary keratin is a nanostructured tissue that functions as an array of coherent scatterers. The nanostructure of the medullary keratin is nearly uniform in all directions. The largest Fourier components of spatial variation in refractive index in the tissue are of the appropriate size to produce the observed colours by constructive interference alone. The peaks of the predicted reflectance spectra calculated from the 2D Fourier power spectra are congruent with the reflectance spectra measured by using microspectrophotometry. The alternative physical models for the production of these colours, the Rayleigh and Mie theories, hypothesize that medullary keratin is an incoherent array and that scattered waves are independent in phase. This assumption is falsified by the ring-like Fourier power spectra of these feathers, and the spacing of the scattering air vacuoles in the medullary keratin. Structural colours of avian feather barbs are produced by constructive interference of coherently scattered light waves from the optically heterogeneous matrix of keratin and air in the spongy medullary layer.

  5. Olfactory epithelium changes in germfree mice

    PubMed Central

    François, Adrien; Grebert, Denise; Rhimi, Moez; Mariadassou, Mahendra; Naudon, Laurent; Rabot, Sylvie; Meunier, Nicolas

    2016-01-01

    Intestinal epithelium development is dramatically impaired in germfree rodents, but the consequences of the absence of microbiota have been overlooked in other epithelia. In the present study, we present the first description of the bacterial communities associated with the olfactory epithelium and explored differences in olfactory epithelium characteristics between germfree and conventional, specific pathogen-free, mice. While the anatomy of the olfactory epithelium was not significantly different, we observed a thinner olfactory cilia layer along with a decreased cellular turn-over in germfree mice. Using electro-olfactogram, we recorded the responses of olfactory sensitive neuronal populations to various odorant stimulations. We observed a global increase in the amplitude of responses to odorants in germfree mice as well as altered responses kinetics. These changes were associated with a decreased transcription of most olfactory transduction actors and of olfactory xenobiotic metabolising enzymes. Overall, we present here the first evidence that the microbiota modulates the physiology of olfactory epithelium. As olfaction is a major sensory modality for most animal species, the microbiota may have an important impact on animal physiology and behaviour through olfaction alteration. PMID:27089944

  6. Differentiating the undifferentiated: immunohistochemical profile of medullary carcinoma of the colon with an emphasis on intestinal differentiation.

    PubMed

    Winn, Brody; Tavares, Rosemarie; Fanion, Jacqueline; Noble, Lelia; Gao, John; Sabo, Edmond; Resnick, Murray B

    2009-03-01

    Undifferentiated or medullary carcinoma is characterized by its distinct histologic appearance and relatively better prognosis compared to poorly differentiated colonic carcinoma. These 2 entities may be difficult to differentiate by light microscopy alone. Only limited immunohistochemical studies investigating medullary carcinoma have been reported. These studies suggest a loss of intestinal differentiation, exemplified by a high percentage of CDX2 negativity. Our aim was to further characterize the immunohistochemical profile of medullary carcinoma, with particular emphasis on intestinal markers. Paraffin blocks from 16 cases of medullary carcinoma and 33 cases of poorly differentiated colonic carcinoma were retrieved, and tissue microarrays were constructed and stained with an immunohistochemical panel including CDX2, CK7, CK20, p53, intestinal trefoil factor 3, chromogranin, synaptophysin, MLH-1, MUC-1, MUC-2, and calretinin. A significantly higher proportion of medullary carcinomas, as opposed to poorly differentiated colonic carcinomas, showed loss of staining for MLH-1 and for the intestinal transcription factor CDX2, in accordance with previous studies. MLH-1 staining was present in only 21% of medullary carcinoma cases compared with 60% of the poorly differentiated colonic carcinoma cases (P = .02), whereas CDX2 was positive in 19% of medullary carcinomas and 55% of poorly differentiated colonic carcinomas (P = .03). Interestingly, calretinin staining was strongly positive in 73% of medullary carcinomas compared to only 12% of poorly differentiated colonic carcinomas (P < .0001). Evidence of intestinal differentiation by MUC-1, MUC-2, and TFF-3 staining was seen in 67%, 60%, and 53% of the medullary carcinomas, respectively. These 3 markers were frequently positive in many of the CDX2-negative medullary carcinoma cases. Medullary carcinoma of the colon retains a significant degree of intestinal differentiation as evidenced by its high percentage of

  7. 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.

  8. Culturing primary rat inner medullary collecting duct cells.

    PubMed

    Faust, Dörte; Geelhaar, Andrea; Eisermann, Beate; Eichhorst, Jenny; Wiesner, Burkhard; Rosenthal, Walter; Klussmann, Enno; Klussman, Enno

    2013-06-21

    Arginine-vasopressin (AVP) facilitates water reabsorption by renal collecting duct principal cells and thereby fine-tunes body water homeostasis. AVP binds to vasopressin V2 receptors (V2R) on the surface of the cells and thereby induces synthesis of cAMP. This stimulates cellular signaling processes leading to changes in the phosphorylation of the water channel aquaporin-2 (AQP2). Protein kinase A phoshorylates AQP2 and thereby triggers the translocation of AQP2 from intracellular vesicles into the plasma membrane facilitating water reabsorption from primary urine. Aberrations of AVP release from the pituitary or AVP-activated signaling in principal cells can cause central or nephrogenic diabetes insipidus, respectively; an elevated blood plasma AVP level is associated with cardiovascular diseases such as chronic heart failure and the syndrome of inappropriate antidiuretic hormone secretion. Here, we present a protocol for cultivation of primary rat inner medullary collecting duct (IMCD) cells, which express V2R and AQP2 endogenously. The cells are suitable for elucidating molecular mechanisms underlying the control of AQP2 and thus to discover novel drug targets for the treatment of diseases associated with dysregulation of AVP-mediated water reabsorption. IMCD cells are obtained from rat renal inner medullae and are used for experiments six to eight days after seeding. IMCD cells can be cultured in regular cell culture dishes, flasks and micro-titer plates of different formats, the procedure only requires a few hours, and is appropriate for standard cell culture laboratories.

  9. Culturing Primary Rat Inner Medullary Collecting Duct Cells

    PubMed Central

    Faust, Dörte; Geelhaar, Andrea; Eisermann, Beate; Eichhorst, Jenny; Wiesner, Burkhard; Rosenthal, Walter; Klussman, Enno

    2013-01-01

    Arginine-vasopressin (AVP) facilitates water reabsorption by renal collecting duct principal cells and thereby fine-tunes body water homeostasis. AVP binds to vasopressin V2 receptors (V2R) on the surface of the cells and thereby induces synthesis of cAMP. This stimulates cellular signaling processes leading to changes in the phosphorylation of the water channel aquaporin-2 (AQP2). Protein kinase A phoshorylates AQP2 and thereby triggers the translocation of AQP2 from intracellular vesicles into the plasma membrane facilitating water reabsorption from primary urine. Aberrations of AVP release from the pituitary or AVP-activated signaling in principal cells can cause central or nephrogenic diabetes insipidus, respectively; an elevated blood plasma AVP level is associated with cardiovascular diseases such as chronic heart failure and the syndrome of inappropriate antidiuretic hormone secretion. Here, we present a protocol for cultivation of primary rat inner medullary collecting duct (IMCD) cells, which express V2R and AQP2 endogenously. The cells are suitable for elucidating molecular mechanisms underlying the control of AQP2 and thus to discover novel drug targets for the treatment of diseases associated with dysregulation of AVP-mediated water reabsorption. IMCD cells are obtained from rat renal inner medullae and are used for experiments six to eight days after seeding. IMCD cells can be cultured in regular cell culture dishes, flasks and micro-titer plates of different formats, the procedure only requires a few hours, and is appropriate for standard cell culture laboratories. PMID:23852264

  10. Diethyl pyrocarbonate inhibits rostral ventrolateral medullary H+ sensitivity.

    PubMed

    Nattie, E E

    1988-04-01

    Diethyl pyrocarbonate (DEPC), an acylating agent that reacts with imidazole-histidine in vitro, inhibits CO2 sensitivity when applied by pledget to the rostral chemosensitive area on the ventrolateral medullary (VLM) surface in glomectomized, chloralose-urethan-anesthetized cats. In this study similar application of DEPC inhibits the phrenic nerve response to CO2 expressed as a function of VLM [H+] measured by surface pH electrode. Attempts to evaluate direct chemoreceptor stimulation by HCL-soaked surface pledgets proved difficult, but rostral DEPC did inhibit the response to intravenous infusion of HCl. As previously reported, the CO2 and intravenous H+ responses are not a unique function of the VLM [H+]. DEPC had similar inhibitory effects on both the CO2 and the intravenous H+ responses, suggesting that the difference between them may reflect more the orientation or accessibility of the central chemoreceptor than a different mechanism for sensing CO2 vs. H+. DEPC did not alter the phrenic nerve response to hypoxia, indicating that DEPC effects on central chemoreception are not the result of a generalized inhibitory process. The results support the hypothesis that imidazolehistidine is involved at the rostral area with chemoreception of both CO2 and H+.

  11. Hormonal regulation of medullary bone metabolism in the laying hen

    SciTech Connect

    Harrison, J.R.

    1987-01-01

    A new organ culture system for the study of bone formation has been developed using medullary bone, a non-structural, metabolically active form of bone which is found in the marrow cavities of egg-laying birds. In the presence of fetal calf serum, bone explants were viable in culture by morphological criteria, and retained large numbers of osteoblasts and osteoclasts. Incorporation of /sup 3/H-proline into collagenase-digestible protein (CDP) and non-collagen protein (NCP) was determined using purified bacterial collagenase. Collagen accounted for over 10% of the total protein labeled. The calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), caused a dose-dependent inhibition of /sup 3/H-proline incorporation into CDP. The effective dose range of 1,25(OH)2D3 was 0.1 nM to 100 nM, while that of PTH was 1.0 nM to 100 nM. The effect of both hormones was specific for collagen, since /sup 3/H-proline incorporation into NCP was unaffected. Hydroxyproline analysis of bone explants and culture medium revealed that both hormones decreased the total hydroxyroline content of the cultures, suggesting that the inhibition of /sup 3/H-proline incorporation into DCP is due to inhibition of collagen synthesis.

  12. Medullary thyroid cancer: RET testing of an archival material.

    PubMed

    Godballe, Christian; Jørgensen, Gita; Gerdes, Anne-Marie; Krogdahl, Annelise S; Tybjaerg-Hansen, Anne; Nielsen, Finn C

    2010-04-01

    Medullary thyroid carcinoma (MTC) might be sporadic (75%) or hereditary (25%). Until the mid nineties the diagnosis of hereditary MTC was based on family history, clinical evaluation, histological detection of C-cell hyperplasia and tumor multifocality. Patients and families with hereditary MTC might be missed? Today mutation analysis of the RET proto-oncogene is routinely performed on DNA. Departments of pathology often store tissue specimens from performed surgical procedures. The purpose of this study was to examine if analysis of DNA extracted from formalin fixed archival tissue might be a possible method to identify not previously known cases of hereditary MTC. In 23 cases, tissue analysis was performed, and in 2 patients (9%) a mutation was identified, but in both cases the most likely explanation was contamination with tumor tissue. The ability to detect RET mutations was confirmed by testing of non-tumor tissue from patients with known hereditary MTC. This study shows that genetic testing of archival MTC material is technically possible and might be a way of identifying patients with previously not recognized hereditary MTC.

  13. Hormone receptor status and survival of medullary breast cancer patients

    PubMed Central

    Aksoy, Asude; Odabas, Hatice; Kaya, Serap; Bozkurt, Oktay; Degirmenci, Mustafa; Topcu, Turkan O.; Aytekin, Aydın; Arpaci, Erkan; Avci, Nilufer; Pilanci, Kezban N.; Cinkir, Havva Y.; Bozkaya, Yakup; Cirak, Yalcin; Gumus, Mahmut

    2017-01-01

    Objectives: To analyze the relationship between clinical features, hormonal receptor status, and survival in patients who were diagnosed with medullary breast cancer (MBC). Methods: Demographic characteristics, histopathological features, and survival statuses of 201 patients diagnosed with MBC between 1995 and 2015 were retrospectively recorded. Survival analyses were conducted with uni- and multivariate cox regression analysis. Results: Median follow-up time was 54 (4-272) months. Median patient age at the time of diagnosis was 47 years old (26-90). Of the patients, 91.5% were triple negative. Five-year recurrence free survival time (RFS) rate was 87.4% and overalll survival (OS) rate 95.7%. For RFS, progesterone receptor (PR) negativity, atypical histopathological evaluation, absence of lymphovascular invasion, smaller tumor, lower nodal involvement were found to be favourable prognostic factors by univariate analysis (p<0.05). The PR negativity and smaller tumor were found to be favourable factors by univariate analysis (p<0.05). However, none of these factors were determined as significant independent prognostic factors for OS (p>0.05). Conclusion: Turkish MBC patients exhibited good prognosis, which was comparable with survival outcomes achieved in the literature. The PR negativity was related to a better RFS and OS rates. PMID:28133688

  14. Pretargeted immunoscintigraphy in patients with medullary thyroid carcinoma.

    PubMed Central

    Magnani, P.; Paganelli, G.; Songini, C.; Samuel, A.; Sudati, F.; Siccardi, A. G.; Fazio, F.

    1996-01-01

    To evaluate the use of pretargeted immunoscintigraphy (ISG) in the diagnosis and follow-up of patients with medullary thyroid carcinoma (MTC), we studied 25 patients with histologically proven disease; ISG was repeated after surgery in two patients. The antibody, either an anticarcinoembryonic antigen (CEA) or an antichromogranin A (CgA) biotinylated monoclonal antibody (MAb) or a cocktail of the two biotinylated MAbs was first injected. After 24 h, avidin was administrated i.v., followed by 111In-labelled biotin 24 h later. Fifty-two lesions were visualised. Six primary tumours, diagnosed by increased calcitonin levels, were all correctly diagnosed; 47 recurrences, also suspected by blood tumour markers, were detected and confirmed by cytology or histology. In one case, single photon emission tomography allowed the detection of small lymph nodes with a diameter of 4-7 mm. These lesions, not judged neoplastic by ultrasound, were confirmed to be neoplastic by fine needle aspiration. Pretargeted ISG correctly localises primary tumours and recurrences in MTC patients, when the only marker of relapse is serum elevation of calcitonin. With this three-step pretargeting method, cocktails of potentially useful MAbs can be used, avoiding false-negative studies that may occur when CEA or CgA are not expressed. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8795589

  15. Recent Updates on the Management of Medullary Thyroid Carcinoma

    PubMed Central

    2016-01-01

    Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor derived from the thyroid C cells producing calcitonin. MTC accounts for 0.6% of all thyroid cancers and incidence of MTC increased steadily between 1997 and 2011 in Korea. It occurs either sporadically or in a hereditary form based on germline rearranged during transfection (RET) mutations. MTC can be cured only by complete resection of the thyroid tumor and any loco-regional metastases. The most appropriate treatment is still less clear in patients with residual or recurrent disease after initial surgery or those with distant metastases because most patients even with metastatic disease have indolent courses with slow progression for several years and MTC is not responsive to either radioactive iodine therapy or thyroid-stimulating hormone suppression. Recently, two tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib, are approved for use in patients with advanced, metastatic or progressive MTC. In this review, we summarize the current approach according to revised American Thyroid Association guidelines and recent advances in systemic treatment such as TKIs for patients with persistent or recurrent MTC after surgery. PMID:27586449

  16. Histochemical carbonic anhydrase in rat inner medullary collecting duct

    NASA Technical Reports Server (NTRS)

    Kleinman, J. G.; Bain, J. L.; Fritsche, C.; Riley, D. A.

    1992-01-01

    Rat inner medullary collecting duct (IMCD) secretes substantial amounts of H+. However, carbonic anhydrase (CA), a concomitant of H+ secretion, has been generally reported absent in this segment. To reexamine this problem, we investigated CA and the morphological phenotypes of cells comprising the IMCD by CA histochemistry, using a modified Hansson technique with light and electron microscopy. Throughout the medulla, tubule cells exhibit histochemical CA activity. In the initial third of the inner medulla, a small proportion have features of intercalated cells and demonstrate some degree of CA activity. However, the majority population in the early portions of the IMCD appears to consist of principal cells. These also show CA staining of widely variable intensity, both among and within cells. A third cell type, previously called "IMCD cells", appears in the middle portion of the IMCD and is the only cell type present near the papilla tip. In contrast to previous reports, these "IMCD cells" have histochemical CA staining, also of highly variable intensity. These results demonstrate that stainable carbonic anhydrase to support acidification is present throughout the rat IMCD, both in intercalated cells and in some cells clearly not of this type. Therefore, the presence of CA is not specific for the intercalated cell type and suggests that other cell types may participate in acid secretion in IMCD.

  17. Central role of interferon-beta in thymic events leading to myasthenia gravis.

    PubMed

    Cufi, Perrine; Dragin, Nadine; Ruhlmann, Nathalie; Weiss, Julia Miriam; Fadel, Elie; Serraf, Alain; Berrih-Aknin, Sonia; Le Panse, Rozen

    2014-08-01

    The thymus plays a primary role in early-onset Myasthenia Gravis (MG) mediated by anti-acetylcholine receptor (AChR) antibodies. As we recently showed an inflammatory and anti-viral signature in MG thymuses, we investigated in detail the contribution of interferon (IFN)-I and IFN-III subtypes in thymic changes associated with MG. We showed that IFN-I and IFN-III subtypes, but especially IFN-β, induced specifically α-AChR expression in thymic epithelial cells (TECs). We also demonstrated that IFN-β increased TEC death and the uptake of TEC proteins by dendritic cells. In parallel, we showed that IFN-β increased the expression of the chemokines CXCL13 and CCL21 by TECs and lymphatic endothelial cells, respectively. These two chemokines are involved in germinal center (GC) development and overexpressed in MG thymus with follicular hyperplasia. We also demonstrated that the B-cell activating factor (BAFF), which favors autoreactive B-cells, was overexpressed by TECs in MG thymus and was also induced by IFN-β in TEC cultures. Some of IFN-β effects were down-regulated when cell cultures were treated with glucocorticoids, a treatment widely used in MG patients that decreases the number of thymic GCs. Similar changes were observed in vivo. The injections of Poly(I:C) to C57BL/6 mice triggered a thymic overexpression of IFN-β and IFN-α2 associated with increased expressions of CXCL13, CCL21, BAFF, and favored the recruitment of B cells. These changes were not observed in the thymus of IFN-I receptor KO mice injected with Poly(I:C), even if IFN-β and IFN-α2 were overexpressed. Altogether, these results demonstrate that IFN-β could play a central role in thymic events leading to MG by triggering the overexpression of α-AChR probably leading to thymic DC autosensitization, the abnormal recruitment of peripheral cells and GC formation.

  18. Pre-transplant thymic function is associated with the risk of cytomegalovirus disease after solid organ transplantation.

    PubMed

    Gracia-Ahufinger, I; Ferrando-Martínez, S; Montejo, M; Muñoz-Villanueva, M C; Cantisán, S; Rivero, A; Solana, R; Leal, M; Torre-Cisneros, J

    2015-05-01

    Cytomegalovirus (CMV) disease is an important complication in solid organ transplant recipients. Thymic function in adults is associated with specific T-cell immunity. Pre-transplant thymic function was analysed in 75 solid organ transplant patients by the use of nested PCR. The primary outcome was the incidence of CMV disease 12 months after transplantation. Using multivariable logistic regression, we studied whether pre-transplant thymic function is an independent risk factor for CMV disease after transplantation. Thymic function was related to the risk of CMV disease in CMV-seropositive recipients. In these recipients, pre-transplant thymic function of <9.5 (OR 11.27, 95% CI 1.11-114.43, p 0.040) and the use of thymoglobulin (OR 8.21, 95% CI 1.09-61.84, p 0.041) were independent risk factors for CMV disease at 12 months after transplantation. Patients with pre-transplant thymic function values of <9.5 had a higher subsequent incidence of CMV disease (24%) than patients with values of ≥ 9.5 (3%) (log-rank test: 5.727; p 0.017). The positive and negative predictive values of these pre-transplant thymic function cut-offs were 0.24 (95% CI 0.10-0.45) and 0.97 (95% CI 0.82-1.00), respectively. Pre-transplant thymic function in CMV-seropositive candidates could be useful in determining the risk of post-transplant CMV disease in solid organ transplant patients, selecting a group of low-risk candidates.

  19. Effects of renal perfusion pressure on renal medullary hydrogen peroxide and nitric oxide production.

    PubMed

    Jin, Chunhua; Hu, Chunyan; Polichnowski, Aaron; Mori, Takefumi; Skelton, Meredith; Ito, Sadayoshi; Cowley, Allen W

    2009-06-01

    Studies were designed to determine the effects of increases of renal perfusion pressure on the production of hydrogen peroxide (H(2)O(2)) and NO(2)(-)+NO(3)(-) within the renal outer medulla. Sprague-Dawley rats were studied with either the renal capsule intact or removed to ascertain the contribution of changes of medullary blood flow and renal interstitial hydrostatic pressure on H(2)O(2) and NO(2)(-)+NO(3)(-) production. Responses to three 30-minute step changes of renal perfusion pressure (from approximately 85 to approximately 115 to approximately 145 mm Hg) were studied using adjustable aortic occluders proximal and distal to the left renal artery. Medullary interstitial H(2)O(2) determined by microdialysis increased at each level of renal perfusion pressure from 640 to 874 to 1593 nmol/L, as did H(2)O(2) urinary excretion rates, and these responses were significantly attenuated by decapsulation. Medullary interstitial NO(2)(-)+NO(3)(-) increased from 9.2 to 13.8 to 16.1 mumol/L, with parallel changes in urine NO(2)(-)+NO(3)(-), but decapsulation did not significantly blunt these responses. Over the range of renal perfusion pressure, medullary blood flow (laser-Doppler flowmetry) rose approximately 30% and renal interstitial hydrostatic pressure rose from 7.8 to 19.7 cm H(2)O. Renal interstitial hydrostatic pressure and the natriuretic and diuretic responses were significantly attenuated with decapsulation, but medullary blood flow was not affected. The data indicate that pressure-induced increases of H(2)O(2) emanated largely from increased tubular flow rates to the medullary thick-ascending limbs of Henle and NO largely from increased medullary blood flow to the vasa recta. The parallel pressure-induced increases of H(2)O(2) and NO indicate a participation in shaping the "normal" pressure-natriuresis relationship and explain why an imbalance in either would affect the blood pressure salt sensitivity.

  20. 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.

  1. Thymic atrophy in acute experimental Chagas disease is associated with an imbalance of stress hormones.

    PubMed

    Lepletier, Ailin; de Frias Carvalho, Vinícius; Morrot, Alexandre; Savino, Wilson

    2012-07-01

    Disorders in the hypothalamic-pituitary-adrenal axis are associated with the pathogenesis of Trypanosoma cruzi infection. During the acute phase of this disease, increased levels of circulating glucocorticoids (GCs) correlate with thymic atrophy. Recently, we demonstrated that this phenomenon is paralleled by a decrease of prolactin (PRL) secretion, another stress hormone that seems to counteract many immunosuppressive effects of GCs. Both GCs and PRL are intrathymically produced and exhibit mutual antagonism through the activation of their respective receptors, GR, and PRLR. Considering that GCs induce apoptosis and inhibit double-positive (DP) thymocyte proliferation and that PRL administration prevents these effects, it seems plausible that a local imbalance of GR-PRLR crosstalk underlies the thymic involution occurring in acute T. cruzi infection. In this respect, preserving PRLR signaling seems to be crucial for protecting DP from GC-induced apoptosis.

  2. 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. PMID:27625910

  3. Thymic epithelial neoplasms: a review of current concepts using an evidence-based pathology approach.

    PubMed

    Marchevsky, Alberto M; McKenna, Robert J; Gupta, Ruta

    2008-06-01

    Evidence-based pathology promotes the critical evaluation of current clinical information and the development of evidence-based diagnostic and prognostic guidelines. No randomized clinical trials of patients who have thymomas or thymic carcinomas are available to evaluate the validity of the current World Health Organization (WHO) histologic classification or the widely used Masaoka staging system. A meta-analysis of over 2000 thymoma patients estimated that only three WHO histologic types of thymomas are associated with significant survival differences. Prospective randomized clinical trials and an international registry of patients who have Thymic epithelial neoplasms are needed to stratify patients who may benefit from neoadjuvant chemotherapy, postoperative radiation therapy, and other nonsurgical modalities.

  4. Neural control of adrenal medullary and cortical blood flow during hemorrhage

    SciTech Connect

    Breslow, M.J.; Jordan, D.A.; Thellman, S.T.; Traystman, R.J.

    1987-03-01

    Hemorrhagic hypotension produces an increase in adrenal medullary blood flow and a decrease in adrenal cortical blood flow. To determine whether changes in adrenal blood flow during hemorrhage are neurally mediated, the authors compared blood flow responses following adrenal denervation (splanchnic nerve section) with changes in the contralateral, neurally intact adrenal. Carbonized microspheres labeled with /sup 153/Gd, /sup 114/In, /sup 113/Sn, /sup 103/Ru, /sup 95/Nb or /sup 46/Se were used. Blood pressure was reduced and maintained at 60 mmHg for 25 min by hemorrhage into a pressurized bottle system. Adrenal cortical blood flow decreased to 50% of control with hemorrhage in both the intact and denervated adrenal. Adrenal medullary blood flow increased to four times control levels at 15 and 25 min posthemorrhage in the intact adrenal, but was reduced to 50% of control at 3, 5, and 10 min posthemorrhage in the denervated adrenal. In a separate group of dogs, the greater splanchnic nerve on one side was electrically stimulated at 2, 5, or 15 Hz for 40 min. Adrenal medullary blood flow increased 5- to 10-fold in the stimulated adrenal but was unchanged in the contralateral, nonstimulated adrenal. Adrenal cortical blood flow was not affected by nerve stimulation. They conclude that activity of the splanchnic nerve profoundly affects adrenal medullary vessels but not adrenal cortical vessels and mediates the observed increase in adrenal medullary blood flow during hemorrhagic hypotension.

  5. Inferior Vena Cava and Renal Vein Thrombosis Associated with Thymic Carcinoma

    PubMed Central

    Paraschiv, Marina; Sorohan, Bogdan

    2017-01-01

    Thymic tumors are rare mediastinal tumors that can present with a wide variety of symptoms. They can cause distant manifestations and are frequently associated with paraneoplastic syndromes. In our case, we describe the evolution of a 68-year-old male whose first manifestation was thrombosis of the inferior vena cava and renal veins. Thrombosis of large abdominal veins is rare, especially without being associated with any other comorbidity or risk factors. PMID:28163719

  6. Rare frequency of gene variation and survival analysis in thymic epithelial tumors

    PubMed Central

    Song, Zhengbo; Yu, Xinmin; Zhang, Yiping

    2016-01-01

    Objective Thymic epithelial tumor (TET) is a rare mediastinal neoplasm and little is known about its genetic variability and prognostic factors. This study investigated the genetic variability and prognostic factors of TET. Patients and methods We sequenced 22 cancer-related hotspot genes in TET tissues and matched normal tissues using Ampliseq Ion Torrent next-generation technology. Overall survival was evaluated using Kaplan–Meier methods and compared with log-rank tests. Results A histological analysis of 52 patients with a median age of 52 years showed 15 patients (28.8%) with thymic carcinoma, five with type A thymoma (9.6%), eight with type AB (15.4%), six with type B1 (11.5%), nine with type B2 (17.3%), and nine with type B3 thymoma (17.3%). Three gene mutations were identified, including two with PIK3CA mutation and one with EGFR mutation. The three patients with mutant genes included two cases of thymoma (one with EGFR and the other with PIK3CA mutation) in addition to a case of thymic carcinoma (PIK3CA mutation). The 5-year survival rates were 77.7% in all patients. The 5-year survival rates were 93.3%, 90.0%, 76.9%, and 22.9% corresponding to Masaoka stages I, II, III, and IV (P<0.001). The 5-year survival rates were 100%, 100%, 83.3%, 88.9%, 65.6%, and 60.9% in the histological subtypes of A, AB, B1, B2, and B3 thymomas, and thymic carcinoma, respectively (P=0.012). Conclusion Hotspot gene mutations are rare in TET. PIK3CA and EGFR mutations represent candidate driver genes and treatment targets in TET. Masaoka stage and histological subtypes predict the survival of TET. PMID:27789964

  7. RET mutation and increased angiogenesis in medullary thyroid carcinomas.

    PubMed

    Verrienti, Antonella; Tallini, Giovanni; Colato, Chiara; Boichard, Amélie; Checquolo, Saula; Pecce, Valeria; Sponziello, Marialuisa; Rosignolo, Francesca; de Biase, Dario; Rhoden, Kerry; Casadei, Gian Piero; Russo, Diego; Visani, Michela; Acquaviva, Giorgia; Ferdeghini, Marco; Filetti, Sebastiano; Durante, Cosimo

    2016-08-01

    Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors.

  8. Altered processing of otolithic information in isolated lateral medullary infarction.

    PubMed

    Kim, Hyo-Jung; Kim, Seoyeon; Park, Jae Han; Kim, Ji-Soo

    2016-12-01

    Ocular and cervical vestibular-evoked myogenic potentials (VEMPs) evaluate the function of otolithic pathways in central as well as peripheral vestibular disorders. This study aimed to determine the associations and dissociations of otolithic dysfunction in lateral medullary infarction (LMI), the most well-known disorder of central vestibulopathy. At the Dizziness Clinic of a referral-based University Hospital, 45 patients with isolated LMI (28 men, mean age = 55.6 ± 12.5) had evaluation of the ocular tilt reaction (OTR), tilt of the subjective visual vertical (SVV), and ocular and cervical VEMPs from Janurary 2011 to August 2015 during the acute phase, 1-11 days from the symptom onset (median = 2 days). Almost all (42/45, 93 %) patients showed at least one component of the OTR or SVV tilt that was invariably ipsiversive. In contrast, oVEMPs were abnormal only in 12 (27 %) and cVEMPs in 13 (29 %) patients. Only three patients showed abnormal results in all the tests of the OTR, SVV tilt, and ocular and cervical VEMPs. Abnormal oVEMPs were more common in patients with the OTR than those without (38 vs 6 %, Pearson X (2) test, p = 0.021). In contrast, abnormality of cVEMPs showed no correlation with the presence of OTR (28 vs 31 %, Pearson X (2) test, p = 0.795). In patients with LMI, ipsiversive OTR is invariable, but abnormalities of oVEMPs and cVEMPs were much less common and mostly dissociated even in the patients with abnormal results. This discrepancy in otolithic dysfunction suggests different anatomical substrates and/or dissimilar reciprocal modulation for processing of each otolithic signal in central vestibular structures located in the dorsolateral medulla.

  9. Medullary carcinoma of the large intestine: a population based analysis.

    PubMed

    Thirunavukarasu, Pragatheeshwar; Sathaiah, Magesh; Singla, Smit; Sukumar, Shyam; Karunamurthy, Arivarasan; Pragatheeshwar, Kothai Divya; Lee, Kenneth K W; Zeh, Herbert; Kane, Kevin M; Bartlett, David L

    2010-10-01

    Medullary carcinoma (MC) of the colorectum is a relatively new histological type of adenocarcinoma characterized by poor glandular differentiation and intraepithelial lymphocytic infiltrate. To date, there has been no epidemiological study of this rare tumor type, which has now been incorporated as a separate entity in the World Health Organization (WHO) classification of colorectal cancers. We used the population-based registries of the Surveillance, Epidemiology and End Results (SEER) database to identify all cases of colorectal MC between 1973 and 2006 and compared them to poorly and undifferentiated colonic adenocarcinomas (PDA and UDA, respectively). We observed that MCs were rare tumors, constituting approximately 5-8 cases for every 10,000 colon cancers diagnosed, with a mean annual incidence of 3.47 (+/-0.75) per 10 million population. Mean age at diagnosis was 69.3 (+/-12.5) years, with incidence increasing with age. MCs were twice as common in females, who presented at a later age, with a lower stage and a trend towards favorable prognosis. MCs were extremely rare among African-Americans. MCs were most common in the proximal colon (74%), where they present at a later age than the sigmoid colon. There were no cases reliably identified in the rectum or appendix. Serum carcinoembryonic antigen levels (CEA) were elevated prior to first course of treatment in 40% of the patients. MCs were more commonly poorly differentiated (72%), with 22% being undifferentiated. MCs commonly presented with Stage II disease, with 10% presenting with metastases. Only one patient presented with N2b disease (>7 positive nodes). Early outcome analyses showed that MCs have 1- and 2-year relative survival rates of 92.7 and 73.8% respectively. Although MCs showed a trend towards better early overall survival, undifferentiated MCs present more commonly with Stage III, with comparatively worse early outcomes.

  10. GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells

    PubMed Central

    Harada, Keita; Matsuoka, Hidetada; Fujihara, Hiroaki; Ueta, Yoichi; Yanagawa, Yuchio; Inoue, Masumi

    2016-01-01

    Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling. PMID:27147972

  11. New drugs for medullary thyroid cancer: new promises?

    PubMed

    Spitzweg, Christine; Morris, John C; Bible, Keith C

    2016-06-01

    Medullary thyroid cancer (MTC) is a rare tumor arising from the calcitonin-producing parafollicular C cells of the thyroid gland, occurring either sporadically or alternatively in a hereditary form based on germline RET mutations in approximately one-third of cases. Historically, patients with advanced, metastasized MTC have had a poor prognosis, partly due to limited response to conventional chemotherapy and radiation therapy. In the past decade, however, considerable progress has been made in identifying key genetic alterations and dysregulated signaling pathways paving the way for the evaluation of a series of multitargeted kinase inhibitors that have started to meaningfully impact clinical practice. Two drugs, vandetanib and cabozantinib, are now approved in the US and EU for use in advanced, progressive MTC, with additional targeted agents also showing promise or awaiting results from clinical trials. However, the potential for toxicities with significant reduction in quality of life and lack of curative outcomes has to be carefully weighed against potential for benefit. Despite significant PFS prolongation observed in randomized clinical trials, most patients even with metastatic disease enjoy indolent courses with slow progression observed over years, wherein watchful waiting is still the preferred strategy. As advanced, progressive MTC is a rare and complex disease, a multidisciplinary approach centered in specialized centers providing interdisciplinary expertise in the individualization of available therapeutic options is preferred. In this review, we summarize current concepts of the molecular pathogenesis of advanced MTC and discuss results from clinical trials of targeted agents and also cytotoxic chemotherapy in the context of clinical implications and future perspectives.

  12. Systemic treatment and management approaches for medullary thyroid cancer.

    PubMed

    Ernani, Vinicius; Kumar, Mukesh; Chen, Amy Y; Owonikoko, Taofeek K

    2016-11-01

    Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.

  13. Neurones in the adult rat anterior medullary velum.

    PubMed

    Ibrahim, M; Menoud, P A; Celio, M R

    2000-03-27

    The presence of neurones in the rat anterior medullary velum (AMV) has been investigated by using antibodies to the calcium-binding proteins, parvalbumin (PV), calretinin (CR), and calbindin-D28k (CB). Disparate populations of mainly GABAergic neurones were located in the rostral and caudal regions of the AMV. The rostral region of the AMV was characterised by GABAergic CR-labelled or PV-labelled neurones. CR-labelled neurones were bipolar or multipolar with round to ovoid somata (diameters between 8 and 12 microm), and rostrocaudally running dendrites forming a network. PV-labelled neurones had round somata (diameters between 6 and 10 microm) and were bi-tufted, with beaded dendrites. Both CR-labelled and PV-labelled dendrites formed punctate pericellular associations with unlabelled somatic profiles. In the caudal region of the AMV, PV-labelled neurones were GABAergic, multipolar cells, having round somata (diameters between 9 and 12 microm), with either beaded or nonbeaded dendrites forming a network of interconnecting dendrites. PV-labelled pericellular associations were made around both PV-labelled and unlabelled somatic profiles. CR labelled unipolar brush cells (UBCs) were not GABAergic. UBCs were characterised by a round to oval somata (10-15 microm in diameter) from which a single primary dendrite emerged to form a distal expansion having small terminal dendrites. From the distal expansion, there also appeared to be CR-labelled processes emanating and extending for up to 250 microm. CB occasionally labelled "Purkinje-like cells" (PLCs). The rat AMV is a more complex structure than first envisaged with the presence of predominantly inhibitory neurones expressing different calcium-binding proteins. Functional and anatomic aspects of this circuitry are further discussed.

  14. nab-Paclitaxel in Combination with Carboplatin for a Previously Treated Thymic Carcinoma

    PubMed Central

    Makimoto, Go; Fujiwara, Keiichi; Watanabe, Hiromi; Kameyama, Nobuhisa; Matsushita, Mizuho; Rai, Kammei; Sato, Ken; Yonei, Toshiro; Sato, Toshio; Shibayama, Takuo

    2014-01-01

    We present the case of a 40-year-old man with previously treated thymic carcinoma, complaining of gradually worsening back pain. Computed tomography scans of the chest showed multiple pleural disseminated nodules with a pleural effusion in the right thorax. The patient was treated with carboplatin on day 1 plus nab-paclitaxel on day 1 and 8 in cycles repeated every 4 weeks. Objective tumor shrinkage was observed after 4 cycles of this regimen. In addition, the elevated serum cytokeratin 19 fragment level decreased, and the patient's back pain was relieved without any analgesics. Although he experienced grade 4 neutropenia and granulocyte colony-stimulating factor (G-CSF) injection, the severity of thrombocytopenia and nonhematological toxicities such as reversible neuropathy did not exceed grade 1 during the treatment. To our knowledge, this is the first report to demonstrate the efficacy of combination chemotherapy consisting of carboplatin and nab-paclitaxel against thymic carcinoma. This case report suggests that nab-paclitaxel in combination with carboplatin can be a favorable chemotherapy regimen for advanced thymic carcinoma. PMID:24575009

  15. Severe Changes in Thymic Microenvironment in a Chronic Experimental Model of Paracoccidioidomycosis

    PubMed Central

    Alves da Costa, Thiago; Di Gangi, Rosária; Thomé, Rodolfo; Barreto Felisbino, Marina; Pires Bonfanti, Amanda; Lumi Watanabe Ishikawa, Larissa; Sartori, Alexandrina; Burger, Eva; Verinaud, Liana

    2016-01-01

    T cell maturation takes place within the thymus, a primary lymphoid organ that is commonly targeted during infections. Previous studies showed that acute infection with Paracoccidioides brasiliensis (Pb), the causative agent of paracoccidioidomycosis (PCM), promotes thymic atrophy that is associated with the presence of yeast cells in the organ. However, as human PCM is a chronic infection, it is imperative to investigate the consequences of Pb infection over the thymic structure and function in chronic infection. In this sense, we developed a new experimental model where Pb yeast cells are injected through the intraperitoneal route and mice are evaluated over 120 days of infection. Thymuses were analyzed in chronically infected mice and we found that the thymus underwent extensive morphological alterations and severe infiltration of P. brasiliensis yeast cells. Further analyses showed an altered phenotype and function of thymocytes that are commonly found in peripheral mature T lymphocytes. We also observed activation of the NLRP3 inflammasome in the thymus. Our data provide new information on the severe changes observed in the thymic microenvironment in a model of PCM that more closely mimics the human infection. PMID:27736987

  16. 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.

  17. An Age-Associated Decline in Thymic Output Differs in Dog Breeds According to Their Longevity

    PubMed Central

    Holder, Angela; Mella, Stephanie; Palmer, Donald B.; Aspinall, Richard; Catchpole, Brian

    2016-01-01

    The age associated decline in immune function is preceded in mammals by a reduction in thymic output. Furthermore, there is increasing evidence of a link between immune competence and lifespan. One approach to determining thymic output is to quantify signal joint T cell receptor excision circles (sj-TRECs), a method which has been developed and used in several mammalian species. Life expectancy and the rate of aging vary in dogs depending upon their breed. In this study, we quantified sj-TRECs in blood samples from dogs of selected breeds to determine whether there was a relationship between longevity and thymic output. In Labrador retrievers, a breed with a median expected lifespan of 11 years, there was an age-associated decline in sj-TREC values, with the greatest decline occurring before 5 years of age, but with sj-TREC still detectable in some geriatric animals, over 13 years of age. In large short-lived breeds (Burnese mountain dogs, Great Danes and Dogue de Bordeaux), the decline in sj-TREC values began earlier in life, compared with small long-lived breeds (Jack Russell terriers and Yorkshire terriers), and the presence of animals with undetectable sj-TRECs occurred at a younger age in the short-lived breeds. The study findings suggest that age-associated changes in canine sj-TRECs are related to breed differences in longevity, and this research highlights the use of dogs as a potential model of immunosenescence. PMID:27824893

  18. Characterization of CD34+ thymic stromal cells located in the subcapsular cortex of the human thymus.

    PubMed

    Martínez-Cáceres, E; Jaleco, A C; Res, P; Noteboom, E; Weijer, K; Spits, H

    1998-07-01

    In this paper we report that suspensions of human fetal thymocytes contain cells that express high levels of CD34 and Thy-1. These cells were characterized with regard to location within the thymus, phenotype, and function. Confocal laser scan analysis of frozen sections of fetal thymus with anti-CD34 and Thy-1 antibodies revealed that the double-labeled cells were located in the pericortical area. In addition, it was found that the CD34+Thy-1+ cells lacked CD45 and CD50, indicating that these cells are not of hematopoietic origin; this was confirmed by the finding that these cells could be cultured as adherent cells in a medium with cholera toxin and dexamethasone, but failed to grow in mixtures of hematopoietic growth factors. Further analysis indicated that most cultured CD34+Thy-1+ cells expressed cytokeratin (CK) 14 but lacked CK 13, suggesting that these cells are immature epithelial cells. Cultured CD34+Thy-1+ cells were able to induce differentiation of CD1-CD34+CD3-CD4-CD8- thymic precursors into CD4+CD8+ cells in a reaggregate culture in the absence of exogenous cytokines. The CD4+CD8+ cells that developed in these cultures did not express CD3, indicating that CD34+Thy-1+ thymic stromal cells are not capable of completing full T cell differentiation of thymic hematopoietic progenitor cells.

  19. 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.

  20. T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation.

    PubMed

    Vago, Luca; Oliveira, Giacomo; Bondanza, Attilio; Noviello, Maddalena; Soldati, Corrado; Ghio, Domenico; Brigida, Immacolata; Greco, Raffaella; Lupo Stanghellini, Maria Teresa; Peccatori, Jacopo; Fracchia, Sergio; Del Fiacco, Matteo; Traversari, Catia; Aiuti, Alessandro; Del Maschio, Alessandro; Bordignon, Claudio; Ciceri, Fabio; Bonini, Chiara

    2012-08-30

    The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell-depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+ -cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.

  1. Efficacy of computed tomography features in predicting stage III thymic tumors

    PubMed Central

    Shen, Yan; Ye, Jianding; Fang, Wentao; Zhang, Yu; Ye, Xiaodan; Ma, Yonghong; Chen, Libo; Li, Minghua

    2017-01-01

    Accurate assessment of the invasion of intrathoracic structures by stage III thymic tumors assists their appropriate management. The present study aimed to evaluate the efficacy of computed tomography (CT) features for the prediction of stage III thymoma invasion. The pre-operative CT images of 66 patients with confirmed stage III thymic tumors were reviewed retrospectively. The CT features of invasion into the mediastinal pleura, lungs, pericardium and great vessels were analyzed, and their sensitivity, specificity, positive predictive value (PPV), negative predictive value and accuracy were calculated. For mediastinal pleural and pericardial invasion, an absence of space between the tumor and the mediastinal pleura/pericardium with mediastinal pleural/pericardial thickening and pleural/pericardial effusion exhibited a specificity and PPV of 100%, respectively. For lung invasion, a multi-lobular tumor convex to the lung with adjacent lung abnormalities exhibited a specificity and PPV of 91.2 and 81.3%, respectively. For vessel invasion, the specificity and PPV were each 100% for tumors abutting ≥50% of the vessel circumference, and for tumor oppression, deformation and occlusion of the vessel. In conclusion, recognition of the appropriate CT features can serve as a guide to invasion by stage III thymic tumors, and can facilitate the selection of appropriate pre-operative treatment. PMID:28123518

  2. Association between thymic function and allogeneic hematopoietic stem cell transplantation outcome: results of a pediatric study.

    PubMed

    Saglio, Francesco; Cena, Silvia; Berger, Massimo; Quarello, Paola; Boccasavia, Viola; Ferrando, Federica; Pittana, Laura; Bruno, Benedetto; Fagioli, Franca

    2015-06-01

    Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities.

  3. Effect of medullary cavity in cancellous bone on two-wave phenomenon

    NASA Astrophysics Data System (ADS)

    Hachiken, Takuma; Nakanishi, Shoko; Matsukawa, Mami

    2016-07-01

    Osteoporotic patients have a larger medullary cavity in their cancellous bone than healthy people. In this study, the effect of the medullary cavity on the two-wave phenomenon was experimentally investigated using a cancellous bone model and a radius bone model. In the cancellous bone model, with the increase in hole (medullary cavity) diameter, the amplitudes of the fast waves became smaller, whereas the amplitudes of the slow waves became larger. In the radius bone model, the fast wave overlapped with the circumferential wave. The slow wave became larger with increasing hole diameter. The analysis of the slow wave thus seems to be useful for the in vivo diagnosis of the degree of osteoporosis.

  4. Lateral medullary infarction presenting as isolated vertigo and unilateral loss of visual suppression.

    PubMed

    Kishi, Masahiko; Sakakibara, Ryuji; Nomura, Toshiyuki; Yoshida, Tomoe; Yamamoto, Masahiko; Kataoka, Manabu; Ogawa, Emina; Tateno, Fuyuki

    2012-02-01

    Isolated vertigo is rare in lateral medullary infarction. We described early diagnostic challenges in such cases by a neuro-otological approach. We report a 56-year-old man who developed a lateral medullary infarction that presented as isolated vertigo. Before the day 4 from disease onset when diffusion-weighted magnetic resonance imaging (MRI) became positive, this patient showed unilateral loss of visual suppression, a central type of vestibular dysfunction. Since MRI abnormalities may not appear in the early few days from disease onset, unilateral loss of visual suppression might become an important diagnostic option for isolated vertigo due to a lateral medullary infarction. This finding is presumably relevant to the inferior olive lesion.

  5. Panmedullary edema with inferior olivary hypertrophy in bilateral medial medullary infarction.

    PubMed

    Inoue, Yasuteru; Miyashita, Fumio; Koga, Masatoshi; Yamada, Naoaki; Toyoda, Kazunori; Minematsu, Kazuo

    2014-03-01

    Bilateral medial medullary infarction (MMI) is a rare type of stroke with poor outcomes. Inferior olivary nucleus hypertrophy results from a pathologic lesion in the Guillain-Mollaret triangle. The relationship between inferior olivary nucleus hypertrophy and the medullary lesion is obscure. To the best of our knowledge, only 1 autopsy case with unilateral medial medullary infarction that was associated with ipsilateral inferior olivary nucleus hypertrophy has been reported. We describe a rare case with acute infarction in the bilateral medial medulla oblongata accompanied by subacute bilateral inferior olivary nucleus hypertrophy and panmedullary edema. The hypertrophy appeared to have been caused by local ischemic damage to the termination of the central tegmental tract at the bilateral inferior olivary nucleus.

  6. [A case of medial medullary infarction with persistent primitive hypoglossal artery].

    PubMed

    Jin, Kazutaka; Aihara, Naoto; Tsukamoto, Tetsuro

    2002-04-01

    A 66-year-old woman was admitted to our hospital because of vomiting, dizziness and vertigo. Neurological examination on admission revealed only upbeat nystagmus without cranial nerve symptoms, paresis, cerebellar signs or sensory disturbances. Magnetic resonance(MR) images demonstrated a new T 2 high intensity and T 1 iso-intensity signal lesion in the right upper medial medulla. This medial medullary infarction caused central vestibular dysfunction. MR angiography and digital subtraction angiography demonstrated a persistent primitive hypoglossal artery (PPHA) originating from the right internal carotid artery to the vertebrobasilar artery associated with the stenosis of the right internal carotid artery at the level of the cervical bifurcation. This is the first report of medullary infarction with persistent carotid-basilar anastomosis. We suspected this medullary infarction was caused by artery to artery embolism in the branch of the right vertebral artery through the PPHA distal originated from the stenosis of the right internal carotid artery.

  7. Adrenocortical hemorrhagic necrosis: the role of catecholamines and retrograde medullary-cell embolism

    SciTech Connect

    Szabo, S.; McComb, D.J.; Kovacs, K.; Huettner, I.

    1981-10-01

    We investigated the pathogenesis of adrenal necrosis using animal models of the disease (induced by administration of acrylonitrile, cysteamine, or pyrazole) and human cases. Results of electron-microscopic and histochemical time-response studies with rat models revealed an early, retrograde embolization of medullary cells and cell fragments in the cortical capillaries that showed prominent endothelial injury. The experimental adrenal lesions were prevented by surgical removal of the medulla one month before administration of adrenocorticolytic chemicals, or by the administration of the alpha-adrenergic antagonist phenoxybenzamine hydrochloride. Histochemical staining for medullary (argyrophil) granules in human cases of adrenal necrosis demonstrated tissue fragments that stained positively for silver in vascular cortical spaces in nine of ten autopsy specimens and in all four surgical cases we reviewed. Thus, catecholamines released from the adrenal medulla and from the retrograde medullary emboli in the cortex may have a role in the pathogenesis of adrenocortical necrosis.

  8. Is Hashimoto's thyroiditis a risk factor for medullary thyroid carcinoma? Our experience and a literature review.

    PubMed

    Zayed, Ayman A; Ali, Moaath K Mustafa; Jaber, Omar I; Suleiman, Moh'd J; Ashhab, Ashraf A; Al Shweiat, Wajdi Mohammed; Momani, Munther Suliaman; Shomaf, Maha; AbuRuz, Salah Mohammed

    2015-03-01

    The etiology of medullary thyroid carcinoma remains unknown. The aim of this study was to determine whether there is a significant association between medullary thyroid carcinoma and Hashimoto's thyroiditis in the histopathologic material of thyroidectomized patients. Retrospective cross-sectional study. In this study, we reviewed the medical records of all patients who underwent total thyroidectomy for different thyroid-related complaints between January 2000 and January 2012 at Jordan University Hospital-Amman, Jordan. To highlight relevant previously published studies addressing this topic, a literature search was conducted for English language studies reporting "medullary thyroid carcinoma" or "C-cell hyperplasia" in patients with Hashimoto's thyroiditis. Of the 863 patients with a mean age of 47.2 ± 12.3 years who underwent total thyroidectomy during the study period, 78 (9.04 %) were diagnosed with Hashimoto's thyroiditis, and 15 (1.74 %) had medullary thyroid carcinoma, 3 (20 %) of whom had coexistent Hashimoto's thyroiditis. A total of 683 (79.1 %) patients had benign thyroid disease, 67 (9.8 %) of whom had Hashimoto's thyroiditis. The difference between these rates was not statistically significant (p = 0.19). When examined by gender, 9 females had medullary thyroid carcinoma, 3 (33.3 %) of whom had coexistent Hashimoto's thyroiditis; by contrast, of 560 females with benign thyroid disease, 62 (11.1 %) had Hashimoto's thyroiditis (p = 0.04). Although this study population represents a small and single-institution experience, our results suggest that there might be an association between Hashimoto's thyroiditis and medullary thyroid carcinoma only in female patients who undergo total thyroidectomy.

  9. Decreased GABAA Receptor Binding in the Medullary Serotonergic System In the Sudden Infant Death Syndrome

    PubMed Central

    Broadbelt, Kevin G.; Paterson, David S.; Belliveau, Richard A.; Trachtenberg, Felicia L.; Haas, Elisabeth A.; Stanley, Christina; Krous, Henry F.; Kinney, Hannah C.

    2011-01-01

    γ-Aminobutyric acid (GABA) neurons in the medulla oblongata help regulate homeostasis, in part through interactions with the medullary serotonergic (5-HT) system. Previously, we reported abnormalities in multiple 5-HT markers in the medullary 5-HT system of infants dying from sudden infant death syndrome (SIDS), suggesting that 5-HT dysfunction is involved in its pathogenesis. Here, we tested the hypothesis that markers of GABAA receptors are decreased in the medullary 5-HT system in SIDS cases compared to controls. Using tissue receptor autoradiography with the radioligand 3H-GABA, we found 25–52% reductions in GABAA receptor binding density in 7 of 10 key nuclei sampled of the medullary 5-HT system in the SIDS cases (postconceptional age [PCA] = 51.7 ± 8.3, n = 28) vs. age-adjusted controls (PCA = 55.3 ± 13.5, n = 8) (p ≤ 0.04). By Western blotting there was 46.2% reduction in GABAAα3 subunit levels in the gigantocellularis (component of the medullary 5-HT system) of SIDS cases (PCA = 53.9 ± 8.4, n = 24) vs. controls (PCA = 55.3 ± 8.3, n = 8) (56.8% standard in SIDS cases vs. 99.35% in controls; p = 0.026). These data suggest that medullary GABAA receptors are abnormal in SIDS infants and that SIDS is a complex disorder of a homeostatic network in the medulla that involves deficits of the GABAergic and 5-HT systems. PMID:21865888

  10. Medullary sponge kidney presenting in a neonate with distal renal tubular acidosis and failure to thrive: a case report

    PubMed Central

    2009-01-01

    Introduction Medullary sponge kidney is a congenital anomaly characterized by diffuse ectasy of the collecting tubules of one or both kidneys. It is usually diagnosed in the second or third decade of life. Case presentation Distal renal tubular acidosis is commonly observed in patients with medullary sponge kidney. We describe here a 50-day-old Egyptian Caucasian girl with medullary sponge kidney who had features of distal renal tubular acidosis, (persistent alkaline urine, hypercalciuria, hypocitraturia) and failure to thrive. Renal ultrasound revealed left renal increased medullary echogenicity and bilateral nephrocalcinosis. Conclusion Early gene(s) expression of medullary sponge kidney disease might be responsible for persistent metabolic acidosis during the neonatal period. PMID:19830120

  11. alpha(2)-adrenergic receptor-mediated increase in NO production buffers renal medullary vasoconstriction.

    PubMed

    Zou, A P; Cowley, A W

    2000-09-01

    The present study was designed to investigate the role of nitric oxide (NO) in modulating the adrenergic vasoconstrictor response of the renal medullary circulation. In anesthetized rats, intravenous infusion of norepinephrine (NE) at a subpressor dose of 0.1 microgram. kg(-1). min(-1) did not alter renal cortical (CBF) and medullary (MBF) blood flows measured by laser-Doppler flowmetry nor medullary tissue PO(2) (P(m)O(2)) as measured by a polarographic microelectrode. In the presence of the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME) in the renal medulla, intravenous infusion of NE significantly reduced MBF by 30% and P(m)O(2) by 37%. With the use of an in vivo microdialysis-oxyhemoglobin NO-trapping technique, we found that intravenous infusion of NE increased interstitial NO concentrations by 43% in the renal medulla. NE-stimulated elevations of tissue NO were completely blocked either by renal medullary interstitial infusion of L-NAME or the alpha(2)-antagonist rauwolscine (30 microgram. kg(-1). min(-1)). Concurrently, intavenous infusion of NE resulted in a significant reduction of MBF in the presence of rauwolscine. The alpha(1)-antagonist prazosin (10 microgram. kg(-1). min(-1) renal medullary interstitial infusion) did not reduce the NE-induced increase in NO production, and NE increased MBF in the presence of prazosin. Microdissection and RT-PCR analyses demonstrated that the vasa recta expressed the mRNA of alpha(2B)-adrenergic receptors and that medullary thick ascending limb and collecting duct expressed the mRNA of both alpha(2A)- and alpha(2B)-adrenergic receptors. These subtypes of alpha(2)-adrenergic receptors may mediate NE-induced NO production in the renal medulla. We conclude that the increase in medullary NO production associated with the activation of alpha(2)-adrenergic receptors counteracts the vasoconstrictor effects of NE in the renal medulla and may play an important role in maintaining a constancy of MBF and medullary

  12. Sporadic bilateral adrenal medullary hyperplasia: apparent false positive MIBG scan and expected MRI findings.

    PubMed

    Yung, B C; Loke, T K; Tse, T W; Tsang, M W; Chan, J C

    2000-10-01

    Adrenal medullary hyperplasia is a rare cause of clinical symptoms and biochemical findings identical to pheochromocytoma occurring mostly in multiple endocrine neoplasia patients. The scenario of positive MIBG scan, but no focal lesion found on CT and MRI led to diagnostic and management difficulties. Like pheochromocytoma, surgical excision can lead to clinical and biochemical recovery. We report this unusual case of sporadic bilateral adrenal medullary hyperplasia, with hypertension and biochemical abnormalities alleviated after surgical adrenalectomy. Based on T2 values reported in literature, high signal focal lesions may not appear on T2-weighted MRI images until development of frank pheochromocytoma. MIBG scan remains the most sensitive imaging modality for this condition.

  13. Transient hyperechogenicity of the renal medullary pyramids: incidence in the healthy term newborn.

    PubMed

    Khoory, B J; Andreis, I A; Vino, L; Fanos, V

    1999-01-01

    A screening program was performed on 1881 clinically healthy term newborns, aimed at detecting eventual pathological conditions not diagnosed during pregnancy. Seventy-three cases of transient hyperechogenicity of the renal medullary pyramids were observed, involving one or both kidneys with either sectorial or diffuse pattern. None of the neonates examined had evidence of renal dysfunction and follow-up ultrasound scans demonstrated complete resolution of the sonographic picture. Medullary hyperechogenicity is not rare in healthy term newborns (3.9%); it presents rapid resolution and should be considered in differential diagnosis of pathological conditions.

  14. Medullary cystic disease of the kidney: its occurrence in two siblings

    PubMed Central

    Handa, Satya Paul; Tennant, Robert

    1968-01-01

    Two cases of medullary cystic disease of the kidney in two siblings are presented. In both siblings there was an insidious onset of azotaemia and anaemia at an early age. The urinalyses were normal except for a trace of proteinuria and persistent low specific gravity. The kidneys were small by radiological studies and this was proved at necropsy. The gross microscopic appearances of the kidneys were consistent with medullary cystic disease. The literature on this subject and current views on the similarities between familial juvenile nephronophthisis and this condition are discussed. ImagesFig. 1Fig. 2Fig. 3Fig. 4 PMID:5705387

  15. Targeting medullary thyroid carcinomas with bispecific antibodies and bivalent haptens. Results and clinical perspectives.

    PubMed

    Rouvier, E; Gautherot, E; Meyer, P; Barbet, J

    1997-01-01

    The present article reviews the clinical trials that have been performed in recurrent medullary thyroid carcinoma patients with the Affinity Enhancement System. This technique uses bispecific antibodies to target radiolabelled bivalent haptens to tumour cells. Its sensitivity in the detection of known tumour sites is high (90%) and this technique also achieves good sensitivity (61%) in the detection of occult disease as revealed by abnormal thyrocalcitonin blood levels. Due to its high targeting capacity, this technique is now considered for use as a therapeutic agent in medullary thyroid carcinoma patients.

  16. Lung alveolar epithelium and interstitial lung disease.

    PubMed

    Corvol, Harriet; Flamein, Florence; Epaud, Ralph; Clement, Annick; Guillot, Loic

    2009-01-01

    Interstitial lung diseases (ILDs) comprise a group of lung disorders characterized by various levels of inflammation and fibrosis. The current understanding of the mechanisms underlying the development and progression of ILD strongly suggests a central role of the alveolar epithelium. Following injury, alveolar epithelial cells (AECs) may actively participate in the restoration of a normal alveolar architecture through a coordinated process of re-epithelialization, or in the development of fibrosis through a process known as epithelial-mesenchymal transition (EMT). Complex networks orchestrate EMT leading to changes in cell architecture and behaviour, loss of epithelial characteristics and gain of mesenchymal properties. In the lung, AECs themselves may serve as a source of fibroblasts and myofibroblasts by acquiring a mesenchymal phenotype. This review covers recent knowledge on the role of alveolar epithelium in the pathogenesis of ILD. The mechanisms underlying disease progression are discussed, with a main focus on the apoptotic pathway, the endoplasmic reticulum stress response and the developmental pathway.

  17. Mechanically patterning the embryonic airway epithelium.

    PubMed

    Varner, Victor D; Gleghorn, Jason P; Miller, Erin; Radisky, Derek C; Nelson, Celeste M

    2015-07-28

    Collections of cells must be patterned spatially during embryonic development to generate the intricate architectures of mature tissues. In several cases, including the formation of the branched airways of the lung, reciprocal signaling between an epithelium and its surrounding mesenchyme helps generate these spatial patterns. Several molecular signals are thought to interact via reaction-diffusion kinetics to create distinct biochemical patterns, which act as molecular precursors to actual, physical patterns of biological structure and function. Here, however, we show that purely physical mechanisms can drive spatial patterning within embryonic epithelia. Specifically, we find that a growth-induced physical instability defines the relative locations of branches within the developing murine airway epithelium in the absence of mesenchyme. The dominant wavelength of this instability determines the branching pattern and is controlled by epithelial growth rates. These data suggest that physical mechanisms can create the biological patterns that underlie tissue morphogenesis in the embryo.

  18. Odors Discrimination by Olfactory Epithelium Biosensor

    NASA Astrophysics Data System (ADS)

    Liu, Qingjun; Hu, Ning; Ye, Weiwei; Zhang, Fenni; Wang, Hua; Wang, Ping

    2011-09-01

    Humans are exploring the bionic biological olfaction to sense the various trace components of gas or liquid in many fields. For achieving the goal, we endeavor to establish a bioelectronic nose system for odor detection by combining intact bioactive function units with sensors. The bioelectronic nose is based on the olfactory epithelium of rat and microelectrode array (MEA). The olfactory epithelium biosensor generates extracellular potentials in presence of odor, and presents obvious specificity under different odors condition. The odor response signals can be distinguished with each other effectively by signal sorting. On basis of bioactive MEA hybrid system and the improved signal processing analysis, the bioelectronic nose will realize odor discrimination by the specific feature of signals response to various odors.

  19. [Neutrophils and monocytes in gingival epithelium

    PubMed

    Meng, H X; Zheng, L P

    1994-06-01

    Neutrophils and monocytes of gingival epithellium in health gingiva(H),marginal gingivitis(MG),juvenile periodontitis(JP),adult periodontitis(AP) and subgingival bacteria were quantitated and analyzed,The results showed that the numbers of PMN within either pocket epithelium or oral gingival epithelium in JP were significantly lower than in AP and G.The amounts of PMN in AP were much larger than other three groups.Positive correlation between the number of PMN in sulcular pocket epitelium and the motile bacteri of subgingival plaque was demonstrated by correlation analysis.Monocytes mainly presented in deep pocket and junctional epithelum which were stained by NAE method,however very few Langhans cells were seen in these areas.

  20. Mechanically patterning the embryonic airway epithelium

    PubMed Central

    Varner, Victor D.; Gleghorn, Jason P.; Miller, Erin; Radisky, Derek C.; Nelson, Celeste M.

    2015-01-01

    Collections of cells must be patterned spatially during embryonic development to generate the intricate architectures of mature tissues. In several cases, including the formation of the branched airways of the lung, reciprocal signaling between an epithelium and its surrounding mesenchyme helps generate these spatial patterns. Several molecular signals are thought to interact via reaction-diffusion kinetics to create distinct biochemical patterns, which act as molecular precursors to actual, physical patterns of biological structure and function. Here, however, we show that purely physical mechanisms can drive spatial patterning within embryonic epithelia. Specifically, we find that a growth-induced physical instability defines the relative locations of branches within the developing murine airway epithelium in the absence of mesenchyme. The dominant wavelength of this instability determines the branching pattern and is controlled by epithelial growth rates. These data suggest that physical mechanisms can create the biological patterns that underlie tissue morphogenesis in the embryo. PMID:26170292

  1. Hypervascularity is more frequent in medullary thyroid carcinoma

    PubMed Central

    Lai, Xingjian; Liu, Meijuan; Xia, Yu; Wang, Liang; Bi, Yalan; Li, Xiaoyi; Zhang, Bo; Yang, Meng; Dai, Qing; Jiang, Yuxin

    2016-01-01

    Abstract This study was designed to retrospectively compare the sonographic features of medullary thyroid carcinoma (MTC) and the features of papillary thyroid carcinoma (PTC). A total of 97 patients with 127 MTCs between January 2000 and January 2016 and 107 consecutive patients with 132 PTCs were included in this study. Two radiologists retrospectively determined the sonographic features and compared the findings of MTCs and PTCs. Compared with the patients with PTCs, the patients with MTCs were older (46.9 years vs 42.9 years, P = 0.016) and the male proportion was higher (53.6% vs 33.6%, P = 0.005). Most of the MTCs had an irregular shape (72.4%), a length/width ratio <1 (75.6%), an unclear boundary (63.8%), no peripheral halo ring (93.7%), hypoechogenicity (96.9%), heterogeneous echotexture (76.4%), no cystic change (78.7%), calcification (63.8%), and hypervascularity (72.4%). There was no significant difference in the boundary, peripheral halo ring, echogenicity, and calcification between the MTCs and PTCs. However, compared with the PTCs, a larger size (2.2 vs 1.2 cm, P <0.001), a regular shape (27.6% vs 7.6%, P <0.001), a length/width ratio <1 (75.6% vs 51.5%, P<0.001), heterogeneous echotexture (76.4% vs 54.5%, P <0.001), cystic change (21.3 vs 8.3%, P = 0.005), and hypervascularity (72.4% vs 47.7%, P <0.001) were more frequent in the MTCs. The sonographic features with a higher likelihood of malignancy are common in MTCs, including a shape taller than the width, irregular infiltrative margins, an absent halo, hypoechogenicity, the presence of microcalcifications, and increased intranodular vascularity. However, MTCs tend to possess these suspicious sonographic features less often than PTCs, with the exception of hypervascularity, which was more frequent in MTCs. PMID:27930537

  2. Shear wave elastography in medullary thyroid carcinoma diagnostics

    PubMed Central

    Gumińska, Anna; Bakuła-Zalewska, Elwira; Mlosek, Krzysztof; Słapa, Rafał Z.; Wareluk, Paweł; Krauze, Agnieszka; Ziemiecka, Agnieszka; Migda, Bartosz; Jakubowski, Wiesław; Dedecjus, Marek

    2015-01-01

    Shear wave elastography (SWE) is a modern method for the assessment of tissue stiffness. There has been a growing interest in the use of this technique for characterizing thyroid focal lesions, including preoperative diagnostics. Aim The aim of the study was to assess the clinical usefulness of SWE in medullary thyroid carcinoma (MTC) diagnostics. Materials and methods A total of 169 focal lesions were identified in the study group (139 patients), including 6 MTCs in 4 patients (mean age: 45 years). B-mode ultrasound and SWE were performed using Aixplorer (SuperSonic, Aix-en-Provence), with a 4–15 MHz linear probe. The ultrasound was performed to assess the echogenicity and echostructure of the lesions, their margin, the halo sign, the height/width ratio (H/W ratio), the presence of calcifications and the vascularization pattern. This was followed by an analysis of maximum and mean Young's (E) modulus values for MTC (EmaxLR, EmeanLR) and the surrounding thyroid tissues (EmaxSR, EmeanSR), as well as mean E-values (EmeanLRz) for 2 mm region of interest in the stiffest zone of the lesion. The lesions were subject to pathological and/or cytological evaluation. Results The B-mode assessment showed that all MTCs were hypoechogenic, with no halo sign, and they contained micro- and/ or macrocalcifications. Ill-defined lesion margin were found in 4 out of 6 cancers; 4 out of 6 cancers had a H/W ratio > 1. Heterogeneous echostructure and type III vascularity were found in 5 out of 6 lesions. In the SWE, the mean value of EmaxLR for all of the MTCs was 89.5 kPa and (the mean value of EmaxSR for all surrounding tissues was) 39.7 kPa Mean values of EmeanLR and EmeanSR were 34.7 kPa and 24.4 kPa, respectively. The mean value of EmeanLRz was 49.2 kPa. Conclusions SWE showed MTCs as stiffer lesions compared to the surrounding tissues. The lesions were qualified for fine needle aspiration biopsy based on B-mode assessment. However, the diagnostic algorithm for MTC is based on the

  3. Airway epithelium stimulates smooth muscle proliferation.

    PubMed

    Malavia, Nikita K; Raub, Christopher B; Mahon, Sari B; Brenner, Matthew; Panettieri, Reynold A; George, Steven C

    2009-09-01

    Communication between the airway epithelium and stroma is evident during embryogenesis, and both epithelial shedding and increased smooth muscle proliferation are features of airway remodeling. Hence, we hypothesized that after injury the airway epithelium could modulate airway smooth muscle proliferation. Fully differentiated primary normal human bronchial epithelial (NHBE) cells at an air-liquid interface were co-cultured with serum-deprived normal primary human airway smooth muscle cells (HASM) using commercially available Transwells. In some co-cultures, the NHBE were repeatedly (x4) scrape-injured. An in vivo model of tracheal injury consisted of gently denuding the tracheal epithelium (x3) of a rabbit over 5 days and then examining the trachea by histology 3 days after the last injury. Our results show that HASM cell number increases 2.5-fold in the presence of NHBE, and 4.3-fold in the presence of injured NHBE compared with HASM alone after 8 days of in vitro co-culture. In addition, IL-6, IL-8, monocyte chemotactic protein (MCP)-1 and, more markedly, matrix metalloproteinase (MMP)-9 concentration increased in co-culture correlating with enhanced HASM growth. Inhibiting MMP-9 release significantly attenuated the NHBE-dependent HASM proliferation in co-culture. In vivo, the injured rabbit trachea demonstrated proliferation in the smooth muscle (trachealis) region and significant MMP-9 staining, which was absent in the uninjured control. The airway epithelium modulates smooth muscle cell proliferation via a mechanism that involves secretion of soluble mediators including potential smooth muscle mitogens such as IL-6, IL-8, and MCP-1, but also through a novel MMP-9-dependent mechanism.

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

    PubMed

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

    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. We conclude, from these data, that scurfy lesions are mediated by T lymphocytes that mature in an abnormal (sf) thymic environment.

  5. 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.

  6. Hydrogen Sulfide Regulates the [Ca2+]i Level in the Primary Medullary Neurons

    PubMed Central

    Liu, Xiaoni; Zhang, Nana; Ding, Yingjiong; Cao, Dongqing; Huang, Ying; Chen, Xiangjun; Wang, Rui

    2016-01-01

    In the present study, we attempted to elucidate mechanisms for the regulation of intracellular calcium levels by H2S in primary rat medullary neurons. Our results showed that NaHS significantly increased the level of [Ca2+]i in rat medullary neurons in a concentration-dependent manner. L-Cysteine and SAM significantly raised the level of [Ca2+]i in the medullary neurons while HA and/or AOAA produced a reversal effect. In addition, L-cysteine and SAM significantly increased but HA and/or AOAA decreased the production of H2S in the cultured neurons. The [Ca2+]i elevation induced by H2S was significantly diminished by EGTA-Ca2+-free solutions, and this elevation was also reduced by nifedipine or nimodipine and mibefradil, suggesting the role of L-type and/or T-type Ca2+ channels. Moreover, the effect of H2S on [Ca2+]i level in neurons was significantly attenuated by BAPTA-AM and thapsigargin, suggesting the source of Ca2+. Therefore, we concluded that both exogenous and endogenous H2S elevates [Ca2+]i level in primarily cultured rat medullary neurons via both increasing calcium influx and mobilizing intracellular Ca2+ stores from ER. PMID:27840667

  7. E-cadherin and beta-catenin expression in breast medullary carcinomas.

    PubMed

    Charpin, C; Bonnier, P; Garcia, S; Andrac, L; Crebassa, B; Dorel, M; Lavaut, M N; Allasia, C

    1999-08-01

    The initial step of cancer invasion and metastasis is the escape of tumour cells from the primary site, involving disruption of normal cell-cell adhesion and E-cadherin (E-cad) and beta-catenin (beta-cat) down-regulation, as shown in various types of human malignancies including breast carcinomas. Medullary carcinomas are high grade and poorly differentiated tumours with syncytial typical pattern, and prognosis unexpectedly better than that in high grade breast carcinomas. In a series of 55 breast typical medullary carcinomas diagnosed according to the strict use of Ridolfi et al (Cancer 40: 1365-1385, 1977) criteria, E-cad and beta-cat were investigated using quantitative (SAMBA 2005 system) immunocytochemical assays on frozen sections. Results were compared to that obtained on paraffin sections and in a series (n=55) of grade 3 ductal carcinomas. It was shown that medullary carcinomas significantly (p<0.001) expressed more E-cad and beta-cat than grade 3 ductal carcinomas. E-cad and beta-cat correlated with high expression of P53, of c-erbB, and of Ki-67 antigens, and with lack of hormone receptors antigenic sites (p<0.001). It was concluded that favourable prognosis and syncytial pattern of typical breast medullary carcinomas likely results, at least partly, from a particular expression of cell-cell adhesion molecules, significantly limiting tumour growth and efficiently mastering the tumour cell dissemination, opposing to high proliferative activity (grade 3).

  8. Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy.

    PubMed

    Sempowski, G D; Hale, L P; Sundy, J S; Massey, J M; Koup, R A; Douek, D C; Patel, D D; Haynes, B F

    2000-02-15

    The roles that thymus cytokines might play in regulating thymic atrophy are not known. Reversing thymic atrophy is important for immune reconstitution in adults. We have studied cytokine mRNA steady-state levels in 45 normal human (aged 3 days to 78 years) and 34 myasthenia gravis thymuses (aged 4 to 75 years) during aging, and correlated cytokine mRNA levels with thymic signal joint (sj) TCR delta excision circle (TREC) levels, a molecular marker for active thymopoiesis. LIF, oncostatin M (OSM), IL-6, M-CSF, and stem cell factor (SCF) mRNA were elevated in normal and myasthenia gravis-aged thymuses, and correlated with decreased levels of thymopoiesis, as determined by either decreased keratin-positive thymic epithelial space or decreased thymic sjTRECs. IL-7 is a key cytokine required during the early stages of thymocyte development. Interestingly, IL-7 mRNA expression did not fall with aging in either normal or myasthenia gravis thymuses. In vivo administration of LIF, OSM, IL-6, or SCF, but not M-CSF, i.p. to mice over 3 days induced thymic atrophy with loss of CD4+, CD8+ cortical thymocytes. Taken together, these data suggest a role for thymic cytokines in the process of thymic atrophy.

  9. Altered bone marrow lymphopoiesis and interleukin-6-dependent inhibition of thymocyte differentiation contribute to thymic atrophy during Trypanosoma cruzi infection.

    PubMed

    Carbajosa, Sofía; Gea, Susana; Chillón-Marinas, Carlos; Poveda, Cristina; Maza, Mª Carmen; Fresno, Manuel; Gironès, Núria

    2017-01-28

    Thymic atrophy occurs during infection being associated with apoptosis of double positive (DP) and premature exit of DP and double negative (DN) thymocytes. We observed for the first time that a significant bone marrow aplasia and a decrease in common lymphoid progenitors (CLPs) preceded thymic alterations in mice infected with Trypanosoma cruzi. In addition, depletion of the DN2 stage was previous to the DN1, indicating an alteration in the differentiation from DN1 to DN2 thymocytes. Interestingly, infected mice deficient in IL-6 expression showed higher numbers of DP and CD4+ thymocytes than wild type infected mice, while presenting similar percentages of DN1 thymocytes. Moreover, the drop in late differentiation stages of DN thymocytes was partially abrogated in comparison with wild type littermates. Thus, our results suggest that thymic atrophy involves a drop in CLPs production in bone marrow and IL-6-dependent and independent mechanisms that inhibits the differentiation of DN thymocytes.

  10. T cell dysfunction in the diabetes-prone BB rat. A role for thymic migrants that are not T cell precursors

    SciTech Connect

    Georgiou, H.M.; Lagarde, A.C.; Bellgrau, D.

    1988-01-01

    Diabetes-prone BB (BB-DP) rats express several T cell dysfunctions which include poor proliferative and cytotoxic responses to alloantigen. The goal of this study was to determine the origin of these T cell dysfunctions. When BB-DP rats were thymectomized, T cell depleted, and transplanted with neonatal thymus tissue from diabetes-resistant and otherwise normal DA/BB F1 rats, the early restoration of T cell function proceeded normally on a cell-for-cell basis; i.e., peripheral T cells functioned like those from the thymus donor. Because the thymus in these experiments was subjected to gamma irradiation before transplantation and there was no evidence of F1 chimerism in the transplanted BB-DP rats, it appeared that the BB-DP T cell precursors could mature into normally functioning T cells if the maturation process occurred in a normal thymus. If the F1 thymus tissue was treated with dGua before transplantation, the T cells of these animals functioned poorly like those from untreated BB-DP rats. dGua poisons bone marrow-derived cells, including gamma radiation-resistant cells of the macrophage/dendritic cell lineages, while sparing the thymic epithelium. Therefore, the reversal of the T cell dysfunction depends on the presence in the F1 thymus of gamma radiation-resistant, dGua-sensitive F1 cells. Conversely, thymectomized and T cell-depleted F1 rats expressed T cell dysfunction when transplanted with gamma-irradiated BB thymus grafts. T cell responses were normal in animals transplanted with dGua-treated BB thymus grafts. With increasing time after thymus transplantation, T cells from all animals gradually expressed the functional phenotype of the bone marrow donor. Taken together these results suggest that BB-DP bone marrow-derived cells that are not T cell precursors influence the maturation environment in the thymus of otherwise normal BB-DP T cell precursors.

  11. 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

  12. Advanced thymic cancer treated with carboplatin and paclitaxel in a patient undergoing hemodialysis.

    PubMed

    Miura, Satoru; Kagamu, Hiroshi; Sakai, Takehito; Nozaki, Koichiro; Asakawa, Katsuaki; Moro, Hiroshi; Okajima, Masaaki; Watanabe, Satoshi; Yamamoto, Suguru; Iino, Noriaki; Goto, Shin; Kazama, Junichiro James; Yoshizawa, Hirohisa; Narita, Ichiei

    2015-01-01

    A 53-year-old man with an asymptomatic anterior mediastinal tumor undergoing hemodialysis was referred to our institution. He was diagnosed with thymic basaloid carcinoma based on the findings of a chest tomography-guided biopsy and successfully treated with carboplatin (300 mg/m(2)/day) and paclitaxel (200 mg/m(2)/day) on day 1 for six three-week cycles. To our knowledge, this is the first report regarding the efficiency of a carboplatin dose-definition method based on the body surface area with paclitaxel in a hemodialysis patient. This report may therefore be useful for treating hemodialysis patients who are candidates for carboplatin and paclitaxel therapy.

  13. Thymic Selection of T-Cell Receptors as an Extreme Value Problem

    NASA Astrophysics Data System (ADS)

    Košmrlj, Andrej; Chakraborty, Arup K.; Kardar, Mehran; Shakhnovich, Eugene I.

    2009-08-01

    T lymphocytes (T cells) orchestrate adaptive immune responses upon activation. T-cell activation requires sufficiently strong binding of T-cell receptors on their surface to short peptides (p) derived from foreign proteins, which are bound to major histocompatibility gene products (displayed on antigen-presenting cells). A diverse and self-tolerant T-cell repertoire is selected in the thymus. We map thymic selection processes to an extreme value problem and provide an analytic expression for the amino acid compositions of selected T-cell receptors (which enable its recognition functions).

  14. 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

  15. Current evidence of epidermal barrier dysfunction and thymic stromal lymphopoietin in the atopic march.

    PubMed

    Li, Mei

    2014-09-01

    It has long been observed that the development of asthma, allergic rhinitis and food allergy are frequently preceded by atopic dermatitis, a phenomenon known as the "atopic march". Clinical, genetic and experimental studies have supported the fact that atopic dermatitis could be the initial step of the atopic march, leading to the subsequent development of other atopic diseases. This brief review will focus on the current evidence showing that epidermal barrier dysfunction and the keratinocyte-derived cytokine thymic stromal lymphopoietin play critical roles in the onset of the atopic march.

  16. A case of thymic Langerhans cell histiocytosis with diabetes insipidus as the first presentation.

    PubMed

    Chen, Xiaoyan; Huang, Xiaochun; Qiu, Yuan; Chen, Hanzhang; Fu, Yingyu; Li, Xinchun

    2013-03-01

    Langerhans cell histiocytosis (LCH) is an idiopathic group of reactive proliferative diseases linked to aberrant immunity, pathologically characterized by clonal proliferation of Langerhans cells. LCH rarely involves the thymus. We report a case of thymic LCH with diabetes insipidus as the first presentation, without evidence of myasthenia gravis and without evidenced involvement of the skin, liver, spleen, bones, lungs and superficial lymph nodes. This present case may have important clinical implications. In screening for LCH lesions, attention should be attached to rarely involved sites in addition to commonly involved organs. Follow-up and imageological examination are very important to a final diagnosis.

  17. The metabolic syndrome induces early changes in the swine renal medullary mitochondria.

    PubMed

    Eirin, Alfonso; Woollard, John R; Ferguson, Christopher M; Jordan, Kyra L; Tang, Hui; Textor, Stephen C; Lerman, Amir; Lerman, Lilach O

    2017-03-11

    The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (0.1 mg/kg SC q.d), and Lean controls (n = 7 each). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were measured in-vivo, whereas cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their renal blood flow and glomerular filtration rate were elevated. Blood oxygen level-dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb. MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis, and antioxidant defenses and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target.

  18. Lgr5 regulates the regeneration of lesioned nasal respiratory epithelium.

    PubMed

    Zhang, Yan-Qiang; Li, Peng; Zhang, Feng-Qin; Sun, Shao-Jun; Cao, Yin-Guang

    2016-12-09

    Nasal respiratory epithelium is a ciliated pseudostratified columnar epithelium. The cellular components of nasal respiratory epithelium include ciliated cells, goblet cells, and basal cells. Until now, our knowledge in the development of nasal respiratory epithelium is still limited and the cellular mechanism of regeneration is still elusive. In this study, we found that adult stem cell marker leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is expressed in the mice nasal respiratory epithelium. Both immunostaining and lineage tracing analysis indicated Lgr5 positive cells in the nasal respiratory epithelium are proliferative stem/progenitor cells. Using the Rosa-Tdtomato and Rosa26-DTR mice, we elucidated that Lgr5(+) cells participate in the regeneration of lesioned nasal respiratory epithelium, and this group of cells is necessary in the process of epithelium recovery. Using the in vitro culture system, we observed the formation of spheres from Lgr5(+) cells and these spheres have the capacity to generate other types of cells. Above all, this study reported a group of previously unidentified progenitor/stem cells in nasal respiratory epithelium, unveiling the potential cellular mechanism in nasal respiratory epithelium regeneration.

  19. Ability of transplanted cultured epithelium to respond to dermal papillae.

    PubMed

    Xing, L; Kobayashi, K

    2001-10-01

    Cultured epithelium has been used successfully in the treatment of extensive burns. Regenerated epidermis, however, lacks such as hair follicles and sweat glands that are common in mammalian skin. We attempted to determine whether cultured epithelium could be induced to form hair follicles by dermal papillae, which are most important for the morphogenesis and growth of hair follicles. We cultivated adult rat sole keratinocytes, obtained the cultured epithelium, and prepared recombinants consisting of cultured epithelium and fresh dermal papillae with or without the sole dermis. These recombinants were then transplanted underneath the dermis of the dorsal skin of syngeneic rats or athymic mice. Histologic examination revealed that the transplanted cultured epithelium formed the follicular structures with sebaceous gland-like structure following induction of the dermal papillae, especially when supported by the dermis. We concluded that transplanted cultured epithelium of adult rat sole keratinocytes can respond to growth signals from adult dermal papillae.

  20. Hypercalcemia of Malignancy in Thymic Carcinoma: Evolving Mechanisms of Hypercalcemia and Targeted Therapies

    PubMed Central

    2017-01-01

    Here we describe, to our knowledge, the first case where an evolution of mechanisms responsible for hypercalcemia occurred in undifferentiated thymic carcinoma and discuss specific management strategies for hypercalcemia of malignancy (HCM). Case Description. We report a 26-year-old male with newly diagnosed undifferentiated thymic carcinoma associated with HCM. Osteolytic metastasis-related hypercalcemia was presumed to be the etiology of hypercalcemia that responded to intravenous hydration and bisphosphonate therapy. Subsequently, refractory hypercalcemia persisted despite the administration of bisphosphonates and denosumab indicative of refractory hypercalcemia. Elevated 1,25-dihydroxyvitamin D was noted from the second admission with hypercalcemia responding to glucocorticoid administration. A subsequent PTHrP was also elevated, further supporting multiple mechanistic evolution of HCM. The different mechanisms of HCM are summarized with the role of tailoring therapies based on the particular mechanism underlying hypercalcemia discussed. Conclusion. Our case illustrates the importance of a comprehensive initial evaluation and reevaluation of all identifiable mechanisms of HCM, especially in the setting of recurrent and refractory hypercalcemia. Knowledge of the known and possible evolution of the underlying mechanisms for HCM is important for application of specific therapies that target those mechanisms. Specific targeting therapies to the underlying mechanisms for HCM could positively affect patient outcomes. PMID:28168064

  1. Murine thymic selection quantified using a unique method to capture deleted T cells.

    PubMed

    Stritesky, Gretta L; Xing, Yan; Erickson, Jami R; Kalekar, Lokesh A; Wang, Xiaodan; Mueller, Daniel L; Jameson, Stephen C; Hogquist, Kristin A

    2013-03-19

    Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77(GFP) transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the thymic cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim(-/-) mice had an increased number of GFP(hi) cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells.

  2. Hypercalcemia of Malignancy in Thymic Carcinoma: Evolving Mechanisms of Hypercalcemia and Targeted Therapies.

    PubMed

    Cheng, Cheng; Kuzhively, Jose; Baim, Sanford

    2017-01-01

    Here we describe, to our knowledge, the first case where an evolution of mechanisms responsible for hypercalcemia occurred in undifferentiated thymic carcinoma and discuss specific management strategies for hypercalcemia of malignancy (HCM). Case Description. We report a 26-year-old male with newly diagnosed undifferentiated thymic carcinoma associated with HCM. Osteolytic metastasis-related hypercalcemia was presumed to be the etiology of hypercalcemia that responded to intravenous hydration and bisphosphonate therapy. Subsequently, refractory hypercalcemia persisted despite the administration of bisphosphonates and denosumab indicative of refractory hypercalcemia. Elevated 1,25-dihydroxyvitamin D was noted from the second admission with hypercalcemia responding to glucocorticoid administration. A subsequent PTHrP was also elevated, further supporting multiple mechanistic evolution of HCM. The different mechanisms of HCM are summarized with the role of tailoring therapies based on the particular mechanism underlying hypercalcemia discussed. Conclusion. Our case illustrates the importance of a comprehensive initial evaluation and reevaluation of all identifiable mechanisms of HCM, especially in the setting of recurrent and refractory hypercalcemia. Knowledge of the known and possible evolution of the underlying mechanisms for HCM is important for application of specific therapies that target those mechanisms. Specific targeting therapies to the underlying mechanisms for HCM could positively affect patient outcomes.

  3. 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.

  4. 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.

  5. Controlled trial of a thymic hormone extract (Thymostimulin) in 'autoimmune' chronic active hepatitis.

    PubMed Central

    Hegarty, J E; Nouri Aria, K T; Eddleston, A L; Williams, R

    1984-01-01

    A randomised controlled trial of thymic hormone extracts (Thymostimulin) (1 mg/kg/day for seven days; 1 mg/kg/weekly thereafter) was undertaken in 30 patients (21 women, nine men) with treated, apparently inactive 'autoimmune' chronic active hepatitis during withdrawal of maintenance corticosteroid and azathioprine therapy. Reactivation of disease occurred in 26 patients (86%) during or after treatment withdrawal and was as frequent in the Thymostimulin treated (11 of 13; 84%) and untreated (15 of 17; 88%; p greater than 0.05) groups. Reactivation of disease was accompanied by a severe defect in concanavalin A induced suppressor cell activity, the magnitude of which was similar in the Thymostimulin treated and untreated groups (mean % suppression = 16.4 and 3.2 respectively; p greater than 0.05 vs 84.4 in control subjects). Further studies assessing the optimal dose, duration of treatment, and mode of administration are required to establish a therapeutic role for thymic hormone extracts in 'autoimmune' chronic active hepatitis. PMID:6230296

  6. Epigenetic Regulation of the Intestinal Epithelium

    PubMed Central

    Elliott, Ellen N.; Kaestner, Klaus H.

    2015-01-01

    The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprised of proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3 to 5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell. PMID:26220502

  7. Effluxing ABC Transporters in Human Corneal Epithelium

    PubMed Central

    Vellonen, Kati-Sisko; Mannermaa, Eliisa; Turner, Helen; Häkli, Marika; Wolosin, J. Mario; Tervo, Timo; Honkakoski, Paavo; Urtti, Arto

    2010-01-01

    ATP-binding cassette (ABC) transporters are able to efflux their substrate drugs from the cells. We compared expression of efflux proteins in normal human corneal epithelial tissue, primary human corneal epithelial cells (HCEpiC), and corneal epithelial cell culture model (HCE model) based on human immortal cell line. Expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1–6 (MRP1–6) and breast cancer resistance protein (BCRP) was studied using quantitative RT-PCR, Western blot, and immunohistochemistry. Only MRP1, MRP5, and BCRP were expressed in the freshly excised human corneal epithelial tissue. Expression of MRP1 and MRP5 was localized predominantly in the basal cells of the central cornea and limbus. Functional efflux activity was shown in the cell models, but they showed over-expression of most efflux transporters compared to that of normal corneal epithelium. In conclusion, MRP1, MRP5, and BCRP are expressed in the corneal epithelium, but MDR1, MRP2, MRP3, MRP4, and MRP6 are not significantly expressed. HCE cell model and commercially available primary cells deviate from this expression profile. PMID:19623615

  8. Acid phosphatase and lipid peroxidation in human cataractous lens epithelium.

    PubMed

    Vasavada, A R; Thampi, P; Yadav, S; Rawal, U M

    1993-12-01

    The anterior lens epithelial cells undergo a variety of degenerative and proliferative changes during cataract formation. Acid phosphatase is primarily responsible for tissue regeneration and tissue repair. The lipid hydroperoxides that are obtained by lipid peroxidation of polysaturated or unsaturated fatty acids bring about deterioration of biological membranes at cellular and tissue levels. Acid phosphatase and lipid peroxidation activities were studied on the lens epithelial cells of nuclear cataract, posterior subcapsular cataract, mature cataract, and mixed cataract. Of these, mature cataractous lens epithelium showed maximum activity for acid phosphatase (516.83 moles of p-nitrophenol released/g lens epithelium) and maximum levels of lipid peroxidation (86.29 O.D./min/g lens epithelium). In contrast, mixed cataractous lens epithelium showed minimum activity of acid phosphatase (222.61 moles of p-nitrophenol released/g lens epithelium) and minimum levels of lipid peroxidation (54.23 O.D./min/g lens epithelium). From our study, we correlated the maximum activity of acid phosphatase in mature cataractous lens epithelium with the increased areas of superimposed cells associated with the formation of mature cataract. Likewise, the maximum levels of lipid peroxidation in mature cataractous lens epithelium was correlated with increased permeability of the plasma membrane. Conversely, the minimum levels of lipid peroxidation in mixed cataractous lens epithelium makes us presume that factors other than lipid peroxidation may also account for the formation of mixed type of cataract.

  9. [Interlocking medullary nailing. Indications, technic with a new guiding instrument. Analysis of the 1st 50 operations].

    PubMed

    Berentley, G

    1976-01-01

    After a review of Küntsher's intramedullary nailing, the author resumed the informations about the interlocking medullary nail and its technique. A new device, as a guide instrument for easier application of the transverse bolts was constructed on the basis of authors concept. Using the new technique and guide instrument X-ray television controll is not necessary for placing the bolts in their right places through a small incision. The time of operation and the risk of infection was also diminished by the new technique. The indications for the interlocking medullary nailing have been completed by the author with the pathologic fractures. The first 50 cases, treated by the new technique of the interlocking medullary nailing are analysed and a few cases are reported in detail. Good results have been obtained as regards both the bone union and the functional results. Based on the good results the new technique of the interlocking medullary nailing is recommended by the author.

  10. Spastic quadriparesis caused by anomalous vertebral artery compression of spinal cord at the cervico-medullary junction.

    PubMed

    Betgeri, Somsharan Shankerappa; Rajesh, S; Adkatalwar, Vijayendra; Shiva, Meyyappan; Agrawal, Nitesh; Ramakrishnan, K G

    2015-02-01

    Vascular compression of medulla or spinal cord at the cervico-medullary junction has been commonly described in the literature and is often attributed to dolichoectasia of the vertebrobasilar arteries. We describe a case of anomalous course of the cervical segments of the bilateral vertebral arteries which were seen entering the spinal canal directly after exiting the transverse foramen of axis and causing significant cord compression at the cervico-medullary region leading to spastic quadriparesis.

  11. Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells.

    PubMed

    He, Wenjuan; Zhang, Min; Zhao, Min; Davis, Linda S; Blackwell, Timothy S; Yull, Fiona; Breyer, Matthew D; Hao, Chuan-Ming

    2014-02-01

    High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E2 (PGE2). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium.

  12. Increased Dietary Sodium Induces COX2 Expression by activating NFκB in Renal Medullary Interstitial Cells

    PubMed Central

    Zhao, Min; Davis, Linda S.; Blackwell, Timothy S.; Yull, Fiona; Breyer, Matthew D.; Hao, Chuan-Ming

    2013-01-01

    High salt diet induces renal medullary COX2 expression. Selective blockade of renal medullary COX2 activity in rats causes salt sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8% NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6J mice. Co-immunofluorescence using a COX2 antibody and antibodies against AQP2, ClC-K, AQP1 and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a 7 fold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of EGFP expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet fed C57Bl/6J mice with selective IκB kinase inhibitor IMD-0354 (8mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary PGE2. These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE2 synthesis in response to increased dietary sodium. PMID:23900806

  13. A rare case of medullary carcinoma of the colon presenting as intussusception in an adult with rectal bleeding.

    PubMed

    Jain, Shilpa; Jain, Ankur; Onizuka, Neil; Boukhar, Sarag A

    2014-11-01

    Medullary carcinoma is a recently recognized rare subtype of colorectal cancer resembling both poorly differentiated adenocarcinoma and neuroendocrine tumors. Medullary carcinoma most commonly presents in the proximal colon and can be differentiated from other right-sided malignant lesions by histology and immunochemical markers. We present here a rare case of an adult patient with rectal bleeding who was found to have an intussusception due to underlying medullary carcinoma of the splenic flexure. A 72-year-old woman presented to our GI clinic with rectal bleeding. Colonoscopy revealed a necrotic mass of the sigmoid colon, later determined by CT to be a colo-colonic intussusception at the level of the splenic flexure. Patient underwent diagnostic laparoscopy with findings of a large splenic flexure mass, which was resected and found to be medullary carcinoma of the colon. The tumor was poorly differentiated and exhibited microsatellite instability but was discovered at an early stage and thus did not require any adjuvant chemotherapy. Unlike most previously reported cases of medullary carcinoma, our patient presented with a left sided tumor. To our knowledge, this is the first report of a medullary colon cancer presenting with intussusception.

  14. Impact of nitric-oxide-mediated vasodilation and oxidative stress on renal medullary oxygenation: a modeling study

    PubMed Central

    Fry, Brendan C.; Edwards, Aurélie

    2015-01-01

    The goal of this study was to investigate the effects of nitric oxide (NO)-mediated vasodilation in preventing medullary hypoxia, as well as the likely pathways by which superoxide (O2−) conversely enhances medullary hypoxia. To do so, we expanded a previously developed mathematical model of solute transport in the renal medulla that accounts for the reciprocal interactions among oxygen (O2), NO, and O2− to include the vasoactive effects of NO on medullary descending vasa recta. The model represents the radial organization of the vessels and tubules, centered around vascular bundles in the outer medulla and collecting ducts in the inner medulla. Model simulations suggest that NO helps to prevent medullary hypoxia both by inducing vasodilation of the descending vasa recta (thus increasing O2 supply) and by reducing the active sodium transport rate (thus reducing O2 consumption). That is, the vasodilative properties of NO significantly contribute to maintaining sufficient medullary oxygenation. The model further predicts that a reduction in tubular transport efficiency (i.e., the ratio of active sodium transport per O2 consumption) is the main factor by which increased O2− levels lead to hypoxia, whereas hyperfiltration is not a likely pathway to medullary hypoxia due to oxidative stress. Finally, our results suggest that further increasing the radial separation between vessels and tubules would reduce the diffusion of NO towards descending vasa recta in the inner medulla, thereby diminishing its vasoactive effects therein and reducing O2 delivery to the papillary tip. PMID:26831340

  15. Glioblastoma multiforme in conus medullaris with intracranial metastasis after postoperative adjuvant therapy

    PubMed Central

    Yan, Chengrui; Kong, Xiangyi; Yin, Hua; Wang, Yu; He, Huayu; Zhang, Hui; Gao, Jun; Li, Yongning; Ma, Wenbin

    2017-01-01

    Abstract Spinal glioblastoma multiforme is not common among spinal cord tumors. According to our literature review, only 27 cases originating from the conus medullaris were reported. We herein reported a case of a 10-year-old child diagnosed with glioblastoma multiforme. The patient received adjuvant radiotherapy and standard temozolomide chemotherapy after total excision. Intracranial lesions were found 1 month after postoperative adjuvant therapy. We described the clinical characteristics and postoperative therapy of the patient, and reviewed all of the published cases of conus medullaris glioblastoma. Location, age, leptomeningeal spread, and secondary hydrocephalus may be predictive factors. Immunohistochemical factors such as p53 and Ki-67 are also important. Combined treatment of surgery and postoperative adjuvant therapy is commonly used, but is controversial. PMID:28353599

  16. Modulation of pressure-natriuresis by renal medullary reactive oxygen species and nitric oxide.

    PubMed

    O'Connor, Paul M; Cowley, Allen W

    2010-04-01

    The renal pressure-natriuresis mechanism is the dominant controller of body fluid balance and long-term arterial pressure. In recent years, it has become clear that the balance of reactive oxygen and nitrogen species within the renal medullary region is a key determinant of the set point of the renal pressure-natriuresis curve. The development of renal medullary oxidative stress causes dysfunction of the pressure-natriuresis mechanism and contributes to the development of hypertension in numerous disease models. The purpose of this review is to point out the known mechanisms within the renal medulla through which reactive oxygen and nitrogen species modulate the pressure-natriuresis response and to update the reader on recent advances in this field.

  17. Sleep and dream suppression following a lateral medullary infarct: a first-person account.

    PubMed

    Allan Hobson, J

    2002-09-01

    Consciousness can be studied only if subjective experience is documented and quantified, yet first-person accounts of the effects of brain injury on conscious experience are as rare as they are potentially useful. This report documents the alterations in waking, sleeping, and dreaming caused by a lateral medullary infarct. Total insomnia and the initial suppression of dreaming was followed by the gradual recovery of both functions. A visual hallucinosis during waking that was associated with the initial period of sleep and dream suppression is described in detail. Since the changes in sleep and their recovery are comparable to results of animal experiments, it can be concluded that damage to the medullary brain stem causes extreme but short-lived alterations in conscious state and that substantial recovery occurs even though the damage to the brain stem endures.

  18. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma

    PubMed Central

    Asa, Sylvia L.; Dralle, Henning; Elisei, Rossella; Evans, Douglas B.; Gagel, Robert F.; Lee, Nancy; Machens, Andreas; Moley, Jeffrey F.; Pacini, Furio; Raue, Friedhelm; Frank-Raue, Karin; Robinson, Bruce; Rosenthal, M. Sara; Santoro, Massimo; Schlumberger, Martin; Shah, Manisha; Waguespack, Steven G.

    2015-01-01

    Introduction: The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. Methods: The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. Results: The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. Conclusions: The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice. PMID:25810047

  19. Perfusion weighted imaging in the assessment of the pathology and outcomes of lateral medullary infarction

    PubMed Central

    Zhang, Dao P.; Zhang, Hong T.; Yin, Suo; Yan, Fu L.

    2016-01-01

    This series case report aimed to elucidate the underlying pathology and outcomes of lateral medullary infarction (LMI) using perfusion weighted imaging (PWI). Four patients were diagnosed with LMI based on high-field diffusion-weighted magnetic resonance imaging (MRI-DWI) and PWI. The national institutes of health stroke scale (NIHSS) scores were recorded on days 1, 7, and 30, and the Barthel index was assessed on days 7 and 30. Three patients exhibited relative regional hypoperfusion of medullary lesion in the perfusion maps. Two cases exhibited ipsilateral hypoperfusion in the inferior cerebellum, whereas one patient exhibited a relatively regional hyperperfusion in the medulla oblongata. The LMI patients with a high NIHSS score and low Barthel index on days 7 and 30 exhibited regional hypoperfusion. This report of 4 LMI cases provides preliminary evidence that regional hypoperfusion may contribute to worse outcomes in LMI. PMID:27744467

  20. Methodology and dosimetry in adrenal medullary imaging with iodine-131 MIBG

    SciTech Connect

    Lindberg, S.; Fjaelling, M.J.; Jacobsson, L.; Jansson, S.; Tisell, L.E.

    1988-10-01

    Iodine-131 MIBG scans were performed in 59 patients in order to localize intra- or extra-adrenal pheochromocytomas (pheos), or to visualize hyperplastic adrenal medulla. Images were obtained from the pelvis to the base of the skull on Days 1, 4, and 7 after tracer injection. The 15 patients with histopathologic confirmation of adrenal medullary disease had positive scans. In three of these, the pheos were visible only on images obtained on Day 7. One scan was false negative. After excluding patients with a predisposition to adrenal medullary disease, nine subjects (28%) without verification of pheo displayed adrenal uptake of the radionuclide. Late images produce a low rate of false-negative scans; the background activity diminishes and even small pheos can be detected. In order to increase the quality of late images, 40 MBq (/sup 131/I)MIBG was used instead of 20 MBq. The dosimetric considerations are discussed.

  1. Paroxysmal sneezing at the onset of lateral medullary syndrome: cause or consequence?

    PubMed

    Swenson, A J; Leira, E C

    2007-04-01

    Sneezing is known to precede lateral medullary syndrome (LMS). It is usually interpreted as the precipitating cause for a vertebral artery dissection that subsequently causes LMS. Through two case reports and a literature review, we aim to challenge the concept that sneezing at the onset of LMS implies that a dissection is the underlying cause. An 82-year-old man and a 54-year-old man both reported unprovoked explosive pathological sneezing at the onset of the LMS without any delay between sneezing and the other LMS symptoms. Both denied neck trauma or neck pain. There was no conclusive evidence for vertebral artery dissection in either case. Paroxysmal sneezing can be an initial manifestation of lateral medullary ischemia and may not necessarily indicate an underlying vertebral artery dissection as the cause.

  2. Renal medullary carcinoma as an incidental finding in a horseshoe kidney: case report and literature review.

    PubMed

    Molgat, Gilles; Afrouzian, Marjan; Trpkov, Kiril

    2005-10-01

    Renal medullary carcinoma is rare and extremely aggressive neoplasm that typically affects young patients of African decent who demonstrate sickle cell trait or disease. Since the original description in 1995, only few cases have been reported outside the United States. A 29 year-old Canadian male of Afro-Caribbean decent with sickle cell trait developed right-sided hemiparesis due to brain infarct. During the clinical work-up, a 3 cm renal tumor was detected in a horseshoe kidney. The patient died suddenly 2 weeks after the presentation of massive non-neoplastic pulmonary thromboembolism, confirmed at autopsy. The final diagnosis of renal medullary carcinoma was established after the autopsy. Due to the small size of the tumor and the limited metastatic spread only to the regional lymph nodes, the tumor was considered an incidental finding, and not the primary cause of patient's death.

  3. Effect of hypocapnia on ventral medullary blood flow and pH during hypoxia in cats

    SciTech Connect

    Davies, D.G.; Nolan, W.F.; Sexton, J.A.

    1986-07-01

    Ventral medullary blood flow was measured in 33 chloralose-urethan-anesthetized cats during 60 min of isocapnia-hypoxia, mild hypocapnia-hypoxia, or severe hypocapnia-hypoxia. In an additional group of six animals the pH of ventral medullary extracellular fluid (ECF) was determined during mild hypocapnia-hypoxia. The increase in blood flow during hypoxia was reduced by mild hypocapnia and eliminated by severe hypocapnia. With the exception of an initial decrease in ECF H(+) concentration, which occurred during the first 10 min of mild hypocapnia-hypoxia, ECF H(+) concentration increased progressively throughout the exposure and recovery periods and was significantly elevated from the control value by the first 10 min of the recovery period. The results suggest that hypocapnia affects the hypoxic cerebrovascular response of the ventral medulla and that this phenomenon could affect the regulation of ventral medudllary ECF H(+) concentration. 17 references.

  4. Renal medullary ETB receptors produce diuresis and natriuresis via NOS1.

    PubMed

    Nakano, Daisuke; Pollock, Jennifer S; Pollock, David M

    2008-05-01

    Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ET(B) receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ET(B) receptor stimulation in vivo. Infusion of the ET(B) receptor agonist sarafotoxin S6c (S6c: 0.45 microg x kg(-1) x h(-1)) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ET(B) receptor-deficient rats. Coinfusion of N(G)-propyl-l-arginine (10 microg x kg(-1) x h(-1)), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 microg x kg(-1) x h(-1)) or RQIKIWFQNRRMKWKK-LRK(5)H-amide (18 microg x kg(-1) x h(-1)), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ET(B) receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

  5. Long-term measurement of renal cortical and medullary tissue oxygenation and perfusion in unanesthetized sheep.

    PubMed

    Calzavacca, Paolo; Evans, Roger G; Bailey, Michael; Lankadeva, Yugeesh R; Bellomo, Rinaldo; May, Clive N

    2015-05-15

    The role of renal cortical and medullary hypoxia in the development of acute kidney injury is controversial, partly due to a lack of techniques for the long-term measurement of intrarenal oxygenation and perfusion in conscious animals. We have, therefore, developed a methodology to chronically implant combination probes to chronically measure renal cortical and medullary tissue perfusion and oxygen tension (tPO2) in conscious sheep and evaluated their responsiveness and reliability. A transit-time flow probe and a vascular occluder were surgically implanted on the left renal artery. At the same operation, dual fiber-optic probes, comprising a fluorescence optode to measure tPO2 and a laser-Doppler probe to assess tissue perfusion, were inserted into the renal cortex and medulla. In recovered conscious sheep (n = 8) breathing room air, mean 24-h cortical and medullary tPO2 were similar (31.4 ± 0.6 and 29.7 ± 0.7 mmHg, respectively). In the renal cortex and medulla, a 20% reduction in renal blood flow (RBF) decreased perfusion (14.6 ± 8.6 and 41.2 ± 8.5%, respectively) and oxygenation (48.1 ± 8.5 and 72.4 ± 8.5%, respectively), with greater decreases during a 50% reduction in RBF. At autopsy, minimal fibrosis was observed around the probes. In summary, we have developed a technique to chronically implant fiber-optic probes in the renal cortex and medulla for recording tissue perfusion and oxygenation over many days. In normal resting conscious sheep, cortical and medullary tPO2 were similar. The responses to and recovery from renal artery occlusion, together with the consistent measurements over a 24-h period, demonstrate the responsiveness and stability of the probes.

  6. Acute increases of renal medullary osmolality stimulate endothelin release from the kidney.

    PubMed

    Boesen, Erika I; Pollock, David M

    2007-01-01

    Experiments conducted in vitro suggest that high osmolality stimulates endothelin production and release by renal tubular epithelial cells. Whether hyperosmotic solutions exert similar effects in vivo is unknown. Therefore, we tested the hypothesis that increasing renal medullary osmolality enhances urinary excretion of endothelin in anesthetized rats. Isosmotic NaCl (284 mosmol/kgH(2)O) was infused either intravenously (1.5 ml/h) or into the renal medullary interstitium (0.5 ml/h) during a 1-h equilibration period and 30-min baseline urine collection period, followed by either isosmotic or hyperosmotic NaCl (921 or 1,664 mosmol/kgH(2)O iv; 1,714 mosmol/kgH(2)O into renal medulla) for two further 30-min periods. Compared with isosmotic NaCl, infusion of hyperosmotic NaCl into the renal medulla significantly increased the endothelin excretion rate (P < 0.05; from 0.30 +/- 0.02 to 0.49 +/- 0.03 fmol/min). Intravenous infusion of hyperosmotic NaCl also significantly increased endothelin excretion rate in a concentration-dependent manner (from 0.79 +/- 0.07 to 1.77 +/- 0.16 fmol/min and 0.59 +/- 0.04 to 1.11 +/- 0.08 fmol/min for 1,664 and 921 mosmol/kgH(2)O, respectively). To differentiate between effects of osmolality and NaCl, similar experiments were performed using mannitol solutions. Compared with isosmotic mannitol, medullary interstitial infusion of hyperosmotic mannitol (1,820 mosmol/kgH(2)O) significantly increased endothelin excretion rate (P < 0.05; from 0.54 +/- 0.03 to 0.94 +/- 0.12 fmol/min). Thus exposing the renal medulla to hyperosmotic concentrations of either NaCl or mannitol stimulates endothelin release in vivo, consistent with medullary osmolality being an important regulator of renal endothelin synthesis.

  7. An investigation of the conus medullaris termination level during the period of fetal development to adulthood.

    PubMed

    Malas, M A; Salbacak, A; Büyükmumcu, M; Seker, M; Köylüoğlu, B; Karabulut, A K

    2001-10-01

    The spinal cord fills the length of the vertebral canal at the early period of intrauterine term. It is reported to extend to the level of the third lumbar vertebra at birth, because the vertebral column is growing more rapidly in the longitudinal direction than the spinal cord. The present investigation aimed to determine the changes in the termination level of conus medullaris (TLCM) from fetus to adulthood in a total of 285 individuals who had no defects in the central or peripheral nervous system, and were obtained from our Faculties of Medicine and Konya Maternity Hospital between 1992-1995. The age distribution was as follows: 36 fetuses, 20 prematures and 50 neonates, 51 children aged 1 to 7 years and 128 adults aged 15 to 68 years. In this study, for fetuses, prematures, neonates and children the TLCM was determined using ultrasonography. In addition, microdissection was used in fetuses to confirm the results obtained from the above technique. Also, magnetic resonance imaging was used in adults. During fetal life the end of the conus altered its levels from S5 to L3 vertebrae. The tip of the conus medullaris of the prematures and neonates ranged from L1 to L3 vertebrae. The tip of the conus medullaris in the children lay between the Th12 and L3 vertebrae, and in the adults it was between the Th12 and L2 vertebrae. There were slight differences between the prematures and neonates in terms of the TLCM. We concluded that there are differences in the TLCM between the age groups and therefore, especially in prematures and infants the determination of the tip of conus medullaris might be important for preventing postoperative neurological complications.

  8. [Medullary layer activity of the rat adrenals after a flight on the Kosmos-1129 biosatellite].

    PubMed

    Kvetnanský, R; Blazicek, P; Tigranian, R A

    1982-01-01

    After a 18.5-day space flight on Cosmos-1129 rat adrenals were investigated for the concentration of catecholamines and activity of enzymes involved in their synthesis, i.e. tyrosine hydroxylase, dopamine-beta-hydroxylase, and phenyl ethanol amine-N-methyl transferase. It was found that inflight the sympatho-adreno-medullary system of rats was not exposed to a prolonged or strong stressogenic effect. Postflight the rats showed an increased reactivity to the immobilization stress.

  9. Medullary nephrocalcinosis and pancreatic calcifications demonstrated by ultrasound and CT in infants after treatment with ACTH

    SciTech Connect

    Rausch, H.P.; Hanefield, F.; Kaufmann, B.J.

    1984-10-01

    Thirteen patients who had undergone prolonged adrenocorticotropic hormone (ACTH) therapy for infantile spasms or encephalopathy were examined with sonography. Nine patients were seen to have appearances characteristic of medullary nephrocalcinosis. Five patients also showed a homogeneously increased echogenicity of the whole pancreas on sonography, and one of these showed increased density on computed tomography. Density measurements were in the range of calcific arterial within the papillae and pancreatic tissue. On abdominal survey radiographs, even in retrospect, no calcifications could be recognized.

  10. Donor lymphocyte count and thymic activity predict lymphocyte recovery and outcomes after matched-sibling hematopoietic stem cell transplant.

    PubMed

    McIver, Zachariah; Melenhorst, Jan Joseph; Wu, Colin; Grim, Andrew; Ito, Sawa; Cho, Irene; Hensel, Nancy; Battiwalla, Minoo; Barrett, Austin John

    2013-03-01

    Delayed immune recovery is a characteristic feature of allogeneic hematopoietic stem cell transplantation in adult recipients. Although recipient thymic T-cell neogenesis contributes to T-cell regeneration after transplantation, thymic recovery in the transplant recipient decreases with increasing age, and is diminished by intensive preconditioning regimens and graft-versus-host disease. In adult recipients, most events that determine transplant success or failure occur during the period when the majority of circulating T cells is derived from the donor's post thymic T-cell repertoire. As a result, the make-up of the donor lymphocyte compartment may strongly influence immune recovery and transplant outcomes. The aim of this study was to examine donor lymphocyte counts in a series of patients undergoing an allogeneic hematopoietic stem cell transplant to identify the potential contribution of donor regulatory and conventional T lymphocyte populations to immune recovery and transplant outcomes. We examined donor lymphocyte subset counts in relation to post-transplant lymphocyte recovery and transplant events in 220 consecutive myeloablative, T-cell-depleted, HLA-identical sibling hematopoietic stem cell transplant recipients with hematologic malignancies. In a multivariate analysis, absolute numbers of donor CD4(+) recent thymic emigrants were associated with overall survival (P=0.032). The donors' absolute lymphocyte count and thymic production of regulatory T cells were both associated with extensive chronic graft-versus-host disease (P=0.002 and P=0.022, respectively). In conclusion, these results identify donor immune characteristics that are associated with lymphocyte recovery, extensive chronic graft-versus-host disease, and survival in the recipient following allogeneic hematopoietic stem cell transplantation. The study reported here was performed using peripheral blood samples drawn from donors and patients enrolled in the ClinicalTrials.gov-registered trials

  11. Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner.

    PubMed

    He, Qiuming; Morillon, Y Maurice; Spidale, Nicholas A; Kroger, Charles J; Liu, Bo; Sartor, R Balfour; Wang, Bo; Tisch, Roland

    2013-12-15

    Inefficient thymic negative selection of self-specific T cells is associated with several autoimmune diseases, including type 1 diabetes. The factors that influence the efficacy of thymic negative selection, as well as the kinetics of thymic output of autoreactive T cells remain ill-defined. We investigated thymic production of β cell-specific T cells using a thymus-transplantation model. Thymi from different aged NOD mice, representing distinct stages of type 1 diabetes, were implanted into NOD.scid recipients, and the diabetogenicity of the resulting T cell pool was examined. Strikingly, the development of diabetes-inducing β cell-specific CD4(+) and CD8(+) T cells was regulated in an age-dependent manner. NOD.scid recipients of newborn NOD thymi developed diabetes. However, recipients of thymi from 7- and 10-d-old NOD donor mice remained diabetes-free and exhibited a progressive decline in islet infiltration and β cell-specific CD4(+) and CD8(+) T cells. A similar temporal decrease in autoimmune infiltration was detected in some, but not all, tissues of recipient mice implanted with thymi from NOD mice lacking expression of the autoimmune regulator transcription factor, which develop multiorgan T cell-mediated autoimmunity. In contrast, recipients of 10 d or older thymi lacked diabetogenic T cells but developed severe colitis marked by increased effector T cells reactive to intestinal microbiota. These results demonstrate that thymic development of autoreactive T cells is limited to a narrow time window and occurs in a reciprocal manner compared with colonic microbiota-responsive T cells in NOD mice.

  12. 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

  13. Persistent disruption of ciliated epithelium following paediatric lung transplantation.

    PubMed

    Thomas, Biju; Aurora, Paul; Spencer, Helen; Elliott, Martin; Rutman, Andrew; Hirst, Robert A; O'Callaghan, Christopher

    2012-11-01

    It is unclear whether ciliary function following lung transplantation is normal or not. Our aim was to study the ciliary function and ultrastructure of epithelium above and below the airway anastomosis and the peripheral airway of children following lung transplantation. We studied the ciliary beat frequency (CBF) and beat pattern, using high speed digital video imaging and ultrastructure by transmission electron microscopy, of bronchial epithelium from above and below the airway anastomosis and the peripheral airway of 10 cystic fibrosis (CF) and 10 non-suppurative lung disease (NSLD) paediatric lung transplant recipients. Compared to epithelium below the anastomosis, the epithelium above the anastomosis in the CF group showed reduced CBF (median (interquartile range): 10.5 (9.0-11.4) Hz versus 7.4 (6.4-9.2) Hz; p<0.01) and increased dyskinesia (median (IQR): 16.5 (12.9-28.2)% versus 42.2 (32.6-56.4)%; p<0.01). In both CF and NSLD groups, compared with epithelium above the anastomosis, the epithelium below the anastomosis showed marked ultrastructural abnormalities (median duration post-transplant 7-12 months). Ciliary dysfunction is a feature of native airway epithelium in paediatric CF lung transplant recipients. The epithelium below the airway anastomosis shows profound ultrastructural abnormalities in both CF and NSLD lung transplant recipients, many months after transplantation.

  14. Challenges and opportunities for tissue-engineering polarized epithelium.

    PubMed

    Paz, Ana C; Soleas, John; Poon, James C H; Trieu, Dennis; Waddell, Thomas K; McGuigan, Alison P

    2014-02-01

    The epithelium is one of the most important tissue types in the body and the specific organization of the epithelial cells in these tissues is important for achieving appropriate function. Since many tissues contain an epithelial component, engineering functional epithelium and understanding the factors that control epithelial maturation and organization are important for generating whole artificial organ replacements. Furthermore, disruption of the cellular organization leads to tissue malfunction and disease; therefore, engineered epithelium could provide a valuable in vitro model to study disease phenotypes. Despite the importance of epithelial tissues, a surprisingly limited amount of effort has been focused on organizing epithelial cells into artificial polarized epithelium with an appropriate structure that resembles that seen in vivo. In this review, we provide an overview of epithelial tissue organization and highlight the importance of cell polarization to achieve appropriate epithelium function. We next describe the in vitro models that exist to create polarized epithelium and summarize attempts to engineer artificial epithelium for clinical use. Finally, we highlight the opportunities that exist to translate strategies from tissue engineering other tissues to generate polarized epithelium with a functional structure.

  15. Characterization of the Immunochemical Forms of Calcitonin Released by a Medullary Thyroid Carcinoma in Tissue Culture

    PubMed Central

    Goltzman, David; Tischler, Arthur S.

    1978-01-01

    Immunoreactive calcitonin released by a medullary thyroid carcinoma in tissue culture has been found to exhibit heterogeneity when analyzed by gel chromatography and radioimmunoassay, in a pattern analogous to that seen in the circulation of the patient from whom the neoplasm was removed. To examine the cause of the heterogeneity, the immunoreactive material released by the tumor into tissue culture medium was further analyzed by gel electrophoresis in the presence of the protein denaturant 8 M urea, by gel chromatography after reduction and alkylation, by affinity chromatography on concanavalin A-agarose, and by bioassay in a renal adenylyl cyclase system of enhanced sensitivity. The results suggest that the larger immunochemical forms of calcitonin described in the circulation of patients with medullary thyroid carcinoma may be released directly from the neoplasm and need not derive from peripheral metabolism of the monomer. It could be demonstrated that a major proportion of the immunochemical enlargement is dependent upon intermolecular disulfide bridge formation whereas aggregation or non-convalent protein binding account for a smaller component of the heterogeneity. In view of the absence of binding of the immunoreactive material to the lectin agarose, carbohydrate side chains, at least of the α-d glucosyl variety, do not seem to contribute significantly to calcitonin enlargement. Additionally, the studies indicate that, at least by in vitro assay, the larger immunochemical forms of calcitonin, representing the majority of the immunoreactivity released by a medullary thyroid carcinoma, are biologically inactive. PMID:621283

  16. Adrenal Medullary Grafts Restore Olfactory Deficits and Catecholamine Levels of 6-OHDA Amygdala Lesioned Animals

    PubMed Central

    Fernández-Ruiz, Juan; Guzmán, Rubén; Martínez, María Dolores; Miranda, María Isabel; Bermúdez-Rattoni, Federico; Drucker-Colín, René

    1993-01-01

    Aside from motor and cognitive deficits, Parkinson patients also manifest a little-studied olfactory deficit. Since in Parkinson's disease there is a dopamine depletion of the amygdala due to mesocorticolimbic system degeneration, we decided to test olfactory and taste performance of 6-OHDA amygdala lesioned rats, as well as the possible restoration of either function with adrenal medullary transplants. Two 6-OHDA lesioned groups and one control group were tested in the potentiation of odor by taste aversion paradigm. On taste aversion none of the groups showed any impairment. In contrast, the 6-OHDA lesioned rats showed a marked impairment in olfactory aversion. At this point, one of the lesioned groups received a bilateral adrenal medullary graft within the lesioned area. After two months, all groups were submitted again to the behavioral paradigm. Taste remained unaffected, but the lesioned only group did not recover either olfactory aversion or normal catecholamine levels. The grafted group, on the other hand, restored olfactory aversion and catecholamine levels. It can be concluded from this study that catecholamine depletion of the amygdala is sufficient to produce a selective olfactory deficit, not accompanied by taste impairments, and that such a deficit can be reversed by adrenal medullary transplants, which in turn restore catecholamine levels. PMID:7948179

  17. Cyst of the medullary conus: malformative persistence of terminal ventricle or compressive dilatation?

    PubMed

    Celli, Paolo; D'Andrea, Giancarlo; Trillò, Giuseppe; Roperto, Raffaelino; Acqui, Michele; Ferrante, Luigi

    2002-03-01

    The ventriculus terminalis is a cavity situated at the level of the conus medullaris, enclosed by ependymal tissue and normally present as a virtual cavity or as a mere ependymal residue. In rare cases, and almost exclusively in pediatric age, the ventriculus terminalis may be visualized by radiological investigations, either by sonography or MRI, and represents a transient finding in children under 5 years of age. In pathological conditions, a cyst of the conus medullaris is probably the result of a persistent ventriculus terminalis and is usually described in children in association with a tethered cord; in a very limited number of cases, it has been described in adults whose clinical symptoms consist of neurological and/or sphincter disturbances not associated with other pathologies. The authors describe the case of a 42-year-old female with a cyst of the conus whose only symptom was imperious minction; she had been suffering from these urinary disorders for many years. The patient was not operated on because the clinical situation remained stable, without modifications of the MRI in follow-up over a 6-year period. The authors therefore suggest that in adult patients, a cyst of the conus medullaris is probably an expression of malformative persistence of the fifth ventricle and does not necessarily have a progressive evolution.

  18. Intermittent pneumatic soft tissue compression: Changes in periosteal and medullary canal blood flow.

    PubMed

    Park, Sang-Hyun; Silva, Mauricio

    2008-04-01

    We previously demonstrated that the use of intermittent pneumatic soft tissue compression (IPC) treatment enhanced fracture healing in an animal model, but the exact mechanism remained unknown. The purpose of this study was to determine the local and remote effects of IPC treatment on blood flow within the medullary canal and outside the periosteum of mid-tibial diaphysis. Blood flow was measured with a Laser Doppler blood flow meter in the lower limbs of 21 rabbits. Laser probes were inserted at three different sites of the mid-diaphysis on the right tibia: in the medullary canal (n = 21), outside the periosteum on the lateral side (n = 11), and outside the periosteum on the medial side (n = 10). IPC was applied for 30 min through cuffs that were placed around the feet and the lower part of the calf. While applying IPC to the left leg, no changes in blood flow occurred on the right leg (remote changes). However, while applying IPC to the right leg, significant localized changes were found on the right leg, including 47 and 89% increases in total amount of blood flow outside the lateral and medial periosteum, respectively. Although an altered blood flow pattern was observed in the medullary canal, no significant change in total amount of blood flow was observed at this level. In summary, the present study demonstrated that the use of IPC in an intact bone model results in a significant local increase in total blood flow, with minimal measurable effects on the contralateral limb.

  19. [Two cases with unilateral lateral medullary infarction associated with central respiratory failure].

    PubMed

    Arai, Noritoshi; Obuchi, Maiko; Matsuhisa, Akiyuki; Takahashi, Yuji; Takatsu, Masami

    2008-05-01

    We reported two patients with unilateral lateral medullary infarction involving severe, long-term respiratory failure. The first patient is an 86-year-old man presenting with gait disturbance, hoarseness and dysphagia. A right lateral medullary infarction was revealed by brain MRI. On the fifth hospitalized day, acute respiratory failure occurred. His condition failed to recover, and he was still attached to a ventilator 10 months after the onset. The second patient is an 83-year-old woman mainly presenting with dysphagia. A tiny infarction in the right lateral medulla was revealed by brain MRI. On the third day after the onset, acute respiratory failure occurred, which was not changed even at 8 months later. Although the symptoms and the lesion in the medulla were quite different between two patients, dysphagia and respiratory failure occurred in both patients. Therefore, it is postulated that the lesion that causes dyspnea may be approximate to the lesion that causes dysphagia. Many previously reported cases presenting respiratory failure seemed to suffer swallowing difficulty as well. We conclude that elderly patients suffering from unilateral lateral medullary infarction with dysphagia can present respiratory failure a few days after the onset, demonstrating the need to observe them under intensive attention.

  20. The unique organization of filamentous actin in the medullary canal of the medulla oblongata.

    PubMed

    Tan, Bai-Hong; Guo, Chun-Yan; Xiong, Tian-Qing; Chen, Ling-Meng; Li, Yan-Chao

    2017-01-24

    In the central canal, F-actin is predominantly localized in the apical region, forming a ring-like structure around the circumference of the lumen. However, an exception is found in the medulla oblongata, where the apical F-actin becomes interrupted in the ventral aspect of the canal. To clarify the precise localization of F-actin, the fluorescence signals for F-actin were converted to the peroxidase/DAB reaction products in this study by a phalloidin-based ultrastructural technique, which demonstrated that F-actin is located mainly in the microvilli and terminal webs in the ependymocytes. It is because the ventrally oriented ependymocytes do not possess well-developed microvilli or terminal web that led to a discontinuous labeling of F-actin in the medullary canal. Since spinal motions can change the shape and size of the central canal, we next examined the cytoskeletons in the medullary canal in both rats and monkeys, because these two kinds of animals show different kinematics at the atlanto-occipital articulation. Our results first demonstrated that the apical F-actin in the medullary canal is differently organized in the animals with different head-neck kinemics, which suggests that the mechanic stretching of spinal motions is capable of inducing F-actin reorganization and the subsequent cell-shape changes in the central canal.

  1. Osmolar regulation of endothelin-1 production by rat inner medullary collecting duct.

    PubMed Central

    Kohan, D E; Padilla, E

    1993-01-01

    Recent evidence has implicated endothelin-1 (ET-1) as an autocrine inhibitor of inner medullary collecting duct (IMCD) sodium and water transport. The regulators of IMCD ET-1 production are, however, largely unknown. Because of the unique hypertonic environment of the IMCD, the effect of varying extracellular tonicity on IMCD ET-1 production was evaluated. Increasing media osmolality from 300 to 450 mosmol with NaCl or mannitol but not urea caused a marked dose- and time-dependent reduction in ET-1 release by and ET-1 mRNA in cultured rat IMCD cells. In contrast, increasing osmolality had no effect on ET-1 production by rat endothelial or mesangial cells. To see if ET-1 varies in a similar manner in vivo, ET-1 production was assessed in volume expanded (lower medullary tonicity) or volume depleted (high medullary tonicity) rats. Urinary ET-1 excretion and inner medulla ET-1 mRNA were significantly reduced in volume depleted as compared to volume expanded animals. These results indicate that extracellular sodium concentration inhibits ET-1 production specifically in IMCD cells. We speculate that extracellular sodium concentration, via regulation of ET-1 production, provides a link between volume status and IMCD sodium and water reabsorption. PMID:8450052

  2. Bronchial epithelium in children: a key player in asthma.

    PubMed

    Carsin, Ania; Mazenq, Julie; Ilstad, Alexandra; Dubus, Jean-Christophe; Chanez, Pascal; Gras, Delphine

    2016-06-01

    Bronchial epithelium is a key element of the respiratory airways. It constitutes the interface between the environment and the host. It is a physical barrier with many chemical and immunological properties. The bronchial epithelium is abnormal in asthma, even in children. It represents a key component promoting airway inflammation and remodelling that can lead to chronic symptoms. In this review, we present an overview of bronchial epithelium and how to study it, with a specific focus on children. We report physical, chemical and immunological properties from ex vivo and in vitro studies. The responses to various deleterious agents, such as viruses or allergens, may lead to persistent abnormalities orchestrated by bronchial epithelial cells. As epithelium dysfunctions occur early in asthma, reprogramming the epithelium may represent an ambitious goal to induce asthma remission in children.

  3. [The new era of epithelium-targeted drug development].

    PubMed

    Shimizu, Yoshimi; Nagase, Shotaro; Yagi, Kiyohito; Kondoh, Masuo

    2014-01-01

    Epithelium plays pivotal roles in biological barrier separating the inside of body and the outside environment. Ninety percent of malignant tumors are derived from epithelium. Most pathological microorganisms invade into the body from mucosal epithelium. Thus, epithelium is potential targets for drug development. Claudins (CLs), a family of tetra-transmembrane protein consisting of over 20 members, are structural and functional components of tight junction-seals in epithelium. Modulation of CL-seals enhanced mucosal absorption of drugs. CLs are often over-expressed in malignant tumors. CL-4 expression is increased in the epithelial cells covering the mucosal immune tissues. Very recently, CLs are also expected to be targets for traumatic brain injury and regenerative therapy. In this review, we overview the past, the present and the future of CLs-targeted drug development.

  4. Clinicopathologic features and long-term outcome of patients with medullary breast carcinoma managed with breast-conserving therapy (BCT)

    SciTech Connect

    Ha Vu-Nishino; Tavassoli, Fattaneh A.; Ahrens, Willam A.; Haffty, Bruce G. . E-mail: hafftybg@umdnj.edu

    2005-07-15

    Purpose: The purpose of this study is to compare the clinical characteristics and outcome of medullary carcinoma to infiltrating ductal carcinoma of the breast in a large cohort of conservatively managed patients with long-term follow-up. Methods and Materials: Chart records of patients with invasive breast cancer managed with breast-conserving therapy (BCT) at the therapeutic radiology facilities of Yale University School of Medicine before 2001 were reviewed. Forty-six cases (1971-2001) were identified with medullary histology; 1,444 patients with infiltrating ductal carcinoma served as a control group. Results: The medullary cohort presented at a younger age with a higher percentage of patients in the 35 years or younger age group (26.1% vs. 6.6%, p < 0.00001). Twelve patients with medullary histology underwent genetic screening, and 6 patients were identified with deleterious mutations. This group showed greater association with BRCA1/2 mutations compared with screened patients in the control group (50.0% vs. 15.8%, p 0.0035). The medullary cohort was also significantly associated with greater T stage and tumor size (37.0% vs. 17.2% T2, mean size 3.2 vs. 2.5 cm, p 0.00097) as well as negative ER (84.9% vs. 37.6%, p < 0.00001) and PR (87.5% vs. 48.1%, p = 0.00001) status. As of February 2003, median follow-up times for the medullary and control groups were 13.9 and 14.0 years, respectively. Although breast relapse-free rates were not significantly different (76.7% vs. 85.2%), 10-year distant relapse-free survival in the medullary cohort was significantly better than in the control group (94.9% vs. 77.5%, p = 0.028). Conclusions: Despite poor clinicopathologic features, patients with medullary histology demonstrate favorable long-term distant relapse-free survival. Local control rates of patients with medullary and infiltrating ductal carcinoma are comparable. These findings suggest that patients diagnosed with medullary carcinoma are appropriate candidates for

  5. Trachea Epithelium as a “Canary” for Cigarette Smoking-induced Biologic Phenotype of the Small Airway Epithelium*

    PubMed Central

    Turetz, Meredith L.; O’Connor, Timothy P.; Tilley, Ann E.; Strulovici-Barel, Yael; Salit, Jacqueline; Dang, David; Teater, Matthew; Mezey, Jason; Clark, Andrew G.; Crystal, Ronald G.

    2013-01-01

    The initial site of smoking-induced lung disease is the small airway epithelium, which is difficult and time consuming to sample by fiberoptic bronchoscopy. We developed a rapid, office-based procedure to obtain trachea epithelium without conscious sedation from healthy nonsmokers (n=26) and healthy smokers (n=19, 27 ± 15 pack-yr). Gene expression differences (fold-change >1.5, p<0.01, Benjamini-Hochberg correction) were assessed with Affymetrix microarrays. 1,057 probe sets were differentially expressed in healthy smokers vs nonsmokers, representing >500 genes. Trachea gene expression was compared to an independent group of small airway epithelial samples (n=23 healthy nonsmokers, n=19 healthy smokers, 25 ± 12 pack-yr). The trachea epithelium is more sensitive to smoking, responding with 3-fold more differentially-expressed genes than small airway epithelium. The trachea transcriptome paralleled the small airway epithelium, with 156 of 167 (93%) genes that are significantly upand down-regulated by smoking in the small airway epithelium showing similar direction and magnitude of response to smoking in the trachea. Trachea epithelium can be obtained without conscious sedation, representing a less invasive surrogate “canary” for smoking-induced changes in the small airway epithelium. This should prove useful in epidemiologic studies correlating gene expression with clinical outcome in assessing smoking-induced lung disease. PMID:20443905

  6. Thymic Selection of T-Cell Receptors as an Extreme Value Problem

    NASA Astrophysics Data System (ADS)

    Kosmrlj, Andrej; Chakraborty, Arup K.; Kardar, Mehran; Shakhnovich, Eugene I.

    2010-03-01

    T lymphocytes (T cells) orchestrate adaptive immune responses that clear pathogens from infected hosts. T cells recognize short peptides (p) derived from foreign proteins, which are bound to major histocompatibility complex (MHC) gene products (displayed on antigen- presenting cells). Recognition occurs when T cell receptor (TCR) proteins expressed on T cells bind sufficiently strongly to antigen- derived pMHC complexes on the surface of antigen-presenting cells. A diverse repertoire of self-tolerant TCR sequences is shaped during development of T cells in the thymus by processes called positive and negative selection. We map thymic selection processes to an extreme value problem and provide analytic expression for the amino acid composition of selected TCR sequences (which enable its recognition functions).

  7. 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

  8. Elevated Epidermal Thymic Stromal Lymphopoietin Levels Establish an Anti-Tumor Environment in the Skin

    PubMed Central

    Demehri, Shadmehr; Turkoz, Ahu; Manivasagam, Sindhu; Yockey, Laura J.; Turkoz, Mustafa; Kopan, Raphael

    2012-01-01

    Summary Thymic Stromal Lymphopoietin (TSLP), a cytokine implicated in induction of T helper 2 (Th2)-mediated allergic inflammation, has recently been shown to stimulate solid tumor growth and metastasis. Conversely, studying mice with clonal loss of Notch signaling in their skin revealed that high levels of TSLP released by barrier-defective skin caused a severe inflammation, resulting in gradual elimination of Notch-deficient epidermal clones and resistance to skin tumorigenesis. We found CD4+ T cells to be both required and sufficient to mediate these effects of TSLP. Importantly, TSLP overexpression in wild-type skin also caused resistance to tumorigenesis, confirming that TSLP functions as a tumor suppressor in the skin. PMID:23079659

  9. Churg-Strauss syndrome presented as paraneoplastic syndrome with thymic neuroendocrine carcinoma: a case report.

    PubMed

    Liu, Tao; Cai, Baiqiang; Feng, Ruie

    2012-11-01

    Churg-Strauss syndrome (CSS) is rarely presented as paraneoplastic syndrome. We reported here a 47-year-old man with refractory asthma for 3 years, and his CT scan showed an anterior mediastinal mass, pulmonary reticular opacities and bilateral maxillary sinusitis. He also presented with elevated peripheral blood eosinophils (EOS). Thoracoscopic resection of the mediastinal mass and a lung biopsy were performed, and thymic neuroendocrine carcinoma (TNC) and pulmonary eosinophilic vasculitis were pathologically diagnosed. The laboratory and clinical findings fulfilled the criteria of the diagnosis of CSS (Masi et al. in Arthritis Rheum 33(8):1094-1100, 1990). Asthma was improved, and elevated EOS was recovered to normal range after surgery and four courses of chemotherapy. This was the first report of CSS manifested as a paraneoplastic syndrome of TNC.

  10. Thymic TFH cells involved in the pathogenesis of myasthenia gravis with thymoma.

    PubMed

    Zhang, Min; Zhou, Yongan; Guo, Jun; Li, Hongzeng; Tian, Feng; Gong, Li; Wang, Xianni; Lan, Miao; Li, Zhuyi; Zhang, Wei

    2014-04-01

    Follicular helper CD4+ T (TFH) cells are the specialized providers of B cell help in germinal centers (GCs). Formation of GCs in thymi is the primary thymi characteristic in MG patients. TFH cells are involved in the pathogenic process of many autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and autoimmune thyroid disease. The role thymic TFH cells played in MG with thymoma has not been elucidated. Here, we analyzed surface markers CXCR5, Bcl-6, ICOS and IL-21 on TFH cells in thymus derived from thymoma patients with ocular MG (OMG), generalized MG (GMG) or without MG using immunohistochemical staining, immunofluorescence, western blotting, and real-time PCR analysis. We show that clinical severity of MG is correlated with higher mRNA expression of the four markers. Indeed, results show higher expression of all four markers in thymoma with GMG patients compared with both OMG and non-MG patients. We found no significant difference in the expression of CXCR5, Bcl-6 and ICOS in OMG compared with non-MG patients. Regression analysis shows a positive correlation between thymic CXCR5, BCL-6, ICOS and IL-21 levels and quantitative MG score (QMGS) in GMG patients. In addition, we found no significant correlation between TFH cell expression and QMGS in OMG patients. Our findings show that higher expression of TFH cells in the thymoma is related to the clinical severity of MG and suggests a role in the pathogenesis of MG. However, the real source of these TFH cells is still uncertain and needs further study.

  11. Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

    PubMed

    Kohda, Yuka; Kawai, Yoshiko; Iwamoto, Noriaki; Matsunaga, Yoshiko; Aiga, Hiromi; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

  12. Protective effect of serum thymic factor, FTS, on cephaloridine-induced nephrotoxicity in rats.

    PubMed

    Kohda, Yuka; Matsunaga, Yoshiko; Yonogi, Katsuya; Kawai, Yoshiko; Awaya, Akira; Gemba, Munekazu

    2005-11-01

    Serum thymic factor (FTS), a thymic peptide hormone, has been reported to increase superoxide disumutase (SOD) levels in senescence-accelerated mice. In the present study, we examined the effect of FTS on cephaloridine (CER)-induced nephrotoxicity in vivo and in vitro. We previously reported that CER led to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney. So, we also investigated whether FTS has an effect on ERK activation induced by CER. Treatment of male Sprague-Dawley rats with intravenous CER (1.2 g/kg) for 24 h markedly increased BUN and plasma creatinine levels and urinary excretion of glucose and protein, decreased creatinine clearance and also led to marked pathological changes in the proximal tubules, as revealed by electron micrographs. An increase in phosphorylated ERK (pERK) was detected in the nuclear fraction prepared from the rat kidney cortex 24 h after CER injection. Pretreatment of rats with FTS (50 microg/kg, i.v.) attenuated the CER-induced renal dysfunction and pathological damage. FTS also suppressed CER-induced ERK activation in the kidney. In vitro treatment of the established cell line, LLC-PK1 cells, with FTS significantly ameliorated CER-induced cell injury, as measured by lactate dehydrogenase (LDH) leakage. Our results, taken together with our previous report that MEK inhibitors ameliorated CER-induced renal cell injury and ERK activation induced by CER, suggest that FTS participates in protection from CER-induced nephrotoxicity by suppressing ERK activation induced by CER.

  13. Characterization of murine lung dendritic cells: similarities to Langerhans cells and thymic dendritic cells

    PubMed Central

    1990-01-01

    Dendritic cells (DC) are potent accessory cells (AC) for the initiation of primary immune responses. Although murine lymphoid DC and Langerhans cells have been extensively characterized, DC from murine lung have been incompletely described. We isolated cells from enzyme-digested murine lungs and bronchoalveolar lavages that were potent stimulators of a primary mixed lymphocyte response (MLR). The AC had a low buoyant density, were loosely adherent and nonphagocytic. AC function was unaffected by depletion of cells expressing the splenic DC marker, 33D1. In addition, antibody and complement depletion of cells bearing the macrophage marker F4/80, or removal of phagocytic cells with silica also failed to decrease AC activity. In contrast, AC function was decreased by depletion of cells expressing the markers J11d and the low affinity interleukin 2 receptor (IL-2R), both present on thymic and skin DC. AC function was approximately equal in FcR+ and FcR- subpopulations, indicating there was heterogeneity within the AC population. Consistent with the functional data, a combined two-color immunofluorescence and latex bead uptake technique revealed that lung cells high in AC activity were enriched in brightly Ia+ dendritic- shaped cells that (a) were nonphagocytic, (b) lacked specific T and B lymphocyte markers and the macrophage marker F4/80, but (c) frequently expressed C3biR, low affinity IL-2R, FcRII, and the markers NLDC-145 and J11d. Taken together, the functional and phenotypic data suggest the lung cells that stimulate resting T cells in an MLR and that might be important in local pulmonary immune responses are DC that bear functional and phenotypic similarity to other tissues DC, such as Langerhans cells and thymic DC. PMID:2162904

  14. Impaired thymic output in patients with chronic hepatitis C virus infection.

    PubMed

    Hartling, H J; Gaardbo, J C; Ronit, A; Salem, M; Laye, M; Clausen, M R; Skogstrand, K; Gerstoft, J; Ullum, H; Nielsen, S D

    2013-10-01

    Altered T cell homeostasis in chronic hepatitis C virus (HCV) infection has been demonstrated. However, it is unknown whether fibrosis is associated with more perturbed T cell homeostasis in chronic HCV infection. The aim of this study was to examine and compare T cell subsets including recent thymic emigrants (RTE), naive, memory, senescent, apoptotic and IL-7 receptor α (CD127) expressing CD4⁺ and CD8⁺ T cells as well as telomere length and interferon-γ production in HCV-infected patients with (n = 25) and without (n = 26) fibrosis as well as in healthy controls (n = 24). Decreased proportions of CD4⁺ and CD8⁺ RTE were found in HCV-infected patients, especially in HCV-infected patients with fibrosis (14.3% (9.7-23.0) and 28.8% (16.1-40.5), respectively) compared with healthy controls (24.2% (16.3-32.1), P = 0.004 and 39.1% (31.6-55.0), P = 0.010, respectively). Furthermore, HCV-infected patients with fibrosis presented with a higher proportion of CD4⁺ T cells expressing CD127 compared with HCV-infected patients without fibrosis [88.4% (84.5-91.0) versus 83.8% (79.9-86.8), P = 0.016]. Thus, impaired thymic output in HCV infection was found, and high proportion of CD127⁺ T cells may illustrate a compensatory mechanism to preserve T cell counts.

  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. 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.

  17. Novel Prognostic Groups in Thymic Epithelial Tumors: Assessment of Risk and Therapeutic Strategy Selection

    SciTech Connect

    D'Angelillo, Rolando M. Trodella, Lucio; Ramella, Sara; Cellini, Numa; Balducci, Mario; Mantini, Giovanna; Cellini, Francesco; Ciresa, Marzia; Fiore, Michele; Evoli, Amelia; Sterzi, Silvia; Russo, Patrizia; Grozio, Alessia; Cesario, Alfredo; Granone, Pierluigi

    2008-06-01

    Purpose: To assess the role of multimodality treatment on patients with thymic epithelial tumors (TETs) (i.e., thymomas and thymic squamous cell carcinoma) and to define the prognostic classes according to the Masaoka and World Health Organization histologic classification systems. Methods and Materials: Primary surgery was the mainstay of therapy. Extended thymectomy was performed in all cases. The cases were primarily staged according to the Masaoka system. Adjuvant radiotherapy was given to patients diagnosed with Masaoka Stage II, III, and IVA TET. Adjuvant chemotherapy was administered in selected cases. Results: We reviewed the records of 120 patients with TETs, with a mean follow-up of 13.8 years. Of the 120 patients, 98 (81.6%) received adjuvant radiotherapy. Of these 98 patients, Grade 1-2 pulmonary or esophageal toxicity was acute in 12 (12.2%) and late in 8 (8.2%). The median overall survival was 21.6 years. Of the 120 patients, 106 were rediagnosed and reclassified according to the World Health Organization system, and the survival rate was correlated with it. Three different prognostic classes were defined: favorable, Masaoka Stage I and histologic grade A, AB, B1, B2 or Masaoka Stage II and histologic grade A, AB, B1; unfavorable, Stage IV disease or histologic grade C or Stage III and histologic grade B3; intermediate, all other combinations. The 10- and 20-year survival rate was 95% and 81% for the favorable group, 90% and 65% for the intermediate group, and 50% and 0% for the unfavorable group, respectively. Local recurrence, distant recurrence, and tumor-related deaths were also evaluated. Conclusion: The analysis of our experience singled out three novel prognostic classes and the assessment of risk identified treatment selection criteria.

  18. In vivo diffusion tensor imaging of chronic spinal cord compression : a rat model with special attention to the conus medullaris.

    PubMed

    Zhao, Peng; Kong, Chao; Chen, Xueming; Guan, Hua; Yu, Zhenshan; Cui, Libin; Wang, Yanhui; Yuan, Xin

    2016-12-01

    Background Few studies have focused on diffusion tensor imaging (DTI) parameters of the conus medullaris after chronic compression in the cervical spinal cord. Purpose To discuss the correlation of DTI parameters between the chronically compressed cervical spinal cord and the conus medullaris in a rat model at different time points. Material and Methods Fifty female Sprague-Dawley rats were randomized into five groups: control group (group A), sham group (group B), and test groups C, D, and E (1, 2, and 3 weeks after compression, respectively). Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of the cervical spinal cord and conus medullaris were compared among different groups. Correlations of ADC and FA values of the cervical spinal cord with those of the conus medullaris were performed in all groups. Results The ADC values at the cervical spinal cord and conus medullaris in all test groups were higher than those of group A and B, while the FA values were lower. The ADC value of the cervical spinal cord was linearly correlated with that of the conus medullaris only in group D. There were no linear correlations of FA values between the cervical spinal cord and the conus medullaris in all test groups. Conclusion After compression of the cervical spinal cord, ADC values of the cervical spinal cord and conus medullaris in test group were significantly increased, while FA values were significantly decreased. The ADC value of the cervical spinal cord was linearly correlated with that of the conus medullaris at 2 weeks after compression.

  19. Glucose metabolism in rat retinal pigment epithelium.

    PubMed

    Coffe, Víctor; Carbajal, Raymundo C; Salceda, Rocío

    2006-01-01

    The retinal pigment epithelium (RPE) is the major transport pathway for exchange of metabolites and ions between choroidal blood supply and the neural retina. To gain insight into the mechanisms controlling glucose metabolism in RPE and its possible relationship to retinopathy, we studied the influence of different glucose concentrations on glycogen and lactate levels and CO(2) production in RPE from normal and streptozotocin-treated diabetic rats. Incubation of normal RPE in the absence of glucose caused a decrease in lactate production and glycogen content. In normal RPE, increasing glucose concentrations from 5.6 mM to 30 mM caused a four-fold increase in glucose accumulation and CO(2) yield, as well as reduction in lactate and glycogen production. In RPE from diabetic rats glucose accumulation did not increase in the presence of high glucose substrate, but it showed a four- and a seven-fold increase in CO(2) production through the mitochondrial and pentose phosphate pathways, respectively. We found high glycogen levels in RPE which can be used as an energy reserve for RPE itself and/or neural retina. Findings further show that the RPE possesses a high oxidative capacity. The large increase in glucose shunting to the pentose phosphate pathway in diabetic retina exposed to high glucose suggests a need for reducing capacity, consistent with increased oxidative stress.

  20. Biochemical studies of the tracheobronchial epithelium

    SciTech Connect

    Mass, M.J.; Kaufman, D.G.

    1984-06-01

    Tracheobronchial epithelium has been a focus of intense investigation in the field of chemical carcinogenesis. We have reviewed some biochemical investigations that have evolved through linkage with carcinogenesis research. These areas of investigation have included kinetics of carcinogen metabolism, identification of carcinogen metabolites, levels of carcinogen binding to DNA, and analysis of carcinogen-DNA adducts. Such studies appear to have provided a reasonable explanation for the susceptibilities of the respiratory tracts of rats and hamsters to carcinogenesis by benzo(a)pyrene. Coinciding with the attempts to understand the initiation of carcinogenesis in the respiratory tract has also been a major thrust aimed at effecting its prevention both in humans and in animal models for human bronchogenic carcinoma. These studies have concerned the effects of derivatives of vitamin A (retinoids) and their influence on normal cell biology and biochemistry of this tissue. Recent investigations have included the effects of retinoid deficiency on the synthesis of RNA and the identification of RNA species associated with this biological state, and also have included the effects of retinoids on the synthesis of mucus-related glycoproteins. Tracheal organ cultures from retinoid-deficient hamsters have been used successfully to indicate the potency of synthetic retinoids by monitoring the reversal of squamous metaplasia. Techniques applied to this tissue have also served to elucidate features of the metabolism of retinoic acid using high pressure liquid chromatography. 94 references, 9 figures, 2 tables.

  1. Human vomeronasal epithelium development: An immunohistochemical overview.

    PubMed

    Dénes, Lóránd; Pap, Zsuzsanna; Szántó, Annamária; Gergely, István; Pop, Tudor Sorin

    2015-06-01

    The vomeronasal organ (VNO) is the receptor structure of the vomeronasal system (VNS) in vertebrates. It is found bilaterally in the submucosa of the inferior part of the nasal septum. There are ongoing controversies regarding the functionality of this organ in humans. In this study we propose the immunohistochemical evaluation of changes in components of the human vomeronasal epithelium during foetal development. We used 45 foetuses of different age, which were included in three age groups. After VNO identification immunohistochemical reactions were performed using primary antibodies against the following: neuron specific enolase, calretinin, neurofilament, chromogranin, synaptophysin, cytokeratin 7, pan-cytokeratin and S100 protein. Digital slides were obtained and following colorimetric segmentation, surface area measurements were performed. The VNO was found in less than half of the studied specimens (42.2%). Neuron specific enolase and calretinin immunoexpression showed a decreasing trend with foetal age, while the other neural/neuroendocrine markers were negative in all specimens. Cytokeratin 7 expression increased with age, while Pan-Ctk had no significant variations. S100 protein immunoexpression also decreased around the VNO. The results of the present work uphold the theory of regression of the neuroepithelium that is present during initial stages of foetal development.

  2. Stem cells of the skin epithelium

    PubMed Central

    Alonso, Laura; Fuchs, Elaine

    2003-01-01

    Tissue stem cells form the cellular base for organ homeostasis and repair. Stem cells have the unusual ability to renew themselves over the lifetime of the organ while producing daughter cells that differentiate into one or multiple lineages. Difficult to identify and characterize in any tissue, these cells are nonetheless hotly pursued because they hold the potential promise of therapeutic reprogramming to grow human tissue in vitro, for the treatment of human disease. The mammalian skin epithelium exhibits remarkable turnover, punctuated by periods of even more rapid production after injury due to burn or wounding. The stem cells responsible for supplying this tissue with cellular substrate are not yet easily distinguishable from neighboring cells. However, in recent years a significant body of work has begun to characterize the skin epithelial stem cells, both in tissue culture and in mouse and human skin. Some epithelial cells cultured from skin exhibit prodigious proliferative potential; in fact, for >20 years now, cultured human skin has been used as a source of new skin to engraft onto damaged areas of burn patients, representing one of the first therapeutic uses of stem cells. Cell fate choices, including both self-renewal and differentiation, are crucial biological features of stem cells that are still poorly understood. Skin epithelial stem cells represent a ripe target for research into the fundamental mechanisms underlying these important processes. PMID:12913119

  3. STUDIES ON SMALL INTESTINAL CRYPT EPITHELIUM

    PubMed Central

    Trier, Jerry S.

    1963-01-01

    Small intestinal crypt epithelium obtained from normal fasting humans by peroral biopsy of the mucosa was studied with the electron microscope. Paneth cells were identified at the base of the crypts by their elaborate highly organized endoplasmic reticulum, large secretory granules, and small lysosome-like dense bodies within the cytoplasm. Undifferentiated cells were characterized by smaller cytoplasmic membrane-bounded granules which were presumed to be secretory in nature, a less elaborate endoplasmic reticulum, many unattached ribosomes and, in some cells, the presence of glycogen. Some undifferentiated cells at the base of the crypts contained lobulated nuclei and striking paranuclear accumulations of mitochondria. Membrane-bounded cytoplasmic fragments, probably originating from undifferentiated and Paneth cells, were frequently apparent within crypt lumina. Of the goblet cells, some were seen actively secreting mucus. In these, apical mucus appeared to exude into the crypt lumen between gaps in the microvilli. The membrane formerly surrounding the apical mucus appeared to fuse with and become part of the plasma membrane of the cell, suggesting a merocrine secretory mechanism. Enterochromaffin cells were identified by their location between the basal regions of other crypt cells and by their unique intracytoplasmic granules. PMID:14064112

  4. Building and maintaining the epithelium of the lung.

    PubMed

    Rackley, Craig R; Stripp, Barry R

    2012-08-01

    Airspaces of the lung are lined by an epithelium whose cellular composition changes along the proximal-to-distal axis to meet local functional needs for mucociliary clearance, hydration, host defense, and gas exchange. Advances in cell isolation, in vitro culture techniques, and genetic manipulation of animal models have increased our understanding of the development and maintenance of the pulmonary epithelium. This review discusses basic cellular mechanisms that regulate establishment of the conducting airway and gas exchange systems as well as the functional maintenance of the epithelium during postnatal life.

  5. 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

  6. 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

  7. IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity

    PubMed Central

    Silva, Susana L.; Albuquerque, Adriana S.; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T.; Victorino, Rui M. M.; Sousa, Ana E.

    2017-01-01

    Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31− subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31+ naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31− naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31+ naive CD4 T-cells, which is essential to secure T-cell diversity throughout life. PMID:28154568

  8. IL-7-Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity.

    PubMed

    Silva, Susana L; Albuquerque, Adriana S; Matoso, Paula; Charmeteau-de-Muylder, Bénédicte; Cheynier, Rémi; Ligeiro, Dário; Abecasis, Miguel; Anjos, Rui; Barata, João T; Victorino, Rui M M; Sousa, Ana E

    2017-01-01

    Naive CD4 T-cell maintenance is critical for immune competence. We investigated here the fine-tuning of homeostatic mechanisms of the naive compartment to counteract the loss of de novo CD4 T-cell generation. Adults thymectomized in early childhood during corrective cardiac surgery were grouped based on presence or absence of thymopoiesis and compared with age-matched controls. We found that the preservation of the CD31(-) subset was independent of the thymus and that its size is tightly controlled by peripheral mechanisms, including prolonged cell survival as attested by Bcl-2 levels. Conversely, a significant contraction of the CD31(+) naive subset was observed in the absence of thymic activity. This was associated with impaired responses of purified naive CD4 T-cells to IL-7, namely, in vitro proliferation and upregulation of CD31 expression, which likely potentiated the decline in recent thymic emigrants. Additionally, we found no apparent constraint in the differentiation of naive cells into the memory compartment in individuals completely lacking thymic activity despite upregulation of DUSP6, a phosphatase associated with increased TCR threshold. Of note, thymectomized individuals featuring some degree of thymopoiesis were able to preserve the size and diversity of the naive CD4 compartment, further arguing against complete thymectomy in infancy. Overall, our data suggest that robust peripheral mechanisms ensure the homeostasis of CD31(-) naive CD4 pool and point to the requirement of continuous thymic activity to the maintenance of IL-7-driven homeostatic proliferation of CD31(+) naive CD4 T-cells, which is essential to secure T-cell diversity throughout life.

  9. Prognostic Influence of Clinical and Pathological Factors in Medullary Thyroid Carcinoma: A Study of 53 Cases

    PubMed Central

    Brandão, Lenine G.; Cavalheiro, Beatriz G.; Junqueira, Consuelo R.

    2009-01-01

    OBJECTIVES AND INTRODUCTION Medullary thyroid carcinoma, a neoplasia of intermediate prognosis and differentiation, does not always respond predictably to known treatments. This study aimed to correlate the clinical progression of surgically treated patients with clinical and pathological data. METHODS A total of 53 patients were followed for 75 months (mean average) in tertiary-care hospital. The clinical status of patients at the end of the study period was characterized to determine correlations with a range of disease aspects. A value of p < 0.05 was considered statistically significant. RESULTS Twenty-two patients (41.5%) were alive and disease-free at the end of the follow-up period; twenty-three patients (43.4%) had persistent disease; and eight patients (15.1%) had recurrent disease. Four patients (7.6%) died from medullary thyroid carcinoma with clinical and/or imaging evidence of neoplasia. The following aspects demonstrated statistically significant correlations with the final medical condition: positive initial cervical examination (p = 0.002); neoplastic extensions to the thyroid capsule (p = 0.004) and adjacent tissues (p = 0.034); cervical lymph node metastases (p < 0.001); diameter of neoplasia (p = 0.018); TNM (tumor, node and metastasis) Stage (p = 0.001) and evidence of distant and/or cervical diseases in the absence of a cure (p = 0.011). Through logistic regression, the presence of cervical lymph node metastases was considered an independent variable (p < 0.001). CONCLUSIONS Clinical and pathological aspects of patients with surgically treated medullary thyroid carcinomas are predictors of disease progression. Specifically, even treated cervical lymph node metastases are significantly correlated with disease progression. PMID:19759878

  10. TRPA1-like channels enhance glycinergic transmission in medullary dorsal horn neurons.

    PubMed

    Cho, Jin-Hwa; Jeong, Moon-Young; Choi, In-Sun; Lee, Heon-Jin; Jang, Il-Sung

    2012-08-01

    The effect of icilin, a potent agonist of transient receptor potential ankyrin 1 (TRPA1) and TRPM8, on glycinergic transmission was examined in mechanically isolated rat medullary dorsal horn neurons by use of the conventional whole-cell patch-clamp technique. Icilin increased the frequency of glycinergic spontaneous miniature inhibitory post-synaptic currents (mIPSCs) in a dose-dependent manner. Either allyl isothiocyanate(AITC) or cinnamaldehyde, other TRPA1 agonists, also increased mIPSC frequency, but the extent of facilitation induced by AITC or cinnamaldehyde was less than that induced by icilin. However, menthol, a TRPM8 agonist, had no facilitatory effect on glycinergic mIPSCs. The icilin-induced increase in mIPSC frequency was significantly inhibited by either HC030031, a selective TRPA1 antagonist, or ruthenium red, a non-selective transient receptor potential channel blocker. Icilin failed to increase glycinergic mIPSC frequency in the absence of extracellular Ca(2+), suggesting that the icilin-induced increase in mIPSC frequency is mediated by the Ca(2+) influx from the extracellular space. In contrast, icilin still increased mIPSC frequency either in the Na(+) -free external solution or in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker. The present results suggest that icilin acts on pre-synaptic TRPA1-like ion channels, which are permeable to Ca(2+), to enhance glycinergic transmission onto medullary dorsal horn neurons. The TRPA1-like channel-mediated enhancement of glycinergic transmission in medullary dorsal horn neurons would contribute to the regulation of pain information from the peripheral tissues.

  11. Differential Activation of Medullary Vagal Nuclei Caused by Stimulation of Different Esophageal Mechanoreceptors

    PubMed Central

    Lang, Ivan M.; Medda, Bidyut K.; Shaker, Reza

    2010-01-01

    Esophageal mechanorecptors, i.e. muscular slowly adapting tension receptors and mucosal rapidly adapting touch receptors, mediate different sets of reflexes. The aim of this study was to determine the medullary vagal nuclei involved in the reflex responses to activation of these receptors. Thirty-three cats were anesthetized with alpha-chloralose and the esophagus was stimulated by slow balloon or rapid air distension. The physiological effects of the stimuli (N=4) were identified by recording responses from the pharyngeal, laryngeal, and hyoid muscles, esophagus, and the lower esophageal sphincter (LES). The effects on the medullary vagal nuclei of the stimuli: slow distension (N=10), rapid distension (N=9), and in control animals (N=10) were identified using the immunohistochemical analysis of c-fos. The experimental groups were stimulated 3 times per minute for 3 hours. After the experiment, the brains were removed and processed for c-fos immunoreactivity or thioinin. We found that slow balloon distension activated the esophago-UES contractile reflex and esophago LES relaxation response, and rapid air injection activated the belch and its component reflexes. Slow balloon distension activated the NTSce, NTSdl, NTSvl, DMNc, DMNr and NAr; and rapid air injection primarily activated AP, NTScd, NTSim, NTSis, NTSdm, NTSvl, NAc and NAr. We concluded that different sets of medullary vagal nuclei mediate different reflexes of the esophagus activated from different sets of mechanoreceptors. The NTScd is the primary NTS subnucleus mediating reflexes from the mucosal rapidly adapting touch receptors, and the NTSce is the primary NTS subnucleus mediating reflexes from the muscular slowly adapting tension receptors. The AP may be involved in mediation of belching. PMID:20971087

  12. Cholinergic modulation of primary afferent glutamatergic transmission in rat medullary dorsal horn neurons.

    PubMed

    Jeong, Seok-Gwon; Choi, In-Sun; Cho, Jin-Hwa; Jang, Il-Sung

    2013-12-01

    Although muscarinic acetylcholine (mACh) receptors are expressed in trigeminal ganglia, it is still unknown whether mACh receptors modulate glutamatergic transmission from primary afferents onto medullary dorsal horn neurons. In this study, we have addressed the cholinergic modulation of primary afferent glutamatergic transmission using a conventional whole cell patch clamp technique. Glutamatergic excitatory postsynaptic currents (EPSCs) were evoked from primary afferents by electrical stimulation of trigeminal tract and monosynaptic EPSCs were recorded from medullary dorsal horn neurons of rat horizontal brain stem slices. Muscarine and ACh reversibly and concentration-dependently decreased the amplitude of glutamatergic EPSCs and increased the paired-pulse ratio. In addition, muscarine reduced the frequency of miniature EPSCs without affecting the current amplitude, suggesting that muscarine acts presynaptically to decrease the probability of glutamate release onto medullary dorsal horn neurons. The muscarine-induced decrease of glutamatergic EPSCs was significantly occluded by methoctramine or AF-DX116, M2 receptor antagonists, but not pirenzepine, J104129 and MT-3, selective M1, M3 and M4 receptor antagonists. The muscarine-induced decrease of glutamatergic EPSCs was highly dependent on the extracellular Ca2+ concentration. Physostigmine and clinically available acetylcholinesterase inhibitors, such as rivastigmine and donepezil, significantly shifted the concentration-inhibition relationship of ACh for glutamatergic EPSCs. These results suggest that muscarine acts on presynaptic M2 receptors to inhibit glutamatergic transmission by reducing the Ca2+ influx into primary afferent terminals, and that M2 receptor agonists and acetylcholinesterase inhibitors could be, at least, potential targets to reduce nociceptive transmission from orofacial tissues.

  13. Cortical thickness and medullary canal dimensions of the bone phalanx are predicted by quantitative ultrasound parameters.

    PubMed

    Guglielmi, Giuseppe; de Terlizzi, Francesca; Scalzo, Giacomo; Battista, Claudia; Scillitani, Alfredo

    2010-01-01

    The aim of the study was to investigate the relationship between quantitative ultrasound (QUS) parameters extracted from the analysis of the ultrasound (US) signal and the geometric properties of the bones. One hundred and one subjects in the age range of 20-7 4yr (mean: 52+/-12 yr) have been measured by QUS at the phalanges for the evaluation of amplitude-dependent speed of sound (AD-SoS), bone transmission time (BTT), US peak amplitude (UPA), signal dynamic (SDY), slope, energy, and fast wave amplitude (FWA). Hand radiograph, lumbar spine dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), and femoral neck DXA forearm peripheral QCT were performed on all patients. BTT is related to cortical thickness (CTh) (r=0.62, p<0.0001), and FWA is related to medullary canal thickness (r=-0.64, p<0.0001). Other parameters are related to both medullary canal thickness (AD-SoS: r=-0.21; UPA: r=-0.53; SDY: r=-0.56; slope: r=-0.64; energy: r=-0.44, p<0.05) and CTh (AD-SoS: r=0.54, p<0.0001; UPA: r=0.51; SDY: r=0.38; slope: r=0.32; energy: r=0.56, p<0.001). Linear multivariate models indicate that BTT, UPA, and energy measured at the phalanges carry independent information on CTh of the bone, whereas FWA, SDY, and slope are related only to medullary canal thickness.

  14. Transport of sodium and urea in outer medullary descending vasa recta.

    PubMed Central

    Pallone, T L; Work, J; Myers, R L; Jamison, R L

    1994-01-01

    We dissected and perfused outer medullary vasa recta (OMVR) from vascular bundles in the rat. Permeabilities of sodium (PNa) and urea (Pu) were simultaneously determined from the lumen-to-bath efflux of 22Na and [14C]urea. PNa and Pu were also measured by in vivo microperfusion of descending (DVR) and ascending vasa recta (AVR) at the papillary tip of Munich-Wistar rats. In some OMVR PNa was indistinguishable from zero. The mean +/- SE of PNa (x 10(-5), cm/s) in OMVR was 76 +/- 9. Pu in OMVR was always very high (x 10(-5), cm/s), 360 +/- 14. There was no correlation between OMVR PNa and Pu. Inner medullary AVR and DVR had PNa of 115 +/- 10 and 75 +/- 10, respectively, and Pu of 121 +/- 10 and 76 +/- 11, respectively. PNa and Pu in papillary vasa recta were always nearly identical and highly correlated. Transport of [14C] urea in OMVR was reversibly inhibited by addition of unlabeled urea or phloretin to the bath and lumen, providing evidence for carrier-mediated transport. These data suggest that sodium and urea might traverse the wall of inner medullary vasa recta by a paracellular pathway while urea also crosses by a transcellular route in OMVR. Electron microscopic examination of seven in vitro perfused OMVR revealed no fenestrations and exposure of these vessels to 10 microM calcium ionophore A23187 or 1 nM angiotensin II resulted in reversible contraction, suggesting that in vitro perfused OMVR are DVR only. Images PMID:8282790

  15. Neonatal transient renal failure with renal medullary hyperechogenicity: clinical and laboratory features.

    PubMed

    Makhoul, Imad R; Soudack, Michalle; Smolkin, Tatiana; Sujov, Polo; Epelman, Monica; Eisenstein, Israel; Magen, Daniela; Zelikovic, Israel

    2005-07-01

    Sonographic findings of renal medullary hyperechogenicity have been observed in the neonate in association with severe perinatal renal injury, kidney malformations or nephrocalcinosis, and, rarely, in newborn infants with transient renal failure. The aim of the study was to describe the entity of neonatal transient renal failure with renal medullary hyperechogenicity (NTRFMH). We studied nine term neonates, born between August 1999 and February 2004 in our institution (0.1% of the live born infants), who developed transient renal dysfunction after birth, and in whom renal sonograms showed bilateral medullary hyperechogenicity. Seven of the infants (78%) had anuria until 30-45 hours of age, and two (22%) had oliguria. Peak serum creatinine levels ranged between 0.61 and 1.62 mg/dL (mean: 1.09+/-0.27 mg/dL) at 2-3 days of life. Additional findings included proteinuria in nine infants (100%), uric acid crystalluria in seven (78%), hyperuricemia in four (44%), and hypertension in one (11%). Hyperuricosuria was demonstrated in one out of the seven patients in whom this parameter was determined. Urinary excretion rates of calcium, phosphorus and oxalic acid were normal, as were urinary levels of amino acids and organic acids. Full clinical recovery accompanied by normalization of all laboratory parameters was observed in all infants by 4-6 days of life. Subsequent follow-up showed normal renal function, no urinary abnormalities, and normal renal sonograms in all infants. Our summary of the nine infants with NTRFMH reported on here and a review of 19 cases of this condition reported in the literature reveal a not-so-rare entity of unclear etiology, but excellent prognosis. Physicians caring for neonates should be aware of this benign and transient condition.

  16. Medullary circuitry regulating rapid eye movement (REM) sleep and motor atonia

    PubMed Central

    Vetrivelan, Ramalingam; Fuller, Patrick M; Tong, Qingchun; Lu, Jun

    2009-01-01

    Considerable data support a role for glycinergic ventromedial medulla neurons in the mediation of the postsynaptic inhibition of spinal motoneurons necessary for the motor atonia of rapid-eye movement (REM) sleep in cats. These data are however difficult to reconcile with the fact that large lesions of the rostral ventral medulla do not result in loss of REM atonia in rats. In the present study, we sought to clarify which medullary networks in rodents are responsible for REM motor atonia by retrogradely tracing inputs to the spinal ventral horn from the medulla, ablating these medullary sources to determine their effects on REM atonia and using transgenic mice to identify the neurotransmitter(s) involved. Our results reveal a restricted region within the ventromedial medulla, termed here the ‘supraolivary medulla’ (SOM), which contains glutamatergic neurons that project to the spinal ventral horn. Cell-body specific lesions of the SOM resulted in an intermittent loss of muscle atonia, taking the form of exaggerated phasic muscle twitches, during REM sleep. A concomitant reduction in REM sleep time was observed in the SOM-lesioned animals. We next used mice with lox-P modified alleles of either the glutamate or GABA/glycine vesicular transporters to selectively eliminate glutamate or GABA/glycine neurotransmission from SOM neurons. Loss of SOM glutamate release, but not SOM GABA/glycine release, resulted in exaggerated muscle twitches during REM sleep that were similar to those observed following SOM lesions in rats. These findings, taken together, demonstrate that SOM glutamatergic neurons comprise key elements of the medullary circuitry mediating REM atonia. PMID:19625526

  17. Detachments of the retinal pigment epithelium at the posterior pole.

    PubMed

    Noble, K G; Levitzky, M J; Carr, R E

    1976-08-01

    Multiple vitelliform cysts of the retina, a disorder of unknown cause in which there are multiple detachments of the retinal pigment epithelium at the posterior pole, occurred in five patients. In four patients all lesions were located outside the parafoveal area while one patient showed bilateral foveal elevations associated with more eccentric detachments. Several patients showed slow resolution of some of the detachments with mild disturbances of the pigment epithelium.

  18. CD4+ Recent Thymic Emigrants Are Recruited into Granulomas during Leishmania donovani Infection but Have Limited Capacity for Cytokine Production

    PubMed Central

    Moore, John W. J.; Beattie, Lynette; Osman, Mohamed; Owens, Benjamin M. J.; Brown, Najmeeyah; Dalton, Jane E.; Maroof, Asher

    2016-01-01

    Recent thymic emigrants (RTEs) represent a source of antigen-naïve T cells that enter the periphery throughout life. However, whether RTEs contribute to the control of chronic parasitic infection and how their potential might be harnessed by therapeutic intervention is currently unclear. Here, we show that CD4+ recent thymic emigrants emerging into the periphery of mice with ongoing Leishmania donovani infection undergo partial activation and are recruited to sites of granulomatous inflammation. However, CD4+ RTEs displayed severely restricted differentiation either into IFNγ+ or IFNγ+TNFα+ effectors, or into IL-10-producing regulatory T cells. Effector cell differentiation in the chronically infected host was not promoted by adoptive transfer of activated dendritic cells or by allowing extended periods of post-thymic differentiation in the periphery. Nevertheless, CD4+ RTEs from infected mice retained the capacity to transfer protection into lymphopenic RAG2-/- mice. Taken together, our data indicate that RTEs emerging into a chronically inflamed environment are not recruited into the effector pool, but retain the capacity for subsequent differentiation into host protective T cells when placed in a disease-free environment. PMID:27658046

  19. Human natural regulatory T cell development, suppressive function and post-thymic maturation in a humanized mouse model

    PubMed Central

    Onoe, Takashi; Kalscheuer, Hannes; Danzl, Nichole; Chittenden, Meredith; Zhao, Guiling; Yang, Yong-Guang; Sykes, Megan

    2011-01-01

    CD4+ regulatory T (Treg) cells control adaptive immune responses and promote self-tolerance. Various humanized mouse models have been developed in efforts to reproduce and study a human immune system. However, in models that require T cell differentiation in the recipient murine thymus, only low numbers of T cells populate the peripheral immune systems. T cells are positively selected by mouse MHC and therefore do not function well in an HLA-restricted manner. In contrast, cotransplantation of human fetal thymus/liver and i.v. injection of CD34+ cells from the same donor achieves multilineage human lymphohematopoietic reconstitution, including dendritic cells (DCs) and formation of secondary lymphoid organs, in NOD/SCID mice. Strong antigen-specific immune responses and homeostatic expansion of human T cells that is dependent on peripheral human APCs occurs. We now demonstrate that FoxP3+ Helios+ “natural” Tregs develop normally in human fetal thymic grafts and are present in peripheral blood, spleen and lymph nodes of these humanized mice. Humanized mice exhibit normal reversal of CD45 isoform expression in association with thymic egress, post-thymic “naïve” to “activated” phenotypic conversion, and suppressive function. These studies demonstrate the utility of this humanized mouse model for the study of human Treg ontogeny, immunobiology and therapy. PMID:21876039

  20. Thymic B lymphocyte clones from patients with myasthenia gravis secrete monoclonal striational autoantibodies reacting with myosin, alpha actinin, or actin

    PubMed Central

    1986-01-01

    Striational autoantibodies (StrAb), which react with elements of skeletal muscle cross-striations, occur frequently in patients with thymoma associated with myasthenia gravis (MG). Dissociated thymic lymphocytes from 22 of 72 MG patients secreted StrAb when cultured with PWM. A high yield of EBV-transformed B cell lines was established from thymus, thymoma, and peripheral blood of seven patients with MG, but clones secreting StrAb arose only from the three patients who had StrAb in their sera. The monoclonal StrAb bound to A bands or I bands in skeletal muscle of human, rat, and frog. One bound to mitochondria in addition to myofibrillar I bands. None bound to nuclei, smooth muscle, or gastric mucosal cells. In immunoblot analyses and ELISAs the monoclonal StrAb bound to muscle and nonmuscle isotypes of myosin, alpha actinin, and/or actin. All bound to contractile proteins common to thymus and muscle, and one selectively immunostained epithelial cells of the thymic medulla. From these antigenic specificities we suggest that StrAb might arise as an immune response directed against the cytoskeletal anchoring proteins associated with nicotinic acetylcholine receptors in thymic epithelial cells undergoing neoplastic transformation to thymoma. PMID:3020150

  1. Are there one million nerve fibres in the human medullary pyramid?

    PubMed

    Wada, A; Goto, J; Goto, N; Kawamura, N; Matsumoto, K

    2001-03-01

    It has been the accepted opinion that there are one million nerve fibres in the human medullary pyramid. This seemed to be confirmed in several old reports. But we cannot agree with this opinion. We made nitrocellulose-embedded sections from three normal male brains, and stained them by our modification of Masson-Goldner method. With this method, myelinated axons appeared in blue, whereas the glial processes were coloured in red, which allowed easy discrimination between the two. After morphometric evaluation of the pyramidal axons under the microscope, it appeared without the slightest doubt, that the number of axons does not exceed one-tenth of one million.

  2. Recognition of a CD4+ mouse medullary thymocyte subpopulation by Amaranthus leucocarpus lectin.

    PubMed Central

    Lascurain, R; Chávez, R; Gorocica, P; Pérez, A; Montaño, L F; Zenteno, E

    1994-01-01

    We have used the Gal beta(1-->3)GalNAc-specific Amaranthus leucocarpus lectin to isolate a thymus cell subpopulation which is different from that sorted with Arachis hypogaea lectin. The cells recognized by A. leucocarpus lectin were predominantly CD4+, whereas a minor proportion of CD8+ cells (approximately 11%) were also identified. The A. leucocarpus-positive cells were located in the thymus medulla and the cortico-medullary junction. The cortex was negative for A. leucocarpus cells. Images Figure 1 Figure 2 Figure 3 PMID:7835965

  3. Renal Medullary Carcinoma with an Aggressive Clinical Course: A Case Report and Review of the Literature

    PubMed Central

    Kalavar, Madhumati R.; Ali, Sami; Safarpour, Damoun; Kunnakkat, Saroj Davi

    2017-01-01

    Renal medullary carcinoma (RMC) is a rare, yet aggressive malignancy of the kidney that is found predominantly in young patients with African descent and sickle cell hemoglobinopathies and most specifically sickle cell trait. Due to its aggressive nature, most cases have metastasis or local invasion at the time of diagnosis. Prognosis is extremely poor with survival less than 1 year after diagnosis. Here we present a case of metastatic RMC in a 29-year-old African female. Despite chemotherapy with cisplatin, gemcitabine, and paclitaxel, and initial shrinkage of the tumor, the patient died 5 months after diagnosis. PMID:28203160

  4. Horner's Syndrome Incidental to Medullary Thyroid Carcinoma Excision: Case Report and Brief Literature Review

    PubMed Central

    Mastronikolis, Nicholas S.; Spiliopoulou, Sofia P.; Zolota, Vassiliki; Papadas, Theodoros A.

    2016-01-01

    Horner's syndrome is characterized by a combination of ipsilateral miosis, blepharoptosis, enophthalmos, facial anhidrosis, and iris heterochromia in existence of congenital lesions. The syndrome results from a disruption of the ipsilateral sympathetic innervation of the eye and ocular adnexa at different levels. Though rare, thyroid and neck surgery could be considered as possible causes of this clinical entity. We present a case of Horner's syndrome in a patient after total thyroidectomy and neck dissection for medullary thyroid cancer with neck nodal disease and attempt a brief review of the relevant literature. PMID:27200201

  5. Multiple endocrine neoplasia similar to human subtype 2A in a dog: Medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma

    PubMed Central

    Arias, E.A. Soler; Castillo, V.A.; Trigo, R.H.; Caneda Aristarain, M.E.

    2016-01-01

    Human multiple endocrine neoplasia subtype 2A (MEN 2A) is characterized by medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia or adenoma in the same individual. In this report, a case of a female Rottweiler with medullary thyroid carcinoma, bilateral pheochromocytoma and parathyroid adenoma was described. Clinical manifestations of muscle weakness, polydipsia, polyuria, diarrhea and weight loss were observed. Two adrenal neoplasms were identified incidentally by ultrasonography, and tumor in the left thyroid lobe was identified by palpation. Primary hyperparathyroidism was diagnosed by biochemical testing. Histopathology report was consistent with diagnosis of bilateral pheochromocytoma and parathyroid adenoma. Immunohistochemical staining was positive for calcitonin and synaptophysin, and negative for thyroglobulin, which confirmed medullary thyroid carcinoma. This case in a dog is presenting neoplastic characteristics similar to human MEN 2A and emphasizing the importance of using immunohistochemistry for confirmation. PMID:27822452

  6. Intramedullary neurenteric cyst of the conus medullaris without associated spinal malformation: a case report and review of the literature.

    PubMed

    Sadeghi-Hariri, Behrouz; Khalatbari, Mahmoud Reza; Hassani, Hajar; Taheri, Behrouz; Abbassioun, Kazem

    2012-01-01

    Spinal neurenteric (NE) cysts are rare congenital anomalies that may occur either alone or in the context of a complex malformative disorder. They are usually intradural-extramedullary lesions. Intramedullary NE cysts not associated with other congenital anomalies are very rare and only a few cases have been reported in the conus medullaris region. Intramedullary neurenteric cysts not associated with other spinal anomalies are very rare especially in the conus medullaris region. MRI is useful to define the cyst and the osseous anomalies associated with this lesion. The goal of treatment of an intramedullary neurenteric cyst is total excision at the first operation, if possible. Life-long follow-up with annual MRI is recommended due to the risk of cyst recurrence. We report an intramedullary NE cyst of the conus medullaris without associated malformation and the relevant literature is briefly reviewed.

  7. Are zinc-bound metallothionein isoforms (I+II and III) involved in impaired thymulin production and thymic involution during ageing?

    PubMed

    Mocchegiani, Eugenio; Giacconi, Robertina; Cipriano, Catia; Muti, Elisa; Gasparini, Nazzarena; Malavolta, Marco

    2004-11-12

    BACKGROUND: With advancing age, thymic efficiency shows progressive decline due to thymic involution allowing impaired cell-mediated immunity and the appearance of age-related diseases. The intrinsic cause of thymic involution is still undefined. Chronic inflammation and high glucocorticoids (GCs) may be involved. However, transgenic mice, with increased GC sensitivity and over expression of GC receptors, display delayed age-associated thymic involution. This fact suggests that other substances may affect thymic involution. Among them, both isoforms of metallothioneins (MTs) I+II and III are the major candidates because their increments leads to organ atrophy in constant stress and are induced by IL-6, which increases in ageing. Enhanced MTs in ageing allows constant sequester of zinc ions and no subsequent zinc release leading to low zinc ion bioavailability for thymic efficiency. This sequester is very limited in very old age. Thus, we have investigated the MTmRNA (I+II and III) in the thymus from young, old and very old mice. METHODS: MTmRNA and IL-6mRNA (RT-PCR) in the thymus from different donors were tested. Concomitantly, TECs proliferation, zinc ion bioavailability (ratio total thymulin/active thymulin), thymulin activity and corticosterone were tested from different donors. RESULTS: Both isoforms of MTmRNA and IL-6mRNA increase in old thymus coupled with low zinc ion bioavailability, reduced TECs proliferation, impaired thymulin activity and enhanced plasma corticosterone in comparison with young. Conversely, although the thymus is involuted in very old mice because of no changes in thymus weight in comparison to old mice, reduced MTmRNA, especially MT-I+II isoforms, and low IL6mRNA occur. Concomitantly, good zinc ion bioavailability, maintained TECs proliferation, satisfactory thymulin activity and reduced corticosterone are observed in very old mice. CONCLUSIONS: The concomitant increments by high IL-6 of both MT isoforms in the thymus from old mice may

  8. Response of mouse thymic cells to radiation after transfusion of mesenchymal stem cells

    PubMed Central

    Zhang, Hongmei; Wang, Ling; Guo, Chunlong; Tong, Zhimin; Liu, Yue; Meng, Xiangkuan; Feng, Hu; Chen, Yubing

    2016-01-01

    Abstract Thymic lymphoma is a highly invasive and even metastatic cancer. This study investigated the effects of mesenchymal stem cells (MSCs) transfusion on cell cycle, cell proliferation, CD3 expression, mutation frequency of T cell receptor using mouse model of thymic lymphoma. C57BL/6J young mouse models of thymoma were injected with MSCs. Six months later, the thymus was taken for pathological examination and flow cytometry studies. The cells were labeled with anti-CD4, CD8, CD3, propidium iodide, or CFDA-SE, cell cycle, proliferation kinetics, and mutation frequency of T cell receptor, respectively. Pathologic results showed that control had clear corticomedular structure with regularly shaped lymphocytes. After radiation, the thymus structure was completely destroyed, with lymphoid tumor cells diffusely distributed and heavily stained, and large nuclei. Transfusion of MSCs resulted in normal thymus structure. Cytometry studies showed that there were more CD4-/CD8- T cells in the thymus of irradiated mice than in control; transfusion of MSCs led to reduced CD4-/CD8- T cells. In irradiated mice, there were less CD4+/CD8+ T cells than in control and MSCs transfusion groups. It was observed that there were more cells arrested in G1 phase in the thymus cells and CD4-/CD8- T cells in irradiated mice than in other 2 groups, whereas there were more cells arrested in S phase in CD4+/CD8+ and CD4+/CD8- T cells in irradiated mice than in the other mice. In the thymus cells, and CD4+/CD8+ and CD4+/CD8- T cells, irradiated mice group had significantly less parent, G2, G3, and G4 cells, and more cells at higher generations, and also higher proliferation index. In CD4-/CD8- T cells, irradiated mice had significantly more parent, G2, and G3 cells, and less G4, G5, G6, and propidium iodide, as compared with the other 2 groups. The expression of CD3 in CD4/CD8 T cells was significantly higher than in control. MSCs transfusion improved CD3 expression, but was still less than

  9. Response of mouse thymic cells to radiation after transfusion of mesenchymal stem cells.

    PubMed

    Zhang, Hongmei; Wang, Ling; Guo, Chunlong; Tong, Zhimin; Liu, Yue; Meng, Xiangkuan; Feng, Hu; Chen, Yubing

    2016-12-01

    Thymic lymphoma is a highly invasive and even metastatic cancer. This study investigated the effects of mesenchymal stem cells (MSCs) transfusion on cell cycle, cell proliferation, CD3 expression, mutation frequency of T cell receptor using mouse model of thymic lymphoma.C57BL/6J young mouse models of thymoma were injected with MSCs. Six months later, the thymus was taken for pathological examination and flow cytometry studies. The cells were labeled with anti-CD4, CD8, CD3, propidium iodide, or CFDA-SE, cell cycle, proliferation kinetics, and mutation frequency of T cell receptor, respectively.Pathologic results showed that control had clear corticomedular structure with regularly shaped lymphocytes. After radiation, the thymus structure was completely destroyed, with lymphoid tumor cells diffusely distributed and heavily stained, and large nuclei. Transfusion of MSCs resulted in normal thymus structure. Cytometry studies showed that there were more CD4-/CD8- T cells in the thymus of irradiated mice than in control; transfusion of MSCs led to reduced CD4-/CD8- T cells. In irradiated mice, there were less CD4+/CD8+ T cells than in control and MSCs transfusion groups. It was observed that there were more cells arrested in G1 phase in the thymus cells and CD4-/CD8- T cells in irradiated mice than in other 2 groups, whereas there were more cells arrested in S phase in CD4+/CD8+ and CD4+/CD8- T cells in irradiated mice than in the other mice. In the thymus cells, and CD4+/CD8+ and CD4+/CD8- T cells, irradiated mice group had significantly less parent, G2, G3, and G4 cells, and more cells at higher generations, and also higher proliferation index. In CD4-/CD8- T cells, irradiated mice had significantly more parent, G2, and G3 cells, and less G4, G5, G6, and propidium iodide, as compared with the other 2 groups. The expression of CD3 in CD4/CD8 T cells was significantly higher than in control. MSCs transfusion improved CD3 expression, but was still less than the control

  10. Modulation of NMDA receptor expression in the rat spinal cord by peripheral nerve injury and adrenal medullary grafting.

    PubMed

    Hama, A T; Unnerstall, J R; Siegan, J B; Sagen, J

    1995-07-31

    Excessive activation of N-methyl-D-aspartate (NMDA) receptors in the spinal cord consequent to peripheral injury has been implicated in the initiation of neuropathologic events leading to a state of chronic hyperexcitability and persistence of exaggerated sensory processing. In other CNS disease or injury states, NMDA-mediated neurotoxic damage is associated with a loss of NMDA receptors, and outcome may be improved by agents reducing NMDA activation. Previous findings in our laboratory have demonstrated that the transplantation of adrenal medullary tissue into the spinal subarachnoid space can alleviate sensory abnormalities and reduce the induction of a putative nitric oxide synthase consequent to peripheral nerve injury. In order to determine changes in NMDA receptor expression in the spinal cord following peripheral nerve injury and adrenal medullary grafting, NMDA receptor binding using a high-affinity competitive NMDA receptor antagonist, CGP-39653, and NMDAR1 subunit distribution using immunocytochemistry were investigated. Two weeks following peripheral nerve injury by loose ligation of the right sciatic nerve, either adrenal medullary or striated muscle (control) tissue pieces were implanted in the spinal subarachnoid space. Binding studies revealed a marked reduction in [3H]CGP-39653 binding at L4-L5 levels ipsilateral to peripheral nerve injury in control transplanted animals. In contrast, NMDA binding was normalized in adrenal medullary grafted animals. In addition, NMDAR1 immunoreactivity was reduced in both the dorsal horn neuropil and motor neurons of the ventral horn in animals with peripheral nerve injury, while levels in adrenal medullary grafted animals appeared similar to intact controls. These results suggest that adrenal medullary transplants reduce abnormal sensory processing resulting from peripheral injury by intervening in the spinal NMDA-excitotoxicity cascade.

  11. Scanning electron microscopic studies of the surface morphology of the vomeronasal epithelium and olfactory epithelium of garter snakes.

    PubMed

    Wang, R T; Halpern, M

    1980-04-01

    Fixed vomeronasal and olfactory epithelia from normal adult garter snakes were microdissected, fractured, and examined with a scanning electron microscope. The method permits a detailed comparative study of the structural organization and morphological characteristics of the constituent cells of the vomeronasal and olfactory epithelia. Despite similarities in the nomenclature of the constituent cells in both epithelia, significant differences exist in their surface morphology. A unique columnar structure composed of non-neuronal elements is present in the vomeronasal epithelium. These columns house the bioplar neurons and undifferentiated cells. Such a columnar organization is absent in the olfactory epithelium. In vomeronasal epithelium the bipolar neurons possess microvillous terminals at their dendritic tips, while the dendritic tips of the bipolar neurons of the olfactory epithelium possess cilia. Vomeronasal supporting cells are covered with microvilli, while olfactory supporting cells are covered with cytoplasmic protuberances in addition to the microvilli. In the vomeronasal epithelium the pear-shaped neurons have a grossly smooth surface and are organized into clusters, while in the olfactory epithelium the elliptical bipolar neurons are spinous, aligned side-by-side and interdigitate. The basal (undifferentiated) cell layer in the vomeronasal epithelium has a high packing density and is composed of several layers of irregularly shaped cells. In the olfactory epithelium the basal cell layer is loosely organized and composed of a single layer of oval cells. This information on the three-dimensional cell structure of both epithelia provides a basis for experimental observations on changes in morphology of the bipolar neurons during genesis, development, maturation, degeneration, and regeneration in postnatal, adult animals.

  12. Medullary lateral line units of rudd, Scardinius erythrophthalmus, are sensitive to Kármán vortex streets.

    PubMed

    Klein, Adrian; Winkelnkemper, Jan; Dylda, Evelyn; Bleckmann, Horst

    2015-07-01

    We investigated the responses of medullary lateral line units of the rudd, Scardinius erythrophthalmus, to bulk water flow (7 cm s(-1)) and to water flow that contained vortices shed by an upstream half cylinder (diameter 1, 2, and 3 cm). Thirty-five percent of the medullary units either increased or decreased their discharge rate with the increasing cylinder diameter. In some units, the spike patterns revealed the vortex shedding frequency, i.e., in these units the amplitude of spike train frequency spectra was similar or identical to the vortex shedding frequency.

  13. [A sudden C3-C4 tetraplegia revealing an intracranial dural arteriovenous draining into the spinal medullary veins].

    PubMed

    Meaudre, E; Kaiser, E; Boret, H; Cantais, E; Artéaga, C; Palmier, B

    2005-10-01

    We report a case of intracranial dural arteriovenous (DAVF) draining into the spinal medullary veins. A 49-year-old woman presented a rapidly progressive ascending myelopathy resulting in a C3-C4 tetraplegia associated with acute respiratory failure at the twelfth hour. MRI revealed swelling of the cervical spinal cord, hyperintensity on T2 and enhancement of enlarged veins on MR angiography. A conventional angiography showed the DAVF with venous drainage into the spinal vein extending to the conus medullaris. After embolization, neurological recovery occurred during the first week, allowing tracheal extubation on day 2. Clinical, radiological and therapeutic aspects of this uncommon pathology are presented.

  14. Potassium transport by medullary collecting tubule of rabbit: Effects of variation in K intake

    SciTech Connect

    Wingo, C.S. Veterans Administration Medical Center, Gainesville, FL )

    1987-12-01

    These studies examine the effect of dietary K content on the rate efflux coefficient (K{sub k}) assessed both isotopically ({sup 42}K) and by net K flux in segments dissected from the inner stripe of the outer medullary collecting tubule (MCT). Female New Zealand White rabbits were given either a K-replete diet (KCl diet) or one of two K-restricted diets with similar K content. After 7 days, renal K excretion varied with K intake. To determine whether alterations in K{sub k} of MCT could contribute to these changes in urinary K excretion, the MCT from the three groups of rabbits was perfused in vitro and volume reabsorption and K{sub k} were measured. Net K flux in the presence of a 15 mM lumen-to-bath K gradient confirmed a significantly greater K reabsorptive flux and net rate coefficient in either K-restricted group than the K-replete control group. A model used to assess the relative contribution of cortical secretory flux and medullary absorptive flux shows that at physiological flow rates for the MCT such alterations in the apparent K permeability of the MCT could have dramatic effects on the reabsorption of K from the lumen and thereby on K excretion. These observations demonstrate that K movement from lumen to interstitium is influenced by dietary K intake and that the MCT participates in K homeostasis.

  15. Renal medullary carcinoma: sonographic, computed tomography, magnetic resonance and angiographic findings.

    PubMed

    Khan, A; Thomas, N; Costello, B; Jobling, L; deKretser, D; Broadfield, E; O'Shea, S

    2000-07-01

    Renal medullary carcinoma is a recently described, highly aggressive tumour, occurring predominantly in young patients of African descent with sickle cell trait (SCT). All have been metastatic at surgery. Surgery, radiotherapy and chemotherapy do not appear to alter the course of the disease. The survival time is very short. Presentation is usually with haematuria, abdominal pain and weight loss. Forty-nine patients have been reported from the USA, of these 47 were African/Americans. The reports have mostly appeared in pathology journals. On review of the imaging findings reported in the radiological journals, it becomes apparent that it is possible for a radiologist to suggest a specific diagnosis in the appropriate demographic and clinical setting. Here the first British patient of Afro-Caribbean decent in whom a pre-operative diagnosis was suggested on the imaging findings of a centrally located renal pelvic tumour, encasing the pelvis on a background of SCT in a 28-year-old is described. It is expected that a high index of suspicion in the appropriate clinical setting may lead to earlier diagnosis, treatment and survival of patients. The patient is alive and reasonably well 9 months after surgery. The full range of imaging findings in renal medullary carcinoma are described.

  16. Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells

    PubMed Central

    Gild, Matti L; Landa, Iñigo; Ryder, Mabel; Ghossein, Ronald A; Knauf, Jeffrey A; Fagin, James A

    2015-01-01

    Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1, and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC2 kinase inhibitor, also resulted in marked growth suppression to levels similar to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells and provide a rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations. PMID:23828865

  17. Ectopic ACTH Production Leading to Diagnosis of Underlying Medullary Thyroid Carcinoma

    PubMed Central

    Matheny, Leslee N.; Wilson, Jessica R.; Baum, Howard B. A.

    2016-01-01

    Medullary thyroid carcinoma (MTC) has been described as a source of ectopic ACTH secretion in patients with Cushing’s syndrome. This is an infrequent association, occurring in less than 1% of MTC cases. Among these, it is even more unusual for an initial diagnosis of hypercortisolism to lead to the discovery of underlying MTC. Here we present a case of a patient with weakness, diarrhea, and hypokalemia who was found first to have Cushing’s syndrome and later diagnosed with metastatic MTC. The patient was treated initially with oral agents to control his hypercortisolism, then with an etomidate infusion after experiencing intestinal perforation. He also received vandetanib therapy targeting his underlying malignancy, as this has been shown to reverse clinical signs of Cushing’s syndrome in patients with MTC and subsequent ectopic ACTH secretion. Bilateral adrenalectomy was ultimately required. Medullary thyroid carcinoma should be considered in patients presenting with Cushing’s syndrome due to ectopic ACTH secretion, and a multimodality treatment approach is often required. PMID:27141514

  18. Immunohistochemical and ultrastructural analysis of medullary carcinoma of the thyroid in relation to hormone production.

    PubMed Central

    Kameya, T.; Shimosato, Y.; Adachi, I.; Abe, K.; Kasai, N.; Kimura, K.; Baba, K.

    1977-01-01

    Eighteen cases of medullary carcinoma of the thyroid were analyzed immunohistochemically for calcitonin- and ACTH-containing cells, and tumor cells in 8 cases were examined by an electron microscope and analyzed by manual and computer procedures with particular attention paid to the size and quality of secretory granules. Calcitonin- and ACTH-containing cells were found singly or in clusters in 14 and 11 tumors, respectively. In 4 cases, calcitonin-positive cell clusters and an increase in number of singly scattered C cells were seen apart from the main tumor, suggesting a multicentric nature of certain medullary carcinomas. Some ACTH-containing cells were apparently also positive for calcitonin. In a case of familial Sipple disease, follicular lining cells were replaced in areas with ACTH-containing cells. Three to five frequency distribution curves of the size of secretory granules were obtained in all of 6 cases analyzed, and at least two different types of granule matrix were identified. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 PMID:202164

  19. Neuropsychological effects of brain autograft of adrenal medullary tissue for the treatment of Parkinson's disease.

    PubMed

    Ostrosky-Solís, F; Quintanar, L; Madrazo, I; Drucker-Colín, R; Franco-Bourland, R; Leon-Meza, V

    1988-09-01

    We describe the pre- and postoperative neuropsychological profiles of seven patients who received an autograft of adrenal medullary tissue to the caudate nucleus for the treatment of Parkinson's Disease (PD). The preoperative neuropsychological evaluations revealed specific cognitive deficits of varying degree. The patients showed frontal lobe-type deficits with alterations in behavioral programming leading to difficulties in the organization of motor sequences and alternating programs. They also showed memory disorders and visuospatial and visuoperceptual deficiences such as a loss of figure-ground perspective and fragmentation. Postoperative evaluations, carried out 3 months after neurosurgery, revealed a significant amelioration of the frontal lobe-type symptoms and visuospatial deficits, as well as an improvement in memory tasks that require an active organization of the response. Immediate and delayed memory difficulties remained unchanged. These observations were compared to neuropsychological data obtained from neurologically intact subjects and from unoperated PD patients. The improvements of the operated PD patients resulted in performance levels close to normal values and clearly distinguishable from those of unoperated PD patients, and were unrelated to improved mood, increased alertness, or sustained attention. Autotransplantation of adrenal medullary tissue to the caudate nucleus of PD patients showing a decreased effective response to L-dopa therapy can partially restore motor functions and frontal-type cognitive symptoms.

  20. Laterality of bolus passage through the pharynx in patients with unilateral medullary infarction.

    PubMed

    Mikushi, Shinya; Kagaya, Hitoshi; Baba, Mikoto; Tohara, Haruka; Saitoh, Eiichi

    2014-02-01

    Laterality of bolus passage in the pharynx is often seen in patients with medullary infarction. We evaluated the dominant side of bolus passage in the pharynx and investigated the factors that cause the passage to dominantly occur on the affected side. Forty-one patients (35 men and 6 women, 64 ± 9 years) with unilateral medullary infarction participated in this study. Bolus passage of 4 mL of thick liquid was evaluated in 3 regions (oropharyngeal, thyropharyngeal, and cricopharyngeal) and classified into 4 patterns (dominantly on the unaffected side [UAS], on both sides without clear laterality [BS], dominantly on the affected side [AS], and nonpassage of the bolus [NP]) by videofluoroscopic examination of swallowing. The bolus passages were as follows: UAS, BS, and AS occurred in 2, 32, and 7 patients in the oropharyngeal region; UAS, BS, and AS occurred in 5, 20, and 16 patients in the thyropharyngeal region; and UAS, BS, AS, and NP occurred in 11, 9, 10, and 11 patients in the cricopharyngeal region, respectively. In the thyropharyngeal region, the proportion of patients in whom the swallowing reflex occurred when the bolus was in the oropharynx and the proportion of patients with unilateral pharyngeal constrictor paralysis were greater in patients whose bolus passage was AS than in patients whose passage was BS. This suggests that the bolus predominantly passed through the affected side of the thyropharyngeal portion because of the asymmetry of pharyngeal contraction during swallowing in the early period after onset.

  1. Adrenal medullary transplantation to the caudate nucleus in Parkinson's disease. Initial clinical results in 18 patients.

    PubMed

    Allen, G S; Burns, R S; Tulipan, N B; Parker, R A

    1989-05-01

    Results from a pilot study of adrenal medullary autotransplantation for Parkinson's disease are presented. Eighteen patients were studied; 12 were followed up for 1 year, and 6 were followed up for 6 months. Four of 12 patients showed distinct improvement in the signs and symptoms of their disease, as assessed using the Columbia Rating Scale, at 1 year; none showed distinct deterioration. The 6 patients who were followed up for only 6 months were an average of 20 years older and generally more severely affected. None distinctly improved. Morbidity was considered to be minor and transient among the first 12 patients, while 4 of the last 6 patients experienced alteration in mental status lasting as long as several months. This problem has led us to conclude that older patients with preexisting cognitive impairment should not be included in future studies until the benefits are more clearly established. However, we believe that the distinct and persistent improvement seen in some of the younger patients warrants the initiation of a well-designed, randomized, and controlled trial of adrenal medullary autotransplantation for the purpose of confirming these results and assessing the effect of the procedure on the natural progression of Parkinson's disease.

  2. Upregulation of norepinephrine transporter function by prolonged exposure to nicotine in cultured bovine adrenal medullary cells.

    PubMed

    Itoh, Hideaki; Toyohira, Yumiko; Ueno, Susumu; Saeki, Satoru; Zhang, Han; Furuno, Yumi; Takahashi, Kojiro; Tsutsui, Masato; Hachisuka, Kenji; Yanagihara, Nobuyuki

    2010-09-01

    Nicotine acts on nicotinic acetylcholine receptors in the adrenal medulla and brain, thereby stimulating the release of monoamines such as norepinephrine (NE). In the present study, we examined the effects of prolonged exposure to nicotine on NE transporter (NET) activity in cultured bovine adrenal medullary cells. Treatment of adrenal medullary cells with nicotine increased [(3)H]NE uptake in both a time- (1-5 days) and concentration-dependent (0.1-10 muM) manner. Kinetic analysis showed that nicotine induced an increase in the V (max) of [(3)H]NE uptake with little change in K (m). This increase in NET activity was blocked by cycloheximide, an inhibitor of ribosomal protein synthesis, but not by actinomycin D, a DNA-dependent RNA polymerase inhibitor. [(3)H]NE uptake induced by nicotine was strongly inhibited by hexamethonium and mecamylamine but not by alpha-bungarotoxin, and was abolished by elimination of Ca(2+) from the culture medium. KN-93, an inhibitor of Ca(2+)/calmodulin-dependent protein kinase II, attenuated not only nicotine-induced [(3)H]NE uptake but also (45)Ca(2+) influx in the cells. The present findings suggest that long-term exposure to nicotine increases NET activity through a Ca(2+)-dependent post-transcriptional process in the adrenal medulla.

  3. Medullary metastasis of a malignant peripheral nerve sheath tumor: A case report

    PubMed Central

    Hagi, Tomohito; Nakamura, Tomoki; Yokoji, Ayumu; Matsumine, Akihiko; Sudo, Akihiro

    2016-01-01

    The present study reports a case of medullary metastasis without lung metastasis that occurred as a result of a malignant peripheral nerve sheath tumor (MPNST). An 81-year-old woman presented with a MPNST in the left brachial plexus, arising from the cervical nerve root. The patient underwent carbon ion radiotherapy; however, tumor recurrence was identified in the left shoulder. Subsequently, the patient underwent wide excision. Three weeks subsequent to surgery, imbalance and dysarthria developed suddenly. Dysphagia emerged and left upper limb pain disappeared on the day after symptom development. Magnetic resonance imaging (MRI) revealed that this was due to metastasis to the medulla. Five days subsequent to the onset of dysarthria, the patient succumbed due to respiratory failure. To the best of our knowledge, no previous cases of medullary metastasis arising from a MPNST in the absence of lung metastasis have been reported. MRI is a useful examination tool for the identification of brain metastases; however, the high cost of MRI as a routine examination must be considered due to the rarity of brain metastases. Therefore, methods to detect brain metastasis warrant further investigation. PMID:27588138

  4. Medullary respiratory neural activity during hypoxia in NREM and REM sleep in the cat.

    PubMed

    Lovering, Andrew T; Fraigne, Jimmy J; Dunin-Barkowski, Witali L; Vidruk, Edward H; Orem, John M

    2006-02-01

    Intact unanesthetized cats hyperventilate in response to hypocapnic hypoxia in both wakefulness and sleep. This hyperventilation is caused by increases in diaphragmatic activity during inspiration and expiration. In this study, we recorded 120 medullary respiratory neurons during sleep in hypoxia. Our goal was to understand how these neurons change their activity to increase breathing efforts and frequency in response to hypoxia. We found that the response of medullary respiratory neurons to hypoxia was variable. While the activity of a small majority of inspiratory (58%) and expiratory (56%) neurons was increased in response to hypoxia, the activity of a small majority of preinspiratory (57%) neurons was decreased. Cells that were more active in hypoxia had discharge rates that averaged 183% (inspiratory decrementing), 154% (inspiratory augmenting), 155% (inspiratory), 230% (expiratory decrementing), 191% (expiratory augmenting), and 136% (expiratory) of the rates in normoxia. The response to hypoxia was similar in non-rapid-eye-movement (NREM) and REM sleep. Additionally, changes in the profile of activity were observed in all cell types examined. These changes included advanced, prolonged, and abbreviated patterns of activity in response to hypoxia; for example, some inspiratory neurons prolonged their discharge into expiration during the postinspiratory period in hypoxia but not in normoxia. Although changes in activity of the inspiratory neurons could account for the increased breathing efforts and activity of the diaphragm observed during hypoxia, the mechanisms responsible for the change in respiratory rate were not revealed by our data.

  5. Activation of K+ channels in renal medullary vesicles by cAMP-dependent protein kinase

    SciTech Connect

    Reeves, W.B.; McDonald, G.A.; Mehta, P.; Andreoli, T.E. )

    1989-07-01

    ADH, acting through cAMP, increases the potassium conductance of apical membranes of mouse medullary thick ascending limbs of Henle. The present studies tested whether exposure of renal medullary apical membranes in vitro to the catalytic subunit of cAMP-dependent protein kinase resulted in an increase in potassium conductance. Apical membrane vesicles prepared from rabbit outer renal medulla demonstrated bumetanide- and chloride-sensitive {sup 22}Na+ uptake and barium-sensitive, voltage-dependent {sup 86}Rb+ influx. When vesicles were loaded with purified catalytic subunit of cAMP-dependent protein kinase (150 mU/ml), 1 mM ATP, and 50 mM KCl, the barium-sensitive {sup 86}Rb+ influx increased from 361 {plus minus} 138 to 528 {plus minus} 120 pM/mg prot.30 sec (P less than 0.01). This increase was inhibited completely when heat-stable protein kinase inhibitor (1 microgram/ml) was also present in the vesicle solutions. The stimulation of {sup 86}Rb+ uptake by protein kinase required ATP rather than ADP. It also required opening of the vesicles by hypotonic shock, presumably to allow the kinase free access to the cytoplasmic face of the membranes. We conclude that cAMP-dependent protein kinase-mediated phosphorylation of apical membranes from the renal medulla increases the potassium conductance of these membranes. This mechanism may account for the ADH-mediated increase in potassium conductance in the mouse mTALH.

  6. Effects of oxalate on IMCD cells: a line of mouse inner medullary collecting duct cells.

    PubMed

    Maroni, Paul D; Koul, Sweaty; Meacham, Randall B; Chandhoke, Paramjit S; Koul, Hari K

    2004-12-01

    Oxalate, a metabolic end product and a major constituent of the majority of renal stones, has been shown to be toxic to renal epithelial cells of cortical origin. However, it is unknown whether inner medullary collecting duct (IMCD) cells that are physiologically exposed to higher concentrations of oxalate also behave in a similar manner. In the present study, we examined the effects of oxalate on IMCD cells. IMCD cells from the mouse were maintained in DMEM/F12 media supplemented with fetal bovine serum and antibiotics. Exposure of IMCD cells to oxalate produced time- and concentration-dependent changes in the light microscopic appearance of the cells. Long-term exposure to oxalate resulted in alterations in cell viability, with net cell loss after exposure to concentrations of 2 mM or greater. The production of free radicals was directly related to the exposure time and the concentration of oxalate. Crystal formation occurred in less than 1 h and cells in proximity to crystals would lose membrane integrity. Compared with IMCD cells, LLC-PK1 cells as well as HK-2 cells showed significant toxicity starting at lower oxalate concentrations (0.4 mM or greater). These results provide the first direct demonstration of toxic effects of oxalate in IMCD cells, a line of renal epithelial cells of the inner medullary collecting duct, and suggest that the cells lining the collecting duct are relatively resistant to oxalate toxicity.

  7. 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.

  8. Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP)

    PubMed Central

    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

  9. TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets

    PubMed Central

    Muñoz-Ruiz, Miguel; Ribot, Julie C.; Grosso, Ana R.; Gonçalves-Sousa, Natacha; Pamplona, Ana; Pennington, Daniel J.; Regueiro, José R.

    2016-01-01

    The murine thymus produces discrete γδ T cell subsets making either interferon-γ (IFN--γ) or interleukin 17 (IL-17), but the role of the TCR in this developmental process remains controversial. Here we show that mice haploinsufficient for both Cd3g and Cd3d (CD3DH, for CD3 double haploinsufficient) have reduced TCR expression and signaling strength selectively on γδ T cells. CD3DH mice had normal numbers and phenotype 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

  10. Murine thymic NK cells are distinct from ILC1s and have unique transcription factor requirements.

    PubMed

    Gabrielli, Sara; Sun, Mengxi; Bell, April; Zook, Erin C; de Pooter, Renee F; Zamai, Loris; Kee, Barbara L

    2017-03-09

    Group 1 innate lymphoid cells include natural killer (NK) cells and ILC1s, which mediate the response to intracellular pathogens. Thymic NK (tNK) cells were described with hybrid features of immature NK cells and ILC1 but whether these cells are related to NK cells or ILC1 has not been fully investigated. We report that murine tNK cells expressed the NK-cell associated transcription factor EOMES and developed independent of the essential ILC1 factor TBET, confirming their placement within the NK lineage. Moreover, tNK cells resemble NK cells rather than ILC1 in their requirements for the E protein transcription factor inhibitor ID2. We provide further insight into the mechanisms governing tNK-cell development by showing that the transcription factor ETS1 prevented tNK cell acquisition of the conventional NK-cell maturation markers CD11b and KLRG1. Our data reveal few ILC1 in the thymus and clarify the identity and developmental requirements of tNK cells. This article is protected by copyright. All rights reserved.

  11. Induction of thymic tolerance as possibility in prevention of recurrent spontaneous abortion.

    PubMed

    Bubanovic, I V

    2003-04-01

    A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive cells in the thymus and/or inhibition of specific Th(1) cells clones. Deletion process includes two selection mechanisms in which the thymus eliminates unwanted thymocytes are known as positive selection and negative selection. The thymus is an antigenically privileged site, mainly for it is discrete by blood-thymus barrier. Many researches were shown that intrathymic inoculation of any antigen resulted in specific tolerance induction. The embryo/fetus and placenta are an allograft to which the mother must remain immunologically tolerant in order for the fetus to survive. Today, there is much interest focused on the immunology of recurrent spontaneous abortion (RSA). Up to 50% of RSA may be mediated by the immune system via inadequate maternal anti-paternal response. Nature of this maternal-fetal disturbance represents disbalance in Th(1)/Th(2) activity. Contra-shift in Th(1)/Th(2) activity is the basis for immunotherapy with paternal leukocyte immunization (PLI). PLI induce some kind of peripheral tolerance on embryonic/fetal/trophoblast antigens, but problems of central tolerance are still open. Intrathymic inoculation of fetal or paternal cells (like leukocyte, thymic dendritic cells, trophoblast cells) or paternal set of MHC molecules may cause central specific tolerance and may be a new possibility for immunotherapy in RSA patients.

  12. Inhibitory effects of nicotine derived from cigarette smoke on thymic stromal lymphopoietin production in epidermal keratinocytes.

    PubMed

    Dong, Jiangxu; Segawa, Ryosuke; Mizuno, Natsumi; Hiratsuka, Masahiro; Hirasawa, Noriyasu

    2016-04-01

    Thymic stromal lymphopoietin (TSLP) is regarded as the main factor responsible for the pathogenesis of atopic dermatitis (AD). Cigarette smoke is an aggravating factor for allergies, but has been reported to decrease the risk of AD. In the present study, we evaluated the role of nicotine, the main constituent in cigarette smoke extract, and its underlying mechanism of action in the regulation of TSLP expression. We found that nicotine significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced TSLP expression in BALB/c mice and the mouse keratinocyte cell line PAM212. Nicotine inhibition of TSLP production was abolished by pretreatments with α7 nicotinic acetylcholine receptor (α7 nAChR) antagonists, AMP-activated protein kinase (AMPK) inhibitor, and phosphoinositide 3-kinase (PI3K) inhibitors. The same inhibitors abolished inhibition of nuclear factor-κB (NF-κB) activation by nicotine. These results suggest that nicotine inhibits the expression of TSLP by suppressing the activation of NF-κB through the α7 nAChR-PI3K-AMPK signaling pathway.

  13. DHEA and testosterone therapies in Trypanosoma cruzi-infected rats are associated with thymic changes.

    PubMed

    Filipin, Marina Del Vecchio; Caetano, Leony Cristina; Brazão, Vânia; Santello, Fabricia Helena; Toldo, Míriam Paula Alonso; do Prado, José Clóvis

    2010-08-01

    The ability of the gonadal hormones to influence diverse immunological functions during the course of several infections has been extensively studied in the latest decades. Testosterone has a suppressive effect on immune response of vertebrates and increases susceptibility toward numerous parasitic diseases. Dehydroepiandrosterone is an abundant steroid hormone secreted by the human adrenal cortex and it is considered potent immune-activator. In this paper, it was examined the effects of DHEA and testosterone supplementation in the thymic atrophy in rats infected with Trypanosoma cruzi, by comparing blood parasitism, thymocyte proliferation, TNF-alpha and IL-12 levels. Our data point in the direction that DHEA treatment triggered enhanced thymocyte proliferation as compared to its infected counterparts and reduced production of TNF-alpha during the acute phase of infection. Oppositely, the lowest values for cells proliferation and IL-12 concentrations were reached in testosterone-supplied animals. The combined treatment testosterone and DHEA improves the effectiveness of the host's immune response, reducing blood parasites and the immunosuppressive effects of male androgens besides increasing IL-12 concentrations and decreasing TNF-alpha levels.

  14. The effect of thymic inoculation to induce tolerance of allogeneic thyroid grafts in the outbred rabbit.

    PubMed

    Torchia, M G; Aitken, R M; Thliveris, A

    1998-10-01

    Many studies have demonstrated that allograft tolerance can be achieved in inbred rats and mice following intrathymic injection of donor cells or antigen and treatment with antilymphocyte serum (ALS). In outbred dogs, xenografts, and inbred rat strains with major MHC antigen difference, tolerance has not similarly been induced. The focus of this study was to determine whether allogeneic thyroid graft tolerance could be achieved in outbred rabbits. In the experimental group (n = 5), recipients received an intrathymic injection of donor lymphocytes and a single treatment of ALS. Controls (n = 5) received intrathymic cell culture medium and ALS treatment. Donor-recipient allogenicity was monitored with mixed lymphocyte culture (MLC) over 18 weeks. Donor thyroid tissue was placed into recipient gluteal muscle fibres one week following the last MLC measurement. A third group of rabbits (n = 4) received thyroid autografts without any other treatment. There were no differences in MLC stimulation indices (SI) between the control and experimental group nor did MLC (SI) change within groups. All thyroid autografts survived the two week monitoring period and demonstrated normal appearing thyroid follicles on histologic examination. All thyroid allografts showed severe acute rejection reactions on biopsy within one week. Further studies using outbred animals to examine the role of thymic inoculation are required to determine whether similar techniques might be successful in the human.

  15. Detection of human cytomegalovirus in normal and neoplastic breast epithelium

    PubMed Central

    2010-01-01

    Introduction Human cytomegalovirus (HCMV) establishes a persistent life-long infection, and can cause severe pathology in the fetus and the immunocompromised host[1]. Breast milk is the primary route of transmission in humans worldwide, and breast epithelium is thus a likely site of persistent infection and/or reactivation, though this phenomenon has not previously been demonstrated. Increasing evidence indicates HCMV infection can modulate signaling pathways associated with oncogenesis. We hypothesized that persistent HCMV infection occurs in normal adult breast epithelium and that persistent viral expression might be associated with normal and neoplastic ductal epithelium. Methods Surgical biopsy specimens of normal breast (n = 38) breast carcinoma (n = 39) and paired normal breast from breast cancer patients (n = 21) were obtained. Specimens were evaluated by immunohistochemistry, in situ hybridization, PCR and DNA sequencing for evidence of HCMV antigens and nucleic acids. Results We detected HCMV expression specifically in glandular epithelium in 17/27 (63%) of normal adult breast cases evaluated. In contrast, HCMV expression was evident in the neoplastic epithelium of 31/32 (97%) patients with ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) cases evaluated (p = 0.0009). Conclusions These findings are the first to demonstrate that persistent HCMV infection occurs in breast epithelium in a significant percentage of normal adult females. HCMV expression was also evident in neoplastic breast epithelium in a high percentage of normal and neoplastic breast tissues obtained from breast cancer patients, raising the possibility that viral infection may be involved in the neoplastic process. PMID:21429243

  16. Effects of formaldehyde on normal xenotransplanted human tracheobronchial epithelium.

    PubMed Central

    Ura, H.; Nowak, P.; Litwin, S.; Watts, P.; Bonfil, R. D.; Klein-Szanto, A. J.

    1989-01-01

    Epithelial cells obtained from autopsies of full-term fetuses or infants less than 1 year old were isolated, amplified in primary cultures and inoculated in deepithelialized rat tracheas. These tracheas were then sealed and transplanted subcutaneously into irradiated athymic nude mice. Four weeks after transplantation the tracheal lumen was completely covered by epithelium, most of which was of mucociliary respiratory type. At this stage, tracheal transplants containing tracheobronchial epithelium from 20 different donors were exposed to silastic devices containing 0, 0.5, 1 and 2 mg paraformaldehyde. The tracheal transplants were examined histologically at 2, 4, 8, and 16 weeks after transplantation. Before sacrifice, all animals were injected with a single pulse of tritiated thymidine. Important epithelial alterations could be seen in the formaldehyde treated transplants with a maximum effect visible at 2 weeks after exposure. The highest dose of 2 mg produced, in most cases, numerous areas of epithelial erosion and inflammation whereas this effect was not as evident with the lower doses. All doses produced areas of hyperplastic epithelium alternating with areas of pleomorphic-atrophic epithelium. Although the differences in predominance of different types of epithelium was not clearly dose-dependent, the labeling index (LI) showed dose dependence between 2 and 4 weeks after initiation of exposure. The maximum mean LI was three to four times higher than normal, although in some focal hyperplastic-metaplastic lesions the LI was increased up to 20 times. These studies show that formaldehyde, although toxic at higher doses, is able to elicit at lower doses a proliferative response of the human respiratory epithelium that is not preceded by a massive toxic effect. This response is similar, although less intense than that of the rat respiratory epithelium in which formaldehyde proved to be a carcinogen. Images Figure 2 Figure 5 PMID:2913828

  17. Signature microRNAs in human cornea limbal epithelium.

    PubMed

    Teng, Yufei; Wong, Hoi Kin; Jhanji, Vishal; Chen, Jian Huan; Young, Alvin Lerrmann; Zhang, Mingzhi; Choy, Kwong Wai; Mehta, Jodhbir Singh; Pang, Chi Pui; Yam, Gary Hin-Fai

    2015-05-01

    This study was aimed to identify the signature microRNAs, which regulate the biological processes of corneal epithelial progenitor cell (CEPC) homeostasis and regulation through characterizing the differential expression profile of microRNAs in human limbal epithelium containing adult CEPC versus central corneal epithelium without CEPC. MicroRNA microarray had identified 37 microRNAs enriched in human corneal epithelium. Among them, nine were significantly upregulated in limbal epithelium and one in central corneal epithelium after validation by TaqMan® real-time polymerase chain reaction. In addition to our previous finding of miR-143 and 145, the expression of miR-10b, 126, and 155 was localized in limbal epithelium (LE) (predominantly basal layers) by using locked nucleic acid-based in situ hybridization. Potential target genes were predicted by TargetScan Human v6.0 and compared to the reported human cornea epithelial gene profile GSE5543. Analyzed by web-based Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and DAVID Functional Annotation Bioinformatics Resources v6.7, the downregulated genes were involved in pathways of immune response and cellular protection, apoptosis, and cell movement whereas upregulated genes with cell survival, cell-matrix interaction, and cell-cell adhesion. We found a constant occurrence of miR-143, 145, and 155 in all KEGG pathways regulating limbal epithelial events. By Ingenuity Systems (IPA®) analysis, these microRNAs could cooperatively regulate cell growth and apoptosis via tumor necrosis factor activation and MYC repression. Our findings thus suggest a unique microRNA signature existing in human limbal epithelium and participating in CEPC homeostasis.

  18. Developmental origin of the posterior pigmented epithelium of iris.

    PubMed

    Wang, Xiaobing; Xiong, Kai; Lu, Lei; Gu, Dandan; Wang, Songtao; Chen, Jing; Xiao, Honglei; Zhou, Guomin

    2015-03-01

    Iris epithelium is a double-layered pigmented cuboidal epithelium. According to the current model, the neural retina and the posterior iris pigment epithelium (IPE) are derived from the inner wall of the optic cup, while the retinal pigment epithelium (RPE) and the anterior IPE are derived from the outer wall of the optic cup during development. Our current study shows evidence, contradicting this model of fetal iris development. We demonstrate that human fetal iris expression patterns of Otx2 and Mitf transcription factors are similar, while the expressions of Otx2 and Sox2 are complementary. Furthermore, IPE and RPE exhibit identical morphologic development during the early embryonic period. Our results suggest that the outer layer of the optic cup forms two layers of the iris epithelium, and the posterior IPE is the inward-curling anterior rim of the outer layer of the optic cup. These findings provide a reasonable explanation of how IPE cells can be used as an appropriate substitute for RPE cells.

  19. Ectopic Cushing syndrome associated with thymic carcinoid tumor as the first presentation of MEN1 syndrome-report of a family with MEN1 gene mutation.

    PubMed

    Hasani-Ranjbar, Shirin; Rahmanian, Masoud; Ebrahim-Habibi, Azadeh; Soltani, Akbar; Soltanzade, Akbar; Mahrampour, Elnaz; Amoli, Mahsa M

    2014-06-01

    Multiple endocrine neoplasia type 1(MEN1) is an autosomal dominant syndrome. Although thymic carcinoid tumor is recognized as a part of MEN1 syndrome but functioning thymic carcinoid tumor as the first presentation of the MEN1 seems to be very rare. In this report, we present a 29-year-old male who developed ectopic Cushing syndrome secondary to thymic carcinoid tumor and was diagnosed as MEN1 syndrome 2 years later. Further evaluation revealed the presence of carcinoid tumor and other MEN 1 manifestations in several other member of family. Genetic evaluation showed presence of a previously reported mutation in exon 10(R527X) of MEN1 gene in these patients. This presentation showed that thymic neuroendocrine tumor could be the first manifestation of the MEN1 syndrome and it might be diagnosed as a dominant manifestation of this syndrome in a family. We suggest biochemical or genetic screening for MEN-1 syndrome for patients with thymic carcinoid.

  20. Expression Analyses Revealed Thymic Stromal Co-Transporter/Slc46A2 Is in Stem Cell Populations and Is a Putative Tumor Suppressor.

    PubMed

    Kim, Ki Yeon; Lee, Gwanghee; Yoon, Minsang; Cho, Eun Hye; Park, Chan-Sik; Kim, Moon Gyo

    2015-06-01

    By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the CD31(+) endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca-1(+) fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation.

  1. Oxygen-dependent expression of hypoxia-inducible factor-1alpha in renal medullary cells of rats.

    PubMed

    Zou, A P; Yang, Z Z; Li, P L; Cowley AW, J R

    2001-08-28

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates the oxygen-dependent expression of a number of genes. This transcription factor may contribute to the abundant expression of many genes in renal medullary cells that function normally under hypoxic conditions. The present study was designed to determine the characteristics of HIF-1alpha cDNA cloned from the rat kidney and the expression profile of HIF-1alpha in different kidney regions and to explore the mechanism activating or regulating HIF-1alpha expression in renal medullary cells. A 3,718-bp HIF-1alpha cDNA from the rat kidney was first cloned and sequenced using RT-PCR and TA cloning technique. It was found that 823 amino acids deduced from this renal HIF-1alpha cDNA had 99%, 96%, and 90% identity with rat, mouse, or human HIF-1alpha deposited in GenBank, respectively. The 3'-untranslated region of HIF-1alpha mRNA from the rat kidney contained seven AUUUA instability elements, five of which were found to be conserved among rat, mouse, and human HIF-1alpha. Northern blot analyses demonstrated a corticomedullary gradient of HIF-1alpha mRNA expression in the kidney, with the greatest abundance in the renal inner medulla. Western blot analyses also detected a higher HIF-1alpha protein level in the nuclear extracts from the renal medulla than the renal cortex. A classic loop diuretic, furosemide (10 mg/kg ip), markedly increased renal medullary Po(2) levels from 22.5 to 52.2 mmHg, which was accompanied by a significant reduction of HIF-1alpha transcripts in renal medullary tissue. In in vitro experiments, low Po(2), but not elevated osmolarity, was found to significantly increase HIF-1alpha mRNA in renal medullary interstitial cells and inner medullary collecting duct cells. These results indicate that HIF-1alpha is more abundantly expressed in the renal medulla compared with the renal cortex. Increased abundance of HIF-1alpha mRNA in the renal medulla may represent an adaptive

  2. Does the position of conus medullaris change with increased thoracolumbar kyphosis in ankylosing spondylitis patients?

    PubMed Central

    Qu, Zhe; Qian, Bang-ping; Qiu, Yong; Zhang, Yun-peng; Hu, Jun; Zhu, Ze-zhang

    2017-01-01

    Abstract To date, only a few reports described the potential factors influencing the position of conus medullaris. One previous study revealed no significant change of conus locations in patients with idiopathic scoliosis; however, the effect of ankylosing spondylitis (AS)-related thoracolumbar kyphosis on conus position remains unexplored. Therefore, we aimed to investigate the variation of conus medullaris terminations in patients with thoracolumbar kyphosis secondary to AS when compared with normal subjects, and evaluated the relationship between conus positions and the magnitude of kyphosis. In this study, MR images of 96 AS patients with thoracolumbar kyphosis, including 86 males and 10 females with an average of 34.6 years (range, 17–65 years), and 100 age-matched normal controls were reviewed to determine the conus terminations in relation to spinal levels. Sagittal parameters of the AS group measured on radiograph included: global kyphosis (GK), thoracic kyphosis (TK), lumbar lordosis (LL), and thoracolumbar junction (TLJ). Finally, conus tips located at the mean level of the lower 3rd of L1 in both groups, there was no significant difference of the conus distributions between AS and control group (P = 0.49). In addition, conus medullaris displayed similar positions in AS patients among various apical region groups (P = 0.88), and no significant difference was found when AS population was stratified into GK ranges of 30° (P = 0.173). Also, no remarkable correlation of the conus positions with GK (r = −0.15, P = 0.15), TK (r = −0.10, P = 0.34), LL (r = −0.10, P = 0.32), and TLJ (r = −0.06, P = 0.54) was identified. This study showed the conus terminations displayed a wide range of distributions in AS patients with thoracolumbar kyphosis, which was similar to normal subjects. Moreover, the conus located at a relatively fixed position and would not be affected by the change of kyphosis magnitude, which is

  3. The mormyrid brainstem--II. The medullary electromotor relay nucleus: an ultrastructural horseradish peroxidase study.

    PubMed

    Elekes, K; Ravaille, M; Bell, C C; Libouban, S; Szabo, T

    1985-06-01

    The medullary relay nucleus of the mormyrid weakly electric fish Gnathonemus petersii is a stage in the command pathway for the electric organ discharge. It receives input from the presumed command or pacemaker nucleus and projects to the electromotoneurons in the spinal cord. Its fine structure and synaptology were investigated by electron microscopy. The origin of the terminals contacting the cell membrane of the neurons of this nucleus was determined by horseradish peroxidase (HRP) injections into different brain structures, namely into the bulbar command- and mesencephalic command-associated nuclei. Twenty-five to thirty large cells of about 45 micron in diameter constitute the medullary electromotor relay. Each cell has a kidney-shaped, lobulated nucleus, a large myelinated axon with a short initial segment and several long, richly arborizing primary dendrites. Many, if not all, cells are interconnected with large somatosomatic or dendrosomatic, dendrodendritic and dendroaxonic gap junctions. These junctions often occur in serial or triadic arrangements. The relay cells receive large club endings as well as small boutons. The club endings are found mainly on the soma and primary dendrites and are morphologically mixed synapses. The boutons are characterized by synapses which are only chemical and are distributed all over the cell membrane, but with a definitely higher frequency on secondary dendrites and more distal parts of dendritic processes. Horseradish peroxidase injections into the mesencephalic command-associated nucleus reveal a large number of labelled boutons on the secondary dendrites of the relay cells. Injections into the bulbar command-associated nucleus label the same type of boutons as mesencephalic injections, but also label club endings on relay cell soma and primary dendrites. The results support the conclusion made on the basis of previous light microscopical observations that boutons originate from the bulbar command-associated nucleus

  4. Nephronophthisis-medullary cystic kidney disease: from bedside to bench and back again.

    PubMed

    Scolari, Francesco; Ghiggeri, Gian Marco

    2003-01-01

    Medullary cystic kidney disease (MCKD) belongs with nephronophthisis (NPH) to the NPH-MCKD complex, a group of inherited tubulointerstitial nephritis which share some morphological and clinical features. Juvenile NPH, the most frequent variant of the complex, is a recessive disease with onset in childhood leading to end stage renal disease (ESRD) within the 2nd decade of life. The most frequent extrarenal involvement is tapeto-retinal degeneration. MCKD is a less frequent disease with dominant inheritance; it is recognized later in life, leading to ESRD at the age of 50 years, and may be associated with hyperuricemia and gout. In an early phase, both NPH and MCKD are pauci-symptomatic, major signs being confined to polyuria. Later in the course, clinical findings are related to the progressive renal insufficiency, such as anemia, uremic symptoms and, in NPH, growth retardation. On renal ultrasound, the kidneys present an increased medullary echogenicity with diminished cortico-medullary differentiation. Renal cysts may be present, usually at corticomedullary boundary. Due to the clinico-pathological identity, the two diseases were considered to be a single disorder, and the compromise appellation of NPH-MCKD complex was suggested. This unifying conception was subsequently refuted following the identification of MCKD dominant families. The recent advances of the molecular genetics changed the traditional classification of NPH-MCKD complex. The majority of cases of juvenile NPH are due to deletion of the NPHP1 gene on chromosome 2q13. Genes for infantile and adolescent NPH have been localized to chromosome 9q22-q31 and 3q22, respectively. A new locus, NPHP4, has been recently mapped on chromosome 1p36. Two genes predisposing to dominant MCKD, MCKD1 and MCKD2, have been localized to chromosome 1q21 and to chromosome 16p12. Moreover, a gene for familial juvenile hyperuricemic nephropathy (FJHN), a phenotype very similar to MCKD, was mapped to 16p12 in a region

  5. Medullary serotonergic network deficiency in the sudden infant death syndrome: review of a 15-year study of a single dataset.

    PubMed

    Kinney, H C; Filiano, J J; White, W F

    2001-03-01

    The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality in the United States today, despite a dramatic 38% decrease in incidence due to a national risk reduction campaign advocating the supine sleep position. Our research in SIDS brainstems, beginning in 1985 and involving a single, large dataset, has become increasingly focused upon a specific neurotransmitter (serotonin) and specific territories (ventral medulla and regions of the medullary reticular formation that contain secrotonergic neurons). Based on this research, we propose that SIDS, or a subset of SIDS, is due to a developmental abnormality in a medullary network composed of (at least in part) rhombic lip-derived, serotonergic neurons, including in the caudal raphé and arcuate nucleus (putative human homologue of the cat respiratory chemosensitive fields); and this abnormality results in a failure of protective responses to life-threatening stressors (e.g. asphyxia, hypoxia, hypercapnia) during sleep as the infant passes through a critical period in homeostatic control. We call this the medullary serotonergic network deficiency hypothesis. We review the triple-risk model for SIDS, the development of the dataset using tissue autoradiography for analyzing neurotransmitter receptor binding; age-dependent baseline neurochemical findings in the human brainstem during early life; the evidence for serotonergic, rhombic lip, and ventral medullary deficits in at least some SIDS victim; possible mechanisms of sudden infant death related to these deficits; and potential causes of the deficits in the medullary serotonergic network in SIDS victims. We conclude with a summary of future directions in SIDS brainstem research.

  6. Morphology of the epithelium of the lower rectum and the anal canal in the adult human.

    PubMed

    Tanaka, Eiichi; Noguchi, Tsuyoshi; Nagai, Kaoruko; Akashi, Yuichi; Kawahara, Katsunobu; Shimada, Tatsuo

    2012-06-01

    The anal canal is an important body part clinically. However, there is no agreement about the epithelium of the anal canal, the anal transitional zone (ATZ) epithelium in particular. The aim of this study is to clarify the structure of the epithelium of the human lower rectum and anal canal. Intact rectum and anus obtained from patients who underwent surgery for rectal carcinoma were examined by light and scanning electron microscopy (LM and SEM). By LM, three types of epithelium were observed in the anal canal: simple columnar epithelium, stratified squamous epithelium, and stratified columnar epithelium. The lower rectum was composed of simple columnar epithelium. SEM findings showed stratified squamous epithelium that consisted of squamous cells with microridges, changing to simple columnar epithelium consisting of columnar cells with short microvilli at the anorectal line. LM and SEM observations in a one-to-one ratio revealed that the area of stratified columnar epithelium based on LM corresponded to the anal crypt and sinus. In conclusion, the epithelium of the human anal canal was fundamentally composed of simple columnar epithelium and stratified squamous epithelium. We found no evidence of the ATZ.

  7. Abnormal Ion Permeation through Cystic Fibrosis Respiratory Epithelium

    NASA Astrophysics Data System (ADS)

    Knowles, M. R.; Stutts, M. J.; Spock, A.; Fischer, N.; Gatzy, J. T.; Boucher, R. C.

    1983-09-01

    The epithelium of nasal tissue excised from subjects with cystic fibrosis exhibited higher voltage and lower conductance than tissue from control subjects. Basal sodium ion absorption by cystic fibrosis and normal nasal epithelia equaled the short-circuit current and was amiloride-sensitive. Amiloride induced chloride ion secretion in normal but not cystic fibrosis tissue and consequently was more effective in inhibiting the short-circuit current in cystic fibrosis epithelia. Chloride ion-free solution induced a smaller hyperpolarization of cystic fibrosis tissue. The increased voltage and amiloride efficacy in cystic fibrosis reflect absorption of sodium ions across an epithelium that is relatively impermeable to chloride ions.

  8. Structural changes in rabbit oral epithelium caused by zinc deficiency.

    PubMed

    Joseph, C E; Ashrafi, S H; Waterhouse, J P

    1981-01-01

    We report the successful establishment of zinc deficiency in rabbits by dietary means. The soybean protein of a standard rabbit diet was replaced by egg albumin. Weanling, New Zealand white rabbits, were fed a low zinc diet containing 1.5 microgram Zn/g of diet. Zinc-deficient rabbits showed stunted growth, weight loss, altered posture, partial alopecia and crusting of skin. Structural alterations in oral epithelium of the zinc-deficient rabbits included in the tongue flattened filiform papillae showing parakeratosis, in the cheek parakeratosis of the normally nonkeratinized epithelium and hyperplasia of the lip epidermis.

  9. Ectopic TBX1 suppresses thymic epithelial cell differentiation and proliferation during thymus organogenesis.

    PubMed

    Reeh, Kaitlin A G; Cardenas, Kim T; Bain, Virginia E; Liu, Zhijie; Laurent, Micheline; Manley, Nancy R; Richie, Ellen R

    2014-08-01

    The thymus and parathyroid glands arise from a shared endodermal primordium in the third pharyngeal pouch (3rd pp). Thymus fate is specified in the ventral 3rd pp between E9.5 and E11, whereas parathyroid fate is specified in the dorsal domain. The molecular mechanisms that specify fate and regulate thymus and parathyroid development are not fully delineated. Previous reports suggested that Tbx1 is required for thymus organogenesis because loss of Tbx1 in individuals with DiGeorge syndrome and in experimental Tbx1 deletion mutants is associated with thymus aplasia or hypoplasia. However, the thymus phenotype is likely to be secondary to defects in pharyngeal pouch formation. Furthermore, the absence of Tbx1 expression in the thymus-fated domain of the wild-type 3rd pp suggested that Tbx1 is instead a negative regulator of thymus organogenesis. To test this hypothesis, we generated a novel mouse strain in which expression of a conditional Tbx1 allele was ectopically activated in the thymus-fated domain of the 3rd pp. Ectopic Tbx1 expression severely repressed expression of Foxn1, a transcription factor that marks the thymus-fated domain and is required for differentiation and proliferation of thymic epithelial cell (TEC) progenitors. By contrast, ectopic Tbx1 did not alter the expression pattern of Gcm2, a transcription factor restricted to the parathyroid-fated domain and required for parathyroid development. Ectopic Tbx1 expression impaired TEC proliferation and arrested TEC differentiation at an early progenitor stage. The results support the hypothesis that Tbx1 negatively regulates TEC growth and differentiation, and that extinction of Tbx1 expression in 3rd pp endoderm is a prerequisite for thymus organogenesis.

  10. Biology of Mouse Thymic Virus, a Herpesvirus of Mice, and the Antigenic Relationship to Mouse Cytomegalovirus

    PubMed Central

    Cross, S. S.; Parker, J. C.; Rowe, W. P.; Robbins, M. L.

    1979-01-01

    Mouse thymic virus (TA) is a herpesvirus which produces extensive necrosis of the thymus of newborn mice 7 to 14 days after infection. Infectious virus can be recovered from the thymus for only 10 days after infection, with highest titers occurring between days 5 and 7. In mice 5 days old or less, TA infects thymus cells and produces massive necrosis. TA also infects the salivary glands and persists as a chronic infection. Newborn mice infected with TA have no detectable humoral immune response. Infected adult mice respond, and humoral antibody is detected 7 days after infection. Titers are maintained for months thereafter. Regardless of the age of the mice inoculated with TA, persistent infection was established in the salivary glands, but no evidence for thymus involvement was observed when adults were infected. TA does not cross-react serologically by immunofluorescent, complement fixation, or virus neutralization tests with mouse cytomegalovirus; however, interestingly, the epidemiology of the two herpesviruses are similar. Both mouse cytomegalovirus and TA were isolated from the same animals in populations of laboratory and wild mice. Evidence of infection with mouse cytomegalovirus and TA were most apparent by virus isolations, since humoral antibody responses are rarely observed. All strains of mice tested were susceptible to TA infection. However, in some strains maximum necrosis occurred at 7 days, compared with 10 to 14 days for other strains. The difference in age susceptibility and the target tissue of thymus in newborn mice suggests that TA is a model herpesvirus for studying the effects of viral infections on humoral and cell-mediated immunological functions. Images PMID:231008

  11. Pre-thymic somatic mutation leads to high mutant frequency at hypoxanthine-guanine phosphoribosyltransferase gene

    SciTech Connect

    Jett, J.

    1994-12-01

    While characterizing the background mutation spectrum of the Hypoxathine-guanine phosphoribosyltransferase (HPRT) gene in a healthy population, an outlier with a high mutant frequency of thioguanine resistant lymphocytes was found. When studied at the age of 46, this individual had been smoking 60 cigarettes per day for 38 years. His mutant frequency was calculated at 3.6 and 4.2x10{sup {minus}4} for two sampling periods eight months apart. Sequencing analysis of the HPRT gene in his mutant thioguanine resistant T lymphocytes was done to find whether the cells had a high rate of mutation, or if the mutation was due to a single occurrence of mutation and, if so, when in the T lymphocyte development the mutation occurred. By T-cell receptor analysis it has been found that out of 35 thioguanine resistant clones there was no dominant gamma T cell receptor gene rearrangement. During my appointment in the Science & Engineering Research Semester, I found that 34 of those clones have the same base substitution of G{yields}T at cDNA position 197. Due to the consistent mutant frequency from both sampling periods and the varying T cell receptors, the high mutant frequency cannot be due to recent proliferation of a mature mutant T lymphocyte. From the TCR and DNA sequence analysis we conclude that the G{yields}T mutation must have occurred in a T lymphocyte precursor before thymic differentiation so that the thioguanine resistant clones share the same base substitution but not the same gamma T cell receptor gene.

  12. Regulation of AP-1 and NFAT transcription factors during thymic selection of T cells.

    PubMed Central

    Rincon, M; Flavell, R A

    1996-01-01

    The ability of thymocytes to express cytokine genes changes during the different stages of thymic development. Although CD4- CD8- thymocytes are able to produce a wide spectrum of cytokines in response to a T-cell receptor (TcR)-independent stimulus, as they approach the double-positive (DP) CD4+ CD8+ stage, they lose the ability to produce cytokine. After the DP stage, thymocytes become single-positive CD4+ or CD8+ thymocytes which reacquire the ability to secrete cytokines. In an attempt to understand the molecular basis of this specific regulatin, we use AP-1-luciferase and newly generated NFAT-luciferase transgenic mice to analyze the transcriptional and DNA-binding activities of these two transcription factors that are involved in the regulation of cytokine gene expression. Here, we show that both AP-1 and NFAT transcriptional activities are not inducible in the majority of DP cells but that during the differentiation of DP cells to the mature single-positive stage, thymocytes regain this inducibility. Subpopulation analysis demonstrates that this inducibility is reacquired at the DP stage before the down-modulation of one of the coreceptors. Indeed AP-1 inducibility, just like the ability to express the interleukin-2 gene, is reacquired during the differentiation of DP TcRlow CD69low heat-stable antigen (HSA)high thymocytes to DP TcRhigh CD69high HSAhigh cells, which is considered to be the consequence of the first signal that initiates positive selection. We therefore propose that the inability of DP thymocytes to induce AP-1 and NFAT activities is one of the causes for the lack of cytokine gene expression at this stage and that this inducibility is reacquired at the latest stage of DP differentiation as a consequence of positive selection. This could be a mechanism to prevent the activation of DP thymocytes before selection has taken place. PMID:8622652

  13. Thymic stromal lymphopoietin activity is increased in nasal polyps of chronic rhinosinusitis

    PubMed Central

    Nagarkar, Deepti R.; Poposki, Julie A.; Tan, Bruce K.; Comeau, Michael R.; Peters, Anju T.; Hulse, Kathryn E.; Suh, Lydia A.; Norton, James; Harris, Kathleen E.; Grammer, Leslie C.; Chandra, Rakesh K.; Conley, David B.; Kern, Robert C.; Schleimer, Robert P.; Kato, Atsushi

    2013-01-01

    Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with Th2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated Th2 inflammatory responses and that enhances IL-1-dependent Th2 cytokine production in mast cells. Although elevated levels of TSLP mRNA have been found in nasal polyps (NPs), expression of TSLP protein and its function in CRS have not been fully explored. Objectives The objective of this study was to investigate the role of TSLP in CRS. Methods We investigated the presence and stability of TSLP protein in NPs by ELISA and western blot, and the function of TSLP in nasal tissue extracts with a bioassay based upon activation of human mast cells. Results Although TSLP mRNA was significantly increased in NP tissue from patients with CRSwNP compared to uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue as detected by the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1β-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NP contain biologically relevant levels of TSLP activity. Conclusion TSLP and its metabolic products may play an important role in the inflammation in CRSwNP. PMID:23688414

  14. Isolated thymic Langerhans cell histiocytosis discovered on F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT).

    PubMed

    Turpin, Sophie; Carret, Anne-Sophie; Dubois, Josée; Buteau, Chantal; Patey, Natalie

    2015-11-01

    The thymic infiltration in young patients with multisystemic Langerhans cell histiocytosis and its radiologic features are well known. However, isolated thymic disease has seldom been reported in the literature. We report the case of a 10-month-old child admitted for fever of unknown origin. Whole-body F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) was performed to identify a focus of infection. It demonstrated an unusual aspect of the thymus, which led to further investigation and revealed isolated infiltration of the thymus by Langerhans cell histiocytosis. The patient was treated accordingly and is now disease free. As evaluation of Langerhans cell histiocytosis patients with F-18 FDG PET/CT is becoming more frequent, it is important to be aware of the scintigraphical characteristics of thymic Langerhans cell histiocytosis.

  15. Normalization of the peripheral blood T cell receptor V beta repertoire after cultured postnatal human thymic transplantation in DiGeorge syndrome.

    PubMed

    Davis, C M; McLaughlin, T M; Watson, T J; Buckley, R H; Schiff, S E; Hale, L P; Haynes, B F; Markert, M L

    1997-03-01

    Complete DiGeorge syndrome is an immunodeficiency disease characterized by thymic aplasia and the absence of functioning peripheral T cells. A patient with this syndrome was transplanted with cultured postnatal human thymic tissue. Within 5 weeks of transplantation, flow cytometry, T cell receptor V beta sequence analysis, and cell function studies showed the presence of oligoclonal populations of nonfunctional clonally expanded peripheral T cells that were derived from pretransplantation T cells present in the skin. However, at 3 months posttransplantation, a biopsy of the transplanted thymus showed normal intrathymic T cell maturation of host T cells with normal TCR V beta expression on thymocytes. By 9 months postransplantation, peripheral T cell function was restored and the TCR V beta repertoire became polyclonal, coincident with the appearance of normal T cell function. These data suggest that the transplanted thymus was responsible for the establishment of a new T cell repertoire via thymopoiesis in the chimeric thymic graft.

  16. Assessment of thymic output in common variable immunodeficiency patients by evaluation of T cell receptor excision circles

    PubMed Central

    GUAZZI, V; AIUTI, F; MEZZAROMA, I; MAZZETTA, F; ANDOLFI, G; Mortellaro, A; Pierdominici, M; FANTINI, R; MARZIALI, M; AIUTI, A

    2002-01-01

    Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by repeated infections and hypogammaglobulinaemia. Additionally, T-cell abnormalities including lymphopenia, decreased proliferation to mitogens and antigens, and the reduced production and expression of cytokines, have also been observed. In this study we have investigated the expression of naive, memory and activation markers in T-cell subpopulations in 17 CVID patients in comparison to age-matched normal controls. The numbers of CD4+ T cells, including CD45RA+CD62L+ and, to a lesser extent, CD45RA−CD62L+/RA+CD62L− were significantly reduced in patients, whereas CD8+ T cells were within normal range. In contrast, HLA-DR+ cells were increased both in CD4+ and CD8+ T cells. To assess the thymic output, we analysed the presence of T-cell receptor excision circles (TRECs) in CD4+ and CD8+ T cells by quantitative PCR. TRECs were decreased significantly in patients and the rate of TREC loss was higher with increasing age. TRECs correlated with naive CD4+ T cells, whereas there was an inverse relationship between TRECs and CD8+HLA−DR+ and CD8+CD45RA−CD62L+/RA+CD62L− T cells. Our results suggest the presence of a defect in the naive T cell compartment with origin at the thymic level in CVID, and indicate that TREC may be a useful marker to monitor thymic function in this primary immunodeficiency. PMID:12165093

  17. Pure Motor Monoparesis in the Leg due to a Lateral Medullary Infarction.

    PubMed

    Tsuda, Hiromasa; Tanaka, Kozue; Kishida, Shuji

    2012-01-01

    A 76-year-old man with essential hypertension abruptly presented with slight left-sided leg weakness, despite normal strength in the other extremities. Left-sided Babinski's reflex was detected. There were no other neurologic abnormalities. Cranial magnetic resonance imaging demonstrated a small infarction in the lower lateral medulla oblongata on the left side. Cranial magnetic resonance angiography demonstrated an absence of flow of the left vertebral artery. He became asymptomatic within 10 days under intravenous antiplatelet agent. The corticospinal tract fibers innervating the lower extremity caudal to the pyramidal decussation might be involved. We emphasize that this is a first reported case of pure motor monoparesis in the leg due to lateral medullary infarction.

  18. Generalized AA-amyloidosis in Siberian tigers (Panthera tigris altaica) with predominant renal medullary amyloid deposition.

    PubMed

    Schulze, C; Brügmann, M; Böer, M; Brandt, H P; Pohlenz, J; Linke, R P

    1998-01-01

    Generalized amyloidosis with predominant renal medullary amyloid deposition was found in four closely related Siberian tigers (Panthera tigris altaica) suffering from end stage kidney diseases. Only minimal to mild amounts of amyloid were deposited in various organs outside the kidneys with individually variable organ involvement. The Congo red staining affinity of amyloid deposits was sensitive to potassium permanganate oxidation. The deposits were further characterized as being of the amyloid-A (AA) type by immunohistochemistry using the mouse monoclonal antibody mc4 directed against a conserved region of the human AA-protein. A combination of immunohistochemistry and Congo red staining was much more sensitive for the diagnosis of amyloid deposits than Congo red staining alone. With this combination, even minimal amyloid deposits were detected that had been missed in the first reading using Congo-red-stained slides alone. Since no common primary cause was identified, the amyloidosis was classified as idiopathic generalized AA-amyloidosis with a potential familial predisposition.

  19. The rhythmic, transverse medullary slice preparation in respiratory neurobiology: contributions and caveats.

    PubMed

    Funk, Gregory D; Greer, John J

    2013-04-01

    Our understanding of the sites and mechanisms underlying rhythmic breathing as well as the neuromodulatory control of respiratory rhythm, pattern, and respiratory motoneuron excitability during perinatal development has advanced significantly over the last 20 years. A major catalyst was the development in 1991 of the rhythmically-active medullary slice preparation, which provided precise mechanical and chemical control over the network as well as enhanced physical and optical access to key brainstem regions. Insights obtained in vitro have informed multiple mechanistic hypotheses. In vivo tests of these hypotheses, performed under conditions of reduced control and precision but more obvious physiological relevance, have clearly established the significance for respiratory neurobiology of the rhythmic slice preparation. We review the contributions of this preparation to current understanding/concepts in respiratory control, and outline the limitations of this approach in the context of studying rhythm and pattern generation, homeostatic control mechanisms and murine models of human genetic disorders that feature prominent breathing disturbances.

  20. Co-existence of L5-S1 disc herniation and conus medullaris ependymoma

    PubMed Central

    Minoğlu, Mustafa; Akkol, İsmail; Özdemir, Nail; Yıldırım, Levent

    2014-01-01

    INTRODUCTION The lumbar disc herniations are seen very common than spinal ependymomas in the neurosurgery polyclinic routine. PRESENTATION OF CASE In our case, both pathologies were seen at the most frequently located levels compatible with the literature. Aim of this case report is, to remind once more that, different pathologies can be found at the same time in a single patient; differential diagnosis must be done very carefully. DISCUSSION The routine Computed Tomography (CT) imaging for low back pain can not show the conus medullaris pathology. Spinal tumors or other similar pathologies should be kept in mind for differential diagnosis. A good medical history and a good physical examination must be completed before the final diagnosis. CONCLUSION Viewing of spinal canal with Magnetic Resonance Imaging (MRI) will be useful for the patients who we intend to do disc surgery. PMID:25460457

  1. Bilateral hamartomatous medullary lipoma within the nasal turbinate bones in a cynomolgus monkey (Macaca fascicularis)

    PubMed Central

    KATSUTA, Osamu; SHIBATA, Toru; KURIKI-YAMAMOTO, Yumi; MOCHIZUKI, Takaharu; YOSHIMI, Miwa; NOTO, Takahisa; MANO, Hidetoshi

    2016-01-01

    A 15-year-old male cynomolgus monkey (Macaca fascicularis) showed large bilateral masses in the maxillary sinus. In histopathological examination, both masses revealed benign medullary lipomas within the turbinate bones. The tumors were composed of well-developed lipocytes, trabecular bones and a few blood vessels. Although we initially diagnosed the tumor as bilateral lipomas in the nasal turbinates, it was not differentiated from lipomatous hamartoma. Findings, such as unique symmetrical proliferation, lack of border from the normal marrow and the intact surrounding tissue, indicated a lipomatous hamartoma/hamartomatous lipoma, thought to be a suitable diagnosis of the lesion. Of most interest was that such a proliferating lesion occurred in the nasal turbinate. PMID:27499062

  2. [Autosomal recessive polycystic kidney disease and complex nephronophtisis medullary cystic disease].

    PubMed

    2008-12-01

    Reseach during the past decade has led to the discovery that defects in some proteins that localize to primary cilia or the basal body are the main contributors to renal cyst development. Autosomal recessive polycystic disease and nephronophthisis- medullary cystic kidney disease are named ciliopathies. The cilium is a microtubule-based organelle that is found on most mammalian cells. Cilia-mediated hypothesis has evolved into the concept of cystogenesis, cilia bend by fluid initiate a calcium influx that prevents cyst formation. Cilia might sense stimuli in the cell enviroment and control cell polarity and mitosis. A new set of pathogenic mechanisms in renal cystic disease defined new therapeutic targets, control of intracellular calcium, inhibition of cAMP and down regulation cannonical Wnt signaling.

  3. Medullary Carcinoma of the Thyroid With Axillary Metastasis: A Case Report

    PubMed Central

    Ozdemir, Murat; Makay, Ozer; Simsir, Ilgin; Ertan, Yeşim; Icoz, Gokhan; Saygili, Füsun; Akyildiz, Mahir

    2015-01-01

    We report a case of axillary lymph node metastasis as a consequence of medullary thyroid carcinoma (MTC) in a 42-year-old man. On January 2009, the patient was referred to us for the management of right cervical lymph node enlargement. Total thyroidectomy was performed with right-sided functional neck dissection. Postoperative histopathology revealed MTC in the right lobe of the thyroid, with extrathyroidal extension and right-sided neck metastases. Multiple left cervical, mediastinal, and right axillary lymphadenopathies were detected at the third year follow-up exam. Left-sided functional neck dissection, axillary lymph node dissection, and mediastinal lymph node dissection were performed, and the pathologic outcomes revealed as the metastatic dissemination of MTC. After a disease-free term for 1 year, multiple metastatic lesions were detected in the patient. PMID:25785315

  4. Renal medullary carcinoma in a white adolescent with sickle cell trait.

    PubMed

    Daher, Paul; Bourgi, Ali; Riachy, Edward; Khoury, Antoine; Rehayem, Caline; Sader-Ghorra, Claude

    2014-07-01

    Renal medullary carcinoma (RMC) is a rare neoplasm of the kidney that has been recently described. It is almost exclusive to young patients of African descent and associated with sickle cell hemoglobinopathy, mainly sickle cell trait and hemoglobin sickle cell disease. The prognosis of RMC is very poor because of the highly aggressive behavior of this neoplasm and its resistance to conventional chemotherapy. Metastatic disease is almost universal at the time of presentation, and the malignancy is minimally responsive to a variety of regimens and/or modalities, including surgery, radiotherapy, chemotherapy, and biological immune-modulation therapy. We report the seventh case of a left RMC occurring in a white child with sickle cell trait, but with a localization of the tumor in the left kidney, considered a nonpredominant side for this type of tumor.

  5. Bone and liver images in medullary carcinoma of the thyroid gland: concise communication

    SciTech Connect

    Johnson, D.G.; Coleman, R.E.; McCook, T.A.; Dale, J.K.; Wells, S.A.

    1984-04-01

    Thirty-four patients with surgically documented medullary carcinoma of the thyroid (MCT) and elevated serum calcitonin levels had Tc-99m phosphate bone and/or Tc-99m sulfur colloid liver images for suspected metastases. Liver images demonstrated metastatic lesions in nine of 32 patients (28%). Bone images were positive for metastases in eight of 30 patients (27%). Four of these eight abnormal bone studies detected only skeletal lesions, two demonstrated only extraosseous metastases, and two showed both kinds. This study demonstrates that radionuclide bone and liver images frequently detect metastatic lesions in patients with MCT and elevated serum calcitonin levels, and that some nonskeletal metastases in patients with this tumor display an unusual affinity for bone-seeking radiotracers.

  6. Vandetanib Successfully Controls Medullary Thyroid Cancer-Related Cushing Syndrome in an Adolescent Patient

    PubMed Central

    Nella, A. A.; Fox, E.; Balis, F. M.; Quezado, M. M.; Whitcomb, P. O.; Derdak, J.; Kebebew, E.; Widemann, B. C.; Stratakis, C. A.

    2014-01-01

    Context: Ectopic Cushing syndrome due to ACTH secretion from metastatic medullary thyroid cancer (MTC) is associated with significant morbidity and mortality. Objective: The aim of the study was to describe the first case of Cushing syndrome associated with MTC in a pediatric patient and the successful reversal of Cushing syndrome with tyrosine kinase inhibitor (vandetanib) therapy. Patient and Methods: A 17-year-old Brazilian adolescent presented with metastatic MTC and associated ACTH-dependent ectopic Cushing syndrome in the context of multiple endocrine neoplasia type 2B. When the patient was treated with the tyrosine kinase inhibitor vandetanib, rapid decrease in serum cortisol and improvement of clinical symptoms were observed. Conclusion: We describe the first pediatric case of clinical and biochemical improvement of paraneoplastic MTC-related Cushing syndrome after treatment with vandetanib. Vandetanib and possibly other tyrosine kinase inhibitors may be a novel beneficial option in patients with neuroendocrine tumor-related ectopic Cushing syndrome. PMID:24617713

  7. Conus medullaris hematomyelia associated with an intradural-extramedullary cavernous angioma.

    PubMed

    Mastronardi, L; Frondizi, D; Guiducci, A; Nardi, M; Maira, G

    1999-01-01

    A unique case of a 50-year-old woman with a conus medullaris hematomyelia associated with a low thoracic intradural-extramedullary cavernous angioma localized 2 cm above is reported. The patient had a 2-month history of progressive paraparesis, hypoesthesia of legs, and bowel and bladder disturbances. The symptoms worsened acutely during the last days before admission. A thoraco-lumbar MRI showed a space-occupying lesion at T10-T11 (vertebral interspace associated with a hematomyelia localized about 2 cm below. A T10-L1 laminectomy was performed and complete removal of both lesions was obtained with microsurgical technique. A non-traumatic hematomyelia should always prompt the suspicion of a spinal AVM or, more rarely, of a cavernous angioma. The possible anatomical and clinical correlations of this unusual association are discussed.

  8. [Secondary medullary aplasia from accidental radiation:therapeutic options and evolution of the concept].

    PubMed

    de Revel, T; Fagot, T; Souleau, B; Dormont, D; Nedellec, G

    2002-07-01

    Bone marrow grafting following accidental irradiation exposure should be viewed in the perspective of a severe myeloablative syndrome linked to high medullary damage for a dose range higher than 6-8 Gy, resulting in very late or no recovery. Prognosis will depend on the presence or absence of radio-combined injuries, the toxicity of the transplant procedure, and the risk of rejection induced by insufficient percritical immunosuppression. It is in this context that new cell therapy modalities, which combine enhanced peripheral hematopoietic cell engraftment and high immunosuppressive conditioning regimen with low extrahematological toxicity, inducing early and stable mixed lymphomyeloid chimerism with minimal morbidity, can be considered. Such an approach is being evaluated in the treatment of patients with hematological malignancies at high risk of transplant-related mortality using conventional bone marrow methods.

  9. A Shunt Model of the Inner Medullary Nephron with Pre-Bend Transitions

    NASA Astrophysics Data System (ADS)

    Gonzalez, M. T.; Hegarty, A. F.; Thomas, S. R.

    2009-09-01

    Mathematical models of the renal medulla face the problem of representing water and solute transfer among tens of thousands of nephrons and blood vessels of various lengths, arranged in countercurrent fashion. Published models fall into two broad categories with respect to this issue: multi-nephron models, which explicitly represent a large number of individual nephrons, or lumped models with virtual shunts that represent the turning back of nephrons and vessels at varying depths. Shunt models have the advantage of a compact description and relatively rapid execution time but are ill-suited to faithfully represent features such as prebend transitions of epithelial permeabilities in nephrons of different lengths. A new shunt model approach that can accommodate pre-bend transitions of nephrons at all medullary depths is presented in this work together with the results of simulation of predicted flows and concentrations.

  10. Cerebrocortical and medullary blood flow changes after general opiate receptor blockade during hemorrhagic shock in cats.

    PubMed

    Komjáti, K; Sandor, P; Sandor, N; Szirmai, L; H-Velkei, M; Kovach, A G

    1997-04-01

    The effect of centrally induced opiate receptor blockade on regional cerebral blood flow (rCBF) was studied in anesthetized, ventilated cats during the course of hemorrhagic shock. The blood flow of the medulla and the parietal cortex was measured with the H2-gas clearance technique. Hemorrhagic shock was produced by lowering the systemic mean arterial pressure to 60 mmHg for 120 min by blood withdrawal. Central opiate receptor blockade was induced by 10 micrograms/kg intracerebroventricularly (i.c.v.) injected naloxone at the 60th min of the bleeding period. Cortical blood flow showed no improvement after i.c.v. naloxone administration. Medullary blood flow, however, increased significantly and approached the pre-bleeding control flow values following central opiate receptor blockade. The results indicate involvement of endogenous opioid mechanisms in the regulation of rCBF during hemorrhage and may provide an explanation for the previously described beneficial effects of naloxone in hemorrhagic shock.

  11. New radionuclide tracers for the diagnosis and therapy of medullary thyroid carcinoma

    SciTech Connect

    Hoefnagel, C.A.; Delprat, C.C.; Zanin, D.; van der Schoot, J.B.

    1988-03-01

    Medullary thyroid carcinoma (MTC), a calcitonin-producing tumor that occurs in familial and sporadic forms, can be monitored satisfactorily with measurements of calcitonin and CEA in serum. However, locating the tumor site may be difficult. In the current review of the experience with four new radionuclide tracers for MTC, the relative value of each of these procedures is outlined. Total body imaging using TI-201 chloride and Tc-99m(V) DMSA are both sensitive techniques that can be used for the detection and follow-up of MTC. Imaging using I-131 MIBG and I-131 anti-CEA antibodies/fragments should be performed once the diagnosis and the tumor site have been established, to evaluate if patients might be amenable for therapy with one of these radiopharmaceuticals.

  12. The ageing and myasthenic thymus: a morphometric study validating a standard procedure in the histological workup of thymic specimens.

    PubMed

    Ströbel, Philipp; Moritz, Regina; Leite, Maria Isabel; Willcox, Nick; Chuang, Wen-Yu; Gold, Ralf; Nix, Wilfred; Schalke, Berthold; Kiefer, Reinhard; Müller-Hermelink, Hans-Konrad; Jaretzki Iii, Alfred; Newsom-Davis, John; Marx, Alexander

    2008-09-15

    The thymus is believed to play an important role in the pathogenesis of myasthenia gravis (MG). The 80% of MG patients with anti-acetylcholine receptor autoantibodies fall into three clinical subgroups: 1) thymoma; 2) early-onset MG (thymic histology. We here describe the validated, standardized histological workup and reporting system used in this trial.

  13. Cardiovascular and respiratory consequences of bilateral involvement of the medullary intermediate reticular formation in syringobulbia.

    PubMed

    Heidel, K M; Benarroch, E E; Gené, R; Klein, F; Meli, F; Saadia, D; Nogués, M A

    2002-12-01

    We studied five patients with clinical and radiological evidence of syringobulbia (SB) to determine whether the distribution of lesions in relationship to the cardiorespiratory control networks in the medullary intermediate reticular zone (IRt) correlates with the presence of abnormalities in autonomic cardiovascular and respiratory control in these patients. All patients underwent high resolution MRI to characterize the size, volume and distribution of the SB lesions, cardiovascular autonomic function testing and polysomnography. One patient with bilateral IRt involvement at both the rostral and caudal medulla had orthostatic hypotension (OH), absent HR(DB), abnormal Valsalva ratio, exaggerated fall of BP during phase II and absent phase IV during VM, and a dramatic fall of BP during head up tilt; this patient also had severe obstructive sleep apnea (OSA) and exhibited BP drops during each respiratory effort. A second patient, with bilateral IRt involvement restricted to the caudal medulla, had less severe cardiovascular autonomic dysfunction but also exhibited severe OSA. The other three patients had small SB cavities sparing the IRt and had sleep apnea but no autonomic dysfunction. Autonomic dysfunction could not be related to the size of the syrinx or the degree of atrophy in the cervical spinal cord in any of the five patients. Bilateral involvement of the IRt by SB produces cardiovascular autonomic failure and sleep apnea. In patients with more restricted lesions, autonomic and respiratory dysfunction may be dissociated. Clinico-radiological correlations using high resolution MRI assessment of medullary lesions can provide insight into the central organization of cardiovascular and respiratory control in humans.

  14. Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation

    PubMed Central

    Miller, Justin Robert; Neumueller, Suzanne; Muere, Clarissa; Olesiak, Samantha; Pan, Lawrence; Hodges, Matthew R.

    2013-01-01

    A current and major unanswered question is why the highly sensitive central CO2/H+ chemoreceptors do not prevent hypoventilation-induced hypercapnia following carotid body denervation (CBD). Because perturbations involving the carotid bodies affect central neuromodulator and/or neurotransmitter levels within the respiratory network, we tested the hypothesis that after CBD there is an increase in inhibitory and/or a decrease in excitatory neurochemicals within the ventrolateral medullary column (VMC) in awake goats. Microtubules for chronic use were implanted bilaterally in the VMC within or near the pre-Bötzinger Complex (preBötC) through which mock cerebrospinal fluid (mCSF) was dialyzed. Effluent mCSF was collected and analyzed for neurochemical content. The goats hypoventilated (peak +22.3 ± 3.4 mmHg PaCO2) and exhibited a reduced CO2 chemoreflex (nadir, 34.8 ± 7.4% of control ΔV̇E/ΔPaCO2) after CBD with significant but limited recovery over 30 days post-CBD. After CBD, GABA and glycine were above pre-CBD levels (266 ± 29% and 189 ± 25% of pre-CBD; P < 0.05), and glutamine and dopamine were significantly below pre-CBD levels (P < 0.05). Serotonin, substance P, and epinephrine were variable but not significantly (P > 0.05) different from control after CBD. Analyses of brainstem tissues collected 30 days after CBD exhibited 1) a midline raphe-specific reduction (P < 0.05) in the percentage of tryptophan hydroxylase–expressing neurons, and 2) a reduction (P < 0.05) in serotonin transporter density in five medullary respiratory nuclei. We conclude that after CBD, an increase in inhibitory neurotransmitters and a decrease in excitatory neuromodulation within the VMC/preBötC likely contribute to the hypoventilation and attenuated ventilatory CO2 chemoreflex. PMID:23869058

  15. Neonatal hyperleptinaemia programmes adrenal medullary function in adult rats: effects on cardiovascular parameters.

    PubMed

    Trevenzoli, I H; Valle, M M R; Machado, F B; Garcia, R M G; Passos, M C F; Lisboa, P C; Moura, E G

    2007-04-15

    Epidemiological studies have shown a strong correlation between stressful events (nutritional, hormonal or environmental) in early life and development of adult diseases such as obesity, diabetes and cardiovascular failure. It is known that gestation and lactation are crucial periods for healthy growth in mammals and that the sympathoadrenal system is markedly influenced by environmental conditions during these periods. We previously demonstrated that neonatal hyperleptinaemia in rats programmes higher body weight, higher food intake and hypothalamic leptin resistance in adulthood. Using this model of programming, we investigated adrenal medullary function and effects on cardiovascular parameters in male rats in adulthood. Leptin treatment during the first 10 days of lactation (8 microg 100 g(-1) day(-1), s.c.) resulted in lower body weight (6.5%, P < 0.05), hyperleptinaemia (10-fold, P < 0.05) and higher catecholamine content in adrenal glands (18.5%, P < 0.05) on the last day of treatment. In adulthood (150 days), the rats presented higher body weight (5%, P < 0.05), adrenal catecholamine content (3-fold, P < 0.05), tyrosine hydroxylase expression (35%, P < 0.05) and basal and caffeine-stimulated catecholamine release (53% and 100%, respectively, P < 0.05). Systolic blood pressure and heart rate were also higher in adult rats (7% and 6%, respectively, P < 0.05). Our results show that hyperleptinaemia in early life increases adrenal medullary function in adulthood and that this may alter cardiovascular parameters. Thus, we suggest that imprinting factors which increase leptin and catecholamine levels during the neonatal period could be involved in development of adult chronic diseases.

  16. Thymic Nurse Cells Participate in Heterotypic Internalization and Repertoire Selection of Immature Thymocytes; Their Removal from the Thymus of Autoimmune Animals May be Important to Disease Etiology

    PubMed Central

    Guyden, J.C.; Martinez, M.; Chilukuri, R.V.E.; Reid, V.; Kelly, F.; Samms, M.-O.D.

    2016-01-01

    Thymic nurse cells (TNCs) are specialized epithelial cells that reside in the thymic cortex. The initial report of their discovery in 1980 showed TNCs to contain up to 200 thymocytes within specialized vacuoles in their cytoplasm. Much has been reported since that time to determine the function of this heterotypic internalization event that exists between TNCs and developing thymocytes. In this review, we discuss the literature reported that describes the internalization event and the role TNCs play during T cell development in the thymus as well as why these multicellular complexes may be important in inhibiting the development of autoimmune diseases.

  17. Quantum Dot Distribution in the Olfactory Epithelium After Nasal Delivery

    NASA Astrophysics Data System (ADS)

    Garzotto, D.; De Marchis, S.

    2010-10-01

    Nanoparticles are used in a wide range of human applications from industrial to bio-medical fields. However, the unique characteristics of nanoparticles, such as the small size, large surface area per mass and high reactivity raises great concern on the adverse effects of these particles on ecological systems and human health. There are several pioneer studies reporting translocation of inhaled particulates to the brain through a potential neuronal uptake mediated by the olfactory nerve (1, 2, 3). However, no direct evidences have been presented up to now on the pathway followed by the nanoparticles from the nose to the brain. In addition to a neuronal pathway, nanoparticles could gain access to the central nervous system through extracellular pathways (perineuronal, perivascular and cerebrospinal fluid paths). In the present study we investigate the localization of intranasally delivered fluorescent nanoparticles in the olfactory epithelium. To this purpose we used quantum dots (QDs), a model of innovative fluorescent semiconductor nanocrystals commonly used in cell and animal biology (4). Intranasal treatments with QDs were performed acutely on adult CD1 mice. The olfactory epithelium was collected and analysed by confocal microscopy at different survival time after treatment. Data obtained indicate that the neuronal components of the olfactory epithelium are not preferentially involved in QDs uptake, thus suggesting nanoparticles can cross the olfactory epithelium through extracellular pathways.

  18. Cigarette smoke inhibition of ion transport in canine tracheal epithelium

    SciTech Connect

    Welsh, M.J.

    1983-06-01

    To determine the effect of cigarette smoke on airway epithelial ion transport, the electrical properties and transepithelial Na and Cl fluxes were measured in canine tracheal epithelium. In vivo, the inhalation of the smoke from one cigarette acutely and reversibly decreased the electrical potential difference across the tracheal epithelium. In vitro, exposure of the mucosal surface of the epithelium to cigarette smoke decreased the short circuit current and transepithelial resistance. The decrease in short circuit current was due to an inhibition of the rate of Cl secretion with minimal effect on the rate of Na absorption. The effect of cigarette smoke was reversible, was not observed upon exposure of the submucosal surface to smoke, and was most pronounced when secretion was stimulated. The particulate phase of smoke was largely responsible for the inhibitory effect, since filtering the smoke minimized the effect. The effect of cigarette smoke was not prevented by addition of antioxidants to the bathing solutions, suggesting that the inhibition of Cl secretion cannot be entirely attributed to an oxidant mechanism. These results indicate that cigarette smoke acutely inhibits active ion transport by tracheal epithelium, both in vivo and in vitro. This effect may explain, in part, both the abnormal mucociliary clearance and the airway disease observed in cigarette smokers.

  19. Examination of the reticular epithelium of the bovine pharyngeal tonsil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The nasopharyngeal tonsil (adenoid), located at the posterior of the nasopharynx is ideally positioned to sample antigens entering through the nasal cavity or oral cavity. Entering antigens will first contact tonsilar epithelium. To better understand the cellular composition of this important epithe...

  20. Coelomic epithelium-derived cells in visceral morphogenesis.

    PubMed

    Ariza, Laura; Carmona, Rita; Cañete, Ana; Cano, Elena; Muñoz-Chápuli, Ramón

    2016-03-01

    Coelomic cavities of vertebrates are lined by a mesothelium which develops from the lateral plate mesoderm. During development, the coelomic epithelium is a highly active cell layer, which locally is able to supply mesenchymal cells that contribute to the mesodermal elements of many organs and provide signals which are necessary for their development. The relevance of this process of mesenchymal cell supply to the developing organs is becoming clearer because genetic lineage tracing techniques have been developed in recent years. Body wall, heart, liver, lungs, gonads, and gastrointestinal tract are populated by cells derived from the coelomic epithelium which contribute to their connective and vascular tissues, and sometimes to specialized cell types such as the stellate cells of the liver, the Cajal interstitial cells of the gut or the Sertoli cells of the testicle. In this review we collect information about the contribution of coelomic epithelium derived cells to visceral development, their developmental fates and signaling functions. The common features displayed by all these processes suggest that the epithelial-mesenchymal transition of the embryonic coelomic epithelium is an underestimated but key event of vertebrate development, and probably it is shared by all the coelomate metazoans.

  1. The multi-tasking gut epithelium of insects.

    PubMed

    Huang, Jia-Hsin; Jing, Xiangfeng; Douglas, Angela E

    2015-12-01

    The insect gut epithelium plays a vital role in multiple processes, including nutrition, immunity and osmoregulation. Recent research is revealing the molecular and biochemical basis of these functions. For example, the pattern of nutrient acquisition by the gut epithelium is integrated into the overall regulation of nutrient allocation, as illustrated by evidence for systemic controls over expression of key genes coding digestive enzymes and transporters in carbohydrate acquisition; and the abundance and diversity of microorganisms in the gut lumen is regulated by multiple molecular properties of the gut epithelial cells, including the synthesis of enzymes that produce reactive oxygen species and anti-microbial peptides. These traits are underpinned by the function of the gut epithelium as a selective barrier which mediates the controlled movement of water, ions, metabolites and macromolecules between the gut lumen and insect tissues. Breakdown of the gut epithelial barrier has been implicated in muscle paralysis of insects at low temperatures (chill coma) and in aging. The key challenge for future research is to understand how the multiple functions of the insect gut epithelium are integrated by signaling interactions among epithelial cells, the gut microbiota and other insect organs.

  2. Increased expression of nestin in human pterygial epithelium

    PubMed Central

    Wen, Dan; Wang, Hua; Heng, Boon Chin; Liu, Hua

    2013-01-01

    AIM To investigate the distribution of nestin-positive cells in pterygium, as well as the relationship between nestin-positive cells and proliferative cells in the pathogenesis of pterygium. METHODS Nine pterygium specimens and 5 normal conjunctiva specimens were investigated. All explanted specimens were immediately immersed in 5-Ethynyl-2′-deoxyuridine, and were subjected to hematoxylin and eosin staining, as well as immunostaining to detect nestin. RESULTS Small sub-populations of nestin-expressing cells in both normal and pterygial conjunctiva epithelium were found. These were located at the superficial layer of the epithelium, and were significantly increased (P=0.007) and spread out in the pterygial conjunctiva epithelium, even though these cells were mitotically quiescent. CONCLUSION In pterygium, more nestin-positive cells were present at the superficial layer of the epithelium. With growing scientific evidence that nestin plays an important role in defining various specialized cell types, such as stem cells, cancer cells and angiogenic cells, further investigations on the roles of nestin-expressing cells in pterygium may help to uncover the mechanisms of initiation, development and the prognosis of this disease. PMID:23826515

  3. The Olfactory Neural Epithelium As a Tool in Neuroscience.

    PubMed

    Lavoie, Joëlle; Gassó Astorga, Patricia; Segal-Gavish, Hadar; Wu, YeeWen Candace; Chung, Youjin; Cascella, Nicola G; Sawa, Akira; Ishizuka, Koko

    2017-02-01

    Capturing both dynamic changes (state) and persistent signatures (trait) directly associated with disease at the molecular level is crucial in modern medicine. The olfactory neural epithelium, easily accessible in clinical settings, is a promising surrogate model in translational brain medicine, complementing the limitations in current engineered cell models.

  4. Transcriptomic profiles differentiate normal rectal epithelium and adenocarcinoma.

    PubMed

    Hogan, J; Dejulius, K; Liu, X; Coffey, J C; Kalady, M F

    2015-05-01

    Adenocarcinoma is a histologic diagnosis based on subjective findings. Transcriptional profiles have been used to differentiate normal tissue from disease and could provide a means of identifying malignancy. The goal of this study was to generate and test transcriptomic profiles that differentiate normal from adenocarcinomatous rectum. Comparisons were made between cDNA microarrays derived from normal epithelium and rectal adenocarcinoma. Results were filtered according to standard deviation to retain only highly dysregulated genes. Genes differentially expressed between cancer and normal tissue on two-groups t test (P < 0.05, Bonferroni P value adjustment) were further analyzed. Genes were rank ordered in terms of descending fold change. For each comparison (tumor versus normal epithelium), those 5 genes with the greatest positive fold change were grouped in a classifier. Five separate tests were applied to evaluate the discriminatory capacity of each classifier. Genetic classifiers derived comparing normal epithelium with malignant rectal epithelium from pooled stages had a mean sensitivity and specificity of 99.6% and 98.2%, respectively. The classifiers derived from comparing normal and stage I cancer had comparable mean sensitivities and specificities (97% and 98%, respectively). Areas under the summary receiver-operator characteristic curves for each classifier were 0.981 and 0.972, respectively. One gene was common to both classifiers. Classifiers were tested in an independent Gene Expression Omnibus-derived dataset. Both classifiers retained their predictive properties. Transcriptomic profiles comprising as few as 5 genes are highly accurate in differentiating normal from adenocarcinomatous rectal epithelium, including early-stage disease.

  5. Circulating and thymic CD4 CD25 T regulatory cells in myasthenia gravis: effect of immunosuppressive treatment.

    PubMed

    Fattorossi, Andrea; Battaglia, Alessandra; Buzzonetti, Alexia; Ciaraffa, Francesca; Scambia, Giovanni; Evoli, Amelia

    2005-09-01

    Accumulating evidence indicates an immunosuppressive role of the thymus-derived CD4+ T-cell population constitutively expressing high level of CD25, T regulatory (Treg) cells, in autoimmune diseases. Here we show that the number of Treg cells in the blood is significantly lower in untreated myasthenia gravis patients than in age-matched healthy subjects, whereas it is normal or elevated in patients on immunosuppressive therapy (prednisone frequently associated with azathioprine). Therapeutic thymectomy (Tx) for either the thymoma or non-neoplastic thymic alterations that are often associated with myasthenia gravis provided unique material for studying intrathymic Treg cells and correlating them with their peripheral counterparts. We observed that Tx prevents the increase of Treg cells in the circulation that follows immunosuppressive therapy (particularly evident if the thymus is not neoplastic), indicating that the thymus contributes to Treg-cell normalization. However, thymic Treg cells are not modulated by immunosuppressive therapy and even in thymectomized patients Treg-cell numbers in the blood eventually recover. The present findings suggest that a deficiency in Treg cells favours the development of myasthenia gravis and that their normalization is an important clinical benefit of immunosuppressive therapy. Treg normalization appears to be largely thymus independent and possibly reflects the reported capacity of corticosteroids to promote Treg-cell development.

  6. Epoc-1: a POU-domain gene expressed in murine epidermal basal cells and thymic stromal cells.

    PubMed

    Yukawa, K; Yasui, T; Yamamoto, A; Shiku, H; Kishimoto, T; Kikutani, H

    1993-11-15

    POU-domain transcription factors are known as developmental regulators which control organ development and cell phenotypes. In order to clarify the roles of POU-domain transcription factors in cell differentiation, we cloned a novel POU family gene, Epoc-1, from a murine thymus cDNA library. The amino acid (aa) sequence of the POU-specific domain of Epoc-1 is almost identical to those of Oct-1 and Oct-2. However, within the POU-homeodomain, 13 out of 60 aa differ between Epoc-1 and Oct-2. Recombinant Epoc-1 products were found to bind specifically to the octamer sequence. Epoc-1 was found to be expressed in skin, thymus, stomach and testis. In situ hybridization experiments and RNase protection assays indicated that Epoc-1 is expressed in the epidermal basal cells of the skin, which contain stem cells unipotent for keratinocyte differentiation and in thymic stromal elements. These results suggest that Epoc-1 might be one of the developmental regulators which controls epidermal development and thymic organogenesis.

  7. Identification of a novel common proviral integration site, flit-1, in feline leukemia virus induced thymic lymphoma.

    PubMed

    Fujino, Yasuhito; Liao, Chun-Peng; Zhao, Yan Shi; Pan, Judong; Mathes, Lawrence E; Hayes, Kathleen A; Ohno, Koichi; Tsujimoto, Hajime; Roy-Burman, Pradip

    2009-03-30

    A new proviral integration site for feline leukemia virus (FeLV), termed flit-1, was identified from feline thymic lymphoma. Among 35 FeLV-related tumors examined, 5 of 25 thymic lymphomas demonstrated proviral insertion within flit-1 locus whereas none of four alimentary and five multicentric lymphomas and one T-lymphoid leukemia examined had rearrangement in this region. Extensive sequence analysis has shown that flit-1, which is noncoding, is conserved on human chromosome 12 and mouse chromosome 15. The human and murine homologs of flit-1 are positioned approximately 30-kb upstream to activin-A receptor type II-like 1 (ACVRL1/ALK1) gene. Expression of ACVRL1 mRNA was examined in two of five lymphomas with flit-1 rearrangement and detected in both of the two whereas normal thymuses and seven lymphoid tumors without flit-1 rearrangement had no detectable expression. Therefore, flit-1 appears to represent a novel FeLV proviral common integration domain that may influence lymphomagenesis as insertional mutagenesis.

  8. Effects of thymic selection of the T cell repertoire on HLA-class I associated control of HIV infection

    PubMed Central

    Košmrlj, Andrej; Read, Elizabeth L.; Qi, Ying; Allen, Todd M.; Altfeld, Marcus; Deeks, Steven G.; Pereyra, Florencia; Carrington, Mary; Walker, Bruce D.; Chakraborty, Arup K.

    2011-01-01

    Without therapy, most persons infected with the human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals (“elite controllers”) maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA Class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B571. Since HLA molecules present viral peptides that activate CD8+ T cells, an immune mediated mechanism is likely responsible for superior control of HIV. We report that the peptide binding characteristics of HLA-B57 molecules impact thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naïve repertoire of B57-restricted clones recognizes a viral epitope and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide binding characteristics that impact thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, with implications for vaccination strategies. PMID:20445539

  9. Cellular transport of l-arginine determines renal medullary blood flow in control rats, but not in diabetic rats despite enhanced cellular uptake capacity.

    PubMed

    Persson, Patrik; Fasching, Angelica; Teerlink, Tom; Hansell, Peter; Palm, Fredrik

    2017-02-01

    Diabetes mellitus is associated with decreased nitric oxide bioavailability thereby affecting renal blood flow regulation. Previous reports have demonstrated that cellular uptake of l-arginine is rate limiting for nitric oxide production and that plasma l-arginine concentration is decreased in diabetes. We therefore investigated whether regional renal blood flow regulation is affected by cellular l-arginine uptake in streptozotocin-induced diabetic rats. Rats were anesthetized with thiobutabarbital, and the left kidney was exposed. Total, cortical, and medullary renal blood flow was investigated before and after renal artery infusion of increasing doses of either l-homoarginine to inhibit cellular uptake of l-arginine or N(ω)-nitro- l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase. l-Homoarginine infusion did not affect total or cortical blood flow in any of the groups, but caused a dose-dependent reduction in medullary blood flow. l-NAME decreased total, cortical and medullary blood flow in both groups. However, the reductions in medullary blood flow in response to both l-homoarginine and l-NAME were more pronounced in the control groups compared with the diabetic groups. Isolated cortical tubular cells displayed similar l-arginine uptake capacity whereas medullary tubular cells isolated from diabetic rats had increased l-arginine uptake capacity. Diabetics had reduced l-arginine concentrations in plasma and medullary tissue but increased l-arginine concentration in cortical tissue. In conclusion, the reduced l-arginine availability in plasma and medullary tissue in diabetes results in reduced nitric oxide-mediated regulation of renal medullary hemodynamics. Cortical blood flow regulation displays less dependency on extracellular l-arginine and the upregulated cortical tissue l-arginine may protect cortical hemodynamics in diabetes.

  10. Cocaine Reduces Thymic Endocrine Function: Another Mechanism for Accelerated HIV Disease Progression

    PubMed Central

    Campa, Adriana; Smith, Sylvia; Huffman, Fatma; Newman, Fred; Baum, Marianna K.

    2011-01-01

    Abstract Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4+ cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4+ cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4+ and CD8+ cell counts and the CD4+/CD8+ ratio, and the covariate effects of substance use cross-sectionally in 80 HIV+ active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (β = −0.908,95% CI: −1.704, −0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4+ cell count was positively associated with thymulin activity (β = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ≥200 cells/μl (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides

  11. Hydrogen sulfide diminishes the levels of thymic stromal lymphopoietin in activated mast cells.

    PubMed

    Han, Na-Ra; Moon, Phil-Dong; Jeong, Hyun-Ja; Kim, Hyung-Min

    2016-03-01

    Bamboo salt (BS) is a Korean traditional type of salt and has been reported to have therapeutic effects on allergic inflammation. Thymic stromal lymphopoietin (TSLP) aggravates inflammation in the pathogenesis of allergic reactions, such as allergic rhinitis (AR). To confirm an active compound of BS, we investigated the effect of sulfur, a compound of BS, on the levels of TSLP in a human mast cell line, HMC-1 cells and a mouse model of AR using hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaSH). We treated NaSH or BS in HMC-1 cells and activated the HMC-1 cells with phorbol myristate acetate and calcium ionophore A23187 (PMACI). ELISA for the production measurement of TSLP, PCR for the mRNA expression measurement of TSLP, and western blot analysis for the expression measurement of upstream mediators were performed. Mice were treated with NaSH and sensitized with ovalbumin (OVA). The levels of TSLP were measured in serum and nasal mucosa tissue in an OVA-induced AR mouse model. NaSH or BS diminished the production and mRNA expression of TSLP as well as interleukin (IL)-6 and tumor necrosis factor (TNF)-α in the PMACI-activated HMC-1 cells. NaSH or BS diminished the level of intracellular calcium in the PMACI-activated HMC-1 cells. NaSH or BS reduced the expression and activity of caspase-1 in the PMACI-activated HMC-1 cells. And NaSH or BS inhibited the expression of receptor interacting protein-2 and the phosphorylation of extracellular signal-regulated kinase in the PMACI-activated HMC-1 cells. The translocation of NF-κB into the nucleus as well as the phosphorylation and degradation of IκBα in the cytoplasm were diminished by NaSH or BS in the PMACI-activated HMC-1 cells. Furthermore, NaSH inhibited the production of TSLP, IL-6, and IL-8 in TNF-α-activated HMC-1 cells. Finally, the administration of NaSH showed a decrease in number of rubs on mice with OVA-induced AR. And the levels of immunoglobulin E and TSLP in the serum and the level of TSLP in the

  12. Cocaine reduces thymic endocrine function: another mechanism for accelerated HIV disease progression.

    PubMed

    Rafie, Carlin; Campa, Adriana; Smith, Sylvia; Huffman, Fatma; Newman, Fred; Baum, Marianna K

    2011-08-01

    Thymulin is a thymic peptide important for the maturation and differentiation of immature thymocytes, which have been found to be depressed in patients with low-level CD4(+) cell recovery despite viral control. Substance use is associated with faster progression of HIV disease, which has been ascribed to poor adherence to antiretroviral medication. Recent findings of an association between cocaine use and decline in CD4(+) cell counts independent of antiretroviral adherence indicate alternative mechanisms for disease progression. We evaluated the relationship between thymulin activity, CD4(+) and CD8(+) cell counts and the CD4(+)/CD8(+) ratio, and the covariate effects of substance use cross-sectionally in 80 HIV(+) active substance users and over 12 months in 40 participants. Thymulin activity was analyzed in plasma using a modification of the sheep rosette bioassay. Thymulin activity was negatively associated with cocaine use (β = -0.908,95% CI: -1.704, -0.112; p = 0.026). Compared to those who do not use cocaine, cocaine users were 37% less likely to have detectable thymulin activity (RR = 0.634, 95% CI: 0.406, 0.989 p = 0.045) and were 75 times more likely to show a decrease in thymulin activity (OR = 74.7, 95% CI: 1.59, 3519.74; p = 0.028) over time. CD4(+) cell count was positively associated with thymulin activity (β = 0.127, 95% CI: 0.048,0.205; p = 0.002), detectable thymulin activity was 2.32 times more likely in those with a CD4 cell count ≥200 cells/μl (RR = 2.324, 95% CI: 1.196, 4.513, p = 0.013), and those with an increase in CD4 cell counts were more likely to show an increase in thymulin activity (OR = 1.02, 95% CI: 1.00, 1.034; p = 0.041) over time. Thymulin activity is predictive of HIV disease progression and is depressed in cocaine users independent of antiretroviral treatment (ART) and HIV viral load. Understanding the mechanisms for accelerated HIV disease progression provides opportunities to find alternative strategies to counteract

  13. Results of a screening program for C-cell disease (medullary thyroid cancer and C-cell hyperplasia).

    PubMed

    Simpson, W J; Carruthers, J S; Malkin, D

    1990-04-01

    In the authors' Medullary Screening Clinic, medullary thyroid cancer (MTC) or C-cell hyperplasia (CCH) has been identified in 26 relatives of 12 apparently "sporadic" patients from 56 families in which calcitonin (CT) testing has been performed. The interpretation of stimulated test results was sometimes difficult: elevated basal levels without a significant increase after the injection of secretagogues; basal levels in the normal range with considerable increases after stimulation but not exceeding two or three times the upper limit of normal; elevated basal or stimulated CT levels that slowly decreased to normal or near-normal levels over relatively short periods of time. The latter results suggest the possibility of CCH disappearing spontaneously in some patients.

  14. Face-arm-trunk-leg sensory loss limited to the contralateral side in lateral medullary infarction: a new variant.

    PubMed

    Vaudens, P; Bogousslavsky, J

    1998-08-01

    Two patients are reported on who experienced loss of pain and temperature sensation in the entire contralateral hemibody but sparing the ispsilateral face (pure sensory stroke pattern) related to acute lateral medullary infarction. In both patients MRI showed a notch-like retro-olivary ischaemic lesion in the ventromedial tegmentum with preservation of the far lateral medulla. The mediolateral lesion involved the crossed lateral spinothalamic tract and the ventral trigeminothalamic tract, corresponding to sensory loss in the contralateral face, arm, and upper trunk. The ventrolateral extension of infarct damaged the far lateral part of the spinothalamic tract, corresponding to sensory loss in the contralateral lower trunk and leg. The findings suggest that hemisensory loss of the spinothalamic type involving-and limited to-the whole hemibody can occur in infarction in the lower brainstem. This form of pure sensory stroke may be classified as type IV of sensory loss in lateral medullary infarction.

  15. [A case of conus medullaris infarction expanding to the vertebral bodies, major psoas and erector spinae muscles].

    PubMed

    Konno, Takuya; Suwabe, Tatsuya; Kasahara, Sou; Umeda, Yoshitaka; Oyake, Mutsuo; Fujita, Nobuya

    2015-01-01

    A 77-year-old woman presented with conus medullaris and cauda equina syndrome following a sudden pain in the bilateral lower abdomen and right buttock. Lumbar magnetic resonance imaging (MRI) showed not only a conus medullaris lesion, but also several lesions in the vertebral bodies (L1, L2), right major psoas muscle, right multifidus muscle and bilateral erector spinae muscles. As these areas receive blood supply from each branch of the same segmental artery, we considered all of the lesions as infarctions that were a result of a single parent vessel occlusion. It is known that a vertebral body lesion can be accompanied by a spinal cord infarction, but in combination with infarction of a muscle has not been reported. This is the first report of a concomitant spinal cord and muscle infarction revealed by MRI. It is noteworthy that a spinal cord infarction could expand not only to neighboring vertebral bodies, but also to muscles.

  16. RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

    PubMed Central

    Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly; Gilbert, Debra; O’Sullivan, T. Norene; Lu, Lucy; Wang, Sophie; Haines, Diana C.; Van Dyke, Terry; Keller, Jonathan R.

    2017-01-01

    Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size. PMID:28158249

  17. The graft-versus-host reaction and immune function. I. T helper cell immunodeficiency associated with graft-versus-host-induced thymic epithelial cell damage

    SciTech Connect

    Seddik, M.; Seemayer, T.A.; Lapp, W.S.

    1984-03-01

    The injection of parental A strain lymphoid cells into adrenalectomized CBAxA F1 (BAF1) mice induced a chronic graft-versus-host (GVH) reaction resulting in T cell and B cell immunosuppression as well as thymic epithelial cell injury, but not stress-related thymic involution. Thymocytes from BAF1 mice undergoing a GVH reaction were studied for their ability to reconstitute T helper cell (TH) function and phytohemagglutinin (PHA) and concanavalin A (Con A) mitogen responses in thymectomized, irradiated, BAF1 mice reconstituted with normal syngeneic bone marrow (ATxBM). Thymocytes from BAF1 mice early after the induction of a GVH reaction (days 10-12) were as effective as normal thymocytes in reconstituting TH and mitogen responses. Thymocytes from BAF1 mice 40 or more days after the induction of a GVH reaction did not reconstitute either the TH function or PHA and Con A responses in ATxBM mice. The inability to reconstitute ATxBM mice was not due to the presence of suppressor cells contained in the thymocyte inoculum. It is proposed that GVH-induced thymic epithelial cell injury blocks or arrests normal T cell differentiation, resulting in a population of thymocytes that lack the potential to become competent T helper cells or mitogen-responsive cells when transferred into ATxBM mice. This thymic functional defect results in a permanent TH immunodeficiency in mice experiencing a chronic GVH reaction.

  18. RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice.

    PubMed

    Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly; Gilbert, Debra; O'Sullivan, T Norene; Lu, Lucy; Wang, Sophie; Haines, Diana C; Van Dyke, Terry; Keller, Jonathan R

    2017-01-01

    Thymic epithelial cells (TEC), as part of thymic stroma, provide essential growth factors/cytokines and self-antigens to support T cell development and selection. Deletion of Rb family proteins in adult thymic stroma leads to T cell hyperplasia in vivo. To determine whether deletion of Rb specifically in keratin (K) 18 positive TEC was sufficient for thymocyte hyperplasia, we conditionally inactivated Rb and its family members p107 and p130 in K18+ TEC in genetically engineered mice (TgK18GT121; K18 mice). We found that thymocyte hyperproliferation was induced in mice with Rb inactivation in K18+ TEC, while normal T cell development was maintained; suggesting that inactivation of Rb specifically in K18+ TEC was sufficient and responsible for the phenotype. Transplantation of wild type bone marrow cells into mice with Rb inactivation in K18+ TEC resulted in donor T lymphocyte hyperplasia confirming the non-cell autonomous requirement for Rb proteins in K18+ TEC in regulating T cell proliferation. Our data suggests that thymic epithelial cells play an important role in regulating lymphoid proliferation and thymus size.

  19. Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death.

    PubMed

    Tada, Mari; Kakita, Akiyoshi; Toyoshima, Yasuko; Onodera, Osamu; Ozawa, Tetsutaro; Morita, Takashi; Nishizawa, Masatoyo; Takahashi, Hitoshi

    2009-07-01

    Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 mum sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 +/- 7.1 versus 75.2 +/- 7.6 cells, P < 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 +/- 5.1 versus 72.8 +/- 13.6 cells, P < 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 +/- 9.2 versus 60.8 +/- 17.0 cells, P < 0.01), nucleus raphe obscurus (19.3 +/- 4.4 versus 75.3 +/- 8.6 cells, P < 0.001), nucleus raphe pallidus (2.1 +/- 2.7 versus 9.0 +/- 3.4 cells, P < 0.03), and arcuate nucleus (0.4 +/- 0.8 versus 2.3 +/- 1.5 cells, P < 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who

  20. Inhibition of medullary raphe serotonergic neurons has age-dependent effects on the CO2 response in newborn piglets.

    PubMed

    Messier, Michelle L; Li, Aihua; Nattie, Eugene E

    2004-05-01

    Medullary raphé serotonergic neurons are chemosensitive in culture and are situated adjacent to blood vessels in the brain stem. Selective lesioning of serotonergic raphé neurons decreases the ventilatory response to systemic CO2 in awake and sleeping adult rats. Abnormalities in the medullary serotonergic system, including the raphé, have been implicated in the sudden infant death syndrome (48). In this study, we ask whether serotonergic neurons in the medullary raphé and extra-raphé regions are involved in the CO2 response in unanesthetized newborn piglets, 3-16 days old. Whole body plethysmography was used to examine the ventilatory response to 5% CO2 before and during focal inhibition of serotonergic neurons by 8-hydroxy-2-di-n-propylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist. 8-OH-DPAT (10 or 30 mM in artificial cerebrospinal fluid) decreased the CO2 response in wakefulness in an age-dependent manner, as revealed by a linear regression analysis that showed a significant negative correlation (P < 0.001) between the percent change in the CO2 response and piglet age. Younger piglets showed an exaggerated CO2 response. Control dialysis with artificial cerebrospinal fluid had no significant effect on the CO2 response. Additionally, 8-OH-DPAT increased blood pressure and decreased heart rate independent of age (P < 0.05). Finally, sleep cycling was disrupted by 8-OH-DPAT, such that piglets were awake more and asleep less (P < 0.05). Because of the fragmentary sleep data, it was not possible to examine the CO2 response in sleep. Inhibition of serotonergic medullary raphé and extra-raphé neurons decreases ventilatory CO2 sensitivity and alters cardiovascular variables and sleep cycling, which may contribute to the sudden infant death syndrome.

  1. Determination of catecholamines in single adrenal medullary cells by capillary electrophoresis and laser-induced native fluorescence

    SciTech Connect

    Chang, H.T.; Yeung, E.S. |

    1995-03-15

    The present study demonstrates that native fluroescence detection combined with capillary electrophoresis separation at low pH provides high sensitivity (down to nanomolar), high resolution, high speed, and low interference for the analysis of catecholamines. Further, this method has been employed successfully for the measurement of the amounts of epinephrine and norepinephrine in individual bovine adrenal medullary cells. Application of this method to the study of neurochemistry is promising. 46 refs., 7 figs., 2 tabs.

  2. Role of renal medullary oxidative and/or carbonyl stress in salt-sensitive hypertension and diabetes.

    PubMed

    Mori, Takefumi; Ogawa, Susumu; Cowely, Allen W; Ito, Sadayoshi

    2012-01-01

    1. Salt-sensitive hypertension is commonly associated with diabetes, obesity and chronic kidney disease. The present review focuses on renal mechanisms involved in the development of this type of hypertension. 2. The renal medullary circulation plays an important role in the development of salt-sensitive hypertension. In vivo animal studies have demonstrated that the balance between nitric oxide (NO) and reactive oxygen species (ROS) in the renal medulla is an important element of salt-sensitive hypertension. The medullary thick ascending limb (mTAL) in the outer medulla is an important source of NO and ROS production and we have explored the mechanisms that stimulate their production, as well as the effects of NO superoxide and hydrogen peroxide on mTAL tubular sodium reabsorption and the regulation of medullary blood flow. 3. Angiotensin II-stimulated NO produced in the mTAL is able to diffuse from the renal mTAL to the surrounding vasa recta capillaries, providing a mechanism by which to increase medullary blood flow and counteract the direct vasoconstrictor effects of angiotensin II. Enhanced oxidative stress attenuates NO diffusion in this region. 4. Carbonyl stress, like oxidative stress, can also play an important role in the pathogenesis of chronic kidney disease, such as insulin resistance, salt-sensitive hypertension and renal vascular complications. 5. Despite the large number of studies undertaken in this area, there is as yet no drug available that directly targets renal ROS. Oxidative and/or carbonyl stress may be the next target of drug discovery to protect against salt-sensitive hypertension and associated end-organ damage.

  3. Vascular complication involving the conus medullaris or cauda equina after vertebral manipulation for an L4-L5 disk herniation.

    PubMed

    Balblanc, J C; Pretot, C; Ziegler, F

    1998-04-01

    A case of injury to the cauda equina or conus medullaris after lumbar vertebral manipulation is reported. In contrast to all other previously reported cases, no migrated disk fragment was demonstrated. Similar to experience at the cervical spine, lumbar vertebral manipulation may carry a risk of vascular injury. The neurological manifestations in our patient were consistent with compression of the Desproges-Gotteron artery by a small L4-L5 disk herniation.

  4. A behavioral analysis of complete unilateral section of the pyramidal tract at the medullary level in Macaca mulatta.

    PubMed

    Schwartzman, R J

    1978-09-01

    Ten Macaca mulatta monkeys were operantly conditioned to perform three motor paradigms designed to evaluate single and combination finger movements. Eight of these monkeys were retested after left medullary pyramidotomy; 2 monkeys underwent left medullary pyramidotomy prior to conditioning. All animals were tested for three years after operation. Monkeys with a completely sectioned medullary pyramid could, with time, perform difficult motor paradigms that required: (1) both individual and combination finger movements; (2) proximal upper extremity motor control; (3) thumb and index finger pincer grasp; and (4) the ability to preprogram and then execute a precision hand movement. The greater the extent of pyramidal tract destruction, the longer the time necessary for recovery of both discrete finger movement and pincer grasp, the greater the effort needed to attain recovery of hand function, and the weaker the affected musculature. The 2 animals in which pyramidotomy of at least 70% of the tract preceded efforts at operant conditioning learned and performed difficult motor paradigms. In all animals, neurological examination revealed that the most enduring and functionally most important deficit that interferes with hand function following pyramidotomy is loss of contactual hand orienting responses and failure of reflex sensorimotor adjustments.

  5. Decreased adrenal medullary tyrosine hydroxylase mRNA in DMBA (7,12-dimethylbenz(a)anthracene)-induced mammary carcinoma

    SciTech Connect

    Bunce, O.R.; Badary, O.A.; Abou El-Ela, S.; Hartle, D.K. )

    1991-03-15

    Adrenal cortical hormones suppress initiation and promotion of DMBA-induced mammary tumorigenesis. The authors found a positive correlation between presence of DMBA-induced adrenal cortical necrosis and mammary tumor incidence. Because they find adrenal medullary as well as cortical lesions in tumor bearing (TB) DMBA-treated rats, they evaluated medullary function by quantitating hybridized cDNA- TH-S{sup 35} with in situ TH-mRNA u sing computer assisted quantitative autoradiographic technique. Virgin female Sprague-Dawley rats were given a 10 mg i.g. dose of DMBA. Three wks later, rats were placed on 20% polyunsaturated (PUFA) fat diets containing omega-6 and omega-3 fatty acids. All were killed 15 wks post-DMBA. TH-mRNA levels in adrenal medullae of TB animals were decreased compared to non-TB rats. Histopathology indicated a high incidence of medullary necrosis in TB rats, whereas, adrenal necrosis did not occur in non-TB animals. Adrenal necrosis correlated positively with tumor burden, but no correlation was found between incidence of adrenal lesions and type of PUFA in the diet. The authors suggest that DMBA adrenal necrosis may reduce TH-mRNA in the medulla, compromise its catecholamine synthetic capability, and thereby contribute to the overall metabolic stress condition of TB rats.

  6. Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region.

    PubMed

    Lkhagvasuren, Battuvshin; Nakamura, Yoshiko; Oka, Takakazu; Sudo, Nobuyuki; Nakamura, Kazuhiro

    2011-11-01

    Psychological stress-induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0  °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe region centered in the rostral raphe pallidus and adjacent raphe magnus nuclei. In this region, Fos expression was observed in a large population of neurons expressing vesicular glutamate transporter 3 (VGLUT3), which are known as sympathetic premotor neurons controlling non-shivering thermogenesis in brown adipose tissue (BAT) and thermoregulatory constriction of skin blood vessels, and also in a small population of tryptophan hydroxylase-positive serotonergic neurons. Intraperitoneal injection of diazepam, an anxiolytic agent, but not indomethacin, an antipyretic, significantly reduced both the stress-induced hyperthermia and Fos expression in these medullary raphe neuronal populations. Systemic blockade of β3 -adrenoreceptors, which are abundantly expressed in BAT, also attenuated the stress-induced hyperthermia. These results suggest that psychological stress signals activate VGLUT3-expressing medullary raphe sympathetic premotor neurons, which then drive hyperthermic effector responses including BAT thermogenesis through β(3) -adrenoreceptors.

  7. Effects of midbrain and medullary stimulation on spinomesencephalic tract cells in the cat.

    PubMed

    Yezierski, R P

    1990-02-01

    1. The effects of electrical stimulation at different rostrocaudal levels of the midbrain, and at sites in the rostral medulla ipsilateral and contralateral to spinal recording sites, were evaluated against the responses of 46 cells belonging to the cat spinomesencephalic tract (SMT). 2. Inhibitory and/or excitatory effects of brain stem stimulation were observed on SMT cells that responded best (26 cells) or exclusively (12 cells) to noxious mechanical or thermal stimuli, as well as on 7 cells responding only to tap and/or stimulation of deep tissues. Recording sites for 32 cells were located in laminae V-VIII (27 cells) and laminae I-III (5 cells). 3. Midbrain stimulation sites were located in the superior colliculus, central gray (CG), red nucleus, and the midbrain reticular formation. Both inhibitory-only and excitatory-only effects were observed, although the most common effect of midbrain stimulation was excitation followed by inhibition (mixed effects). The effects of stimulation at different midbrain levels were determined for each cell. Stimulation in the caudal, middle, or rostral midbrain was often found to exert different effects on the same SMT cell. 4. Stimulation in the rostral medulla at sites located in nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis, and nucleus reticularis magnocellularis produced the same complement of effects observed with midbrain stimulation. Excitation followed by inhibition was the most common effect observed. 5. Stimulus intensities required to produce excitatory or inhibitory effects from midbrain were 114 +/- 85 (SD) microA and 210 +/- 91 microA, respectively. Stimulus currents required to produce excitatory or inhibitory effects from medullary stimulation sites were 124 +/- 56 microA and 70 +/- 60 microA, respectively. The mean currents required to produce mixed effects were 221 +/- 120 microA (midbrain) and 127 +/- 71 microA (medulla). Increasing the stimulus intensity used to evaluate brain stem

  8. Long-term correlations in the spike trains of medullary sympathetic neurons.

    PubMed

    Lewis, C D; Gebber, G L; Larsen, P D; Barman, S M

    2001-04-01

    Fano factor analysis was used to characterize the spike trains of single medullary neurons with sympathetic nerve-related activity in cats that were decerebrate or anesthetized with Dial-urethan or urethan. For this purpose, values (Fano factor) of the variance of the number of extracellularly recorded spikes divided by the mean number of spikes were calculated for window sizes of systematically varied length. For window sizes < or =10 ms, the Fano factor was close to one, as expected for a Bernoulli process with a low probability of success. The Fano factor dipped below one as the window size approached the shortest interspike interval (ISI) and reached its nadir at window sizes near the modal ISI. The extent of the dip reflected the shape (skewness) of the ISI histogram with the dip being smallest for the most asymmetric distributions. Most importantly, for a wide range of window sizes exceeding the modal ISI, the Fano factor curve took the form of a power law function. This was the case independent of the component (cardiac related, 10 Hz, or 2--6 Hz) of inferior cardiac sympathetic nerve discharge to which unit activity was correlated or the medullary region (lateral tegmental field, raphe, caudal and rostral ventrolateral medulla) in which the neuron was located. The power law relationship in the Fano factor curves was eliminated by randomly shuffling the ISIs even though the distribution of the intervals was unchanged. Thus the power law relationship arose from long-term correlations among ISIs that were disrupted by shuffling the data. The presence of long-term correlations across different time scales reflects the property of statistical self-similarity that is characteristic of fractal processes. In most cases, we found that mean ISI and variance for individual spike trains increased as a function of the number of intervals counted. This can be attributed to the clustering of long and short ISIs, which also is an inherent property of fractal time series

  9. Responses of the Rat Olfactory Epithelium to Retronasal Air Flow

    PubMed Central

    Scott, John W.; Acevedo, Humberto P.; Sherrill, Lisa; Phan, Maggie

    2008-01-01

    Responses of the rat olfactory epithelium were assessed with the electroolfactogram while odorants were presented to the external nares with an artificial sniff or to the internal nares by positive pressure. A series of seven odorants that varied from very polar, hydrophilic odorants to very non-polar, hydrophobic odorants were used. While the polar odorants activated the dorsal olfactory epithelium when presented by the external nares (orthonasal presentation), they were not effective when forced through the nasal cavity from the internal nares (retronasal presentation). However, the non-polar odorants were effective in both stimulus modes. These results were independent of stimulus concentration or of humidity of the carrier air. Similar results were obtained with multiunit recording from olfactory bulb. These results help to explain why human investigations often report differences in the sensation or ability to discriminate odorants presented orthonasally vs. retronasally. The results also strongly support the importance of odorant sorption in normal olfactory processes. PMID:17215498

  10. Hydrodynamics of stratified epithelium: Steady state and linearized dynamics

    NASA Astrophysics Data System (ADS)

    Yeh, Wei-Ting; Chen, Hsuan-Yi

    2016-05-01

    A theoretical model for stratified epithelium is presented. The viscoelastic properties of the tissue are assumed to be dependent on the spatial distribution of proliferative and differentiated cells. Based on this assumption, a hydrodynamic description of tissue dynamics at the long-wavelength, long-time limit is developed, and the analysis reveals important insights into the dynamics of an epithelium close to its steady state. When the proliferative cells occupy a thin region close to the basal membrane, the relaxation rate towards the steady state is enhanced by cell division and cell apoptosis. On the other hand, when the region where proliferative cells reside becomes sufficiently thick, a flow induced by cell apoptosis close to the apical surface enhances small perturbations. This destabilizing mechanism is general for continuous self-renewal multilayered tissues; it could be related to the origin of certain tissue morphology, tumor growth, and the development pattern.

  11. Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies

    PubMed Central

    Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

    2016-01-01

    Background Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. Methods PubMed, Cochrane’s Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Results Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55–1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Conclusion Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors. PMID:27524907

  12. Nanoparticle incorporation of melittin reduces sperm and vaginal epithelium cytotoxicity.

    PubMed

    Jallouk, Andrew P; Moley, Kelle H; Omurtag, Kenan; Hu, Grace; Lanza, Gregory M; Wickline, Samuel A; Hood, Joshua L

    2014-01-01

    Melittin is a cytolytic peptide component of bee venom which rapidly integrates into lipid bilayers and forms pores resulting in osmotic lysis. While the therapeutic utility of free melittin is limited by its cytotoxicity, incorporation of melittin into the lipid shell of a perfluorocarbon nanoparticle has been shown to reduce its toxicity in vivo. Our group has previously demonstrated that perfluorocarbon nanoparticles containing melittin at concentrations <10 µM inhibit HIV infectivity in vitro. In the current study, we assessed the impact of blank and melittin-containing perfluorocarbon nanoparticles on sperm motility and the viability of both sperm and vaginal epithelial cells. We found that free melittin was toxic to sperm and vaginal epithelium at concentrations greater than 2 µM (p<0.001). However, melittin nanoparticles were not cytotoxic to sperm (p = 0.42) or vaginal epithelium (p = 0.48) at an equivalent melittin concentration of 10 µM. Thus, nanoparticle formulation of melittin reduced melittin cytotoxicity fivefold and prevented melittin toxicity at concentrations previously shown to inhibit HIV infectivity. Melittin nanoparticles were toxic to vaginal epithelium at equivalent melittin concentrations ≥20 µM (p<0.001) and were toxic to sperm at equivalent melittin concentrations ≥40 µM (p<0.001). Sperm cytotoxicity was enhanced by targeting of the nanoparticles to the sperm surface antigen sperm adhesion molecule 1. While further testing is needed to determine the extent of cytotoxicity in a more physiologically relevant model system, these results suggest that melittin-containing nanoparticles could form the basis of a virucide that is not toxic to sperm and vaginal epithelium. This virucide would be beneficial for HIV serodiscordant couples seeking to achieve natural pregnancy.

  13. Gallbladder epithelium as a niche for chronic Salmonella carriage.

    PubMed

    Gonzalez-Escobedo, Geoffrey; Gunn, John S

    2013-08-01

    Although typhoid fever has been intensively studied, chronic typhoid carriage still represents a problem for the transmission and persistence of the disease in areas of endemicity. This chronic state is highly associated with the presence of gallstones in the gallbladder of infected carriers upon which Salmonella can form robust biofilms. However, we hypothesize that in addition to gallstones, the gallbladder epithelium aids in the establishment/maintenance of chronic carriage. In this work, we present evidence of the role of the gallbladder epithelium in chronic carriage by a mechanism involving invasion, intracellular persistence, and biofilm formation. Salmonella was able to adhere to and invade polarized gallbladder epithelial cells apically in the absence and presence of bile in a Salmonella pathogenicity island 1 (SPI-1)-dependent manner. Intracellular replication of Salmonella was also evident at 12 and 24 h postinvasion. A flowthrough system revealed that Salmonella is able to adhere to and form extensive bacterial foci on gallbladder epithelial cells as early as 12 h postinoculation. In vivo experiments using a chronic mouse model of typhoid carriage showed invasion and damage of the gallbladder epithelium and lamina propria up to 2 months after Salmonella infection, with an abundant presence of macrophages, a relative absence of neutrophils, and extrusion of infected epithelial cells. Additionally, microcolonies of Salmonella cells were evident on the surface of the mouse gallbladder epithelia up to 21 days postinfection. These data reveal a second potential mechanism, intracellular persistence and/or bacterial aggregation in/on the gallbladder epithelium with luminal cell extrusion, for Salmonella maintenance in the gallbladder.

  14. CD40 expressed on thymic epithelial cells provides costimulation for proliferation but not for apoptosis of human thymocytes.

    PubMed

    Ruggiero, G; Martinez Cáceres, E; Voordouw, A; Noteboom, E; Graf, D; Kroczek, R A; Spits, H

    1996-05-15

    Human thymic epithelial cells express CD40, so we examined the possible role of CD40 in activation of thymocytes. We observed that both CD4+CD8- and CD4-CD8+ thymocytes proliferate after stimulation by anti-CD3 mAb in the presence of cultured thymic epithelial cells. Costimulation of CD4+ thymocytes by thymic epithelial cells is partly inhibited by an anti-CD40 mAb, but this mAb has no effect on costimulation of CD8+ thymocytes. The selective costimulatory ability of CD40 for CD4+ thymocytes was confirmed in experiments in which thymocytes were stimulated with anti-CD3 in the presence of murine P815 cells transfected with CD40 cDNA. The level of costimulation induced by P815-CD40 was comparable with that induced by P815 cells expressing CD80 (B7.1). Treatment of thymocytes with the Ca2+ ionophore ionomycin and the phorbol ester PMA or with anti-CD3 mAb resulted in up-regulation of the CD40 ligand, suggesting that this molecule is involved in CD40-mediated costimulation of human thymocytes. Costimulation of thymocytes by CD80 strongly increased anti-CD3-induced death of fetal thymocytes. In contrast, costimulation by CD40 did not increase anti-CD3-mediated apoptosis of these thymocytes. To confirm that CD40 does not affect anti-CD3-induced cell death, we established a variant of the Jurkat T leukemic cell line that constitutively expresses CD40L and analyzed the sensitivity of this cell line for activation-induced apoptosis. In contrast to CD80, CD40 failed to increase anti-CD3-mediated apoptosis in CD40L+ Jurkat cells, whereas both CD40 and CD80 strongly increased IL-2 production induced by anti-CD3. These findings suggest that costimulation by CD40 is involved in clonal expansion of CD4+ thymocytes but not in activation-induced cell death.

  15. Biomechanics of liquid-epithelium interactions in pulmonary airways

    PubMed Central

    Ghadiali, Samir N.; Gaver, Donald P.

    2008-01-01

    The delicate structure of the lung epithelium makes it susceptible to surface tension induced injury. For example, the cyclic reopening of collapsed and/or fluid-filled airways during the ventilation of injured lungs generates hydrodynamic forces that further damage the epithelium and exacerbate lung injury. The interactions responsible for epithelial injury during airway reopening are fundamentally multiscale, since air-liquid interfacial dynamics affect global lung mechanics, while surface tension forces operate at the molecular and cellular scales. This article will review the current state-of-knowledge regarding the effect of surface tension forces on a) the mechanics of airway reopening and b) epithelial cell injury. Due to the complex nature of the liquid-epithelium system, a combination of computational and experimental techniques are being used to elucidate the mechanisms of surface-tension induced lung injury. Continued research is leading to an integrated understanding of the biomechanical and biological interactions responsible for cellular injury during airway reopening. This information may lead to novel therapies that minimize ventilation induced lung injury. PMID:18511356

  16. Activin Potentiates Proliferation in Mature Avian Auditory Sensory Epithelium

    PubMed Central

    McCullar, Jennifer S.; Ty, Sidya; Campbell, Sean; Oesterle, Elizabeth C.

    2010-01-01

    Humans and other mammals are highly susceptible to permanent hearing and balance deficits due to an inability to regenerate sensory hair cells lost to inner ear trauma. In contrast, nonmammalian vertebrates, such as birds, robustly regenerate replacement hair cells and restore hearing and balance functions to near-normal levels. There is considerable interest in understanding the cellular mechanisms responsible for this difference in regenerative capacity. Here we report on involvement of the TGFβ superfamily type II activin receptors, Acvr2a and Acvr2b, in regulating proliferation in mature avian auditory sensory epithelium. Cultured, posthatch avian auditory sensory epithelium treated with Acvr2a and Acvr2b inhibitors shows decreased proliferation of support cells, the cell type that gives rise to new hair cells. Conversely, addition of activin A, an Acvr2a/b ligand, potentiates support cell proliferation. Neither treatment (inhibitor or ligand) affected hair cell survival, suggesting a specific effect of Acvr2a/b signaling on support cell mitogenicity. Using immunocytochemistry, Acvr2a, Acvr2b, and downstream Smad effector proteins were differentially localized in avian and mammalian auditory sensory epithelia. Collectively, these data suggest that signaling through Acvr2a/b promotes support cell proliferation in mature avian auditory sensory epithelium and that this signaling pathway may be incomplete, or actively blocked, in the adult mammalian ear. PMID:20071511

  17. Mucosal adenosine stimulates chloride secretion in canine tracheal epithelium

    SciTech Connect

    Pratt, A.D.; Clancy, G.; Welsh, M.J.

    1986-08-01

    Adenosine is a local regulator of a variety of physiological functions in many tissues and has been observed to stimulate secretion in several Cl-secreting epithelia. In canine tracheal epithelium the authors found that adenosine stimulates Cl secretion from both the mucosal and submucosal surfaces. Addition of adenosine, or its analogue 2-chloroadenosine, to the mucosal surface potently stimulated Cl secretion with no effect on the rate of Na absorption. Stimulation resulted from an interaction of adenosine with adenosine receptors, because it was blocked by the adenosine receptor blocker, 8-phenyltheophylline. The adenosine receptor was a stimulatory receptor as judged by the rank-order potency of adenosine and its analogues and by the increase in cellular adenosine 3',5'-cyclic monophosphate levels produced by 2-chloroadenosine. Adenosine also stimulated Cl secretion when it was added to the submucosal surface, although the maximal increase in secretion was less and it was much less potent. The observation that mucosal 8-phenyletheophylline blocked the effect of submucosal 2-chloroadenosine, whereas submucosal 8-phenyltheophylline did not prevent a response to mucosal or submucosal 2-chloroadenosine, suggests that adenosine receptors are located on the mucosal surface. Thus submucosal adenosine may stimulate secretion by crossing the epithelium and interacting with receptors located on the mucosal surface. Because adenosine can be released from mast cells located in the airway lumen in response to inhaled material, and because adenosine stimulated secretion from the mucosal surface, it may be in a unique position to control the epithelium on a regional level.

  18. Olfactory receptor gene expression in tiger salamander olfactory epithelium.

    PubMed

    Marchand, James E; Yang, Xinhai; Chikaraishi, Dona; Krieger, Jurgen; Breer, Heinz; Kauer, John S

    2004-06-28

    Physiological studies of odor-elicited responses from the olfactory epithelium and bulb in the tiger salamander, Ambystoma tigrinum, have elucidated a number of features of olfactory coding that appear to be conserved across several vertebrate species. This animal model has provided an accessible in vivo system for observing individual and ensemble olfactory responses to odorant stimulation using biochemical, neurophysiological, and behavioral assays. In this paper we have complemented these studies by characterizing 35 candidate odorant receptor genes. These receptor sequences are similar to those of the large families of olfactory receptors found in mammals and fish. In situ hybridization, using RNA probes to 20 of these sequences, demonstrates differential distributions of labeled cells across the extent and within the depth of the olfactory epithelium. The distributions of cells labeled with probes to different receptors show spatially restricted patterns that are generally localized to different degrees in medial-lateral and anterior-posterior directions. The patterns of receptor expression in the ventral olfactory epithelium (OE) are mirrored in the dorsal OE. We present a hypothesis as to how the sensory neuron populations expressing different receptor types responding to a particular odorant may relate to the distribution patterns of epithelial and bulbar responses previously characterized using single-unit and voltage-sensitive dye recording methods.

  19. Passive Electrical Properties of Toad Urinary Bladder Epithelium

    PubMed Central

    Reuss, Luis; Finn, Arthur L.

    1974-01-01

    The electrical resistances of the transcellular and paracellular pathways across the toad urinary bladder epithelium (a typical "tight" sodium-transporting epithelium) were determined by two independent sets of electrophysiological measurements: (a) the measurement of the total transepithelial resistance, the ratio of resistance of the apical to the basal cell membrane, and cable analysis of the voltage spread into the epithelium; (b) the measurement of the total transepithelial resistance and the ratio of resistances of both cell membranes before and after replacing all mucosal sodium with potassium (thus, increasing selectively the resistance of the apical membrane). The results obtained with both methods indicate the presence of a finite transepithelial shunt pathway, whose resistance is about 1.8 times the resistance of the transcellular pathway. Appropriate calculations show that the resistance of the shunt pathway is almost exclusively determined by the zonula occludens section of the limiting junctions. The mean resistance of the apical cell membrane is 1.7 times that of the basal cell membrane. The use of nonconducting materials on the mucosal side allowed us to demonstrate that apparently all epithelial cells are electrically coupled, with a mean space constant of 460 µm, and a voltage spread consistent with a thin sheet model. PMID:4209766

  20. Expression of interleukin-18 by porcine airway and intestinal epithelium.

    PubMed

    Muneta, Yoshihiro; Goji, Noriko; Tsuji, Noriko M; Mikami, Osamu; Shimoji, Yoshihiro; Nakajima, Yasuyuki; Yokomizo, Yuichi; Mori, Yasuyuki

    2002-08-01

    In this study, we investigated the expression of interleukin-18 (IL-18) in porcine airway and intestinal epithelium. We found constitutive protein expression of precursor IL-18 in primary culture of porcine airway epithelium. Immunohistochemical staining revealed that porcine IL-18 was localized in the porcine airway epithelium and that it was significantly upregulated with experimental endotoxemia induced by Escherichia coli lipopolysaccharide (LPS) inoculation. We also confirmed by immunohistochemical staining that IL-18 was expressed in porcine intestinal epithelial cells. Moreover, the concentration of IL-18 in intestinal cell lysates of 1-day-old piglets was about 3-fold and 6-fold less than that in those of 1-month-old and 6-month-old piglets, respectively. Exogenous IL-18 was able to induce interferon-gamma (IFN-gamma) in the peripheral blood of 1-day-old piglets, whereas concanavalin A (ConA) was not able to induce IFN-gamma in the same condition. These results suggest that mucosal epithelial cells are among the major sources of IL-18 in pig and that IL-18 may be useful as a therapeutic agent for the enhancement of immune responses and as a vaccine adjuvant, especially in neonatal piglets.