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Sample records for connective tissue growth

  1. Connective tissue growth factor in tumor pathogenesis

    PubMed Central

    2012-01-01

    Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood. High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors. PMID:23259759

  2. Connective tissue progenitor cell growth characteristics on textured substrates.

    PubMed

    Mata, Alvaro; Boehm, Cynthia; Fleischman, Aaron J; Muschler, George F; Roy, Shuvo

    2007-01-01

    Growth characteristics of human connective tissue progenitor (CTP) cells were investigated on smooth and textured substrates, which were produced using MEMS (microelectromechanical systems) fabrication technology. Human bone marrow derived cells were cultured for 9 days under conditions promoting osteoblastic differentiation on polydimethylsiloxane (PDMS) substrates comprising smooth (non-patterned) surfaces (SMOOTH), 4 different cylindrical post micro-textures (POSTS) that were 7-10 microm high and 5, 10, 20, and 40 microm diameter, respectively, and channel micro-textures (CHANNELS) with curved cross-sections that were 11 microm high, 45 microm wide, and separated by 5 microm wide ridges. Standard glass-tissue culture surfaces were used as controls. Micro-textures resulted in the modification of CTP morphology, attachment, migration, and proliferation characteristics. Specifically, cells on POSTS exhibited more contoured morphology with closely packed cytoskeletal actin microfilaments compared to the more random orientation in cells grown on SMOOTH. CTP colonies on 10 gm-diameter POSTS exhibited higher cell number than any other POSTS, and a significant increase in cell number (442%) compared to colonies on SMOOTH (71%). On CHANNELS, colonies tended to be denser (229%) than on POSTS (up to 140% on 10 microm POSTS), and significantly more so compared to those on SMOOTH (104%). PMID:18019838

  3. Connective tissue growth factor is a substrate of ADAM28

    SciTech Connect

    Mochizuki, Satsuki; Tanaka, Rena; Shimoda, Masayuki; Onuma, Junko; Fujii, Yutaka; Jinno, Hiromitsu; Okada, Yasunori

    2010-11-26

    Research highlights: {yields} The hyper-variable region in the cysteine-rich domain of ADAM28 binds to C-terminal domain of CTGF. {yields} ADAM28 cleaves CTGF alone and CTGF in the CTGF/VEGF{sub 165} complex. {yields} CTGF digestion by ADAM28 releases biologically active VEGF{sub 165} from the complex. {yields} ADAM28, CTGF and VEGF{sub 165} are commonly co-expressed by carcinoma cells in human breast carcinoma tissues. {yields} These suggest that ADAM28 promotes VEGF{sub 165}-induced angiogenesis in the breast carcinomas by selective CTGF digestion in the CTGF/VEGF{sub 165} complex. -- Abstract: ADAM28, a member of the ADAM (a disintegrin and metalloproteinase) gene family, is over-expressed by carcinoma cells and the expression correlates with carcinoma cell proliferation and progression in human lung and breast carcinomas. However, information about substrates of ADAM28 is limited. We screened interacting molecules of ADAM28 in human lung cDNA library by yeast two-hybrid system and identified connective tissue growth factor (CTGF). Binding of CTGF to proADAM28 was demonstrated by yeast two-hybrid assay and protein binding assay. ADAM28 cleaved CTGF in dose- and time-dependent manners at the Ala{sup 181}-Tyr{sup 182} and Asp{sup 191}-Pro{sup 192} bonds in the hinge region of the molecule. ADAM28 selectively digested CTGF in the complex of CTGF and vascular endothelial growth factor{sub 165} (VEGF{sub 165}), releasing biologically active VEGF{sub 165} from the complex. RT-PCR and immunohistochemical analyses demonstrated that ADAM28, CTGF and VEGF are commonly co-expressed in the breast carcinoma tissues. These data provide the first evidence that CTGF is a novel substrate of ADAM28 and suggest that ADAM28 may promote VEGF{sub 165}-induced angiogenesis in the breast carcinomas by the CTGF digestion in the CTGF/VEGF{sub 165} complex.

  4. Connective tissue growth factor induces cardiac hypertrophy through Akt signaling

    SciTech Connect

    Hayata, Nozomi; Fujio, Yasushi; Yamamoto, Yasuhiro; Iwakura, Tomohiko; Obana, Masanori; Takai, Mika; Mohri, Tomomi; Nonen, Shinpei; Maeda, Makiko; Azuma, Junichi

    2008-05-30

    In the process of cardiac remodeling, connective tissue growth factor (CTGF/CCN2) is secreted from cardiac myocytes. Though CTGF is well known to promote fibroblast proliferation, its pathophysiological effects in cardiac myocytes remain to be elucidated. In this study, we examined the biological effects of CTGF in rat neonatal cardiomyocytes. Cardiac myocytes stimulated with full length CTGF and its C-terminal region peptide showed the increase in cell surface area. Similar to hypertrophic ligands for G-protein coupled receptors, such as endothelin-1, CTGF activated amino acid uptake; however, CTGF-induced hypertrophy is not associated with the increased expression of skeletal actin or BNP, analyzed by Northern-blotting. CTGF treatment activated ERK1/2, p38 MAPK, JNK and Akt. The inhibition of Akt by transducing dominant-negative Akt abrogated CTGF-mediated increase in cell size, while the inhibition of MAP kinases did not affect the cardiac hypertrophy. These findings indicate that CTGF is a novel hypertrophic factor in cardiac myocytes.

  5. Changes in connective tissue of M. semitendinosus as a response to different growth paths in steers.

    PubMed

    Harper, G S; Allingham, P G; Le Feuvre, R P

    1999-10-01

    The effect of growth path, as opposed to advancing age, on the biophysical and biochemical properties of muscle connective tissue was investigated. Nine-month old Brahman-cross steers were grown across either an uninterrupted path, or paths that incorporated weight-loss and then weight gain on two different diets: one group was realimented on pasture, whilst the other was realimented on a grain-based diet. Biophysical attributes of connective tissue toughness (Compression and Adhesion) in the semitendinosus muscle, were significantly reduced by treatment (P<0.05): weight loss with grain realimentation being the least tough in regard to the connective tissue component. Variance within the biophysical attributes was modelled statistically. Statistically significant models included terms for the post-slaughter connective tissue content as well as tissue contents of the enzymes lactate dehydrogenase and isocitrate dehydrogenase. The data suggest that biochemical measurements made up to 100 days prior to slaughter, may have value as indicators of final connective tissue toughness. PMID:22063087

  6. Undifferentiated Connective Tissue Disease

    MedlinePlus

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... L. Goldstein, MD, MMSc (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

  7. Connective Tissue Disorders

    MedlinePlus

    Connective tissue is the material inside your body that supports many of its parts. It is the "cellular ... their work. Cartilage and fat are examples of connective tissue. There are over 200 disorders that impact connective ...

  8. [THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE].

    PubMed

    Rudoi, A S; Moskalev, A V; Sboitchakov, V B

    2016-02-01

    The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-β (TGFβ). The involvement of TGFβ in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem. PMID:27455564

  9. Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex.

    PubMed

    Mercurio, Sara; Latinkic, Branko; Itasaki, Nobue; Krumlauf, Robb; Smith, J C

    2004-05-01

    Connective-tissue growth factor (CTGF) is a member of the CCN family of secreted proteins. CCN family members contain four characteristic domains and exhibit multiple activities: they associate with the extracellular matrix, they can mediate cell adhesion, cell migration and chemotaxis, and they can modulate the activities of peptide growth factors. Many of the effects of CTGF are thought to be mediated by binding to integrins, whereas others may be because of its recently identified ability to interact with BMP4 and TGF beta. We demonstrate, using Xenopus embryos, that CTGF also regulates signalling through the Wnt pathway, in accord with its ability to bind to the Wnt co-receptor LDL receptor-related protein 6 (LRP6). This interaction is likely to occur through the C-terminal (CT) domain of CTGF, which is distinct from the BMP- and TGF beta-interacting domain. Our results define new activities of CTGF and add to the variety of routes through which cells regulate growth factor activity in development, disease and tissue homeostasis. PMID:15105373

  10. Influence of biologic therapy on growth in children with chronic inflammatory connective tissue diseases

    PubMed Central

    Zygmunt, Agnieszka; Biernacka-Zielińska, Małgorzata; Stańczyk, Jerzy; Smolewska, Elżbieta

    2015-01-01

    Objectives Connective tissue diseases (CTD) are a heterogeneous group of chronic inflammatory conditions. One of their complications in children is the inhibition of growth velocity. Due to direct inflammation within the musculoskeletal system as well as glucocorticoid therapy, this feature is the most essential and is mainly expressed in the course of juvenile spondyloarthropathies and juvenile idiopathic arthritis (JIA). Duration of the disease, but predominantly the activity of the inflammatory process, seems to have a significant impact on the abnormal growth profile in children. Effective biological therapy leads to improvement of the patient's clinical condition and also, through the extinction of disease activity and reduction of daily doses of glucocorticosteroids (GCS), it gradually accelerates and normalizes the growth rate in children with CTD. Our objective was to evaluate the impact of biological therapy on growth in children with chronic inflammatory CTD. Material and methods Data from 24 patients with CTD treated with tumor necrosis factor-α-blockers (etanercept, adalimumab, golimumab) and an interleukin-6 receptor blocker (tocilizumab) were reviewed at the time of disease onset, biological treatment initiation and at least 12 up to 24 months onwards. The rate of growth was correlated with the daily doses of GCS, and the type and duration of biological therapy. Results Patient median height, measured as the change in height standard deviation score, was 0.36 ±1.07 at disease onset and –0.13 ±1.02 at biologic therapy initiation. The growth velocity accelerated in 17 patients (70.1%) during the biological treatment. Mean height-SDS improvement between biological treatment initiation up to two years was 0.51 ±0.58. In 47% of patients daily doses of GCS were reduced to 0 mg/kg/day. Conclusions In the treatment of CTD, biological agents restore growth velocity not only by inflammation inhibition, but also through limiting GCS daily doses.

  11. Recombinant Expression, Purification, and Functional Characterisation of Connective Tissue Growth Factor and Nephroblastoma-Overexpressed Protein

    PubMed Central

    Bohr, Wilhelm; Kupper, Michael; Hoffmann, Kurt; Weiskirchen, Ralf

    2010-01-01

    The CCN family of proteins, especially its prominent member, the Connective tissue growth factor (CTGF/CCN2) has been identified as a possible biomarker for the diagnosis of fibrotic diseases. As a downstream mediator of TGF-β1 signalling, it is involved in tissue scarring, stimulates interstitial deposition of extracellular matrix proteins, and promotes proliferation of several cell types. Another member of this family, the Nephroblastoma-Overexpressed protein (NOV/CCN3), has growth-inhibiting properties. First reports further suggest that these two CCN family members act opposite to each other in regulating extracellular matrix protein expression and reciprocally influence their own expression when over-expressed. We have established stable HEK and Flp-In-293 clones as productive sources for recombinant human CCN2/CTGF. In addition, we generated an adenoviral vector for recombinant expression of rat NOV and established protocols to purify large quantities of these CCN proteins. The identity of purified human CCN2/CTGF and rat CCN3/NOV was proven by In-gel digest followed by ESI-TOF/MS mass spectrometry. The biological activity of purified proteins was demonstrated using a Smad3-sensitive reporter gene and BrdU proliferation assay in permanent cell line EA•hy 926 cells. We further demonstrate for the first time that both recombinant CCN proteins are N-glycosylated. PMID:21209863

  12. Activin A-Smad Signaling Mediates Connective Tissue Growth Factor Synthesis in Liver Progenitor Cells

    PubMed Central

    Ding, Ze-Yang; Jin, Guan-Nan; Wang, Wei; Sun, Yi-Min; Chen, Wei-Xun; Chen, Lin; Liang, Hui-Fang; Datta, Pran K.; Zhang, Ming-Zhi; Zhang, Bixiang; Chen, Xiao-Ping

    2016-01-01

    Liver progenitor cells (LPCs) are activated in chronic liver damage and may contribute to liver fibrosis. Our previous investigation reported that LPCs produced connective tissue growth factor (CTGF/CCN2), an inducer of liver fibrosis, yet the regulatory mechanism of the production of CTGF/CCN2 in LPCs remains elusive. In this study, we report that Activin A is an inducer of CTGF/CCN2 in LPCs. Here we show that expression of both Activin A and CTGF/CCN2 were upregulated in the cirrhotic liver, and the expression of Activin A positively correlates with that of CTGF/CCN2 in liver tissues. We go on to show that Activin A induced de novo synthesis of CTGF/CCN2 in LPC cell lines LE/6 and WB-F344. Furthermore, Activin A contributed to autonomous production of CTGF/CCN2 in liver progenitor cells (LPCs) via activation of the Smad signaling pathway. Smad2, 3 and 4 were all required for this induction. Collectively, these results provide evidence for the fibrotic role of LPCs in the liver and suggest that the Activin A-Smad-CTGF/CCN2 signaling in LPCs may be a therapeutic target of liver fibrosis. PMID:27011166

  13. Dynamic vibration cooperates with connective tissue growth factor to modulate stem cell behaviors.

    PubMed

    Tong, Zhixiang; Zerdoum, Aidan B; Duncan, Randall L; Jia, Xinqiao

    2014-07-01

    Vocal fold disorders affect 3-9% of the U.S. population. Tissue engineering offers an alternative strategy for vocal fold repair. Successful engineering of vocal fold tissues requires a strategic combination of therapeutic cells, biomimetic scaffolds, and physiologically relevant mechanical and biochemical factors. Specifically, we aim to create a vocal fold-like microenvironment to coax stem cells to adopt the phenotype of vocal fold fibroblasts (VFFs). Herein, high frequency vibratory stimulations and soluble connective tissue growth factor (CTGF) were sequentially introduced to mesenchymal stem cells (MSCs) cultured on a poly(ɛ-caprolactone) (PCL)-derived microfibrous scaffold for a total of 6 days. The initial 3-day vibratory culture resulted in an increased production of hyaluronic acids (HA), tenascin-C (TNC), decorin (DCN), and matrix metalloproteinase-1 (MMP1). The subsequent 3-day CTGF treatment further enhanced the cellular production of TNC and DCN, whereas CTGF treatment alone without the vibratory preconditioning significantly promoted the synthesis of collagen I (Col 1) and sulfated glycosaminoglycans (sGAGs). The highest level of MMP1, TNC, Col III, and DCN production was found for cells being exposed to the combined vibration and CTGF treatment. Noteworthy, the vibration and CTGF elicited a differential stimulatory effect on elastin (ELN), HA synthase 1 (HAS1), and fibroblast-specific protein-1 (FSP-1). The mitogenic activity of CTGF was only elicited in naïve cells without the vibratory preconditioning. The combined treatment had profound, but opposite effects on mitogen-activated protein kinase (MAPK) pathways, Erk1/2 and p38, and the Erk1/2 pathway was critical for the observed mechano-biochemical responses. Collectively, vibratory stresses and CTGF signals cooperatively coaxed MSCs toward a VFF-like phenotype and accelerated the synthesis and remodeling of vocal fold matrices. PMID:24456068

  14. Molecular insights into connective tissue growth factor action in rat pancreatic stellate cells.

    PubMed

    Karger, Anna; Fitzner, Brit; Brock, Peter; Sparmann, Gisela; Emmrich, Jörg; Liebe, Stefan; Jaster, Robert

    2008-10-01

    Pancreatic fibrosis, a key feature of chronic pancreatitis and pancreatic cancer, is mediated by activated pancreatic stellate cells (PSC). Connective tissue growth factor (CTGF) has been suggested to play a major role in fibrogenesis by enhancing PSC activation after binding to alpha5beta1 integrin. Here, we have focussed on molecular determinants of CTGF action. Inhibition of CTGF expression in PSC by siRNA was associated with decreased proliferation, while application of exogenous CTGF stimulated both cell growth and collagen synthesis. Real-time PCR studies revealed that CTGF target genes in PSC not only include mediators of matrix remodelling but also the proinflammatory cytokines interleukin (IL)-1beta and IL-6. CTGF stimulated binding of NF-kappaB to the IL-6 promoter, and siRNA targeting the NF-kappaB subunit RelA interfered with CTGF-induced IL-6 expression, implicating the NF-kappaB pathway in the mediation of the CTGF effect. In further studies, we have analyzed regulation of CTGF expression in PSC. Transforming growth factor-beta1, activin A and tumor necrosis factor-alpha enhanced expression of the CTGF gene, while interferon-gamma displayed the opposite effect. The region from -74 to -125 of the CTGF promoter was revealed to be critical for its activity in PSC as well as for the inhibitory effect of interferon-gamma. Taken together, our results indicate a tight control of CTGF expression in PSC at the transcriptional level. CTGF promotes fibrogenesis both directly by enhancing PSC proliferation and matrix protein synthesis, and indirectly through the release of proinflammatory cytokines that may accelerate the process of chronic inflammation. PMID:18639630

  15. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    PubMed

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  16. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer

    PubMed Central

    Moran-Jones, Kim; Gloss, Brian S.; Murali, Rajmohan; Chang, David K.; Colvin, Emily K.; Jones, Marc D.; Yuen, Samuel; Howell, Viive M.; Brown, Laura M.; Wong, Carol W.; Spong, Suzanne M.; Scarlett, Christopher J.; Hacker, Neville F.; Ghosh, Sue; Mok, Samuel C.; Birrer, Michael J.; Samimi, Goli

    2015-01-01

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer. PMID:26575166

  17. Alteration of Connective Tissue Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with Graves’ Ophthalmopathy

    PubMed Central

    Chang, Pei-Chen; Wei, Yau-Huei

    2015-01-01

    Graves’ ophthalmopathy (GO) is a disfiguring and sometimes blinding disease, which is characterized by inflammation and swelling of orbital tissues, with fibrosis and adipogenesis being predominant features. The aim of this study is to investigate whether the expression levels of fibrosis-related genes, especially that of connective tissue growth factor (CTGF), are altered in orbital fibroblasts of patients with GO. The role of oxidative stress in the regulation of CTGF expression in GO orbital fibroblasts is also examined. By a SYBR Green-based real time quantitative PCR (RT-QPCR), we demonstrated that the mRNA expression levels of fibronectin, apolipoprotein J, and CTGF in cultured orbital fibroblasts from patients with GO were significantly higher than those of age-matched normal controls (p = 0.007, 0.037, and 0.002, respectively). In addition, the protein expression levels of fibronectin, apolipoprotein J, and CTGF analyzed by Western blot were also significantly higher in GO orbital fibroblasts (p = 0.046, 0.032, and 0.008, respectively) as compared with the control. Furthermore, after treatment of orbital fibroblasts with a sub-lethal dose of hydrogen peroxide (200 μM H2O2), we found that the H2O2-induced increase of CTGF expression was more pronounced in the GO orbital fibroblasts as compared with those in normal controls (20% vs. 7%, p = 0.007). Importantly, pre-incubation with antioxidants including N-acetylcysteine (NAC) and vitamin C, respectively, resulted in significant attenuation of the induction of CTGF in GO orbital fibroblasts in response to H2O2 (p = 0.004 and 0.015, respectively). Taken together, we suggest that oxidative stress plays a role in the alteration of the expression of CTGF in GO orbital fibroblasts that may contribute to the pathogenesis and progression of GO. Antioxidants may be used in combination with the therapeutic agents for effective treatment of GO. PMID:26599235

  18. Hypoxia induces expression of connective tissue growth factor in scleroderma skin fibroblasts

    PubMed Central

    Hong, K-H; Yoo, S-A; Kang, S-S; Choi, J-J; Kim, W-U; Cho, C-S

    2006-01-01

    Connective tissue growth factor (CTGF) plays a role in the fibrotic process of systemic sclerosis (SSc). Because hypoxia is associated with fibrosis in several profibrogenic conditions, we investigated whether CTGF expression in SSc fibroblasts is regulated by hypoxia. Dermal fibroblasts from patients with SSc and healthy controls were cultured in the presence of hypoxia or cobalt chloride (CoCl2), a chemical inducer of hypoxia-inducible factor (HIF)-1α. Expression of CTGF was evaluated by Northern and Western blot analyses. Dermal fibroblasts exposed to hypoxia (1% O2) or CoCl2 (1–100 µM) enhanced expression of CTGF mRNA. Skin fibroblasts transfected with HIF-1α showed the increased levels of CTGF protein and mRNA, as well as nuclear staining of HIF-1α, which was enhanced further by treatment of CoCl2. Simultaneous treatment of CoCl2 and transforming growth factor (TGF)-β additively increased CTGF mRNA in dermal fibroblasts. Interferon-γ inhibited the TGF-β-induced CTGF mRNA expression dose-dependently in dermal fibroblasts, but they failed to hamper the CoCl2-induced CTGF mRNA expression. In addition, CoCl2 treatment increased nuclear factor (NF)-κB binding activity for CTGF mRNA, while decreasing IκBα expression in dermal fibroblasts. Our data suggest that hypoxia, caused possibly by microvascular alterations, up-regulates CTGF expression through the activation of HIF-1α in dermal fibroblasts of SSc patients, and thereby contributes to the progression of skin fibrosis. PMID:17034590

  19. Connective tissue growth factor hammerhead ribozyme attenuates human hepatic stellate cell function

    PubMed Central

    Gao, Run-Ping; Brigstock, David R

    2009-01-01

    AIM: To determine the effect of hammerhead ribozyme targeting connective tissue growth factor (CCN2) on human hepatic stellate cell (HSC) function. METHODS: CCN2 hammerhead ribozyme cDNA plus two self-cleaving sequences were inserted into pTriEx2 to produce pTriCCN2-Rz. Each vector was individually transfected into cultured LX-2 human HSCs, which were then stimulated by addition of transforming growth factor (TGF)-β1 to the culture medium. Semi-quantitative RT-PCR was used to determine mRNA levels for CCN2 or collagen I, while protein levels of each molecule in cell lysates and conditioned medium were measured by ELISA. Cell-cycle progression of the transfected cells was assessed by flow cytometry. RESULTS: In pTriEx2-transfected LX-2 cells, TGF-β1 treatment caused an increase in the mRNA level for CCN2 or collagen I, and an increase in produced and secreted CCN2 or extracellular collagen I protein levels. pTriCCN2-Rz-transfected LX-2 cells showed decreased basal CCN2 or collagen mRNA levels, as well as produced and secreted CCN2 or collagen I protein. Furthermore, the TGF-β1-induced increase in mRNA or protein for CCN2 or collagen I was inhibited partially in pTriCCN2-Rz-transfected LX-2 cells. Inhibition of CCN2 using hammerhead ribozyme cDNA resulted in fewer of the cells transitioning into S phase. CONCLUSION: Endogenous CCN2 is a mediator of basal or TGF-β1-induced collagen I production in human HSCs and regulates entry of the cells into S phase. PMID:19673024

  20. Hammerhead Ribozyme-Mediated Knockdown of mRNA for Fibrotic Growth Factors: Transforming Growth Factor-Beta 1 and Connective Tissue Growth Factor

    PubMed Central

    Robinson, Paulette M.; Blalock, Timothy D.; Yuan, Rong; Lewin, Alfred S.; Schultz, Gregory S.

    2013-01-01

    Excessive scarring (fibrosis) is a major cause of pathologies in multiple tissues, including lung, liver, kidney, heart, cornea, and skin. The transforming growth factor- β (TGF- β) system has been shown to play a key role in regulating the formation of scar tissue throughout the body. Furthermore, connective tissue growth factor (CTGF) has been shown to mediate most of the fibrotic actions of TGF- β, including stimulation of synthesis of extracellular matrix and differentiation of fibroblasts into myofibroblasts. Currently, no approved drugs selectively and specifically regulate scar formation. Thus, there is a need for a drug that selectively targets the TGF- β cascade at the molecular level and has minimal off-target side effects. This chapter focuses on the design of hammerhead ribozymes, measurement of kinetic activity, and assessment of knockdown mRNAs of TGF- β and CTGF in cell cultures. PMID:22131029

  1. Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer.

    PubMed

    Wells, Julia E; Howlett, Meegan; Cole, Catherine H; Kees, Ursula R

    2015-08-01

    Connective tissue growth factor (CTGF/CCN2) has long been associated with human cancers. The role it plays in these neoplasms is diverse and tumour specific. Recurring patterns in clinical outcome, histological desmoplasia and mechanisms of action have been found. When CTGF is overexpressed compared to low-expressing normal tissue or is underexpressed compared to high-expressing normal tissue, the functional outcome favours tumour survival and disease progression. CTGF acts by altering proliferation, drug resistance, angiogenesis, adhesion and migration contributing to metastasis. The pattern of CTGF expression and tumour response helps to clarify the role of this matricellular protein across a multitude of human cancers. PMID:24832082

  2. Connective tissue growth factor and its regulation: a new element in diabetic glomerulosclerosis.

    PubMed

    Riser, B L; Cortes, P

    2001-01-01

    Connective tissue growth factor (CTGF), a member of the closely related CCN family of cytokines appears to be fibrotic in skin. To determine whether CTGF is implicated in diabetic glomerulosclerosis we studied cultured rat mesangial cells (MC) as well as kidney cortex and microdissected glomeruli from obese, diabetic db/db mice and their normal counterparts. Exposure of MC to rhCTGF significantly increased fibronectin and collagen type I secretion. Further, unstimulated MC expressed low levels of CTGF message and secreted minimal amounts of CTGF protein (36-38 kDa). However, exposure to TGF-beta, increased glucose concentrations, or cyclic mechanical strain, all causal factors in glomerulosclerosis, markedly induced the expression of CTGF transcripts. With all but mechanical strain there was a concomitant stimulation of CTGF protein secretion. TGF-beta also induced abundant quantities of a small molecular weight form of CTGF (18 kDa). The induction of CTGF protein by a high glucose concentration was mediated by TGF-beta, since a TGF-beta neutralizing antibody blocked this stimulation. In vivo studies using quantitative RT-PCR demonstrated that while CTGF transcripts were low in the glomeruli of control mice, expression was increased 27-fold after approximately 3.5 months of diabetes. These changes occurred early in diabetic nephropathy when mesangial expansion was mild, and interstitial disease and proteinuria were absent. A substantially reduced elevation of CTGF mRNA (2-fold) observed in whole kidney cortices indicted that the primary alteration of CTGF expression was in the glomerulus. These results suggest that CTGF upregulation is an important factor in the pathogenesis of mesangial matrix accumulation in both diabetic and non-diabetic glomerulosclerosis, acting downstream of TGF-beta. PMID:11499561

  3. Regulation of pancreatic inflammation by connective tissue growth factor (CTGF/CCN2).

    PubMed

    Charrier, Alyssa; Chen, Ruju; Kemper, Sherri; Brigstock, David R

    2014-04-01

    Pancreatitis is caused by long-term heavy alcohol consumption, which results in injury and death of pancreatic acinar cells (PAC). The PAC play a pivotal role in mediating early inflammatory responses but the underlying mechanisms remain poorly understood. Treatment of C57BL/6 mice with ethanol and cerulein resulted in increased staining for acinar interleukin- 1b (IL-1b), chemokine (C-C motif) ligand 3 (CCL3), or connective tissue growth factor (CTGF/CCN2) by Day 16 and this was associated with increased infiltration of F4/80-positive macrophages and increased expression of pancreatic CTGF/CCN2 mRNA. Compared with wild-type Swiss Webster mice, ethanol treatment of pan-green fluorescent protein (GFP)-CTGF/CCN2 transgenic mice caused enhanced acinar staining for GFP or CTGF/CCN2 and a significant increase in pancreatic infiltration of F4/80-positive macrophages or NIMP-R14-positive neutrophils. Treatment of primary mouse PAC or the rat AR42J PAC line with ethanol or CTGF/CCN2 resulted in enhanced expression of IL-1b or CCL3. Conditioned medium from CTGF/CCN2-treated AR42J cells induced chemotaxis in NR8383 macrophages and this response was abrogated in a dose dependent manner by addition of BX471, an inhibitor of chemokine (C-C motif) receptor 1. These results reveal that acinar CTGF/CCN2 plays a novel role in alcohol-induced inflammatory processes in the pancreas by increasing infiltration of macrophages and neutrophils and increasing acinar production of inflammatory mediators such as IL-1b or CCL3. The early production of CTGF/CCN2 by PAC to drive inflammation is distinct from its previously reported production by pancreatic stellate cells to drive fibrosis at later stages of pancreatic injury. PMID:24754049

  4. Regulation of pancreatic inflammation by connective tissue growth factor (CTGF/CCN2)

    PubMed Central

    Charrier, Alyssa; Chen, Ruju; Kemper, Sherri; Brigstock, David R

    2014-01-01

    Pancreatitis is caused by long-term heavy alcohol consumption, which results in injury and death of pancreatic acinar cells (PAC). The PAC play a pivotal role in mediating early inflammatory responses but the underlying mechanisms remain poorly understood. Treatment of C57BL/6 mice with ethanol and cerulein resulted in increased staining for acinar interleukin-1β (IL-1β), chemokine (C-C motif) ligand 3 (CCL3), or connective tissue growth factor (CTGF/CCN2) by Day 16 and this was associated with increased infiltration of F4/80-positive macrophages and increased expression of pancreatic CTGF/CCN2 mRNA. Compared with wild-type Swiss Webster mice, ethanol treatment of pan-green fluorescent protein (GFP)-CTGF/CCN2 transgenic mice caused enhanced acinar staining for GFP or CTGF/CCN2 and a significant increase in pancreatic infiltration of F4/80-positive macrophages or NIMP-R14-positive neutrophils. Treatment of primary mouse PAC or the rat AR42J PAC line with ethanol or CTGF/CCN2 resulted in enhanced expression of IL-1β or CCL3. Conditioned medium from CTGF/CCN2-treated AR42J cells induced chemotaxis in NR8383 macrophages and this response was abrogated in a dose-dependent manner by addition of BX471, an inhibitor of chemokine (C-C motif) receptor 1. These results reveal that acinar CTGF/CCN2 plays a novel role in alcohol-induced inflammatory processes in the pancreas by increasing infiltration of macrophages and neutrophils and increasing acinar production of inflammatory mediators such as IL-1β or CCL3. The early production of CTGF/CCN2 by PAC to drive inflammation is distinct from its previously reported production by pancreatic stellate cells to drive fibrosis at later stages of pancreatic injury. PMID:24754049

  5. Optimum scratch assay condition to evaluate connective tissue growth factor expression for anti-scar therapy.

    PubMed

    Moon, Heekyung; Yong, Hyeyoung; Lee, Ae-Ri Cho

    2012-02-01

    To evaluate a potential anti-scar therapy, we first need to have a reliable in vitro wound model to understand dermal fibroblast response upon cell injury and how cytokine levels are changed upon different wound heal phases. An in vitro wound model with different scratch assay conditions on primary human foreskin fibroblast monolayer cultures was prepared and cytokine levels and growth properties were evaluated with the aim of determining optimum injury conditions and observation time. Morphological characteristics of differently scratched fibroblasts from 0 to 36 h post injury (1 line, 2 lines and 3 lines) were investigated. The expression of connective tissue growth factor, CTGF, which is a key mediator in hyper-tropic scarring, and relative intensity of CTGF as a function of time were determined by western blot and gelatin Zymography. After injury (1 line), CTGF level was increased more than 2-fold within 1 h and continuously increased up to 3-fold at 6 h and was leveled down to reach normal value at 36 h, at which cell migration was complete. In more serious injury (2 lines), higher expression of CTGF was observed. The down regulation of CTGF expression after CTGF siRNA/lipofectamine transfection in control, 1 line and 2 lines scratch conditions were 40%, 75% and 55%, respectively. As a model anti-CTGF based therapy, CTGF siRNA with different ratios of linear polyethyleneimine (PEI) complexes (1:1, 1:5, 1:10, 1:20 and 1:30) were prepared and down-regulation efficacy of CTGF was evaluated with our optimized scratch assay, which is 1 line injury at 6 h post injury observation time. As the cationic linear PEI ratio increased, the down regulation efficacy was increased from 20% (1:20) to 55% (1:30). As CTGF level was increased to the highest at 6 h and leveled down afterwards, CTGF level at 6 h could provide the most sensitive response upon CTGF siRNA transfection. The scratch assay in the present study can be employed as a useful experimental tool to differentiate

  6. Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-{beta} responsiveness

    SciTech Connect

    Mori, Yasuji; Hinchcliff, Monique; Wu, Minghua; Warner-Blankenship, Matthew; Lyons, Karen M.

    2008-03-10

    Background: The matricellular protein connective tissue growth factor (CCN2) has been implicated in pathological fibrosis, but its physiologic role remains elusive. In vitro, transforming growth factor-{beta} (TGF-{beta}) induces CCN2 expression in mesenchymal cells. Because CCN2 can enhance profibrotic responses elicited by TGF-{beta}, it has been proposed that CCN2 functions as an essential downstream signaling mediator for TGF-{beta}. To explore this notion, we characterized TGF-{beta}-induced activation of fibroblasts from CCN2-null (CCN2{sup -/-}) mouse embryos. Methods: The regulation of CCN2 expression was examined in vivo in a model of fibrosis induced by bleomycin. Cellular TGF-{beta} signal transduction and regulation of collagen gene expression were examined in CCN2{sup -/-} MEFs by immunohistochemistry, Northern, Western and RT-PCR analysis, immunocytochemistry and transient transfection assays. Results: Bleomycin-induced skin fibrosis in the mouse was associated with substantial CCN2 up-regulation in lesional fibroblasts. Whereas in vitro proliferation rate of CCN2{sup -/-} MEFs was markedly reduced compared to wild type MEFs, TGF-{beta}-induced activation of the Smad pathways, including Smad2 phosphorylation, Smad2/3 and Smad4 nuclear accumulation and Smad-dependent transcriptional responses, were unaffected by loss of CCN2. The stimulation of COL1A2 and fibronectin mRNA expression and promoter activity, and of corresponding protein levels, showed comparable time and dose-response in wild type and CCN2{sup -/-} MEFs, whereas stimulation of alpha smooth muscle actin and myofibroblast transdifferentiation showed subtle impairment in MEFs lacking CCN2. Conclusion: Whereas endogenous CCN2 plays a role in regulation of proliferation and TGF-{beta}-induced myofibroblast transdifferentiation, it appears to be dispensable for Smad-dependent stimulation of collagen and extracellular matrix synthesis in murine embryonic fibroblasts.

  7. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    PubMed

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury. PMID:25815693

  8. Connective Tissue Ulcers

    PubMed Central

    Dabiri, Ganary; Falanga, Vincent

    2013-01-01

    Connective tissue disorders (CTD), which are often also termed collagen vascular diseases, include a number of related inflammatory conditions. Some of these diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), localized scleroderma (morphea variants localized to the skin), Sjogren’s syndrome, dermatomyositis, polymyositis, and mixed connective tissue disease. In addition to the systemic manifestations of these diseases, there are a number of cutaneous features that make these conditions recognizable on physical exam. Lower extremity ulcers and digital ulcers are an infrequent but disabling complication of long-standing connective tissue disease. The exact frequency with which these ulcers occur is not known, and the cause of the ulcerations is often multifactorial. Moreover, a challenging component of CTD ulcerations is that there are still no established guidelines for their diagnosis and treatment. The morbidity associated with these ulcerations and their underlying conditions is very substantial. Indeed, these less common but intractable ulcers represent a major medical and economic problem for patients, physicians and nurses, and even well organized multidisciplinary wound healing centers. PMID:23756459

  9. Influence of corticosteroids on connective tissue.

    PubMed

    Asboe-Hansen, G

    1976-01-01

    All glucocorticosteroids inhibit growth, regeneration and repair of cellular or intercellular components of dermal connective tissues, when penetrated through the skin barrier. The resulting atrophy is a logical manifestation of the action of these compounds. PMID:133835

  10. Mixed connective tissue disease.

    PubMed

    Gunnarsson, Ragnar; Hetlevik, Siri Opsahl; Lilleby, Vibke; Molberg, Øyvind

    2016-02-01

    The concept of mixed connective tissue disease (MCTD) as a separate connective tissue disease (CTD) has persisted for more than four decades. High titers of antibodies targeting the U1 small nuclear ribonucleoprotein particle (U1 snRNP) in peripheral blood are a sine qua non for the diagnosis of MCTD, in addition to distinct clinical features including Raynaud's phenomenon (RP), "puffy hands," arthritis, myositis, pleuritis, pericarditis, interstitial lung disease (ILD), and pulmonary hypertension (PH). Recently, population-based epidemiology data from Norway estimated the point prevalence of adult-onset MCTD to be 3.8 per 100,000 and the mean annual incidence to be 2.1 per million per year, supporting the notion that MCTD is the least common CTD. Little is known about the etiology of MCTD, but recent genetic studies have confirmed that MCTD is a strongly HLA (​human leukocyte antigen)-linked disease, as the HLA profiles of MCTD differ distinctly from the corresponding profiles of ethnically matched healthy controls and other CTDs. In the first section of this review, we provide an update on the clinical, immunological, and genetic features of MCTD and discuss the relationship between MCTD and the other CTDs. Then we proceed to discuss the recent advances in therapy and our current understanding of prognosis and prognostic factors, especially those that are associated with the more serious pulmonary and cardiovascular complications of the disease. In the final section, we discuss some of the key, unresolved questions related to anti-RNP-associated diseases and indicate how these questions may be approached in future studies. PMID:27421219

  11. Connective tissue growth factor is activated by gastrin and involved in gastrin-induced migration and invasion.

    PubMed

    Bhandari, Sabin; Bakke, Ingunn; Kumar, J; Beisvag, Vidar; Sandvik, Arne K; Thommesen, Liv; Varro, Andrea; Nørsett, Kristin G

    2016-06-17

    Connective tissue growth factor (CTGF) has been reported in gastric adenocarcinoma and in carcinoid tumors. The aim of this study was to explore a possible link between CTGF and gastrin in gastric epithelial cells and to study the role of CTGF in gastrin induced migration and invasion of AGS-GR cells. The effects of gastrin were studied using RT-qPCR, Western blot and assays for migration and invasion. We report an association between serum gastrin concentrations and CTGF abundancy in the gastric corpus mucosa of hypergastrinemic subjects and mice. We found a higher expression of CTGF in gastric mucosa tissue adjacent to tumor compared to normal control tissue. We showed that gastrin induced expression of CTGF in gastric epithelial AGS-GR cells via MEK, PKC and PKB/AKT pathways. CTGF inhibited gastrin induced migration and invasion of AGS-GR cells. We conclude that CTGF expression is stimulated by gastrin and involved in remodeling of the gastric epithelium. PMID:27179776

  12. A Mouse Strain Where Basal Connective Tissue Growth Factor Gene Expression Can Be Switched from Low to High

    PubMed Central

    Doherty, Heather E.; Kim, Hyung-Suk; Hiller, Sylvia; Sulik, Kathleen K.; Maeda, Nobuyo

    2010-01-01

    Connective tissue growth factor (CTGF) is a signaling molecule that primarily functions in extracellular matrix maintenance and repair. Increased Ctgf expression is associated with fibrosis in chronic organ injury. Studying the role of CTGF in fibrotic disease in vivo, however, has been hampered by perinatal lethality of the Ctgf null mice as well as the limited scope of previous mouse models of Ctgf overproduction. Here, we devised a new approach and engineered a single mutant mouse strain where the endogenous Ctgf-3′ untranslated region (3′UTR) was replaced with a cassette containing two 3′UTR sequences arranged in tandem. The modified Ctgf allele uses a 3′UTR from the mouse FBJ osteosarcoma oncogene (c-Fos) and produces an unstable mRNA, resulting in 60% of normal Ctgf expression (Lo allele). Upon Cre-expression, excision of the c-Fos-3′UTR creates a transcript utilizing the more stable bovine growth hormone (bGH) 3′UTR, resulting in increased Ctgf expression (Hi allele). Using the Ctgf Lo and Hi mutants, and crosses to a Ctgf knockout or Cre-expressing mice, we have generated a series of strains with a 30-fold range of Ctgf expression. Mice with the lowest Ctgf expression, 30% of normal, appear healthy, while a global nine-fold overexpression of Ctgf causes abnormalities, including developmental delay and craniofacial defects, and embryonic death at E10-12. Overexpression of Ctgf by tamoxifen-inducible Cre in the postnatal life, on the other hand, is compatible with life. The Ctgf Lo-Hi mutant mice should prove useful in further understanding the function of CTGF in fibrotic diseases. Additionally, this method can be used for the production of mouse lines with quantitative variations in other genes, particularly with genes that are broadly expressed, have distinct functions in different tissues, or where altered gene expression is not compatible with normal development. PMID:20877562

  13. Connective tissue growth factor mediates growth differentiation factor 8-induced increase of lysyl oxidase activity in human granulosa-lutein cells.

    PubMed

    Chang, Hsun-Ming; Fang, Ying; Liu, Pang-Pin; Cheng, Jung-Chien; Yang, Xiaokui; Leung, Peter C K

    2016-10-15

    Lysyl oxidase (LOX) is an essential enzyme for the stabilization of the extracellular matrix (ECM) and the subsequent follicle and oocyte maturation. Currently, there is limited information pertaining to the regulation of LOX activity in human ovarian tissue. Growth differentiation factor 8 (GDF8) is a unique member of the transforming growth factor-β superfamily that is expressed in human granulosa cells and has important roles in regulating a variety of ovarian functions. The aim of the present study was to investigate the effects of GDF8 on the regulation of LOX expression and activity in human granulosa cells and to examine the underlying molecular determinants. An established immortalized human granulosa cell line (SVOG) and primary granulosa-lutein cells were used as study models. Using dual inhibition approaches (TGF-β type I inhibitor SB505124 and small interfering RNAs) and ChIP analyses, we have demonstrated that GDF8 up-regulated the expression of connective tissue growth factor (CTGF) through the activin receptor-like kinase 5-mediated SMAD2/3-SMAD4 signaling pathways. In addition, the increase in CTGF expression contributed to the GDF8-induced increase in LOX expression and activity. Our findings suggest that GDF8 and CTGF may play critical roles in the regulation of ECM formation in human granulosa cells. PMID:27392496

  14. Cucurbitacin I Attenuates Cardiomyocyte Hypertrophy via Inhibition of Connective Tissue Growth Factor (CCN2) and TGF- β/Smads Signalings

    PubMed Central

    Kang, Hara; Park, Kye Won; Park, Woo Jin; Yang, Seung Yul; Yang, Dong Kwon

    2015-01-01

    Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and β-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and β-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-β/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-β1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- β/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I’s utility as a novel therapeutic agent for the management of heart diseases. PMID:26296085

  15. Induction of connective tissue growth factor (CTGF) in human endothelial cells by lysophosphatidic acid, sphingosine-1-phosphate, and platelets.

    PubMed

    Muehlich, Susanne; Schneider, Nadine; Hinkmann, Fabian; Garlichs, Christoph D; Goppelt-Struebe, Margarete

    2004-08-01

    Endothelial dysfunction is characterized by multiple interactions between endothelial cells and components of the blood. This study focussed on the induction of the pro-atherogenic connective tissue growth factor (CTGF) in endothelial cells by bioactive lipids and platelets. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) led to a time- and concentration-dependent increase in CTGF mRNA and protein expression in the human endothelial cell line EAHY 926 and in primary cultures of human umbilical vein endothelial cells (HUVEC). As both cell types expressed various receptors for LPA and S1P, signaling pathways were further characterized by pharmacological means: induction of CTGF was pertussis toxin-insensitive and inhibition of activation of p42/44 MAP kinases only partially reduced CTGF expression. On the contrary, interference with the RhoA signaling pathway by simvastatin, an inhibitor of geranylgeranyltransferases, or the Rho-kinase inhibitor Y27632 prevented induction of CTGF. Co-incubation of endothelial cells with freshly isolated human platelets significantly increased the expression of CTGF mRNA in endothelial cells, which was also sensitive to simvastatin. Up-regulation of CTGF in endothelial cells, induced by LPA, S1P, or platelets, may contribute to the initiation and progression of atherosclerosis. Interference of simvastatin with the synthesis of this pro-atherogenic factor further supports the anti-atherogenic role of statins. PMID:15262182

  16. Cucurbitacin I Attenuates Cardiomyocyte Hypertrophy via Inhibition of Connective Tissue Growth Factor (CCN2) and TGF- β/Smads Signalings.

    PubMed

    Jeong, Moon Hee; Kim, Shang-Jin; Kang, Hara; Park, Kye Won; Park, Woo Jin; Yang, Seung Yul; Yang, Dong Kwon

    2015-01-01

    Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and β-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and β-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-β/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-β1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- β/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I's utility as a novel therapeutic agent for the management of heart diseases. PMID:26296085

  17. Subepithelial connective tissue graft with and without the use of plasma rich in growth factors for treating root exposure

    PubMed Central

    Lafzi, Ardeshir; Shirmohammadi, Adileh; Behrozian, Ahmad; Kashefimehr, Atabak; Khashabi, Ehsan

    2012-01-01

    Purpose The aim of this study was to evaluate the clinical efficiency of the subepithelial connective tissue graft (SCTG) with and without plasma rich in growth factor (PRGF) in the treatment of gingival recessions. Methods Twenty bilateral buccal gingival Miller's Class I and II recessions were selected. Ten of the recessions were treated with SCTG and PRGF (test group). The rest ten of the recessions were treated with SCTG (control group). The clinical parameters including recession depth (RD), percentage of root coverage (RC), mucogingival junction (MGJ) position, clinical attachment level (CAL), and probing depth (PD) were measured at the baseline, and 1 and 3 months later. The data were analyzed using the Wilcoxon signed rank and Mann-Whitney U tests. Results After 3 months, both groups showed a significant improvement in all of the mentioned criteria except PD. Although the amount of improvement was better in the SCTG+PRGF group than the SCTG only group, this difference was not statistically significant. The mean RC was 70.85±12.57 in the test group and 75.83±24.68 in the control group. Conclusions Both SCTG+PRGF and SCTG only result in favorable clinical outcomes, but the added benefit of PRGF is not evident. PMID:23346462

  18. [Connective tissue diseases in adolescents].

    PubMed

    Peitz, J; Tantcheva-Poór, I

    2016-04-01

    In this article we provide a brief review of systemic lupus erythematosus, juvenile dermatomyositis, systemic scleroderma, and mixed connective tissue disease in adolescents. As skin manifestations often belong to the presenting symptoms and may have a significant impact on the quality of life, dermatologists play an important role in the management of patients with connective tissue diseases. Early diagnosis and therapy onset are crucial for the patients' long-term outcome. PMID:27000182

  19. Extraocular connective tissue architecture.

    PubMed

    Miller, Joel M; Demer, Joseph L; Poukens, Vadims; Pavlovski, Dmitri S; Nguyen, Hien N; Rossi, Ethan A

    2003-01-01

    Extraocular muscle pulleys, now well known to be kinematically significant extraocular structures, have been noted in passing and described in fragments several times over the past two centuries. They were late to be fully appreciated because biomechanical modeling of the orbit was not available to derive their kinematic consequences, and because pulleys are distributed condensations of collagen, elastin and smooth muscle (SM) that are not sharply delineated. Might other mechanically significant distributed extraocular structures still be awaiting description?An imaging approach is useful for describing distributed structures, but does not seem suitable for assessing mechanical properties. However, an image that distinguished types and densities of constituent tissues could give strong hints about mechanical properties. Thus, we have developed methods for producing three dimensional (3D) images of extraocular tissues based on thin histochemically processed slices, which distinguish collagen, elastin, striated muscle and SM. Overall tissue distortions caused by embedding for sectioning, and individual-slice distortions caused by thin sectioning and subsequent histologic processing were corrected by ordered image warping with intrinsic fiducials. We describe an extraocular structure, partly included in Lockwood's ligament, which contains dense elastin and SM bands, and which might refine horizontal eye alignment as a function of vertical gaze, and torsion in down-gaze. This active structure might therefore be a factor in strabismus and a target of therapeutic intervention. PMID:12723968

  20. mTOR Complexes Repress Hypertrophic Agonist-Stimulated Expression of Connective Tissue Growth Factor in Adult Cardiac Muscle Cells.

    PubMed

    Sundararaj, Kamala; Pleasant, Dorea L; Moschella, Phillip C; Panneerselvam, Kavin; Balasubramanian, Sundaravadivel; Kuppuswamy, Dhandapani

    2016-02-01

    Connective tissue growth factor (CTGF) is a fibrogenic cytokine that promotes fibrosis in various organs. In the heart, both cardiomyocytes (CM) and cardiac fibroblasts have been reported as a source of CTGF expression, aiding cardiac fibrosis. Although the mammalian target of rapamycin (mTOR) forms 2 distinct complexes, mTORC1 and mTORC2, and plays a central role in integrating biochemical signals for protein synthesis and cellular homeostasis, we explored its role in CTGF expression in adult feline CM. CM were stimulated with 10 μM phenylephrine (PE), 200 nM angiotensin (Ang), or 100 nM insulin for 24 hours. PE and Ang, but not insulin, caused an increase in CTGF mRNA expression with the highest expression observed with PE. Inhibition of mTOR with torin1 but not rapamycin significantly enhanced PE-stimulated CTGF expression. Furthermore, silencing of raptor and rictor using shRNA adenoviral vectors to suppress mTORC1 and mTORC2, respectively, or blocking phosphatidylinositol 3-kinase (PI3K) signaling with LY294002 (LY) or Akt signaling by dominant-negative Akt expression caused a substantial increase in PE-stimulated CTGF expression as measured by both mRNA and secreted protein levels. However, studies with dominant-negative delta isoform of protein kinase C demonstrate that delta isoform of protein kinase C is required for both agonist-induced CTGF expression and mTORC2/Akt-mediated CTGF suppression. Finally, PE-stimulated CTGF expression was accompanied with a corresponding increase in Smad3 phosphorylation and pretreatment of cells with SIS3, a Smad3 specific inhibitor, partially blocked the PE-stimulated CTGF expression. Therefore, a PI3K/mTOR/Akt axis plays a suppressive role on agonist-stimulated CTGF expression where the loss of this mechanism could be a contributing factor for the onset of cardiac fibrosis in the hypertrophying myocardium. PMID:26371948

  1. Regulation of connective tissue growth factor activity in cultured rat mesangial cells and its expression in experimental diabetic glomerulosclerosis.

    PubMed

    Riser, B L; Denichilo, M; Cortes, P; Baker, C; Grondin, J M; Yee, J; Narins, R G

    2000-01-01

    Connective tissue growth factor (CTGF) is a peptide secreted by cultured endothelial cells and fibroblasts when stimulated by transforming growth factor-beta (TGF-beta), and is overexpressed during fibrotic processes in coronary arteries and in skin. To determine whether CTGF is implicated in the pathogenesis of diabetic glomerulosclerosis, cultured rat mesangial cells (MC) as well as kidney cortex and microdissected glomeruli were examined from obese, diabetic db/db mice and their normal counterparts. Exposure of MC to recombinant human CTGF significantly increased fibronectin and collagen type I production. Furthermore, unstimulated MC expressed low levels of CTGF message and secreted minimal amounts of CTGF protein (36 to 38 kD) into the media. However, sodium heparin treatment resulted in a greater than fourfold increase in media-associated CTGF, suggesting that the majority of CTGF produced was cell- or matrix-bound. Exposure of MC to TGF-beta, increased glucose concentrations, or cyclic mechanical strain, all causal factors in diabetic glomerulosclerosis, markedly induced the expression of CTGF transcripts, while recombinant human CTGF was able to autoinduce its own expression. TGF-, and high glucose, but not mechanical strain, stimulated the concomitant secretion of CTGF protein, the former also inducing abundant quantities of a small molecular weight form of CTGF (18 kD) containing the heparin-binding domain. The induction of CTGF protein by a high glucose concentration was mediated by TGF-beta, since a TGF-beta-neutralizing antibody blocked this stimulation. In vivo studies using quantitative reverse transcription-PCR demonstrated that although CTGF transcripts were low in the glomeruli of control mice, expression was increased 28-fold after approximately 3.5 mo of diabetes. This change occurred early in the course of diabetic nephropathy when mesangial expansion was mild, and interstitial disease and proteinuria were absent. A substantially reduced

  2. Advanced Glycation End-Products Induce Connective Tissue Growth Factor-Mediated Renal Fibrosis Predominantly through Transforming Growth Factor β-Independent Pathway

    PubMed Central

    Zhou, Guihua; Li, Cai; Cai, Lu

    2004-01-01

    Advanced glycation end-products (AGEs) play a critical role in diabetic nephropathy by stimulating extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) is a potent inducer of ECM synthesis and increases in the diabetic kidneys. To determine the critical role of CTGF in AGE-induced ECM accumulation leading to diabetic nephropathy, rats were given AGEs by intravenous injection for 6 weeks. AGE treatment induced a significant renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) accumulation in glomeruli, and a mild renal dysfunction, as shown by increases in urinary volume and protein content. AGE treatment also caused significant increases in renal CTGF and transforming growth factor (TGF)-β1 mRNA and protein expression. Direct exposure of rat mesangial cells to AGEs in vitro significantly induced increases in fibronectin and Col IV production, which could be completely prevented by pretreatment with anti-CTGF antibody. AGE treatment also significantly increased both TGF-β1 and CTGF mRNA expression; however, inhibition of TGF-β1 mRNA expression by shRNA or neutralization of TGF-β1 protein by anti-TGF-β1 antibody did not significantly prevent AGE-increased expression of CTGF mRNA and protein. These results suggest that AGE-induced CTGF expression, predominantly through a TGF-β1-independent pathway, plays a critical role in renal ECM accumulation leading to diabetic nephropathy. PMID:15579446

  3. Connective tissue growth factor differentially binds to members of the cystine knot superfamily and potentiates platelet-derived growth factor-B signaling in rabbit corneal fibroblast cells

    PubMed Central

    Pi, Liya; Chung, Pei-Yu; Sriram, Sriniwas; Rahman, Masmudur M; Song, Wen-Yuan; Scott, Edward W; Petersen, Bryon E; Schultz, Gregory S

    2015-01-01

    AIM: To study the binding of connective tissue growth factor (CTGF) to cystine knot-containing ligands and how this impacts platelet-derived growth factor (PDGF)-B signaling. METHODS: The binding strengths of CTGF to cystine knot-containing growth factors including vascular endothelial growth factor (VEGF)-A, PDGF-B, bone morphogenetic protein (BMP)-4, and transforming growth factor (TGF)-β1 were compared using the LexA-based yeast two-hybrid system. EYG48 reporter strain that carried a wild-type LEU2 gene under the control of LexA operators and a lacZ reporter plasmid (p80p-lacZ) containing eight high affinity LexA binding sites were used in the yeast two-hybrid analysis. Interactions between CTGF and the tested growth factors were evaluated based on growth of transformed yeast cells on selective media and colorimetric detection in a liquid β-galactosidase activity assay. Dissociation constants of CTGF to VEGF-A isoform 165 or PDGF-BB homo-dimer were measured in surface plasma resonance (SPR) analysis. CTGF regulation in PDGF-B presentation to the PDGF receptor β (PDGFRβ) was also quantitatively assessed by the SPR analysis. Combinational effects of CTGF protein and PDGF-BB on activation of PDGFRβ and downstream signaling molecules ERK1/2 and AKT were assessed in rabbit corneal fibroblast cells by Western analysis. RESULTS: In the LexA-based yeast two-hybrid system, cystine knot motifs of tested growth factors were fused to the activation domain of the transcriptional factor GAL4 while CTGF was fused to the DNA binding domain of the bacterial repressor protein LexA. Yeast co-transformants containing corresponding fusion proteins for CTGF and all four tested cystine knot motifs survived on selective medium containing galactose and raffinose but lacking histidine, tryptophan, and uracil. In liquid β-galactosidase assays, CTGF expressing cells that were co-transformed with the cystine knot of VEGF-A had the highest activity, at 29.88 ± 0.91 fold above controls

  4. Growth and maturational changes in dense fibrous connective tissue following 14 days of rhGH supplementation in the dwarf rat

    NASA Technical Reports Server (NTRS)

    Kyparos, Antonios; Orth, Michael W.; Vailas, Arthur C.; Martinez, Daniel A.

    2002-01-01

    The purpose of this study was to investigate the impact of recombinant human growth hormone (rhGH) on patella tendon (PT), medial collateral ligament (MCL), and lateral collateral ligament (LCL) on collagen growth and maturational changes in dwarf GH-deficient rats. Twenty male Lewis mutant dwarf rats, 37 days of age, were randomly assigned to Dwarf + rhGH (n = 10) and Dwarf + vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt twice daily for 14 days. rhGH administration stimulated dense fibrous connective tissue growth, as demonstrated by significant increases in hydroxyproline specific activity and significant decreases in the non-reducible hydroxylysylpyridinoline (HP) collagen cross-link contents. The increase in the accumulation of newly accreted collagen was 114, 67, and 117% for PT, MCL, and LCL, respectively, in 72 h. These findings suggest that a short course rhGH treatment can affect the rate of new collagen production. However, the maturation of the tendon and ligament tissues decreased 18-25% during the rapid accumulation of de novo collagen. We conclude that acute rhGH administration in a dwarf rat can up-regulate new collagen accretion in dense fibrous connective tissues, while causing a reduction in collagen maturation. Copyright 2002 Elsevier Science Ltd.

  5. Pediatric Mixed Connective Tissue Disease.

    PubMed

    Berard, Roberta A; Laxer, Ronald M

    2016-05-01

    Pediatric-onset mixed connective tissue disease is among the rare disease entities in pediatric rheumatology and includes features of arthritis, polymyositis/dermatomyositis, systemic lupus erythematosus, and systemic sclerosis. Accurate recognition and diagnosis of the disease is paramount to prevent long-term morbidity. Advances in the genetic and immunologic understanding of the factors involved in the etiopathogenesis provide an opportunity for improvements in prognostication and targeted therapy. The development of a multinational cohort of patients with mixed connective tissue disease would be invaluable to provide more updated data regarding the clinical presentation, to develop a standardized treatment approach, disease activity and outcome tools, and to provide data on long-term outcomes and comorbidities. PMID:27032791

  6. A virus-like particle-based connective tissue growth factor vaccine suppresses carbon tetrachloride-induced hepatic fibrosis in mice.

    PubMed

    Li, Shuang; Lv, Yi-Fei; Su, Hou-Qiang; Zhang, Qian-Nan; Wang, Li-Rong; Hao, Zhi-Ming

    2016-01-01

    Connective tissue growth factor (CTGF) has been recognized as a central mediator and promising therapeutic target in hepatic fibrosis. In this study, we generated a novel virus-like particle (VLP) CTGF vaccine by inserting the 138-159 amino acid (aa) fragment of CTGF into the central c/e1 epitope of C-terminus truncated hepatitis B virus core antigen (HBc, aa 1-149) using a prokaryotic expression system. Immunization of BALB/c mice with the VLP vaccine efficiently elicited the production of anti-CTGF neutralizing antibodies. Vaccination with this CTGF vaccine significantly protected BALB/c mice from carbon tetrachloride (CCl4)-induced hepatic fibrosis, as indicated by decreased hepatic hydroxyproline content and lower fibrotic score. CCl4 intoxication-induced hepatic stellate cell activation was inhibited by the vaccination, as indicated by decreased α-smooth muscle actin expression and Smad2 phosphorylation. Vaccination against CTGF also attenuated the over-expression of some profibrogenic factors, such as CTGF, transforming growth factor-β1, platelet-derived growth factor-B and tissue inhibitor of metalloproteinase-1 in the fibrotic mouse livers, decreased hepatocyte apoptosis and accelerated hepatocyte proliferation in the fibrotic mouse livers. Our results clearly indicate that vaccination against CTGF inhibits fibrogenesis, alleviates hepatocyte apoptosis and facilitate hepatic regeneration. We suggest that the vaccine should be developed into an effective therapeutic measure for hepatic fibrosis. PMID:27562139

  7. A virus-like particle-based connective tissue growth factor vaccine suppresses carbon tetrachloride-induced hepatic fibrosis in mice

    PubMed Central

    Li, Shuang; Lv, Yi-Fei; Su, Hou-Qiang; Zhang, Qian-Nan; Wang, Li-Rong; Hao, Zhi-Ming

    2016-01-01

    Connective tissue growth factor (CTGF) has been recognized as a central mediator and promising therapeutic target in hepatic fibrosis. In this study, we generated a novel virus-like particle (VLP) CTGF vaccine by inserting the 138–159 amino acid (aa) fragment of CTGF into the central c/e1 epitope of C-terminus truncated hepatitis B virus core antigen (HBc, aa 1–149) using a prokaryotic expression system. Immunization of BALB/c mice with the VLP vaccine efficiently elicited the production of anti-CTGF neutralizing antibodies. Vaccination with this CTGF vaccine significantly protected BALB/c mice from carbon tetrachloride (CCl4)-induced hepatic fibrosis, as indicated by decreased hepatic hydroxyproline content and lower fibrotic score. CCl4 intoxication-induced hepatic stellate cell activation was inhibited by the vaccination, as indicated by decreased α-smooth muscle actin expression and Smad2 phosphorylation. Vaccination against CTGF also attenuated the over-expression of some profibrogenic factors, such as CTGF, transforming growth factor-β1, platelet-derived growth factor-B and tissue inhibitor of metalloproteinase-1 in the fibrotic mouse livers, decreased hepatocyte apoptosis and accelerated hepatocyte proliferation in the fibrotic mouse livers. Our results clearly indicate that vaccination against CTGF inhibits fibrogenesis, alleviates hepatocyte apoptosis and facilitate hepatic regeneration. We suggest that the vaccine should be developed into an effective therapeutic measure for hepatic fibrosis. PMID:27562139

  8. Patients with Encapsulating Peritoneal Sclerosis Have Increased Peritoneal Expression of Connective Tissue Growth Factor (CCN2), Transforming Growth Factor-β1, and Vascular Endothelial Growth Factor

    PubMed Central

    Abrahams, Alferso C.; Habib, Sayed M.; Dendooven, Amélie; Riser, Bruce L.; van der Veer, Jan Willem; Toorop, Raechel J.; Betjes, Michiel G. H.; Verhaar, Marianne C.; Watson, Christopher J. E.; Nguyen, Tri Q.; Boer, Walther H.

    2014-01-01

    Introduction Encapsulating peritoneal sclerosis (EPS) is a devastating complication of peritoneal dialysis (PD). The pathogenesis is not exactly known and no preventive strategy or targeted medical therapy is available. CCN2 has both pro-fibrotic and pro-angiogenic actions and appears an attractive target. Therefore, we studied peritoneal expression of CCN2, as well as TGFβ1 and VEGF, in different stages of peritoneal fibrosis. Materials and methods Sixteen PD patients were investigated and compared to 12 hemodialysis patients and four pre-emptively transplanted patients. Furthermore, expression was investigated in 12 EPS patients in comparison with 13 PD and 12 non-PD patients without EPS. Peritoneal tissue was taken during kidney transplantation procedure or during EPS surgery. In a subset of patients, CCN2 protein levels in peritoneal effluent and plasma were determined. Samples were examined by qPCR, histology, immunohistochemistry, and ELISA. Results Peritoneal CCN2 expression was 5-fold higher in PD patients compared to pre-emptively transplanted patients (P<0.05), but did not differ from hemodialysis patients. Peritoneal expression of TGFβ1 and VEGF were not different between the three groups; neither was peritoneal thickness. Peritoneum of EPS patients exhibited increased expression of CCN2 (35-fold, P<0.001), TGFβ1 (24-fold, P<0.05), and VEGF (77-fold, P<0.001) compared to PD patients without EPS. In EPS patients, CCN2 protein was mainly localized in peritoneal endothelial cells and fibroblasts. CCN2 protein levels were significantly higher in peritoneal effluent of EPS patients compared to levels in dialysate of PD patients (12.0±4.5 vs. 0.91±0.92 ng/ml, P<0.01), while plasma CCN2 levels were not increased. Conclusions Peritoneal expression of CCN2, TGFβ1, and VEGF are significantly increased in EPS patients. In early stages of peritoneal fibrosis, only CCN2 expression is slightly increased. Peritoneal CCN2 overexpression in EPS patients is a

  9. TGF-β1, in association with the increased expression of connective tissue growth factor, induce the hypertrophy of the ligamentum flavum through the p38 MAPK pathway.

    PubMed

    Cao, Yan-Lin; Duan, Yang; Zhu, Li-Xin; Zhan, Ye-Nan; Min, Shao-Xiong; Jin, An-Min

    2016-08-01

    Hypertrophy of the ligamentum flavum (LF) is one of the key pathomechanisms of lumbar spinal stenosis (LSS). Transforming growth factor (TGF)-β1 is abundantly expressed in hypertrophied degenerative LF tissues from LSS. However, the molecular mechanisms underling the association between TGF-β1 and LF hypertrophy have not yet been fully elucidated. In this study, we investigated the important role of the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of LSS by analyzing the expression of connective tissue growth factor (CTGF) and extracellular matrix (ECM) components (collagen I and collagen III) in TGF-β1-treated LF cells. Cell growth assay revealed that TGF-β1, in association with CTGF, enhanced the the proliferation of LF cells, and we found that TGF-β1 also elevated CTGF expression and subsequently enhanced the mRNA expression of collagen I and collagen III. The increased mRNA expression levels of CTGF, collagen I and collagen III were abolished by p38 inhibitors. Both immunofluorescence imaging and western blot analysis of p38 and p-p38 revealed the increased expression and phosphorylation of p38. Silencing the expression of p38 by siRNA in LF cells decreased the protein expression of p38, p-p38 and CTGF, as well as the mRNA expression of CTGF, collagen I and collagen III. Taken together, our findings indicate that TGF-β1, in association with the increased expression of CTGF, contribute to the homeostasis of the ECM and to the hypertrophy of LF through the p38 MAPK pathway. PMID:27279555

  10. TGF-β1, in association with the increased expression of connective tissue growth factor, induce the hypertrophy of the ligamentum flavum through the p38 MAPK pathway

    PubMed Central

    Cao, Yan-Lin; Duan, Yang; Zhu, Li-Xin; Zhan, Ye-Nan; Min, Shao-Xiong; Jin, An-Min

    2016-01-01

    Hypertrophy of the ligamentum flavum (LF) is one of the key pathomechanisms of lumbar spinal stenosis (LSS). Transforming growth factor (TGF)-β1 is abundantly expressed in hypertrophied degenerative LF tissues from LSS. However, the molecular mechanisms underling the association between TGF-β1 and LF hypertrophy have not yet been fully elucidated. In this study, we investigated the important role of the mitogen-activated protein kinase (MAPK) pathway in the pathogenesis of LSS by analyzing the expression of connective tissue growth factor (CTGF) and extracellular matrix (ECM) components (collagen I and collagen III) in TGF-β1-treated LF cells. Cell growth assay revealed that TGF-β1, in association with CTGF, enhanced the the proliferation of LF cells, and we found that TGF-β1 also elevated CTGF expression and subsequently enhanced the mRNA expression of collagen I and collagen III. The increased mRNA expression levels of CTGF, collagen I and collagen III were abolished by p38 inhibitors. Both immunofluorescence imaging and western blot analysis of p38 and p-p38 revealed the increased expression and phosphorylation of p38. Silencing the expression of p38 by siRNA in LF cells decreased the protein expression of p38, p-p38 and CTGF, as well as the mRNA expression of CTGF, collagen I and collagen III. Taken together, our findings indicate that TGF-β1, in association with the increased expression of CTGF, contribute to the homeostasis of the ECM and to the hypertrophy of LF through the p38 MAPK pathway. PMID:27279555

  11. MicroRNA-143-3p inhibits hyperplastic scar formation by targeting connective tissue growth factor CTGF/CCN2 via the Akt/mTOR pathway.

    PubMed

    Mu, Shengzhi; Kang, Bei; Zeng, Weihui; Sun, Yaowen; Yang, Fan

    2016-05-01

    Post-traumatic hypertrophic scar (HS) is a fibrotic disease with excessive extracellular matrix (ECM) production, which is a response to tissue injury by fibroblasts. Although emerging evidence has indicated that miRNA contributes to hypertrophic scarring, the role of miRNA in HS formation remains unclear. In this study, we found that miR-143-3p was markedly downregulated in HS tissues and fibroblasts (HSFs) using qRT-PCR. The expression of connective tissue growth factor (CTGF/CCN2) was upregulated both in HS tissues and HSFs, which is proposed to play a key role in ECM deposition in HS. The protein expression of collagen I (Col I), collagen III (Col III), and α-smooth muscle actin (α-SMA) was obviously inhibited after treatment with miR-143-3p in HSFs. The CCK-8 assay showed that miR-143-3p transfection reduced the proliferation ability of HSFs, and flow cytometry showed that either early or late apoptosis of HSFs was upregulated by miR-143-3p. In addition, the activity of caspase 3 and caspase 9 was increased after miR-143-3p transfection. On the contrary, the miR-143-3p inhibitor was demonstrated to increase cell proliferation and inhibit apoptosis of HSFs. Moreover, miR-143-3p targeted the 3'-UTR of CTGF and caused a significant decrease of CTGF. Western blot demonstrated that Akt/mTOR phosphorylation and the expression of CTGF, Col I, Col III, and α-SMA were inhibited by miR-143-3p, but increased by CTGF overexpression. In conclusion, we found that miR-143-3p inhibits hypertrophic scarring by regulating the proliferation and apoptosis of human HSFs, inhibiting ECM production-associated protein expression by targeting CTGF, and restraining the Akt/mTOR pathway. PMID:27075467

  12. Urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers for progression of diabetic nephropathy.

    PubMed

    Tam, Frederick W K; Riser, Bruce L; Meeran, Karim; Rambow, JoAnn; Pusey, Charles D; Frankel, Andrew H

    2009-07-01

    Profibrotic growth factors and inflammatory chemokines have been implicated in the pathogenesis of diabetic nephropathy (DN). However, measurement of urinary monocyte chemoattractant protein-1 (MCP-1) and connective tissue growth factor (CCN2) as prognostic markers has not previously been reported, and neither have two such molecules in urine been examined in a single study of DN. In this prospective observational study, 43 adult diabetic patients were studied, 40 were followed up for 6years. Urinary MCP-1/creatinine ratios were found to be significantly higher in patients with macroalbuminuria (3.3- and 2.1-fold higher (p<0.01) than normoalbuminuric and microalbuminuric patients, respectively). CCN2 exhibited a pattern different from that of urinary MCP-1. Urinary CCN2/creatinine ratios were greatly elevated in both microalbuminuric and macroalbuminuric patients (125- and 74-fold higher than normoalbuminuric patients, respectively, p<0.01 and p<0.05, respectively). Further, urinary CCN2, but not MCP-1, correlated with progression of microalbuminuria (R=0.49, p<0.05). In contrast, MCP-1, but not CCN2, correlated with the rate of eGFR decline for all patients (R=0.61, p<0.0001), reflective of its predictive value in patients with macroalbuminuria, but not for patients with microalbuminuria or normoalbuminuria. In conclusion, increased urinary CCN2 is associated with the early progression of DN, whereas MCP-1 is associated with later stage disease. PMID:19409809

  13. The Genetics of Soft Connective Tissue Disorders.

    PubMed

    Vanakker, Olivier; Callewaert, Bert; Malfait, Fransiska; Coucke, Paul

    2015-01-01

    Over the last few years, the field of hereditary connective tissue disorders has changed tremendously. This review highlights exciting insights into three prototypic disorders affecting the soft connective tissue: Ehlers-Danlos syndrome, pseudoxanthoma elasticum, and cutis laxa. For each of these disorders, the identification and characterization of several novel but related conditions or subtypes have widened the phenotypic spectrum. In parallel, the vast underlying molecular network connecting these phenotypes is progressively being uncovered. Identification and characterization (both clinical and molecular) of new phenotypes within the connective tissue disorder spectrum are often key to further unraveling the pathways involved in connective tissue biology and delineating the clinical spectrum and pathophysiology of the disorders. Although difficult challenges remain, recent findings have expanded our pathophysiological understanding and may lead to targeted therapies in the near future. PMID:26002060

  14. Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells.

    PubMed

    Luo, Qing; Kang, Quan; Si, Weike; Jiang, Wei; Park, Jong Kyung; Peng, Ying; Li, Xinmin; Luu, Hue H; Luo, Jeffrey; Montag, Anthony G; Haydon, Rex C; He, Tong-Chuan

    2004-12-31

    Osteoblast lineage-specific differentiation of mesenchymal stem cells is a well regulated but poorly understood process. Both bone morphogenetic proteins (BMPs) and Wnt signaling are implicated in regulating osteoblast differentiation and bone formation. Here we analyzed the expression profiles of mesenchymal stem cells stimulated with Wnt3A and osteogenic BMPs, and we identified connective tissue growth factor (CTGF) as a potential target of Wnt and BMP signaling. We confirmed the microarray results, and we demonstrated that CTGF was up-regulated at the early stage of BMP-9 and Wnt3A stimulations and that Wnt3A-regulated CTGF expression was beta-catenin-dependent. RNA interference-mediated knockdown of CTGF expression significantly diminished BMP-9-induced, but not Wnt3A-induced, osteogenic differentiation, suggesting that Wnt3A may also regulate osteoblast differentiation in a CTGF-independent fashion. However, constitutive expression of CTGF was shown to inhibit both BMP-9- and Wnt3A-induced osteogenic differentiation. Exogenous expression of CTGF was shown to promote cell migration and recruitment of mesenchymal stem cells. Our findings demonstrate that CTGF is up-regulated by Wnt3A and BMP-9 at the early stage of osteogenic differentiation, which may regulate the proliferation and recruitment of osteoprogenitor cells; however, CTGF is down-regulated as the differentiation potential of committed pre-osteoblasts increases, strongly suggesting that tight regulation of CTGF expression may be essential for normal osteoblast differentiation of mesenchymal stem cells. PMID:15496414

  15. Stroma-Derived Connective Tissue Growth Factor Maintains Cell Cycle Progression and Repopulation Activity of Hematopoietic Stem Cells In Vitro

    PubMed Central

    Istvánffy, Rouzanna; Vilne, Baiba; Schreck, Christina; Ruf, Franziska; Pagel, Charlotta; Grziwok, Sandra; Henkel, Lynette; Prazeres da Costa, Olivia; Berndt, Johannes; Stümpflen, Volker; Götze, Katharina S.; Schiemann, Matthias; Peschel, Christian; Mewes, Hans-Werner; Oostendorp, Robert A.J.

    2015-01-01

    Summary Hematopoietic stem cells (HSCs) are preserved in co-cultures with UG26-1B6 stromal cells or their conditioned medium. We performed a genome-wide study of gene expression changes of UG26-1B6 stromal cells in contact with Lineage− SCA-1+ KIT+ (LSK) cells. This analysis identified connective tissue growth factor (CTGF) to be upregulated in response to LSK cells. We found that co-culture of HSCs on CTGF knockdown stroma (shCtgf) shows impaired engraftment and long-term quality. Further experiments demonstrated that CD34− CD48− CD150+ LSK (CD34− SLAM) cell numbers from shCtgf co-cultures increase in G0 and senescence and show delayed time to first cell division. To understand this observation, a CTGF signaling network model was assembled, which was experimentally validated. In co-culture experiments of CD34− SLAM cells with shCtgf stromal cells, we found that SMAD2/3-dependent signaling was activated, with increasing p27Kip1 expression and downregulating cyclin D1. Our data support the view that LSK cells modulate gene expression in the niche to maintain repopulating HSC activity. PMID:26527384

  16. Connective tissue growth factor is critical for proper β-cell function and pregnancy-induced β-cell hyperplasia in adult mice.

    PubMed

    Pasek, Raymond C; Dunn, Jennifer C; Elsakr, Joseph M; Aramandla, Mounika; Matta, Anveetha R; Gannon, Maureen

    2016-09-01

    During pregnancy, maternal β-cells undergo compensatory changes, including increased β-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein connective tissue growth factor (CTGF) is critical for normal β-cell development and promotes regeneration after partial β-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and β-cells. In adult pancreas, CTGF is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (Ctgf(LacZ/+)) have an impairment in maternal β-cell proliferation; no difference was observed in virgin Ctgf(LacZ/+) females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (Ctgf(ΔEndo)) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal β-cell proliferation. Moreover, virgin Ctgf(ΔEndo) females also display impaired GSIS with glucose intolerance, indicating that underlying β-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in β-cell function has been reported. PMID:27460898

  17. Exosomes mediate intercellular transfer of pro-fibrogenic connective tissue growth factor (CCN2) between hepatic stellate cells, the principal fibrotic cells in the liver

    PubMed Central

    Charrier, Alyssa; Chen, Ruju; Chen, Li; Kemper, Sherri; Hattori, Takako; Takigawa, Masaharu; Brigstock, David R.

    2014-01-01

    Background Fibrogenic pathways in the liver are principally regulated by hepatic stellate cells (HSC) which produce and respond to fibrotic mediators such as connective tissue growth factor (CCN2). The aim of this study was to determine whether CCN2 is shuttled between HSC in membraneous nanovesicles, or “exosomes”. Methods Exosomes were incubated with HSC after isolation from conditioned medium of control or CCN2-GFP-transfected primary mouse HSC or human LX-2 HSC. Some exosomes were flourescently stained with PKH26. HSC co-culture experiments were performed in the presence of GW4869 exosome inhibitor. CCN2 or CCN2-GFP were evaluated by qRT-PCR or Western blot. Results HSC-derived exosomes contained CCN2 or CCN2 mRNA, each of which increased in concentration during HSC activation or after transfection of HSC with CCN2-GFP. Exosomes, stained with either PKH26 or purified from CCN2-GFP-transfected cells, were taken up by activated or quiescent HSC resulting in CCN2-GFP delivery, as shown by their direct addition to recipient cells or by the GW4869-dependency of donor HSC. Conclusions CCN2 is packaged into secreted nano-sized exosomes which mediate its intercellular transfer between HSC. Exosomal CCN2 may amplify or fine-tune fibrogenic signaling and may, in conjunction with other exosome constituents, have utility as a noninvasive biomarker to assess hepatic fibrosis. PMID:24882759

  18. FG-3019 anti-connective tissue growth factor monoclonal antibody: results of an open-label clinical trial in idiopathic pulmonary fibrosis.

    PubMed

    Raghu, Ganesh; Scholand, Mary Beth; de Andrade, João; Lancaster, Lisa; Mageto, Yolanda; Goldin, Jonathan; Brown, Kevin K; Flaherty, Kevin R; Wencel, Mark; Wanger, Jack; Neff, Thomas; Valone, Frank; Stauffer, John; Porter, Seth

    2016-05-01

    FG-3019 is a fully human monoclonal antibody that interferes with the action of connective tissue growth factor, a central mediator in the pathogenesis of fibrosis.This open-label phase 2 trial evaluated the safety and efficacy of two doses of FG-3019 administered by intravenous infusion every 3 weeks for 45 weeks in patients with idiopathic pulmonary fibrosis (IPF). Subjects had a diagnosis of IPF within the prior 5 years defined by either usual interstitial pneumonia (UIP) pattern on a recent high-resolution computed tomography (HRCT) scan, or a possible UIP pattern on HRCT scan and a recent surgical lung biopsy showing UIP pattern. Pulmonary function tests were performed every 12 weeks, and changes in the extent of pulmonary fibrosis were measured by quantitative HRCT scans performed at baseline and every 24 weeks.FG-3019 was safe and well-tolerated in IPF patients participating in the study. Changes in fibrosis were correlated with changes in pulmonary function.Further investigation of FG-3019 in IPF with a placebo-controlled clinical trial is warranted and is underway. PMID:26965296

  19. Testicular complications in connective tissue disease

    PubMed Central

    Tangney, N J

    1981-01-01

    Acute testicular symptoms are described in 2 patients with Schönlein-Henoch syndrome and in 1 with juvenile rheumatoid arthritis. The literature on testicular involvement in connective tissue disease of childhood is reviewed. PMID:7271306

  20. The decrease in silicon concentration of the connective tissues with age in rats is a marker of connective tissue turnover.

    PubMed

    Jugdaohsingh, Ravin; Watson, Abigail I E; Pedro, Liliana D; Powell, Jonathan J

    2015-06-01

    previously estimated which could explain why absolute silicon deficiency is difficult to achieve but, when it is achieved in young growing animals, it results in stunted growth and abnormal development of bone and other connective tissues. PMID:25687224

  1. The decrease in silicon concentration of the connective tissues with age in rats is a marker of connective tissue turnover☆

    PubMed Central

    Jugdaohsingh, Ravin; Watson, Abigail I.E.; Pedro, Liliana D.; Powell, Jonathan J.

    2015-01-01

    lower than previously estimated which could explain why absolute silicon deficiency is difficult to achieve but, when it is achieved in young growing animals, it results in stunted growth and abnormal development of bone and other connective tissues. PMID:25687224

  2. Extracellular acidification induces connective tissue growth factor production through proton-sensing receptor OGR1 in human airway smooth muscle cells

    SciTech Connect

    Matsuzaki, Shinichi; Ishizuka, Tamotsu; Yamada, Hidenori; Kamide, Yosuke; Hisada, Takeshi; Ichimonji, Isao; Aoki, Haruka; Yatomi, Masakiyo; Komachi, Mayumi; Tsurumaki, Hiroaki; Ono, Akihiro; Koga, Yasuhiko; Dobashi, Kunio; Mogi, Chihiro; Sato, Koichi; Tomura, Hideaki; Mori, Masatomo; Okajima, Fumikazu

    2011-10-07

    Highlights: {yields} The involvement of extracellular acidification in airway remodeling was investigated. {yields} Extracellular acidification alone induced CTGF production in human ASMCs. {yields} Extracellular acidification enhanced TGF-{beta}-induced CTGF production in human ASMCs. {yields} Proton-sensing receptor OGR1 was involved in acidic pH-stimulated CTGF production. {yields} OGR1 may play an important role in airway remodeling in asthma. -- Abstract: Asthma is characterized by airway inflammation, hyper-responsiveness and remodeling. Extracellular acidification is known to be associated with severe asthma; however, the role of extracellular acidification in airway remodeling remains elusive. In the present study, the effects of acidification on the expression of connective tissue growth factor (CTGF), a critical factor involved in the formation of extracellular matrix proteins and hence airway remodeling, were examined in human airway smooth muscle cells (ASMCs). Acidic pH alone induced a substantial production of CTGF, and enhanced transforming growth factor (TGF)-{beta}-induced CTGF mRNA and protein expression. The extracellular acidic pH-induced effects were inhibited by knockdown of a proton-sensing ovarian cancer G-protein-coupled receptor (OGR1) with its specific small interfering RNA and by addition of the G{sub q/11} protein-specific inhibitor, YM-254890, or the inositol-1,4,5-trisphosphate (IP{sub 3}) receptor antagonist, 2-APB. In conclusion, extracellular acidification induces CTGF production through the OGR1/G{sub q/11} protein and inositol-1,4,5-trisphosphate-induced Ca{sup 2+} mobilization in human ASMCs.

  3. HBX Protein-Induced Downregulation of microRNA-18a is Responsible for Upregulation of Connective Tissue Growth Factor in HBV Infection-Associated Hepatocarcinoma

    PubMed Central

    Liu, Xiaomin; Zhang, Yingjian; Wang, Ping; Wang, Hongyun; Su, Huanhuan; Zhou, Xin; Zhang, Lamei

    2016-01-01

    Background This study was designed to improve our understanding of the role of miR-18a and its target (connective tissue growth factor (CTGF), which are mediators in HBX-induced hepatocellular carcinoma (HCC). Material/Methods We first investigated the expression of several candidate microRNAs (miRNAs) reported to have been aberrantly expressed between HepG2 and HepG2.2.15, which is characterized by stable HBV infection, while the CTGF is identified as a target of miR-18a. Furthermore, the expression of CTGF evaluated in HepG2 was transfected with HBX, while the HepG2.2.15 was transfected with miR-18a and CTGF siRNA. We examined the cell cycle at the same time. Results We found that the expression of miR-18a was abnormally reduced in the HBV-positive HCC tissue samples compared with HBV-negative HCC samples. Through the use of a luciferase reporter system, we also identified CTGF 3′UTR (1046–1052 bp) as the exact binding site for miR-18a. We also observed a clear increase in CTGF mRNA and protein expression levels in HBV-positive HCC human tissue samples in comparison with the HBV-negative controls, indicating a possible negatively associated relationship between miR-18a and CTGF. Furthermore, we investigated the effect of HBX overexpression on miR-18a and CTGF, as well as the viability and cell cycle status of HepG2 cells. In addition, we found that HBX introduction downregulated miR-18a, upregulated CTGF, elevated the viability, and promoted cell cycle progression. We transfected HepG2.2.15 with miR-18a mimics and CTGF siRNA, finding that upregulated miR-18a and downregulated CTGF suppress the viability and cause cell cycle arrest. Conclusions Our study shows the role of the CTGF gene as a target of miR-18a, and identifies the function of HBV/HBX/miR-18a/CTGF as a key signaling pathway mediating HBV infection-induced HCC. PMID:27421245

  4. Comparison of prostaglandin F2alpha, bimatoprost (prostamide), and butaprost (EP2 agonist) on Cyr61 and connective tissue growth factor gene expression.

    PubMed

    Liang, Yanbin; Li, Chen; Guzman, Victor M; Evinger, Albert J; Protzman, Charles E; Krauss, Achim H-P; Woodward, David F

    2003-07-18

    Connective tissue growth factor (CTGF) and Cyr61 (cysteine-rich angiogenic protein 61) are members of the CCN gene family that encode multifunctional, extracellular matrix-associated signaling proteins. Because the mechanism of action of certain anti-glaucoma drugs involves extracellular matrix remodeling of ocular ciliary muscle, with a resultant increase in drainage of aqueous humor from the eye, we compared the effects of three pharmacologically distinct ocular hypotensive agents on Cyr61 and CTGF gene expression. Thus, prostaglandin F2alpha (PGF2alpha) (FP receptor agonist), Butaprost (EP2 receptor agonist), and Bimatoprost (a prostamide) were compared. Using Affymetrix gene chip technology, we first identified that PGF2alpha dramatically up-regulated Cyr61 and CTGF mRNA expression in HEK 293/EBNA cells (hFP-HEK 293/EBNA). Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner. PGF2alpha-induced up-regulation of Cyr61 appeared to exclusively involve the Rho pathway, and up-regulation of CTGF was via multiple intracellular pathways. Because prostamide receptors are, to date, defined only at the pharmacological level, Bimatoprost effects on Cyr61 and CTGF were studied in the isolated feline iris sphincter preparation, a tissue highly responsive to prostamides. Both PGF2alpha and Bimatoprost up-regulated Cyr61 mRNA expression in the cat iris tissue. Only PGF2alpha up-regulated CTGF mRNA expression in the cat iris. Therefore, PGF2alpha and Bimatoprost appear to interact with different receptors populations in the cat iris, according to their markedly different effects on CTGF. Activation of prostaglandin EP2 receptors (Gs-coupled) also up-regulated Cyr61 but not CTGF mRNA expression in the isolated cat iris. Similar data were observed in human primary ciliary smooth muscle cells. Thus, despite quite different signal transduction pathways, FP receptor stimulation up-regulates CTGF and Cyr61. The prostamide analog

  5. [T-LYMPHOCYTES AND TISSUE GROWTH FACTORS].

    PubMed

    Tishevskaya, N V; Gevorkyan, N M; Kozlova, N I

    2015-08-01

    Lympnoici regulation, in aciaition to ensuring tne protection of tne antigen, is aimecl at maintaining a qualitative, quantitative, structural and functional integrity of the body. T-lymphocytes and growth factors are involved in cell proliferation, differentiation, and tissue and organ regeneration. Lymphocyte's, sensitivity to homeostasis changes and their morphogenetic function are connected with a large number of receptors to bioactive substances and with their ability to syn- thesize and secrete hormones and tissue growth factors. At the same time tissue growth factors are involved in the development of thymocytes, in the differentiation of T helper and cytotoxic lymphocytes. Growth factors modulate the functions of Thl, Th2, Treg, Thl7, Th9. The important aspects of the interaction of T cells and EGF, TGF-P, FGF, VEGF, PlGF, HGF/SF in normal and pathological conditions are shown in this review. PMID:26591583

  6. A disintegrin and metalloprotease with thrombospondin type I motif 7: a new protease for connective tissue growth factor in hepatic progenitor/oval cell niche.

    PubMed

    Pi, Liya; Jorgensen, Marda; Oh, Seh-Hoon; Protopapadakis, Yianni; Gjymishka, Altin; Brown, Alicia; Robinson, Paulette; Liu, Chuanju; Scott, Edward W; Schultz, Gregory S; Petersen, Bryon E

    2015-06-01

    Hepatic progenitor/oval cell (OC) activation occurs when hepatocyte proliferation is inhibited and is tightly associated with the fibrogenic response during severe liver damage. Connective tissue growth factor (CTGF) is important for OC activation and contributes to the pathogenesis of liver fibrosis. By using the Yeast Two-Hybrid approach, we identified a disintegrin and metalloproteinase with thrombospondin repeat 7 (ADAMTS7) as a CTGF binding protein. In vitro characterization demonstrated CTGF binding and processing by ADAMTS7. Moreover, Adamts7 mRNA was induced during OC activation, after the implantation of 2-acetylaminofluorene with partial hepatectomy in rats or on feeding a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet in mice. X-Gal staining showed Adamts7 expression in hepatocyte nuclear factor 4α(+) hepatocytes and desmin(+) myofibroblasts surrounding reactive ducts in DDC-treated Adamts7(-/-) mice carrying a knocked-in LacZ gene. Adamts7 deficiency was associated with higher transcriptional levels of Ctgf and OC markers and enhanced OC proliferation compared to Adamts7(+/+) controls during DDC-induced liver injury. We also observed increased α-smooth muscle actin and procollagen type I mRNAs, large fibrotic areas in α-smooth muscle actin and Sirius red staining, and increased production of hepatic collagen by hydroxyproline measurement. These results suggest that ADAMTS7 is a new protease for CTGF protein and a novel regulator in the OC compartment, where its absence causes CTGF accumulation, leading to increased OC activation and biliary fibrosis. PMID:25843683

  7. Involvement of Connective Tissue Growth Factor (CTGF) in Insulin-like Growth Factor-I (IGF1) Stimulation of Proliferation of a Bovine Mammary Epithelial Cell Line

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insulin-like growth factor I (IGF1) plays an important role in mammary gland development and lactation in part by stimulating proliferation of the milk-producing epithelial cells. In this study, we used the bovine mammary epithelial cell line MAC-T cells as a model to understand the mechanism by whi...

  8. CXCL12 induces connective tissue growth factor expression in human lung fibroblasts through the Rac1/ERK, JNK, and AP-1 pathways.

    PubMed

    Lin, Chien-Huang; Shih, Chung-Huang; Tseng, Chih-Chieh; Yu, Chung-Chi; Tsai, Yuan-Jhih; Bien, Mauo-Ying; Chen, Bing-Chang

    2014-01-01

    CXCL12 (stromal cell-derived factor-1, SDF-1) is a potent chemokine for homing of CXCR4+ fibrocytes to injury sites of lung tissue, which contributes to pulmonary fibrosis. Overexpression of connective tissue growth factor (CTGF) plays a critical role in pulmonary fibrosis. In this study, we investigated the roles of Rac1, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein-1 (AP-1) in CXCL12-induced CTGF expression in human lung fibroblasts. CXCL12 caused concentration- and time-dependent increases in CTGF expression and CTGF-luciferase activity. CXCL12-induced CTGF expression was inhibited by a CXCR4 antagonist (AMD3100), small interfering RNA of CXCR4 (CXCR4 siRNA), a dominant negative mutant of Rac1 (RacN17), a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor (PD98059), a JNK inhibitor (SP600125), a p21-activated kinase inhibitor (PAK18), c-Jun siRNA, and an AP-1 inhibitor (curcumin). Treatment of cells with CXCL12 caused activations of Rac1, Rho, ERK, and c-Jun. The CXCL12-induced increase in ERK phosphorylation was inhibited by RacN17. Treatment of cells with PD98059 and SP600125 both inhibited CXCL12-induced c-Jun phosphorylation. CXCL12 caused the recruitment of c-Jun and c-Fos binding to the CTGF promoter. Furthermore, CXCL12 induced an increase in α-smooth muscle actin (α-SMA) expression, a myofibroblastic phenotype, and actin stress fiber formation. CXCL12-induced actin stress fiber formation and α-SMA expression were respectively inhibited by AMD3100 and CTGF siRNA. Taken together, our results suggest that CXCL12, acting through CXCR4, activates the Rac/ERK and JNK signaling pathways, which in turn initiates c-Jun phosphorylation, and recruits c-Jun and c-Fos to the CTGF promoter and ultimately induces CTGF expression in human lung fibroblasts. Moreover, overexpression of CTGF mediates CXCL12-induced α-SMA expression. PMID:25121739

  9. Bioreactors for connective tissue engineering: design and monitoring innovations.

    PubMed

    El Haj, A J; Hampson, K; Gogniat, G

    2009-01-01

    The challenges for the tissue engineering of connective tissue lie in creating off-the-shelf tissue constructs which are capable of providing organs for transplantation. These strategies aim to grow a complex tissue with the appropriate mechanical integrity necessary for functional load bearing. Monolayer culture systems lack correlation with the in vivo environment and the naturally occur ring cell phenotypes. Part of the development of more recent models is to create growth environments or bioreactors which enable three-dimensional culture. Evidence suggests that in order to grow functional load-bearing tissues in a bioreactor, the cells must experience mechanical loading stimuli similar to that experienced in vivo which sets out the requirements for mechanical loading bioreactors. An essential part of developing new bioreactors for tissue growth is identifying ways of routinely and continuously measuring neo-tissue formation and in order to fully identify the successful generation of a tissue implant, the appropriate on-line monitoring must be developed. New technologies are being developed to advance our efforts to grow tissue ex vivo. The bioreactor is a critical part of these developments in supporting growth of biological implants and combining this with new advances in the detection of tissue formation allows us to refine our protocols and move nearer to off-the-shelf implants for clinical applications. PMID:19290498

  10. Bioreactors for Connective Tissue Engineering: Design and Monitoring Innovations

    NASA Astrophysics Data System (ADS)

    Haj, A. J. El; Hampson, K.; Gogniat, G.

    The challenges for the tissue engineering of connective tissue lie in creating off-the-shelf tissue constructs which are capable of providing organs for transplantation. These strategies aim to grow a complex tissue with the appropri ate mechanical integrity necessary for functional load bearing. Monolayer culture systems lack correlation with the in vivo environment and the naturally occur ring cell phenotypes. Part of the development of more recent models is to create growth environments or bioreactors which enable three-dimensional culture. Evidence suggests that in order to grow functional load-bearing tissues in a bioreactor, the cells must experience mechanical loading stimuli similar to that experienced in vivo which sets out the requirements for mechanical loading bioreactors. An essential part of developing new bioreactors for tissue growth is identifying ways of routinely and continuously measuring neo-tissue formation and in order to fully identify the successful generation of a tissue implant, the appropriate on-line monitoring must be developed. New technologies are being developed to advance our efforts to grow tissue ex vivo. The bioreactor is a critical part of these develop ments in supporting growth of biological implants and combining this with new advances in the detection of tissue formation allows us to refine our protocols and move nearer to off-the-shelf implants for clinical applications.

  11. Expression of the Elm1 Gene, a Novel Gene of the CCN (Connective Tissue Growth Factor, Cyr61/Cef10, and Neuroblastoma Overexpressed Gene) Family, Suppresses In Vivo Tumor Growth and Metastasis of K-1735 Murine Melanoma Cells

    PubMed Central

    Hashimoto, Yasunobu; Shindo-Okada, Nobuko; Tani, Masachika; Nagamachi, Yasuhiro; Takeuchi, Kaori; Shiroishi, Toshihiko; Toma, Hiroshi; Yokota, Jun

    1998-01-01

    We previously isolated a partial cDNA fragment of a novel gene, Elm1 (expressed in low-metastatic cells), that is expressed in low-metastatic but not in high-metastatic K-1735 mouse melanoma cells. Here we determined the full-length cDNA structure of Elm1 and investigated the effect of Elm1 expression on growth and metastatic potential of K-1735 cells. The Elm1 gene encodes a predicted protein of 367 amino acids showing ∼40% amino acid identity with the CCN (connective tissue growth factor [CTGF], Cyr61/Cef10, neuroblastoma overexpressed gene [Nov]) family proteins, which consist of secreted cysteine-rich proteins with growth regulatory functions. Elm1 is also a cysteine-rich protein and contains a signal peptide and four domains conserved in the CCN family proteins. Elm1 was highly conserved, expressed ubiquitously in diverse organs, and mapped to mouse chromosome 15. High-metastatic K-1735 M-2 cells, which did not express Elm1, were transfected with an Elm1 expression vector, and several stable clones with Elm1 expression were established. The in vivo growth rates of cells expressing a high level of Elm1 were remarkably slower than those of cells expressing a low level of Elm1. Metastatic potential of transfectants was reduced in proportion to the level of Elm1 expression. Thus, Elm1 is a novel gene of CCN family that can suppress the in vivo growth and metastatic potential of K-1735 mouse melanoma cells. PMID:9449709

  12. Epigenetic regulation of connective tissue growth factor by microRNA-214 delivery in exosomes from mouse or human hepatic stellate cells

    PubMed Central

    Chen, Li; Charrier, Alyssa; Zhou, Yu; Chen, Ruju; Yu, Bo; Agarwal, Kitty; Tsukamoto, Hidekazu; Lee, L. James; Paulaitis, Michael E; Brigstock, David R

    2013-01-01

    Connective tissue growth factor (CCN2) drives fibrogenesis in hepatic stellate cells (HSC). Here we show that CCN2 up-regulation in fibrotic or steatotic livers, or in culture-activated or ethanol-treated primary mouse HSC is associated with a reciprocal down-regulation of microRNA-214 (miR-214). By using protector or reporter assays to investigate the 3′-untranslated region (UTR) of CCN2 mRNA, we found that induction of CCN2 expression in HSC by fibrosis-inducing stimuli was due to reduced expression of miR-214 which otherwise inhibited CCN2 expression by directly binding to the CCN2 3′-UTR. Additionally, miR-214 was present in HSC exosomes, which were bi-membrane vesicles, 50–150nm in diameter, negatively charged (−26mV), and positive for CD9. MiR-214 levels in exosomes but not in cell lysates were reduced by pre-treatment of the cells with the exosome inhibitor, GW4869. Co-culture of miR-214-transfected donor HSC with CCN2 3′-UTR luciferase reporter-transfected recipient HSC resulted in miR-214- and exosome-dependent regulation of a wild type CCN2 3′-UTR reporter but not of a mutant CCN2 3′-UTR reporter lacking the miR-214 binding site. Exosomes from HSC were a conduit for uptake of miR-214 by primary mouse hepatocytes. Down-regulation of CCN2 expression by miR-214 also occurred in human LX-2 HSC, consistent with a conserved miR-214 binding site in the human CCN2 3′-UTR. MiR-214 in LX-2 cells was shuttled via exosomes to recipient LX-2 cells or human HepG2 hepatocytes, resulting in suppression of CCN2 3′-UTR activity or expression of CCN2 downstream targets, including αSMA or collagen. Experimental fibrosis in mice was associated with reduced circulating miR-214 levels. Conclusion Exosomal transfer of miR-214 is a paradigm for the regulation of CCN2-dependent fibrogenesis and identifies fibrotic pathways as targets of epigenetic regulation by exosomal miRs. PMID:24122827

  13. [Pulmonary involvement in connective tissue disease].

    PubMed

    Bartosiewicz, Małgorzata

    2016-01-01

    The connective tissue diseases are a variable group of autoimmune mediated disorders characterized by multiorgan damage. Pulmonary complications are common, usually occur after the onset of joint symptoms, but can also be initially presenting complaint. The respiratory system may be involved in all its component: airways, vessels, parenchyma, pleura and respiratory muscles. Lung involvement is an increasing cause of morbidity and mortality in the connective tissue diseases. Clinical course is highly variable - can range from mild to rapidly progressive, some processes are reversible, while others are irreversible. Thus, the identification of reversible disease , and separately progressive disease, are important clinical issues. The frequency, clinical presentation, prognosis and responce to therapy are different, depending on the pattern of involvement as well as on specyfic diagnostic method used to identify it. High- resolution computed tompography plays an important role in identifying patients with respiratory involvement. Pulmonary function tests are a sensitive tool detecting interstitial lung disease. In this article, pulmonary lung involvement accompanying most frequently apperaing connective tissue diseases - rheumatoid arthritis, systemic sclerosis, lupus erythematosus, polymyositis/dermatomyositis, Sjögrens syndrome and mixed connective tissue disaese are reviewed. PMID:27421127

  14. Stretching Impacts Inflammation Resolution in Connective Tissue.

    PubMed

    Berrueta, Lisbeth; Muskaj, Igla; Olenich, Sara; Butler, Taylor; Badger, Gary J; Colas, Romain A; Spite, Matthew; Serhan, Charles N; Langevin, Helene M

    2016-07-01

    Acute inflammation is accompanied from its outset by the release of specialized pro-resolving mediators (SPMs), including resolvins, that orchestrate the resolution of local inflammation. We showed earlier that, in rats with subcutaneous inflammation of the back induced by carrageenan, stretching for 10 min twice daily reduced inflammation and improved pain, 2 weeks after carrageenan injection. In this study, we hypothesized that stretching of connective tissue activates local pro-resolving mechanisms within the tissue in the acute phase of inflammation. In rats injected with carrageenan and randomized to stretch versus no stretch for 48 h, stretching reduced inflammatory lesion thickness and neutrophil count, and increased resolvin (RvD1) concentrations within lesions. Furthermore, subcutaneous resolvin injection mimicked the effect of stretching. In ex vivo experiments, stretching of connective tissue reduced the migration of neutrophils and increased tissue RvD1 concentration. These results demonstrate a direct mechanical impact of stretching on inflammation-regulation mechanisms within connective tissue. PMID:26588184

  15. Connective tissue: Vascular and hematological (blood) support

    PubMed Central

    Calvino, Nick

    2003-01-01

    Abstract Connective Tissue (CT) is a ubiquitous component of all major tissues and structures of the body (50% of all body protein is CT), including that of the blood, vascular, muscle, tendon, ligament, fascia, bone, joint, IVD's (intervertebral discs) and skin. Because of its ubiquitous nature, CT is an often overlooked component of any essential nutritional program that may address the structure, and/or function of these tissues. The central role of CT in the health of a virtually all cells, tissues, organs, and organ systems, is discussed. General nutritional CT support strategies, as well as specific CT support strategies that focus on blood, vascular, structural system (eg, muscles, tendons, ligaments, fascia, bone, and joints), integument (skin) and inflammatory and immune mediation will be discussed here and will deal with connective tissue dynamics and dysfunction. An overview of the current scientific understanding and possible options for naturally enhancing the structure and function of CT through the application of these concepts will be discussed in this article, with specific attention on the vascular and hematological systems. PMID:19674592

  16. Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Rheumatology.

    PubMed

    Pepmueller, Peri Hickman

    2016-01-01

    Autoimmune diseases often have overlapping symptoms and laboratory somewhat unfamiliar to the non-rheumatologist. Characteristic signs, symptoms, and autoantibodies define specific connective tissue diseases. Some patients have some characteristic symptoms, but cannot be definitively classified. Still other patients meet criteria for more than one specific connective tissue disease. These patients can be confusing with regard to diagnosis and prognosis. Clarification of each patient's condition can lead to improved patient care. PMID:27311225

  17. [Pulmonary manifestations of connective tissue diseases].

    PubMed

    Rehbock, B

    2015-03-01

    Systemic autoimmune diseases are responsible for about 25% of all deaths due to interstitial lung disease; therefore, an early identification of patients with pulmonary manifestation changes the management. Detection, differential diagnostic classification and staging of the pneumological pattern of findings are largely based on high-resolution computed tomography (HR-CT). The main differential diagnostic challenges are interstitial manifestations which present with radiological-histopathological phenotypes of interstitial pneumonia. The most common form of interstitial pulmonary reaction form of connective tissue diseases is the nonspecific interstitial pneumonia (NSIP) pattern. In rheumatoid arthritis, a usual interstitial pneumonia (UIP) pattern is dominant. Uncharacteristic reactions of airways and pleura can be the leading symptom or present as accompanying findings. A serious complication is pulmonary hypertension. Drug-induced lung lesions can present with similar HR-CT morphology as connective tissue diseases and can only be differentiated in the temporal and clinical context. PMID:25693496

  18. Pregnancy and autoimmune connective tissue diseases.

    PubMed

    Marder, Wendy; Littlejohn, Emily A; Somers, Emily C

    2016-02-01

    Autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before pregnancy, during pregnancy, and in the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy. PMID:27421217

  19. Latest advances in connective tissue disorders

    PubMed Central

    Rao, Vijay

    2013-01-01

    The connective tissue disorders comprise a number of related conditions that include systemic lupus erythematosus (SLE) and the antiphospholipid (Hughes) syndrome, scleroderma, myositis and Sjögren’s syndrome. They are characterized by autoantibody production and other immune-mediated dysfunction. There are common clinical and serological features with some patients having multiple overlapping connective tissue disorders. The latest advances include new approaches to therapy, including more focused utilization of existing therapies and the introduction of biological therapies in SLE, more precise protocols for assessment of severe disease manifestations such as in interstitial lung disease and pulmonary artery hypertension in scleroderma, new antibodies for disease characterization in myositis and new approaches to patient assessment in Sjögren’s syndrome. B cells have a critical role in most, if not all of these disorders such that B-cell depletion or suppression of B-cell activating cytokines improves disease in many patients. In particular, the introduction of rituximab, a monoclonal antibody targeting the CD20 molecule on B cells, into clinical practice for rheumatoid arthritis and B-cell lymphoma has been a key driver of experimental approaches to therapy in connective tissue disorders. Genetic studies also suggest a role for the innate immune system in disease pathogenesis, suggesting further future targets for biological therapies over the next few years. PMID:23904866

  20. Changes in the growth and metabolism of cells cultured from normal, sclerotic and rheumatoid connective tissue brought about by D-penicillamine and by sodium salicylate.

    PubMed

    Priestley, G C

    1980-06-01

    D-penicillamine and sodium salicylate were equally effective in suppressing the proliferation of fibroblasts from normal and scleroderma skin and rheumatoid synovial cells. The effects were concentration-dependent, beginning at around 100 microgram/ml, and proliferation was almost halted at 1600 microgram/ml. Individual cell strains of each type showed differences in drug susceptibility but there was no consistent difference between cells from normal and abnormal tissues. Acid mucopolysaccharide secretion was more clearly inhibited in scleroderma fibroblasts than in synovial cells, and penicillamine produced greater inhibition than salicylate, beginning at 10 microgram/ml and reaching almost 50% at 500 microgram/ml. Confluent cultures of scleroderma fibroblasts showed 23% less incorporation of 3H-proline into collagenase-sensitive protein in the presence of 1600 microgram/ml penicillamine, without significant effect on other protein synthesis; sodium salicylate had no effect. These data suggest that D-penicillamine may affect connective tissue metabolism in other ways than by interfering with collagen synthesis or cross-linking. PMID:6445922

  1. l-Theanine prevents carbon tetrachloride-induced liver fibrosis via inhibition of nuclear factor κB and down-regulation of transforming growth factor β and connective tissue growth factor.

    PubMed

    Pérez-Vargas, J E; Zarco, N; Vergara, P; Shibayama, M; Segovia, J; Tsutsumi, V; Muriel, P

    2016-02-01

    Here we evaluated the ability of L-theanine in preventing experimental hepatic cirrhosis and investigated the roles of nuclear factor-κB (NF-κB) activation as well as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) regulation. Experimental hepatic cirrhosis was established by the administration of carbon tetrachloride (CCl4) to rats (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks), and at the same time, adding L-theanine (8.0 mg/kg) to the drinking water. Rats had ad libitum access to water and food throughout the treatment period. CCl4 treatment promoted NF-κB activation and increased the expression of both TGF-β and CTGF. CCl4 increased the serum activities of alanine aminotransferase and γ-glutamyl transpeptidase and the degree of lipid peroxidation, and it also induced a decrease in the glutathione and glutathione disulfide ratio. L-Theanine prevented increased expression of NF-κB and down-regulated the pro-inflammatory (interleukin (IL)-1β and IL-6) and profibrotic (TGF-β and CTGF) cytokines. Furthermore, the levels of messenger RNA encoding these proteins decreased in agreement with the expression levels. L-Theanine promoted the expression of the anti-inflammatory cytokine IL-10 and the fibrolytic enzyme metalloproteinase-13. Liver hydroxyproline contents and histopathological analysis demonstrated the anti-fibrotic effect of l-theanine. In conclusion, L-theanine prevents CCl4-induced experimental hepatic cirrhosis in rats by blocking the main pro-inflammatory and pro-fibrogenic signals. PMID:25852135

  2. Connective Tissue Disorder-Associated Vasculitis.

    PubMed

    Sharma, Aman; Dhooria, Aadhaar; Aggarwal, Ashish; Rathi, Manish; Chandran, Vinod

    2016-06-01

    Vasculitides secondary to connective tissue diseases are classified under the category of 'vasculitis associated with systemic disease' in the revised International Chapel Hill Consensus Conference (CHCC) nomenclature. These secondary vasculitides may affect any of the small, medium or large vessels and usually portend a poor prognosis. Any organ system can be involved and the presentation would vary depending upon that involvement. Treatment depends upon the type and severity of presentation. In this review, we describe secondary vasculitis associated with rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, relapsing polychondritis, systemic sclerosis, Sjogren's syndrome and idiopathic inflammatory myositis, focusing mainly on recent advances in the past 3 years. PMID:27097818

  3. Effect of growth hormone on aging connective tissue in muscle and tendon: gene expression, morphology, and function following immobilization and rehabilitation.

    PubMed

    Boesen, A P; Dideriksen, K; Couppé, C; Magnusson, S P; Schjerling, P; Boesen, M; Aagaard, P; Kjaer, M; Langberg, H

    2014-01-15

    It is unknown whether loss in musculotendinous tissue during inactivity can be counteracted by growth hormone (GH), and whether GH accelerate rehabilitation in aging individuals. Elderly men (65-75 yr; n = 12) had one leg immobilized 2 wk followed by 6 wk of retraining and were randomly assigned to daily injections of recombinant GH (rhGH; n = 6) or placebo (Plc; n = 6). Cross-sectional area (CSA), muscle strength (MVC), and biomechanical properties of m. quadriceps and patellar tendon were determined. Muscle and tendon biopsies were analyzed for gene expressions (mRNA) of collagen (COL1A1/3A1) and insulin-like growth factors (IGF-1Ea/Ec). Fibril morphology was analyzed by transmission electron microscope (TEM). In tendon, CSA and biomechanical properties did not change following immobilization, but an increase in CSA was found after 6 wk of rehabilitation in both groups. The changes were more pronounced when GH was injected. Furthermore, tendon stiffness increased in the GH group. Muscle CSA declined after immobilization in the Plc but not in the GH group. Muscle CSA increased during retraining, with a significantly larger increase in the GH group compared with the Plc group. Both a time and a group effect were seen for IGF-1Ea/Ec and COL1A1/3A1 mRNA expression in muscle, with a difference between GH and Plc. IGF-1Ea/Ec and COL-1A1/3A1 mRNA expression increased in muscle following immobilization and retraining in subjects receiving GH, whereas an increase in IGF-1Ec mRNA expression was seen in the Plc group only after retraining. In conclusion, in elderly humans, GH seems to have a matrix stabilizing effect during inactivity and rehabilitation by stimulating collagen expression in the musculotendinous tissue and increasing tendon CSA and stiffness. PMID:24235105

  4. Generalized Connective Tissue Disease in Crtap-/- Mouse

    PubMed Central

    Baldridge, Dustin; Lennington, Jennifer; Weis, MaryAnn; Homan, Erica P.; Jiang, Ming-Ming; Munivez, Elda; Keene, Douglas R.; Hogue, William R.; Pyott, Shawna; Byers, Peter H.; Krakow, Deborah; Cohn, Daniel H.; Eyre, David R.; Lee, Brendan; Morello, Roy

    2010-01-01

    Mutations in CRTAP (coding for cartilage-associated protein), LEPRE1 (coding for prolyl 3-hydroxylase 1 [P3H1]) or PPIB (coding for Cyclophilin B [CYPB]) cause recessive forms of osteogenesis imperfecta and loss or decrease of type I collagen prolyl 3-hydroxylation. A comprehensive analysis of the phenotype of the Crtap-/- mice revealed multiple abnormalities of connective tissue, including in the lungs, kidneys, and skin, consistent with systemic dysregulation of collagen homeostasis within the extracellular matrix. Both Crtap-/- lung and kidney glomeruli showed increased cellular proliferation. Histologically, the lungs showed increased alveolar spacing, while the kidneys showed evidence of segmental glomerulosclerosis, with abnormal collagen deposition. The Crtap-/- skin had decreased mechanical integrity. In addition to the expected loss of proline 986 3-hydroxylation in α1(I) and α1(II) chains, there was also loss of 3Hyp at proline 986 in α2(V) chains. In contrast, at two of the known 3Hyp sites in α1(IV) chains from Crtap-/- kidneys there were normal levels of 3-hydroxylation. On a cellular level, loss of CRTAP in human OI fibroblasts led to a secondary loss of P3H1, and vice versa. These data suggest that both CRTAP and P3H1 are required to maintain a stable complex that 3-hydroxylates canonical proline sites within clade A (types I, II, and V) collagen chains. Loss of this activity leads to a multi-systemic connective tissue disease that affects bone, cartilage, lung, kidney, and skin. PMID:20485499

  5. Connective tissue metabolism in chikungunya patients

    PubMed Central

    Lokireddy, Sudarsanareddy; Vemula, Sarojamma; Vadde, Ramakrishna

    2008-01-01

    Background Chikungunya (CHIK) fever is a viral disease transmitted to humans by the bite of Chikungunya virus (CHIK virus) infected Aedes mosquitoes. CHIK virus is a member of the Alphavirus genus of the family Togaviridae. Previous reports have indicated that infection with CHIK virus produces an acute arthritis in human hosts by large area of necrosis and collagenosis or fibrosis. Results We carried out the present study to determine the effect of chikungunya on the collagen and connective tissue metabolism in 75 chikungunya-affected people. First, we screened for mucopolysaccharides in urine by Cetyl Trimethyl Ammonium Bromide (CTAB) test. Appearance of heavy precipitate indicates the presence of higher levels of mucopolysaccharides and later quantified by DMB dye method. The urinary mucopolysaccharide in CHIK patients was 342 ± 45 mg/l compared to healthy controls (45 ± 5.6 mg/l). The collagen building blocks, proline and hydroxyproline were also measured in CHIK patients and observed higher excretion compared to healthy controls. Urinary excretions hydroxyproline was greater than the proline levels. Conclusion These results indicate that CHIK virus infection affects and damage the cartilage and connective metabolism and releases the degraded products from the tissue and responsible for increasing the levels of proline, hydroxyproline and mucopolysaccharides in CHIK affected patients. PMID:18302795

  6. Pulmonary arterial hypertension in connective tissue diseases.

    PubMed

    Goldberg, Avram

    2010-01-01

    Pulmonary arterial hypertension (PAH) is an entity that is known to complicate connective tissue diseases (CTD). PAH in CTD is a very important diagnosis which greatly affects treatment and prognosis. The most commonly affected CTD is scleroderma, although lupus, inflammatory myopathies such as poly and dermatomyositis, and mixed CTD are also associated with PAH. The manifestations of PAH have both similarities and differences when occurring in the setting of CTD as compared with idiopathic PAH. These differences are most notable in scleroderma. In this section we will discuss the features of PAH as they appear in CTDs, and in particular, scleroderma. The focus of this article is an approach to the diagnosis and treatment of PAH in CTD, and how this setting might differ from idiopathic and other forms of PAH. PMID:20160534

  7. Pulmonary hypertension complicating connective tissue disease.

    PubMed

    Lynch, Joseph P; Belperio, John A; Saggar, Rajeev; Fishbein, Michael C; Saggar, Rajan

    2013-10-01

    Pulmonary hypertension (PH) may complicate connective tissue disease (CTD), particularly systemic sclerosis (SSc, scleroderma), and markedly increases mortality. More than 70% of cases of PH complicating CTD occur in SSc, which is the major focus of this article. Pulmonary complications (i.e., interstitial lung disease [ILD] and PH) are the leading causes of scleroderma-related deaths. "Isolated" PH (i.e., without ILD) complicates SSc in 7.5 to 20% of cases; secondary PH may also occur in patients with SSc-associated ILD. Several clinical markers and specific autoantibody profiles have been associated with PH in SSc. The role of PH-specific therapy is controversial, as prognosis and responsiveness to therapy are worse in SSc-associated PH compared with idiopathic pulmonary arterial hypertension. We discuss medical therapies for CTD-associated PH and the role of lung transplantation for patients failing medical therapy. PMID:24037627

  8. Fibroblast involvement in soft connective tissue calcification

    PubMed Central

    Ronchetti, Ivonne; Boraldi, Federica; Annovi, Giulia; Cianciulli, Paolo; Quaglino, Daniela

    2013-01-01

    Soft connective tissue calcification is not a passive process, but the consequence of metabolic changes of local mesenchymal cells that, depending on both genetic and environmental factors, alter the balance between pro- and anti-calcifying pathways. While the role of smooth muscle cells and pericytes in ectopic calcifications has been widely investigated, the involvement of fibroblasts is still elusive. Fibroblasts isolated from the dermis of pseudoxanthoma elasticum (PXE) patients and of patients exhibiting PXE-like clinical and histopathological findings offer an attractive model to investigate the mechanisms leading to the precipitation of mineral deposits within elastic fibers and to explore the influence of the genetic background and of the extracellular environment on fibroblast-associated calcifications, thus improving the knowledge on the role of mesenchymal cells on pathologic mineralization. PMID:23467434

  9. Rare inflammatory and hereditary connective tissue diseases.

    PubMed

    Klipple, G L; Riordan, K K

    1989-05-01

    Polyarteritis nodosa developing during gestation has an extremely grave prognosis. To an uncertain extent, this results from a delay in recognition and therapy. The diagnosis of PAN is complicated by the expanded differential of common conditions associated with pregnancy such as pre-eclampsia and toxemia which can present with similar symptoms and signs. On the other hand, the pregnant woman with known, quiescent disease has a much better prognosis with only one of four women experiencing exacerbation. In women with Behcet's disease, convincing reports of both pregnancy-related flares and remissions involving primarily mucocutaneous manifestations are found in the literature. Gestational exacerbation of the more serious manifestations including chorioretinitis, vasculitis and CNS disease does not appear to be a problem. Also, a significant effect on fetal development or survival is not evident. The pregnant woman with the Marfan syndrome and pre-existing cardiovascular disease, particularly dilatation of the aortic root, has a substantially increased risk of developing a major complication during gestation most commonly aortic aneurysm, dissection, rupture or insufficiency. Echocardiographic determination of the aortic root diameter is prognostic with a decreased risk at a diameter of 40 mm or less. A diameter of greater than 40 to 45 mm constitutes a significant contraindication to pregnancy. All pregnancies in patients with the Marfan syndrome are considered high risk and frequent evaluations and echocardiograms are required. The EDS patient is subject to a wide range of gestational complications resulting from the basic connective tissue defect manifested clinically by hyperextensible skin, joint hypermobility, connective tissue and vascular fragility, and poor wound healing. The most serious complications occur in type I EDS (gravis) and type IV (ecchymotic) and include extensive perineal tears and hematoma after vaginal delivery, uterine prolapse and rupture

  10. Structure of the tendon connective tissue.

    PubMed

    Kannus, P

    2000-12-01

    Tendons consist of collagen (mostly type I collagen) and elastin embedded in a proteoglycan-water matrix with collagen accounting for 65-80% and elastin approximately 1-2% of the dry mass of the tendon. These elements are produced by tenoblasts and tenocytes, which are the elongated fibroblasts and fibrocytes that lie between the collagen fibers, and are organized in a complex hierarchical scheme to form the tendon proper. Soluble tropocollagen molecules form cross-links to create insoluble collagen molecules which then aggregate progressively into microfibrils and then into electronmicroscopically clearly visible units, the collagen fibrils. A bunch of collagen fibrils forms a collagen fiber, which is the basic unit of a tendon. A fine sheath of connective tissue called endotenon invests each collagen fiber and binds fibers together. A bunch of collagen fibers forms a primary fiber bundle, and a group of primary fiber bundles forms a secondary fiber bundle. A group of secondary fiber bundles, in turn, forms a tertiary bundle, and the tertiary bundles make up the tendon. The entire tendon is surrounded by a fine connective tissue sheath called epitenon. The three-dimensional ultrastructure of tendon fibers and fiber bundles is complex. Within one collagen fiber, the fibrils are oriented not only longitudinally but also transversely and horizontally. The longitudinal fibers do not run only parallel but also cross each other, forming spirals. Some of the individual fibrils and fibril groups form spiral-type plaits. The basic function of the tendon is to transmit the force created by the muscle to the bone, and, in this way, make joint movement possible. The complex macro- and microstructure of tendons and tendon fibers make this possible. During various phases of movements, the tendons are exposed not only to longitudinal but also to transversal and rotational forces. In addition, they must be prepared to withstand direct contusions and pressures. The above

  11. Modeling Tissue Growth Within Nonwoven Scaffolds Pores

    PubMed Central

    Church, Jeffrey S.; Alexander, David L.J.; Russell, Stephen J.; Ingham, Eileen; Ramshaw, John A.M.; Werkmeister, Jerome A.

    2011-01-01

    In this study we present a novel approach for predicting tissue growth within the pores of fibrous tissue engineering scaffolds. Thin nonwoven polyethylene terephthalate scaffolds were prepared to characterize tissue growth within scaffold pores, by mouse NR6 fibroblast cells. On the basis of measurements of tissue lengths at fiber crossovers and along fiber segments, mathematical models were determined during the proliferative phase of cell growth. Tissue growth at fiber crossovers decreased with increasing interfiber angle, with exponential relationships determined on day 6 and 10 of culture. Analysis of tissue growth along fiber segments determined two growth profiles, one with enhanced growth as a result of increased tissue lengths near the fiber crossover, achieved in the latter stage of culture. Derived mathematical models were used in the development of a software program to visualize predicted tissue growth within a pore. This study identifies key pore parameters that contribute toward tissue growth, and suggests models for predicting this growth, based on fibroblast cells. Such models may be used in aiding scaffold design, for optimum pore infiltration during the tissue engineering process. PMID:20687775

  12. Connective tissue disorders in domestic animals.

    PubMed

    Halper, Jaroslava

    2014-01-01

    Though soft tissue disorders have been recognized and described to some detail in several types of domestic animals and small mammals for some years, not much progress has been made in our understanding of the biochemical basis and pathogenesis of these diseases in animals. Ehlers-Danlos syndrome described in dogs already in 1943 and later in cats affects mainly skin in these animals. The involved skin is thin and hyperextensible with easily inflicted injuries resulting in hemorrhagic wounds and atrophic scars. Joint laxity and dislocation common in people are less frequently found in dogs. No systemic complications, such as organ rupture or cardiovascular problems which have devastating consequences in people have been described in cats and dogs. The diagnosis is based on clinical presentation and on light or electron microscopic features of disorganized and fragmented collagen fibrils. Several cases of bovine and ovine dermatosparaxis analogous to human Ehlers-Danlos syndrome type VIIC were found to be caused by mutations in the procollagen I N-proteinase (pnPI) or ADAMTS2 gene, though mutations in other sites are likely responsible for other types of dermatosparaxis. Cattle suffering from a form of Marfan syndrome were described to have aortic dilatation and aneurysm together with ocular abnormalities and skeletal involvement. As in people mutations at different sites of bovine FBN1 may be responsible for Marfan phenotype. Hereditary equine regional dermal asthenia (HERDA), or hyperelastosis cutis, has been recognized in several horse breeds as affecting primarily skin, and, occasionally, tendons. A mutation in cyclophilin B, a chaperon involved in proper folding of collagens, has been identified in some cases. Degenerative suspensory ligament desmitis (DSLD) affects primarily tendons and ligaments of certain horse breeds. New data from our laboratory showed excessive accumulation of proteoglycans in organs with high content of connective tissues. We have

  13. [Autoimmune connective tissue diseases and vaccination].

    PubMed

    Więsik-Szewczyk, Ewa; Jahnz-Różyk, Karina

    2015-01-01

    The idea that infectious agents can induce autoimmune diseases in genetically susceptible subjects has been a matter of discussion for years. Moreover, increased incidence of autoimmune diseases and introduction of prophylactic vaccinations from early childhood suggest that these two trends are linked. In the medical literature and even non-professional media, case reports or events temporally related to vaccination are reported. It raises the issue of vaccination safety. In everyday practice medical professionals, physicians, rheumatologists and other specialists will be asked their opinion of vaccination safety. The decision should be made according to evidence-based medicine and the current state of knowledge. The purpose of this paper is to discuss a potential mechanism which links infections, vaccinations and autoimmunity. We present an overview of published case reports, especially of systemic connective tissue diseases temporally related to vaccination and results from case-nested studies. As yet, no conclusive evidence supports a causal relationship between vaccination and autoimmune diseases. It has to be determined whether the performed studies are sufficiently sensitive to detect the link. The debate is ongoing, and new data may be required to explain the pathogenesis of autoimmunity. We would like to underscore the need for prophylactic vaccination in patients with autoimmune rheumatic diseases and to break down the myth that the vaccines are contraindicated in this target group. PMID:27259225

  14. Renal involvement in autoimmune connective tissue diseases

    PubMed Central

    2013-01-01

    Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation, leading to autoantibody production. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. Alterations of kidney function in Sjögren syndrome, systemic scleroderma (SSc), auto-immune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus (SLE), antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that. In SLE, renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings. Patients with scleroderma renal crisis (SRC), which is usually characterized by severe hypertension, progressive decline of renal function and thrombotic microangiopathy, show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome, auto-immune myopathies, APSN and RA. In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions. PMID:23557013

  15. Connective tissue alterations in Fkbp10−/− mice

    PubMed Central

    Lietman, Caressa D.; Rajagopal, Abbhirami; Homan, Erica P.; Munivez, Elda; Jiang, Ming-Ming; Bertin, Terry K.; Chen, Yuqing; Hicks, John; Weis, MaryAnn; Eyre, David; Lee, Brendan; Krakow, Deborah

    2014-01-01

    Osteogenesis imperfecta (OI) is an inherited brittle bone disorder characterized by bone fragility and low bone mass. Loss of function mutations in FK506-binding protein 10 (FKBP10), encoding the FKBP65 protein, result in recessive OI and Bruck syndrome, of which the latter is additionally characterized by joint contractures. FKBP65 is thought to act as a collagen chaperone, but it is unknown how loss of FKBP65 affects collagen synthesis and extracellular matrix formation. We evaluated the developmental and postnatal expression of Fkbp10 and analyzed the consequences of its generalized loss of function. Fkbp10 is expressed at low levels in E13.5 mouse embryos, particularly in skeletal tissues, and steadily increases through E17.5 with expression in not only skeletal tissues, but also in visceral tissues. Postnatally, expression is limited to developing bone and ligaments. In contrast to humans, with complete loss of function mutations, Fkbp10−/− mice do not survive birth, and embryos present with growth delay and tissue fragility. Type I calvarial collagen isolated from these mice showed reduced stable crosslink formation at telopeptide lysines. Furthermore, Fkbp10−/− mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated endoplasmic reticulum. These data suggest a requirement for FKBP65 function during embryonic connective tissue development in mice, but the restricted expression postnatally in bone, ligaments and tendons correlates with the bone fragility and contracture phenotype in humans. PMID:24777781

  16. Comparative connective tissue structure-function relationships in biologic pumps.

    PubMed

    Factor, S M; Robinson, T F

    1988-02-01

    A complex connective tissue framework exists in mammalian hearts that surrounds and interconnects individual myocytes and fascicles of cells. Recent evidence suggests that this connective tissue plays a role in maintaining shape, modulating contractile forces, and mediating elastic recoil during cavity filling and contraction. In order to analyze the involvement of connective tissue in pump contraction and recoil, we examined silver impregnated connective tissue in rat hearts which spontaneously jet through fluid ex vivo by contracting their cavities forcefully and then sucking fluid for the next cycle, and compared them to frog hearts which beat actively under the same conditions, but do not demonstrate jet propulsion. A further analysis was carried out in unrelated but analogous models: the squid and octopus. The former jets rapidly through the ocean, while the latter moves sinuously along the seabed. We observed highly interconnected myocytes in the rat heart, whereas frog myocytes are individually wrapped by connective tissue but are not interconnected. The squid mantle muscle is surrounded by a complex connective tissue grid that is tethered to each muscle cell, whereas the octopus mantle muscle cells are surrounded by connective tissue but are not tethered. These observations suggest that myocyte connective tissue tethering may be necessary for muscle cavities to generate forceful and coordinated contractions sufficient for rapid ejection and suction of fluid. PMID:2448546

  17. Microrna-199a-5p Functions as a Tumor Suppressor via Suppressing Connective Tissue Growth Factor (CTGF) in Follicular Thyroid Carcinoma

    PubMed Central

    Sun, Dawei; Han, Shen; Liu, Chao; Zhou, Rui; Sun, Weihai; Zhang, Zhijun; Qu, Jianjun

    2016-01-01

    Background The objective of this study was to explore the role of miR-199a-5p in the development of thyroid cancer, including its anti-proliferation effect and downstream signaling pathway. Material/Methods We conducted qRT-PCR analysis to detect the expressions of several microRNAs in 42 follicular thyroid carcinoma patients and 42 controls. We identified CTGF as target of miR-491, and viability and cell cycle status were determined in FTC-133 cells transfected with CTGF siRNA, miR-199a mimics, or inhibitors. Results We identified an underexpression of miR-199a-5p in follicular thyroid carcinoma tissue samples compared with controls. Then we confirmed CTGF as a target of miR-199a-5p thyroid cells by using informatics analysis and luciferase reporter assay. Additionally, we found that mRNA and protein expression levels of CTGF were both clearly higher in malignant tissues than in benign tissues. miR-199a-5p mimics and CTGF siRNA similarly downregulated the expression of CTGF, and reduced the viability of FTC-133 cells by arresting the cell cycle in G0 phase. Transfection of miR-199a-5p inhibitors increased the expression of CTGF and promoted the viability of the cells by increasing the fraction of cells in G2/M and S phases. Conclusions Our study proves that the CTGF gene is a target of miR-199a-5p, demonstrating the negatively related association between CTGF and miR-199a. These findings suggest that miR-199a-5p might be a novel therapeutic target in the treatment of follicular thyroid carcinoma. PMID:27062921

  18. Microrna-199a-5p Functions as a Tumor Suppressor via Suppressing Connective Tissue Growth Factor (CTGF) in Follicular Thyroid Carcinoma.

    PubMed

    Sun, Dawei; Han, Shen; Liu, Chao; Zhou, Rui; Sun, Weihai; Zhang, Zhijun; Qu, Jianjun

    2016-01-01

    BACKGROUND The objective of this study was to explore the role of miR-199a-5p in the development of thyroid cancer, including its anti-proliferation effect and downstream signaling pathway. MATERIAL AND METHODS We conducted qRT-PCR analysis to detect the expressions of several microRNAs in 42 follicular thyroid carcinoma patients and 42 controls. We identified CTGF as target of miR-491, and viability and cell cycle status were determined in FTC-133 cells transfected with CTGF siRNA, miR-199a mimics, or inhibitors. RESULTS We identified an underexpression of miR-199a-5p in follicular thyroid carcinoma tissue samples compared with controls. Then we confirmed CTGF as a target of miR-199a-5p thyroid cells by using informatics analysis and luciferase reporter assay. Additionally, we found that mRNA and protein expression levels of CTGF were both clearly higher in malignant tissues than in benign tissues. miR-199a-5p mimics and CTGF siRNA similarly downregulated the expression of CTGF, and reduced the viability of FTC-133 cells by arresting the cell cycle in G0 phase. Transfection of miR-199a-5p inhibitors increased the expression of CTGF and promoted the viability of the cells by increasing the fraction of cells in G2/M and S phases. CONCLUSIONS Our study proves that the CTGF gene is a target of miR-199a-5p, demonstrating the negatively related association between CTGF and miR-199a. These findings suggest that miR-199a-5p might be a novel therapeutic target in the treatment of follicular thyroid carcinoma. PMID:27062921

  19. Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing

    PubMed Central

    Henshaw, F. R.; Boughton, P.; Lo, L.; McLennan, S. V.; Twigg, S. M.

    2015-01-01

    Aims/Hypothesis. Topical application of CTGF/CCN2 to rodent diabetic and control wounds was examined. In parallel research, correlation of CTGF wound fluid levels with healing rate in human diabetic foot ulcers was undertaken. Methods. Full thickness cutaneous wounds in diabetic and nondiabetic control rats were treated topically with 1 μg rhCTGF or vehicle alone, on 2 consecutive days. Wound healing rate was observed on day 14 and wound sites were examined for breaking strength and granulation tissue. In the human study across 32 subjects, serial CTGF regulation was analyzed longitudinally in postdebridement diabetic wound fluid. Results. CTGF treated diabetic wounds had an accelerated closure rate compared with vehicle treated diabetic wounds. Healed skin withstood more strain before breaking in CTGF treated rat wounds. Granulation tissue from CTGF treatment in diabetic wounds showed collagen IV accumulation compared with nondiabetic animals. Wound α-smooth muscle actin was increased in CTGF treated diabetic wounds compared with untreated diabetic wounds, as was macrophage infiltration. Endogenous wound fluid CTGF protein rate of increase in human diabetic foot ulcers correlated positively with foot ulcer healing rate (r = 0.406; P < 0.001). Conclusions/Interpretation. These data collectively increasingly substantiate a functional role for CTGF in human diabetic foot ulcers. PMID:25789327

  20. Comment on "Topically Applied Connective Tissue Growth Factor/CCN2 Improves Diabetic Preclinical Cutaneous Wound Healing: Potential Role for CTGF in Human Diabetic Foot Ulcer Healing".

    PubMed

    Li, Hongling; Cao, Cong; Huang, Ai; Man, Yi

    2015-01-01

    A recent paper in this journal, presented a novel method by topical application of growth factors in stimulating diabetic cutaneous wound healing that caught our attention. We believe that the experimental method in the article is efficient and creative, but it also has some controversies and shortcomings to be discussed. We noted that the authors used "Tegaderm" as a semiocclusive dressing film and stated that it exerted a "splinting effect" on the wound margins and controlled contraction. Indeed, the "Tegaderm" itself can serve as a dressing film to isolate the wound bed with outside environments while the "splinting effect" is mainly achieved by adding silicone splints around the wound. Considering the unique properties of silicone splints and "Tegaderm," our experimental group propose an alternative method named "combined-suturing" technique that is not only suturing the silicone splints but also securing the "Tegaderm" around the wound. The specific reasons and operative procedures are explained in detail in this letter. PMID:26457307

  1. Imaging of connective tissue diseases of the head and neck.

    PubMed

    Abdel Razek, Ahmed Abdel Khalek

    2016-06-01

    We review the imaging appearance of connective tissue diseases of the head and neck. Bilateral sialadenitis and dacryoadenitis are seen in Sjögren's syndrome; ankylosis of the temporo-mandibular joint with sclerosis of the crico-arytenoid joint are reported in rheumatoid arthritis and lupus panniculitis with atypical infection are reported in patients with systemic lupus erythematosus. Relapsing polychondritis shows subglottic stenosis, prominent ear and saddle nose; progressive systemic sclerosis shows osteolysis of the mandible, fibrosis of the masseter muscle with calcinosis of the subcutaneous tissue and dermatomyositis/polymyositis shows condylar erosions and autoimmune thyroiditis. Vascular thrombosis is reported in antiphospholipid antibodies syndrome; cervical lymphadenopathy is seen in adult-onset Still's disease, and neuropathy with thyroiditis reported in mixed connective tissue disorder. Imaging is important to detect associated malignancy with connective tissue disorders. Correlation of the imaging findings with demographic data and clinical findings are important for the diagnosis of connective tissue disorders. PMID:26988082

  2. Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

    SciTech Connect

    Lim, Taekyu; Lee, Inkyoung; Kim, Jungmin; Kang, Won Ki

    2015-10-01

    Purpose: We investigated the synergistic effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor plus radiation therapy, on the proliferation and survival of gastric cancer (GC) and colorectal cancer (CRC) cells. We also studied several genes involved in the simvastatin/radiation-induced effects. Methods and Materials: Gastric cancer (AGS, SNU601, MKN1, and MKN28) and CRC (CoLo320, SW48, HT29, and HCT8) cell lines were treated with 0.2 μM simvastatin alone, or in combination with 0 to 4 Gy of radiation, and subjected to clonogenic survival and proliferation assays in vitro. To assess the molecular mechanism of the combination treatment, we performed microarray analysis, immunoblot assays, small interfering RNA knockdown experiments, and plasmid rescue assays. The antitumoral effects of simvastatin and radiation were evaluated in vivo using xenograft models. Results: The combination therapy of simvastatin plus radiation inhibited basal clonogenic survival and proliferation of GC and CRC cells in vitro. Simvastatin suppressed the expression of BIRC5 and CTGF genes in these cancer cells. In vivo, the combined treatment with simvastatin and radiation significantly reduced the growth of xenograft tumors compared with treatment with radiation alone. Conclusion: We suggest that simvastatin has a synergistic effect with radiation on GC and CRC through the induction of apoptosis, which may be mediated by a simultaneous inhibition of BIRC5 and CTGF expression. A clinical trial of simvastatin in combination with radiation in patients with GC or CRC is warranted.

  3. Micromechanics and constitutive modeling of connective soft tissues.

    PubMed

    Fallah, A; Ahmadian, M T; Firozbakhsh, K; Aghdam, M M

    2016-07-01

    In this paper, a micromechanical model for connective soft tissues based on the available histological evidences is developed. The proposed model constituents i.e. collagen fibers and ground matrix are considered as hyperelastic materials. The matrix material is assumed to be isotropic Neo-Hookean while the collagen fibers are considered to be transversely isotropic hyperelastic. In order to take into account the effects of tissue structure in lower scales on the macroscopic behavior of tissue, a strain energy density function (SEDF) is developed for collagen fibers based on tissue hierarchical structure. Macroscopic response and properties of tissue are obtained using the numerical homogenization method with the help of ABAQUS software. The periodic boundary conditions and the proposed constitutive models are implemented into ABAQUS using the DISP and the UMAT subroutines, respectively. The existence of the solution and stable material behavior of proposed constitutive model for collagen fibers are investigated based on the poly-convexity condition. Results of the presented micromechanics model for connective tissues are compared and validated with available experimental data. Effects of geometrical and material parameters variation at microscale on macroscopic mechanical behavior of tissues are investigated. The results show that decrease in collagen content of the connective tissues like the tendon due to diseases leads 20% more stretch than healthy tissue under the same load which can results in connective tissue malfunction and hypermobility in joints. PMID:26807767

  4. Silica associated mixed connective tissue disorder in a stone crusher.

    PubMed

    Khanna, Arjun; Suri, Jagdish Chander; Ray, Animesh; Sharma, Rahul Kumar

    2013-05-01

    Silica exposure has been implicated with the development of various connective tissue diseases. We report a case of 32-year-old stone crusher who developed silicosis with mixed connective tissue disorder (MCTD) 6 years after exposure to silica. This association of silicosis with MCTD has never been reported from the Indian subcontinent, although the problem of this pneumoconiosis remains rampant. This rare association urges us to report this case. PMID:24421595

  5. Silica associated mixed connective tissue disorder in a stone crusher

    PubMed Central

    Khanna, Arjun; Suri, Jagdish Chander; Ray, Animesh; Sharma, Rahul Kumar

    2013-01-01

    Silica exposure has been implicated with the development of various connective tissue diseases. We report a case of 32-year-old stone crusher who developed silicosis with mixed connective tissue disorder (MCTD) 6 years after exposure to silica. This association of silicosis with MCTD has never been reported from the Indian subcontinent, although the problem of this pneumoconiosis remains rampant. This rare association urges us to report this case. PMID:24421595

  6. FIBROBLAST CYTOSKELETAL REMODELING CONTRIBUTES TO CONNECTIVE TISSUE TENSION

    PubMed Central

    Langevin, Helene M.; Bouffard, Nicole A.; Fox, James R.; Palmer, Bradley M.; Wu, Junru; Iatridis, James C.; Barnes, William D.; Badger, Gary J.; Howe, Alan K.

    2011-01-01

    The viscoelastic behavior of connective tissue is generally attributed to the material properties of the extracellular matrix rather than cellular activity. We have previously shown that fibroblasts within areolar connective tissue exhibit dynamic cytoskeletal remodeling within minutes in response to tissue stretch ex vivo and in vivo. Here, we tested the hypothesis that fibroblasts, through this cytoskeletal remodeling, actively contribute to the viscoelastic behavior of the whole tissue. We measured significantly increased tissue tension when cellular function was broadly inhibited by sodium azide and when cytoskeletal dynamics were compromised by disrupting microtubules (with colchicine) or actomyosin contractility (via Rho kinase inhibition). These treatments led to a decrease in cell body cross-sectional area and cell field perimeter (obtained by joining the end of all of a fibroblast’s processes). Suppressing lamellipodia formation by inhibiting Rac-1 decreased cell body cross-sectional area but did not affect cell field perimeter or tissue tension. Thus, by changing shape, fibroblasts can dynamically modulate the viscoelastic behavior of areolar connective tissue through Rho-dependent cytoskeletal mechanisms. These results have broad implications for our understanding of the dynamic interplay of forces between fibroblasts and their surrounding matrix, as well as for the neural, vascular and immune cell populations residing within connective tissue. PMID:20945345

  7. Hypericin-mediated selective photomodification of connective tissues

    SciTech Connect

    Hovhannisyan, V. Guo, H. W.; Chen, Y. F.; Hovhannisyan, A.; Ghukasyan, V.; Dong, C. Y.

    2014-12-29

    Controllable modification of biological molecules and supramolecular components of connective tissue are important for biophysical and biomedical applications. Through the use of second harmonic generation imaging, two-photon fluorescence microscopy, and spectrofluorimetry, we found that hypericin, a natural pigment, induces photosensitized destruction of collagen fibers but does not affect elastic fibers and lipids in chicken tendon, skin, and blood vessels. We demonstrated the dynamics and efficiency of collagen photomodification and investigated mechanisms of this processes. Our results suggest that hypericin–mediated photoprocesses in biological tissues may be useful in biomedical applications that require selective modification of connective tissues.

  8. Hypericin-mediated selective photomodification of connective tissues

    NASA Astrophysics Data System (ADS)

    Hovhannisyan, V.; Hovhannisyan, A.; Ghukasyan, V.; Guo, H. W.; Chen, Y. F.; Dong, C. Y.

    2014-12-01

    Controllable modification of biological molecules and supramolecular components of connective tissue are important for biophysical and biomedical applications. Through the use of second harmonic generation imaging, two-photon fluorescence microscopy, and spectrofluorimetry, we found that hypericin, a natural pigment, induces photosensitized destruction of collagen fibers but does not affect elastic fibers and lipids in chicken tendon, skin, and blood vessels. We demonstrated the dynamics and efficiency of collagen photomodification and investigated mechanisms of this processes. Our results suggest that hypericin-mediated photoprocesses in biological tissues may be useful in biomedical applications that require selective modification of connective tissues.

  9. [Progress of Autoantibody Examinations for Connective Tissue Diseases].

    PubMed

    Akashi, Kengo; Saegusa, Jun; Morinobu, Akio

    2015-05-01

    Connective tissue diseases are chronic inflammatory diseases that can affect multiple organs and, thus, have a broad spectrum of clinical presentations. Various autoantibodies are detected in patients with connective tissue diseases, represented by anti-nuclear antibody for systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), Sjögren's syndrome, and mixed connective tissue disease. Assessment of the autoantibody profile is fundamental for the clinical management of patients with connective tissue diseases, providing important data for the diagnosis, clinical characterization, and disease activity evaluation. Anti-ribosomal P antibody and anti-NMDA receptor antibody are associated with neuropsychiatric SLE. Anti-synthetase syndrome comprises the association of myositis (PM/DM), interstitial lung disease, fever, Raynaud's phenomenon, mechanic's hands, and anti-aminoacyl tRNA synthetase antibodies. Anti-MDA5 antibody is detected in patients with clinically amyopathic DM, often complicated by rapidly progressive interstitial lung disease. Between 50 and 75% of malignancy-associated DM patients are positive for anti-TIF1-γ antibody. Anti-RNA polymerase III antibody is associated with diffuse cutaneous SSc and renal crisis. This review focuses on the importance and usefulness of these autoantibodies for the diagnosis and management of patients with connective tissue diseases in clinical practice. PMID:26524895

  10. Connective tissue fibroblasts and Tcf4 regulate myogenesis

    PubMed Central

    Mathew, Sam J.; Hansen, Jody M.; Merrell, Allyson J.; Murphy, Malea M.; Lawson, Jennifer A.; Hutcheson, David A.; Hansen, Mark S.; Angus-Hill, Melinda; Kardon, Gabrielle

    2011-01-01

    Muscle and its connective tissue are intimately linked in the embryo and in the adult, suggesting that interactions between these tissues are crucial for their development. However, the study of muscle connective tissue has been hindered by the lack of molecular markers and genetic reagents to label connective tissue fibroblasts. Here, we show that the transcription factor Tcf4 (transcription factor 7-like 2; Tcf7l2) is strongly expressed in connective tissue fibroblasts and that Tcf4GFPCre mice allow genetic manipulation of these fibroblasts. Using this new reagent, we find that connective tissue fibroblasts critically regulate two aspects of myogenesis: muscle fiber type development and maturation. Fibroblasts promote (via Tcf4-dependent signals) slow myogenesis by stimulating the expression of slow myosin heavy chain. Also, fibroblasts promote the switch from fetal to adult muscle by repressing (via Tcf4-dependent signals) the expression of developmental embryonic myosin and promoting (via a Tcf4-independent mechanism) the formation of large multinucleate myofibers. In addition, our analysis of Tcf4 function unexpectedly reveals a novel mechanism of intrinsic regulation of muscle fiber type development. Unlike other intrinsic regulators of fiber type, low levels of Tcf4 in myogenic cells promote both slow and fast myogenesis, thereby promoting overall maturation of muscle fiber type. Thus, we have identified novel extrinsic and intrinsic mechanisms regulating myogenesis. Most significantly, our data demonstrate for the first time that connective tissue is important not only for adult muscle structure and function, but is a vital component of the niche within which muscle progenitors reside and is a critical regulator of myogenesis. PMID:21177349

  11. Tissue Engineering Using Transfected Growth-Factor Genes

    NASA Technical Reports Server (NTRS)

    Madry, Henning; Langer, Robert S.; Freed, Lisa E.; Trippel, Stephen; Vunjak-Novakovic, Gordana

    2005-01-01

    A method of growing bioengineered tissues includes, as a major component, the use of mammalian cells that have been transfected with genes for secretion of regulator and growth-factor substances. In a typical application, one either seeds the cells onto an artificial matrix made of a synthetic or natural biocompatible material, or else one cultures the cells until they secrete a desired amount of an extracellular matrix. If such a bioengineered tissue construct is to be used for surgical replacement of injured tissue, then the cells should preferably be the patient s own cells or, if not, at least cells matched to the patient s cells according to a human-leucocyteantigen (HLA) test. The bioengineered tissue construct is typically implanted in the patient's injured natural tissue, wherein the growth-factor genes enhance metabolic functions that promote the in vitro development of functional tissue constructs and their integration with native tissues. If the matrix is biodegradable, then one of the results of metabolism could be absorption of the matrix and replacement of the matrix with tissue formed at least partly by the transfected cells. The method was developed for articular chondrocytes but can (at least in principle) be extended to a variety of cell types and biocompatible matrix materials, including ones that have been exploited in prior tissue-engineering methods. Examples of cell types include chondrocytes, hepatocytes, islet cells, nerve cells, muscle cells, other organ cells, bone- and cartilage-forming cells, epithelial and endothelial cells, connective- tissue stem cells, mesodermal stem cells, and cells of the liver and the pancreas. Cells can be obtained from cell-line cultures, biopsies, and tissue banks. Genes, molecules, or nucleic acids that secrete factors that influence the growth of cells, the production of extracellular matrix material, and other cell functions can be inserted in cells by any of a variety of standard transfection techniques.

  12. Growth Hormone and Craniofacial Tissues. An update

    PubMed Central

    Litsas, George

    2015-01-01

    Growth hormone is an important regulator of bone homeostasis. In childhood, it determines the longitudinal bone growth, skeletal maturation, and acquisition of bone mass. In adulthood, it is necessary to maintain bone mass throughout life. Although an association between craniofacial and somatic development has been clearly established, craniofacial growth involves complex interactions of genes, hormones and environment. Moreover, as an anabolic hormone seems to have an important role in the regulation of bone remodeling, muscle enhancement and tooth development. In this paper the influence of growth hormone on oral tissues is reviewed. PMID:25674165

  13. Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes.

    PubMed

    Charrier, Alyssa; Chen, Ruju; Chen, Li; Kemper, Sherri; Hattori, Takako; Takigawa, Masaharu; Brigstock, David R

    2014-06-01

    Pancreatitis is an inflammatory condition of the pancreas which, in its chronic form, involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer, and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). In response to noxious agents such as alcohol-excessive consumption of which is a major cause of pancreatitis in the West-normally quiescent PSC undergo a phenotypic and functional transition to activated myofibroblasts which produce and deposit collagen at high levels. This process is regulated by connective tissue growth factor (CCN2), expression of which is highly up-regulated in activated PSC. We show that CCN2 production by activated PSC is associated with enhanced expression of microRNA-21 (miR-21) which was detected at high levels in activated PSC in a murine model of alcoholic chronic pancreatitis. A positive feedback loop between CCN2 and miR-21 was identified that resulted in enhancement of their respective expression as well as that of collagen α1(I). Both miR-21 and CCN2 mRNA were present in PSC-derived exosomes, which were characterized as 50-150 nm CD9-positive nano-vesicles. Exosomes from CCN2-GFP- or miR-21-GFP-transfected PSC were taken up by other PSC cultures, as shown by direct fluorescence or qRT-PCR for GFP. Collectively these studies establish miR-21 and CCN2 as participants in a positive feedback loop during PSC activation and as components of the molecular payload in PSC-derived exosomes that can be delivered to other PSC. Thus interactions between cellular or exosomal miR-21 and CCN2 represent novel aspects of fibrogenic regulation in PSC. Summary Chronic injury in the pancreas is associated with fibrotic pathology which is driven in large part by CCN2-dependent collagen production in pancreatic stellate cells. This study shows that CCN2 up-regulation in PSC is associated with increased expression of miR-21 which, in turn, is able to

  14. Connective tissue anomalies in patients with spontaneous cervical artery dissection

    PubMed Central

    Giossi, Alessia; Ritelli, Marco; Costa, Paolo; Morotti, Andrea; Poli, Loris; Del Zotto, Elisabetta; Volonghi, Irene; Chiarelli, Nicola; Gamba, Massimo; Bovi, Paolo; Tomelleri, Giampaolo; Carletti, Monica; Checcarelli, Nicoletta; Meneghetti, Giorgio; Morra, Michele; Chinaglia, Mauro; De Giuli, Valeria; Colombi, Marina; Padovani, Alessandro

    2014-01-01

    Objective: To investigate the prevalence of connective tissue abnormalities in patients with spontaneous cervical artery dissections (sCeAD). Methods: We systematically assessed clinically detectable signs of connective tissue aberration in a series of consecutive patients with sCeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) by a standard examination protocol including 68 items, and performed extensive molecular investigation for hereditary connective tissue disorders in all patients with sCeAD. Results: The study group included 84 patients with sCeAD (mean age, 44.5 ± 7.8 years; 66.7% men) and 84 patients with non-CeAD IS. None of the patients with sCeAD met clinical or molecular diagnostic criteria for established hereditary connective tissue disorder. Connective tissue abnormalities were detected more frequently in the group of patients with sCeAD than in the group of those with non-CeAD IS (mean number of pathologic findings, 4.5 ± 3.5 vs 1.9 ± 2.3; p < 0.001). Eighty-one patients (96.4%) in the sCeAD group had at least one detectable sign compared with 55 patients (66.7%) in the group with non-CeAD IS (p < 0.001). Skeletal, ocular, and skin abnormalities, as well as craniofacial dysmorphisms, were the clinical signs more strongly associated with sCeAD. Signs suggesting connective tissue abnormality were also more frequently represented in patients with sCeAD than in patients with traumatic CeAD (28.6%, p < 0.001; mean number of pathologic findings, 1.7 ± 3.7, p = 0.045). Conclusions: Connective tissue abnormalities are frequent in patients with sCeAD. This reinforces the hypothesis that systemic aberrations of the connective tissue might be implicated in the pathogenesis of the disease. PMID:25355826

  15. Histopathology of lung disease in the connective tissue diseases.

    PubMed

    Vivero, Marina; Padera, Robert F

    2015-05-01

    The pathologic correlates of interstitial lung disease (ILD) secondary to connective tissue disease (CTD) comprise a diverse group of histologic patterns. Lung biopsies in patients with CTD-associated ILD tend to demonstrate simultaneous involvement of multiple anatomic compartments of the lung. Certain histologic patterns tend to predominate in each defined CTD, and it is possible in many cases to confirm connective tissue-associated lung disease and guide patient management using surgical lung biopsy. This article will cover the pulmonary pathologies seen in rheumatoid arthritis, systemic sclerosis, myositis, systemic lupus erythematosus, Sjögren syndrome, and mixed CTD. PMID:25836637

  16. Connective tissue disease-associated pulmonary arterial hypertension.

    PubMed

    Sung, Yon K; Chung, Lorinda

    2015-05-01

    Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival. PMID:25836644

  17. The C-Terminal Module IV of Connective Tissue Growth Factor, Through EGFR/Nox1 Signaling, Activates the NF-κB Pathway and Proinflammatory Factors in Vascular Smooth Muscle Cells

    PubMed Central

    Rodrigues-Diez, Raúl R.; Orejudo, Macarena; Rodrigues-Diez, Raquel; Briones, Ana Maria; Bosch-Panadero, Enrique; Kery, Gyorgy; Pato, Janos; Ortiz, Alberto; Salaices, Mercedes; Egido, Jesus; Ruiz-Ortega, Marta

    2015-01-01

    Abstract Aims: Connective tissue growth factor (CTGF/CCN2) is a developmental gene upregulated in pathological conditions, including cardiovascular diseases, whose product is a matricellular protein that can be degraded to biologically active fragments. Among them, the C-terminal module IV [CCN2(IV)] regulates many cellular functions, but there are no data about redox process. Therefore, we investigated whether CCN2(IV) through redox signaling regulates vascular responses. Results: CCN2(IV) increased superoxide anion (O2•−) production in murine aorta (ex vivo and in vivo) and in cultured vascular smooth muscle cells (VSMCs). In isolated murine aorta, CCN2(IV), via O2•−, increased phenylephrine-induced vascular contraction. CCN2(IV) in vivo regulated several redox-related processes in mice aorta, including increased nonphagocytic NAD(P)H oxidases (Nox)1 activity, protein nitrosylation, endothelial dysfunction, and activation of the nuclear factor-κB (NF-κB) pathway and its related proinflammatory factors. The role of Nox1 in CCN2(IV)-mediated vascular responses in vivo was investigated by gene silencing. The administration of a Nox1 morpholino diminished aortic O2•− production, endothelial dysfunction, NF-κB activation, and overexpression of proinflammatory genes in CCN2(IV)-injected mice. The link CCN2(IV)/Nox1/NF-κB/inflammation was confirmed in cultured VSMCs. Epidermal growth factor receptor (EGFR) is a known CCN2 receptor. In VSMCs, CCN2(IV) activates EGFR signaling. Moreover, EGFR kinase inhibition blocked vascular responses in CCN2(IV)-injected mice. Innovation and Conclusion: CCN2(IV) is a novel prooxidant factor that in VSMCs induces O2•− production via EGFR/Nox1 activation. Our in vivo data demonstrate that CCN2(IV) through EGFR/Nox1 signaling pathway induces endothelial dysfunction and activation of the NF-κB inflammatory pathway. Therefore, CCN2(IV) could be considered a potential therapeutic target for redox-related cardiovascular

  18. [Connective tissue: big unifying element of the organism].

    PubMed

    Kapandji, A-I

    2012-10-01

    The anatomical unity of the organism is realized by the connective tissue, which assumes five functions: the filling of the spaces between organs; the connexion between these organs; the driving of the vascular and nervous pedicles to these organs; the stocking of nutritive reserves in fat pads; an aesthetic role with hollows and bumps erasing. The space filling is done with jointed polyedric volumes, which are constituted, according to the theories of J.-C. Guimberteau, with microvacuoles, filled with under pressure fundamental substance. This is a status of preconstraint resulting in a form memory. So, the connective tissue under constraint get back its initial status after this constraint is over, according to the laws of a new science, the tensegrity. The explorations of the connective tissue with a 25× magnifying micro endoscopes are showing micro fibrillar structures, evoluting under constraint. Its arrangement, that seems chaotic, is in fractal disposition, in reality, and follows the "universal parcimony law" established by Williams of Ockham. The structure of the connective tissue can be integrated in a holistic conception of the organism. Many characteristics of this tissue have still to be discovered. PMID:22884219

  19. The role of intramuscular connective tissue in meat texture.

    PubMed

    Nishimura, Takanori

    2010-02-01

    The structure, composition and amount of intramuscular connective tissue (IMCT) vary tremendously between muscles, species and breeds, and certainly contribute to meat texture. With animal growth, collagen crosslinks become more stable, and the structural integrity of IMCT increases. These changes increase the mechanical properties of IMCT, contributing to the toughening of meat. Intramuscular fat deposits, mainly in the perimysium between muscle fiber bundles, result in marbling. This causes the remodeling of IMCT structures and reduces the mechanical strength of IMCT, contributing to the tenderization of beef. The IMCT has been thought to be rather immutable compared to myofibrils during postmortem ageing of meat. However, recent studies have shown the disintegration of IMCT during postmortem ageing of meat and its relationship to tenderization of raw meat, although its contribution to cooked meat is still controversial. Given the large influence of IMCT on meat texture, further elucidations of molecular mechanisms which change the structural integrity of IMCT during chronological ageing of animals and postmortem ageing of meat are needed. PMID:20163668

  20. Alveolar ridge augmentation by connective tissue grafting using a pouch method and modified connective tissue technique: A prospective study

    PubMed Central

    Agarwal, Ashish; Gupta, Narinder Dev

    2015-01-01

    Background: Localized alveolar ridge defect may create physiological and pathological problems. Developments in surgical techniques have made it simpler to change the configuration of a ridge to create a more aesthetic and more easily cleansable shape. The purpose of this study was to compare the efficacy of alveolar ridge augmentation using a subepithelial connective tissue graft in pouch and modified connective tissue graft technique. Materials and Methods: In this randomized, double blind, parallel and prospective study, 40 non-smoker individuals with 40 class III alveolar ridge defects in maxillary anterior were randomly divided in two groups. Group I received modified connective tissue graft, while group II were treated with subepithelial connective tissue graft in pouch technique. The defect size was measured in its horizontal and vertical dimension by utilizing a periodontal probe in a stone cast at base line, after 3 months, and 6 months post surgically. Analysis of variance and Bonferroni post-hoc test were used for statistical analysis. A two-tailed P < 0.05 was considered to be statistically significant. Results: Mean values in horizontal width after 6 months were 4.70 ± 0.87 mm, and 4.05 ± 0.89 mm for group I and II, respectively. Regarding vertical heights, obtained mean values were 4.75 ± 0.97 mm and 3.70 ± 0.92 mm for group I and group II, respectively. Conclusion: Within the limitations of this study, connective tissue graft proposed significantly more improvement as compare to connective tissue graft in pouch. PMID:26759591

  1. [The Marfan syndrome and related connective tissue disorders].

    PubMed

    Siepe, Matthias; Löffelbein, Florian

    2009-06-01

    The Marfan syndrome is an inherited disorder of the connective tissue which is mainly caused by a mutation in the fibrillin-1 gene. The defect in the connective tissue protein can lead to several organ dysfunctions. For the life expectancy, the cardiovascular aspect is of paramount importance. Patients with Marfan syndrome may develop aortic aneurysms and valvular heart defects. The risk of aortic aneurysms consists in the development of aortic dissection or rupture with their fatal consequences. Besides the cardiovascular manifestation, the skeletal and ocular system can also be affected. The skeletal manifestation is often characterised by long limbs, arachnodactyly, and abnormal joint flexibility along with other signs. Patients may also have dislocated lenses, ectasia of the dural sac, stretch marks, spontaneous pneumothorax, recurrent hernia, or a family history suspicious for Marfan. During the past years, other related connective tissue disorders with analogous organ manifestation have been described (e.g., Loeys-Dietz syndrome). In this article we present the basic knowledge about these connective tissue disorders, and we mention new insights in the recently explored pathophysiology of the disorder which is a possible target for future medical treatment options. Furthermore, recent new concepts for the prophylactic treatment of the aortic manifestation are explained. PMID:19554831

  2. Mechanical behavior of carpal tunnel subsynovial connective tissue under compression.

    PubMed

    Goetz, Jessica E; Baer, Thomas E

    2011-01-01

    Subsynovial connective tissue (SSCT) is a fluid-permeated loose connective tissue that occupies the majority of the space in the carpal tunnel not occupied by the digital flexor tendons or the median nerve. It is arranged in layers around these more discrete structures, presumably to assist with tendon gliding. As a result of this arrangement, the compressive behavior and the fluid permeability of this tissue may substantially affect the stresses in the median nerve resulting from contact with its neighboring tendons or with the walls of the tunnel itself. These stresses may contribute to damage of the median nerve and the development of carpal tunnel syndrome. In this study, the fluid permeability and the compressive behavior of the SSCT were investigated to better understand the mechanics of this tissue and how it may mediate mechanical insult to the median nerve. A custom experimental apparatus was built to allow simultaneous measurement of tissue compression and fluid flow. Using Darcy's law, the average SSCT fluid permeability was 8.78×10(15) m(4)/Ns. The compressive behavior of the SSCT demonstrated time dependence, with an initial modulus of 395kPa gradually decreasing to a value of 285kPa. These baseline tissue data may serve as a mechanical norm (toward which pathological tissue might be returned, therapeutically) and may serve as essential properties to include in future mechanical models of the carpal tunnel. PMID:22096431

  3. MECHANICAL BEHAVIOR OF CARPAL TUNNEL SUBSYNOVIAL CONNECTIVE TISSUE UNDER COMPRESSION

    PubMed Central

    Goetz, Jessica E; Baer, Thomas E

    2011-01-01

    Subsynovial connective tissue (SSCT) is a fluid-permeated loose connective tissue that occupies the majority of the space in the carpal tunnel not occupied by the digital flexor tendons or the median nerve. It is arranged in layers around these more discrete structures, presumably to assist with tendon gliding. As a result of this arrangement, the compressive behavior and the fluid permeability of this tissue may substantially affect the stresses in the median nerve resulting from contact with its neighboring tendons or with the walls of the tunnel itself. These stresses may contribute to damage of the median nerve and the development of carpal tunnel syndrome. In this study, the fluid permeability and the compressive behavior of the SSCT were investigated to better understand the mechanics of this tissue and how it may mediate mechanical insult to the median nerve. A custom experimental apparatus was built to allow simultaneous measurement of tissue compression and fluid flow. Using Darcy’s law, the average SSCT fluid permeability was 8.78×1015 m4/Ns. The compressive behavior of the SSCT demonstrated time dependence, with an initial modulus of 395kPa gradually decreasing to a value of 285kPa. These baseline tissue data may serve as a mechanical norm (toward which pathological tissue might be returned, therapeutically) and may serve as essential properties to include in future mechanical models of the carpal tunnel. PMID:22096431

  4. Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways

    PubMed Central

    Cheng, Yi; Lin, Chien-huang; Chen, Jing-Yun; Li, Chien-Hua; Liu, Yu-Tin; Chen, Bing-Chang

    2016-01-01

    Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time-dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF-luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF-luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c-Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in α-smooth muscle actin (α-SMA) and collagen production, which was blocked by GLI-1 siRNA and

  5. Anisotropic Tissue Motion Induced by Acupuncture Needling Along Intermuscular Connective Tissue Planes

    PubMed Central

    Fox, James R.; Gray, Weili; Koptiuch, Cathryn; Badger, Gary J.

    2014-01-01

    Abstract Objectives: Acupuncture needle manipulation causes mechanical deformation of connective tissue, which in turn results in mechanical stimulation of fibroblasts, with active changes in cell shape and autocrine purinergic signaling. We have previously shown using ultrasound elastography in humans that acupuncture needle manipulation causes measurable movement of tissue up to several centimeters away from the needle. The goal of this study was to quantify the spatial pattern of tissue displacement and deformation (shear strain) in response to acupuncture needling along an intermuscular connective tissue plane compared with needling over the belly of a muscle. Design: Eleven (11) healthy human subjects underwent a single testing session during which robotic acupuncture needling was performed while recording tissue displacement using ultrasound. Outcome measures were axial and lateral tissue displacement as well as lateral shear strain calculated using ultrasound elastography postprocessing. Results: Tissue displacement and strain extended further in the longitudinal direction when needling between muscles, and in the transverse direction when needling over the belly of a muscle. Conclusions: The anisotropic tissue motion observed in this study may influence the spatial distribution of local connective tissue cellular responses following acupuncture needle manipulation. PMID:24593827

  6. Systemic connective tissue features in women with fibromuscular dysplasia.

    PubMed

    O'Connor, Sarah; Kim, Esther Sh; Brinza, Ellen; Moran, Rocio; Fendrikova-Mahlay, Natalia; Wolski, Kathy; Gornik, Heather L

    2015-10-01

    Fibromuscular dysplasia (FMD) is a non-atherosclerotic disease associated with hypertension, headache, dissection, stroke, and aneurysm. The etiology is unknown but hypothesized to involve genetic and environmental components. Previous studies suggest a possible overlap of FMD with other connective tissue diseases that present with dissections and aneurysms. The aim of this study was to investigate the prevalence of connective tissue physical features in FMD. A total of 142 FMD patients were consecutively enrolled at a single referral center (97.9% female, 92.1% of whom had multifocal FMD). Data are reported for 139 female patients. Moderately severe myopia (29.1%), high palate (33.1%), dental crowding (29.7%), and early-onset arthritis (15.6%) were prevalent features. Classic connective features such as hypertelorism, cleft palate, and hypermobility were uncommon. The frequency of systemic connective tissue features was compared between FMD patients with a high vascular risk profile (having had ⩾1 dissection and/or ⩾2 aneurysms) and those with a standard vascular risk profile. A history of spontaneous pneumothorax (5.9% high risk vs 0% standard risk) and atrophic scarring (17.6% high risk vs 6.8% standard risk) were significantly more prevalent in the high risk group, p<0.05. High palate was observed in 43.1% of the high risk group versus 27.3% in the standard risk group, p=0.055. In conclusion, in a cohort of women with FMD, there was a prevalence of moderately severe myopia, high palate, dental crowding, and early-onset osteoarthritis. However, a characteristic phenotype was not discovered. Several connective tissue features such as high palate and pneumothorax were more prominent among FMD patients with a high vascular risk profile. PMID:26156071

  7. [Basement membranes as the regulatory system between epithelial cell connections and connective tissue].

    PubMed

    Heine, H

    1986-01-01

    Basement membranes develop by an interaction between epithelium and underlying mesenchymal. Basement membranes are to an great extend involved in the metabolic induced informational exchange between these 2 compartments. Informational selectivity is not only given with the construction of basement membranes. By redox systems like ascorbic acid/dehydroascorbic acid, preferentially located in basement membranes, the capability exists of scavenging free oxygen radicals on the border line between epithelia and connective tissue. This seems to be a very important factor in coupling the biorhythms between epithelia and connective tissue. PMID:3743995

  8. Clinical Evaluation of Papilla Reconstruction Using Subepithelial Connective Tissue Graft

    PubMed Central

    Kaushik, Alka; PK, Pal; Chopra, Deepak; Chaurasia, Vishwajit Rampratap; Masamatti, Vinaykumar S; DK, Suresh; Babaji, Prashant

    2014-01-01

    Objective: The aesthetics of the patient can be improved by surgical reconstruction of interdental papilla by using an advanced papillary flap interposed with subepithelial connective tissue graft. Materials and Methods: A total of fifteen sites from ten patients having black triangles/papilla recession in the maxillary anterior region were selected and subjected to presurgical evaluation. The sites were treated with interposed subepithelial connective tissue graft placed under a coronally advance flap. The integrity of the papilla was maintained by moving the whole of gingivopapillary unit coronally. The various parameters were analysed at different intervals. Results: There was a mean decrease in the papilla presence index score and distance from contact point to gingival margin, but it was statistically not significant. Also, there is increase in the width of the keratinized gingiva which was statistically highly significant. Conclusion: Advanced papillary flap with interposed sub–epithelial connective tissue graft can offer predictable results for the reconstruction of interdental papilla. If papilla loss occurs solely due to soft-tissue damage, reconstructive techniques can completely restore it; but if due to periodontal disease involving bone loss, reconstruction is generally incomplete and multiple surgical procedures may be required. PMID:25386529

  9. Smooth Muscle-Mediated Connective Tissue Remodeling in Pulmonary Hypertension

    NASA Astrophysics Data System (ADS)

    Mecham, Robert P.; Whitehouse, Loren A.; Wrenn, David S.; Parks, William C.; Griffin, Gail L.; Senior, Robert M.; Crouch, Edmond C.; Stenmark, Kurt R.; Voelkel, Norbert F.

    1987-07-01

    Abnormal accumulation of connective tissue in blood vessels contributes to alterations in vascular physiology associated with disease states such as hypertension and atherosclerosis. Elastin synthesis was studied in blood vessels from newborn calves with severe pulmonary hypertension induced by alveolar hypoxia in order to investigate the cellular stimuli that elicit changes in pulmonary arterial connective tissue production. A two- to fourfold increase in elastin production was observed in pulmonary artery tissue and medial smooth muscle cells from hypertensive calves. This stimulation of elastin production was accompanied by a corresponding increase in elastin messenger RNA consistent with regulation at the transcriptional level. Conditioned serum harvested from cultures of pulmonary artery smooth muscle cells isolated from hypertensive animals contained one or more low molecular weight elastogenic factors that stimulated the production of elastin in both fibroblasts and smooth muscle cells and altered the chemotactic responsiveness of fibroblasts to elastin peptides. These results suggest that connective tissue changes in the pulmonary vasculature in response to pulmonary hypertension are orchestrated by the medial smooth muscle cell through the generation of specific differentiation factors that alter both the secretory phenotype and responsive properties of surrounding cells.

  10. A Framework for Modelling Connective Tissue Changes in VIIP Syndrome

    NASA Technical Reports Server (NTRS)

    Ethier, C. R.; Best, L.; Gleason, R.; Mulugeta, L.; Myers, J. G.; Nelson, E. S.; Samuels, B. C.

    2014-01-01

    Insertion of astronauts into microgravity induces a cascade of physiological adaptations, notably including a cephalad fluid shift. Longer-duration flights carry an increased risk of developing Visual Impairment and Intracranial Pressure (VIIP) syndrome, a spectrum of ophthalmic changes including posterior globe flattening, choroidal folds, distension of the optic nerve sheath, kinking of the optic nerve and potentially permanent degradation of visual function. The slow onset of changes in VIIP, their chronic nature, and the similarity of certain clinical features of VIIP to ophthalmic findings in patients with raised intracranial pressure strongly suggest that: (i) biomechanical factors play a role in VIIP, and (ii) connective tissue remodeling must be accounted for if we wish to understand the pathology of VIIP. Our goal is to elucidate the pathophysiology of VIIP and suggest countermeasures based on biomechanical modeling of ocular tissues, suitably informed by experimental data, and followed by validation and verification. We specifically seek to understand the quasi-homeostatic state that evolves over weeks to months in space, during which ocular tissue remodeling occurs. This effort is informed by three bodies of work: (i) modeling of cephalad fluid shifts; (ii) modeling of ophthalmic tissue biomechanics in glaucoma; and (iii) modeling of connective tissue changes in response to biomechanical loading.

  11. Identification of Candidate Angiogenic Inhibitors Processed by Matrix Metalloproteinase 2 (MMP-2) in Cell-Based Proteomic Screens: Disruption of Vascular Endothelial Growth Factor (VEGF)/Heparin Affin Regulatory Peptide (Pleiotrophin) and VEGF/Connective Tissue Growth Factor Angiogenic Inhibitory Complexes by MMP-2 Proteolysis▿ †

    PubMed Central

    Dean, Richard A.; Butler, Georgina S.; Hamma-Kourbali, Yamina; Delbé, Jean; Brigstock, David R.; Courty, José; Overall, Christopher M.

    2007-01-01

    Matrix metalloproteinases (MMPs) exert both pro- and antiangiogenic functions by the release of cytokines or proteolytically generated angiogenic inhibitors from extracellular matrix and basement membrane remodeling. In the Mmp2−/− mouse neovascularization is greatly reduced, but the mechanistic aspects of this remain unclear. Using isotope-coded affinity tag labeling of proteins analyzed by multidimensional liquid chromatography and tandem mass spectrometry we explored proteome differences between Mmp2−/− cells and those rescued by MMP-2 transfection. Proteome signatures that are hallmarks of proteolysis revealed cleavage of many known MMP-2 substrates in the cellular context. Proteomic evidence of MMP-2 processing of novel substrates was found. Insulin-like growth factor binding protein 6, follistatin-like 1, and cystatin C protein cleavage by MMP-2 was biochemically confirmed, and the cleavage sites in heparin affin regulatory peptide (HARP; pleiotrophin) and connective tissue growth factor (CTGF) were sequenced by matrix-assisted laser desorption ionization-time of flight mass spectrometry. MMP-2 processing of HARP and CTGF released vascular endothelial growth factor (VEGF) from angiogenic inhibitory complexes. The cleaved HARP N-terminal domain increased HARP-induced cell proliferation, whereas the HARP C-terminal domain was antagonistic and decreased cell proliferation and migration. Hence the unmasking of cytokines, such as VEGF, by metalloproteinase processing of their binding proteins is a new mechanism in the control of cytokine activation and angiogenesis. PMID:17908800

  12. Connective Tissue Disease-Associated Interstitial Lung Diseases: Unresolved Issues.

    PubMed

    Aparicio, Irene Jarana; Lee, Joyce S

    2016-06-01

    Interstitial lung disease (ILD) complicating connective tissue disorders, such as scleroderma and rheumatoid arthritis, is associated with significant morbidity and mortality. Progress has been made in our understanding of these collective diseases; however, there are still many unanswered questions. In this review, we describe the current views on epidemiology, clinical presentation, treatment, and prognosis in patients with connective tissue disease (CTD)-associated ILD. We also highlight several areas that remain unresolved and in need of further investigation, including interstitial pneumonia with autoimmune features, histopathologic phenotype, and pharmacologic management. A multidisciplinary and multidimensional approach to diagnosis, management, and investigation of CTD-associated ILD patients is essential to advance our understanding of the epidemiology and pathobiology of this challenging group of diseases. PMID:27231868

  13. New perspectives on rare connective tissue calcifying diseases.

    PubMed

    Rashdan, Nabil A; Rutsch, Frank; Kempf, Hervé; Váradi, András; Lefthériotis, Georges; MacRae, Vicky E

    2016-06-01

    Connective tissue calcifying diseases (CTCs) are characterized by abnormal calcium deposition in connective tissues. CTCs are caused by multiple factors including chronic diseases (Type II diabetes mellitus, chronic kidney disease), the use of pharmaceuticals (e.g. warfarin, glucocorticoids) and inherited rare genetic diseases such as pseudoxanthoma elasticum (PXE), generalized arterial calcification in infancy (GACI) and Keutel syndrome (KTLS). This review explores our current knowledge of these rare inherited CTCs, and highlights the most promising avenues for pharmaceutical intervention. Advancing our understanding of rare inherited forms of CTC is not only essential for the development of therapeutic strategies for patients suffering from these diseases, but also fundamental to delineating the mechanisms underpinning acquired chronic forms of CTC. PMID:26930168

  14. Connective tissue disease-related pulmonary arterial hypertension.

    PubMed

    Thakkar, Vivek; Lau, Edmund M T

    2016-02-01

    Over the past two decades, there have been several advances in the assessment and management of connective tissue disease-related pulmonary arterial hypertension (CTD-PAH) that improved outcomes of the treatment of this lethal disease, and this will be the focus of this study. Systemic sclerosis is the leading cause of CTD-PAH, followed by systemic lupus erythematosus, mixed connective tissue disease, idiopathic inflammatory myositis, rheumatoid arthritis, and Sjogren's syndrome. Clinical registries have been invaluable in informing about the burden of disease, risk and prognostic factors, and temporal trends with respect to treatment and outcome in CTD-PAH. The major advances have centered on improved disease classification and diagnostic criteria, screening and early diagnosis, the emergence of evidence-based therapies including combination goal-orientated treatment strategies, and the establishment of centers with expertise in PAH. PMID:27421214

  15. Pauci-Immune Crescentic Glomerulonephritis in Connective Tissue Disease

    PubMed Central

    Cronin, Mary; Robin, Adam; Lorna, Campbell; Rosenthal, Ann K.

    2016-01-01

    Pauci-immune crescentic glomerulonephritis is commonly seen in ANCA-associated vasculitis but it is rarely seen during the course of other connective tissue diseases like lupus or Sjogren's syndrome or MCTD. We report 3 cases of pauci-immune crescentic glomerulonephritis in patients with connective tissue disease other than vasculitis. We reviewed literature and made summary of previously reported cases of this rare entity. Clinical and laboratory features of these patients varied widely, but most of patients have met criteria for lupus. In this small population of patients there is no correlation with ANCAs. Most of the patients were treated with aggressive immunosuppression and did well if they were treated early in the course of their disease. One of our patients required renal transplant, but she presented late in the course of her disease, as evidenced by chronicity on her renal biopsy. Whether these patients are overlap of vasculitis and other connective tissue diseases or to be considered as a separate entity is yet to be described. Clinicians must be aware of these presentations because initial presentation can be severe. PMID:27504208

  16. [Connective tissue diseases in hospital practice in Ouagadougou (Burkina Faso)].

    PubMed

    Ouédraogo, D D; Korsaga-Somé, N; Zabsonné Tiendrébéogo, J; Tiéno, H; Kaboré, H; Niamba, P; Drabo, J

    2014-01-01

    To describe the semiological and immunological features of connective tissue diseases seen at the Yalgado Ouédraogo University Hospital in Ouagadougou. A retrospective study reviewed the records of patients seen in the hospital dermatology and internal medicine departments from January 1, 2004, through December 31, 2009 and diagnosed with systemic lupus erythematosus (SLE), systemic sclerosis (ScS), dermatopolymyositis (DPM), primary Gougerot-Sjögren disease (GS), polymyositis (PM) or indeterminate connective tissue disease (ICTD) meeting the criteria of the American College of Rheumatology. The study included 42 patients, 36 women and 6 men. Their mean age was 41.2 years ±11.97 (range: 15-75). SLE was the diagnosis for 10 patients, ScS for 14, DPM for 7, primary GS for 1, PM for 1, and ICTD for 9. Hematologic (93%), cutaneous (88%), and rheumatologic (81%) abnormalities were the most frequent manifestations. The specific auto-antibodies associated with SLE patients were: anti-native DNA (3/6), anti-Sm (3/6), anti-RNP (3/6), and anti-SSA (4/6); anti-Scl 70 antibodies were present in 5 patients with ScS. Connective tissue diseases seem to be rare in Africa, south of the Sahara. However, the very fragmentary studies and the weak healthcare coverage do not allow any definitive conclusions. PMID:24921183

  17. Pauci-Immune Crescentic Glomerulonephritis in Connective Tissue Disease.

    PubMed

    Yeturi, Supraja; Cronin, Mary; Robin, Adam; Lorna, Campbell; Rosenthal, Ann K

    2016-01-01

    Pauci-immune crescentic glomerulonephritis is commonly seen in ANCA-associated vasculitis but it is rarely seen during the course of other connective tissue diseases like lupus or Sjogren's syndrome or MCTD. We report 3 cases of pauci-immune crescentic glomerulonephritis in patients with connective tissue disease other than vasculitis. We reviewed literature and made summary of previously reported cases of this rare entity. Clinical and laboratory features of these patients varied widely, but most of patients have met criteria for lupus. In this small population of patients there is no correlation with ANCAs. Most of the patients were treated with aggressive immunosuppression and did well if they were treated early in the course of their disease. One of our patients required renal transplant, but she presented late in the course of her disease, as evidenced by chronicity on her renal biopsy. Whether these patients are overlap of vasculitis and other connective tissue diseases or to be considered as a separate entity is yet to be described. Clinicians must be aware of these presentations because initial presentation can be severe. PMID:27504208

  18. [Wounds in autoimmune bullous dermatoses and systemic connective tissue diseases].

    PubMed

    Marinović, Branka; Jukić, Ines Lakos; Lipozencić, Jasna

    2012-10-01

    Autoimmune bullous dermatoses are a group of skin and/or mucous membrane diseases characterized by blisters and erosions, which are the results of autoantibodies directed to structural components of desmosomes and structural proteins of the basement membrane zone. In this group of diseases, the diagnosis is based on history, clinical presentation, histopathologic findings, findings of direct and indirect immunofluorescence, and specific evidence of circulating antibodies by the enzyme linked immunosorbent assay (ELISA) method. Connective tissue diseases are a heterogeneous group of diseases with some common pathogenetic mechanisms and frequent involvement of the skin. This group of diseases commonly includes lupus erythematosus, dermatomyositis/polymyositis, localized and systemic scleroderma. As most of the diseases in this group have positive one of the antinuclear antibodies, in clinical practice these diseases are often called autoimmune connective tissue diseases. In the group of autoimmune bullous dermatoses, wounds occur as the result of breaking of blisters, and consequently affect the epidermis alone or epidermis and upper dermis, while in the group of systemic diseases of connective tissue, wounds occur in advanced stages of disease as a result of vascular tissue damage, causing necrosis of tissue and wounds. When wounds in these diseases last for a longer period (longer than 3 months), they are considered as chronic wounds and in these cases it is necessary to determine the reason for slow healing. In patients with wounds as a symptom of disease, besides systemic therapy, special attention should be paid to local therapy in order to prevent superinfection and accelerate epithelialization and wound healing. PMID:23193815

  19. Myocardial Tissue Doppler Velocity in Child Growth

    PubMed Central

    Choi, Sun-Ha; Kim, Nam Kyun; Jung, Jo Won; Choi, Jae Young

    2016-01-01

    Background In adults, tissue Doppler imaging (TDI) is a recommended component of routine echocardiography. However, TDI velocities are less accepted in pediatrics, due to their strong variability and age dependence in children. This study examines the distribution of myocardial tissue Doppler velocities in healthy children to assess the effect of age with cardiac growth on the various echocardiographic measurements. Methods Total 144 healthy children were enrolled in this study. They were recruited from the pediatric outpatient clinic for routine well-child visits. The statistical relationships between age and TDI values were analyzed. Also, the statistical relationships between body surface area (BSA) and TDI values, left ventricle end-diastolic dimension (LVEDD) and TDI values were analyzed. Also, we conducted multivariate analysis of cardiac growth parameters such as, age, BSA, LVEDD and TDI velocity data. Results All of the age, BSA, and LVEDD had positive correlations with deceleration time (DT), pressure half-time (PHT), peak early diastolic myocardial velocity, peak systolic myocardial velocity, and had negative correlations with peak late diastolic velocity (A) and the ratio of trans-mitral inflow velocity to early diastolic velocity of mitral annulus (E/E'). In the multivariate analysis, all of the age, BSA, and LVEDD had positive correlations with DT, PHT, and negative correlations with A and E/E'. Conclusion The cardiac growth parameters related alterations of E/E' may suggest that diastolic myocardial velocities are cardiac growth dependent, and diastolic function has positive correlation with cardiac growth in pediatric group. This cardiac growth related myocardial functional variation would be important for assessment of cardiac involvement either in healthy and sick child. PMID:27081443

  20. Mechanisms of lamellar collagen formation in connective tissues.

    PubMed

    Ghazanfari, Samaneh; Khademhosseini, Ali; Smit, Theodoor H

    2016-08-01

    The objective of tissue engineering is to regenerate functional tissues. Engineering functional tissues requires an understanding of the mechanisms that guide the formation and evolution of structure in the extracellular matrix (ECM). In particular, the three-dimensional (3D) collagen fiber arrangement is important as it is the key structural determinant that provides mechanical integrity and biological function. In this review, we survey the current knowledge on collagen organization mechanisms that can be applied to create well-structured functional lamellar tissues and in particular intervertebral disc and cornea. Thus far, the mechanisms behind the formation of cross-aligned collagen fibers in the lamellar structures is not fully understood. We start with cell-induced collagen alignment and strain-stabilization behavior mechanisms which can explain a single anisotropically aligned collagen fiber layer. These mechanisms may explain why there is anisotropy in a single layer in the first place. However, they cannot explain why a consecutive collagen layer is laid down with an alternating alignment. Therefore, we explored another mechanism, called liquid crystal phasing. While dense concentrations of collagen show such behavior, there is little evidence that the conditions for liquid crystal phasing are actually met in vivo. Instead, lysyl aldehyde-derived collagen cross-links have been found essential for correct lamellar matrix deposition. Furthermore, we suggest that supra-cellular (tissue-level) shear stress may be instrumental in the alignment of collagen fibers. Understanding the potential mechanisms behind the lamellar collagen structure in connective tissues will lead to further improvement of the regeneration strategies of functional complex lamellar tissues. PMID:27162076

  1. Ibuprofen-induced meningitis in mixed connective tissue disease.

    PubMed

    Hoffman, M; Gray, R G

    1982-06-01

    A young Black woman with mixed connective tissue disease (MCTD) developed an aseptic meningitis after receiving ibuprofen. The meningeal reaction, reported infrequently in systemic lupus erythematosus (SLE) and only once previously in MCTD, was characterized by a predominantly polymorphonuclear cerebrospinal fluid (CSF) pleocytosis and depression of CSF glucose. Reversible renal insufficiency also occurred. Features suggestive of a hypersensitivity reaction included pruritus, conjunctivitis, facial oedema, desquamation of the palms and soles, and subsequent near total alopecia. Meningeal signs responded rapidly to systemic corticosteroid therapy. Patients with MCTD as well as those with SLE may be at peculiar risk of developing this uncommon reaction to ibuprofen. PMID:6985377

  2. [Ultrasonography in chronic inflammatory rheumatic and connective tissue disorders].

    PubMed

    Mérot, O; Le Goff, B

    2014-08-01

    Musculoskeletal ultrasonography is now widely used by almost all rheumatologists thanks to an improvement in the quality of ultrasound unit and probe and to the systematic teaching of this imaging technique to the rheumatology fellows. Applications have broadened from the study of degenerative and mechanical diseases to inflammatory rheumatic diseases. Ultrasound is more sensitive than clinical examination. Power Doppler allows the direct visualisation of inflammation within the tissues. Finally, it is a prognostic tool helping the physician in the management of the disease. This review will focus on the value and applications of ultrasonography in the 2 most frequent rheumatic diseases: rheumatoid arthritis and spondyloarthritis. We will also give some recent data on the usefulness of this imaging technique in the study of musculoskeletal manifestations associated with connective tissue disease. PMID:24439720

  3. Microvascular filtration in subjects with connective tissue disorders.

    PubMed Central

    Edwards, J C; Snaith, M L

    1984-01-01

    A simple non-invasive method for studying microvascular filtration in the non-articular tissues of the forearm is described. Rates of filtration under a standard hydrostatic pressure were measured in 20 normal female subjects and 44 female subjects with connective tissue disorders. An increased mean filtration rate was found in 14 subjects with rheumatoid arthritis. In 20 subjects with systemic lupus erythematosus and 10 subjects with scleroderma no such generalised increase in filtration rates was seen, but isolated cases had very high filtration rates, suggesting a more heterogeneous physiological disturbance. Increased filtration was not associated with the presence of oedema. This confirms doubts raised by other workers about the importance of filtration in the genesis of clinical oedema. Images PMID:6476914

  4. Connective tissue photodamage in the hairless mouse is partially reversible

    SciTech Connect

    Kligman, L.H.

    1987-03-01

    Photodamaged connective tissue in animal and human skin is characterized by excessive accumulations of elastic fibers, loss of mature collagen, concomitant overproduction of new collagen, and greatly increased levels of glycosaminoglycans. Formerly considered irreversible changes, we recently showed in hairless mice, post irradiation, that a band of normal connective tissue was laid down subepidermally. The present studies focused on 2 aspects of this repair: whether repair would occur if animals were protected by sunscreens after dermal damage was induced and irradiation continued; whether retinoic acid could enhance the repair process. To examine the first aspect, albino hairless mice were irradiated with Westinghouse FS 20 sunlamps thrice weekly for 30 weeks. Sunscreens of high sun-protection factors were applied after 10 and 20 weeks. Not only was further damage prevented, but the damage incurred before sunscreen application was repaired. This appeared as subepidermal reconstruction zones containing normal, mature collagen and a network of fine elastic fibers. The second aspect was examined by applying 0.05% retinoic acid, topically, to animals preirradiated for 10 weeks. In contrast to controls treated with vehicle, the reconstruction zone was significantly wider in retinoic acid-treated mice. The enhanced repair was dose-related.

  5. Connective tissue disease-associated pulmonary arterial hypertension

    PubMed Central

    Howard, Luke S.

    2015-01-01

    Although rare in its idiopathic form, pulmonary arterial hypertension (PAH) is not uncommon in association with various associated medical conditions, most notably connective tissue disease (CTD). In particular, it develops in approximately 10% of patients with systemic sclerosis and so these patients are increasingly screened to enable early detection. The response of patients with systemic sclerosis to PAH-specific therapy appears to be worse than in other forms of PAH. Survival in systemic sclerosis-associated PAH is inferior to that observed in idiopathic PAH. Potential reasons for this include differences in age, the nature of the underlying pulmonary vasculopathy and the ability of the right ventricle to cope with increased afterload between patients with systemic sclerosis-associated PAH and idiopathic PAH, while coexisting cardiac and pulmonary disease is common in systemic sclerosis-associated PAH. Other forms of connective tissue-associated PAH have been less well studied, however PAH associated with systemic lupus erythematosus (SLE) has a better prognosis than systemic sclerosis-associated PAH and likely responds to immunosuppression. PMID:25705389

  6. Cell-based and biomaterial approaches to connective tissue repair

    NASA Astrophysics Data System (ADS)

    Stalling, Simone Suzette

    Connective tissue injuries of skin, tendon and ligament, heal by a reparative process in adults, filling the wound site with fibrotic, disorganized scar tissue that poorly reflects normal tissue architecture or function. Conversely, fetal skin and tendon have been shown to heal scarlessly. Complete regeneration is not intrinsically ubiquitous to all fetal tissues; fetal diaphragmatic and gastrointestinal injuries form scars. In vivo studies suggest that the presence of fetal fibroblasts is essential for scarless healing. In the orthopaedic setting, adult anterior cruciate ligament (ACL) heals poorly; however, little is known about the regenerative capacity of fetal ACL or fetal ACL fibroblasts. We characterized in vitro wound healing properties of fetal and adult ACL fibroblasts demonstrating that fetal ACL fibroblasts migrate faster and elaborate greater quantities of type I collagen, suggesting the healing potential of the fetal ACL may not be intrinsically poor. Similar to fetal ACL fibroblasts, fetal dermal fibroblasts also exhibit robust cellular properties. We investigated the age-dependent effects of dermal fibroblasts on tendon-to-bone healing in rat supraspinatus tendon injuries, a reparative injury model. We hypothesized delivery of fetal dermal fibroblasts would increase tissue organization and mechanical properties in comparison to adult dermal fibroblasts. However, at 1 and 8 weeks, the presence of dermal fibroblasts, either adult or fetal, had no significant effect on tissue histology or mechanical properties. There was a decreasing trend in cross-sectional area of repaired tendons treated with fetal dermal fibroblasts in comparison to adult, but this finding was not significant in comparison to controls. Finally, we synthesized a novel polysaccharide, methacrylated methylcellulose (MA-MC), and fabricated hydrogels using a well-established photopolymerization technique. We characterized the physical and mechanical properties of MA-MC hydrogels in

  7. Effects of microgravity on rat bone, cartlage and connective tissues

    NASA Technical Reports Server (NTRS)

    Doty, S.

    1990-01-01

    The response to hypogravity by the skeletal system was originally thought to be the result of a reduction in weight bearing. Thus a reduced rate of new bone formation in the weight-bearing bones was accepted, when found, as an obvious result of hypogravity. However, data on non-weight-bearing tissues have begun to show that other physiological changes can be expected to occur to animals during spaceflight. This overview of the Cosmos 1887 data discusses these results as they pertain to individual bones or tissues because the response seems to depend on the architecture and metabolism of each tissue under study. Various effects were seen in different tissues from the rats flown on Cosmos 1887. The femur showed a reduced bone mineral content but only in the central region of the diaphysis. This same region in the tibia showed changes in the vascularity of bone as well as some osteocytic cell death. The humerus demonstrated reduced morphometric characteristics plus a decrease in mechanical stiffness. Bone mineral crystals did not mature normally as a result of flight, suggesting a defect in the matrix mineralization process. Note that these changes relate directly to the matrix portion of the bone or some function of bone which slowly responds to changes in the environment. However, most cellular functions of bone are rapid responders. The stimulation of osteoblast precursor cells, the osteoblast function in collagen synthesis, a change in the proliferation rate of cells in the epiphyseal growth plate, the synthesis and secretion of osteocalcin, and the movement of water into or out of tissues, are all processes which respond to environmental change. These rapidly responding events produced results from Cosmos 1887 which were frequently quite different from previous space flight data.

  8. [Microflora in patients with systemic connective tissue diseases].

    PubMed

    Romanov, V A; Shilkina, N P; Gul'neva, M Iu; Ivanov, D V

    2008-01-01

    The study of microflora of skin, mucous tunic of nose and mouth, and the quantitative and qualitative structure of the intestinal and urinal microflora in cases of systemic connective tissues diseases, are reproduced. The decrease of the dominant state of typical representatives, and the increase of the role of pseudopathogenic bacteria in various biotypes, were observed. The frequency of S. aureus detection increased in skin, mucous tunic of nose and mouth. Pseudopathogenic microbes acquired greater significance in the forming of microbiocenosis of intestine, while the number of E. coli, Bifidobacterium and Lactobacterium decreased. The frequency of detection of microbes in urine decreased. The comparative analyses of the microflora in patients with systemic lupus erythromatosis and progressive systemic sclerosis demonstrated the common peculiarities for microflora character change. PMID:18488449

  9. Cutaneous Connective Tissue Diseases: Epidemiology, Diagnosis, and Treatment

    PubMed Central

    Reddy, Bobby Y.; Hantash, Basil M.

    2010-01-01

    Connective tissue diseases (CTDs) are a group of clinical disorders that have an underlying autoimmune pathogenesis. These include a diverse set of diseases such as relapsing polychondritis, rheumatoid arthritis, and eosinophilic fasciitis, along with more common entities like Sjogren’s syndrome, dermatomyositis, scleroderma, and lupus erythematosus. The latter three will be the focus of this review, as they constitute the most significant and common CTD with cutaneous manifestations. The cutaneous signs often represent the preliminary stages of disease and the presenting clinical symptoms. Therefore, comprehensive knowledge of CTD manifestations is essential for accurate diagnosis, better assessment of prognosis, and effective management. Although the precise etiologies of CTDs remain obscure, recent advances have allowed for further understanding of their pathogenesis and improved disease classifications. In addition, there have been developments in therapeutic options for CTDs. This review provides an overview of the epidemiology, clinical presentations, and current treatment options of cutaneous lupus erythematous, dermatomyositis and scleroderma. PMID:21218179

  10. Connective tissue adaptations in the fingers of performance sport climbers.

    PubMed

    Schreiber, Tonja; Allenspach, Philippe; Seifert, Burkhardt; Schweizer, Andreas

    2015-01-01

    This study investigates the changes of the connective tissue in the fingers of performance sport climbers resulting after a minimum of 15 years of climbing. Evaluation was performed by ultrasonography on the palmar side of the fingers (Dig) II-V to measure the thickness of the A2 and A4 annular pulleys, the flexor digitorum superficialis (FDS) and profundus (FDP) tendons and the palmar plates (PP's) of the proximal interphalangeal (PIP) as well as distal interphalangeal (DIP) joint in sagittal and axial direction. Totally, 31 experienced male sport climbers (mean age 37y, 30-48y grade French scale median 8b, range 7b+ to 9a+) participated in the study. The control-group consisted of 20 male non-climbers (age 37y, 30-51y). The A2 and A4 pulleys in climbers were all significantly thicker (A2 Dig III 62%, Dig IV 69%; A4 Dig III 69%, Dig IV 76%) as compared to non-climbers pulleys. All PP's of the DIP joints were also significantly thicker, particularly at Dig III and IV (76 and 67%), whereas the PP's at PIP joints were only scarce significant for three joints. Differences of the diameter of the flexor tendons were less distinct (1-21%) being significant only over the middle phalanx. High load to the fingers of rock climbers after a minimum of 15 years of climbing years induced considerable connective tissue adaptions in the fingers, most distinct at the flexor tendon pulleys and joint capsule (PP) of the DIP joints and well detectable by ultrasound. PMID:26267120

  11. Management of interstitial lung disease associated with connective tissue disease.

    PubMed

    Mathai, Stephen C; Danoff, Sonye K

    2016-01-01

    The lung is a common site of complications of systemic connective tissue disease (CTD), and lung involvement can present in several ways. Interstitial lung disease (ILD) and pulmonary hypertension are the most common lung manifestations in CTD. Although it is generally thought that interstitial lung disease develops later on in CTD it is often the initial presentation ("lung dominant" CTD). ILD can be present in most types of CTD, including rheumatoid arthritis, scleroderma, systemic lupus erythematosus, polymyositis or dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease. Despite similarities in clinical and pathologic presentation, the prognosis and treatment of CTD associated ILD (CTD-ILD) can differ greatly from that of other forms of ILD, such as idiopathic pulmonary fibrosis. Pulmonary hypertension (PH) can present as a primary vasculopathy in pulmonary arterial hypertension or in association with ILD (PH-ILD). Therefore, detailed history, physical examination, targeted serologic testing, and, occasionally, lung biopsy are needed to diagnose CTD-ILD, whereas both non-invasive and invasive assessments of pulmonary hemodynamics are needed to diagnose pulmonary hypertension. Immunosuppression is the mainstay of treatment for ILD, although data from randomized controlled trials (RCTs) to support specific treatments are lacking. Furthermore, treatment strategies vary according to the clinical situation-for example, the treatment of a patient newly diagnosed as having CTD-ILD differs from that of someone with an acute exacerbation of the disease. Immunosuppression is indicated only in select cases of pulmonary arterial hypertension related to CTD; more commonly, selective pulmonary vasodilators are used. For both diseases, comorbidities such as sleep disordered breathing, symptoms of dyspnea, and cough should be evaluated and treated. Lung transplantation should be considered in patients with advanced disease but is not always feasible because

  12. Electric utility growth: The small business connection

    SciTech Connect

    Stafford, J.R. )

    1990-08-02

    In today's competitive environment utilities must seek new strategies to insure future growth. Economic development is but one of many utility strategies being implemented today. Traditionally, most utility economic development efforts involve the recruitment of targeted industries. This recruitment strategy involves the identification of attractive industries and companies, and subsequent marketing efforts to encourage company relocation or expansion in the utility's service territory. This strategy is the most practiced by utilities, yet ironically it has been judged as relatively ineffective. The purpose of this study is to evaluate the merits of utilities refocusing their economic development efforts on a new strategy currently employed by state and local growth organizations and oriented toward business retention and expansion rather than industrial targeting and recruitment. Many utilities have retention/expansion strategies, but target them at their largest industrial customers. The focus of this article is on the value of small business retention/expansion activities and the feasibility of implementing a successful plan.

  13. The reggie/flotillin connection to growth.

    PubMed

    Stuermer, Claudia A O

    2010-01-01

    The proteins reggie-1 and reggie-2 were originally discovered in neurons during axon regeneration. Subsequently, they were independently identified as markers of lipid rafts in flotation assays and were hence named flotillins. Since then, reggie/flotillin proteins have been found to be evolutionarily conserved and are present in all vertebrate cells - yet their function has remained elusive and controversial. Recent results now show that reggie/flotillin proteins are indeed necessary for axon regeneration and growth: no axons form when reggies/flotillins are downregulated and signaling pathways controlling actin dynamics are perturbed. Their widespread expression and conservation, however, suggest that these proteins regulate basic cellular functions beyond regeneration. It is argued here that the reggie/flotillin proteins regulate processes vital to all cells - the targeted delivery of bulk membrane and specific membrane proteins from internal vesicle pools to strategically important sites including cell contact sites, the T cell cap, regenerating axons and growth cones and other protrusions. PMID:19896850

  14. Stress-dependent finite growth in soft elastic tissues.

    PubMed

    Rodriguez, E K; Hoger, A; McCulloch, A D

    1994-04-01

    Growth and remodeling in tissues may be modulated by mechanical factors such as stress. For example, in cardiac hypertrophy, alterations in wall stress arising from changes in mechanical loading lead to cardiac growth and remodeling. A general continuum formulation for finite volumetric growth in soft elastic tissues is therefore proposed. The shape change of an unloaded tissue during growth is described by a mapping analogous to the deformation gradient tensor. This mapping is decomposed into a transformation of the local zero-stress reference state and an accompanying elastic deformation that ensures the compatibility of the total growth deformation. Residual stress arises from this elastic deformation. Hence, a complete kinematic formulation for growth in general requires a knowledge of the constitutive law for stress in the tissue. Since growth may in turn be affected by stress in the tissue, a general form for the stress-dependent growth law is proposed as a relation between the symmetric growth-rate tensor and the stress tensor. With a thick-walled hollow cylinder of incompressible, isotropic hyperelastic material as an example, the mechanics of left ventricular hypertrophy are investigated. The results show that transmurally uniform pure circumferential growth, which may be similar to eccentric ventricular hypertrophy, changes the state of residual stress in the heart wall. A model of axially loaded bone is used to test a simple stress-dependent growth law in which growth rate depends on the difference between the stress due to loading and a predetermined growth equilibrium stress. PMID:8188726

  15. Biomarkers in connective tissue disease-associated interstitial lung disease.

    PubMed

    Bonella, Francesco; Costabel, Ulrich

    2014-04-01

    This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies. PMID:24668534

  16. The diagnosis and classification of mixed connective tissue disease.

    PubMed

    Tani, Chiara; Carli, Linda; Vagnani, Sabrina; Talarico, Rosaria; Baldini, Chiara; Mosca, Marta; Bombardieri, Stefano

    2014-01-01

    The term "mixed connective tissue disease" (MCTD) concerns a systemic autoimmune disease typified by overlapping features between two or more systemic autoimmune diseases and the presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP). Since the first description of this condition in 1972, the understanding of clinical manifestations and long-term outcome of MCTD have significantly advanced. Polyarthritis, Raynaud's phenomenon, puffy fingers, lung involvement and esophageal dysmotility are the most frequently reported symptoms among the different cohorts during the course of the disease. Moreover, in recent years a growing interest has been focused on severe organ involvement such as pulmonary arterial hypertension and interstitial lung disease which can accrue during the long-term follow-up and can still significantly influence disease prognosis. Over the last years, significant advances have been made also in disease pathogenesis understanding and a central pathogenetic role of anti-U1RNP autoantibodies has clearly emerged. Although controversies on disease definition and classification still persist, MCTD identifies a group of patients in whom increased surveillance for specific manifestations and prognostic stratification became mandatory to improve patient's outcomes. PMID:24461387

  17. Neutrophilic Skin Lesions in Autoimmune Connective Tissue Diseases

    PubMed Central

    Hau, Estelle; Vignon Pennamen, Marie-Dominique; Battistella, Maxime; Saussine, Anne; Bergis, Maud; Cavelier-Balloy, Benedicte; Janier, Michel; Cordoliani, Florence; Bagot, Martine; Rybojad, Michel; Bouaziz, Jean-David

    2014-01-01

    Abstract The pathophysiology of neutrophilic dermatoses (NDs) and autoimmune connective tissue diseases (AICTDs) is incompletely understood. The association between NDs and AICTDs is rare; recently, however, a distinctive subset of cutaneous lupus erythematosus (LE, the prototypical AICTD) with neutrophilic histological features has been proposed to be included in the spectrum of lupus. The aim of our study was to test the validity of such a classification. We conducted a monocentric retrospective study of 7028 AICTDs patients. Among these 7028 patients, a skin biopsy was performed in 932 cases with mainly neutrophilic infiltrate on histology in 9 cases. Combining our 9 cases and an exhaustive literature review, pyoderma gangrenosum, Sweet syndrome (n = 49), Sweet-like ND (n = 13), neutrophilic urticarial dermatosis (n = 6), palisaded neutrophilic granulomatous dermatitis (n = 12), and histiocytoid neutrophilic dermatitis (n = 2) were likely to occur both in AICTDs and autoinflammatory diseases. Other NDs were specifically encountered in AICTDs: bullous LE (n = 71), amicrobial pustulosis of the folds (n = 28), autoimmunity-related ND (n = 24), ND resembling erythema gyratum repens (n = 1), and neutrophilic annular erythema (n = 1). The improvement of AICTDS neutrophilic lesions under neutrophil targeting therapy suggests possible common physiopathological pathways between NDs and AICTDs. PMID:25546688

  18. Treatment of pulmonary arterial hypertension in connective tissue disease.

    PubMed

    Grünig, Ekkehard

    2012-05-28

    Pulmonary arterial hypertension (PAH) is a group of distinct disorders that includes idiopathic PAH (IPAH), familial PAH and PAH associated with other conditions (APAH) such as connective tissue disease (CTD-APAH) or congenital heart disease. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. If left untreated, PAH can lead to right heart failure and premature death. CTD-APAH represents an important clinical subgroup of APAH that has a higher risk of death than IPAH. The European treatment guidelines advocate the use of PAH-targeted therapies including bosentan, ambrisentan, sildenafil, inhaled iloprost, intravenous epoprostenol (I-A recommendations), tadalafil or treprostinil (I-B recommendations) for patients in WHO functional class II-III. Not all randomized clinical studies of the approved PAH-targeted therapies have included patients with CTD-APAH. The purpose of this review is to describe the clinical characteristics of CTD-APAH and discuss the approved pharmacological treatments, with a focus on data specific to this subgroup where possible. PMID:22621693

  19. Laparoscopic Antireflux Surgery in Patients with Connective Tissue Diseases.

    PubMed

    Menezes, Mariano A; Herbella, Fernando A M; Patti, Marco G

    2016-04-01

    Different connective tissue diseases (CTDs), such as dermatomyositis, mixed CTD, rheumatoid arthritis, polymyositis, lupus, and Behçet's, may affect the esophagus, impairing its motor function. The muscular atrophy and fibrosis caused by the autoimmune vasculitis and neuronal dysfunction affect the esophageal body and the lower esophageal sphincter, leading to a clinical presentation of dysphagia and gastroesophageal reflux disease (GERD). The belief that the impaired esophageal motility may negatively affect surgical outcome has led to the common recommendation of avoiding laparoscopic antireflux surgery (LARS) for fear of creating or worsening dysphagia. This review focuses on the evaluation of the outcome of LARS in patients with CTD. Specifically, this review shows that the literature on LARS and CTDs is scarce and most studies have a small number of patients and a short follow-up. Furthermore, a subanalysis of the outcome based on the type of CTD or the manometric profile is still elusive. In the setting of these limitations, it appears that results are good and comparable to those of patients with GERD and without a CTD. Morbidity and mortality are insignificant even considering the systemic manifestations of the CTD. LARS should not be denied to patients with CTD and GERD. PMID:27027697

  20. Viscoelastic properties of bovine orbital connective tissue and fat: constitutive models

    PubMed Central

    Yoo, Lawrence; Gupta, Vijay; Lee, Choongyeop; Kavehpore, Pirouz

    2012-01-01

    Reported mechanical properties of orbital connective tissue and fat have been too sparse to model strain–stress relationships underlying biomechanical interactions in strabismus. We performed rheological tests to develop a multi-mode upper convected Maxwell (UCM) model of these tissues under shear loading. From 20 fresh bovine orbits, 30 samples of connective tissue were taken from rectus pulley regions and 30 samples of fatty tissues from the posterior orbit. Additional samples were defatted to determine connective tissue weight proportion, which was verified histologically. Mechanical testing in shear employed a triborheometer to perform: strain sweeps at 0.5–2.0 Hz; shear stress relaxation with 1% strain; viscometry at 0.01–0.5 s−1 strain rate; and shear oscillation at 1% strain. Average connective tissue weight proportion was 98% for predominantly connective tissue and 76% for fatty tissue. Connective tissue specimens reached a long-term relaxation modulus of 668 Pa after 1,500 s, while corresponding values for fatty tissue specimens were 290 Pa and 1,100 s. Shear stress magnitude for connective tissue exceeded that of fatty tissue by five-fold. Based on these data, we developed a multimode UCM model with variable viscosities and time constants, and a damped hyperelastic response that accurately described measured properties of both connective and fatty tissues. Model parameters differed significantly between the two tissues. Viscoelastic properties of predominantly connective orbital tissues under shear loading differ markedly from properties of orbital fat, but both are accurately reflected using UCM models. These viscoelastic models will facilitate realistic global modeling of EOM behavior in binocular alignment and strabismus. PMID:21207094

  1. Mechanical properties of orbital fat and its encapsulating connective tissue.

    PubMed

    Chen, Kinon; Weiland, James D

    2011-06-01

    There is an increasing need to understand the mechanical properties of human orbital fat and its encapsulating connective tissue (OFCT), but such knowledge is not available in the current literature. The purpose of the present study is to examine the mechanical properties of the OFCT. From 5 pairs of 76- to 92-year-old Caucasian human eyes and 33 5- to 7-month-old porcine eyes, 5 human and 11 porcine OFCT samples were dissected at the posterior pole or adjacent to the pole in the vertical, horizontal, and radial directions. Sample dimensions were fixed or measured. Tensile tests were performed on the samples in body-temperature saline. The stress-strain relationship was first approximately linear and then became nonlinear. The linear, the neo-Hookean, and the Mooney-Rivlin constants are reported in Tables 1 and 2. No statistical difference was found among their properties in the different directions in either the human or the porcine samples. Statistical differences were found between the human and the porcine material constants in the horizontal and radial directions. Among our material models, only the Mooney-Rivlin model was able to capture the mechanical properties of the OFCT in large deformation properly. The Mooney-Rivlin model was especially adaptive to the human data. This is the first time the mechanical properties of the human and porcine OFCT have been examined in the literature. We believe our data will provide valuable information to others regarding designing implant biomaterials in orbital treatments and developing computer models to study orbital biomechanics. PMID:21744934

  2. Brown Adipose Tissue Growth and Development

    PubMed Central

    Symonds, Michael E.

    2013-01-01

    Brown adipose tissue is uniquely able to rapidly produce large amounts of heat through activation of uncoupling protein (UCP) 1. Maximally stimulated brown fat can produce 300 watts/kg of heat compared to 1 watt/kg in all other tissues. UCP1 is only present in small amounts in the fetus and in precocious mammals, such as sheep and humans; it is rapidly activated around the time of birth following the substantial rise in endocrine stimulatory factors. Brown adipose tissue is then lost and/or replaced with white adipose tissue with age but may still contain small depots of beige adipocytes that have the potential to be reactivated. In humans brown adipose tissue is retained into adulthood, retains the capacity to have a significant role in energy balance, and is currently a primary target organ in obesity prevention strategies. Thermogenesis in brown fat humans is environmentally regulated and can be stimulated by cold exposure and diet, responses that may be further modulated by photoperiod. Increased understanding of the primary factors that regulate both the appearance and the disappearance of UCP1 in early life may therefore enable sustainable strategies in order to prevent excess white adipose tissue deposition through the life cycle. PMID:24278771

  3. [Peculiarities of the action of hyaluronidase of different origin to the connective tissue].

    PubMed

    Habriyev, R U; Kamayev, N O; Danilova, T I; Kakhoyan, E G

    2016-01-01

    The lecture is devoted to consideration of mechanism of therapeutic action of the enzyme hyaluronidase in hyperplastic connective tissue. Drugs based on hyaluronidase increase bioavailability of other drugs used in adjuvant therapy; they significantly increase effectiveness of treatment, and also provide targeted synthesis of hyaluronic acid, ths regulating the regeneration process of connective tissue. PMID:26973193

  4. Experiment K-7-29: Connective Tissue Studies. Part 3; Rodent Tissue Repair: Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    Stauber, W.; Fritz, V. K.; Burkovskaya, T. E.; Ilyina-Kakueva, E. I.

    1994-01-01

    Myofiber injury-repair was studied in the rat gastrocnemius following a crush injury to the lower leg prior to flight in order to understand if the regenerative responses of muscles are altered by the lack of gravitational forces during Cosmos 2044 flight. After 14 days of flight, the gastrocnemius muscle was removed from the 5 injured flight rodents and various Earth-based treatment groups for comparison. The Earth-based animals consisted of three groups of five rats with injured muscles from a simulated, tail-suspended, and vivarium as well as an uninjured basal group. The gastrocnemius muscle from each was evaluated by histochemical and immunohistochemical techniques to document myofiber, vascular, and connective tissue alterations following injury. In general the repair process was somewhat similar in all injured muscle samples with regard to extracellular matrix organization and myofiber regeneration. Small and large myofibers were present with a newly organized extracellular matrix indicative of myogenesis and muscle regeneration. In the tail-suspended animals, a more complete repair was observed with no enlarged area of non-muscle cells or matrix material visible. In contrast, the muscle samples from the flight animals were less well differentiated with more macrophages and blood vessels in the repair region but small myofibers and proteoglycans, nevertheless, were in their usual configuration. Thus, myofiber repair did vary in muscles from the different groups, but for the most part, resulted in functional muscle tissue.

  5. Leucine supplementation accelerates connective tissue repair of injured tibialis anterior muscle.

    PubMed

    Pereira, Marcelo G; Silva, Meiricris T; Carlassara, Eduardo O C; Gonçalves, Dawit A; Abrahamsohn, Paulo A; Kettelhut, Isis C; Moriscot, Anselmo S; Aoki, Marcelo S; Miyabara, Elen H

    2014-10-01

    This study investigated the effect of leucine supplementation on the skeletal muscle regenerative process, focusing on the remodeling of connective tissue of the fast twitch muscle tibialis anterior (TA). Young male Wistar rats were supplemented with leucine (1.35 g/kg per day); then, TA muscles from the left hind limb were cryolesioned and examined after 10 days. Although leucine supplementation induced increased protein synthesis, it was not sufficient to promote an increase in the cross-sectional area (CSA) of regenerating myofibers (p > 0.05) from TA muscles. However, leucine supplementation reduced the amount of collagen and the activation of phosphorylated transforming growth factor-β receptor type I (TβR-I) and Smad2/3 in regenerating muscles (p < 0.05). Leucine also reduced neonatal myosin heavy chain (MyHC-n) (p < 0.05), increased adult MyHC-II expression (p < 0.05) and prevented the decrease in maximum tetanic strength in regenerating TA muscles (p < 0.05). Our results suggest that leucine supplementation accelerates connective tissue repair and consequent function of regenerating TA through the attenuation of TβR-I and Smad2/3 activation. Therefore, future studies are warranted to investigate leucine supplementation as a nutritional strategy to prevent or attenuate muscle fibrosis in patients with several muscle diseases. PMID:25268835

  6. Leucine Supplementation Accelerates Connective Tissue Repair of Injured Tibialis Anterior Muscle

    PubMed Central

    Pereira, Marcelo G.; Silva, Meiricris T.; Carlassara, Eduardo O. C.; Gonçalves, Dawit A.; Abrahamsohn, Paulo A.; Kettelhut, Isis C.; Moriscot, Anselmo S.; Aoki, Marcelo S.; Miyabara, Elen H.

    2014-01-01

    This study investigated the effect of leucine supplementation on the skeletal muscle regenerative process, focusing on the remodeling of connective tissue of the fast twitch muscle tibialis anterior (TA). Young male Wistar rats were supplemented with leucine (1.35 g/kg per day); then, TA muscles from the left hind limb were cryolesioned and examined after 10 days. Although leucine supplementation induced increased protein synthesis, it was not sufficient to promote an increase in the cross-sectional area (CSA) of regenerating myofibers (p > 0.05) from TA muscles. However, leucine supplementation reduced the amount of collagen and the activation of phosphorylated transforming growth factor-β receptor type I (TβR-I) and Smad2/3 in regenerating muscles (p < 0.05). Leucine also reduced neonatal myosin heavy chain (MyHC-n) (p < 0.05), increased adult MyHC-II expression (p < 0.05) and prevented the decrease in maximum tetanic strength in regenerating TA muscles (p < 0.05). Our results suggest that leucine supplementation accelerates connective tissue repair and consequent function of regenerating TA through the attenuation of TβR-I and Smad2/3 activation. Therefore, future studies are warranted to investigate leucine supplementation as a nutritional strategy to prevent or attenuate muscle fibrosis in patients with several muscle diseases. PMID:25268835

  7. Mesenchymal Stem Cells in Tissue Growth and Repair

    PubMed Central

    Kalinina, N.I.; Sysoeva, V.Yu.; Rubina, K.A.; Parfenova, Ye.V.; Tkachuk, V.A.

    2011-01-01

    It has been established in the recent several decades that stem cells play a crucial role in tissue renewal and regeneration. Mesenchymal stem cells (MSCs) are part of the most important population of adult stem cells. These cells have hereby been identified for the very first time and subsequently isolated from bone marrow stroma. Bone marrow-derived MSCs have been believed to play the role of a source of cells for the renewal and repair of connective tissues, including bone, cartilage and adipose tissues. Cells similar to bone marrow-derived MSCs have now been identified in all postnatal tissues. Data on the distribution and function of MSCsin vivocollected using novel approaches pertaining to the identification of MSCsin situ, to their isolation from tissues, and finally to the determination of their biological properties have enabled successful revision of the role of MSCs in various organs and tissues. This review summarizes our own, as well as others’, data concerning the role of MSCs in the regulation processes of tissue repair and regeneration. In our opinion, MSCs provide the connection between the blood-vascular, immune, endocrine, and nervous systems and tissue-specific stem cells in the body. PMID:22649702

  8. Phosphaturic mesenchymal tumour mixed connective tissue variant: report of three cases with unusual histological findings.

    PubMed

    Shustik, David A; Ng, David Ce; Sittampalam, Kesavan

    2015-01-01

    Phosphaturic mesenchymal tumour mixed connective tissue variant (PMTMCT) is a rare tumour occurring in bone and soft tissue that usually behaves in a benign manner. Elaboration of biologically active substances by this tumour gives rise to a paraneoplastic syndrome known as oncogenic osteomalacia, manifesting clinically as bone pain, generalized weakness and pathological fractures. Recognition of PMTMCT and its associated syndrome is important, as resection of the tumour in most instances results in prompt resolution of symptoms. Previously reported cases of this tumour have emphasized the consistent presence of certain histological features that are considered prerequisite for making the diagnosis of PMTMCT. We describe three cases of PMTMCT, of which two first presented with progressive symptoms of osteomalacia and one remained clinically silent aside from the symptom of a palpable lump. Our cases highlight the wide-ranging histological patterns displayed by these tumours, and draw attention to certain microscopic findings that until now have been given little if any mention. Tentacular growth pattern and satellite nodules appear to be common findings in PMTMCTs, and can make complete surgical excision of these tumours challenging. The ability of this otherwise histologically benign tumour to permeate vascular spaces has to our knowledge never been described previously. One tumour lacked the characteristic calcifying matrix of PMTMCT, suggesting that in some tumours this defining feature may be focal if not entirely absent. PMTMCT shares features with and can resemble a variety of bone and soft tissue neoplasms, requiring the surgical pathologist to be familiar with this entity. PMID:26261662

  9. Clinical Features of Neuropsychiatric Syndromes in Systemic Lupus Erythematosus and Other Connective Tissue Diseases

    PubMed Central

    Kasama, Tsuyoshi; Maeoka, Airi; Oguro, Nao

    2016-01-01

    Systemic lupus erythematosus (SLE) and related disorders are chronic inflammatory diseases characterized by abnormalities and, in some cases, even complete failure of immune responses as the underlying pathology. Although almost all connective tissue diseases and related disorders can be complicated by various neuropsychiatric syndromes, SLE is a typical connective tissue disease that can cause neurological and psychiatric syndromes. In this review, neuropsychiatric syndromes complicating connective tissue diseases, especially SLE are outlined, and pathological and other conditions that should be considered in the differential diagnosis are also discussed. PMID:26819561

  10. Growth factor effects on costal chondrocytes for tissue engineering fibrocartilage.

    PubMed

    Johns, D E; Athanasiou, K A

    2008-09-01

    Tissue-engineered fibrocartilage could become a feasible option for replacing tissues such as the knee meniscus or temporomandibular joint disc. This study employed five growth factors (insulin-like growth factor-I, transforming growth factor-beta1, epidermal growth factor, platelet-derived growth factor-BB, and basic fibroblast growth factor) in a scaffoldless approach with costal chondrocytes, attempting to improve biochemical and mechanical properties of engineered constructs. Samples were quantitatively assessed for total collagen, glycosaminoglycans, collagen type I, collagen type II, cells, compressive properties, and tensile properties at two time points. Most treated constructs had lower biomechanical and biochemical properties than the controls with no growth factors, suggesting a detrimental effect, but the treatment with insulin-like growth factor-I tended to improve the constructs. Additionally, the 6-week time point was consistently better than that at 3 weeks, with total collagen, glycosaminoglycans, and aggregate modulus doubling during this time. Further optimization of the time in culture and exogenous stimuli will be important in making a more functional replacement tissue. PMID:18597118

  11. Pulmonary manifestations of Sjögren syndrome, systemic lupus erythematosus, and mixed connective tissue disease.

    PubMed

    Mira-Avendano, Isabel C; Abril, Andy

    2015-05-01

    Interstitial lung disease is a common and often life-threatening manifestation of different connective tissue disorders, often affecting its overall prognosis. Systemic lupus erythematosus, Sjögren syndrome, and mixed connective tissue disease, although all unique diseases, can have lung manifestations as an important part of these conditions. This article reviews the different pulmonary manifestations seen in these 3 systemic rheumatologic conditions. PMID:25836642

  12. Life-threatening acute pneumonitis in mixed connective tissue disease: a case report and literature review.

    PubMed

    Rath, Eva; Zandieh, Shahin; Löckinger, Alexander; Hirschl, Mirko; Klaushofer, Klaus; Zwerina, Jochen

    2015-10-01

    Mixed connective tissue disease (MCTD) is a rare connective tissue disease frequently involving the lungs. The main characteristic is a systemic sclerosis-like picture of slowly progressing interstitial lung disease consistent with lung fibrosis, while pulmonary arterial hypertension is rare. Herein, we present a case of a newly diagnosed MCTD patient developing life-threatening acute pneumonitis similar to lupus pneumonitis. Previous literature on this exceptionally rare complication of MCTD is reviewed and differential diagnosis and management discussed. PMID:26142172

  13. Interstitial growth and remodeling of biological tissues: tissue composition as state variables.

    PubMed

    Myers, Kristin; Ateshian, Gerard A

    2014-01-01

    Growth and remodeling of biological tissues involves mass exchanges between soluble building blocks in the tissue's interstitial fluid and the various constituents of cells and the extracellular matrix. As the content of these various constituents evolves with growth, associated material properties, such as the elastic modulus of the extracellular matrix, may similarly evolve. Therefore, growth theories may be formulated by accounting for the evolution of tissue composition over time in response to various biological and mechanical triggers. This approach has been the foundation of classical bone remodeling theories that successfully describe Wolff's law by establishing a dependence between Young's modulus and bone apparent density and by formulating a constitutive relation between bone mass supply and the state of strain. The goal of this study is to demonstrate that adding tissue composition as state variables in the constitutive relations governing the stress-strain response and the mass supply represents a very general and straightforward method to model interstitial growth and remodeling in a wide variety of biological tissues. The foundation for this approach is rooted in the framework of mixture theory, which models the tissue as a mixture of multiple solid and fluid constituents. A further generalization is to allow each solid constituent in a constrained solid mixture to have its own reference (stress-free) configuration. Several illustrations are provided, ranging from bone remodeling to cartilage tissue engineering and cervical remodeling during pregnancy. PMID:23562499

  14. Evaluation of Three Growth Factors for TMJ Disc Tissue Engineering

    PubMed Central

    Detamore, Michael S.; Athanasiou, Kyriacos A.

    2015-01-01

    Arguably one of the most complex joints in the body, the temporomandibular joint (TMJ) presents one of the most difficult problems in modern medicine. Tissue engineering, for the TMJ disc in particular, has been proposed as a potential breakthrough treatment strategy for TMJ disorders. Central to tissue engineering is understanding growth factor effects on TMJ disc cells, and to the best of our knowledge, this is the first 3D growth factor study for these cells. The purpose was to examine the effects of high and low concentrations of basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF), and transforming growth factor-β1 (TGF-β) on porcine TMJ disc cells. Cells were seeded onto non-woven PGA scaffolds (95% porosity) in spinner flasks, then cultured with a growth factor for 6 weeks. Constructs were analyzed for mechanical and structural integrity, cell number, and matrix biosynthesis. All growth factors improved mechanical and structural integrity compared to the control. IGF and TGF-β were most effective at promoting collagen synthesis, although there were no significant differences in glycosaminoglycan synthesis or cell number between any groups. After considering the economic advantage of IGF over TGF-β, the conclusion of this study is to use IGF in future TMJ disc tissue engineering experiments. PMID:15868729

  15. Growth versus metabolic tissue replacement in mouse tissues determined by stable carbon and nitrogen isotope analysis

    NASA Astrophysics Data System (ADS)

    Macavoy, S. E.; Jamil, T.; Macko, S. A.; Arneson, L. S.

    2003-12-01

    Stable isotope analysis is becoming an extensively used tool in animal ecology. The isotopes most commonly used for analysis in terrestrial systems are those of carbon and nitrogen, due to differential carbon fractionation in C3 and C4 plants, and the approximately 3‰ enrichment in 15N per trophic level. Although isotope signatures in animal tissues presumably reflect the local food web, analysis is often complicated by differential nutrient routing and fractionation by tissues, and by the possibility that large organisms are not in isotopic equilibrium with the foods available in their immediate environment. Additionally, the rate at which organisms incorporate the isotope signature of a food through both growth and metabolic tissue replacement is largely unknown. In this study we have assessed the rate of carbon and nitrogen isotopic turnover in liver, muscle and blood in mice following a diet change. By determining growth rates, we were able to determine the proportion of tissue turnover caused by growth versus that caused by metabolic tissue replacement. Growth was found to account for approximately 10% of observed tissue turnover in sexually mature mice (Mus musculus). Blood carbon was found to have the shortest half-life (16.9 days), followed by muscle (24.7 days). Liver carbon turnover was not as well described by the exponential decay equations as other tissues. However, substantial liver carbon turnover was observed by the 28th day after diet switch. Surprisingly, these tissues primarily reflect the carbon signature of the protein, rather than carbohydrate, source in their diet. The nitrogen signature in all tissues was enriched by 3 - 5‰ over their dietary protein source, depending on tissue type, and the isotopic turnover rates were comparable to those observed in carbon.

  16. Numerical Methods for Two-Dimensional Stem Cell Tissue Growth.

    PubMed

    Ovadia, Jeremy; Nie, Qing

    2014-01-01

    Growth of developing and regenerative biological tissues of different cell types is usually driven by stem cells and their local environment. Here, we present a computational framework for continuum tissue growth models consisting of stem cells, cell lineages, and diffusive molecules that regulate proliferation and differentiation through feedback. To deal with the moving boundaries of the models in both open geometries and closed geometries (through polar coordinates) in two dimensions, we transform the dynamic domains and governing equations to fixed domains, followed by solving for the transformation functions to track the interface explicitly. Clustering grid points in local regions for better efficiency and accuracy can be achieved by appropriate choices of the transformation. The equations resulting from the incompressibility of the tissue is approximated by high-order finite difference schemes and is solved using the multigrid algorithms. The numerical tests demonstrate an overall spatiotemporal second-order accuracy of the methods and their capability in capturing large deformations of the tissue boundaries. The methods are applied to two biological systems: stratified epithelia for studying the effects of two different types of stem cell niches and the scaling of a morphogen gradient with the size of the Drosophila imaginal wing disc during growth. Direct simulations of both systems suggest that that the computational framework is robust and accurate, and it can incorporate various biological processes critical to stem cell dynamics and tissue growth. PMID:24415847

  17. Biodynamic profiling of three-dimensional tissue growth techniques

    NASA Astrophysics Data System (ADS)

    Sun, Hao; Merrill, Dan; Turek, John; Nolte, David

    2016-03-01

    Three-dimensional tissue culture presents a more biologically relevant environment in which to perform drug development than conventional two-dimensional cell culture. However, obtaining high-content information from inside three dimensional tissue has presented an obstacle to rapid adoption of 3D tissue culture for pharmaceutical applications. Biodynamic imaging is a high-content three-dimensional optical imaging technology based on low-coherence interferometry and digital holography that uses intracellular dynamics as high-content image contrast. In this paper, we use biodynamic imaging to compare pharmaceutical responses to Taxol of three-dimensional multicellular spheroids grown by three different growth techniques: rotating bioreactor, hanging-drop and plate-grown spheroids. The three growth techniques have systematic variations among tissue cohesiveness and intracellular activity and consequently display different pharmacodynamics under identical drug dose conditions. The in vitro tissue cultures are also compared to ex vivo living biopsies. These results demonstrate that three-dimensional tissue cultures are not equivalent, and that drug-response studies must take into account the growth method.

  18. Intracranial phosphaturic mesenchymal tumor, mixed connective tissue variant presenting without oncogenic osteomalacia

    PubMed Central

    Bower, Regina S.; Daugherty, Wilson P.; Giannini, Caterina; Parney, Ian F.

    2012-01-01

    Background: Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) is a rare tumor typically occurring in soft tissues and bone, causing oncogenic (tumor-induced) osteomalacia (TIO) through secretion of the phosphaturic hormone, fibroblast growth factor-23 (FGF-23). Rare tumors identical to PMTMCT occur without known TIO. Intracranial localization of PMTMCT is extremely rare, with only two cases reported in the literature. We present a very unusual case of a patient with an intracranial PMTMCT that presented with neurologic changes without osteomalacia. Case Description: A 67-year-old woman presented with progressive incontinence, apathy, and abulia after having undergone a total knee replacement 1 month earlier. Imaging disclosed a large left frontal anterior fossa mass. She underwent uncomplicated surgical resection of this tumor. Surprisingly, histopathology suggested PMTMCT. Reverse transcription polymerase chain reaction (RT-PCR) assay demonstrating FGF-23 expression in the tumor confirmed the diagnosis. Serum FGF-23 levels postoperatively were normal and she had no clinical or laboratory evidence of osteomalacia or phosphaturia. Conclusion: This report should serve to alert clinicians to the possibility that PMTMCT can be included in the differential diagnosis of intracranial masses even in the absence of tumor-induced osteomalacia. PMID:23372968

  19. Interstitial Growth and Remodeling of Biological Tissues: Tissue Composition as State Variables

    PubMed Central

    Myers, Kristin; Ateshian, Gerard A.

    2013-01-01

    Growth and remodeling of biological tissues involves mass exchanges between soluble building blocks in the tissue’s interstitial fluid and the various constituents of cells and the extracellular matrix. As the content of these various constituents evolves with growth, associated material properties, such as the elastic modulus of the extracellular matrix, may similarly evolve. Therefore, growth theories may be formulated by accounting for the evolution of tissue composition over time in response to various biological and mechanical triggers. This approach has been the foundation of classical bone remodeling theories that successfully describe Wolff’s law by establishing a dependence between Young’s modulus and bone apparent density and by formulating a constitutive relation between bone mass supply and the state of strain. The goal of this study is to demonstrate that adding tissue composition as state variables in the constitutive relations governing the stress-strain response and the mass supply represents a very general and straightforward method to model interstitial growth and remodeling in a wide variety of biological tissues. The foundation for this approach is rooted in the framework of mixture theory, which models the tissue as a mixture of multiple solid and fluid constituents. A further generalization is to allow each solid constituent in a constrained solid mixture to have its own reference (stress-free) configuration. Several illustrations are provided, ranging from bone remodeling to cartilage tissue engineering and cervical remodeling during pregnancy. PMID:23562499

  20. Connective tissue responses to some heavy metals. II. Lead: histology and ultrastructure.

    PubMed Central

    Ellender, G.; Ham, K. N.

    1987-01-01

    Lead loaded ion exchange resin beads implanted into the loose connective tissue of the rat pinna induced local lesions which differed widely from those of the control (sodium loaded) beads (Ellender & Ham 1987). These lesions were characterized by changes in the granulation tissue and the approximating connective tissue. Granulation tissue contained mononuclear phagocytes in various guises, and some cells with intranuclear inclusion bodies. The matrix of the granulation tissue contained collagen fibrils having a wide range of diameters suggestive of altered collagen biosynthesis. Foci of collagen mineralization occurred in zones of combined trauma and lead impregnation. Once mineralized they became enveloped by giant cells and epithelioid cells. Lead in damaged tissues is thought to modify the protective mechanism of calcification inhibition and the biosynthesis of the matrix. Images Fig. 6 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 PMID:3040063

  1. Lipid signaling in adipose tissue: Connecting inflammation & metabolism.

    PubMed

    Masoodi, Mojgan; Kuda, Ondrej; Rossmeisl, Martin; Flachs, Pavel; Kopecky, Jan

    2015-04-01

    Obesity-associated low-grade inflammation of white adipose tissue (WAT) contributes to development of insulin resistance and other disorders. Accumulation of immune cells, especially macrophages, and macrophage polarization from M2 to M1 state, affect intrinsic WAT signaling, namely anti-inflammatory and proinflammatory cytokines, fatty acids (FA), and lipid mediators derived from both n-6 and n-3 long-chain PUFA such as (i) arachidonic acid (AA)-derived eicosanoids and endocannabinoids, and (ii) specialized pro-resolving lipid mediators including resolvins derived from both eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), lipoxins (AA metabolites), protectins and maresins (DHA metabolites). In this respect, potential differences in modulating adipocyte metabolism by various lipid mediators formed by inflammatory M1 macrophages typical of obese state, and non-inflammatory M2 macrophages typical of lean state remain to be established. Studies in mice suggest that (i) transient accumulation of M2 macrophages could be essential for the control of tissue FA levels during activation of lipolysis, (ii) currently unidentified M2 macrophage-borne signaling molecule(s) could inhibit lipolysis and re-esterification of lipolyzed FA back to triacylglycerols (TAG/FA cycle), and (iii) the egress of M2 macrophages from rebuilt WAT and removal of the negative feedback regulation could allow for a full unmasking of metabolic activities of adipocytes. Thus, M2 macrophages could support remodeling of WAT to a tissue containing metabolically flexible adipocytes endowed with a high capacity of both TAG/FA cycling and oxidative phosphorylation. This situation could be exemplified by a combined intervention using mild calorie restriction and dietary supplementation with EPA/DHA, which enhances the formation of "healthy" adipocytes. This article is part of a Special Issue entitled Oxygenated metabolism of PUFA: analysis and biological relevance." PMID:25311170

  2. Cartilage, bone, and intermandibular connective tissue in the Australian lungfish, Neoceratodus forsteri (Osteichthyes: Dipnoi).

    PubMed

    Kemp, Anne

    2013-10-01

    The connective tissue that links the bones of the mandible in the Australian lungfish, Neoceratodus forsteri, has been described as an intermandibular cartilage, and as such has been considered important for phylogenetic analyses among lower vertebrates. However, light and electron microscopy of developing lungfish jaws demonstrates that the intermandibular tissue, like the connective tissue that links the bones of the upper jaw, contains fibroblasts and numerous bundles of collagen fibrils, extending from the trabeculae of the bones supporting the tooth plates. It differs significantly in structure and in staining reactions from the cartilage and the bone found in this species. In common with the cladistian Polypterus and with actinopterygians and some amphibians, lungfish have no intermandibular cartilage. The connective tissue linking the mandibular bones has no phylogenetic significance for systematic grouping of lungfish, as it is present in a range of different groups among lower vertebrates. PMID:23801584

  3. Efficacy of Connective Tissue with and without Periosteum in Regeneration of Intrabony Defects

    PubMed Central

    Esfahanian, Vahid; Golestaneh, Hedayatollah; Moghaddas, Omid; Ghafari, Mohammad Reza

    2014-01-01

    Background and aims. Connective tissue grafts with and without periosteum is used in regenerative treatments of bone and has demonstrated successful outcomes in previous investigations. The aim of present study was to evaluate the effectiveness of connective tissue graft with and without periosteum in regeneration of intrabony defects. Materials and methods. In this single-blind randomized split-mouth clinical trial, 15 pairs of intrabony defects in 15 patients with moderate to advanced periodontitis were treated by periosteal connective tissue graft + ABBM (test group) or non-periosteal connective tissue graft + ABBM (control group). Probing pocket depth, clinical attachment level, free gingival margin position, bone crestal position, crest defect depth and defect depth to stent were measured at baseline and after six months by surgical re-entry. Data was analyzed by Student’s t-test and paired t-tests (α=0.05). Results. Changes in clinical parameters after 6 months in the test and control groups were as follows: mean of PPD reduction: 3.1±0.6 (P<0.0001); 2.5±1.0 mm (P<0.0001), CAL gain: 2.3±0.9 (P<0.0001); 2.2±1.0 mm (P<0.0001), bone fill: 2.2±0.7 mm (P<0.0001); 2.2±0.7 mm (P<0.0001), respectively. No significant differences in the position of free gingival margin were observed during 6 months compared to baseline in both groups. Conclusion. Combinations of periosteal connective tissue graft + ABBM and non-periosteal connective tissue graft + ABBM were similarly effective in treating intrabony defects without any favor for any group. Connective tissue and perio-steum can be equally effective in regeneration of intrabony defects. PMID:25587379

  4. Adipose tissue and sustainable development: a connection that needs protection

    PubMed Central

    Tremblay, Angelo; Picard-Deland, Éliane; Panahi, Shirin; Marette, André

    2015-01-01

    Obesity is generally considered as an excess body fat that increases the risk to develop ergonomic, metabolic, and psychosocial problems. As suggested in this paper, body fat gain is also a protective adaptation that prevents body lipotoxicity, contributes to the secretion of molecules involved in metabolic regulation, and dilutes lipid soluble persistent organic pollutants. Recent literature shows that this protective role of adipose tissue is more solicited in a modern context in which unsuspected factors can affect energy balance to a much greater extent than what is generally perceived by health care professionals. These factors include short sleep duration, demanding mental work, and chemical pollution whose impact is more detectable in a context dominated by economic productivity and competitiveness. Since these factors might also include the increase in atmospheric CO2, it is likely that obesity prevention will need the support of a promotion in sustainable development, whether it is for human health, and well-being or global ecological protection. PMID:26074821

  5. Functional role of periostin in development and wound repair: implications for connective tissue disease

    PubMed Central

    2008-01-01

    Integrity of the extracellular matrix (ECM) is essential for maintaining the normal structure and function of connective tissues. ECM is secreted locally by cells and organized into a complex meshwork providing physical support to cells, tissues, and organs. Initially thought to act only as a scaffold, the ECM is now known to provide a myriad of signals to cells regulating all aspects of their phenotype from morphology to differentiation. Matricellular proteins are a class of ECM related molecules defined through their ability to modulate cell–matrix interactions. Matricellular proteins are expressed at high levels during development, but typically only appear in postnatal tissue in wound repair or disease, where their levels increase substantially. Members of the CCN family, tenascin-C, osteopontin, secreted protein acidic rich in cysteine (SPARC), bone sialoprotein, thrombospondins, and galectins have all been classed as matricellular proteins. Periostin, a 90 kDa secreted homophilic cell adhesion protein, was recently added to matricellular class of proteins based on its expression pattern and function during development as well as in wound repair. Periostin is expressed in connective tissues including the periodontal ligament, tendons, skin and bone, and is also prominent in neoplastic tissues, cardiovascular disease, as well as in connective tissue wound repair. This review will focus on the functional role of periostin in tissue physiology. Fundamentally, it appears that periostin influences cell behaviour as well as collagen fibrillogenesis, and therefore exerts control over the structural and functional properties of connective tissues in both health and disease. Periostin is a novel matricellular protein with close homology to Drosophila fasciclin 1. In this review, the functional role of periostin is discussed in the context of connective tissue physiology, in development, disease, and wound repair. PMID:18642132

  6. Growth factor-eluting technologies for bone tissue engineering.

    PubMed

    Nyberg, Ethan; Holmes, Christina; Witham, Timothy; Grayson, Warren L

    2016-04-01

    Growth factors are essential orchestrators of the normal bone fracture healing response. For non-union defects, delivery of exogenous growth factors to the injured site significantly improves healing outcomes. However, current clinical methods for scaffold-based growth factor delivery are fairly rudimentary, and there is a need for greater spatial and temporal regulation to increase their in vivo efficacy. Various approaches used to provide spatiotemporal control of growth factor delivery from bone tissue engineering scaffolds include physical entrapment, chemical binding, surface modifications, biomineralization, micro- and nanoparticle encapsulation, and genetically engineered cells. Here, we provide a brief review of these technologies, describing the fundamental mechanisms used to regulate release kinetics. Examples of their use in pre-clinical studies are discussed, and their capacities to provide tunable, growth factor delivery are compared. These advanced scaffold systems have the potential to provide safer, more effective therapies for bone regeneration than the systems currently employed in the clinic. PMID:25967594

  7. Morphometric Analysis of Connective Tissue Sheaths of Sural Nerve in Diabetic and Nondiabetic Patients

    PubMed Central

    Kundalić, Braca; Ugrenović, Slađana; Jovanović, Ivan; Stefanović, Natalija; Petrović, Vladimir; Kundalić, Jasen; Stojanović, Vesna; Živković, Vladimir; Antić, Vladimir

    2014-01-01

    One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index (P < 0.05) and endoneurial connective tissue percentage (P < 0.01). The diabetic group showed significantly higher epineurial area (P < 0.01), as well as percentage of endoneurial connective tissue (P < 0.01), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. PMID:25147820

  8. Morphometric analysis of connective tissue sheaths of sural nerve in diabetic and nondiabetic patients.

    PubMed

    Kundalić, Braca; Ugrenović, Slađana; Jovanović, Ivan; Stefanović, Natalija; Petrović, Vladimir; Kundalić, Jasen; Stojanović, Vesna; Živković, Vladimir; Antić, Vladimir

    2014-01-01

    One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index (P < 0.05) and endoneurial connective tissue percentage (P < 0.01). The diabetic group showed significantly higher epineurial area (P < 0.01), as well as percentage of endoneurial connective tissue (P < 0.01), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. PMID:25147820

  9. Cells of the connective tissue differentiate and migrate into pollen sacs

    NASA Astrophysics Data System (ADS)

    Iqbal, M. C. M.; Wijesekara, Kolitha B.

    2002-01-01

    In angiosperms, archesporial cells in the anther primordium undergo meiosis to form haploid pollen, the sole occupants of anther sacs. Anther sacs are held together by a matrix of parenchyma cells, the connective tissue. Cells of the connective tissue are not known to differentiate. We report the differentiation of parenchyma cells in the connective tissue of two Gordonia species into pollen-like structures (described as pseudopollen), which migrate into the anther sacs before dehiscence. Pollen and pseudopollen were distinguishable by morphology and staining. Pollen were tricolpate to spherical while pseudopollen were less rigid and transparent with a ribbed surface. Both types were different in size, shape, staining and surface architecture. The ratio of the number of pseudopollen to pollen was 1:3. During ontogeny in the connective tissue, neither cell division nor tetrad formation was observed and hence pseudopollen were presumed to be diploid. Only normal pollen germinated on a germination medium. Fixed preparations in time seemed to indicate that pseudopollen migrate from the connective tissue into the anther sac.

  10. Phototherapy, photodynamic therapy and photophoresis in the treatment of connective-tissue diseases: a review.

    PubMed

    Gordon Spratt, E A; Gorcey, L V; Soter, N A; Brauer, J A

    2015-07-01

    Connective-tissue disorders, which include lupus erythematosus, morphoea/scleroderma and dermatomyositis, are characterized by cutaneous manifestations that are sometimes resistant to conventional therapy. Light treatments, which include phototherapy, photodynamic therapy (PDT) and photopheresis, are routinely utilized in the treatment of dermatological conditions and may provide unique mechanisms of action in the treatment of these connective-tissue disorders. The objective of this study is to conduct a review of the literature that describes the use of phototherapy, PDT and photopheresis in the treatment of lupus erythematosus, morphoea/scleroderma and dermatomyositis. A MEDLINE search was conducted to find articles that discuss treatment of connective-tissue diseases with light therapies and more than 30 publications that discuss light therapy for these diseases were identified. These range in design from case reports to randomized, prospective trials. Study outcomes and details were summarized and presented within each connective-tissue disease by light therapy modality, which includes phototherapy, PDT and photopheresis. Although there is a known association between photosensitivity and connective-tissue diseases, light therapies, when used appropriately, may be legitimate therapeutic options for recalcitrant cutaneous manifestations in lupus erythematosus, morphoea/scleroderma and dermatomyositis. PMID:25400115

  11. Should Endovascular Therapy Be Considered for Patients With Connective Tissue Disorder?

    PubMed

    Gagné-Loranger, Maude; Voisine, Pierre; Dagenais, François

    2016-01-01

    Because of early diagnosis, strict imaging follow-up, and advances in medical and surgical management, life expectancy of Marfan patients has dramatically improved since the 1970s. Although disease of the root and ascending aorta are more frequent in patients with connective tissue disorders, a subset of patients present with diffuse disease that might involve any portion of the thoracoabdominal aorta. Thoracic endovascular aortic repair (TEVAR) has gained widespread acceptance for the treatment of different pathologies of the descending aorta. In contrast, TEVAR in patients with connective tissue disorders is associated with a high risk of early and mid-term complications and reinterventions. Currently, a consensus of experts recommend that an open approach should be reserved for use in acceptable risk candidates with connective tissue disorders. TEVAR should be considered solely in patients in a complex repeat surgical setting or in patients judged to have prohibitive open surgical risk. Finally, as a bridge to a definite open repair, TEVAR might be life-saving in patients with connective tissue disorders who present with exsanguination or severe malperfusion. Future developments in stent-graft technology might decrease stent-graft-related complications in patients with connective tissue disorders, although securing a device with radial force in a fragile aorta in the long-term will be challenging. PMID:26577892

  12. Robotic Scaffolds for Tissue Engineering and Organ Growth

    NASA Technical Reports Server (NTRS)

    Stoica, Adrian

    2011-01-01

    The aim of tissue engineering (TE) is to restore tissue and organ functions with minimal host rejection. TE is seen as a future solution to solve the crisis of donor organs for transplant, which faces a shortage expected only to increase in the future. In this innovation, a flexible and configurable scaffold has been conceived that mechanically stresses cells that are seeded on it, stimulating them to increased growth. The influence of mechanical stress/ loading on cell growth has been observed on all forms of cells. For example, for cartilages, studies in animals, tissue explants, and engineered tissue scaffolds have all shown that cartilage cells (chondrocytes) modify their extracellular matrix in response to loading. The chondrocyte EMC production response to dynamics of the physical environment (in vivo cartilage development) illustrates a clear benefit (better growth) when stressed. It has been shown that static and dynamic compression regulates PRG4 biosynthesis by cartilage explants. Mechanical tissue stimulation is beneficial and (flexible) scaffolds with movable components, which are able to induce mechanical stimulation, offer advantages over the fixed, rigid scaffold design. In addition to improved cell growth from physical/mechanical stimulation, additional benefits include the ability to increase in size while preserving shape, or changing shape. By making scaffolds flexible, allowing relative movement between their components, adding sensing (e.g., for detecting response of cells to drug release and to mechanical actions), building controls for drug release and movement, and building even simple algorithms for mapping sensing to action, these structures can actually be made into biocompatible and biodegradable robots. Treating them as robots is a perspective shift that may offer advantages in the design and exploitation of these structures of the future.

  13. An update of neurological manifestations of vasculitides and connective tissue diseases: a literature review

    PubMed Central

    Bougea, Anastasia; Anagnostou, Evangelos; Spandideas, Nikolaos; Triantafyllou, Nikolaos; Kararizou, Evangelia

    2015-01-01

    Vasculitides comprise a heterogeneous group of autoimmune disorders, occurring as primary or secondary to a broad variety of systemic infectious, malignant or connective tissue diseases. The latter occur more often but their pathogenic mechanisms have not been fully established. Frequent and varied central and peripheral nervous system complications occur in vasculitides and connective tissue diseases. In many cases, the neurological disorders have an atypical clinical course or even an early onset, and the healthcare professionals should be aware of them. The purpose of this brief review was to give an update of the main neurological disorders of common vasculitis and connective tissue diseases, aiming at accurate diagnosis and management, with an emphasis on pathophysiologic mechanisms. PMID:26313435

  14. Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias

    PubMed Central

    Merrell, Allyson J.; Ellis, Benjamin J.; Fox, Zachary D.; Lawson, Jennifer A.; Weiss, Jeffrey A.; Kardon, Gabrielle

    2015-01-01

    The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDH), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), transient embryonic structures, are the source of the diaphragm’s muscle connective tissue, regulate muscle development, and their striking migration controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant and lead to CDH. Thus the PPFs and muscle connective tissue are critical for diaphragm development and mutations in PPF-derived fibroblasts are a source of CDH. PMID:25807280

  15. Tissue Stretch Decreases Soluble TGF-β1 and Type-1 Procollagen in Mouse Subcutaneous Connective Tissue: Evidence From Ex Vivo and In Vivo Models

    PubMed Central

    Bouffard, Nicole A.; Cutroneo, Kenneth R.; Badger, Gary J.; White, Sheryl L.; Buttolph, Thomas R.; Ehrlich, H. Paul; Stevens-Tuttle, Debbie; Langevin, Helene M.

    2011-01-01

    Transforming growth factor beta 1 (TGF-β1) plays a key role in connective tissue remodeling, scarring, and fibrosis. The effects of mechanical forces on TGF-β1 and collagen deposition are not well understood. We tested the hypothesis that brief (10 min) static tissue stretch attenuates TGF-β1-mediated new collagen deposition in response to injury. We used two different models: (1) an ex vivo model in which excised mouse subcutaneous tissue (N = 44 animals) was kept in organ culture for 4 days and either stretched (20% strain for 10 min 1 day after excision) or not stretched; culture media was assayed by ELISA for TGF-β1; (2) an in vivo model in which mice (N = 22 animals) underwent unilateral subcutaneous microsurgical injury on the back, then were randomized to stretch (20–30% strain for 10 min twice a day for 7 days) or no stretch; subcutaneous tissues of the back were immunohistochemically stained for Type-1 procollagen. In the ex vivo model, TGF-β1 protein was lower in stretched versus non-stretched tissue (repeated measures ANOVA, P < 0.01). In the in vivo model, microinjury resulted in a significant increase in Type-1 procollagen in the absence of stretch (P < 0.001), but not in the presence of stretch (P = 0.21). Thus, brief tissue stretch attenuated the increase in both soluble TGF-β1 (ex vivo) and Type-1 procollagen (in vivo) following tissue injury. These results have potential relevance to the mechanisms of treatments applying brief mechanical stretch to tissues (e.g., physical therapy, respiratory therapy, mechanical ventilation, massage, yoga, acupuncture). PMID:17654495

  16. Cell density signal protein suitable for treatment of connective tissue injuries and defects

    DOEpatents

    Schwarz, Richard I.

    2002-08-13

    Identification, isolation and partial sequencing of a cell density protein produced by fibroblastic cells. The cell density signal protein comprising a 14 amino acid peptide or a fragment, variant, mutant or analog thereof, the deduced cDNA sequence from the 14 amino acid peptide, a recombinant protein, protein and peptide-specific antibodies, and the use of the peptide and peptide-specific antibodies as therapeutic agents for regulation of cell differentiation and proliferation. A method for treatment and repair of connective tissue and tendon injuries, collagen deficiency, and connective tissue defects.

  17. Fibroblast Growth Factors: Biology, Function, and Application for Tissue Regeneration

    PubMed Central

    Yun, Ye-Rang; Won, Jong Eun; Jeon, Eunyi; Lee, Sujin; Kang, Wonmo; Jo, Hyejin; Jang, Jun-Hyeog; Shin, Ueon Sang; Kim, Hae-Won

    2010-01-01

    Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. The FGF signal pathways are the RAS/MAP kinase pathway, PI3 kinase/AKT pathway, and PLCγ pathway, among which the RAS/MAP kinase pathway is known to be predominant. Several studies have recently implicated the in vitro biological functions of FGFs for tissue regeneration. However, to obtain optimal outcomes in vivo, it is important to enhance the half-life of FGFs and their biological stability. Future applications of FGFs are expected when the biological functions of FGFs are potentiated through the appropriate use of delivery systems and scaffolds. This review will introduce the biology and cellular functions of FGFs and deal with the biomaterials based delivery systems and their current applications for the regeneration of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve tissues. PMID:21350642

  18. Transplantable tissue growth-a commercial space venture

    NASA Astrophysics Data System (ADS)

    Giuntini, Ronald E.; Vardaman, William K.

    1997-01-01

    Rantek was incorporated in 1984 to pursue research toward product development in space based biotechnology. The company has maintained an aggressive experiment flight program since 1989 having flown biotechnology experiments in six Consort rockets flights, one Joust rocket flight and eight Space Shuttle missions. The objective of these flights was to conduct a series of research experiments to resolve issues affecting transplantable tissue growth feasibility. The purpose of the flight research was to determine the behavior of lymphocyte mixing, activation, magnetic mixing and process control, drug studies in a model leukemia cell line, and various aspects of the hardware system process control in the low gravity of space. The company is now preparing for a two Space Shuttle flight program as precursors to a sustained, permanent, commercial venture at the Space Station. The shuttle flights will enable new, larger scale tissue growth systems to be tested to determine fundamental process control sensitivity and growth rates unique to a number of tissue types. The answer to these issues will ultimately determine the commercial viability of the Rantek Biospace program. This paper addresses considerations that will drive the cost of a space venture-the largest cost driver will be the cost to and from the station and the cost at the station.

  19. Modified connective tissue punch technique to increase the vestibular/buccal keratinized tissue on flapless implant surgery: a case series.

    PubMed

    Andreasi Bassi, M; Andrisani, C; Lopez, M A; Gaudio, R M; Lombardo, L; Lauritano, D

    2016-01-01

    The aim of this article is to show a simple and predictable technique to enhance both the vestibular/buccal (V/B) gingival thickness (GT) and keratinized tissue width (KTW) improving the soft-tissue profile after flapless implant placement. The technique proposed was named Modified Connective Tissue Punch (MCTP). Fourteen patients (6 men and 8 women) aged between 35 and 69 years (mean value 48.07±13.023 years) were enrolled in this case series. Seventeen implant sites were submitted to flapless procedure. The connective punch (CP) was harvested with a motor-driven circular tissue punch and then a full-split dissection was executed, in order to create a deep pouch, beyond the mucogingival junction, on the V/B side. In this recipient site the CP was placed. The normal flapless surgical protocol was used; implants were inserted and covered with transgingival healing cap screws. GT and KTW were measured: both immediately before and after surgery; at the time of the prosthetic finalization (3-4months, respectively, for mandible and maxilla); 1 year post surgery follow-up. GT was measured at 1 mm, 2 mm and 5 mm on the V/B side, from the outline of the punch. Both KTW and GT at 1 and 2 mm can be effectively increased, while no significant effects for GT at 5 mm can be expected from this technique. Furthermore, the mean values of KTW and GT at 1 mm and 2 mm show significant increases at 3-4 months post-operative, while no further significant increments are shown at 1 year post-operative follow-up. The Authors recommend the use of the MCTP technique to reduce the number of aesthetic complications and soft tissue defects in flapless implant surgery. Longer follow-ups are needed to evaluate the stability of peri-implant tissues over time. PMID:27469545

  20. Ex Vivo Growth of Bioengineered Ligaments and Other Tissues

    NASA Technical Reports Server (NTRS)

    Altman, Gregory; Kaplan, David L.; Martin, Ivan; Vunjak-Novakovic, Gordana

    2005-01-01

    A method of growing bioengineered tissues for use in surgical replacement of damaged anterior cruciate ligaments has been invented. An anterior cruciate ligament is one of two ligaments (the other being the posterior cruciate ligament) that cross in the middle of a knee joint and act to prevent the bones in the knee from sliding forward and backward relative to each other. Anterior cruciate ligaments are frequently torn in sports injuries and traffic accidents, resulting in pain and severe limitations on mobility. By making it possible to grow replacement anterior cruciate ligaments that structurally and functionally resemble natural ones more closely than do totally synthetic replacements, the method could create new opportunities for full or nearly full restoration of functionality in injured knees. The method is also adaptable to the growth of bioengineered replacements for other ligaments (e.g., other knee ligaments as well as those in the hands, wrists, and elbows) and to the production of tissues other than ligaments, including cartilage, bones, muscles, and blood vessels. The method is based on the finding that the histomorphological properties of a bioengineered tissue grown in vitro from pluripotent cells within a matrix are affected by the direct application of mechanical force to the matrix during growth generation. This finding provides important new insights into the relationships among mechanical stress, biochemical and cell-immobilization methods, and cell differentiation, and is applicable to the production of the variety of tissues mentioned above. Moreover, this finding can be generalized to nonmechanical (e.g., chemical and electromagnetic) stimuli that are experienced in vivo by tissues of interest and, hence, the method can be modified to incorporate such stimuli in the ex vivo growth of replacements for the various tissues mentioned above. In this method, a three-dimensional matrix made of a suitable material is seeded with pluripotent stem

  1. Connective tissue disorders associated with vasculitis and vaso-occlusive disease of the hand.

    PubMed

    Michelotti, Brett; Rizzo, Marco; Moran, Steven L

    2015-02-01

    Hand ischemia caused by vasculitis is a secondary finding in many autoimmune processes. Many of these autoimmune diseases are managed primarily with medications that can prevent the development of occlusive disease, tissue ischemia, and tissue loss. Unfortunately several disease conditions can be recalcitrant to medical management and can result in ischemic changes within the hand, which may require operative intervention. This article briefly reviews the major connective tissue disorders associated with vasculitis and vaso-occlusive disease of the hand, including scleroderma, lupus, and Buerger disease, and their surgical treatment. PMID:25455357

  2. Microstructure alterations in beef intramuscular connective tissue caused by hydrodynamic pressure processing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Scanning electron microscopy (SEM) was utilized to evaluate microstructural changes in intramuscular connective tissue of beef semimembranosus muscle subjected to hydrodynamic pressure processing (HDP). Samples were HDP treated in a plastic container (HDP-PC) or a steel commercial unit (HDP-CU). C...

  3. Adult Bone Marrow-Derived Stem Cells in Muscle Connective Tissue and Satellite Cell Niches

    PubMed Central

    Dreyfus, Patrick A.; Chretien, Fabrice; Chazaud, Bénédicte; Kirova, Youlia; Caramelle, Philippe; Garcia, Luis; Butler-Browne, Gillian; Gherardi, Romain K.

    2004-01-01

    Skeletal muscle includes satellite cells, which reside beneath the muscle fiber basal lamina and mainly represent committed myogenic precursor cells, and multipotent stem cells of unknown origin that are present in muscle connective tissue, express the stem cell markers Sca-1 and CD34, and can differentiate into different cell types. We tracked bone marrow (BM)-derived stem cells in both muscle connective tissue and satellite cell niches of irradiated mice transplanted with green fluorescent protein (GFP)-expressing BM cells. An increasing number of GFP+ mononucleated cells, located both inside and outside of the muscle fiber basal lamina, were observed 1, 3, and 6 months after transplantation. Sublaminal cells expressed unambiguous satellite cell markers (M-cadherin, Pax7, NCAM) and fused into scattered GFP+ muscle fibers. In muscle connective tissue there were GFP+ cells located close to blood vessels that expressed the ScaI or CD34 stem-cell antigens. The rate of settlement of extra- and intralaminal compartments by BM-derived cells was compatible with the view that extralaminal cells constitute a reservoir of satellite cells. We conclude that both muscle satellite cells and stem cell marker-expressing cells located in muscle connective tissue can derive from BM in adulthood. PMID:14982831

  4. Membranous glomerulonephritis in rheumatoid arthritis unrelated to gold, D-penicillamine or other connective tissue disease.

    PubMed

    Zarza, L P; Sanchez, E N; Acin, P A; Ara, J M; Baños, J G

    1996-07-01

    We report a 58-year-old woman with classical rheumatoid arthritis (RA) who developed a membranous glomerulonephritis (MGN). She had never been treated with gold or D-penicillamine; other connective tissue diseases as well as hepatitis B were excluded. We suggest that the responsible cause of MGN is RA. PMID:8853174

  5. Microstructure alterations in beef intramuscular connective tissue caused by hydrodynamic pressure processing.

    PubMed

    Zuckerman, H; Bowker, B C; Eastridge, J S; Solomon, M B

    2013-11-01

    Scanning electron microscopy (SEM) was utilized to evaluate microstructural changes in intramuscular connective tissue of beef semimembranosus muscle subjected to hydrodynamic pressure processing (HDP). Samples were HDP treated in a plastic container (HDP-PC) or a steel commercial unit (HDP-CU). Control and HDP samples were obtained immediately post-treatment and after 14days of aging for SEM and Warner-Bratzler shear force (WBSF) analysis. Immediately post-treatment, HDP treated samples exhibited lower (P<0.01) WBSF than did controls. After aging, HDP-PC samples had lower (P<0.01) WBSF than that of aged controls. SEM analysis indicated that HDP-PC treatment disrupted the integrity of the collagen fibril network of the endomysium in both the non-aged and aged samples. Aging effects on the intramuscular connective tissue were observed in the HDP-PC and control samples. Both WBSF and connective tissue changes were greater in the HDP-PC than in the HDP-CU treated samples. Data suggest that shockwave alterations to connective tissue contribute to the meat tenderization of HDP. PMID:23803280

  6. Connective tissue integrity is lost in vitamin B-6-deficient chicks

    NASA Technical Reports Server (NTRS)

    Masse, P. G.; Yamauchi, M.; Mahuren, J. D.; Coburn, S. P.; Muniz, O. E.; Howell, D. S.

    1995-01-01

    The objective of the present investigation was to characterize further the connective tissue disorder produced by pyridoxine (vitamin B-6) deficiency, as previously evidenced by electron microscopy. Following the second post-natal week, fast growing male chicks were deprived of pyridoxine for a 1-mo period. Six weeks post-natally, blood concentrations in the experimental deficiency group had declined to deficiency levels as registered by low concentrations of pyridoxal phosphate (coenzyme form) in erythrocytes, but did not reach levels associated with neurological symptoms. Light microscopic study showed abnormalities in the extracellular matrix of the connective tissues. Collagen cross-links and the aldehyde contents were not significantly lower in cartilage and tendon collagens of vitamin B-6-deficient animals than in age-matched controls; also, their proteoglycan degrading protease and collagenase activities measured in articular cartilages were not greater. Thus, proteolysis was an unlikely alternative mechanism to account for the loss of connective tissue integrity. These results point to the need for further investigation into adhesive properties of collagen associated proteoglycans or other proteins in vitamin B-6-deficient connective tissue.

  7. Mediastinal lymphadenopathy and pulmonary arterial hypertension in mixed connective tissue disease

    SciTech Connect

    Guit, G.L.; Shaw, P.C.; Ehrlich, J.; Kroon, H.M.; Oudkerk, M.

    1985-02-01

    A case of mixed connective tissue disease (MCTD) is presented in which mediastinal lymphadenopathy was the most prominent radiological finding detected by plain chest radiographs and computed tomography. Pulmonary arterial hypertension, which is a rare and often fatal complication of MCTD, also developed in this patient.

  8. Rn for treatment of periocular fibrous connective tissue sarcomas in the horse

    SciTech Connect

    Frauenfelder, H.C.; Blevins, W.E.; Page, E.H.

    1982-02-01

    Twelve periocular fibrous connective tissue sarcomas in 11 horses were treated with 222Rn. Follow-up periods ranged from 1 to 6 years; the overall nonrecurrence rate at 12 months after therapy was 92%. Two lesions recurred 2 years after treatment, and 1 after 3 years. One of the former lesions has not recurred after a 2nd 222Rn treatment.

  9. Contribution of myofibrillar and connective tissue components to the Warner-Bratzler shear force of cooked beef.

    PubMed

    Girard, I; Bruce, H L; Basarab, J A; Larsen, I L; Aalhus, J L

    2012-12-01

    Myofibrillar (MF-SF) and connective tissue (CT-SF) peak shear forces were interpolated from Warner-Bratzler shear force (SF) deformation curves of cooked bovine M. gluteus medius (GM) and M. semitendinosus (ST) from 112 crossbred steers in a 2×2×2 factorial experiment examining the interactions between slaughter age, growth promotants and breed cross (British versus Continental). Mixed model analyses, Pearson correlations and stepwise multiple regression identified relationships between shear forces, meat quality measurements and production treatments. Connective tissue contribution to SF increased with slaughter age and implantation in the ST and with slaughter age only in the GM. Myofibrillar contribution to SF increased with slaughter age for the ST and with Continental genetics for the GM. Variation in ST SF and MF-SF was best described by muscle weight, which increased with animal age, while GM SF and MF-SF variation was best described by cooking loss, indicating that ST and GM SF were most affected by connective and myofibrillar proteins, respectively. PMID:22842042

  10. Extracellular Wound Matrices:A Novel Regenerative Tissue Matrix (RTM) Technology for Connective Tissue Reconstruction.

    PubMed

    Harper, John R; McQuillan, David J

    2007-06-01

    The restoration of structure, function, and physiology to damaged or missing tissue through the use of a regenerative tissue matrix (RTM) leads to regenerative healing rather than reparative scarring. While many processes exist to transform biologic materials into an extracellular matrix (ECM), only those that maintain the required structural and biochemical properties necessary to capture the intrinsic regenerative abilities of the body are suitable to produce an RTM. Histological examination using differential staining with hematoxylin and eosin stain or Verhoeff von Geisen stain of human biopsies of RTM obtained from 2 different abdominal surgery patients taken at 8- and 12 months were consistent with RTM remodeling into fascia-like tissue. A synopsis of recent studies on the use of the RTM GraftJacket® (Wright Medical Technologies, Memphis, Tenn) in successful closure of diabetic foot wounds is presented. Collectively, these reports indicate that LifeCell produced ECMs exemplified by GraftJacket exhibit the required clinical outcomes associated with an RTM. PMID:26110325

  11. Morphometric analysis of nonsclerosed Glomeruli size and connective tissue content during the aging process.

    PubMed

    Stojanović, Vesna R; Jovanović, Ivan D; Ugrenović, Sladjana Z; Vasović, Ljiljana P; Živković, Vladimir S; Jocić, Miodrag V; Kundalić, Braca K; Pavlović, Miljana N

    2012-01-01

    Number of sclerotic glomeruli increases during the aging process. Consequently, majority of remained nonsclerosed glomeruli become hypertrophic and some of them sclerotic, too. The aim of this study was to quantify the size and connective tissue content of nonsclerosed glomeruli and to evaluate the percentage of hypertrophic ones in examined human cases during the aging. Material was right kidney's tissue of 30 cadavers obtained during routine autopsies. Cadavers were without previously diagnosed kidney disease, diabetes, hypertension, or any other systemic disease. Tissue specimens were routinely prepared for histological and morphometric analysis. Images of the histological slices were analyzed and captured under 400x magnification with digital camera. Further they were morphometrically and statistically analyzed with ImageJ and NCSS-PASS software. Multiple and linear regression of obtained morphometric parameters showed significant increase of glomerular connective tissue area and percentage. Cluster analysis showed the presence of two types of glomeruli. Second type was characterized with significantly larger size, connective tissue content, and significantly lower cellularity, in relation to the first type. Such glomeruli might be considered as hypertrophic. First type of glomeruli was predominant in younger cases, while second type of glomeruli was predominant in cases older than 55 years. PMID:22654637

  12. Ultrasound evidence of altered lumbar connective tissue structure in human subjects with chronic low back pain

    PubMed Central

    2009-01-01

    Background Although the connective tissues forming the fascial planes of the back have been hypothesized to play a role in the pathogenesis of chronic low back pain (LBP), there have been no previous studies quantitatively evaluating connective tissue structure in this condition. The goal of this study was to perform an ultrasound-based comparison of perimuscular connective tissue structure in the lumbar region in a group of human subjects with chronic or recurrent LBP for more than 12 months, compared with a group of subjects without LBP. Methods In each of 107 human subjects (60 with LBP and 47 without LBP), parasagittal ultrasound images were acquired bilaterally centered on a point 2 cm lateral to the midpoint of the L2-3 interspinous ligament. The outcome measures based on these images were subcutaneous and perimuscular connective tissue thickness and echogenicity measured by ultrasound. Results There were no significant differences in age, sex, body mass index (BMI) or activity levels between LBP and No-LBP groups. Perimuscular thickness and echogenicity were not correlated with age but were positively correlated with BMI. The LBP group had ~25% greater perimuscular thickness and echogenicity compared with the No-LBP group (ANCOVA adjusted for BMI, p < 0.01 and p < 0.001 respectively). Conclusion This is the first report of abnormal connective tissue structure in the lumbar region in a group of subjects with chronic or recurrent LBP. This finding was not attributable to differences in age, sex, BMI or activity level between groups. Possible causes include genetic factors, abnormal movement patterns and chronic inflammation. PMID:19958536

  13. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.

    PubMed

    Alazami, Anas M; Al-Qattan, Sarah M; Faqeih, Eissa; Alhashem, Amal; Alshammari, Muneera; Alzahrani, Fatema; Al-Dosari, Mohammed S; Patel, Nisha; Alsagheir, Afaf; Binabbas, Bassam; Alzaidan, Hamad; Alsiddiky, Abdulmonem; Alharbi, Nasser; Alfadhel, Majid; Kentab, Amal; Daza, Riza M; Kircher, Martin; Shendure, Jay; Hashem, Mais; Alshahrani, Saif; Rahbeeni, Zuhair; Khalifa, Ola; Shaheen, Ranad; Alkuraya, Fowzan S

    2016-05-01

    Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome. PMID:27023906

  14. Control of tissue growth by locally produced activator: Liver regeneration

    NASA Astrophysics Data System (ADS)

    Zhdanov, Vladimir P.

    2015-03-01

    In general, the tissue development is controlled by growth factors and depends on the biomechanics of cells. The corresponding kinetic models are focused primarily on the early stages of the development. The attempts to construct such models for the later stages are still rare. One of the notable examples here is liver regeneration. Referring to this process, the author proposes and analyzes a generic kinetic model describing the regulation of tissue growth by locally produced activator. The model includes activator diffusion and control of the rate of cell proliferation which is described by using the Hill expression. Although this control may be moderately or strongly non-linear, the qualitative changes in the regeneration kinetics are predicted to be modest. For moderately non-linear control, the evolution of the tissue volume to the steady-state value exhibits an initial relatively short linear stage and then becomes slightly slower so that the whole kinetics is close to exponential. For strongly non-linear control, the linear stage dominates and/or the kinetics may exhibit a S-like shape feature which is, however, rather weak. The identification of such qualitative features in experimentally measured kinetics is shown to be difficult, because the error bars in the experiments are typically too large.

  15. Near-infrared lipophilic fluorophores for tracing tissue growth

    PubMed Central

    Kim, Soon Hee; Park, Gwangli; Hyun, Hoon; Lee, Jeong Heon; Ashitate, Yoshitomo; Choi, Jungmun; Hong, Gloria H; Owens, Eric A; Henary, Maged; Choi, Hak Soo

    2013-01-01

    Longitudinal monitoring of cell migration, division and differentiation is of paramount importance in cell-based medical treatment. However, currently available optical techniques for tracing cell growth and tissue development are limited in applications due to genetic modification, toxicity and inaccurate detection when utilizing the visible spectrum. We have developed lipophilic near-infrared (NIR) fluorophores with high optical properties and a low background signal that allows longitudinal monitoring of cell proliferation and differentiation. Intracellular labeling efficacy was highly dependent on the physicochemical properties of fluorophores such as lipophilicity, charge, polar surface area and rotational bonds. Among the series of NIR cyanine fluorophores, ESNF 13 showed high solubility in aqueous buffer, high membrane penetration, low cytotoxicity and a long-term signal maintainability with a high signal intensity. This study will guide tissue engineers in designing long-term cell trafficking agents with better physicochemical and optical properties. PMID:23353894

  16. Connective Tissue Reaction to White and Gray MTA Mixed With Distilled Water or Chlorhexidine in Rats

    PubMed Central

    Yavari, Hamid Reza; Shahi, Shahriar; Rahimi, Saeed; Shakouie, Sahar; Roshangar, Leila; Mesgari Abassi, Mehran; Sattari Khavas, Sahar

    2009-01-01

    INTRODUCTION: The purpose of this study was to compare the histocompatibility of white (WMTA) and gray (GMTA) mineral trioxide aggregate mixed with 0.12% chlorhexidine (CHX) and distilled water (DW) in subcutaneous connective tissues of rats. MATERIALS AND METHODS: The freshly mixed WMTA and GMTA with CHX or DW were inserted in polyethylene tubes and implanted into dorsal subcutaneous connective tissue of 50 Wistar Albino rats; tissue biopsies were collected and were then examined histologically 7, 15, 30, 60 and 90 days after the implantation procedure. The histology results were scored from 1-4; score 4 was considered as the worst finding. Data were analyzed using one-way ANOVA tests. RESULTS: All experimented materials were tolerated well by the connective tissues after 90-day evaluation, except for the WMTA/CHX group that had significantly more mean inflammatory scores (P<0.001). There was a statistically significant difference in the mean inflammation grades between experimental groups in each interval (P<0.001). After 90 days, GMTA/CHX group had the lowest inflammatory score. CONCLUSION: Although adding CHX to WMTA produces significantly higher inflammatory response, it seems a suitable substitute for DW in combination with GMTA. Further research is necessary to recommend this mixture for clinical use. PMID:23864873

  17. Fractal analysis of the structural complexity of the connective tissue in human carotid bodies

    PubMed Central

    Guidolin, Diego; Porzionato, Andrea; Tortorella, Cinzia; Macchi, Veronica; De Caro, Raffaele

    2014-01-01

    The carotid body (CB) may undergo different structural changes during perinatal development, aging, or in response to environmental stimuli. In the previous literature, morphometric approaches to evaluate these changes have considered quantitative first order parameters, such as volumes or densities, while changes in spatial disposition and/or complexity of structural components have not yet been considered. In the present study, different strategies for addressing morphological complexity of CB, apart from the overall amount of each tissue component, were evaluated and compared. In particular, we considered the spatial distribution of connective tissue in the carotid bodies of young control subjects, young opiate-related deaths and aged subjects, through analysis of dispersion (Morisita's index), gray level co-occurrence matrix (entropy, angular second moment, variance, correlation), and fractal analysis (fractal dimension, lacunarity). Opiate-related deaths and aged subjects showed a comparable increase in connective tissue with respect to young controls. However, the Morisita's index (p < 0.05), angular second moment (p < 0.05), fractal dimension (p < 0.01), and lacunarity (p < 0.01) permitted to identify significant differences in the disposition of the connective tissue between these two series. A receiver operating characteristic (ROC) curve was also calculated to evaluate the efficiency of each parameter. The fractal dimension and lacunarity, with areas under the ROC curve of 0.9651 (excellent accuracy) and 0.8835 (good accuracy), respectively, showed the highest discriminatory power. They evidenced higher level of structural complexity in the carotid bodies of opiate-related deaths than old controls, due to more complex branching of intralobular connective tissue. Further analyses will have to consider the suitability of these approaches to address other morphological features of the CB, such as different cell populations, vascularization, and innervation

  18. [Antinuclear antibodies without connective tissue disease : Antibodies against LEDGF/DSF70].

    PubMed

    Mierau, R

    2016-05-01

    Testing for antinuclear antibodies (ANA) by the indirect immunofluorescence test (IFT) is regarded as a fundamental serological screening method for diagnosing connective tissue diseases (CTD). In the case of a negative result exclusion of certain CTDs is indicated, especially systemic lupus erythematosus, and a positive ANA result is the starting point for further tests aimed at finding disease-specific autoantibodies. The recently discovered antibodies against lens epithelium-derived growth factor (LEDGF/DSF70) deviate from the normal interpretation pattern in ANA diagnostics. These antibodies give rise to a characteristic dense fine speckled (DSF) immunofluorescence pattern in IFT and target the ubiquitously expressed nuclear stress protector protein LEDGFp75. They can be detected, sometimes in high titers, not only in patients with diverse disorders of the skin or eyes and with neoplasms but also in persons with relatively mild or unspecific complaints and even in apparently healthy individuals; however, they are less frequent in CTD. These anti-LEDGF antibodies can be found in all age groups with a tendency to a higher prevalence in younger people and the frequency does not increase in advanced age. The vast majority of anti-LEDGF carriers are female. The CTDs with isolated anti-LEDGF antibodies, i. e. unaccompanied by autoantibodies typical for the respective CTD, are extremely rare. Detection of ANA exclusively with a DSF immunofluorescence pattern and confirmed by a specific anti-LEDGF binding assay, does not therefore indicate the presence of CTD but is indicative of exclusion of systemic lupus erythematosus, systemic sclerosis and an ANA-associated overlap syndrome, similar to a completely negative ANA result. PMID:26820723

  19. A New Variant of Connective Tissue Nevus with Elastorrhexis and Predilection for the Upper Chest.

    PubMed

    Chu, Derek H; Goldbach, Hayley; Wanat, Karolyn A; Rubin, Adam I; Yan, Albert C; Treat, James R

    2015-01-01

    Localized changes in cutaneous elastic tissue often manifest with flesh-colored, hypopigmented, or yellow papules, plaques, and nodules. We present five children with clinically similar cobblestone plaques composed of multiple hypopigmented, nonfollicular, pinpoint papules located unilaterally over the upper chest. All lesions first appeared at birth or during early infancy. No associated extracutaneous abnormalities have been identified. Histopathology was remarkable for many, thick elastic fibers with elastorrhexis. We believe that these cases represent a distinct and unique variant of connective tissue nevi. PMID:25545833

  20. Gingival Cyst of the Adult as Early Sequela of Connective Tissue Grafting

    PubMed Central

    Gil Escalante, Mariana; Tatakis, Dimitris N.

    2015-01-01

    The subepithelial connective tissue graft (SCTG) is a highly predictable procedure with low complication rate. The reported early complications consist of typical postsurgical sequelae, such as pain and swelling. This case report describes the development and management of a gingival cyst following SCTG to obtain root coverage. Three weeks after SCTG procedure, a slightly raised, indurated, ~5 mm diameter asymptomatic lesion was evident. Excisional biopsy was performed and the histopathological evaluation confirmed the gingival cyst diagnosis. At the 1-year follow-up, the site had complete root coverage and normal tissue appearance and the patient remained asymptomatic. PMID:26236510

  1. Temporomandibular joint dysfunction. Connective tissue variations in skin biopsy and mitral valve function.

    PubMed

    Westling, L; Holm, S; Wallentin, I

    1992-12-01

    Ten women with temporomandibular joint dysfunction and general joint hypermobility (score, 4 to 8) and 10 symptom-free female volunteers without systemic laxity (score, 0 to 2) were selected for the study. A biopsy of connective tissue from arm skin found that the total collagen concentrations were lower and the proteoglycan values were higher in the hypermobile TMJ patients than in the control subjects. The mitral region of the heart was inspected by echocardiography. Eight patients and four controls had slightly abnormal echocardiographic findings. Two patients fulfilled the criteria for mitral valve prolapse. The patients had significantly more musculoskeletal complaints than did the controls. The study suggests an association between joint hypermobility, abnormal skin connective tissue composition, mitral valve malfunction, and musculoskeletal disorders in young women with TMJ dysfunction, especially internal derangement. PMID:1488224

  2. Application of exogenous enzymes to beef muscle of high and low-connective tissue.

    PubMed

    Sullivan, G A; Calkins, C R

    2010-08-01

    Exogenous enzymes tenderize meat through proteolysis. Triceps brachii and Supraspinatus were randomly assigned to the seven enzyme treatments, papain, ficin, bromelain, homogenized fresh ginger, Bacillus subtilis protease, and two Aspergillus oryzae proteases or control to determine the extent of tenderization (Warner-Bratzler shear and sensory evaluation) and mode of action (myofibrillar or collagen degradation). Sensory evaluation showed improvement (P<0.0009) for tenderness and connective tissue component and all except ginger had a lower shear force than the control (P<0.003). Ginger produced more off-flavor than all other treatments (P<0.0001). Only papain increased soluble collagen (P<0.0001). Control samples were only significantly less than ficin for water soluble (P=0.0002) and A. oryzae concentrate for salt soluble proteins (P=0.0148). All enzyme treatments can increase tenderness via myofibrillar and collagenous protein degradation with no difference among high and low-connective tissue muscles. PMID:20416788

  3. Subpedicle connective tissue graft versus guided tissue regeneration with bioabsorbable membrane in the treatment of human gingival recession defects.

    PubMed

    Trombelli, L; Scabbia, A; Tatakis, D N; Calura, G

    1998-11-01

    The purpose of the present clinical study was to evaluate the effect of guided tissue regeneration (GTR) in comparison to subpedicle connective tissue graft (SCTG) in the treatment of gingival recession defects. A total of 12 patients, each contributing a pair of Miller's Class I or II buccal gingival recessions, was treated. According to a randomization list, one defect in each patient received a polyglycolide/lactide bioabsorbable membrane, while the paired defect received a SCTG. Treatment effect was evaluated 6 months postsurgery. Clinical recordings included full-mouth and defect-specific oral hygiene standards and gingival health, recession depth (RD), recession width (RW), probing depth (PD), clinical attachment level (CAL), and keratinized tissue width (KT). Mean RD significantly decreased from 3.1 mm presurgery to 1.5 mm at 6 months postsurgery for the GTR group (48% root coverage), and from 3.0 mm to 0.5 mm for the SCTG group (81% root coverage). RD reduction and root coverage were significantly greater in SCTG group compared to GTR group. Mean CAL gain amounted to 1.7 mm for the GTR group, and 2.3 mm in the SCTG group. No significant differences in PD changes were observed within and between groups. KT increased significantly from presurgery for both treatment groups, however gingival augmentation was significantly greater in the SCTG group compared to GTR group. Results indicate that: 1) treatment of human gingival recession defects by means of both GTR and SCTG procedures results in clinically and statistically significant improvement of the soft tissue conditions of the defect; and 2) treatment outcome was significantly better following SCTG compared to GTR in terms of recession depth reduction, root coverage, and keratinized tissue increase. PMID:9848537

  4. Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-)).

    PubMed

    LaRusso, Jennifer; Li, Qiaoli; Jiang, Qiujie; Uitto, Jouni

    2009-06-01

    Pseudoxanthoma elasticum (PXE) is an autosomal recessive multisystem disorder characterized by ectopic connective tissue mineralization, with clinical manifestations primarily in the skin, eyes, and cardiovascular system. There is considerable, both intra- and interfamilial, variability in the spectrum of phenotypic presentation. Previous studies have suggested that mineral content of the diet may modify the severity of the clinical phenotype in PXE. In this study, we utilized a targeted mutant mouse (Abcc6(-/-)) as a model system for PXE. We examined the effects of changes in dietary phosphate and magnesium on the mineralization process using calcification of the connective tissue capsule surrounding the vibrissae as an early phenotypic biomarker. Mice placed on custom-designed diets either high or low in phosphate did not show changes in mineralization, which was similar to that noted in Abcc6(-/-) mice on control diet. However, mice placed on diet enriched in magnesium (fivefold) showed no evidence of connective tissue mineralization in this mouse model of PXE. The inhibitory capacity of magnesium was confirmed in a cell-based mineralization assay system in vitro. Collectively, our observations suggest that assessment of dietary magnesium in patients with PXE may be warranted. PMID:19122649

  5. Interpretation of autoantibody positivity in interstitial lung disease and lung-dominant connective tissue disease*

    PubMed Central

    Pereira, Daniel Antunes Silva; Kawassaki, Alexandre de Melo; Baldi, Bruno Guedes

    2013-01-01

    The initial evaluation of patients with interstitial lung disease (ILD) primarily involves a comprehensive, active search for the cause. Autoantibody assays, which can suggest the presence of a rheumatic disease, are routinely performed at various referral centers. When interstitial lung involvement is the condition that allows the definitive diagnosis of connective tissue disease and the classical criteria are met, there is little debate. However, there is still debate regarding the significance, relevance, specificity, and pathophysiological role of autoimmunity in patients with predominant pulmonary involvement and only mild symptoms or formes frustes of connective tissue disease. The purpose of this article was to review the current knowledge of autoantibody positivity and to discuss its possible interpretations in patients with ILD and without clear etiologic associations, as well as to enhance the understanding of the natural history of an allegedly new disease and to describe the possible prognostic implications. We also discuss the proposition of a new term to be used in the classification of ILDs: lung-dominant connective tissue disease. PMID:24473767

  6. Mineralization and growth of cultured embryonic skeletal tissue in microgravity

    NASA Technical Reports Server (NTRS)

    Klement, B. J.; Spooner, B. S.

    1999-01-01

    Microgravity provides a unique environment in which to study normal and pathological phenomenon. Very few studies have been done to examine the effects of microgravity on developing skeletal tissue such as growth plate formation and maintenance, elongation of bone primordia, or the mineralization of growth plate cartilage. Embryonic mouse premetatarsal triads were cultured on three space shuttle flights to study cartilage growth, differentiation, and mineralization, in a microgravity environment. The premetatarsal triads that were cultured in microgravity all formed cartilage rods and grew in length. However, the premetatarsal cartilage rods cultured in microgravity grew less in length than the ground control cartilage rods. Terminal chondrocyte differentiation also occurred during culture in microgravity, as well as in the ground controls, and the matrix around the hypertrophied chondrocytes was capable of mineralizing in both groups. The same percentage of premetatarsals mineralized in the microgravity cultures as mineralized in the ground control cultures. In addition, the sizes of the mineralized areas between the two groups were very similar. However, the amount of 45Ca incorporated into the mineralized areas was significantly lower in the microgravity cultures, suggesting that the composition or density of the mineralized regions was compromised in microgravity. There was no significant difference in the amount of 45Ca liberated from prelabeled explants in microgravity or in the ground controls.

  7. Migration of connective tissue-derived cells is mediated by ultra-low concentration gradient fields of EGF

    PubMed Central

    Kong, Qingjun; Majeska, Robert J.; Vazquez, Maribel

    2011-01-01

    The directed migration of cells towards chemical stimuli incorporates simultaneous changes in both the concentration of a chemotactic agent and its concentration gradient, each of which may influence cell migratory response. In this study, we utilized a microfluidic system to examine the interactions between Epidermal Growth Factor (EGF) concentration and EGF gradient in stimulating the chemotaxis of connective-tissue derived fibroblast cells. Cells seeded within microfluidic devices were exposed to concentration gradients established by EGF concentrations that matched or exceeded those required for maximum chemotactic responses seen in transfilter migration assays. The migration of individual cells within the device was measured optically after steady-state gradients had been experimentally established. Results illustrate that motility was maximal at EGF concentration gradients between .01- and 0.1-ng/(mL.mm) for all concentrations used. In contrast, the numbers of motile cells continually increased with increasing gradient steepness for all concentrations examined. Microfluidics-based experiments exposed cells to minute changes in EGF concentration and gradient that were in line with the acute EGFR phosphorylation measured. Correlation of experimental data with established mathematical models illustrated that the fibroblasts studied exhibit an unreported chemosensitivity to minute changes in EGF concentration, similar to that reported for highly motile cells, such as macrophages. Our results demonstrate that shallow chemotactic gradients, while previously unexplored, are necessary to induce the rate of directed cellular migration and the number of motile cells in the connective tissue-derived cells examined. PMID:21536028

  8. Repair of Dense Connective Tissues via Biomaterial-Mediated Matrix Reprogramming of the Wound Interface

    PubMed Central

    Qu, Feini; Pintauro, Michael P.; Haughan, Joanne; Henning, Elizabeth A.; Esterhai, John L.; Schaer, Thomas P.; Mauck, Robert L.; Fisher, Matthew B.

    2014-01-01

    Repair of dense connective tissues in adults is limited by their intrinsic hypocellularity and is exacerbated by a dense extracellular matrix (ECM) that impedes cellular migration to and local proliferation at the wound site. Conversely, healing in fetal tissues occurs due in part to an environment conducive to cell mobility and division. Here, we investigated whether the application of a degradative enzyme, collagenase, could reprogram the adult wound margin to a more fetal-like state, and thus abrogate the biophysical impediments that hinder migration and proliferation. We tested this concept using the knee meniscus, a commonly injured structure for which few regenerative approaches exist. To focus delivery and degradation to the wound interface, we developed a system in which collagenase was stored inside poly(ethylene oxide) (PEO) electrospun nanofibers and released upon hydration. Through a series of in vitro and in vivo studies, our findings show that partial digestion of the wound interface improves repair by creating a more compliant and porous microenvironment that expedites cell migration to and/or proliferation at the wound margin. This innovative approach of targeted manipulation of the wound interface, focused on removing the naturally occurring barriers to adult tissue repair, may find widespread application in the treatment of injuries to a variety of dense connective tissues. PMID:25477175

  9. Repair of dense connective tissues via biomaterial-mediated matrix reprogramming of the wound interface.

    PubMed

    Qu, Feini; Pintauro, Michael P; Haughan, Joanne E; Henning, Elizabeth A; Esterhai, John L; Schaer, Thomas P; Mauck, Robert L; Fisher, Matthew B

    2015-01-01

    Repair of dense connective tissues in adults is limited by their intrinsic hypocellularity and is exacerbated by a dense extracellular matrix (ECM) that impedes cellular migration to and local proliferation at the wound site. Conversely, healing in fetal tissues occurs due in part to an environment conducive to cell mobility and division. Here, we investigated whether the application of a degradative enzyme, collagenase, could reprogram the adult wound margin to a more fetal-like state, and thus abrogate the biophysical impediments that hinder migration and proliferation. We tested this concept using the knee meniscus, a commonly injured structure for which few regenerative approaches exist. To focus delivery and degradation to the wound interface, we developed a system in which collagenase was stored inside poly(ethylene oxide) (PEO) electrospun nanofibers and released upon hydration. Through a series of in vitro and in vivo studies, our findings show that partial digestion of the wound interface improves repair by creating a more compliant and porous microenvironment that expedites cell migration to and/or proliferation at the wound margin. This innovative approach of targeted manipulation of the wound interface, focused on removing the naturally occurring barriers to adult tissue repair, may find widespread application in the treatment of injuries to a variety of dense connective tissues. PMID:25477175

  10. Dynamic morphometric characterization of local connective tissue network structure in humans using ultrasound

    PubMed Central

    Langevin, Helene M; Rizzo, Donna M; Fox, James R; Badger, Gary J; Wu, Junru; Konofagou, Elisa E; Stevens-Tuttle, Debbie; Bouffard, Nicole A; Krag, Martin H

    2007-01-01

    Background In humans, connective tissue forms a complex, interconnected network throughout the body that may have mechanosensory, regulatory and signaling functions. Understanding these potentially important phenomena requires non-invasive measurements of collagen network structure that can be performed in live animals or humans. The goal of this study was to show that ultrasound can be used to quantify dynamic changes in local connective tissue structure in vivo. We first performed combined ultrasound and histology examinations of the same tissue in two subjects undergoing surgery: in one subject, we examined the relationship of ultrasound to histological images in three dimensions; in the other, we examined the effect of a localized tissue perturbation using a previously developed robotic acupuncture needling technique. In ten additional non-surgical subjects, we quantified changes in tissue spatial organization over time during needle rotation vs. no rotation using ultrasound and semi-variogram analyses. Results 3-D renditions of ultrasound images showed longitudinal echogenic sheets that matched with collagenous sheets seen in histological preparations. Rank correlations between serial 2-D ultrasound and corresponding histology images resulted in high positive correlations for semi-variogram ranges computed parallel (r = 0.79, p < 0.001) and perpendicular (r = 0.63, p < 0.001) to the surface of the skin, indicating concordance in spatial structure between the two data sets. Needle rotation caused tissue displacement in the area surrounding the needle that was mapped spatially with ultrasound elastography and corresponded to collagen bundles winding around the needle on histological sections. In semi-variograms computed for each ultrasound frame, there was a greater change in the area under the semi-variogram curve across successive frames during needle rotation compared with no rotation. The direction of this change was heterogeneous across subjects. The frame

  11. [Scanning electron microscopic study of films of the loose connective tissue of mice exposed to DMBA].

    PubMed

    Ol'shevskaia, L V

    1979-01-01

    Under examination by scanning electron microscopy were film samples of the subcutaneous connective tissue. The surface of the films from intact mice was even and smooth, fibroblasts have a spread pattern. Following the saline injection the film was even, collagen fibres, differing in the character of surface and the size of diameter, were readily seen. The collagen fibres formed a multilayer system with a definite orientation inside the layer. After DMBA injection the film surface would get uneven and tuberous, the fibroblast body rising over the film surface, thus the orientation of fibres and all strata was disturbed. There was a spacial rearrangement of all tissue components. It is suggested that carcinogenic agents affecting the relationship between tissue components could interfere the contact inhibition of cell division and result in the development of focal cell proliferates. PMID:113934

  12. Biomimetic scaffold combined with electrical stimulation and growth factor promotes tissue engineered cardiac development.

    PubMed

    Park, Hyoungshin; Larson, Benjamin L; Kolewe, Martin E; Vunjak-Novakovic, Gordana; Freed, Lisa E

    2014-02-15

    Toward developing biologically sound models for the study of heart regeneration and disease, we cultured heart cells on a biodegradable, microfabricated poly(glycerol sebacate) (PGS) scaffold designed with micro-structural features and anisotropic mechanical properties to promote cardiac-like tissue architecture. Using this biomimetic system, we studied individual and combined effects of supplemental insulin-like growth factor-1 (IGF-1) and electrical stimulation (ES). On culture day 8, all tissue constructs could be paced and expressed the cardiac protein troponin-T. IGF-1 reduced apoptosis, promoted cell-to-cell connectivity, and lowered excitation threshold, an index of electrophysiological activity. ES promoted formation of tissue-like bundles oriented in parallel to the electrical field and a more than ten-fold increase in matrix metalloprotease-2 (MMP-2) gene expression. The combination of IGF-1 and ES increased 2D projection length, an index of overall contraction strength, and enhanced expression of the gap junction protein connexin-43 and sarcomere development. This culture environment, designed to combine cardiac-like scaffold architecture and biomechanics with molecular and biophysical signals, enabled functional assembly of engineered heart muscle from dissociated cells and could serve as a template for future studies on the hierarchy of various signaling domains relative to cardiac tissue development. PMID:24240126

  13. Fibroblast growth factors as tissue repair and regeneration therapeutics.

    PubMed

    Nunes, Quentin M; Li, Yong; Sun, Changye; Kinnunen, Tarja K; Fernig, David G

    2016-01-01

    Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine) or systemically (endocrine). The fibroblast growth factor (FGF) family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR) tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West. PMID:26793421

  14. Fibroblast growth factors as tissue repair and regeneration therapeutics

    PubMed Central

    Kinnunen, Tarja K.

    2016-01-01

    Cell communication is central to the integration of cell function required for the development and homeostasis of multicellular animals. Proteins are an important currency of cell communication, acting locally (auto-, juxta-, or paracrine) or systemically (endocrine). The fibroblast growth factor (FGF) family contributes to the regulation of virtually all aspects of development and organogenesis, and after birth to tissue maintenance, as well as particular aspects of organism physiology. In the West, oncology has been the focus of translation of FGF research, whereas in China and to an extent Japan a major focus has been to use FGFs in repair and regeneration settings. These differences have their roots in research history and aims. The Chinese drive into biotechnology and the delivery of engineered clinical grade FGFs by a major Chinese research group were important enablers in this respect. The Chinese language clinical literature is not widely accessible. To put this into context, we provide the essential molecular and functional background to the FGF communication system covering FGF ligands, the heparan sulfate and Klotho co-receptors and FGF receptor (FGFR) tyrosine kinases. We then summarise a selection of clinical reports that demonstrate the efficacy of engineered recombinant FGF ligands in treating a wide range of conditions that require tissue repair/regeneration. Alongside, the functional reasons why application of exogenous FGF ligands does not lead to cancers are described. Together, this highlights that the FGF ligands represent a major opportunity for clinical translation that has been largely overlooked in the West. PMID:26793421

  15. Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions

    PubMed Central

    Monument, Michael J.; Hart, David A.; Salo, Paul T.; Befus, A. Dean; Hildebrand, Kevin A.

    2015-01-01

    Significance: The pathogenesis of fibrogenic wound and connective tissue healing is complex and incompletely understood. Common observations across a vast array of human and animal models of fibroproliferative conditions suggest neuroinflammatory mechanisms are important upstream fibrogenic events. Recent Advances: As detailed in this review, mast cell hyperplasia is a common observation in fibrotic tissue. Recent investigations in human and preclinical models of hypertrophic wound healing and post-traumatic joint fibrosis provides evidence that fibrogenesis is governed by a maladaptive neuropeptide-mast cell-myofibroblast signaling pathway. Critical Issues: The blockade and manipulation of these factors is providing promising evidence that if timed correctly, the fibrogenic process can be appropriately regulated. Clinically, abnormal fibrogenic healing responses are not ubiquitous to all patients and the identification of those at-risk remains an area of priority. Future Directions: Ultimately, an integrated appreciation of the common pathobiology shared by many fibrogenic connective tissue conditions may provide a scientific framework to facilitate the development of novel antifibrotic prevention and treatment strategies. PMID:25785237

  16. An opioid system in connective tissue: a study of achilles tendon in the rat.

    PubMed

    Ackermann, P W; Spetea, M; Nylander, I; Ploj, K; Ahmed, M; Kreicbergs, A

    2001-11-01

    The occurrence of endogenous opioids and their receptors in rat achilles tendon was analyzed by immunohistochemistry (IHC), radioimmunoassay (RIA), and in vitro binding assays. The investigation focused on four enkephalins, dynorphin B, and nociceptin/orphanin FQ. Nerve fibers immunoreactive to all enkephalins (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Gly-Lys, Met-enkephalin-Arg-Phe) were consistently found in the loose connective tissue and the paratenon, whereas dynorphin B and nociceptin/orphanin FQ could not be detected. The majority of enkephalin-positive nerve fibers exhibited varicosities predominantly seen in blood vessel walls. Measurable levels of Met-enkephalin-Arg-Phe and nociceptin/orphanin FQ were found in tendon tissue using RIA, whereas dynorphin B could not be detected. In addition to the endogenous opioids identified, delta-opioid receptors on nerve fibers were also detected by IHC. Binding assays to characterize the opioid binding sites showed that they were specific and saturable for [3H]-naloxone (Kd 7.01 +/- 0.98 nM; Bmax 23.52 +/- 2.23 fmol/mg protein). Our study demonstrates the occurrence of an opioid system in rat achilles tendon, which may be assumed to be present also in other connective tissues of the locomotor apparatus. This system may prove to be a useful target for pharmacological therapy in painful and inflammatory conditions by new drugs acting selectively in the periphery. PMID:11668192

  17. Histological changes in connective tissue of rat tails after bipolar radiofrequency treatment.

    PubMed

    Beltrán-Frutos, E; Bernal-Mañas, C M; Navarro, S; Zuasti, A; Ferrer, C; Canteras, M; Seco-Rovira, V; García-Collado, A J; Pastor, L M

    2012-09-01

    Radiofrequency (RF) has been included in the techniques used in aesthetic surgery/medicine. To date, no studies have performed a histological assessment of changes in the tissue after application of bipolar radiofrequency (BRF) with low energy and frequency. The aim of this study was to examine changes that are produced in connective tissue, principally in the fibroblasts, following BRF treatment. Four groups of rats received a different number of RF sessions (1, 2, 3 and 5). The following parameters were determined: the number of fibroblasts/unit area (FA), the proliferation index (PI), the Heat shock Protein 47 index (HSPI) and the percentage of connective tissue (PC). For statistical analysis, two subgroups (A and B) were made for the variables FA, PI and PC, and another two subgroups (C and D) for the variable HSPI. Significant differences for FA, PI and PC were observed between subgroups A and B, FA and PI having higher values in A, while PC had higher values in B. The HSPI in subgroup C showed significantly higher values than in D. Low energy and frequency BRF led to an increase in the number, proliferation and biosynthetic activity of fibroblasts. The resulting stress suffered by fibroblasts as a result of heat may be associated with the phenomenon of hormesis. PMID:22806911

  18. State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD).

    PubMed

    Ohno, Yoshiharu; Koyama, Hisanobu; Yoshikawa, Takeshi; Seki, Shinichiro

    2015-12-01

    Involvement of the respiratory system is common in connective tissue diseases (CTDs), and the resultant lung injury can affect every part of the lung: the pleura, alveoli, interstitium, vasculature, lymphatic tissue, and large and/or small airways. Most of the parenchymal manifestations of CTD are similar to those found in interstitial lung diseases (ILDs), especially idiopathic interstitial pneumonias, and can be classified using the same system. Although there is some overlap, each CTD is associated with a characteristic pattern of pulmonary involvement. For this reason, thin-section CT as well as pulmonary function tests and serum markers are utilized for diagnosis, disease severity assessment, and therapeutic efficacy evaluation of ILD associated with CTD. In addition, newly developed pulmonary magnetic resonance imaging (MRI) procedures have been recommended as useful alternative imaging options for patients with CTD. This review article will (1) address radiological findings for chest radiography and conventional or thin-section CT currently used for six major types of CTD, rheumatoid arthritis, scleroderma (progressive systemic sclerosis), polymyositis/dermatomyositis, systemic lupus erythematosus, Sjögren syndrome and mixed connective tissue disease; (2) briefly deal with radiation dose reduction for thin-section CT examination; and (3) discuss clinically applicable or state-of-the-art MR imaging for CTD patients. PMID:26483318

  19. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration

    PubMed Central

    Murphy, Malea M.; Lawson, Jennifer A.; Mathew, Sam J.; Hutcheson, David A.; Kardon, Gabrielle

    2011-01-01

    Muscle regeneration requires the coordinated interaction of multiple cell types. Satellite cells have been implicated as the primary stem cell responsible for regenerating muscle, yet the necessity of these cells for regeneration has not been tested. Connective tissue fibroblasts also are likely to play a role in regeneration, as connective tissue fibrosis is a hallmark of regenerating muscle. However, the lack of molecular markers for these fibroblasts has precluded an investigation of their role. Using Tcf4, a newly identified fibroblast marker, and Pax7, a satellite cell marker, we found that after injury satellite cells and fibroblasts rapidly proliferate in close proximity to one another. To test the role of satellite cells and fibroblasts in muscle regeneration in vivo, we created Pax7CreERT2 and Tcf4CreERT2 mice and crossed these to R26RDTA mice to genetically ablate satellite cells and fibroblasts. Ablation of satellite cells resulted in a complete loss of regenerated muscle, as well as misregulation of fibroblasts and a dramatic increase in connective tissue. Ablation of fibroblasts altered the dynamics of satellite cells, leading to premature satellite cell differentiation, depletion of the early pool of satellite cells, and smaller regenerated myofibers. Thus, we provide direct, genetic evidence that satellite cells are required for muscle regeneration and also identify resident fibroblasts as a novel and vital component of the niche regulating satellite cell expansion during regeneration. Furthermore, we demonstrate that reciprocal interactions between fibroblasts and satellite cells contribute significantly to efficient, effective muscle regeneration. PMID:21828091

  20. Depression and seizures as the main neuropsychiatric manifestation of mixed connective tissue disorder.

    PubMed

    Kiani, Ismaa Ghazanfar; Qureshi, Safina Hameed; Shah, Faridullah

    2014-05-01

    A 38 years female presented with arthralgia, dyspnoea, progressive proximal muscle weakness, seizures, weight loss, dysphagia, alopecia, and dryness of the eyes and mouth with tightening of the skin. Psychiatric evaluation revealed major depression. She had oral ulcers, tightening of the skin of the hands with restricted mouth opening, and proximal muscle weakness. Mixed connective tissue disorder (MCTD) with predominant polymyositis and neuropsychiatric manifestations was diagnosed as the patient had anti-RNP positive with significantly raised muscle enzymes. This case is unique because major depression in MCTD is rarely documented, severe polymyositis is a rarity and ANA was negative but characteristic anti-RNP antibody was positive. PMID:24906270

  1. Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues

    PubMed Central

    Nichols, Scott P.; Storm, Wesley L.; Koh, Ahyeon; Schoenfisch, Mark H.

    2012-01-01

    Non-invasive treatment of injuries and disorders affecting bones and connective tissue is a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair. PMID:22433782

  2. Intrapleural Corticosteroid Injection in Eosinophilic Pleural Effusion Associated with Undifferentiated Connective Tissue Disease

    PubMed Central

    Kim, Eunjung; Yang, Bokyung; Kim, Mihee; Kang, Jingu; Lee, Jiun

    2013-01-01

    Eosinophilic pleural effusion (EPE) is defined as a pleural effusion that contains at least 10% eosinophils. EPE occurs due to a variety of causes such as blood or air in the pleural space, infection, malignancy, or an autoimmune disease. Undifferentiated connective tissue disease (UCTD) associated with eosinophilic pleural effusion is a rare condition generally characterized by the presence of the signs and symptoms but not fulfilling the existing classification criteria. We report a case involving a 67-year-old man with UCTD and EPE, who has been successfully treated with a single intrapleural corticosteroid injection. PMID:24265645

  3. Mutation of fibulin-1 causes a novel syndrome involving the central nervous system and connective tissues

    PubMed Central

    Bohlega, Saeed; Al-Ajlan, Huda; Al-Saif, Amr

    2014-01-01

    Fibulin-1 is an extracellular matrix protein that has an important role in the structure of elastic fibers and basement membranes of various tissues. Using homozygosity mapping and exome sequencing, we discovered a missense mutation, p.(Cys397Phe), in fibulin-1 in three patients from a consanguineous family presented with a novel syndrome of syndactyly, undescended testes, delayed motor milestones, mental retardation and signs of brain atrophy. The mutation discovered segregated with the phenotype and was not found in 374 population-matched alleles. The affected cysteine is highly conserved across vertebrates and its mutation is predicted to abolish a disulfide bond that defines the tertiary structure of fibulin-1. Our findings emphasize the crucial role fibulin-1 has in development of the central nervous system and various connective tissues. PMID:24084572

  4. [Connective tissue dysplasia in patients with celiac desease as a problem of violation of adaptation reserve islands of the body].

    PubMed

    Tkachenko, E; Oreshko, L S; Soloveva, E A; Shabanova, A A; Zhuravleva, M S

    2015-01-01

    Clinically significant dysplasia of connective tissue in patients with celiac disease is often responsible for various visceral disorders. Different disturbances of motor and evacuation functions are often determined in this patients (gastroesophageal reflux, duodenogastral reflux, spastic and hyperkinetic dyskinesia). The clinical course of the celiac disease, associated with connective tissue dysplasia, is characterized by asthenovegetative syndrome, reduced tolerance to physical activity, general weakness, fatigue and emotional instability. These data should be considered in choosing a treatment. PMID:25993866

  5. Targeted Ablation of the Abcc6 Gene Results in Ectopic Mineralization of Connective Tissues

    PubMed Central

    Klement, John F.; Matsuzaki, Yasushi; Jiang, Qiu-Jie; Terlizzi, Joseph; Choi, Hae Young; Fujimoto, Norihiro; Li, Kehua; Pulkkinen, Leena; Birk, David E.; Sundberg, John P.; Uitto, Jouni

    2005-01-01

    Pseudoxanthoma elasticum (PXE), characterized by connective tissue mineralization of the skin, eyes, and cardiovascular system, is caused by mutations in the ABCC6 gene. ABCC6 encodes multidrug resistance-associated protein 6 (MRP6), which is expressed primarily in the liver and kidneys. Mechanisms producing ectopic mineralization as a result of these mutations remain unclear. To elucidate this complex disease, a transgenic mouse was generated by targeted ablation of the mouse Abcc6 gene. Abcc6 null mice were negative for Mrp6 expression in the liver, and complete necropsies revealed profound mineralization of several tissues, including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wild-type mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6−/− mice but was not observed in Abcc6+/− or Abcc6+/+ mice up to 2 years of age. A total body computerized tomography scan of Abcc6−/− mice revealed mineralization in skin and subcutaneous tissue as well as in the kidneys. These data demonstrate aberrant mineralization of soft tissues in PXE-affected organs, and, consequently, these mice recapitulate features of this complex disease. PMID:16135817

  6. Genome-Wide Transcriptional Profiling Reveals Connective Tissue Mast Cell Accumulation in Bronchopulmonary Dysplasia

    PubMed Central

    Bhattacharya, Soumyaroop; Go, Diana; Krenitsky, Daria L.; Huyck, Heidi L.; Solleti, Siva Kumar; Lunger, Valerie A.; Metlay, Leon; Srisuma, Sorachai; Wert, Susan E.; Pryhuber, Gloria S.

    2012-01-01

    Rationale: Bronchopulmonary dysplasia (BPD) is a major complication of premature birth. Risk factors for BPD are complex and include prenatal infection and O2 toxicity. BPD pathology is equally complex and characterized by inflammation and dysmorphic airspaces and vasculature. Due to the limited availability of clinical samples, an understanding of the molecular pathogenesis of this disease and its causal mechanisms and associated biomarkers is limited. Objectives: Apply genome-wide expression profiling to define pathways affected in BPD lungs. Methods: Lung tissue was obtained at autopsy from 11 BPD cases and 17 age-matched control subjects without BPD. RNA isolated from these tissue samples was interrogated using microarrays. Standard gene selection and pathway analysis methods were applied to the data set. Abnormal expression patterns were validated by quantitative reverse transcriptase–polymerase chain reaction and immunohistochemistry. Measurements and Main Results: We identified 159 genes differentially expressed in BPD tissues. Pathway analysis indicated previously appreciated (e.g., DNA damage regulation of cell cycle) as well as novel (e.g., B-cell development) biological functions were affected. Three of the five most highly induced genes were mast cell (MC)-specific markers. We confirmed an increased accumulation of connective tissue MCTC (chymase expressing) mast cells in BPD tissues. Increased expression of MCTC markers was also demonstrated in an animal model of BPD-like pathology. Conclusions: We present a unique genome-wide expression data set from human BPD lung tissue. Our data provide information on gene expression patterns associated with BPD and facilitated the discovery that MCTC accumulation is a prominent feature of this disease. These observations have significant clinical and mechanistic implications. PMID:22723293

  7. Evaluation of muscular lesions in connective tissue diseases: thallium 201 muscular scans

    SciTech Connect

    Guillet, G.; Guillet, J.; Sanciaume, C.; Maleville, J.; Geniaux, M.; Morin, P.

    1988-04-01

    We performed thallium 201 muscle scans to assess muscular involvement in 40 patients with different connective tissue diseases (7 with dermatomyositis, 7 with systemic lupus erythematosus, 12 with progressive systemic scleroderma, 2 with calcinosis, Raynaud's phenomenon, esophageal involvement, sclerodactyly, and telangiectasia (CREST) syndrome, 3 with monomelic scleroderma, 6 with morphea, and 3 with Raynaud's disease). Only 12 of these patients complained of fatigability and/or myalgia. Electromyography was performed and serum levels of muscle enzymes were measured in all patients. Comparison of thallium 201 exercise recording with the other tests revealed that scan sensitivity is greater than electromyographic and serum muscle enzymes levels. Thallium 201 scans showed abnormal findings in 32 patients and revealed subclinical lesions in 18 patients, while electromyography findings were abnormal in 25 of these 32 patients. Serum enzyme levels were raised in only 8 patients. Thallium 201 scanning proved to be a useful guide for modifying therapy when laboratory data were conflicting. It was useful to evaluate treatment efficacy. Because our data indicate a 100% positive predictive value, we believe that thallium 201 scanning should be advised for severe systemic connective tissue diseases with discordant test results.

  8. Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain.

    PubMed

    Castori, Marco; Morlino, Silvia; Ghibellini, Giulia; Celletti, Claudia; Camerota, Filippo; Grammatico, Paola

    2015-03-01

    Ehlers-Danlos syndrome (EDS) is an umbrella term for a growing group of hereditary disorders of the connective tissue mainly manifesting with generalized joint hypermobility, skin hyperextensibility, and vascular and internal organ fragility. In contrast with other well known heritable connective tissue disorders with severe cardiovascular involvement (e.g., Marfan syndrome), most EDS patients share a nearly normal life span, but are severely limited by disabling features, such as pain, fatigue and headache. In this work, pertinent literature is reviewed with focus on prevalence, features and possible pathogenic mechanisms of headache in EDSs. Gathered data are fragmented and generally have a low level of evidence. Headache is reported in no less than 1/3 of the patients. Migraine results the most common type in the hypermobility type of EDS. Other possibly related headache disorders include tension-type headache, new daily persistent headache, headache attributed to spontaneous cerebrospinal fluid leakage, headache secondary to Chiari malformation, cervicogenic headache and neck-tongue syndrome, whose association still lacks of reliable prevalence studies. The underlying pathogenesis seems complex and variably associated with cardiovascular dysautonomia, cervical spine and temporomandibular joint instability/dysfunction, meningeal fragility, poor sleep quality, pain-killer drugs overuse and central sensitization. Particular attention is posed on a presumed subclinical cervical spine dysfunction. Standard treatment is always symptomatic and usually unsuccessful. Assessment and management procedures are discussed in order to put some basis for ameliorating the actual patients' needs and nurturing future research. PMID:25655119

  9. Development of human connective tissue mast cells from purified blood monocytes.

    PubMed Central

    Czarnetzki, B M; Figdor, C G; Kolde, G; Vroom, T; Aalberse, R; de Vries, J E

    1984-01-01

    Highly purified subfractions of human peripheral blood monocytes, when cultured in the presence of 30% L cell supernatant and 30% horse serum, assumed all the characteristics that define human connective tissue mast cells. After three weeks of culture, 75% of the cells developed metachromasia and granular chloroacetate esterase staining, and their intracellular histamine levels increased from 0.0 to 50.5 ng/10(6) cells. On electron microscopy, the cells developed intracytoplasmic granules with all the features typical for mature and immature mast cells. Cultured cells bound 55 pg 125I-IgE/10(6) cells, while labelling was negligible with cells prior to culture and with heat-denatured 125I-IgE. Fluorescent staining with anti-IgE increased slightly as well, while staining with monoclonal anti-monocyte and anti-HLA-Dr markers decreased. Purified lymphocytes did not assume mast cell characteristics, and lymphokines did not induce or enhance in vitro mast cell development or IgE binding. The data therefore further support the concept that connective tissue mast cells arise from the monocytoid lineage. Images Figure 1 PMID:6698581

  10. Development of an autologous connective tissue tube as a small caliber vascular substitute.

    PubMed

    Satoh, S; Niu, S; Shirakata, S; Oka, T; Noishiki, Y

    1988-01-01

    A small-caliber vascular graft with good healing properties was developed using an autologous connective tissue tube (ACTT) and in situ heparinization. ACTT is the best material for implantable grafts, but as a small-caliber vascular graft, both the high thrombogenicity and requirement for time to preparation in situ were serious problems. To overcome these difficulties, an ultrafine polyester fiber (UFPF) mesh was used for the framework of the graft. it has been shown that UFPF provides a good framework for fibroblast migration and proliferation both in vivo and in vitro. The granulomatous connective tissue tube could be constructed very rapidly and had numerous capillary blood vessels, which opened onto the luminal surface of the graft when it was implanted as a vascular substitute and provided colonies of endothelial cells. These colonies spread rapidly all over the luminal surface, and the graft developed permanent antithrombogenicity by endothelialization. The next problem was attainment of temporary antithrombogenicity of the graft before complete endothelialization. Since collagen fibrils are highly thrombogenic, the fact that ACTT collagen fibrils face the luminal surface requires greater antithrombogenicity. A new technique for binding heparin to collagen fibrils in situ was also developed. This was proved to be useful in maintaining the antithrombogenicity of the grafts (3 mm in inner diameter, 6 to 7 cm in length) in the animal studies. The graft showed rapid healing of the neonintima with endothelialization and long-term stability of the graft wall. PMID:3196580

  11. Massage-induced morphological changes of dense connective tissue in rat's tendon.

    PubMed

    Kassolik, Krzysztof; Andrzejewski, Waldemar; Dziegiel, Piotr; Jelen, Michal; Fulawka, Lukasz; Brzozowski, Marcin; Kurpas, Donata; Gworys, Bohdan; Podhorska-Okolow, Marzenna

    2013-01-01

    The aim of the experiment was to determine if possible changes in connective tissue induced by massage could have a positive effect justifing the use of massage in all post-traumatic connective tissue conditions, e.g. tendon injuries. The investigations were performed in a group of 18 Buffalo rats. The rats were divided into two groups (experimental and control). To standardize the massage procedure, it was performed with an algometer probe of 0.5 cm2 with constant pressure force of 1 kG (9,81 N). To analyse the number and diameter of collagen fibrils, two electron micrographs were performed for each rat of the collected segments of tendons of rat tail lateral extensor muscle. After image digitalization and calibration, the measurements were carried out using iTEM 5.0 software. The number of fibrils, their diameter and area were measured in a cross-sectional area. An increase of the number of collagen fibrils was observed in the tendons of massaged animals compared to the control group. Our study demonstrated that massage may cause a beneficial effect on metabolic activity of tendon's fibroblasts and, in consequence, may be applied for more effective use of massage for the prevention of tendon injury as well as after the injury has occurred. (Folia Histochemica et Cytobiologica 2013, Vol. 51, No. 1, 103-106). PMID:23690224

  12. Severe eczema and Hyper-IgE in Loeys-Dietz-syndrome - contribution to new findings of immune dysregulation in connective tissue disorders.

    PubMed

    Felgentreff, Kerstin; Siepe, Matthias; Kotthoff, Stefan; von Kodolitsch, Yskert; Schachtrup, Kristina; Notarangelo, Luigi D; Walter, Jolan E; Ehl, Stephan

    2014-01-01

    Loeys-Dietz syndrome (LDS) is a connective tissue disorder caused by monoallelic mutations in TGFBR1 and TGFBR2, which encode for subunits of the transforming growth factor beta (TGFβ) receptor. Affected patients are identified by vascular aneurysms with tortuosity and distinct morphological presentations similar to Marfan syndrome; however, an additional predisposition towards asthma and allergy has recently been found. We describe two patients with a novel missense mutation in TGFBR1 presenting with highly elevated levels of IgE and severe eczema similar to autosomal-dominant Hyper-IgE syndrome (HIES). Mild allergic manifestations with normal up to moderately increased IgE were observed in 3 out of 6 additional LDS patients. A comparison of this cohort with 4 HIES patients illustrates the significant overlap of both syndromes including eczema and elevated IgE as well as skeletal and connective tissue manifestations. PMID:24333532

  13. Clinical evaluation of subepithelial connective tissue graft and guided tissue regeneration for treatment of Miller’s class 1 gingival recession (comparative, split mouth, six months study)

    PubMed Central

    Bhavsar, Neeta-V.; Dulani, Kirti; Trivedi, Rahul

    2014-01-01

    Objectives: The present study aims to clinically compare and evaluate subepithelial connective tissue graft and the GTR based root coverage in treatment of Miller’s Class I gingival recession. Study Design: 30 patients with at least one pair of Miller’s Class I gingival recession were treated either with Subepithelial connective tissue graft (Group A) or Guided tissue regeneration (Group B). Clinical parameters monitored included recession RD, width of keratinized gingiva (KG), probing depth (PD), clinical attachment level (CAL), attached gingiva (AG), residual probing depth (RPD) and % of Root coverage(%RC). Measurements were taken at baseline, three months and six months. A standard surgical procedure was used for both Group A and Group B. Data were recorded and statistical analysis was done for both intergroup and intragroup. Results: At end of six months % RC obtained were 84.47% (Group A) and 81.67% (Group B). Both treatments resulted in statistically significant improvement in clinical parameters. When compared, no statistically significant difference was found between both groups except in RPD, where it was significantly greater in Group A. Conclusions: GTR technique has advantages over subepithelial connective tissue graft for shallow Miller’s Class I defects and this procedure can be used to avoid patient discomfort and reduce treatment time. Key words:Collagen membrane, comparative split mouth study, gingival recession, subepithelial connective tissue graft, guided tissue regeneration (GTR). PMID:25136420

  14. Effect of administration of oral contraceptives in vivo on collagen synthesis in tendon and muscle connective tissue in young women.

    PubMed

    Hansen, M; Miller, B F; Holm, L; Doessing, S; Petersen, S G; Skovgaard, D; Frystyk, J; Flyvbjerg, A; Koskinen, S; Pingel, J; Kjaer, M; Langberg, H

    2009-04-01

    Women are at greater risk than men for certain kinds of diseases and injuries, which may at least partly be caused by sex hormonal differences. We aimed to test the influence of estradiol in vivo on collagen synthesis in tendon, bone, and muscle. Two groups of young, healthy women similar in age, body composition, and exercise-training status were included. The two groups were either habitual users of oral contraceptives exposed to a high concentration of synthetic estradiol and progestogens (OC, n = 11), or non-OC-users tested in the follicular phase of the menstrual cycle characterized by low concentrations of estradiol and progesterone (control, n = 12). Subjects performed 1 h of one-legged kicking exercise. The next day collagen fractional synthesis rates (FSR) in tendon and muscle connective tissue were measured after a flooding dose of [(13)C]proline followed by biopsies from the patellar tendon and vastus lateralis in both legs. Simultaneously, microdialysis catheters were inserted in vastus lateralis and in front of the patellar tendon for measurement of insulin-like growth factor I (IGF-I) and its binding proteins. Serum NH(2)-terminal propeptide of type I collagen (PINP) and urine COOH-terminal telopeptides of type-I collagen (CTX-I) were measured as markers for bone synthesis and breakdown, respectively. Tendon FSR and PINP were lower in OC compared with control. An increase in muscle collagen FSR postexercise was only observed in control (P < 0.05). Furthermore, the results indicate a lower bioavailability of IGF-I in OC. In conclusion, synthetic female sex hormones administered as OC had an inhibiting effect on collagen synthesis in tendon, bone, and muscle connective tissue, which may be related to a lower bioavailability of IGF-I. PMID:18845777

  15. Alveolar Ridge Contouring with Free Connective Tissue Graft at Implant Placement: A 5-Year Consecutive Clinical Study.

    PubMed

    Hanser, Thomas; Khoury, Fouad

    2016-01-01

    This study evaluated volume stability after alveolar ridge contouring with free connective tissue grafts at implant placement in single-tooth gaps. A total of 52 single-tooth gaps with labial volume deficiencies in the maxilla (incisors, canines, and premolars) were consecutively treated with implants and concomitant free palatal connective tissue grafts in 46 patients between 2006 and 2009. Implants had to be covered with at least 2 mm peri-implant local bone after insertion. At implant placement, a free connective tissue graft from the palate was fixed inside a labial split-thickness flap to form an existing concave buccal alveolar ridge contour due to tissue volume deficiency into a convex shape. Standardized volumetric measurements of the labial alveolar contour using a template were evaluated before connective tissue grafting and at 2 weeks, 1 year, and 5 years after implantprosthetic incorporation. Tissue volume had increased significantly (P < .05) in all six reference points representing the outer alveolar soft tissue contour of the implant before connective tissue grafting to baseline (2 weeks after implant-prosthetic incorporation). Statistically, 50% of the reference points (P > .05) kept their volume from baseline to 1 year after prosthetic incorporation and from baseline to 5 years after prosthetic incorporation, respectively, whereas reference points located within the area of the implant sulcus showed a significant (P < .05) decrease in volume. Clinically, 5 years after prosthetic incorporation the originally concave buccal alveolar contour was still convex in all implants, leading to a continuous favorable anatomical shape and improved esthetic situation. Intraoral radiographs confirmed osseointegration and stable peri-implant parameters with a survival rate of 100% after a follow-up of approximately 5 years. Implant placement with concomitant free connective tissue grafting appears to be an appropriate long-term means to contour preexisting buccal

  16. A novel stiffening factor inducing the stiffest state of holothurian catch connective tissue.

    PubMed

    Yamada, Akira; Tamori, Masaki; Iketani, Tomoaki; Oiwa, Kazuhiro; Motokawa, Tatsuo

    2010-10-15

    The dermis of sea cucumbers is a catch connective tissue or mutable collagenous tissue that shows large changes in stiffness. Extensive studies on the dermis revealed that it can adopt three different states having different mechanical properties that can be reversibly converted. These are the stiff, standard and soft states. The standard state is readily produced when a dermal piece is immersed in the sea water containing Ca²+, whereas the soft state can be produced by removal of Ca²+. A stiffening protein, tensilin, has been isolated from some sea cucumbers (Cucumaria frondosa and Holothuria leucospilota). Although tensilin converts the state of the dermis from soft to standard, it cannot convert from standard to stiff. In this study, we isolated and partially purified a novel stiffening factor from the dermis of Holothuria leucospilota. The factor stiffened the dermis in normal artificial sea water (ASW) but did not stiffen the soft dermis in Ca²+-free ASW. It also stiffened the dermis that had been converted to the standard state in Ca²+-free ASW by the action of tensilin. These results suggest that the factor produces the stiff dermis from the standard state but cannot work as a stiffener on the soft dermis. Its addition to longitudinal muscles of the sea cucumber produced no effects, suggesting that its effect is specific to the catch connective tissue. Its stiffening activity was susceptible to trypsin, meaning that it is a polypeptide, and its molecular mass estimated from gel filtration chromatography was 2.4 kDa. PMID:20889821

  17. Characterization of connective tissue progenitors through phase contrast and multicolor fluorescence time-lapse microscopy

    NASA Astrophysics Data System (ADS)

    Kwee, Edward; Powell, Kimerly; Muschler, George

    2015-03-01

    Connective tissue progenitors (CTPs) are defined as the heterogeneous population of tissue resident stem and progenitor cells capable of proliferating and differentiating into connective tissue phenotypes. The prevalence and variation in clonal progeny of CTPs can be characterized using a colony formation assay. However, colony assays do not directly assess the characteristics of the colony founding CTP. We developed a large field of view, time lapse microscopy system with phase contrast and fluorescence capabilities that enables tracking from seeding through colony formation. Cells derived from the trabecular surface of bone were prepared and seeded in an Ibidi-Ph+ chamber slide. Phase contrast images of the slide were obtained every hour using a DMI6000 Leica microscope, 10X objective, and Retiga 2000R camera. Cells were stained using fluorescent antibodies for multiple markers at the time of plating to determine marker expression on seeded cells and re-stained to determine expression on their progeny. Colonies were identified and characterized using automated image processing and quantitative analysis methods. Following colony identification, the time lapse was reversed to identify and characterize the colony founding CTP according to morphology and marker expression. As a representative example, a CD73+/CD90-/CD105- and a CD73+/CD90+/CD105- CTP resulted in a colony with an area of 3720826 microns2 and percent area expression of 2.98%, 3.62%, and 1.13% for CD73, CD90, and CD105, respectively. This method can be used to study CTPs and other stem and progenitor cell populations to benefit point-of-care methods for assay and isolation in cell based therapies.

  18. The integrin-collagen connection--a glue for tissue repair?

    PubMed

    Zeltz, Cédric; Gullberg, Donald

    2016-02-15

    The α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens. Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1). Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events--such as wound healing--where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamily--integrins α10β1 and α11β1. PMID:26857815

  19. Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010.

    PubMed

    Elfving, P; Marjoniemi, O; Niinisalo, H; Kononoff, A; Arstila, L; Savolainen, E; Rutanen, J; Kaipiainen-Seppänen, O

    2016-07-01

    Objective of the study was to evaluate the annual incidence and distribution of autoimmune connective tissue diseases and vasculitides during 2010. All units practicing rheumatology in the Northern Savo area, Finland, participated in the study by collecting data on newly diagnosed adult patients with autoimmune connective tissue disease or vasculitis over 1-year period. Seventy-two cases with autoimmune connective tissue disease were identified. The annual incidence rates were as follows: systemic lupus erythematosus 3.4/100,000 (95 % CI 1.4-7.0), idiopathic inflammatory myopathies 1.9 (0.5-5.0), systemic sclerosis 4.4 (2.0-8.3), mixed connective tissue disease 1.0 (0.1-3.5), Sjögren's syndrome 10.7 (6.7-16.1) and undifferentiated connective tissue disease 13.6 (9.0-19.6). The annual incidence rates among vasculitis category were as follows: antineutrophil cytoplasmic antibody-associated vasculitis 1.5/100,000 (95 % CI 0.3-4.3), central nervous system vasculitis 0.5 (0-2.7) and Henoch-Schönlein purpura 1.5 (0.3-4.3). The annual incidence of giant cell arteritis in the age group of 50 years or older was 7.5/100,000 (95 % CI 3.2-14.8). The longest delay from symptom onset to diagnosis occurred in systemic sclerosis. The incidences of autoimmune connective tissue diseases and vasculitides were comparable with those in published literature. The present study showed female predominance in all connective tissue diseases, excluding idiopathic inflammatory muscle diseases and mean age at onset of disease around 50 years of age. Despite improved diagnostic tools, diagnostic delay is long especially among patients with systemic sclerosis. PMID:27053177

  20. Peptide-modified Substrate for Modulating Gland Tissue Growth and Morphology In Vitro

    PubMed Central

    Taketa, Hiroaki; Sathi, Gulsan Ara; Farahat, Mahmoud; Rahman, Kazi Anisur; Sakai, Takayoshi; Hirano, Yoshiaki; Kuboki, Takuo; Torii, Yasuhiro; Matsumoto, Takuya

    2015-01-01

    In vitro fabricated biological tissue would be a valuable tool to screen newly synthesized drugs or understand the tissue development process. Several studies have attempted to fabricate biological tissue in vitro. However, controlling the growth and morphology of the fabricated tissue remains a challenge. Therefore, new techniques are required to modulate tissue growth. RGD (arginine-glycine-aspartic acid), which is an integrin-binding domain of fibronectin, has been found to enhance cell adhesion and survival; it has been used to modify substrates for in vitro cell culture studies or used as tissue engineering scaffolds. In addition, this study shows novel functions of the RGD peptide, which enhances tissue growth and modulates tissue morphology in vitro. When an isolated submandibular gland (SMG) was cultured on an RGD-modified alginate hydrogel sheet, SMG growth including bud expansion and cleft formation was dramatically enhanced. Furthermore, we prepared small RGD-modified alginate beads and placed them on the growing SMG tissue. These RGD-modified beads successfully induced cleft formation at the bead position, guiding the desired SMG morphology. Thus, this RGD-modified material might be a promising tool to modulate tissue growth and morphology in vitro for biological tissue fabrication. PMID:26098225

  1. Antibodies against distinct nuclear matrix proteins are characteristic for mixed connective tissue disease.

    PubMed Central

    Habets, W J; de Rooij, D J; Salden, M H; Verhagen, A P; van Eekelen, C A; van de Putte, L B; van Venrooij, W J

    1983-01-01

    Specific nuclear proteins, separated according to their molecular weight (mol. wt) by polyacrylamide gel electrophoresis (PAGE) and subsequently transferred to nitrocellulose sheets, are able to bind antibodies in sera from patients suffering from different types of connective tissue diseases. Antibodies against a characteristic set of nuclear protein antigens are found in sera from patients with mixed connective tissue disease (MCTD). Screening of 21 MCTD sera revealed a typical immunoblot pattern with major protein antigens of mol. wt 70,000 (20/21) (not identical with the Scl-70 antigen characteristic for scleroderma), mol. wt 31,000 (17/21), two proteins around mol. wt 23,000 (15/21) and two around mol. wt 19,000 (10/21). The 70,000, 23,000 and 19,000 antigens appeared to be rather insoluble nuclear proteins (i.e. components of the nuclear matrix). On behalf of their structural character they were present in nuclei from several types of cells but only in low amounts detectable in salt extracts of thymus acetone powder. The presence of antibodies directed against the mol. wt 70,000 antigen correlated strongly with the diagnosis of MCTD. This 70,000 antigen is not identical with the RNP antigen, a soluble ribonuclease sensitive ribonucleoprotein, since antibodies against nuclear RNP can be separated from anti-nuclear matrix antibodies by affinity chromatography using immobilized thymus salt extract. The distinct character of soluble nuclear RNP and structural nuclear matrix antigens is further supported by the fact that from 14 other anti-RNP sera obtained from patients with systemic lupus erythematosus (SLE), only three contained antibodies against the mol. wt 70,000 protein. Since the immunoblot pattern obtained with MCTD sera mostly was clearly distinguishable from the patterns obtained with sera from patients with related connective tissue diseases our results suggest that the immunoblotting technique might be useful as a diagnostic tool and support the

  2. Matriptase activation connects tissue factor-dependent coagulation initiation to epithelial proteolysis and signaling.

    PubMed

    Le Gall, Sylvain M; Szabo, Roman; Lee, Melody; Kirchhofer, Daniel; Craik, Charles S; Bugge, Thomas H; Camerer, Eric

    2016-06-23

    The coagulation cascade is designed to sense tissue injury by physical separation of the membrane-anchored cofactor tissue factor (TF) from inactive precursors of coagulation proteases circulating in plasma. Once TF on epithelial and other extravascular cells is exposed to plasma, sequential activation of coagulation proteases coordinates hemostasis and contributes to host defense and tissue repair. Membrane-anchored serine proteases (MASPs) play critical roles in the development and homeostasis of epithelial barrier tissues; how MASPs are activated in mature epithelia is unknown. We here report that proteases of the extrinsic pathway of blood coagulation transactivate the MASP matriptase, thus connecting coagulation initiation to epithelial proteolysis and signaling. Exposure of TF-expressing cells to factors (F) VIIa and Xa triggered the conversion of latent pro-matriptase to an active protease, which in turn cleaved the pericellular substrates protease-activated receptor-2 (PAR2) and pro-urokinase. An activation pathway-selective PAR2 mutant resistant to direct cleavage by TF:FVIIa and FXa was activated by these proteases when cells co-expressed pro-matriptase, and matriptase transactivation was necessary for efficient cleavage and activation of wild-type PAR2 by physiological concentrations of TF:FVIIa and FXa. The coagulation initiation complex induced rapid and prolonged enhancement of the barrier function of epithelial monolayers that was dependent on matriptase transactivation and PAR2 signaling. These observations suggest that the coagulation cascade engages matriptase to help coordinate epithelial defense and repair programs after injury or infection, and that matriptase may contribute to TF-driven pathogenesis in cancer and inflammation. PMID:27114461

  3. [Anti-ENA antibody determination in various connective tissue diseases: comparison of 2 detection techniques].

    PubMed

    Vaccai, D; Cataldi, V; Morozzi, G; Bacarelli, M R; Ciali, A; Pucci, G; Marcolongo, R

    1993-01-01

    The authors compared two different techniques for the detection of anti-ENA antibodies (anti-Sm, anti-RNP, anti-SSA, anti-SSB) in several different connective tissue diseases, using double immunodiffusion (ID) and a new membrane-based enzyme immunoassay. The aim of the work was to research the assay sensibility and specificity of the results obtained with the two different methods. Notwithstanding the fact that the two techniques are equivalent in their performance, the recombinant DNA appears to have greater sensibility and less specificity compared to ID. The former requires less time of execution although it presents difficulty in interpreting low scale positive results. Although the number of sera examined was low, the authors assert that the recombinant DNA technique will require further development. PMID:8329190

  4. Antinuclear antibodies and their detection methods in diagnosis of connective tissue diseases: a journey revisited

    PubMed Central

    Kumar, Yashwant; Bhatia, Alka; Minz, Ranjana Walker

    2009-01-01

    It has been more than 50 years since antinuclear antibodies were first discovered and found to be associated with connective tissue diseases. Since then different methods have been described and used for their detection or confirmation. For many decades immunofluorescent antinuclear antibody test has been the "gold standard" in the diagnosis of these disorders. However to increase the sensitivity and specificity of antinuclear antibody detection further approaches were explored. Today a battery of newer techniques are available some of which are now considered better and are competing with the older methods. This article provides an overview on advancement in antinuclear antibody detection methods, their future prospects, advantages, disadvantages and guidelines for use of these tests. PMID:19121207

  5. CCN2: a mechanosignaling sensor modulating integrin-dependent connective tissue remodeling in fibroblasts?

    PubMed

    Leask, Andrew

    2013-08-01

    Tensegrity (tensional integrity) is an emerging concept governing the structure of the body. Integrin-mediated mechanical tension is essential for connective tissue function in vivo. For example, in adult skin fibroblasts, the integrin β1 subunit mediates adhesion to collagen and fibronectin. Moreover, integrin β1, through its abilities to activate latent TGFβ1 and promote collagen production through focal adhesion kinase/rac1/nicotinamide adenine dinucleotide phosphate oxidase (NOX)/reactive oxygen species (ROS), is essential for dermal homeostasis, repair and fibrosis. The integrin β1-interacting protein CCN2, a member of the CCN family of proteins, is induced by TGFβ1; yet, CCN2 is not a simple downstream mediator of TGFβ1, but instead synergistically promote TGFβ1-induced adhesive signaling and fibrosis. Due to its selective ability to sense mechanical forces in the microenvironment, CCN2 may represent an exquisitely precise target for therapeutic intervention. PMID:23729366

  6. Ischemic Colitis Due to a Mesenteric Arteriovenous Malformation in a Patient with a Connective Tissue Disorder

    PubMed Central

    Poullos, Peter D.; Thompson, Atalie C.; Holz, Grant; Edelman, Lauren A.; Jeffrey, R. Brooke

    2014-01-01

    Ischemic colitis is a rare, life-threatening, consequence of mesenteric arteriovenous malformations. Ischemia ensues from a steal phenomenon through shunting, and may be compounded by the resulting portal hypertension. Computed tomographic angiography is the most common first-line test because it is quick, non-invasive, and allows for accurate anatomic characterization. Also, high-resolution three-dimensional images can be created for treatment planning. Magnetic resonance angiography is similarly sensitive for vascular mapping. Conventional angiography remains the gold standard for diagnosis and also allows for therapeutic endovascular embolization. Our patient underwent testing using all three of these modalities. We present the first reported case of this entity in a patient with a vascular connective tissue disorder. PMID:25926912

  7. Exome analysis of connective tissue dysplasia: death and rebirth of clinical genetics?

    PubMed

    Wilson, Golder N

    2014-05-01

    Exome results are reported for two patients with connective tissue dysplasia, one refining a clinical diagnosis of Ehlers-Danlos to Marfan syndrome, the other suggesting arthrogryposis derived from maternofetal Stickler syndrome. Patient 1 had mutations in transthyretin (TTR), fibrillin (FBN1), and a calcium channel (CACNA1A) gene suggesting diagnoses of transthyretin amyloidosis, Marfan syndrome, and familial hemiplegic migraines, respectively. Patient 2 presented with arthrogryposis that was correlated with his mother's habitus and arthritis once COL2A1 mutations suggestive of Stickler syndrome were defined. Although DNA results often defy prediction by the best of clinicians, these patients illustrate needs for ongoing clinical scholarship (e.g., to delineate guidelines for management of mutations like that for hyperekplexia in Patient 2) and for interpretation of polygenic change that is optimized by clinical genetic/syndromology experience (e.g., suggesting acetazolamide therapy for Patient 1 and explaining arthrogryposis in Patient 2). PMID:24664531

  8. [Clinical features and physical fitness parameters in athletes with cardiac connective tissue dysplasia syndrome].

    PubMed

    Mikhaĭlova, A V; Smolenskiĭ, A V

    2004-01-01

    Seventy-seven athletes with different manifestations of the cardiac connective tissue dysplasia (CCTD) syndrome (mitral prolapse (MP), anomalously located chordae (ALC) of the left ventricle and/or their combination) and 23 athletes without signs of CCTD syndrome were examined. The purpose of the study was to determine the specific features of the phenotypic picture, ECG data, and physical fitness in athletes with the manifestations of CCTD syndrome. The characteristic features of anthropometric data (higher heights and decreased body mass index), a larger number of the phenotypic signs of CCTD, the specific features of ECG, and lower parameters of physical fitness and aerobic capacities in the groups of MP, ALC, and/or their combination were identified; the impact of MP and ALC on these parameters was evaluated. PMID:15468725

  9. Nonspecific interstitial pneumonia overlaps organizing pneumonia in lung-dominant connective tissue disease.

    PubMed

    Li, Xue-Ren; Peng, Shou-Chun; Wei, Lu-Qing

    2015-01-01

    Here, we reported two cases of nonspecific interstitial pneumonia overlap organizing pneumonia (NSIP/OP) with lung-dominant connective tissue disease (LD-ILD). The first case is a patient with hands of chapped skin, right-sided pleuritic chest discomfort, weakness, positive ANA and antibodies to Ro/SS-A (+++) and Ro-52 (++). In the second case, there were Reynaud's disease, and nucleolus-ANA increased (1:800). Chest high resolution CT scan in both cases showed ground-glass opacifications, predominantly in basal and subpleural region and the pathologic manifestation were correlated with NSIP/OP, which were previously discovered in Sjogren syndrome, PM/DM and other rheumatic diseases. The two cases of NSIP/OP with LD-CTD we reported expand disease spectrum of NSIP/OP pathological types in ILD. However, it is necessary to process large-scale studies. PMID:26617847

  10. Spontaneous Esophageal Perforation in a Patient with Mixed Connective Tissue Disease

    PubMed Central

    Lyman, David

    2011-01-01

    Spontaneous esophageal perforation is a rare and life-threatening disorder. Failure to diagnosis within the first 24-48 hours of presentation portends a poor prognosis. A patient with mixed connective tissue disease (MCTD) on low-dose prednisone and methotrexate presented moribund with chest and shoulder pain, a left hydropneumothorax, progressive respiratory failure and shock. Initial management focussed on presumed community acquired pneumonia (CAP) in a patient on immunosuppressants. Bilateral yeast empyemas were treated and attributed to immunosuppression. On day 26, the patient developed mediastinitis, and the diagnosis of esophageal perforation was first considered. A review of the literature suggests that the diagnosis and management of spontaneous esophageal perforation could have been more timely and the outcome less catastrophic. PMID:22279514

  11. Photothermal effects in connective tissues mediated by laser-activated gold nanorods.

    PubMed

    Ratto, Fulvio; Matteini, Paolo; Rossi, Francesca; Menabuoni, Luca; Tiwari, Neha; Kulkarni, Sulabha K; Pini, Roberto

    2009-06-01

    We report a study on the application of laser-activated nanoparticles in the direct welding of connective tissues, which may become a valuable technology in biomedicine. We use colloidal gold nanorods as new near-infrared chromophores to mediate functional photothermal effects in the eye lens capsules. Samples obtained ex vivo from porcine eyes are treated to simulate heterotransplants with 810-nm diode laser radiation in association with a stain of gold nanorods of aspect ratio approximately 4. This stain is applied at the interface between a patch of capsule from a donor eye and the capsule of a recipient eye. Then, by administration of laser pulses of 40 msec and approximately 100-140 J/cm(2), we achieved the local denaturation of the endogenous collagen filaments, which reveals that the treated area reached temperatures above 50 degrees C. The thermal damage is confined within 50-70 mum in a radial distance from the irradiated area. PMID:19223241

  12. Impedance Changes and Fibrous Tissue Growth after Cochlear Implantation Are Correlated and Can Be Reduced Using a Dexamethasone Eluting Electrode

    PubMed Central

    Mugridge, Kenneth; Jolly, Claude; Fehr, Michael; Lenarz, Thomas; Scheper, Verena

    2016-01-01

    Background The efficiency of cochlear implants (CIs) is affected by postoperative connective tissue growth around the electrode array. This tissue formation is thought to be the cause behind post-operative increases in impedance. Dexamethasone (DEX) eluting CIs may reduce fibrous tissue growth around the electrode array subsequently moderating elevations in impedance of the electrode contacts. Methods For this study, DEX was incorporated into the silicone of the CI electrode arrays at 1% and 10% (w/w) concentration. Electrodes prepared by the same process but without dexamethasone served as controls. All electrodes were implanted into guinea pig cochleae though the round window membrane approach. Potential additive or synergistic effects of electrical stimulation (60 minutes) were investigated by measuring impedances before and after stimulation (days 0, 7, 28, 56 and 91). Acoustically evoked auditory brainstem responses were recorded before and after CI insertion as well as on experimental days 7, 28, 56, and 91. Additionally, histology performed on epoxy embedded samples enabled measurement of the area of scala tympani occupied with fibrous tissue. Results In all experimental groups, the highest levels of fibrous tissue were detected in the basal region of the cochlea in vicinity to the round window niche. Both DEX concentrations, 10% and 1% (w/w), significantly reduced fibrosis around the electrode array of the CI. Following 3 months of implantation impedance levels in both DEX-eluting groups were significantly lower compared to the control group, the 10% group producing a greater effect. The same effects were observed before and after electrical stimulation. Conclusion To our knowledge, this is the first study to demonstrate a correlation between the extent of new tissue growth around the electrode and impedance changes after cochlear implantation. We conclude that DEX-eluting CIs are a means to reduce this tissue reaction and improve the functional benefits of

  13. Contribution of Underlying Connective Tissue Cells to Taste Buds in Mouse Tongue and Soft Palate

    PubMed Central

    Mederacke, Ingmar; Komatsu, Yoshihiro; Stice, Steve; Schwabe, Robert F.; Mistretta, Charlotte M.; Mishina, Yuji; Liu, Hong-Xiang

    2016-01-01

    Taste buds, the sensory organs for taste, have been described as arising solely from the surrounding epithelium, which is in distinction from other sensory receptors that are known to originate from neural precursors, i.e., neural ectoderm that includes neural crest (NC). Our previous study suggested a potential contribution of NC derived cells to early immature fungiform taste buds in late embryonic (E18.5) and young postnatal (P1-10) mice. In the present study we demonstrated the contribution of the underlying connective tissue (CT) to mature taste buds in mouse tongue and soft palate. Three independent mouse models were used for fate mapping of NC and NC derived connective tissue cells: (1) P0-Cre/R26-tdTomato (RFP) to label NC, NC derived Schwann cells and derivatives; (2) Dermo1-Cre/RFP to label mesenchymal cells and derivatives; and (3) Vimentin-CreER/mGFP to label Vimentin-expressing CT cells and derivatives upon tamoxifen treatment. Both P0-Cre/RFP and Dermo1-Cre/RFP labeled cells were abundant in mature taste buds in lingual taste papillae and soft palate, but not in the surrounding epithelial cells. Concurrently, labeled cells were extensively distributed in the underlying CT. RFP signals were seen in the majority of taste buds and all three types (I, II, III) of differentiated taste bud cells, with the neuronal-like type III cells labeled at a greater proportion. Further, Vimentin-CreER labeled cells were found in the taste buds of 3-month-old mice whereas Vimentin immunoreactivity was only seen in the CT. Taken together, our data demonstrate a previously unrecognized origin of taste bud cells from the underlying CT, a conceptually new finding in our knowledge of taste bud cell derivation, i.e., from both the surrounding epithelium and the underlying CT that is primarily derived from NC. PMID:26741369

  14. [The role of connective tissue dysplasia in the forming of mitral valve prolapse].

    PubMed

    Filipenko, P S; Malookaia, Iu S

    2006-01-01

    Connective tissue (CT) is a multifunctional universal structure of great importance to the human organism. Constituting about 50% of the body mass, CT forms a frame (skeleton) and outer cover (skin), as well as the inner medium, through which all structural elements receive nutrients and extract metabolic products. The great number of links, constituting the CT system, each of which is controlled genetically and is liable to genetic lesions, creates conditions for heterogeneity of malformations and diseases involving CT. Non-differentiated CT dysplasia (NDCTD) is a genetically heterogenous group, presenting a basis for various chronic diseases. NDCTD may present the cause of dysplastic changes in the CT of different organs and systems. Thanks to modern diagnostic techniques, NDCTD is revealed frequently. NDCTD is underlied by molecular-, onto-, and pathogenetic mechanisms, leading to structural and functional changes in CT. This CT "weakness" is manifested by the peculiarities of the structure of various organs and systems. Mesenchimal heart dysplasias are the most widespread visceral markers of the given CT pathology. CT dysplasias of the heart are often combined with varied manifestations of system CT anomaly. Mitral valve prolapse (MVP) is the most wide-spread and well-studied minor heart anomalies. Primary MVP is a hereditary or congenital pathology and is not connected with a particular disease. It is a genetic pathology--CT dysplasia with autosomal dominant inheritance. Patients with MVP have an increased expression of Bw35 antigen of HLA system, which causes dysmetabolism of collagen in the mitral cusps. It has been revealed that tissue deficiency of magnesium is associated with antigen expression and correlates with clinical symptoms in MVP. Exogenic factors influencing MVP have been described. PMID:17294876

  15. Connective tissue reflex massage for type 2 diabetic patients with peripheral arterial disease: randomized controlled trial.

    PubMed

    Castro-Sánchez, Adelaida María; Moreno-Lorenzo, Carmen; Matarán-Peñarrocha, Guillermo A; Feriche-Fernández-Castanys, Belen; Granados-Gámez, Genoveva; Quesada-Rubio, José Manuel

    2011-01-01

    The objective of this study was to evaluate the efficacy of connective tissue massage to improve blood circulation and intermittent claudication symptoms in type 2 diabetic patients. A randomized, placebo-controlled trial was undertaken. Ninety-eight type 2 diabetes patients with stage I or II-a peripheral arterial disease (PAD) (Leriche-Fontaine classification) were randomly assigned to a massage group or to a placebo group treated using disconnected magnetotherapy equipment. Peripheral arterial circulation was determined by measuring differential segmental arterial pressure, heart rate, skin temperature, oxygen saturation and skin blood flow. Measurements were taken before and at 30 min, 6 months and 1 year after the 15-week treatment. After the 15-week program, the groups differed (P < .05) in differential segmental arterial pressure in right lower limb (lower one-third of thigh, upper and lower one-third of leg) and left lower limb (lower one-third of thigh and upper and lower one-third of leg). A significant difference (P < .05) was also observed in skin blood flow in digits 1 and 4 of right foot and digits 2, 4 and 5 of left foot. ANOVA results were significant (P < .05) for right and left foot oxygen saturation but not for heart rate and temperature. At 6 months and 1 year, the groups differed in differential segmental arterial pressure in upper third of left and right legs. Connective tissue massage improves blood circulation in the lower limbs of type 2 diabetic patients at stage I or II-a and may be useful to slow the progression of PAD. PMID:19933770

  16. Hypercatabolism of normal IgG; an unexplained immunoglobulin abnormality in the connective tissue diseases

    PubMed Central

    Wochner, R. Dean

    1970-01-01

    The metabolism of radioiodinated IgG was studied in a series of 42 patients with connective tissue diseases (16 systemic lupus erythematosus, nine rheumatoid arthritis, five polymyositis, five vasculitis, and seven miscellaneous diagnoses). Fractional catabolic rates were increased and survival half-lives were shortened in all diagnostic categories indicating hypercatabolism of IgG. This hypercatabolism was masked by increased IgG synthesis, resulting in elevated serum concentrations of IgG in patients with systemic lupus erythematosus and rheumatoid arthritis and in generally normal concentrations in the others. The metabolism of iodinated IgM was also studied in eight patients with systemic lupus erythematosus, in seven with rheumatoid arthritis, and in 12 controls. The fractional catabolic rates were normal in both groups of patients. Serum concentrations of both IgM and IgA were moderately elevated in all diagnostic categories. Serum albumin metabolism was entirely normal in the nine subjects studied who were not receiving corticosteroids; in three who were receiving them, moderate hypercatabolism was observed. The hypercatabolism of IgG could not be accounted for by factors previously known to alter IgG metabolism. It was not observed in 15 patients with other chronic, inflammatory diseases and was not explained by concomitant administration of adrenal corticosteroids to some patients. Identical results were obtained whether the IgG was obtained from a patient himself or from a normal donor, demonstrating that the hypercatabolism is a host defect and not an abnormality of the protein. Thus, patients with connective tissue disease of several different diagnostic categories have been shown to have an unexplained immunoglobulin abnormality: they catabolize normal IgG at an accelerated rate. PMID:5415673

  17. [Lower limb varicose veins as a manifestation of undifferentiated connective tissue dysplasia].

    PubMed

    Potapov, M P; Potapov, P P; Staver, E V; Mazepina, L S

    2016-01-01

    Analysed herein are the data of 737 patients (a total of 745 lower limbs) suffering from lower-limb varicose veins (LLVV) and subjected to treatment at the Surgical Department consisting of crossectomy, truncal and tributary phlebectomy, dissection of perforant veins exclusively in the basin of the great saphenous vein. Relapses during five-year follow up occurred in 13.8% (102/745) of cases. Based on clinical signs and laboratory findings we studied the effect of the factor of undifferentiated connective tissue dysplasia (UDCTD) on the development of lower-limb varicosity. We carried out comparative analysis in the groups with relapsing LLVV (n=43), without relapses (n=39) and control group comprising volunteers not suffering from LLVV (n=37). The median of blood serum total oxiprolin concentration in LLVV patients both with and without relapses was elevated and amounted to 18.4 (IR 14.9-19.65) and 14.3 (IR 13.1-16.5) versus 8.35 (5.75-9.75) μmol/l, respectively. The mode of the clinical parameter of UDCTD degree in accordance with the rating scale of Smolnova T.Yu. (2003) in the group of patients with LLVV relapses turned out to be higher (Mo=19) than in the group of patients without relapses (Mo=10, p=0.003). The lowest score was in the control group. In patients having immediate relatives with LLVV the level of blood serum total oxiprolin and clinical scores of LLVV turned out to be statistically significantly higher. Hence, based on the obtained during the study clinical and laboratory findings it may be supposed that undifferentiated connective tissue dysplasia plays an important part in the development of both lower limb varicosity and relapses thereof. PMID:27100544

  18. The Fine Structure of Experimentally Induced Connective Tissue Complexes in the Human

    PubMed Central

    Stinson, W. W.; Richter, K. M.; Schilling, J. A.

    1974-01-01

    The growth, development and cellular activity of fibrocollagenous tissue complexes induced by the implantation of specially structured wire mesh cylinders in 22 human male volunteers were studied during the time course of fibroplasia utilizing light and electron microscopic techniques. The fibrocollagenous tissue complexes after 4 to 16 weeks of development demonstrated highly ordered lamellations made of zones consisting primarily of fibroblasts and zones consisting primarily of collagenous fibers. The development of the ordered lamellations is referable to specific fibrillogenic activities by the constituent fibroblasts. The initial role of the fibroblast in fibrillogenesis is indicative of an apocrine-like secretory process followed by a holocrine-like role which results in cytodestruction and concurrent formation of an avascular collagenic tissue referable to an organizing cicatrix in a healing wound. ImagesFigs. 1-3.Figs. 4-9.Fig. 10.Fig. 11.Fig. 12.Figs. 13, 14.Fig. 15.Fig. 16.Fig. 17.Fig. 18, 19.Figs. 20-22.Fig. 23.Fig. 24. PMID:4599224

  19. Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin

    PubMed Central

    Argyropoulos, Angela J.; Robichaud, Patrick; Balimunkwe, Rebecca Mutesi; Fisher, Gary J.; Hammerberg, Craig; Yan, Yan

    2016-01-01

    Alterations of the collagen, the major structural protein in skin, contribute significantly to human skin connective tissue aging. As aged-appearing skin is more common in diabetes, here we investigated the molecular basis of aged-appearing skin in diabetes. Among all known human matrix metalloproteinases (MMPs), diabetic skin shows elevated levels of MMP-1 and MMP-2. Laser capture microdissection (LCM) coupled real-time PCR indicated that elevated MMPs in diabetic skin were primarily expressed in the dermis. Furthermore, diabetic skin shows increased lysyl oxidase (LOX) expression and higher cross-linked collagens. Atomic force microscopy (AFM) further indicated that collagen fibrils were fragmented/disorganized, and key mechanical properties of traction force and tensile strength were increased in diabetic skin, compared to intact/well-organized collagen fibrils in non-diabetic skin. In in vitro tissue culture system, multiple MMPs including MMP-1 and MM-2 were induced by high glucose (25 mM) exposure to isolated primary human skin dermal fibroblasts, the major cells responsible for collagen homeostasis in skin. The elevation of MMPs and LOX over the years is thought to result in the accumulation of fragmented and cross-linked collagen, and thus impairs dermal collagen structural integrity and mechanical properties in diabetes. Our data partially explain why old-looking skin is more common in diabetic patients. PMID:27104752

  20. Subsynovial Connective Tissue is Sensitive to Surgical Interventions in a Rabbit Model of Carpal Tunnel Syndrome

    PubMed Central

    Sun, Yu-Long; Moriya, Tamami; Zhao, Chunfeng; Kirk, Ramona L.; Chikenji, Takako; Passe, Sandra M.; An, Kai-Nan; Amadio, Peter C.

    2011-01-01

    The most common histological finding in carpal tunnel syndrome (CTS) is non-inflammatory fibrosis and thickening of the subsynovial connective tissue (SSCT) in the tunnel. While the cause of SSCT fibrosis and the relationship of SSCT fibrosis and CTS are unknown, one hypothesis is that SSCT injury causes fibrosis, and that the fibrosis then leads to CTS. We investigated the sensitivity of the SSCT to injuries. Two types of surgical intervention were performed in a rabbit model: a skin incision with tendon laceration and SSCT stretching sufficient to damage the SSCT, and skin incision alone,. Twelve weeks after surgery, the rabbit carpal tunnel tissues were studied with immunochemistry for TGF-β receptors 1, 2, and 3, collagen III, and collagen VI. All TGF-β receptors were expressed. The percentages of the TGF-β receptors’ expressions were less in the control SSCT fibroblasts than in the fibroblasts from rabbits with surgical interventions. The surgical interventions did not result in any alteration of collagen III expression. However, both surgical interventions resulted in a significant decrease in collagen VI expression compared to the control group. The two surgical interventions achieved similar expression of TGF-β receptors and collagens. Our results provide evidence that the SSCT is sensitive to surgical interventions, even when these are modest. Since SSCT fibrosis is a hallmark of carpal tunnel syndrome, these data also suggest that such fibrosis could result from relatively minor trauma. PMID:22009518

  1. Cold acclimation alters the connective tissue content of the zebrafish (Danio rerio) heart.

    PubMed

    Johnson, Amy C; Turko, Andy J; Klaiman, Jordan M; Johnston, Elizabeth F; Gillis, Todd E

    2014-06-01

    Thermal acclimation can alter cardiac function and morphology in a number of fish species, but little is known about the regulation of these changes. The purpose of the present study was to determine how cold acclimation affects zebrafish (Danio rerio) cardiac morphology, collagen composition and connective tissue regulation. Heart volume, the thickness of the compact myocardium, collagen content and collagen fiber composition were compared between control (27°C) and cold-acclimated (20°C) zebrafish using serially sectioned hearts stained with Picrosirius Red. Collagen content and fiber composition of the pericardial membrane were also examined. Cold acclimation did not affect the volume of the contracted heart; however, there was a significant decrease in the thickness of the compact myocardium. There was also a decrease in the collagen content of the compact myocardium and in the amount of thick collagen fibers throughout the heart. Cold-acclimated zebrafish also increased expression of the gene transcript for matrix metalloproteinase 2, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 2 and collagen Type I α1. We propose that the reduction in the thickness of the compact myocardium as well as the change in collagen content may help to maintain the compliance of the ventricle as temperatures decrease. Together, these results clearly demonstrate that the zebrafish heart undergoes significant remodeling in response to cold acclimation. PMID:24577447

  2. Control of connective tissue metabolism by lasers: recent developments and future prospects

    SciTech Connect

    Abergel, R.P.; Meeker, C.A.; Lam, T.S.; Dwyer, R.M.; Lesavoy, M.A.; Uitto, J.

    1984-12-01

    Various laser modalities are currently in extensive use in dermatology and plastic surgery, particularly for treatment of vascular and pigmented lesions. A relatively new area of laser utilization involves the possible biologic effects of the lasers. In this overview, recent studies are summarized which indicate that lasers at specific wavelengths and energy densities modulate the connective tissue metabolism by skin fibroblasts both in vitro and in vivo. Specifically, the neodymium-yttrium-aluminum-garnet (Nd: YAG) laser was shown to selectively suppress collagen production both in fibroblast cultures and in normal skin in vivo, thus suggesting that this laser modality may be useful for the treatment of fibrotic conditions such as keloids and hypertrophic scars. Furthermore, two low-energy lasers, helium-neon (He-Ne) and gallium-arsenide (Ga-As), were shown to stimulate collagen production in human skin fibroblast cultures, suggesting that these lasers could be used for enhancement of wound healing processes. These experimental approaches illustrate the future possibilities for applying lasers for the modulation of various biologic functions of cells in tissues and attest to the potential role of lasers in the treatment of cutaneous disorders.

  3. Ultrastructural Changes Associated with Reversible Stiffening in Catch Connective Tissue of Sea Cucumbers

    PubMed Central

    Tamori, Masaki; Ishida, Kinji; Matsuura, Eri; Ogasawara, Katsutoshi; Hanasaka, Tomohito; Takehana, Yasuhiro; Motokawa, Tatsuo; Osawa, Tokuji

    2016-01-01

    The dermis of sea cucumbers is a catch connective tissue or a mutable collagenous tissue that shows rapid, large and reversible stiffness changes in response to stimulation. The main component of the dermis is the extracellular material composed of collagen fibrils embedded in a hydrogel of proteoglycans. The stiffness of the extracellular material determines that of the dermis. The dermis has three mechanical states: soft (Sa), standard (Sb) and stiff (Sc). We studied the ultrastructural changes associated with the stiffness changes. Transverse sections of collagen fibrils in the dermis showed irregular perimeters with electron-dense protrusions or arms that cross-bridged between fibrils. The number of cross-bridges increased in stiffer dermis. The distance between the fibrils was shorter in Sc than that in other states, which was in accord with the previous report that water exuded from the tissue in the transition Sb→Sc. The ultrastructure of collagen fibrils that had been isolated from the dermis was also studied. Fibrils aggregated by tensilin, which causes the transition Sa→Sb possibly through an increase in cohesive forces between fibrils, had larger diameter than those dispersed by softenin, which antagonizes the effect of tensilin. No cross-bridges were found in isolated collagen fibrils. From the present ultrastructural study we propose that three different mechanisms work together to increase the dermal stiffness. 1.Tensilin makes collagen fibrils stronger and stiffer in Sa→Sb through an increase in cohesive forces between subfibrils that constituted fibrils; 2. Cross-bridging by arms caused the fibrils to be a continuous network of bundles both in Sa→Sb and in Sb→Sc; 3. The matrix embedding the fibril network became stiffer in Sb→Sc, which was produced by bonding associated with water exudation. PMID:27192546

  4. Ultrastructural Changes Associated with Reversible Stiffening in Catch Connective Tissue of Sea Cucumbers.

    PubMed

    Tamori, Masaki; Ishida, Kinji; Matsuura, Eri; Ogasawara, Katsutoshi; Hanasaka, Tomohito; Takehana, Yasuhiro; Motokawa, Tatsuo; Osawa, Tokuji

    2016-01-01

    The dermis of sea cucumbers is a catch connective tissue or a mutable collagenous tissue that shows rapid, large and reversible stiffness changes in response to stimulation. The main component of the dermis is the extracellular material composed of collagen fibrils embedded in a hydrogel of proteoglycans. The stiffness of the extracellular material determines that of the dermis. The dermis has three mechanical states: soft (Sa), standard (Sb) and stiff (Sc). We studied the ultrastructural changes associated with the stiffness changes. Transverse sections of collagen fibrils in the dermis showed irregular perimeters with electron-dense protrusions or arms that cross-bridged between fibrils. The number of cross-bridges increased in stiffer dermis. The distance between the fibrils was shorter in Sc than that in other states, which was in accord with the previous report that water exuded from the tissue in the transition Sb→Sc. The ultrastructure of collagen fibrils that had been isolated from the dermis was also studied. Fibrils aggregated by tensilin, which causes the transition Sa→Sb possibly through an increase in cohesive forces between fibrils, had larger diameter than those dispersed by softenin, which antagonizes the effect of tensilin. No cross-bridges were found in isolated collagen fibrils. From the present ultrastructural study we propose that three different mechanisms work together to increase the dermal stiffness. 1.Tensilin makes collagen fibrils stronger and stiffer in Sa→Sb through an increase in cohesive forces between subfibrils that constituted fibrils; 2. Cross-bridging by arms caused the fibrils to be a continuous network of bundles both in Sa→Sb and in Sb→Sc; 3. The matrix embedding the fibril network became stiffer in Sb→Sc, which was produced by bonding associated with water exudation. PMID:27192546

  5. The wound/burn guidelines - 4: Guidelines for the management of skin ulcers associated with connective tissue disease/vasculitis.

    PubMed

    Fujimoto, Manabu; Asano, Yoshihide; Ishii, Takayuki; Ogawa, Fumihide; Kawakami, Tamihiro; Kodera, Masanari; Abe, Masatoshi; Isei, Taiki; Ito, Takaaki; Inoue, Yuji; Imafuku, Shinichi; Irisawa, Ryokichi; Ohtsuka, Masaki; Ohtsuka, Mikio; Kadono, Takafumi; Kawaguchi, Masakazu; Kukino, Ryuichi; Kono, Takeshi; Sakai, Keisuke; Takahara, Masakazu; Tanioka, Miki; Nakanishi, Takeshi; Nakamura, Yasuhiro; Hashimoto, Akira; Hasegawa, Minoru; Hayashi, Masahiro; Fujiwara, Hiroshi; Maekawa, Takeo; Matsuo, Koma; Madokoro, Naoki; Yamasaki, Osamu; Yoshino, Yuichiro; Le Pavoux, Andres; Tachibana, Takao; Ihn, Hironobu

    2016-07-01

    The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS. PMID:26972733

  6. Connectivity

    ERIC Educational Resources Information Center

    Grush, Mary, Ed.

    2006-01-01

    Connectivity has dramatically changed the landscape of higher education IT. From "on-demand" services for net-gen students and advanced eLearning systems for faculty, to high-performance computing grid resources for researchers, IT now provides more networked services than ever to connect campus constituents to each other and to the world.…

  7. Uncoupling of Secretion From Growth in Some Hormone Secretory Tissues

    PubMed Central

    2014-01-01

    Context: Most syndromes with benign primary excess of a hormone show positive coupling of hormone secretion to size or proliferation in the affected hormone secretory tissue. Syndromes that lack this coupling seem rare and have not been examined for unifying features among each other. Evidence Acquisition: Selected clinical and basic features were analyzed from original reports and reviews. We examined indices of excess secretion of a hormone and indices of size of secretory tissue within the following three syndromes, each suggestive of uncoupling between these two indices: familial hypocalciuric hypercalcemia, congenital diazoxide-resistant hyperinsulinism, and congenital primary hyperaldosteronism type III (with G151E mutation of the KCNJ5 gene). Evidence Synthesis: Some unifying features among the three syndromes were different from features present among common tumors secreting the same hormone. The unifying and distinguishing features included: 1) expression of hormone excess as early as the first days of life; 2) normal size of tissue that oversecretes a hormone; 3) diffuse histologic expression in the hormonal tissue; 4) resistance to treatment by subtotal ablation of the hormone-secreting tissue; 5) causation by a germline mutation; 6) low potential of the same mutation to cause a tumor by somatic mutation; and 7) expression of the mutated molecule in a pathway between sensing of a serum metabolite and secretion of hormone regulating that metabolite. Conclusion: Some shared clinical and basic features of uncoupling of secretion from size in a hormonal tissue characterize three uncommon states of hormone excess. These features differ importantly from features of common hormonal neoplasm of that tissue. PMID:25004249

  8. Growth factor and small molecule influence on urological tissue regeneration utilizing cell seeded scaffolds.

    PubMed

    Sharma, Arun K; Cheng, Earl Y

    2015-03-01

    Regenerative medicine strategies combine various attributes from multiple disciplines including stem cell biology, chemistry, materials science and medicine. The junction at which these disciplines intersect provides a means to address unmet medical needs in an assortment of pathologies with the goal of creating sustainable, functional replacement tissues. Tissue damage caused by trauma for example, requires rapid responses in order to mitigate further tissue deterioration. Cell/scaffold composites have been utilized to initiate and stabilize regenerative responses in vivo with the hope that functional tissue can be attained. Along with the gross reconfiguration of regenerating tissues, small molecules and growth factors also play a pivotal role in tissue regeneration. Several regenerative studies targeting a variety of urological tissues demonstrate the utility of these small molecules or growth factors in an in vivo setting. PMID:25446138

  9. Connections between Student Explanations and Arguments from Evidence about Plant Growth

    ERIC Educational Resources Information Center

    Dauer, Jenny M.; Doherty, Jennifer H.; Freed, Allison L.; Anderson, Charles W.

    2014-01-01

    We investigate how students connect explanations and arguments from evidence about plant growth and metabolism--two key practices described by the "Next Generation Science Standards". This study reports analyses of interviews with 22 middle and high school students postinstruction, focusing on how their sense-making strategies led them…

  10. Saudi Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Pulmonary arterial hypertension associated with connective tissue diseases

    PubMed Central

    Boueiz, Adel; Hassoun, Paul M.

    2014-01-01

    The explosive growth of medical literature on pulmonary hypertension (PH) has led to a steady increase in awareness of this disease within the medical community during the past decade. The recent revision of the classification of PH is presented in in the main guidelines. Group 1 PH or pulmonary arterial hypertension (PAH) is a heterogeneous group and includes PH due to inheritable, drug-induced, and toxin-induced causes and to such underlying systemic causes as connective tissue diseases, human immunodeficiency viral infection, portal hypertension, congenital heart disease, and schistosomiasis. Systemic sclerosis (SSc) is an autoimmune multisystem disorder, which affects over 240 persons per million in the United States.[1] Its manifestations are not confined to the skin but may also involve the lungs, kidneys, peripheral circulation, musculoskeletal system, gastrointestinal tract, and heart. The outcome of PAH associated with SSc is worse when compared to other subtypes of PAH. In this review, we summarize available information about the pulmonary vascular and cardiac manifestations of SSc with special emphasis on their prognostic implications as well as the peculiarity of their detection. PMID:25076994

  11. Collagen gel contraction as a measure of fibroblast function in an animal model of subsynovial connective tissue fibrosis.

    PubMed

    Yang, Tai-Hua; Thoreson, Andrew R; Gingery, Anne; Larson, Dirk R; Passe, Sandra M; An, Kai-Nan; Zhao, Chunfeng; Amadio, Peter C

    2015-05-01

    Carpal tunnel syndrome (CTS) is a peripheral neuropathy characterized by non-inflammatory fibrosis of the subsynovial connective tissues (SSCT). A rabbit model of CTS was developed to test the hypothesis that SSCT fibrosis causes the neuropathy. We used a cell-seeded collagen-gel contraction model to characterize the fibrosis in this model in terms of cellular mechanics, specifically to compare the ability of SSCT cells from the rabbit model and normal rabbits to contract the gel, and to assess the effect of transforming growth factor-β1,which is upregulated in CTS, on these cells. SSCT fibrosis was induced in six retired breeder female rabbits which were sacrificed at 6 weeks (N = 3) and 12 weeks (n = 3). An additional two rabbits served as controls. SSCT was harvested according to a standard protocol. Gels seeded with SSCT cells from rabbits sacrificed at 6 weeks had significantly higher tensile strength (p < 0.001) and Young's modulus (p < 0.001) than gels seeded with cells from rabbits sacrificed at 12 weeks or control animals. TGF-β1 significantly increased the decay time constant (p < 0.001), tensile strength (p < 0.001), and Young's modulus (p < 0.001) regardless of the cell source. This model may be useful in screening therapeutic agents that may block SSCT fibrosis, identifying possible candidates for CTS treatment. PMID:25626430

  12. Mycobacterium chelonae cutaneous infection in a patient with mixed connective tissue disease*

    PubMed Central

    Lage, Renan; Biccigo, Danilo Guerreiro Zeolo; Santos, Felipe Borba Calixto; Chimara, Erica; Pereira, Elisangela Samartin Pegas; da Costa, Adilson

    2015-01-01

    Around 50 mycobacteria species cause human disease. Immunosuppressive states predispose to non-tuberculous mycobaterium infection, such as Mycobacterium chelonae: AFB, non-tuberculous, fast growth of low virulence and uncommon as a human pathogen. It may compromise the skin and soft tissues, lungs, lymph nodes and there is also a disseminated presentation. The diagnosis involves AFB identification and culture on Agar and Lowenstein-Jensen medium base. A 41-year-old female with MCTD (LES predominance) is reported, presenting painless nodules in the right forearm. She denied local trauma. Immunosuppressed with prednisone and cyclophosphamide for 24 months. Lesion biopsy has demonstrated positive bacilloscopy (Ziehl-Neelsen stain) and M.chelonae in culture (Lowenstein-Jensen medium base), therefore clarithromycin treatment has been started (best therapy choice in the literature). PMID:25672306

  13. [Research advances in the controlled release of growth factor related to blood vessel tissue engineering].

    PubMed

    Wu, Lili; Yuan, Xiaoyan; Yao, Kangde

    2006-08-01

    Growth factors play an important role in cell adhesion and proliferation as well as in tissue regeneration. By incorporating growth factors into polymer scaffolds, controlled release of them can be performed. The release mechanism is varied with the incorporation methods. In this paper, the latest advances in the controlled release of growth factors by blending, hydrogel, microsphere embedding and chemical bonding are reviewed. The potential application of ultrafine fibric embedding in growth factor delivery is described as well. PMID:17002137

  14. A stress driven growth model for soft tissue considering biological availability

    NASA Astrophysics Data System (ADS)

    Oller, S.; Bellomo, F. J.; Armero, F.; Nallim, L. G.

    2010-06-01

    Some of the key factors that regulate growth and remodeling of tissues are fundamentally mechanical. However, it is important to take into account the role of bioavailability together with the stresses and strains in the processes of normal or pathological growth. In this sense, the model presented in this work is oriented to describe the growth of soft biological tissue under "stress driven growth" and depending on the biological availability of the organism. The general theoretical framework is given by a kinematic formulation in large strain combined with the thermodynamic basis of open systems. The formulation uses a multiplicative decomposition of deformation gradient, splitting it in a growth part and visco-elastic part. The strains due to growth are incompatible and are controlled by an unbalanced stresses related to a homeostatic state. Growth implies a volume change with an increase of mass maintaining constant the density. One of the most interesting features of the proposed model is the generation of new tissue taking into account the contribution of mass to the system controlled through biological availability. Because soft biological tissues in general have a hierarchical structure with several components (usually a soft matrix reinforced with collagen fibers), the developed growth model is suitable for the characterization of the growth of each component. This allows considering a different behavior for each of them in the context of a generalized theory of mixtures. Finally, we illustrate the response of the model in case of growth and atrophy with an application example.

  15. Experiment K-6-02. Biomedical, biochemical and morphological alterations of muscle and dense, fibrous connective tissues during 14 days of spaceflight

    NASA Technical Reports Server (NTRS)

    Vailas, A.; Zernicke, R.; Grindeland, R.; Kaplanski, A.

    1990-01-01

    Findings on the connective tissue response to short-term space flight (12 days) are discussed. Specifically, data regarding the biochemical, biomechanical and morphological characteristics of selected connective tissues (humerus, vertebral body, tendon and skeletal muscle) of growing rats is given. Results are given concerning the humerus cortical bone, the vertebral bone, nutritional effects on bone biomechanical properties, and soft tense fiber connective tissue response.

  16. Examining the connectivity between different cellular processes in the Barrett tissue microenvironment.

    PubMed

    Phelan, J J; Feighery, R; Eldin, O S; Meachair, S Ó; Cannon, A; Byrne, R; MacCarthy, F; O'Toole, D; Reynolds, J V; O'Sullivan, J

    2016-02-28

    In Barrett associated tumorigenesis, oxidative phosphorylation and glycolysis are reprogrammed early in the disease sequence and act mutually to promote disease progression. However, the link between energy metabolism and its connection with other central cellular processes within the Barrett microenvironment is unknown. The aim of this study was to examine the relationship between metabolism (ATP5B/GAPDH), hypoxia (HIF1α), inflammation (IL1β/SERPINA3), p53 and obesity status using in-vivo and ex-vivo models of Barrett oesophagus. At the protein level, ATP5B (r = 0.71, P < 0.0001) and p53 (r = 0.455, P = 0.015) were found to be strongly associated with hypoxia. In addition, levels of ATP5B (r = 0.53, P = 0.0031) and GAPDH (r = -0.39, P = 0.0357) were positively associated with p53 expression. Moreover, we demonstrate that ATP5B (r = 0.8, P < 0.0001) and GAPDH (r = 0.43, P = 0.022) were positively associated with IL1β expression. Interestingly, obesity was negatively associated with oxidative phosphorylation (r = -0.6016, P = 0.0177) but positively associated with glycolysis (r = 0.743, P = 0.0015). Comparable correlations were exhibited in the ex-vivo explant tissue between metabolism, p53, hypoxia, inflammation and angiogenesis (P < 0.05). We have shown that metabolism is closely linked with many cellular processes in the Barrett tissue microenvironment. PMID:26688097

  17. Development of a hyperelastic material model of subsynovial connective tissue using finite element modeling.

    PubMed

    Matsuura, Yusuke; Thoreson, Andrew R; Zhao, Chunfeng; Amadio, Peter C; An, Kai-Nan

    2016-01-01

    Carpal tunnel syndrome (CTS) is one of the most common disorders of the hand. Assessment of carpal tunnel tissue mechanical behavior, especially that of the subsynovial connective tissue (SSCT), is important to better understand the mechanisms of CTS. The aim of this study was to develop a hyperelastic material model of human SSCT using mechanical test data and finite element modeling (FEM). Experimental shear test data of SSCT from 7 normal subjects and 7 CTS patients collected in a prior study was used to define material response. Hyperelastic coefficients (μ and α) from the first-order Ogden material property definition were iteratively solved using specimen-specific FEM models simulating the mechanical test conditions. A typical Ogden hyperelastic response for the normal and CTS SSCT was characterized by doing the same with data from all samples averaged together. The mean Ogden coefficients (μ/α) for the normal cadaver and CTS patient SSCT were 1.25×10(-5)MPa/4.51 and 1.99×10(-6)MPa/10.6, respectively when evaluating coefficients for individual specimens. The Ogden coefficients for the typical (averaged data) model for normal cadaver and CTS patient SSCT were 1.63×10(-5)MPa/3.93 and 5.00×10(-7)MPa/9.55, respectively. Assessment of SSCT mechanical response with a hyperelastic material model demonstrated significant differences between patient and normal cadaver. The refined assessment of these differences with this model may be important for future model development and in understanding clinical presentation of CTS. PMID:26482734

  18. The cytotoxic evaluation of mineral trioxide aggregate and bioaggregate in the subcutaneous connective tissue of rats

    PubMed Central

    Acar, Gözde; Yalcin, Yagmur; Dindar, Seckin; Sancakli, Hande; Erdemir, Ugur

    2013-01-01

    Objectives: The purpose of this study was to evaluate and compare the cytotoxic effects of ProRoot MTA and DiaRoot BA, a bioceramic nanoparticulate cement, on subcutaneous rat tissue. Study Design: Fifty Sprouge Dawley rats were used in this study. Polyethylene tubes filled with ProRoot MTA and DiaRoot BioAggregate, along with a control group of empty, were implanted into dorsal connective tissue of rats for 7, 15, 30, 60, and 90 days. After estimated time intervals the rats were sacrificed. The specimens were fixed, stained with hematoxylin and eosin, and then evaluated under a light microscope for inflammatory reactions and mineralization. Results: All groups evoked a severe to moderate chronic inflammatory reaction at 7 and 15 days, which decreased with time. Both the MTA and BioAggregate groups showed similar inflammatory reactions, except at 90 days when MTA showed statistically significant greater inflammation (p>0.05). The MTA group showed foreign body reaction at all times. Compared to BioAggregate, MTA showed significantly more foreign body reaction at 60 and 90 days (p<0.0001). After 30 days foreign body reaction of BioAggregate decreased significantly. Both MTA and BioAggregate groups showed similar necrosis at 7 and 15 days (p=0.094 and p=0.186 respectively). No necrosis was observed after 15 days. Similarly there was no fibrosis after 30 days for both MTA and BioAggregate groups (p>0.05). Conclusions: Since DiaRoot BioAggregate showed significantly better results than MTA, we can conclude that it is more biocompatible. However, further studies are required to confirm this result. Key words:Biocompatibility, mineral trioxide aggregate, bioAggregate. PMID:23722144

  19. Intramuscular Connective Tissue Differences in Spastic and Control Muscle: A Mechanical and Histological Study

    PubMed Central

    de Bruin, Marije; Smeulders, Mark J.; Kreulen, Michiel; Huijing, Peter A.; Jaspers, Richard T

    2014-01-01

    Cerebral palsy (CP) of the spastic type is a neurological disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks. Secondary to the spasticity, muscle adaptation is presumed to contribute to limitations in the passive range of joint motion. However, the mechanisms underlying these limitations are unknown. Using biopsies, we compared mechanical as well as histological properties of flexor carpi ulnaris muscle (FCU) from CP patients (n = 29) and healthy controls (n = 10). The sarcomere slack length (mean 2.5 µm, SEM 0.05) and slope of the normalized sarcomere length-tension characteristics of spastic fascicle segments and single myofibre segments were not different from those of control muscle. Fibre type distribution also showed no significant differences. Fibre size was significantly smaller (1933 µm2, SEM 190) in spastic muscle than in controls (2572 µm2, SEM 322). However, our statistical analyses indicate that the latter difference is likely to be explained by age, rather than by the affliction. Quantities of endomysial and perimysial networks within biopsies of control and spastic muscle were unchanged with one exception: a significant thickening of the tertiary perimysium (3-fold), i.e. the connective tissue reinforcement of neurovascular tissues penetrating the muscle. Note that this thickening in tertiary perimysium was shown in the majority of CP patients, however a small number of patients (n = 4 out of 23) did not have this feature. These results are taken as indications that enhanced myofascial loads on FCU is one among several factors contributing in a major way to the aetiology of limitation of movement at the wrist in CP and the characteristic wrist position of such patients. PMID:24977410

  20. U1-RNP and TLR receptors in the pathogenesis of mixed connective tissue diseasePart I. The U1-RNP complex and its biological significance in the pathogenesis of mixed connective tissue disease

    PubMed Central

    2015-01-01

    Mixed connective tissue disease (MCTD) is a rare autoimmune syndrome, signified by complex interactions between disease-related phenomena, including inflammation, proliferative vascular arteriopathy, thrombotic events and humoral autoimmune processes. It is still controversial whether MCTD is a distinct clinical entity among systemic connective tissue diseases, although several authors consider that it is distinct and underline characteristic, distinct clinical, serological and immunogenetic features. The putative target of autoimmunity in MCTD is U1-RNP, which is a complex of U1-RNA and small nuclear RNP. Both the U1-RNA component and the specific proteins, particularly U1-70K, engage immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. U1-RNA is capable of inducing manifestations consistent with TLR activation. Stimulation of innate immunity by native RNA molecules with a double-stranded secondary structure may help explain the high prevalence of autoimmunity to RNA binding proteins.

  1. Tissue types (image)

    MedlinePlus

    ... are 4 basic types of tissue: connective tissue, epithelial tissue, muscle tissue, and nervous tissue. Connective tissue supports ... binds them together (bone, blood, and lymph tissues). Epithelial tissue provides a covering (skin, the linings of the ...

  2. Research Advances in Tissue Engineering Materials for Sustained Release of Growth Factors

    PubMed Central

    Zhao, Hai-yang; Wu, Jiang; Zhu, Jing-jing; Xiao, Ze-cong; He, Chao-chao; Shi, Hong-xue; Li, Xiao-kun; Yang, Shu-lin; Xiao, Jian

    2015-01-01

    Growth factors are a class of cytokines that stimulate cell growth and are widely used in clinical practice, such as wound healing, revascularization, bone repair, and nervous system disease. However, free growth factors have a short half-life and are instable in vivo. Therefore, the search of excellent carriers to enhance sustained release of growth factors in vivo has become an area of intense research interest. The development of controlled-release systems that protect the recombinant growth factors from enzymatic degradation and provide sustained delivery at the injury site during healing should enhance the growth factor's application in tissue regeneration. Thus, this study reviews current research on commonly used carriers for sustained release of growth factors and their sustained release effects for preservation of their bioactivity and their accomplishment in tissue engineering approaches. PMID:26347885

  3. The response of the rabbit subsynovial connective tissue to a stress-relaxation test.

    PubMed

    Morizaki, Yutaka; Vanhees, Matthias; Thoreson, Andrew R; Larson, Dirk; Zhao, Chunfeng; An, Kai-Nan; Amadio, Peter C

    2012-03-01

    The subsynovial connective tissue (SSCT) in the carpal tunnel may play a role in the etiology of carpal tunnel syndrome (CTS), yet the material properties of the SSCT remain unclear. Thus, we investigated the mechanical response of the SSCT in a rabbit model. Twenty-four rabbit cadaver paws were used for mechanical testing; two paws were used for scanning electron microscopy (SEM) imaging. After testing normal tendon excursion, the divided third digit flexor digitorum superficialis (FDS) tendon was pulled to displacements of 2, 3.5, 5, or 8 mm, maintained at that position until force decay, and then the process was repeated. Normal excursion of the FDS averaged 4.8 mm. The ratio of the second peak force to the first peak force in the 2 mm group was 0.98 (SD = 0.16), which was significantly higher than the other groups (3.5 mm: 0.74, 5 mm, 0.63, and 8 mm: 0.59; p < 0.05). SEM showed ruptured fibrils in the displaced specimen. The declining force ratio with displacements >2 mm suggests damage to the SSCT within the physiological tendon excursion. These data may be useful in understanding SSCT mechanics in CTS, which is associated with SSCT fibrosis. PMID:21898581

  4. Chronological ageing and photoageing of the fibroblasts and the dermal connective tissue.

    PubMed

    Ma, W; Wlaschek, M; Tantcheva-Poór, I; Schneider, L A; Naderi, L; Razi-Wolf, Z; Schüller, J; Scharffetter-Kochanek, K

    2001-10-01

    In recent years, the exposure of human skin to environmental and artificial UV irradiation has increased dramatically. This is due not only to increased solar UV irradiation as a consequence of stratospheric ozone depletion, but also to inappropriate social behaviour with the use of tanning salons still being very popular in the public view. Besides this, leisure activities and a lifestyle that often includes travel to equatorial regions add to the individual annual UV load. In addition to the common long-term detrimental effects such as immunosuppression and skin cancer, the photo-oxidative damage due to energy absorption of UV photons in an oxygenized environment leads to quantitative and qualitative alterations of cells and structural macromolecules of the dermal connective tissue responsible for tensile strength, resilience and stability of the skin. The clinical manifestations of UV/reactive oxygen species (ROS)-induced disturbances result in photoaged skin with wrinkle formation, laxity, leathery appearance as well as fragility, impaired wound healing capacities and higher vulnerability. Strategies to prevent or at least minimize ROS-induced photo-ageing and intrinsic ageing of the skin necessarily include protection against UV irradiation and antioxidant homeostasis. PMID:11696063

  5. Connective tissue and related disorders and preterm birth: clues to genes contributing to prematurity.

    PubMed

    Anum, E A; Hill, L D; Pandya, A; Strauss, J F

    2009-03-01

    To identify candidate genes contributing to preterm birth, we examined the existing literature on the association between known disorders of connective tissue synthesis and metabolism and related diseases and prematurity. Our hypothesis was that abnormal matrix metabolism contributes to prematurity by increasing risk of preterm premature rupture of membranes (PPROM) and cervical incompetence. Based on this review, we identified gene mutations inherited by the fetus that could predispose to preterm birth as a result of PPROM. The responsible genes include COL5A1, COL5A2, COL3A1, COL1A1, COL1A2, TNXB, PLOD1, ADAMTS2, CRTAP, LEPRE1 and ZMPSTE24. Marfan syndrome, caused by FBN1 mutations, and polymorphisms in the COL1A1 and TGFB1 genes have been associated with cervical incompetence. We speculate that an analysis of sequence variation at the loci noted above will reveal polymorphisms that may contribute to susceptibility to PPROM and cervical incompetence in the general population. PMID:19152976

  6. Successful Immunosuppressive Treatment of Mixed Connective Tissue Disease Complicated by Microscopic Polyangiitis.

    PubMed

    Sato, Shuzo; Yashiro, Makiko; Matsuoka, Naoki; Uematsu, Manabu; Asano, Tomoyuki; Kobayashi, Hiroko; Watanabe, Hiroshi; Ohira, Hiromasa

    2016-01-01

    Mixed connective tissue disease (MCTD) is characterized by a combination of clinical features of systemic lupus erythematosus, systemic sclerosis, and polymyositis with elevated antibodies to U1 small nuclear ribonucleoprotein (U1-RNP). MCTD is often accompanied by interstitial lung disease as pulmonary involvement. On the other hand, microscopic polyangiitis (MPA) is a systemic autoimmune disease characterized by the inflammation of small vessels (arterioles, capillaries, and venules) mainly affecting the lung and kidney. MPA is associated with elevated serum anti-neutrophil cytoplasmic antibody (ANCA). Complication of MPA in patients with MCTD is rare. So far, only nine case reports of MCTD complicated by MPA with serum myeloperoxidase-specific ANCA (MPO-ANCA) are available. Here, we describe a 64-year-old male suffering from MCTD with MPA. The patient developed interstitial pneumonia with alveolar hemorrhage accompanied by myositis, scleroderma, and elevated anti-U1-RNP antibody and MPO-ANCA levels with substantial systemic inflammation. Strong immunosuppressive therapy (corticosteroid, intravenous immunoglobulin, and cyclosporine A) ameliorated the myositis, interstitial lung disease, and inflammation, with the decrease of MPO-ANCA levels, despite that severe lung complications are often associated with poor outcomes. In conclusion, MCTD may be accompanied by MPA with alveolar hemorrhage. Severe lung complications may indicate a poor outcome, and therefore prompt immunosuppressive treatment should be performed in such patients. PMID:27238624

  7. Direct determination of fatty acids in fish tissues: quantifying top predator trophic connections.

    PubMed

    Parrish, Christopher C; Nichols, Peter D; Pethybridge, Heidi; Young, Jock W

    2015-01-01

    Fatty acids are a valuable tool in ecological studies because of the large number of unique structures synthesized. They provide versatile signatures that are being increasingly employed to delineate the transfer of dietary material through marine and terrestrial food webs. The standard procedure for determining fatty acids generally involves lipid extraction followed by methanolysis to produce methyl esters for analysis by gas chromatography. By directly transmethylating ~50 mg wet samples and adding an internal standard it was possible to greatly simplify the analytical methodology to enable rapid throughput of 20-40 fish tissue fatty acid analyses a day including instrumental analysis. This method was verified against the more traditional lipid methods using albacore tuna and great white shark muscle and liver samples, and it was shown to provide an estimate of sample dry mass, total lipid content, and a condition index. When large fatty acid data sets are generated in this way, multidimensional scaling, analysis of similarities, and similarity of percentages analysis can be used to define trophic connections among samples and to quantify them. These routines were used on albacore and skipjack tuna fatty acid data obtained by direct methylation coupled with literature values for krill. There were clear differences in fatty acid profiles among the species as well as spatial differences among albacore tuna sampled from different locations. PMID:25376156

  8. Benefit of adjunctive tacrolimus in connective tissue disease-interstitial lung disease.

    PubMed

    Witt, Leah J; Demchuk, Carley; Curran, James J; Strek, Mary E

    2016-02-01

    We evaluated the safety and effectiveness of adjunctive tacrolimus therapy with conventional immunosuppression in patients with severe connective tissue disease-related interstitial lung disease (CTD-ILD). We included patients from our interstitial lung disease (ILD) registry with CTD-ILD, in whom tacrolimus was added to corticosteroids and an additional immunosuppressive agent. Demographic data, clinical features, lung function, radiographic images, and pathologic findings were reviewed. Effectiveness was assessed by comparing pulmonary function tests (PFTs) closest to tacrolimus initiation to PFTs approximately 6-12 months later. Corticosteroid dose at these time points was also evaluated. We report adverse events attributed to tacrolimus. Seventeen patients with CTD-ILD were included in adverse event analysis; twelve were included in efficacy analysis. Length of tacrolimus therapy ranged from 6 to 110 months (mean 38.8 months ± 31.4). The mean improvement in percent predicted total lung capacity was 7.5% ± 11.7 (p = 0.02). Forced vital capacity mean improvement was 7.4% ± 12.5 (p = 0.06). The average decrease in corticosteroid dose at follow-up was 20.3 mg ± 25.2 (p = 0.02) with complete discontinuation in six patients. No patients experienced a life-threatening adverse event attributed to tacrolimus. Tacrolimus can be effective and is well tolerated as an adjunctive therapy and allows tapering of corticosteroids. PMID:26762710

  9. Gene therapy with growth factors for periodontal tissue engineering–A review

    PubMed Central

    Gupta, Shipra; Mahendra, Aneet

    2012-01-01

    The treatment of oral and periodontal diseases and associated anomalies accounts for a significant proportion of the healthcare burden, with the manifestations of these conditions being functionally and psychologically debilitating. A challenge faced by periodontal therapy is the predictable regeneration of periodontal tissues lost as a consequence of disease. Growth factors are critical to the development, maturation, maintenance and repair of oral tissues as they establish an extra-cellular environment that is conducive to cell and tissue growth. Tissue engineering principles aim to exploit these properties in the development of biomimetic materials that can provide an appropriate microenvironment for tissue development. The aim of this paper is to review emerging periodontal therapies in the areas of materials science, growth factor biology and cell/gene therapy. Various such materials have been formulated into devices that can be used as vehicles for delivery of cells, growth factors and DNA. Different mechanisms of drug delivery are addressed in the context of novel approaches to reconstruct and engineer oral and tooth supporting structure. Key words: Periodontal disease, gene therapy, regeneration, tissue repair, growth factors, tissue engineering. PMID:22143705

  10. [INFLUENCE OF QUINAPRIL IN COMBINATION WITH ANGIOLINE ON THE CONNECTIVE TISSUE COMPONENTS IN THE RATS SERUM WITH EXPERIMENTAL HYPERTENSION].

    PubMed

    Nagornaya, A A; Magomedov, S; Gorchakova, N A; Belenichev, I F; Ghekman, I S; Kuzub, T A

    2015-01-01

    One of the most active inhibitors angiotensin-converting enzyme is quinapril that has a high affinity for tissue ACE, improves endothelial vasodilation, has a wide therapeutic range and beneficient influence on heart rate. A new biological active compound with antioxidant action that has endothelioprotective, cardioprotective, antiischemic action is angiolin. In experimental arterial hypertension in the animals blood serum the activity of collagenase, the content of free and protein connecting fractions of hydroxyproline and indicators that reflect the metabolism of glycosaminoglycans have been increased. Angiolin increases the activity of collagenase free and protein connecting fractions of hydroxyproline comparing to control. Concentration glycosoaminoglycan (GAG) also exceeds the standard data. Quinapril has similar to angiolin action directed effect to the connective tissue components, though losing as proteinconecting of hydroxiproline action. Cooperative application quinapril with angioline most effectively influence the metabolic processes stabilization in experimental animals. PMID:27089728

  11. On the genetic control of planar growth during tissue morphogenesis in plants.

    PubMed

    Enugutti, Balaji; Kirchhelle, Charlotte; Schneitz, Kay

    2013-06-01

    Tissue morphogenesis requires extensive intercellular communication. Plant organs are composites of distinct radial cell layers. A typical layer, such as the epidermis, is propagated by stereotypic anticlinal cell divisions. It is presently unclear what mechanisms coordinate cell divisions relative to the plane of a layer, resulting in planar growth and maintenance of the layer structure. Failure in the regulation of coordinated growth across a tissue may result in spatially restricted abnormal growth and the formation of a tumor-like protrusion. Therefore, one way to approach planar growth control is to look for genetic mutants that exhibit localized tumor-like outgrowths. Interestingly, plants appear to have evolved quite robust genetic mechanisms that govern these aspects of tissue morphogenesis. Here we provide a short summary of the current knowledge about the genetics of tumor formation in plants and relate it to the known control of coordinated cell behavior within a tissue layer. We further portray the integuments of Arabidopsis thaliana as an excellent model system to study the regulation of planar growth. The value of examining this process in integuments was established by the recent identification of the Arabidopsis AGC VIII kinase UNICORN as a novel growth suppressor involved in the regulation of planar growth and the inhibition of localized ectopic growth in integuments and other floral organs. An emerging insight is that misregulation of central determinants of adaxial-abaxial tissue polarity can lead to the formation of spatially restricted multicellular outgrowths in several tissues. Thus, there may exist a link between the mechanisms regulating adaxial-abaxial tissue polarity and planar growth in plants. PMID:22983223

  12. Nanotechnology and picotechnology to increase tissue growth: a summary of in vivo studies

    PubMed Central

    Alpaslan, Ece; Webster, Thomas J

    2014-01-01

    The aim of tissue engineering is to develop functional substitutes for damaged tissues or malfunctioning organs. Since only nanomaterials can mimic the surface properties (ie, roughness) of natural tissues and have tunable properties (such as mechanical, magnetic, electrical, optical, and other properties), they are good candidates for increasing tissue growth, minimizing inflammation, and inhibiting infection. Recently, the use of nanomaterials in various tissue engineering applications has demonstrated improved tissue growth compared to what has been achieved until today with our conventional micron structured materials. This short report paper will summarize some of the more relevant advancements nanomaterials have made in regenerative medicine, specifically improving bone and bladder tissue growth. Moreover, this short report paper will also address the continued potential risks and toxicity concerns, which need to be accurately addressed by the use of nanomaterials. Lastly, this paper will emphasize a new field, picotechnology, in which researchers are altering electron distributions around atoms to promote surface energy to achieve similar increased tissue growth, decreased inflammation, and inhibited infection without potential nanomaterial toxicity concerns. PMID:24872699

  13. Connective tissue cells expressing fibro/adipogenic progenitor markers increase under chronic damage: relevance in fibroblast-myofibroblast differentiation and skeletal muscle fibrosis.

    PubMed

    Contreras, Osvaldo; Rebolledo, Daniela L; Oyarzún, Juan Esteban; Olguín, Hugo C; Brandan, Enrique

    2016-06-01

    Fibrosis occurs in skeletal muscle under various pathophysiological conditions such as Duchenne muscular dystrophy (DMD), a devastating disease characterized by fiber degeneration that results in progressive loss of muscle mass, weakness and increased extracellular matrix (ECM) accumulation. Fibrosis is also observed after skeletal muscle denervation and repeated cycles of damage followed by regeneration. The ECM is synthesized largely by fibroblasts in the muscle connective tissue under normal conditions. Myofibroblasts, cells that express α-smooth muscle actin (α-SMA), play a role in many tissues affected by fibrosis. In skeletal muscle, fibro/adipogenic progenitors (FAPs) that express cell-surface platelet-derived growth factor receptor-α (PDGFR-α) and the transcription factor Tcf4 seem to be responsible for connective tissue synthesis and are good candidates for the origin of myofibroblasts. We show that cells positive for Tcf4 and PDGFR-α are expressed in skeletal muscle under normal conditions and are increased in various skeletal muscles of mdx mice, a murine model for DMD, wild type muscle after sciatic denervation and muscle subjected to chronic damage. These cells co-label with the myofibroblast marker α-SMA in dystrophic muscle but not in normal tissue. The Tcf4-positive cells lie near macrophages mainly concentrated in dystrophic necrotic-regenerating foci. The close proximity of Tcf4-positive cells to inflammatory cells and their previously described role in muscle regeneration might reflect an active interaction between these cell types and growth factors, possibly resulting in a muscular regenerative or fibrotic condition. PMID:26742767

  14. Hybrid models of cell and tissue dynamics in tumor growth.

    PubMed

    Kim, Yangjin; Othmer, Hans G

    2015-12-01

    Hybrid models of tumor growth, in which some regions are described at the cell level and others at the continuum level, provide a flexible description that allows alterations of cell-level properties and detailed descriptions of the interaction with the tumor environment, yet retain the computational advantages of continuum models where appropriate. We review aspects of the general approach and discuss applications to breast cancer and glioblastoma. PMID:26775860

  15. Connective tissue responses to some heavy metals. III. Silver and dietary supplements of ascorbic acid. Histology and ultrastructure.

    PubMed Central

    Ellender, G.; Ham, K. N.

    1989-01-01

    Silver-loaded ion exchange resin beads implanted into loose connective tissue of the rat pinna produced a local reaction. Initially the lesion comprised local necrosis and tissue disruption with predominantly small round cell infiltration. The subsequent organization was delayed and disordered. Fibroblasts developed grossly dilated cisternae of the rough endoplasmic reticulum. The matrix contained poorly orientated collagen fibrils of varying size and ground substance appeared condensed and granular. Distorted collagen fibrils were identified within membrane-bound vacuoles in the cytoplasm of both fibroblasts and macrophages. Abnormalities of the silver lesion were indicative of disordered collagen biosynthesis. Silver interfered with the biosynthesis and assembly of matrix components of the connective tissue. The reaction to silver beads in rats maintained on a diet heavily supplemented with ascorbic acid approached that of the control (sodium-loaded bead) with respect to the time scale, tissue reaction and tissue organization. The collagen matrix which formed was more organized and of greater density than that in the rat maintained on a normal diet. However, the repair tissue retained some of the morphological features of the legacy of silver toxicity, in particular delayed repair and dense intracellular fibrils within fibroblasts and macrophages. The excess of ascorbic acid partially ameliorated the effect of silver, possibly by compensating catabolysis of ascorbic acid caused by the presence of the released silver. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 PMID:2923787

  16. Brachial Neuritis With Phrenic Nerve Involvement in a Patient With a Possible Connective Tissue Disease

    PubMed Central

    Subash, Meera; Patel, Gaurav; Welker, John

    2014-01-01

    Background. Brachial neuritis (BN) is a rare inflammatory condition of peripheral nerves, usually involving the cervicobrachial plexus. These patients present with sudden onset of shoulder and arm pain that evolves into muscle weakness and atrophy.. Case Report. A 33-year-old woman presented with a 1-month history of diffuse pain in her thorax. She had no trauma or inciting incident prior to the onset of this pain and was initially treated for muscle spasms. The patient was seen in the emergency room multiple times and was treated with several courses of antibiotics for pneumonia on the basis of clinical symptoms and abnormal x-rays. The pleuritic chest pain persisted for at least 4 months, and the patient was eventually admitted for worsening pain and dyspnea. On physical examination, crackles were heard at both lung bases, and chest inspection revealed increased expansion in the upper thorax but poor expansion of the lower thorax and mild paradoxical respiration. “Sniff” test revealed no motion of the left hemidiaphragm and reduced motion on the right hemidiaphragm. Her computed tomography scan revealed bilateral atelectasis, more severe at the left base. She reported no symptoms involving her joints or skin or abdomen. Her presentation and clinical course are best explained by BN with a bilateral diaphragmatic weakness. However, she had a positive ANA, RF, anti-RNP antibody, and anti SS-A. Conclusion. Patients with BN can present with diffuse thoracic pain, pleuritic chest pain, and diaphragmatic weakness. Our patient may represent a case of connective tissue disease presenting with brachial plexus neuritis. PMID:26425609

  17. Diagnosis and Treatment of Connective Tissue Disease-Associated Interstitial Lung Disease

    PubMed Central

    Strek, Mary E.

    2013-01-01

    Interstitial lung disease (ILD) is one of the most serious pulmonary complications associated with connective tissue diseases (CTDs), resulting in significant morbidity and mortality. Although the various CTDs associated with ILD often are considered together because of their shared autoimmune nature, there are substantial differences in the clinical presentations and management of ILD in each specific CTD. This heterogeneity and the cross-disciplinary nature of care have complicated the conduct of prospective multicenter treatment trials and hindered our understanding of the development of ILD in patients with CTD. In this update, we present new information regarding the diagnosis and treatment of patients with ILD secondary to systemic sclerosis, rheumatoid arthritis, dermatomyositis and polymyositis, and Sjögren syndrome. We review information on risk factors for the development of ILD in the setting of CTD. Diagnostic criteria for CTD are presented as well as elements of the clinical evaluation that increase suspicion for CTD-ILD. We review the use of medications in the treatment of CTD-ILD. Although a large, randomized study has examined the impact of immunosuppressive therapy for ILD secondary to systemic sclerosis, additional studies are needed to determine optimal treatment strategies for each distinct form of CTD-ILD. Finally, we review new information regarding the subgroup of patients with ILD who meet some, but not all, diagnostic criteria for a CTD. A careful and systematic approach to diagnosis in patients with ILD may reveal an unrecognized CTD or evidence of autoimmunity in those previously believed to have idiopathic ILD. PMID:23460159

  18. Volumetric imaging of oral epithelial neoplasia by MPM-SHGM: epithelial connective tissue interface (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Pal, Rahul; Yang, Jinping; Qiu, Suimin; Resto, Vicente; McCammon, Susan; Vargas, Gracie

    2016-03-01

    The majority of oral cancers are comprised of oral squamous cell carcinoma in which neoplastic epithelial cells invade across the epithelial connective tissue interface (ECTI). Invasion is preceded by a multi-component process including epithelial hyperproliferation, loss of cell polarity, and remodeling of the extracellular matrix. Multiphoton Autofluorescence Microscopy (MPAM) and Second Harmonic Generation Microscopy (SHGM) show promise for revealing indicators of neoplasia. In particular, volumetric imaging by these methods can reveal aspects of the 3D microstructure that are not possible by other methods and which could both further our understanding of neoplastic transformation and be explored for development of diagnostic approaches in this disease having only 55% 5-year survival rate. MPAM-SHG were applied to reveal the 3D structure of the critical ECTI interface that plays an integral part toward invasion. Epithelial dysplasia was induced in an established hamster model. MPAM-SHGM was applied to lesion sites, using 780 nm excitation (450-600nm emission) for autofluroescence of cellular and extracellular components; 840 nm using 420 nm bandpass filter for SHG. The ECTI surface was identified as the interface at which SHG signal began following the epithelium and was modeled as a 3D surface using Matlab. ECTI surface area and cell features at sites of epithelial expansion where ECTI was altered were measured; Imaged sites were biopsied and processed for histology. ROC analysis using ECTI image metrics indicated the ability to delineate normal from neoplasia with high sensitivity and specificity and it is noteworthy that inflammation did not significantly alter diagnostic potential of MPAM-SHGM .

  19. Brachial Neuritis With Phrenic Nerve Involvement in a Patient With a Possible Connective Tissue Disease.

    PubMed

    Subash, Meera; Patel, Gaurav; Welker, John; Nugent, Kenneth

    2014-01-01

    Background. Brachial neuritis (BN) is a rare inflammatory condition of peripheral nerves, usually involving the cervicobrachial plexus. These patients present with sudden onset of shoulder and arm pain that evolves into muscle weakness and atrophy.. Case Report. A 33-year-old woman presented with a 1-month history of diffuse pain in her thorax. She had no trauma or inciting incident prior to the onset of this pain and was initially treated for muscle spasms. The patient was seen in the emergency room multiple times and was treated with several courses of antibiotics for pneumonia on the basis of clinical symptoms and abnormal x-rays. The pleuritic chest pain persisted for at least 4 months, and the patient was eventually admitted for worsening pain and dyspnea. On physical examination, crackles were heard at both lung bases, and chest inspection revealed increased expansion in the upper thorax but poor expansion of the lower thorax and mild paradoxical respiration. "Sniff" test revealed no motion of the left hemidiaphragm and reduced motion on the right hemidiaphragm. Her computed tomography scan revealed bilateral atelectasis, more severe at the left base. She reported no symptoms involving her joints or skin or abdomen. Her presentation and clinical course are best explained by BN with a bilateral diaphragmatic weakness. However, she had a positive ANA, RF, anti-RNP antibody, and anti SS-A. Conclusion. Patients with BN can present with diffuse thoracic pain, pleuritic chest pain, and diaphragmatic weakness. Our patient may represent a case of connective tissue disease presenting with brachial plexus neuritis. PMID:26425609

  20. Effects of interleukins on connective tissue type mast cells co-cultured with fibroblasts.

    PubMed Central

    Levi-Schaffer, F; Segal, V; Shalit, M

    1991-01-01

    We investigated the effects of interleukin-2 (IL-2), interleukin-3 (IL-3) and interleukin-4 (IL-4) on mouse and rat peritoneal mast cells (MC) co-cultured with 3T3 fibroblasts (MC/3T3). The continuous presence of these cytokines for 7-9 days in the culture media was neither toxic nor caused proliferation of MC, as determined by the stability of MC numbers in culture. Long-term incubation of mouse MC/3T3 with IL-2 (100 U/ml), IL-3 (50 U/ml), IL-4 (50 U/ml) or a mixture of IL-3 and IL-4 (25 U/ml) induced an increase in basal histamine release of 79.3 +/- 19.0%, 41.0 +/- 17.3%, 25.2 +/- 10.4% and 30.2 +/- 3.2%, respectively, over control cells incubated with medium alone. When rat MC/3T3 were incubated for 7 days with the various interleukins an enhancement in histamine release similar to that observed with mouse MC/3T3 was found. Preincubation (1 hr) of rat MC/3T3 with interleukins prior to immunological activation with anti-IgE antibodies enhanced histamine release. The highest effect was observed with IL-3 + IL-4 (60.4 +/- 10.8% increase) followed by IL-2 (51.5 +/- 4.5%), IL-4 (28.6 +/- 10.3%) and IL-3 (13.2 +/- 4.2%). This study demonstrates that when mouse and rat peritoneal MC are cultured with fibroblasts in the presence of interleukins they do not proliferate, suggesting that they preserve their connective tissue type MC phenotype. Moreover, interleukins display a pro-inflammatory effect on these cells by enhancing both basal and anti-IgE-mediated histamine release. PMID:2016117

  1. Efficacy and Safety of Grapefruit Juice Intake Accompanying Tacrolimus Treatment in Connective Tissue Disease Patients.

    PubMed

    Tsuji, Hideaki; Ohmura, Koichiro; Nakashima, Ran; Hashimoto, Motomu; Imura, Yoshitaka; Yukawa, Naoichiro; Yoshifuji, Hajime; Fujii, Takao; Mimori, Tsuneyo

    2016-01-01

    Objective It is well known that grapefruit juice (GFJ) elevates the blood tacrolimus (TAC) concentration. We investigated the efficacy and safety of GFJ intake with TAC in cases of connective tissue diseases in which the TAC blood concentration was insufficiently high for clinical improvement, even when 3 mg/day or more of TAC was administered. Methods Seven patients took 200 mL of GFJ every day. The trough levels of the TAC blood concentration were measured before and after GFJ intake and the clinical courses were monitored thereafter. Results First, we surveyed the blood TAC trough levels of 30 recent patients who took 3 mg/day of TAC, and found that 21 patients (70%) did not achieve the minimum target TAC concentration (>5 ng/mL). Seven patients took GFJ due to a lack of efficacy and a relatively low TAC blood concentration. GFJ increased the TAC level from 4.3±2.4 ng/mL to 13.8±6.9 ng/mL (average increase: 3.3-fold). GFJ was also effective in achieving a clinical improvement in most cases without causing any severe adverse events, and it helped to decrease the dosages of glucocorticoid and TAC. In some cases, the blood TAC concentration fluctuated for no apparent reason. Conclusion GFJ intake was effective for the elevation of TAC concentration by approximately three fold and clinical improvement, but special care is required for monitoring its influence on concomitantly used drugs as well as TAC concentration. The addition of GFJ to TAC treatment could be an efficacious treatment option, when the plasma TAC concentration does not reach the minimal target concentration. PMID:27301503

  2. Expression of fibroblast growth factor 23 by canine soft tissue sarcomas.

    PubMed

    Hardcastle, M R; Dittmer, K E

    2016-09-01

    Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of humans. Some mesenchymal tumours (often resembling haemangiopericytomas) express molecules that normally regulate phosphorus metabolism; most frequently, fibroblast growth factor 23. Patients develop renal phosphate wasting and inappropriately low serum concentrations of 1, 25 (OH)2 vitamin D3 , leading to osteomalacia. Surgical removal of the tumour is curative. The authors examined expression of canine fibroblast growth factor 23 in 49 soft tissue sarcomas, and control tissues from normal adult dogs. RNA extracted from bone or formalin-fixed, paraffin-embedded tissues was analysed by end point and quantitative reverse transcriptase-polymerase chain reaction. Fibroblast growth factor 23 expression was detected in bone, lung, kidney, lymph node and thymus. Fifteen of 49 sarcomas (31%) expressed fibroblast growth factor 23, three of these had high relative expression and some features resembling phosphatonin-expressing mesenchymal tumours of humans. Further work is required to determine whether TIO may occur in dogs. PMID:24923416

  3. Changes in pulmonary connective tissue proteins after a single intratracheal instillation of cadmium chloride in the rat

    SciTech Connect

    Kobrle, V.; Mirejovska, E.; Holusa, R.; Hurych, J.

    1986-06-01

    Changes of soluble and insoluble fractions of pulmonary connective tissue proteins were studied in rats for 2-84 days following a single intratracheal instillation of cadmium chloride (10 micrograms Cd/sup 2 +//lung). A transient decrease in body weight and an immediate increase in lung wet weight (200% of control value, P less than 0.01) were observed. Incorporation of (/sup 14/C)proline and its conversion to (/sup 14/C)hydroxyproline in vivo into different soluble and insoluble fractions of connective tissue revealed an increased metabolic turnover elicited by cadmium intoxication. A lag in the maturation of collagen into higher functional forms in the early phase of the process was demonstrated. A striking decrease in elastin was found in first 7 days (40-50%). However, this acute damage of pulmonary connective tissue was followed by a permanent increase of collagen and elastin concentration in the later phase of recovery. Histopathologic examination 14-84 days after cadmium instillation confirmed the presence of lesions in pulmonary tissue with an initial inflammation followed by reparatory changes.

  4. Gelatinase A (MMP-2) and cysteine proteinases are essential for the degradation of collagen in soft connective tissue.

    PubMed

    Creemers, L B; Jansen, I D; Docherty, A J; Reynolds, J J; Beertsen, W; Everts, V

    1998-04-01

    The degradation of soft connective tissue collagen is considered to depend on the activity of various proteolytic enzymes, particularly those belonging to the group of matrix metalloproteinases and cysteine proteinases. In the present study, we investigated the contribution of these enzymes to this process. Using a general inhibitor of MMPs (SC44463), collagen degradation was strongly inhibited, by about 40% after 24 h and up to 80% after 72 h of culturing. Blockage of cysteine proteinase activity (with leupeptin or E-64) reduced breakdown at these time intervals by 50% and 20%, respectively. Given the abundant presence of gelatinases--in particular gelatinase A (MMP-2)--in the tissue, the effect of an inhibitor selective for gelatinases (CT1166) was studied. Gelatinase inhibition resulted in a dose-dependent decrease of collagen breakdown up to 90% after 48 h. The ability of gelatinase A to degrade collagens was demonstrated by the induction of breakdown in devitalized explants by addition of activated gelatinase A, or by activation of endogenous enzyme with 4-aminophenylmercuric acetate. This latter effect was not found with plasmin, an activator of MMPs other than gelatinase A. Finally, the relevance of gelatinase A to the in vivo degradation of soft connective tissue collagen was implicated by the significant correlation found between its activity and the collagen turnover rates of four soft connective tissues (tooth pulp, periodontal ligament, molar gingiva and skin). We conclude that collagen degradation in soft connective tissue is mediated by MMPs and to a lesser extent by cysteine proteinases. Our data are the first to attach a key role to gelatinase A in this process. PMID:9628251

  5. Proteoglycan metabolism in the connective tissue of pregnant and non-pregnant human cervix. An in vitro study.

    PubMed

    Norman, M; Ekman, G; Ulmsten, U; Barchan, K; Malmström, A

    1991-04-15

    Profound changes occur in the cervix during pregnancy. In particular, the connective tissue is remodelled. To elucidate the mechanisms behind this process, the metabolism of cervical connective tissue was studied using tissue cultures. Cervical biopsies from non-pregnant and pregnant women were incubated with [35S]sulphate. The proteoglycans of the tissue specimens were purified by ion-exchange and gel chromatography and characterized by SDS/PAGE and by enzymic degradation. In the non-pregnant cervix, the incorporation of [35S]sulphate into the proteoglycans was linear for 48 h. During the first 6 h of incubation the accumulation of chiefly one small labelled proteoglycan (apparent Mr 110,000) substituted with dermatan sulphate was recorded. This is in accordance with the known proteoglycan composition of non-pregnant cervical tissue. In addition, small amounts of two larger radioactive dermatan/chondroitin sulphate proteoglycans (apparent Mr values 220,000 and greater than 500,000) were recorded. After longer periods of incubation the proportion of heparan sulphate proteoglycans increased considerably. The pregnant tissue showed a clearly different composition of labelled proteoglycans. An increased accumulation of the two larger dermatan/chondroitin sulphate proteoglycans was seen in addition to the dominant small dermatan sulphate proteoglycan of the non-pregnant cervix. The rate of accumulation of these two proteoglycans was about 3 times higher in the pregnant tissue, whereas that of the small dermatan sulphate proteoglycan was only increased 2-fold. The fact that the concentration of proteoglycans in the pregnant cervix is approximately one-half of that in the non-pregnant cervix indicates that the turnover of proteoglycans in pregnant cervical tissue is significantly increased. The major effect of this profound change of metabolism was a 50% decrease in proteoglycan content and a 2-fold increased proportion of a dermatan sulphate proteoglycan with an

  6. Proteoglycan metabolism in the connective tissue of pregnant and non-pregnant human cervix. An in vitro study.

    PubMed Central

    Norman, M; Ekman, G; Ulmsten, U; Barchan, K; Malmström, A

    1991-01-01

    Profound changes occur in the cervix during pregnancy. In particular, the connective tissue is remodelled. To elucidate the mechanisms behind this process, the metabolism of cervical connective tissue was studied using tissue cultures. Cervical biopsies from non-pregnant and pregnant women were incubated with [35S]sulphate. The proteoglycans of the tissue specimens were purified by ion-exchange and gel chromatography and characterized by SDS/PAGE and by enzymic degradation. In the non-pregnant cervix, the incorporation of [35S]sulphate into the proteoglycans was linear for 48 h. During the first 6 h of incubation the accumulation of chiefly one small labelled proteoglycan (apparent Mr 110,000) substituted with dermatan sulphate was recorded. This is in accordance with the known proteoglycan composition of non-pregnant cervical tissue. In addition, small amounts of two larger radioactive dermatan/chondroitin sulphate proteoglycans (apparent Mr values 220,000 and greater than 500,000) were recorded. After longer periods of incubation the proportion of heparan sulphate proteoglycans increased considerably. The pregnant tissue showed a clearly different composition of labelled proteoglycans. An increased accumulation of the two larger dermatan/chondroitin sulphate proteoglycans was seen in addition to the dominant small dermatan sulphate proteoglycan of the non-pregnant cervix. The rate of accumulation of these two proteoglycans was about 3 times higher in the pregnant tissue, whereas that of the small dermatan sulphate proteoglycan was only increased 2-fold. The fact that the concentration of proteoglycans in the pregnant cervix is approximately one-half of that in the non-pregnant cervix indicates that the turnover of proteoglycans in pregnant cervical tissue is significantly increased. The major effect of this profound change of metabolism was a 50% decrease in proteoglycan content and a 2-fold increased proportion of a dermatan sulphate proteoglycan with an

  7. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. Purpose: The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, medial gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  8. An Evaluation of Collagen Metabolism in Non Human Primates Associated with the Bion 11 Space Program-Markers of Urinary Collagen Turnover and Muscle Connective Tissue

    NASA Technical Reports Server (NTRS)

    Vailas, Arthur C.; Martinez, Daniel A.

    1999-01-01

    Patients exhibiting changes in connective tissue and bone metabolism also show changes in urinary by-products of tissue metabolism. Furthermore, the changes in urinary connective tissue and bone metabolites precede alterations at the tissue macromolecular level. Astronauts and Cosmonauts have also shown suggestive increases in urinary by-products of mineralized and non-mineralized tissue degradation. Thus, the idea of assessing connective tissue and bone response in spaceflight monkeys by measurement of biomarkers in urine has merit. Other investigations of bone and connective histology, cytology and chemistry in the Bion 11 monkeys will allow for further validation of the relationship of urinary biomarkers and tissue response. In future flights the non-invasive procedure of urinary analysis may be useful in early detection of changes in these tissues. The purpose of this grant investigation was to evaluate mineralized and non-mineralized connective tissue responses of non-human primates to microgravity by the non-invasive analysis of urinary biomarkers. Secondly, we also wanted to assess muscle connective tissue adaptive changes in three weight-bearing skeletal muscles: the soleus, media] gastrocnemius and tibialis anterior by obtaining pre-flight and post-flight small biopsy specimens in collaboration with Dr. V. Reggie Edgerton's laboratory at the University of California at Los Angeles.

  9. Species-specific contribution of volumetric growth and tissue convergence to posterior body elongation in vertebrates.

    PubMed

    Steventon, Ben; Duarte, Fernando; Lagadec, Ronan; Mazan, Sylvie; Nicolas, Jean-François; Hirsinger, Estelle

    2016-05-15

    Posterior body elongation is a widespread mechanism propelling the generation of the metazoan body plan. The posterior growth model predicts that a posterior growth zone generates sufficient tissue volume to elongate the posterior body. However, there are energy supply-related differences between vertebrates in the degree to which growth occurs concomitantly with embryogenesis. By applying a multi-scalar morphometric analysis in zebrafish embryos, we show that posterior body elongation is generated by an influx of cells from lateral regions, by convergence-extension of cells as they exit the tailbud, and finally by a late volumetric growth in the spinal cord and notochord. Importantly, the unsegmented region does not generate additional tissue volume. Fibroblast growth factor inhibition blocks tissue convergence rather than volumetric growth, showing that a conserved molecular mechanism can control convergent morphogenesis through different cell behaviours. Finally, via a comparative morphometric analysis in lamprey, dogfish, zebrafish and mouse, we propose that elongation via posterior volumetric growth is linked to increased energy supply and is associated with an overall increase in volumetric growth and elongation. PMID:26989170

  10. A structure-based extracellular matrix expansion mechanism of fibrous tissue growth

    PubMed Central

    Kalson, Nicholas S; Lu, Yinhui; Taylor, Susan H; Starborg, Tobias; Holmes, David F; Kadler, Karl E

    2015-01-01

    Embryonic growth occurs predominately by an increase in cell number; little is known about growth mechanisms later in development when fibrous tissues account for the bulk of adult vertebrate mass. We present a model for fibrous tissue growth based on 3D-electron microscopy of mouse tendon. We show that the number of collagen fibrils increases during embryonic development and then remains constant during postnatal growth. Embryonic growth was explained predominately by increases in fibril number and length. Postnatal growth arose predominately from increases in fibril length and diameter. A helical crimp structure was established in embryogenesis, and persisted postnatally. The data support a model where the shape and size of tendon is determined by the number and position of embryonic fibroblasts. The collagen fibrils that these cells synthesise provide a template for postnatal growth by structure-based matrix expansion. The model has important implications for growth of other fibrous tissues and fibrosis. DOI: http://dx.doi.org/10.7554/eLife.05958.001 PMID:25992598

  11. Tenascin-Y: a protein of novel domain structure is secreted by differentiated fibroblasts of muscle connective tissue.

    PubMed

    Hagios, C; Koch, M; Spring, J; Chiquet, M; Chiquet-Ehrismann, R

    1996-09-01

    Tenascin-Y was identified in chicken as a novel member of the tenascin (TN) family of ECM proteins. Like TN-C, TN-R, and TN-X, TN-Y is a multidomain protein consisting of heptad repeats, epidermal growth factor-like repeats, fibronectin type III-like (FNIII) domains and a domain homologous to fibrinogen. In contrast to all other known TNs, the series of FNIII domains is interrupted by a novel domain, rich in serines (S) and prolines (P) that occur as repeated S-P-X-motifs, where X stands for any amino acid. Interestingly, the TN-Y-type FNIII domains are 70-100% identical with respect to their DNA sequence. Different TN-Y variants are created by alternative splicing of FNIII domains. Although, based on sequence comparisons TN-Y is most similar to mammalian TN-X, these molecules are not species homologues. TN-Y is predominantly expressed in embryonic and adult chicken heart and skeletal muscle and, to a lower extent, also in several non-muscular tissues. Two major transcripts of approximately 6.5 and 9.5 kb are differentially expressed during heart and skeletal muscle development and are also present in the adult. Anti-TN-Y antibodies recognize a approximately 400-kD double band and a approximately 300-kD form of TN-Y on immunoblots of chicken heart extracts. In situ hybridization and immunofluorescence analysis of aortic smooth muscle, heart, and skeletal muscle revealed that TN-Y is mainly expressed and secreted by cells within muscle-associated connective tissue. Cultured primary muscle fibroblasts released a approximately 220-kD doublet and a approximately 170-kD single TN-Y variant only when cultured in 10% horse serum but not in medium containing 10% fetal calf serum. All TN-Y variants isolated bind to heparin under physiologically relevant conditions that may indicate an important function retained in all tenascins. PMID:8830777

  12. Structural changes in connective tissues caused by a moderate laser heating

    SciTech Connect

    Bagratashvili, Viktor N; Bagratashvili, N V; Sviridov, A P; Shakh, G Sh; Ignat'eva, Natalia Yu; Lunin, Valery V; Grokhovskaya, T E; Averkiev, S V

    2002-10-31

    The structural changes in adipose and fibrous tissues caused by 2- and 3-W IR laser irradiation are studied by the methods of IR and Raman spectroscopy and differential scanning calorimetry. It is shown that heating of fibrous tissue samples to 50 {sup 0}C and adipose tissue samples to 75 {sup 0}C by IR laser radiation changes the supramolecular structure of their proteins and triacylglycerides, respectively, without the intramolecular bond breaking. Heating of fibrous tissue to 70 {sup 0}C and adipose tissue to 90 - 110 {sup 0}C leads to a partial reversible denaturation of proteins and to oxidation of fats.

  13. [Chosen problems of mental functioning in patients with chronic systemic connective tissue diseases base on example of rheumatoid arthritis].

    PubMed

    Nasiłowska-Barud, Alicja; Żuk, Mariola

    2015-01-01

    Disorders in mental functioning are indicated as the cause of all connective tissue diseases and also as their consequences. That is why psychologist's help may be very important for patients with rheumatoid arthritis. Psychological observations of patients with chronic systemic connective tissue diseases show a number of negative emotional states such as fear, anxiety, insecurity, depressed mood, depression, impatience, anger and a sense of loss These patients constantly experience pain of varying intensity and location. In many of them progressive disease leads to the advancement of mental crisis. Methods of psychological therapy must be focused on strenghtening mental resilience and helping in surviving mental crisis. Psychological therapy should concentrate on raising self-esteem, training interpersonal skills and teaching relaxation techniques to cope better with pain and suffering. Psychological therapy should support the patient in struggling with the problems caused by the disease and developing ways of adapting to life with the disease. PMID:26753214

  14. Surgical treatment of localized gingival recessions using coronally advanced flaps with or without subepithelial connective tissue graft

    PubMed Central

    Bellver-Fernández, Ricardo; Martínez-Rodriguez, Ana-María; Gioia-Palavecino, Claudio; Caffesse, Raul-Guillermo

    2016-01-01

    Background A coronally advanced flap with subepithelial connective tissue graft is the gold standard surgical treatment of gingival recessions, since it offers a higher probability of achieving complete root coverage compared with other techniques. However, optimum short- and middle-term clinical results have also been obtained with coronally advanced flaps alone. The aim of the present study was to evaluate the results obtained by the surgical treatment of localized gingival recessions using coronally advanced flaps with or without subepithelial connective tissue graft. Material and Methods The reduction of recession height was assessed, together with the gain in gingival attachment apical to the recession, and total reduction of recession, in a comparative study of two techniques. Twenty-two gingival recessions were operated upon: 13 in the control group (coronally advanced flap) and 9 in the test group (coronally advanced flap associated to subepithelial connective tissue graft). Results After 18 months, the mean reduction of recession height was 2.2 ± 0.8 mm in the control group and 2.3 ± 0.7 mm in the test group, with a mean gain in gingival attachment of 1.3 ± 0.9 mm and 2.3 ± 1.3 mm, respectively. In percentage terms, the mean reduction of recession height was 84.6 ± 19.6% in the control group and 81.7 ± 17.8% in the test group, with a mean gain in gingival attachment of 20.5 ± 37.4% and 184.4 ± 135.5%, respectively. Conclusions Significant reduction of gingival recession was achieved with both techniques, though the mean gain in gingival attachment (in mm and as a %) was greater in test group. Key words:Gingival recession, coronally advanced flap, subepthelial connective tissue graft. PMID:26595836

  15. A case of mixed connective tissue disease with pseudo-pseudo Meigs' syndrome (PPMS)-like features.

    PubMed

    Cheah, C K; Ramanujam, S; Mohd Noor, N; Gandhi, C; D Souza, Beryl A; Gun, S C

    2016-02-01

    Pseudo-pseudo Meigs' syndrome (PPMS) has been reported to be a rare presentation of patients with systemic lupus erythematosus (SLE). However, such a presentation is not common in other forms of connective tissue disease. We presented a case of gross ascites, pleural effusion, and marked elevation of CA-125 level (PPMS-like features) that led to a diagnosis of MCTD. The patient responded to systemic steroid therapy. PMID:26377236

  16. Adverse Events in Connective Tissue Disease–Associated Pulmonary Arterial Hypertension

    PubMed Central

    Rhee, Rennie L.; Gabler, Nicole B.; Praestgaard, Amy; Merkel, Peter A.; Kawut, Steven M.

    2016-01-01

    Objective Patients with connective tissue disease (CTD)–associated pulmonary arterial hypertension (PAH) have a poorer prognosis compared to those with idiopathic PAH, but little is known about the differences in treatment-related adverse events (AEs) and serious adverse events (SAEs) between these groups. This study was undertaken to characterize these differences. Methods Individual patient-level data from 10 randomized controlled trials of therapies for PAH were obtained from the US Food and Drug Administration. Patients diagnosed as having either CTD-associated PAH or idiopathic PAH were included. A treatment-by-diagnosis interaction term was used to examine whether the effect of treatment on occurrence of AEs differed between patients with CTD-associated PAH and those with idiopathic PAH. Studies were pooled using fixed-effect models. Results The study sample included 2,370 participants: 716 with CTD-associated PAH and 1,654 with idiopathic PAH. In the active treatment group compared to the placebo group, the risk of AEs was higher among patients with CTD-associated PAH than among those with idiopathic PAH (odds ratio [OR] 1.57, 95% confidence interval [95% CI] 1.00–2.47 versus OR 0.94, 95% CI 0.69–1.26; P for interaction = 0.061), but there was no difference in the risk of SAEs in analyses adjusted for age, race, sex, hemodynamic findings, and laboratory values. Despite the higher occurrence of AEs in patients with CTD-associated PAH assigned to active therapy compared to those receiving placebo, the risk of drug discontinuation due to an AE was similar to that in patients with idiopathic PAH assigned to active therapy (P for interaction = 0.27). Conclusion Patients with CTD-associated PAH experienced more treatment-related AEs compared to those with idiopathic PAH in therapeutic clinical trials. These findings suggest that the overall benefit of advanced therapies for PAH may be attenuated by the greater frequency of AEs. PMID:26016953

  17. Short- and Long-term Outcomes in Patients with Connective Tissue Diseases Undergoing Percutaneous Coronary Intervention

    PubMed Central

    Zhou, Li; Chen, Hui; Li, Wei-Ping; Gao, Hong-Li; Li, Dong-Bao; Zhao, Hui-Qiang; Yao, Dao-Kuo; Li, Hong-Wei

    2016-01-01

    Background: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in patients with connective tissue diseases (CTDs). Risk factors and clinical characteristics in these patients are not equivalent to those in traditional CAD patients. The objective of this study was to report short- and long-term clinical outcomes in a consecutive series of patients with CTD who underwent percutaneous coronary intervention (PCI) with stent implantation. Methods: The study group comprised 106 consecutive patients with CTD who underwent PCI in Beijing Friendship Hospital between January 2009 and June 2012. Medical records were analyzed retrospectively including clinical basic material, coronary angiogram data, and the incidence of major adverse cardiac events (MACEs) during the short- and long-term (median 3 years) follow-up. Results: Ninety-two of the patients (86.8%) had one or more traditional CAD risk factors. Multivessel disease was present in more than 2/3 of patients (73.6%). The left anterior descending coronary artery was the most commonly affected vessel (65.1%). Five bare-metal stents and 202 drug-eluting stents were implanted. After a median follow-up period of 36 months, thirteen patients (12.3%) died from cardiac causes, the rate of stent thrombosis was 9.4%, and the rate of target vessel revascularization (TVR) was 14.2%. Multivariate analysis revealed that hypertension (hazard ratio [HR] = 3.07, 95% confidence interval [CI]: 1.30–7.24, P = 0.041), anterior myocardial infarction (HR = 2.77, 95% CI: 1.06–7.03, P = 0.04), longer duration of steroid treatment (HR = 3.60, 95% CI: 1.43–9.08, P = 0.032), and C-reactive protein level >10 mg/L (HR = 3.98, 95% CI: 1.19–12.56, P = 0.036) were independent predictors of MACEs. Conclusions: Patients with CTD and CAD may have severe coronary lesions. PCI in these patients tends to result in an increased rate of stent thrombosis and TVR during long-term follow-up, which may be influenced by traditional

  18. Frequency of Autoantibodies and Connective Tissue Diseases in Chinese Patients with Optic Neuritis

    PubMed Central

    Yi, Zuohuizi; Huang, Dehui; Wei, Shihui

    2014-01-01

    Background Optic neuritis (ON) is often associated with other clinical or serological markers of connective tissue diseases (CTDs). To date, the effects of autoantibodies on ON are not clear. Purpose To assess the prevalence, clinical patterns, and short outcomes of autoantibodies and Sjögren’s syndrome (SS) involvement in Chinese ON patients and evaluate the relationship between ON, including their subtypes, and autoantibodies. Methods A total of 190 ON patients were divided into recurrent ON (RON), bilateral ON (BON), and isolated monocular ON (ION). Demographic, clinical, and serum autoantibodies data were compared between them with and without SS involvement. Serum was drawn for antinuclear antibody (ANA), extractable nuclear antigen antibodies (SSA/SSB), rheumatoid factor (RF), anticardiolipin antibodies (ACA), and anti-double-stranded DNA antibody (A-ds DNA), anticardiolipin antibody (ACLs), anti-β2-glycoprotein I (β2-GPI) and Aquaporin-4 antibodies (AQP4-Ab). Spectral-domain optical coherence tomography (SD-OCT) was used to evaluate the atrophy of the optic nerve. Results 68 patients (35.79%) had abnormal autoantibodies, 26(13.68%) patients met diagnostic criteria for CTDs, including 15(7.89%) patients meeting the criteria for SS. Antibodies including SSA/SSB 23 (30.26%) (p1 and p 2<0.001) and AQP4–Ab10 (13.16%) (p1 = 0.044, p2 = 0.01) were significantly different in patients in the RON group when compared with those in the BON (P1 = RON VS ION) and ION (p2 = RON VS ION) groups. SS was more common in RON patients (p1 = 0.04, p2 = 0.028). There was no significant difference between SSA/SSB positive and negative patients in disease characteristics or severity. Similar results were obtained when SS was diagnosed in SSA/SSB positive patients. Conclusion RON and BON were more likely associated with abnormal autoantibodies; furthermore, AQP4 antibody, SSA/SSB and SS were more common in the RON patients. AQP4 antibodydetermination is

  19. Predictors of mortality in connective tissue disease-associated pulmonary arterial hypertension: a cohort study

    PubMed Central

    2012-01-01

    Introduction Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). We sought to quantify survival and determine factors predictive of mortality in a cohort of patients with CTD-associated PAH (CTD-PAH) in the current era of advanced PAH therapy. Methods Patients with right heart catheter proven CTD-PAH were recruited from six specialised PAH treatment centres across Australia and followed prospectively. Using survival methods including Cox proportional hazards regression, we modelled for all-cause mortality. Independent variables included demographic, clinical and hemodynamic data. Results Among 117 patients (104 (94.9%) with systemic sclerosis), during 2.6 ± 1.8 (mean ± SD) years of follow-up from PAH diagnosis, there were 32 (27.4%) deaths. One-, two- and three-year survivals were 94%, 89% and 73%, respectively. In multiple regression analysis, higher mean right atrial pressure (mRAP) at diagnosis (hazard ratio (HR) = 1.13, 95% CI: 1.04 to 1.24, P = 0.007), lower baseline six-minute walk distance (HR = 0.64, 95% CI: 0.43 to 0.97, P = 0.04), higher baseline World Health Organization functional class (HR = 3.42, 95% CI: 1.25 to 9.36, P = 0.04) and presence of a pericardial effusion (HR = 3.39, 95% CI: 1.07 to 10.68, P = 0.04) were predictive of mortality. Warfarin (HR = 0.20, 95% CI: 0.05 to 0.78, P = 0.02) and combination PAH therapy (HR = 0.20, 95% CI: 0.05 to 0.83, P = 0.03) were protective. Conclusions In this cohort of CTD-PAH patients, three-year survival was 73%. Independent therapeutic predictors of survival included warfarin and combination PAH therapy. Our findings suggest that anticoagulation and combination PAH therapy may improve survival in CTD-PAH. This observation merits further evaluation in randomised controlled trials. PMID:23039366

  20. Purification and characterization of pepsin-solubilized collagen from skin and connective tissue of giant red sea cucumber (Parastichopus californicus).

    PubMed

    Liu, Zunying; Oliveira, Alexandra C M; Su, Yi-Cheng

    2010-01-27

    Pepsin-solubilized collagen (PSC) was extracted from giant red sea cucumbers ( Parastichopus californicus ) and characterized for denaturation temperature (T(d)), maximum transition temperature (T(m)), enzyme-digested peptide maps, and gel-forming capability. SDS-PAGE showed that PSCs from giant red sea cucumber skin and connective tissue were both type I collagens, consisting of three alpha(1) chains of approximately 138 kDa each. The amino acid composition and peptide maps of PSCs digested by V8 protease were different from those of calf skin type I collagen. The T(d) and T(m) are 18.5 and 33.2 degrees C, respectively, for skin PSC and are 17.9 and 32.7 degrees C, respectively, for connective tissue PSC. Both skin and connective tissue PSCs exhibited good gel-forming capability at pH 6.5 and at an ionic strength of 300 mM salt (NaCl). Collagen isolated from giant red sea cucumbers might be used as an alternative to mammalian collagen in the food and pharmaceutical industries. PMID:20085374

  1. Association of HLA-DRB1 alleles with susceptibility to mixed connective tissue disease in Polish patients.

    PubMed

    Paradowska-Gorycka, A; Stypińska, B; Olesińska, M; Felis-Giemza, A; Mańczak, M; Czuszynska, Z; Zdrojewski, Z; Wojciechowicz, J; Jurkowska, M

    2016-01-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disease, originally defined as a connective tissue inflammatory syndrome with overlapping features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM) and systemic sclerosis (SSc), characterized by the presence of antibodies against components of the U1 small nuclear ribonucleoprotein (U1snRNP). The aim of the study was to assess the frequency of (high-resolution-typed) DRB1 alleles in a cohort of Polish patients with MCTD (n = 103). Identification of the variants potentially associated with risk and protection was carried out by comparison with the DKMS Polish Bone Marrow Donor Registry (41306 alleles). DRB1*15:01 (odds ratio (OR): 6.06; 95% confidence interval (CI) 4.55-8.06), DRB1*04 (OR: 3.69; 95% CI 2.69-5.01) and *09:01 (OR: 8.12; 95% CI 2.15-21.75) were identified as risk alleles for MCTD, while HLA-DRB1*07:01 allele was found to be protective (OR: 0.50; 95% CI 0.28-0.83). The carrier frequency of the DRB1*01 was higher in MCTD patients compared with controls, although the differences were not statistically significant. Our results confirm the modulating influence of HLA-DRB1 genotypes on development of connective tissue diseases such as MCTD. PMID:26818120

  2. Spatial arrangement of the heart muscle fascicles and intramyocardial connective tissue in the Spanish fighting bull (Bos taurus).

    PubMed Central

    Sánchez-Quintana, D; Climent, V; Garcia-Martinez, V; Rojo, M; Hurlé, J M

    1994-01-01

    The spatial arrangement of the muscle fascicles and intramyocardial connective tissue was examined in the ventricles of the heart of the Spanish fighting bull (Bos taurus). In both ventricles, the muscle fascicles of the myocardium are arranged in 3 main directions, forming 3 muscle layers within the ventricular wall. The preferentially vertical arrangement of the muscle fascicles in the superficial and deep layers at the level of the fibrous aortic rings and the base of the semilunar valve leaflets suggests that these fascicles are actively involved in valvular dynamics. After controlled digestion of myocytes and elastic fibres with NaOH, a 3-dimensional arrangement of the scaffolding of connective tissue that supports the muscle fascicles and myocytes was observed. The arrangement and structure of this scaffolding may influence the order of contraction of muscle fascicles in different layers of the ventricle. In addition, differences were observed between the connective tissue scaffolding surrounding the myocytes of the 2 ventricles; these variations were correlated with the different biomechanical properties. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 8 Fig. 9 Fig. 10 PMID:8014119

  3. UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review

    PubMed Central

    Breuckmann, Frank; Gambichler, Thilo; Altmeyer, Peter; Kreuter, Alexander

    2004-01-01

    Background Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare. Methods Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders. Results Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities. Conclusions Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications. PMID:15380024

  4. Immunohistochemical localization of the epidermal growth factor receptor in normal human tissues.

    PubMed

    Damjanov, I; Mildner, B; Knowles, B B

    1986-11-01

    A monoclonal antibody recognizing an epitope of the external domain of the human epidermal growth factor (EGF) receptor was used to localize this protein in selected normal human tissues. Two patterns of reactivity were recognized: strong linear or granular cell surface staining, and granular cytoplasmic staining. In one tissue, the endometrium, a change in the reaction pattern associated with changes in hormonal stimulation was observed. In some tissues such as epididymis and skin, the antibody showed surface reactivity with cells considered to represent part of the proliferating cell compartment, whereas in liver, pancreas, and prostate, all cells were reactive with the antibody, though the predominant reactivity was localized in the cytoplasm. The differential distribution of the epidermal growth factor receptor to specific cell types and cellular compartments may signify adaptations that permit growth factor responsiveness in a milieu of available ligand. PMID:3534450

  5. Clinical Comparison of Full and Partial Double Pedicle Flaps with Connective Tissue Grafts for Treatment of Gingival Recession

    PubMed Central

    Ranjbari, Ardeshir; Gholami, Gholam Ali; Amid, Reza; Kadkhodazadeh, Mahdi; Youssefi, Navid; Mehdizadeh, Amir Reza; Aghaloo, Maryam

    2016-01-01

    Statement of the Problem Gingival recession has been considered as the most challenging issue in the field of periodontal plastic surgery. Purpose The purpose of this study was to evaluate the clinical efficacy of root coverage procedures by using partial thickness double pedicle graft and compare it with full thickness double pedicle graft. Materials and Method Eight patients, aged 15 to 58 years including 6 females and 2 males with 20 paired (mirror image) defects with class I and II gingival recession were randomly assigned into two groups. Clinical parameters such as recession depth, recession width, clinical attachment level, probing depth, and width of keratinized tissue were measured at the baseline and 6 months post-surgery. A mucosal double papillary flap was elevated and the respective root was thoroughly planed. The connective tissue graft was harvested from the palate, and then adapted over the root. The pedicle flap was secured over the connective tissue graft and sutured. The surgical technique was similar in the control group except for the prepared double pedicle graft which was full thickness. Results The mean root coverage was 88.14% (2.83 mm) in the test group and 85.7% (2.75 mm) in the control group. No statistical differences were found in the mean reduction of vertical recession, width of recession, or probing depth between the test and control groups. In both procedures, the width of keratinized tissue increased after three months and the difference between the two groups was not statistically significant in this respect. Conclusion Connective tissue with partial and full thickness double pedicle grafts can be successfully used for treatment of marginal gingival recession. PMID:27602394

  6. New insights into the structure, assembly and biological roles of 10-12 nm connective tissue microfibrils from fibrillin-1 studies.

    PubMed

    Jensen, Sacha A; Handford, Penny A

    2016-04-01

    The 10-12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10-12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10-12 nm diameter microfibril and perform such diverse roles. PMID:27026396

  7. Prostaglandins of the E-series inhibit connective tissue proliferation in the liver wound of the rat.

    PubMed

    Arend, A; Aunapuu, M; Masso, R; Selstam, G

    2005-03-01

    The present study was undertaken to relate wound healing of an internal organ to prostaglandins of the E and F series. A small liver wound was induced by a galvanic cauter via the abdominal route under general anesthesia and prostaglandin E1, E2 and F2alpha were injected twice daily at a dose of 250 microg/kg. Proliferation of the connective tissue in the liver wound was estimated morphometrically 6 days after liver wound infliction. Levels of prostaglandins E2 and F2alpha were measured in the liver wound as well as in normal liver tissue from adjacent lobes using radioimmunoassay. The results show that exogenous prostaglandins of the E-series suppress connective tissue proliferation. Three minutes after the last prostaglandin E2 injection, high prostaglandin concentrations were measured both in the liver wound and in the liver tissue of the adjacent lobe. Prostaglandin F2alpha injections had no effect on wound healing. We believe that the rat thermic liver wound model can be used for different studies on wound healing mechanisms and that prostaglandins of the E-series are involved in wound healing in the specific time period studied. PMID:15835401

  8. Drosophila E-cadherin is required for the maintenance of ring canals anchoring to mechanically withstand tissue growth

    PubMed Central

    Loyer, Nicolas; Kolotuev, Irina; Pinot, Mathieu; Le Borgne, Roland

    2015-01-01

    Intercellular bridges called “ring canals” (RCs) resulting from incomplete cytokinesis play an essential role in intercellular communication in somatic and germinal tissues. During Drosophila oogenesis, RCs connect the maturing oocyte to nurse cells supporting its growth. Despite numerous genetic screens aimed at identifying genes involved in RC biogenesis and maturation, how RCs anchor to the plasma membrane (PM) throughout development remains unexplained. In this study, we report that the clathrin adaptor protein 1 (AP-1) complex, although dispensable for the biogenesis of RCs, is required for the maintenance of the anchorage of RCs to the PM to withstand the increased membrane tension associated with the exponential tissue growth at the onset of vitellogenesis. Here we unravel the mechanisms by which AP-1 enables the maintenance of RCs’ anchoring to the PM during size expansion. We show that AP-1 regulates the localization of the intercellular adhesion molecule E-cadherin and that loss of AP-1 causes the disappearance of the E-cadherin–containing adhesive clusters surrounding the RCs. E-cadherin itself is shown to be required for the maintenance of the RCs’ anchorage, a function previously unrecognized because of functional compensation by N-cadherin. Scanning block-face EM combined with transmission EM analyses reveals the presence of interdigitated, actin- and Moesin-positive, microvilli-like structures wrapping the RCs. Thus, by modulating E-cadherin trafficking, we show that the sustained E-cadherin–dependent adhesion organizes the microvilli meshwork and ensures the proper attachment of RCs to the PM, thereby counteracting the increasing membrane tension induced by exponential tissue growth. PMID:26424451

  9. Drosophila E-cadherin is required for the maintenance of ring canals anchoring to mechanically withstand tissue growth.

    PubMed

    Loyer, Nicolas; Kolotuev, Irina; Pinot, Mathieu; Le Borgne, Roland

    2015-10-13

    Intercellular bridges called "ring canals" (RCs) resulting from incomplete cytokinesis play an essential role in intercellular communication in somatic and germinal tissues. During Drosophila oogenesis, RCs connect the maturing oocyte to nurse cells supporting its growth. Despite numerous genetic screens aimed at identifying genes involved in RC biogenesis and maturation, how RCs anchor to the plasma membrane (PM) throughout development remains unexplained. In this study, we report that the clathrin adaptor protein 1 (AP-1) complex, although dispensable for the biogenesis of RCs, is required for the maintenance of the anchorage of RCs to the PM to withstand the increased membrane tension associated with the exponential tissue growth at the onset of vitellogenesis. Here we unravel the mechanisms by which AP-1 enables the maintenance of RCs' anchoring to the PM during size expansion. We show that AP-1 regulates the localization of the intercellular adhesion molecule E-cadherin and that loss of AP-1 causes the disappearance of the E-cadherin-containing adhesive clusters surrounding the RCs. E-cadherin itself is shown to be required for the maintenance of the RCs' anchorage, a function previously unrecognized because of functional compensation by N-cadherin. Scanning block-face EM combined with transmission EM analyses reveals the presence of interdigitated, actin- and Moesin-positive, microvilli-like structures wrapping the RCs. Thus, by modulating E-cadherin trafficking, we show that the sustained E-cadherin-dependent adhesion organizes the microvilli meshwork and ensures the proper attachment of RCs to the PM, thereby counteracting the increasing membrane tension induced by exponential tissue growth. PMID:26424451

  10. Use of fibroblast growth factor 2 for expansion of chondrocytes and tissue engineering

    NASA Technical Reports Server (NTRS)

    Martin, Ivan (Inventor); Freed, Lisa E. (Inventor); Langer, Robert (Inventor); Vunjak-Novakovic, Gordana (Inventor)

    2003-01-01

    The present invention provides an improved method for expanding cells for use in tissue engineering. In particular the method provides specific biochemical factors to supplement cell culture medium during the expansion process in order to reproduce events occurring during embryonic development with the goal of regenerating tissue equivalents that resemble natural tissues both structurally and functionally. These specific biochemical factors improve proliferation of the cells and are capable of de-differentiation mature cells isolated from tissue so that the differentiation potential of the cells is preserved. The bioactive molecules also maintain the responsiveness of the cells to other bioactive molecules. Specifically, the invention provides methods for expanding chondrocytes in the presence of fibroblast growth factor 2 for use in regeneration of cartilage tissue.

  11. [Expression of tissue factor and vascular endothelial growth factor in colorectal carcinoma].

    PubMed

    Altomare, D F; Rotelli, M T; Memeo, V; Martinelli, E; Guglielmi, A; DeFazio, M; D'Elia, G; Pentimone, A; Colucci, M; Semeraro, N

    2003-01-01

    Tissue factor (TF) and vascular endothelial growth factor (VEGF) play an important role in tumor progression and metastasis. We analyzed their expression in the carcinoma and normal mucosa of 53 colorectal cancer patients. VEGF levels were significantly higher in the tumor and correlated with TF expression. No correlation was found with tumor stage. TF may influence tumor growth and metastasis by modulating VEGF expression and neoangiogenesis. PMID:12903530

  12. The scope and sequence of growth factor delivery for vascularized bone tissue regeneration.

    PubMed

    Bayer, E A; Gottardi, R; Fedorchak, M V; Little, S R

    2015-12-10

    Bone regeneration is a complex process, that in vivo, requires the highly coordinated presentation of biochemical cues to promote the various stages of angiogenesis and osteogenesis. Taking inspiration from the natural healing process, a wide variety of growth factors are currently being released within next generation tissue engineered scaffolds (in a variety of ways) in order to heal non-union fractures and bone defects. This review will focus on the delivery of multiple growth factors to the bone regeneration niche, specifically 1) dual growth factor delivery signaling and crosstalk, 2) the importance of growth factor timing and temporal separation, and 3) the engineering of delivery systems that allow for temporal control over presentation of soluble growth factors. Alternative methods for growth factor presentation, including the use of gene therapy and platelet-rich plasma scaffolds, are also discussed. PMID:26264834

  13. Comparison of ADM and Connective Tissue Graft as the Membrane in Class II Furcation Defect Regeneration: A Randomized Clinical Trial

    PubMed Central

    Esfahanian, Vahid; Farhad, Shirin; Sadighi Shamami, Mehrnaz

    2014-01-01

    Background and aims. Furcally-involved teeth present unique challenges to the success of periodontal therapy and influence treatment outcomes. This study aimed to assess to compare use of ADM and connective tissue membrane in class II furcation defect regeneration. Materials and methods. 10 patient with 2 bilaterally class II furcation defects in first and/or second maxilla or man-dibular molar without interproximal furcation involvement, were selected. Four weeks after initial phase of treatment, before and thorough the surgery pocket depth (PD), clinical attachment level to stent (CAL-S), free gingival margin to stent(FGM-S) , crestal bone to stent (Crest-S), horizontal defect depth to stent (HDD-S) and vertical defect depth to stent (VDD-S) and crestal bone to defect depth measured from stent margin. Thereafter, one side randomly treated using connective tissue and DFDBA (study group) and opposite side received ADM and DFDBA (control group). After 6 months, soft and hard tissue parameters measured again in re-entry. Results. Both groups presented improvements after therapies (P & 0.05). No inter-group differences were seen in PD re-duction (P = 0.275), CAL gain (P = 0.156), free gingival margin (P = 0.146), crest of the bone (P = 0.248), reduction in horizontal defects depth (P = 0.139) and reduction in vertical defects depth (P = 0.149). Conclusion. Both treatments modalities have potential of regeneration without any adverse effect on healing process. Connective tissue grafts did not have significant higher bone fill compared to that of ADM. PMID:25093054

  14. Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease

    PubMed Central

    2010-01-01

    Introduction The aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease. Methods Fifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed. Results The endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7 ± 4.2% vs. 8.7 ± 5.0%; P < 0.001), while the percentage NMD did not differ (%NMD: 14.3 ± 6.6% vs. 17.1 ± 6.7%; P = 0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64 ± 0.13 mm vs. controls, 0.53 ± 0.14 mm; P < 0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5 ± 2.9 vs. 5.8 ± 4.8, P < 0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and

  15. Quantitative analysis of tissue deformation dynamics reveals three characteristic growth modes and globally aligned anisotropic tissue deformation during chick limb development

    PubMed Central

    Morishita, Yoshihiro; Kuroiwa, Atsushi; Suzuki, Takayuki

    2015-01-01

    Tissue-level characterization of deformation dynamics is crucial for understanding organ morphogenetic mechanisms, especially the interhierarchical links among molecular activities, cellular behaviors and tissue/organ morphogenetic processes. Limb development is a well-studied topic in vertebrate organogenesis. Nevertheless, there is still little understanding of tissue-level deformation relative to molecular and cellular dynamics. This is mainly because live recording of detailed cell behaviors in whole tissues is technically difficult. To overcome this limitation, by applying a recently developed Bayesian approach, we here constructed tissue deformation maps for chick limb development with high precision, based on snapshot lineage tracing using dye injection. The precision of the constructed maps was validated with a clear statistical criterion. From the geometrical analysis of the map, we identified three characteristic tissue growth modes in the limb and showed that they are consistent with local growth factor activity and cell cycle length. In particular, we report that SHH signaling activity changes dynamically with developmental stage and strongly correlates with the dynamic shift in the tissue growth mode. We also found anisotropic tissue deformation along the proximal-distal axis. Morphogenetic simulation and experimental studies suggested that this directional tissue elongation, and not local growth, has the greatest impact on limb shaping. This result was supported by the novel finding that anisotropic tissue elongation along the proximal-distal axis occurs independently of cell proliferation. Our study marks a pivotal point for multi-scale system understanding in vertebrate development. PMID:25858459

  16. Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal‐Dominant Hereditary Connective Tissue Disease

    PubMed Central

    Capuano, Alessandra; Bucciotti, Francesco; Farwell, Kelly D.; Tippin Davis, Brigette; Mroske, Cameron; Hulick, Peter J.; Weissman, Scott M.; Gao, Qingshen; Spessotto, Paola; Doliana, Roberto

    2015-01-01

    ABSTRACT Heritable connective tissue diseases are a highly heterogeneous family of over 200 disorders that affect the extracellular matrix. While the genetic basis of several disorders is established, the etiology has not been discovered for a large portion of patients, likely due to rare yet undiscovered disease genes. By performing trio‐exome sequencing of a 55‐year‐old male proband presenting with multiple symptoms indicative of a connective disorder, we identified a heterozygous missense alteration in exon 1 of the Elastin Microfibril Interfacer 1 (EMILIN1) gene, c.64G>A (p.A22T). The proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Sanger sequencing confirmed that the EMILIN1 alteration, which maps around the signal peptide cleavage site, segregated with disease in the affected proband, mother, and son. The impaired secretion of EMILIN‐1 in cells transfected with the mutant p.A22T coincided with abnormal protein accumulation within the endoplasmic reticulum. In skin biopsy of the proband, we detected less EMILIN‐1 with disorganized and abnormal coarse fibrils, aggregated deposits underneath the epidermis basal lamina, and dermal cells apoptosis. These findings collectively suggest that EMILIN1 may represent a new disease gene associated with an autosomal‐dominant connective tissue disorder. PMID:26462740

  17. Organic tissues in rotating bioreactors: fluid-mechanical aspects, dynamic growth models, and morphological evolution.

    PubMed

    Lappa, Marcello

    2003-12-01

    This analysis deals with advances in tissue-engineering models and computational methods as well as with novel results on the relative importance of "controlling forces" in the growth of organic constructs. Specifically, attention is focused on the rotary culture system, because this technique has proven to be the most practical solution for providing a suitable culture environment supporting three-dimensional tissue assemblies. From a numerical point of view, the growing biological specimen gives rise to a moving boundary problem. A "volume-of-fraction" method is specifically and carefully developed according to the complex properties and mechanisms of organic tissue growth and, in particular, taking into account the sensitivity of the construct/liquid interface to the effect of the fluid-dynamic shear stress (it induces changes in tissue metabolism and function that elicit a physiological response from the biological cells). The present study uses available data to introduce a set of growth models. The surface conditions are coupled to the transfer of mass and momentum at the specimen/culture-medium interface and lead to the introduction of a group of differential equations for the nutrient concentration around the sample and for the evolution of tissue mass displacement. The models are then used to show how the proposed surface kinetic laws can predict (through sophisticated numerical simulations) many of the known characteristics of biological tissues grown using rotating-wall perfused vessel bioreactors. This procedure provides a validation of the models and associated numerical method and also gives insight into the mechanisms of the phenomena. The interplay between the increasing size of the tissue and the structure of the convective field is investigated. It is shown that this interaction is essential in determining the time evolution of the tissue shape. The size of the growing specimen plays a critical role with regard to the intensity of convection and

  18. Radiosensitivity of different tissues from carrot root at different phases of growth in culture

    SciTech Connect

    Degani, N.; Pickholtz, D.

    1980-09-01

    The present work compares the effect of ..gamma..-radiation dose and time in culture on the growth of cambium and phloem carrot (Daucus carota) root explants. It was found that the phloem is more radiosensitive than the cambium and that both tissues were more radiosensitive when irradiated on excision at the G/sub 1/ phase rather than at the end of the lag phase on the ninth day of growth in culture when cells were predominantly at the G/sub 2/ phase. The nuclear volumes of cells from both tissues were similar but were larger at the end of the more radioresistant lag phase than those of the G/sub 1/ phase on excision. However, nuclear volume could not account for the differences in radiosensitivity between either the tissues or irradiation times in culture.

  19. Connections between Student Explanations and Arguments from Evidence about Plant Growth

    PubMed Central

    Doherty, Jennifer H.; Freed, Allison L.; Anderson, Charles W.

    2014-01-01

    We investigate how students connect explanations and arguments from evidence about plant growth and metabolism—two key practices described by the Next Generation Science Standards. This study reports analyses of interviews with 22 middle and high school students postinstruction, focusing on how their sense-making strategies led them to interpret—or misinterpret—scientific explanations and arguments from evidence. The principles of conservation of matter and energy can provide a framework for making sense of phenomena, but our results show that some students reasoned about plant growth as an action enabled by water, air, sunlight, and soil rather than a process of matter and energy transformation. These students reinterpreted the hypotheses and results of standard investigations of plant growth, such as van Helmont's experiment, to match their own understanding of how plants grow. Only the more advanced students consistently interpreted mass changes in plants or soil as evidence of movement of matter. We also observed that a higher degree of scaffolding during some of the interview questions allowed mid-level students to improve their responses. We describe our progress and challenges developing teaching materials with scaffolding to improve students’ understanding of plant growth and metabolism. PMID:25185224

  20. U1-RNP and Toll-like receptors in the pathogenesis of mixed connective tissue diseasePart II. Endosomal TLRs and their biological significance in the pathogenesis of mixed connective tissue disease

    PubMed Central

    2015-01-01

    Mixed connective tissue disease (MCTD) is a chronic autoimmune immunopathological disease of unknown etiology, which is characterized by the presence of various clinical symptoms and the presence of autoantibodies against U1-RNP particles. The U1-RNP component engages immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. The anti-U1-RNP autoantibodies form an immune complex with self-RNA, present in MCTD serum, which can act as endosomal Toll-like receptor (TLR) ligands. Inhibition of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, tumorigenesis and autoimmunity. In this review we summarize current knowledge of endogenous TLRs and discuss their biological significance in the pathogenesis of MCTD. In part I we described the structure, biological function and significance of the U1-RNP complex in MCTD.

  1. Nutrient/TOR-dependent regulation of RNA polymerase III controls tissue and organismal growth in Drosophila.

    PubMed

    Marshall, Lynne; Rideout, Elizabeth J; Grewal, Savraj S

    2012-04-18

    The nutrient/target-of-rapamycin (TOR) pathway has emerged as a key regulator of tissue and organismal growth in metazoans. The signalling components of the nutrient/TOR pathway are well defined; however, the downstream effectors are less understood. Here, we show that the control of RNA polymerase (Pol) III-dependent transcription is an essential target of TOR in Drosophila. We find that TOR activity controls Pol III in growing larvae via inhibition of the repressor Maf1 and, in part, via the transcription factor Drosophila Myc (dMyc). Moreover, we show that loss of the Pol III factor, Brf, leads to reduced tissue and organismal growth and prevents TOR-induced cellular growth. TOR activity in the larval fat body, a tissue equivalent to vertebrate fat or liver, couples nutrition to insulin release from the brain. Accordingly, we find that fat-specific loss of Brf phenocopies nutrient limitation and TOR inhibition, leading to decreased systemic insulin signalling and reduced organismal growth. Thus, stimulation of Pol III is a key downstream effector of TOR in the control of cellular and systemic growth. PMID:22367393

  2. Brain Structural Integrity and Intrinsic Functional Connectivity Forecast 6 Year Longitudinal Growth in Children's Numerical Abilities

    PubMed Central

    Kochalka, John; Ngoon, Tricia J.; Wu, Sarah S.; Qin, Shaozheng; Battista, Christian

    2015-01-01

    Early numerical proficiency lays the foundation for acquiring quantitative skills essential in today's technological society. Identification of cognitive and brain markers associated with long-term growth of children's basic numerical computation abilities is therefore of utmost importance. Previous attempts to relate brain structure and function to numerical competency have focused on behavioral measures from a single time point. Thus, little is known about the brain predictors of individual differences in growth trajectories of numerical abilities. Using a longitudinal design, with multimodal imaging and machine-learning algorithms, we investigated whether brain structure and intrinsic connectivity in early childhood are predictive of 6 year outcomes in numerical abilities spanning childhood and adolescence. Gray matter volume at age 8 in distributed brain regions, including the ventrotemporal occipital cortex (VTOC), the posterior parietal cortex, and the prefrontal cortex, predicted longitudinal gains in numerical, but not reading, abilities. Remarkably, intrinsic connectivity analysis revealed that the strength of functional coupling among these regions also predicted gains in numerical abilities, providing novel evidence for a network of brain regions that works in concert to promote numerical skill acquisition. VTOC connectivity with posterior parietal, anterior temporal, and dorsolateral prefrontal cortices emerged as the most extensive network predicting individual gains in numerical abilities. Crucially, behavioral measures of mathematics, IQ, working memory, and reading did not predict children's gains in numerical abilities. Our study identifies, for the first time, functional circuits in the human brain that scaffold the development of numerical skills, and highlights potential biomarkers for identifying children at risk for learning difficulties. SIGNIFICANCE STATEMENT Children show substantial individual differences in math abilities and ease of math

  3. Ack promotes tissue growth via phosphorylation and suppression of the Hippo pathway component Expanded

    PubMed Central

    Hu, Lianxin; Xu, Jiajun; Yin, Meng-Xin; Zhang, Liguo; Lu, Yi; Wu, Wenqing; Xue, Zhaoyu; Ho, Margaret S; Gao, Guanjun; Zhao, Yun; Zhang, Lei

    2016-01-01

    Non-receptor tyrosine kinase activated cdc42 kinase was reported to participate in several types of cancers in mammals. It is also believed to have an anti-apoptotic function in Drosophila. Here, we report the identification of Drosophila activated cdc42 kinase as a growth promoter and a novel Hippo signaling pathway regulator. We find that activated cdc42 kinase promotes tissue growth through modulating Yorkie activity. Furthermore, we demonstrate that activated cdc42 kinase interacts with Expanded and induces tyrosine phosphorylation of Expanded on multiple sites. We propose a model that activated cdc42 kinase negatively regulates Expanded by changing its phosphorylation status to promote tissue growth. Moreover, we show that ack genetically interacts with merlin and expanded. Thus, we identify Drosophila activated cdc42 kinase as a Hippo pathway regulator. PMID:27462444

  4. Directed cell growth in multi-zonal scaffolds for cartilage tissue engineering.

    PubMed

    Camarero-Espinosa, Sandra; Rothen-Rutishauser, Barbara; Weder, Christoph; Foster, E Johan

    2016-01-01

    Articular cartilage serves as a low-friction cushion in synovial joints and is vital for mammalian skeletal movements. Due to its avascular nature and the low cell density, the tissue has a limited ability to regenerate, and damage due to injury, wear and tear, or disease usually requires surgical intervention. While articular cartilage had been predicted to be one of the first tissues to be successfully engineered, it proved to be challenging to reproduce the complex architecture and biomechanical properties of the native tissue. Here we report the fabrication of multi-layer polymer nanocomposite scaffolds that mimic the structural design, chemical cues, and mechanical characteristics of mature articular cartilage. These scaffolds guide the morphology, orientation, and phenotypic state of cultured chondrocytes in a spatially controlled manner, support the growth of tissue with features that are reminiscent of the natural analogue, and promote localized hydroxyapatite formation to permit integration with the subchondral bone. PMID:26447554

  5. The saddle connective tissue graft: a periodontal plastic surgery technique to obtain soft tissue coronal gain on immediate implants. A case report.

    PubMed

    González, David; Cabello, Gustavo; Olmos, Gema; Niñoles, Carlos L

    2015-01-01

    Based on recent studies regarding the advantages of flapless immediate implants on the maintenance of the soft tissue architecture (especially at papillae level) in those situations where it is necessary to extract an anterior tooth, this case report describes a clinical procedure designed to replace a hopeless central incisor (2.1) showing root resorption adjacent to an implant-supported crown (1.1), whose gingival margin is 2 mm coronal regarding the hopeless tooth to be replaced. After the extraction of the hopeless tooth (2.1), a flapless immediate implant was placed. The implant-bone gap was then filled with bone substitute and a palatal connective tissue graft was placed ad modum saddle extending at buccal level from apical to the mucogingival line, sealing the socket and extending until 6 mm at palatal level ad modum saddle. This procedure allowed symmetry of the soft tissue margins between the two implants (1.1 and 2.1) to be obtained as well as the preservation of the inter-implant papillae (1.1). PMID:26171446

  6. Regulation of synaptic connectivity: levels of Fasciclin II influence synaptic growth in the Drosophila CNS.

    PubMed

    Baines, Richard A; Seugnet, Laurent; Thompson, Annemarie; Salvaterra, Paul M; Bate, Michael

    2002-08-01

    Much of our understanding of synaptogenesis comes from studies that deal with the development of the neuromuscular junction (NMJ). Although well studied, it is not clear how far the NMJ represents an adequate model for the formation of synapses within the CNS. Here we investigate the role of Fasciclin II (Fas II) in the development of synapses between identified motor neurons and cholinergic interneurons in the CNS of Drosophila. Fas II is a neural cell adhesion molecule homolog that is involved in both target selection and synaptic plasticity at the NMJ in Drosophila. In this study, we show that levels of Fas II are critical determinants of synapse formation and growth in the CNS. The initial establishment of synaptic contacts between these identified neurons is seemingly independent of Fas II. The subsequent proliferation of these synaptic connections that occurs postembryonically is, in contrast, significantly retarded by the absence of Fas II. Although the initial formation of synaptic connectivity between these neurons is seemingly independent of Fas II, we show that their formation is, nevertheless, significantly affected by manipulations that alter the relative balance of Fas II in the presynaptic and postsynaptic neurons. Increasing expression of Fas II in either the presynaptic or postsynaptic neurons, during embryogenesis, is sufficient to disrupt the normal level of synaptic connectivity that occurs between these neurons. This effect of Fas II is isoform specific and, moreover, phenocopies the disruption to synaptic connectivity observed previously after tetanus toxin light chain-dependent blockade of evoked synaptic vesicle release in these neurons. PMID:12151538

  7. The Connective Tissue Components of Optic Nerve Head Cupping in Monkey Experimental Glaucoma Part 1: Global Change

    PubMed Central

    Yang, Hongli; Ren, Ruojin; Lockwood, Howard; Williams, Galen; Libertiaux, Vincent; Downs, Crawford; Gardiner, Stuart K.; Burgoyne, Claude F.

    2015-01-01

    Purpose To characterize optic nerve head (ONH) connective tissue change within 21 monkey experimental glaucoma (EG) eyes, so as to identify its principal components. Methods Animals were imaged three to five times at baseline then every 2 weeks following chronic unilateral IOP elevation, and euthanized early through end-stage confocal scanning laser tomographic change. Optic nerve heads were serial-sectioned, three-dimensionally (3D) reconstructed, delineated, and quantified. Overall EG versus control eye differences were assessed by general estimating equations (GEE). Significant, animal-specific, EG eye change was required to exceed the maximum physiologic intereye differences in six healthy animals. Results Overall EG eye change was significant (P < 0.0026) and animal-specific EG eye change most frequent, for five phenomena (number of EG eyes and range of animal-specific change): posterior laminar deformation (21, −29 to −437 μm), laminar thickening (11, 20–73 μm) and thinning (3, −23 to −31 μm), scleral canal expansion (17, 20–139 μm), outward anterior (16, −16 to −124 μm) and posterior (17, −22 to −279 μm) laminar insertion migration, and peripapillary scleral bowing (11, 21–77 μm). Experimental glaucoma versus control eye laminar thickness differences were bimodal in behavior, being thickened in most EG eyes demonstrating the least deformation and less thickened or thinned in most EG eyes demonstrating the greatest deformation. Conclusions Our postmortem studies retrospectively identify five connective tissue components of ONH “cupping” in monkey EG which serve as targets for longitudinally staging and phenotyping ONH connective tissue alteration within all forms of monkey and human optic neuropathy. PMID:26641545

  8. Cementogenesis and the induction of periodontal tissue regeneration by the osteogenic proteins of the transforming growth factor-beta superfamily.

    PubMed

    Ripamonti, U; Petit, J-C; Teare, J

    2009-04-01

    The antiquity and severity of periodontal diseases are demonstrated by the hard evidence of alveolar bone loss in gnathic remains of the Pliocene/Pleistocene deposits of the Bloubank Valley at Sterkfontein, Swartkrans and Kromdrai in South Africa. Extant Homo has characterized and cloned a superfamily of proteins which include the bone morphogenetic proteins that regulate tooth morphogenesis at different stages of development as temporally and spatially connected events. The induction of cementogenesis, periodontal ligament and alveolar bone regeneration are regulated by the co-ordinated expression of bone morphogenetic proteins. Naturally derived and recombinant human bone morphogenetic proteins induce periodontal tissue regeneration in mammals. Morphological analyses on undecalcified sections cut at 3-6 mum on a series of mandibular molar Class II and III furcation defects induced in the non-human primate Papio ursinus show the induction of cementogenesis. Sharpey's fibers nucleate as a series of composite collagen bundles within the cementoid matrix in close relation to embedded cementocytes. Osteogenic protein-1 and bone morphogenetic protein-2 possess a structure-activity profile, as shown by the morphology of tissue regeneration, preferentially cementogenic and osteogenic, respectively. In Papio ursinus, transforming growth factor-beta(3) also induces cementogenesis, with Sharpey's fibers inserting into newly formed alveolar bone. Capillary sprouting and invasion determine the sequential insertion and alignment of individual collagenic bundles. The addition of responding stem cells prepared by finely mincing fragments of autogenous rectus abdominis muscle significantly enhances the induction of periodontal tissue regeneration when combined with transforming growth factor-beta(3) implanted in Class II and III furcation defects of Papio ursinus. PMID:18842117

  9. [Effect of metabolic therapy on the course of heart failure in patients after myocarditis complicated with systemic connecting tissue diseases].

    PubMed

    Kuriata, A V; Karavanskaia, I L; Pavlichenko, N A

    2010-01-01

    In the course of observation over 40 patients after an old myocarditis against general systemic diseases of connective tissue who had been given a pharmacotherapy regarding main disease and a chronic heart failure, additionally Vazonat (campaign of "Olajnfarm", Latvia), preparation of the myocardial cytoprotection was prescribed in a therapeutic dose of 500 mg per day. Vazonat inclusion in basic therapy during 1 month was accompanied by improvement of a clinical condition of the patients, reduction of heart failure signs, and improvement of life quality. PMID:21488376

  10. Morphometric analysis of cellular and vascular changes in gingival connective tissue in long-term insulin-dependent diabetes.

    PubMed

    Seppälä, B; Sorsa, T; Ainamo, J

    1997-12-01

    This study examined cellular and vascular changes in gingival connective tissue samples by stereologic point-counting procedures and interactive digital analyzing systems in long-term insulin-dependent diabetes mellitus patients. Gingival connective tissue capillaries representing a clinically healthy sulcus with no evidence of periodontal disease at the site of biopsy were studied in 29 patients with diabetes. Based upon their long-term medical records, 19 were identified as having poorly controlled (PIDD) and 10 as controlled insulin-dependent diabetes mellitus (CIDD). Ten nondiabetic, age- and gender-matched individuals served as controls. Thirty-nine biopsies were processed for light microscopy, and the blood vessel area was analyzed using an interactive digital analyzing system; 9 gingival biopsies, 5 diabetic and 4 controls, were processed for morphometric electron microscopic analysis. For each individual, site-specific recordings were made for the plaque index, bleeding index, probing depth, loss of attachment, and radiographic loss of interproximal alveolar bone. No evident signs of periodontitis occurred at the biopsy sites. For each PIDD patient, respective volumetric and numeric densities of cellular components including fibroblasts, neutrophilic granulocytes, monocyte/macrophages, mast cells, lymphocytes, blast cells, and plasma cells were recorded in the inflamed connective tissue (ICT). Non-cellular components such as collagen fibers and blood vessels were also recorded. PIDD patients had elevated plasma cell levels relative to controls and they appeared also to have a decreased collagen fiber density. In addition, fibroblasts occupied less volume in the ICT of PIDD patients than in controls. PIDD patients had the largest mean area of cross-section of the blood vessels, but this difference was not statistically significant (P > or = 0.211; t-test). No specific characteristics of ICT or vascular changes were detectable in adult well-controlled long

  11. Comprehensive characterization of skeletal tissue growth anomalies of the finger coral Porites compressa

    NASA Astrophysics Data System (ADS)

    Domart-Coulon, Isabelle J.; Traylor-Knowles, Nikki; Peters, Esther; Elbert, David; Downs, Craig A.; Price, Kathy; Stubbs, Joanne; McLaughlin, Shawn; Cox, Evelyn; Aeby, Greta; Brown, P. Randy; Ostrander, Gary K.

    2006-11-01

    The scleractinian finger coral Porites compressa has been documented to develop raised growth anomalies of unknown origin, commonly referred to as “tumors”. These skeletal tissue anomalies (STAs) are circumscribed nodule-like areas of enlarged skeleton and tissue with fewer polyps and zooxanthellae than adjacent tissue. A field survey of the STA prevalence in Oahu, Kaneohe Bay, Hawaii, was complemented by laboratory analysis to reveal biochemical, histological and skeletal differences between anomalous and reference tissue. MutY, Hsp90a1, GRP75 and metallothionein, proteins known to be up-regulated in hyperplastic tissues, were over expressed in the STAs compared to adjacent normal-appearing and reference tissues. Histological analysis was further accompanied by elemental and micro-structural analyses of skeleton. Anomalous skeleton was of similar aragonite composition to adjacent skeleton but more porous as evidenced by an increased rate of vertical extension without thickening. Polyp structure was retained throughout the lesion, but abnormal polyps were hypertrophied, with increased mass of aboral tissue lining the skeleton, and thickened areas of skeletogenic calicoblastic epithelium along the basal floor. The latter were highly metabolically active and infiltrated with chromophore cells. These observations qualify the STAs as hyperplasia and are the first report in poritid corals of chromophore infiltration processes in active calicoblastic epithelium areas.

  12. Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury

    PubMed Central

    Huang, Lu; Beiting, Daniel P.; Gebreselassie, Nebiat G.; Gagliardo, Lucille F.; Ruyechan, Maura C.; Lee, Nancy A.; Lee, James J.; Appleton, Judith A.

    2015-01-01

    It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth. PMID:26720604

  13. Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury.

    PubMed

    Huang, Lu; Beiting, Daniel P; Gebreselassie, Nebiat G; Gagliardo, Lucille F; Ruyechan, Maura C; Lee, Nancy A; Lee, James J; Appleton, Judith A

    2015-12-01

    It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4 (GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth. PMID:26720604

  14. Lactococcus lactis Metabolism and Gene Expression during Growth on Plant Tissues

    PubMed Central

    Golomb, Benjamin L.

    2014-01-01

    Lactic acid bacteria have been isolated from living, harvested, and fermented plant materials; however, the adaptations these bacteria possess for growth on plant tissues are largely unknown. In this study, we investigated plant habitat-specific traits of Lactococcus lactis during growth in an Arabidopsis thaliana leaf tissue lysate (ATL). L. lactis KF147, a strain originally isolated from plants, exhibited a higher growth rate and reached 7.9-fold-greater cell densities during growth in ATL than the dairy-associated strain L. lactis IL1403. Transcriptome profiling (RNA-seq) of KF147 identified 853 induced and 264 repressed genes during growth in ATL compared to that in GM17 laboratory culture medium. Genes induced in ATL included those involved in the arginine deiminase pathway and a total of 140 carbohydrate transport and metabolism genes, many of which are involved in xylose, arabinose, cellobiose, and hemicellulose metabolism. The induction of those genes corresponded with L. lactis KF147 nutrient consumption and production of metabolic end products in ATL as measured by gas chromatography-time of flight mass spectrometry (GC-TOF/MS) untargeted metabolomic profiling. To assess the importance of specific plant-inducible genes for L. lactis growth in ATL, xylose metabolism was targeted for gene knockout mutagenesis. Wild-type L. lactis strain KF147 but not an xylA deletion mutant was able to grow using xylose as the sole carbon source. However, both strains grew to similarly high levels in ATL, indicating redundancy in L. lactis carbohydrate metabolism on plant tissues. These findings show that certain strains of L. lactis are well adapted for growth on plants and possess specific traits relevant for plant-based food, fuel, and feed fermentations. PMID:25384484

  15. Non-marfan idiopathic medionecrosis (cystic medial necrosis) presenting with multiple visceral artery aneurysms and diffuse connective tissue fragility: Two brothers

    SciTech Connect

    Kubota, Jun; Tsunemura, Mami; Amano, Shigeko; Tokizawa, Shigemi; Oowada, Susumu; Shinkai, Hiroko; Maehara, Yasunobu; Endo, Keigo

    1997-05-15

    Two brothers with multiple visceral artery aneurysms or dilatations and diffuse connective tissue fragility who did not have clinical features of Marfan syndrome are reported. One presented with retroperitoneal hemorrhage during angiography, and idiopathic medionecrosis was proved by resection of the aneurysms. These cases belong to the heterogeneous group of Marfan syndrome. The angiographical features (multiple dilation of visceral arteries) suggests fragility of connective tissue and is predictive of hazards during and after a catheterization and operation.

  16. Softenin, a Novel Protein That Softens the Connective Tissue of Sea Cucumbers through Inhibiting Interaction between Collagen Fibrils

    PubMed Central

    Takehana, Yasuhiro; Yamada, Akira; Tamori, Masaki; Motokawa, Tatsuo

    2014-01-01

    The dermis in the holothurian body wall is a typical catch connective tissue or mutable collagenous tissue that shows rapid changes in stiffness. Some chemical factors that change the stiffness of the tissue were found in previous studies, but the molecular mechanisms of the changes are not yet fully understood. Detection of factors that change the stiffness by working directly on the extracellular matrix was vital to clarify the mechanisms of the change. We isolated from the body wall of the sea cucumber Stichopus chloronotus a novel protein, softenin, that softened the body-wall dermis. The apparent molecular mass was 20 kDa. The N-terminal sequence of 17 amino acids had low homology to that of known proteins. We performed sequential chemical and physical dissections of the dermis and tested the effects of softenin on each dissection stage by dynamic mechanical tests. Softenin softened Triton-treated dermis whose cells had been disrupted by detergent. The Triton-treated dermis was subjected to repetitive freeze-and-thawing to make Triton-Freeze-Thaw (TFT) dermis that was softer than the Triton-treated dermis, implying that some force-bearing structure had been disrupted by this treatment. TFT dermis was stiffened by tensilin, a stiffening protein of sea cucumbers. Softenin softened the tensilin-stiffened TFT dermis while it had no effect on the TFT dermis without tensilin treatment. We isolated collagen from the dermis. When tensilin was applied to the suspending solution of collagen fibrils, they made a large compact aggregate that was dissolved by the application of softenin or by repetitive freeze-and-thawing. These results strongly suggested that softenin decreased dermal stiffness through inhibiting cross-bridge formation between collagen fibrils; the formation was augmented by tensilin and the bridges were broken by the freeze-thaw treatment. Softenin is thus the first softener of catch connective tissue shown to work on the cross-bridges between

  17. Melt Connectivity and Its Effect on Grain Growth in Natural Olivine Aggregates: An Experimental Study

    NASA Astrophysics Data System (ADS)

    Hashim, L.; Sifre, D.; Précigout, J.; Gardés, E.; Le Trong, E.; Gaillard, F.

    2014-12-01

    To better constrain the rheology of the mantle, experimental studies on olivine grain growth have been conducted (Faul and Scott, 2006; Karato, 1989; Nichols and Mackwell, 1991) since the grain size is an important parameter under dynamic regimes (e.g. diffusion creep and grain boundary sliding). In order to better define the melt effect on the rheological response of a partially molten olivine aggregate, we have experimentally investigated the effect of melt on olivine grain growth and the connectivity of this melt phase. Experiments were performed in 3/4" piston cylinders at 500 MPa confining pressure, different temperatures (i.e. 1100°C, 1250°C and 1400°C) and four durations (1h, 12h, 72h and 15 days). Starting material was composed of natural San Carlos olivine (5 μmconnectivity was assessed through scanning electron microscope (SEM) images in backscattered electron mode. Electron backscatter diffraction (EBSD) maps of each sample were also collected in order to determine the olivine grain sizes as a function of time and melt content. References Faul, U. H., Scott, D., 2006. Grain growth in partially molten olivine aggregates. Contributions to Mineralogy and Petrology 151 (1), 101-111. Karato, S.-I., 1989. Grain growth kinetics in olivine aggregates. Tectonophysics 168 (4), 255-273. Nichols, S. J., Mackwell, S. J., 1991. Grain growth in porous olivine aggregates. Physics and Chemistry of Minerals 18 (4), 269-278. Sifré, D., Gardés, E., Massuyeau, M., Hashim, L., Hier-Majumder, S., Gaillard, F., 2014. Electrical conductivity during incipient melting in the oceanic low-velocity zone. Nature 509 (7498), 81-85.

  18. Unusual Glycosaminoglycans from a Deep Sea Hydrothermal Bacterium Improve Fibrillar Collagen Structuring and Fibroblast Activities in Engineered Connective Tissues

    PubMed Central

    Senni, Karim; Gueniche, Farida; Changotade, Sylvie; Septier, Dominique; Sinquin, Corinne; Ratiskol, Jacqueline; Lutomski, Didier; Godeau, Gaston; Guezennec, Jean; Colliec-Jouault, Sylvia

    2013-01-01

    Biopolymers produced by marine organisms can offer useful tools for regenerative medicine. Particularly, HE800 exopolysaccharide (HE800 EPS) secreted by a deep-sea hydrothermal bacterium displays an interesting glycosaminoglycan-like feature resembling hyaluronan. Previous studies demonstrated its effectiveness to enhance in vivo bone regeneration and to support osteoblastic cell metabolism in culture. Thus, in order to assess the usefulness of this high-molecular weight polymer in tissue engineering and tissue repair, in vitro reconstructed connective tissues containing HE800 EPS were performed. We showed that this polysaccharide promotes both collagen structuring and extracellular matrix settle by dermal fibroblasts. Furthermore, from the native HE800 EPS, a low-molecular weight sulfated derivative (HE800 DROS) displaying chemical analogy with heparan-sulfate, was designed. Thus, it was demonstrated that HE800 DROS mimics some properties of heparan-sulfate, such as promotion of fibroblast proliferation and inhibition of matrix metalloproteinase (MMP) secretion. Therefore, we suggest that the HE800EPS family can be considered as an innovative biotechnological source of glycosaminoglycan-like compounds useful to design biomaterials and drugs for tissue engineering and repair. PMID:23612369

  19. Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection.

    PubMed

    Imai, Denise M; Feng, Sunlian; Hodzic, Emir; Barthold, Stephen W

    2013-08-01

    The etiologic agent of Lyme disease, Borrelia burgdorferi, localizes preferentially in the extracellular matrix during persistence. In chronically infected laboratory mice, there is a direct association between B. burgdorferi and the proteoglycan decorin, which suggests that decorin has a role in defining protective niches for persistent spirochetes. In this study, the tissue colocalization of B. burgdorferi with decorin and the dynamics of borrelial decorin tropism were evaluated during chronic infection. Spirochetes were found to colocalize absolutely with decorin, but not collagen I in chronically infected immunocompetent C3H mice. Passive immunization of infected C3H-scid mice with B. burgdorferi-specific immune serum resulted in the localization of spirochetes in decorin-rich microenvironments, with clearance of spirochetes from decorin-poor microenvironments. In passively immunized C3H-scid mice, tissue spirochete burdens were initially reduced, but increased over time as the B. burgdorferi-specific antibody levels waned. Concurrent repopulation of the previously cleared decorin-poor microenvironments was observed with the rising tissue spirochete burden and declining antibody titer. These findings indicate that the specificity of B. burgdorferi tissue localization during chronic infection is determined by decorin, driven by the borrelia-specific antibody response, and fluctuates with the antibody response. PMID:23797360

  20. Differential Expression of Cell Cycle Regulators During Hyperplastic and Hypertrophic Growth of Broiler Subcutaneous Adipose Tissue.

    PubMed

    Zhang, J; Suh, Y; Choi, Y M; Chen, P R; Davis, M E; Lee, K

    2015-10-01

    Hyperplastic growth and hypertrophic growth within adipose tissue is tightly associated with cell cycle activity. In this study, CCNG2 and CDKN2C were found to be correlated with cell cycle inhibition during fat cell differentiation, whereas CCND3, CCNA1, and ANAPC5 were positively associated with cell cycle activity during fat cell proliferation after selection based on GEO datasets available on the NCBI website. The findings were validated through comparison of expressions of these genes among different tissues/fractions in broiler chickens and time points during primary cell culture using quantitative real-time PCR. Development of broiler subcutaneous adipose tissue was investigated on embryonic days 15 and 17 and on post-hatch days 0, 5, 11, and 33 using H&E staining and PCNA immunostaining with DAPI counter stain. In addition, mRNA expressions of five cell cycle regulators as well as precursor cell and adipocyte markers were measured at those time points. The results suggest that cellular proliferation activity decreased as the fat pad grows, but a population of precursor cells seemed to be maintained until post-hatch day 5 despite increasing differentiation activity. Hypertrophic growth gradually intensified despite a slight cessation on post-hatch day 0 due to increased energy expenditure during hatching and delayed food access. From post-hatch day 5 to day 11, most of the precursor cells may become differentiated. After post-hatch day 11, hyperplastic growth seemed to slow, while hypertrophic growth may become dominant. This study provides further understanding about broiler fat tissue development which is imperative for effective control of fat deposition. PMID:26017028

  1. Muscle Tissue Engineering Using Gingival Mesenchymal Stem Cells Encapsulated in Alginate Hydrogels Containing Multiple Growth Factors.

    PubMed

    Ansari, Sahar; Chen, Chider; Xu, Xingtian; Annabi, Nasim; Zadeh, Homayoun H; Wu, Benjamin M; Khademhosseini, Ali; Shi, Songtao; Moshaverinia, Alireza

    2016-06-01

    Repair and regeneration of muscle tissue following traumatic injuries or muscle diseases often presents a challenging clinical situation. If a significant amount of tissue is lost the native regenerative potential of skeletal muscle will not be able to grow to fill the defect site completely. Dental-derived mesenchymal stem cells (MSCs) in combination with appropriate scaffold material, present an advantageous alternative therapeutic option for muscle tissue engineering in comparison to current treatment modalities available. To date, there has been no report on application of gingival mesenchymal stem cells (GMSCs) in three-dimensional scaffolds for muscle tissue engineering. The objectives of the current study were to develop an injectable 3D RGD-coupled alginate scaffold with multiple growth factor delivery capacity for encapsulating GMSCs, and to evaluate the capacity of encapsulated GMSCs to differentiate into myogenic tissue in vitro and in vivo where encapsulated GMSCs were transplanted subcutaneously into immunocompromised mice. The results demonstrate that after 4 weeks of differentiation in vitro, GMSCs as well as the positive control human bone marrow mesenchymal stem cells (hBMMSCs) exhibited muscle cell-like morphology with high levels of mRNA expression for gene markers related to muscle regeneration (MyoD, Myf5, and MyoG) via qPCR measurement. Our quantitative PCR analyzes revealed that the stiffness of the RGD-coupled alginate regulates the myogenic differentiation of encapsulated GMSCs. Histological and immunohistochemical/fluorescence staining for protein markers specific for myogenic tissue confirmed muscle regeneration in subcutaneous transplantation in our in vivo animal model. GMSCs showed significantly greater capacity for myogenic regeneration in comparison to hBMMSCs (p < 0.05). Altogether, our findings confirmed that GMSCs encapsulated in RGD-modified alginate hydrogel with multiple growth factor delivery capacity is a promising

  2. Effects of epidermal growth factor-loaded mucoadhesive films on wounded oral tissue rafts.

    PubMed

    Ramineni, Sandeep K; Fowler, Craig B; Fisher, Paul D; Cunningham, Larry L; Puleo, David A

    2015-02-01

    Current treatments for traumatic oral mucosal wounds include the gold standard of autologous tissue and alternative tissue-engineered grafts. While use of autografts has disadvantages of minimal availability of oral keratinized tissue, second surgery, and donor site discomfort, tissue-engineered grafts are limited by their unavailability as off-the-shelf products owing to their fabrication time of 4-8 weeks. Hence, the current work aimed to develop a potentially cost-effective, readily available device capable of enhancing native mucosal regeneration. Considering the key role of epidermal growth factor (EGF) in promoting mucosal wound regeneration and the advantages of mucoadhesive delivery systems, mucoadhesive films composed of polyvinylpyrrolidone and carboxymethylcellulose were developed to provide sustained release of EGF for a minimum of 6 h. Bioactivity of released EGF supernatants was then confirmed by its ability to promote proliferation of BALB/3T3 fibroblasts. Efficacy of the developed system was then investigated in vitro using buccal tissues (ORL 300-FT) as a potential replacement for small animal studies. Although the mucoadhesive films achieved their desired role of delivering bioactive EGF in a sustained manner, treatment with EGF, irrespective of its release from the films or solubilized in medium, caused a hyperparakeratotic response from in vitro tissues with distinguishable histological features including thickening of the spinous layer, intra- and intercellular edema, and pyknotic nuclei. These significant morphological changes were associated with no improvements in wound closure. These observations raise questions about the potential of using in vitro tissues as a wound healing model and substitute for small animal studies. The mucoadhesive delivery system developed, however, with its potential for sustained release of bioactive growth factors and small molecules, may be loaded with other desired compounds, with or without EGF, to accelerate

  3. Effects of Epidermal Growth Factor-Loaded Mucoadhesive Films on Wounded Oral Tissue Rafts

    PubMed Central

    Ramineni, Sandeep K.; Fowler, Craig B.; Fisher, Paul D.; Cunningham, Larry L.; Puleo, David A.

    2015-01-01

    Current treatments for traumatic oral mucosal wounds include the gold standard of autologous tissue and alternative tissue engineered grafts. While use of autografts has disadvantages of minimal availability of oral keratinized tissue, second surgery, and donor site discomfort, tissue engineered grafts are limited by their unavailability as off-the-shelf products owing to their fabrication time of 4–8 weeks. Hence, the current work aimed to develop a potentially cost-effective, readily available device capable of enhancing native mucosal regeneration. Considering the key role of epidermal growth factor (EGF) in promoting mucosal wound regeneration and the advantages of mucoadhesive delivery systems, mucoadhesive films composed of polyvinylpyrrolidone and carboxymethylcellulose were developed to provide sustained release of EGF for minimum of 6 hours. Bioactivity of released EGF supernatants was then confirmed by its ability to promote proliferation of BALB/3T3 fibroblasts. Efficacy of the developed system was then investigated in vitro using buccal tissues (ORL 300-FT) as a potential replacement for small animal studies. Although the mucoadhesive films achieved their desired role of delivering bioactive EGF in a sustained manner, treatment with EGF, irrespective of its release from the films or solubilized in medium, caused a hyperparakeratotic response from in vitro tissues with distinguishable histological features including thickening of the spinous layer, intra- and intercellular edema, and pyknotic nuclei. These significant morphological changes were associated with no improvements in wound closure. These observations raise questions about the potential of using in vitro tissues as a wound healing model and substitute for small animal studies. The mucoadhesive delivery system developed, however, with its potential for sustained release of bioactive growth factors and small molecules, may be loaded with other desired compounds, with or without EGF, to

  4. Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction

    PubMed Central

    Shah, Nisarg J.; Hyder, Md. Nasim; Quadir, Mohiuddin A.; Dorval Courchesne, Noémie-Manuelle; Seeherman, Howard J.; Nevins, Myron; Spector, Myron; Hammond, Paula T.

    2014-01-01

    Traumatic wounds and congenital defects that require large-scale bone tissue repair have few successful clinical therapies, particularly for craniomaxillofacial defects. Although bioactive materials have demonstrated alternative approaches to tissue repair, an optimized materials system for reproducible, safe, and targeted repair remains elusive. We hypothesized that controlled, rapid bone formation in large, critical-size defects could be induced by simultaneously delivering multiple biological growth factors to the site of the wound. Here, we report an approach for bone repair using a polyelectrolye multilayer coating carrying as little as 200 ng of bone morphogenetic protein-2 and platelet-derived growth factor-BB that were eluted over readily adapted time scales to induce rapid bone repair. Based on electrostatic interactions between the polymer multilayers and growth factors alone, we sustained mitogenic and osteogenic signals with these growth factors in an easily tunable and controlled manner to direct endogenous cell function. To prove the role of this adaptive release system, we applied the polyelectrolyte coating on a well-studied biodegradable poly(lactic-co-glycolic acid) support membrane. The released growth factors directed cellular processes to induce bone repair in a critical-size rat calvaria model. The released growth factors promoted local bone formation that bridged a critical-size defect in the calvaria as early as 2 wk after implantation. Mature, mechanically competent bone regenerated the native calvaria form. Such an approach could be clinically useful and has significant benefits as a synthetic, off-the-shelf, cell-free option for bone tissue repair and restoration. PMID:25136093

  5. Ehlers-Danlos Syndrome, Hypermobility Type: An Underdiagnosed Hereditary Connective Tissue Disorder with Mucocutaneous, Articular, and Systemic Manifestations

    PubMed Central

    Castori, Marco

    2012-01-01

    Ehlers-Danlos syndrome, hypermobility type, constituting a phenotypic continuum with or, perhaps, corresponding to the joint hypermobility syndrome (JHS/EDS-HT), is likely the most common, though the least recognized, heritable connective tissue disorder. Known for decades as a hereditary condition with predominant rheumatologic manifestations, it is now emerging as a multisystemic disorder with widespread manifestations. Nevertheless, the practitioners' awareness of this condition is generally poor and most patients await years or, perhaps, decades before reaching the correct diagnosis. Among the various sites of disease manifestations, skin and mucosae represent a neglected organ where the dermatologist can easily spot diagnostic clues, which consistently integrate joint hypermobility and other orthopedic/neurologic manifestations at physical examination. In this paper, actual knowledge on JHS/EDS-HT is summarized in various sections. Particular attention has been posed on overlooked manifestations, including cutaneous, mucosal, and oropharyngeal features, and early diagnosis techniques, as a major point of interest for the practicing dermatologist. Actual research progresses on JH/EDS-HT envisage an unexpected link between heritable dysfunctions of the connective tissue and a wide range of functional somatic syndromes, most of them commonly diagnosed in the office of various specialists, comprising dermatologists. PMID:23227356

  6. Ehlers-danlos syndrome, hypermobility type: an underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations.

    PubMed

    Castori, Marco

    2012-01-01

    Ehlers-Danlos syndrome, hypermobility type, constituting a phenotypic continuum with or, perhaps, corresponding to the joint hypermobility syndrome (JHS/EDS-HT), is likely the most common, though the least recognized, heritable connective tissue disorder. Known for decades as a hereditary condition with predominant rheumatologic manifestations, it is now emerging as a multisystemic disorder with widespread manifestations. Nevertheless, the practitioners' awareness of this condition is generally poor and most patients await years or, perhaps, decades before reaching the correct diagnosis. Among the various sites of disease manifestations, skin and mucosae represent a neglected organ where the dermatologist can easily spot diagnostic clues, which consistently integrate joint hypermobility and other orthopedic/neurologic manifestations at physical examination. In this paper, actual knowledge on JHS/EDS-HT is summarized in various sections. Particular attention has been posed on overlooked manifestations, including cutaneous, mucosal, and oropharyngeal features, and early diagnosis techniques, as a major point of interest for the practicing dermatologist. Actual research progresses on JH/EDS-HT envisage an unexpected link between heritable dysfunctions of the connective tissue and a wide range of functional somatic syndromes, most of them commonly diagnosed in the office of various specialists, comprising dermatologists. PMID:23227356

  7. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A.

    PubMed

    Reinstein, Eyal; Frentz, Sophia; Morgan, Tim; García-Miñaúr, Sixto; Leventer, Richard J; McGillivray, George; Pariani, Mitchel; van der Steen, Anthony; Pope, Michael; Holder-Espinasse, Muriel; Scott, Richard; Thompson, Elizabeth M; Robertson, Terry; Coppin, Brian; Siegel, Robert; Bret Zurita, Montserrat; Rodríguez, Jose I; Morales, Carmen; Rodrigues, Yuri; Arcas, Joaquín; Saggar, Anand; Horton, Margaret; Zackai, Elaine; Graham, John M; Rimoin, David L; Robertson, Stephen P

    2013-05-01

    Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance. PMID:23032111

  8. Assessment of three types of spaceflight hardware for tissue culture studies: Comparison of skeletal tissue growth and differentiation

    NASA Astrophysics Data System (ADS)

    Klement, Brenda J.; Spooner, Brian S.

    1997-01-01

    Three different types of spaceflight hardware, the BioProcessing Module (BPM), the Materials Dispersion Apparatus (MDA), and the Fluid Processing Apparatus (FPA), were assessed for their ability to support pre-metatarsal growth and differentiation in experiments conducted on five space shuttle flights. BPM-cultured pre-metatarsal tissue showed no difference in flight and ground control lengths. Flight and ground controls cultured in the MDA grew 135 μm and 141 μm, respectively, in an 11 day experiment. Only five control rods and three flight rods mineralized. In another MDA experiment, pre-metatarsals were cultured at 4 °C (277K) or 20 °C (293K) for the 16 day mission, then cultured an additional 16 days in laboratory dishes at 37 °C (310K). The 20 °C (293K) cultures died post-flight. The 4 °C (277K) flight pre-metatarsals grew 417 μm more than the 4 °C (277K) ground controls post-flight. In 5 and 6 day experiments done in FPAs, flight rods grew longer than ground control rods. In a 14 day experiment, ground control and flight rods also expanded in length, but there was no difference between them. The pre-metatarsals cultured in the FPAs did not mineralize, or terminally differentiate. These experiments demonstrate, that while supporting pre-metatarsal growth in length, the three types of hardware are not suitable to support routine differentiation.

  9. Increased connective tissue attachment to silicone implants by a water vapor plasma treatment.

    PubMed

    Jensen, C; Gurevich, L; Patriciu, A; Struijk, J J; Zachar, V; Pennisi, C P

    2012-12-01

    Polydimethylsiloxane (PDMS) is the most common type of silicone polymer for the fabrication of implantable medical devices. Because of its inherent hydrophobic nature, the PDMS surface does not readily promote cellular adhesion, which leads to diverse clinical issues. Previously, we reported a simple water vapor plasma treatment of PDMS surfaces that resulted in stable long-term wettability and excellent in vitro cell compatibility. In this work, we report investigation of the in vivo local responses to PDMS implants treated by water vapor plasma using a subcutaneous rat model. The local tissue responses were assessed after 2 and 4 weeks of implantation by means of macroscopic and histomorphometric analysis. After 2 weeks of implantation, the plasma-treated implants elicited the formation of fibrous tissue capsules that were significantly thinner, more adherent, and vascularized than the control counterparts. The improved cell adhesion was correlated with an increased amount of cells attached to the implant surface after retrieval. There was no difference in the inflammatory response between untreated and treated samples. This study provides a rational approach to optimize the long-term performance of silicone implants, which is likely to have a significant impact in clinical applications demanding enhanced tissue integration of the implants. PMID:22767530

  10. Tracing Growth of Teachers' Classroom Interactions with Representations of Functions in the Connected Classroom

    NASA Astrophysics Data System (ADS)

    Morton, Brian Lee

    The purpose of this study is to create an empirically based theoretic model of change of the use and treatment of representations of functions with the use of Connected Classroom Technology (CCT) using data previously collected for the Classroom Connectivity in Promoting Mathematics and Science Achievement (CCMS) project. Qualitative analysis of videotapes of three algebra teachers' instruction focused on different categories thought to influence teaching representations with technology: representations, discourse, technology, and decisions. Models for rating teachers low, medium, or high for each of these categories were created using a priori codes and grounded methodology. A cross case analysis was conducted after the completion of the case studies by comparing and contrasting the three cases. Data revealed that teachers' decisions shifted to incorporate the difference in student ideas/representations made visible by the CCT into their instruction and ultimately altered their orientation to mathematics teaching. The shift in orientation seemed to lead to the teachers' growth with regards to representations, discourse, and technology.

  11. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features

    PubMed Central

    Ganesh, Santhi K.; Xu, Zhi; Schoenhoff, Florian; Griswold, Benjamin F.; Yang, Jiandong; Tong, Lan; Yang, Min-Lee; Hunker, Kristina; Sloper, Leslie; Kuo, Shinie; Raza, Rafi; Milewicz, Dianna M.; Francomano, Clair A.; Dietz, Harry C.; Van Eyk, Jennifer; McDonnell, Nazli B.

    2014-01-01

    Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.—Ganesh, S. K., Morissette, R., Xu, Z., Schoenhoff, F., Griswold, B. F., Yang, J., Tong, L., Yang, M.-L., Hunker, K., Sloper, L., Kuo, S., Raza, R., Milewicz, D. M., Francomano, C. A., Dietz, H. C., Van Eyk, J., McDonnell, N. B. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features. PMID:24732132

  12. Bioengineering Organized, Multilamellar Human Corneal Stromal Tissue by Growth Factor Supplementation on Highly Aligned Synthetic Substrates

    PubMed Central

    Wu, Jian; Du, Yiqin; Mann, Mary M.; Yang, Enzhi; Funderburgh, James L.

    2013-01-01

    Recapitulating the microstructure of the native human corneal stromal tissue is believed to be a key feature in successfully engineering the corneal tissue. The stratified multilayered collagen fibril lamellae with orthogonal orientation determine the robust biomechanical properties of this tissue, and the uniform collagen fibril size and interfibrillar spacing are critical to its optical transparency. The objective of this investigation was to develop a highly organized collagen-fibril construct secreted by human corneal stromal stem cells (hCSSCs) to mimic the human corneal stromal tissue. In culture on a highly aligned fibrous substrate made from poly(ester urethane) urea, the fibroblast growth factor-2 (FGF-2, 10 ng/mL) and transforming growth factor-beta 3 (TGF-β3, 0.1 ng/mL) impacted the organization and abundance of the secreted collagen fibril matrix. hCSSCs differentiated into keratocytes with significant upregulation of the typical gene markers, including KERA, B3GnT7, and CHST6. FGF-2 treatment stimulated hCSSCs to secrete collagen fibrils strongly aligned in a single direction, whereas TGF-β3 induced collagenous layers with orthogonal fibril orientation. The combination of FGF-2 and TGF-β3 induced multilayered lamellae with orthogonally oriented collagen fibrils, in a pattern mimicking the human corneal stromal tissue. The constructs were 60–70 μm thick and had an increased content of cornea-specific extracellular matrix components, including keratan sulfate, lumican, and keratocan. The approach of combining substrate cues with growth factor augmentation offers a new means to engineer well-organized, collagen-based constructs with an appropriate nanoscale structure for corneal repair and regeneration. PMID:23557404

  13. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling.

    PubMed

    Kamimoto, Kenji; Kaneko, Kota; Kok, Cindy Yuet-Yin; Okada, Hajime; Miyajima, Atsushi; Itoh, Tohru

    2016-01-01

    Dynamic remodeling of the intrahepatic biliary epithelial tissue plays key roles in liver regeneration, yet the cellular basis for this process remains unclear. We took an unbiased approach based on in vivo clonal labeling and tracking of biliary epithelial cells in the three-dimensional landscape, in combination with mathematical simulation, to understand their mode of proliferation in a mouse liver injury model where the nascent biliary structure formed in a tissue-intrinsic manner. An apparent heterogeneity among biliary epithelial cells was observed: whereas most of the responders that entered the cell cycle upon injury exhibited a limited and tapering growth potential, a select population continued to proliferate, making a major contribution in sustaining the biliary expansion. Our study has highlighted a unique mode of epithelial tissue dynamics, which depends not on a hierarchical system driven by fixated stem cells, but rather, on a stochastically maintained progenitor population with persistent proliferative activity. PMID:27431614

  14. Biomaterials with persistent growth factor gradients in vivo accelerate vascularized tissue formation.

    PubMed

    Akar, Banu; Jiang, Bin; Somo, Sami I; Appel, Alyssa A; Larson, Jeffery C; Tichauer, Kenneth M; Brey, Eric M

    2015-12-01

    Gradients of soluble factors play an important role in many biological processes, including blood vessel assembly. Gradients can be studied in detail in vitro, but methods that enable the study of spatially distributed soluble factors and multi-cellular processes in vivo are limited. Here, we report on a method for the generation of persistent in vivo gradients of growth factors in a three-dimensional (3D) biomaterial system. Fibrin loaded porous poly (ethylene glycol) (PEG) scaffolds were generated using a particulate leaching method. Platelet derived growth factor BB (PDGF-BB) was encapsulated into poly (lactic-co-glycolic acid) (PLGA) microspheres which were placed distal to the tissue-material interface. PLGA provides sustained release of PDGF-BB and its diffusion through the porous structure results in gradient formation. Gradients within the scaffold were confirmed in vivo using near-infrared fluorescence imaging and gradients were present for more than 3 weeks. The diffusion of PDGF-BB was modeled and verified with in vivo imaging findings. The depth of tissue invasion and density of blood vessels formed in response to the biomaterial increased with magnitude of the gradient. This biomaterial system allows for generation of sustained growth factor gradients for the study of tissue response to gradients in vivo. PMID:26344364

  15. Nifedipine and phenytoin induce matrix synthesis, but not proliferation, in intact human gingival connective tissue ex vivo.

    PubMed

    Kim, Shawna S; Michelsons, Sarah; Creber, Kendal; Rieder, Michael J; Hamilton, Douglas W

    2015-12-01

    Drug-induced gingival enlargement (DIGE) is a fibrotic condition that can be caused by the antihypertensive drug nifedipine and the anti-seizure drug phenytoin, but the molecular etiology of this type of fibrosis is not well understood and the role of confounding factors such as inflammation remains to be fully investigated. The aim of this study was to develop an ex vivo gingival explant system to allow investigation of the effects of nifedipine and phenytoin alone on human gingival tissue. Comparisons were made to the histology of human DIGE tissue retrieved from individuals with DIGE. Increased collagen, fibronectin, and proliferating fibroblasts were evident, but myofibroblasts were not detected in DIGE samples caused by nifedipine and phenytoin. In healthy gingiva cultured in nifedipine or phenytoin-containing media, the number of cells positive for p-SMAD2/3 increased, concomitant with increased CCN2 and periostin immunoreactivity compared to untreated explants. Collagen content assessed through hydroxyproline assays was significantly higher in tissues cultured with either drug compared to control tissues, which was confirmed histologically. Matrix fibronectin levels were also qualitatively greater in tissues treated with either drug. No significant differences in proliferating cells were observed between any of the conditions. Our study demonstrates that nifedipine and phenytoin activate canonical transforming growth factor-beta signaling, CCN2 and periostin expression, as well as increase collagen density, but do not influence cell proliferation or induce myofibroblast differentiation. We conclude that in the absence of confounding variables, nifedipine and phenytoin alter matrix homeostasis in gingival tissue explants ex vivo, and drug administration is a significant factor influencing ECM accumulation in gingival enlargement. PMID:26296421

  16. The specific growth rates of tissues: a review and a re-evaluation.

    PubMed

    Cowin, Stephen C

    2011-04-01

    The first objective of this review and re-evaluation is to present a brief history of efforts to mathematically model the growth of tissues. The second objective is to place this historical material in a current perspective where it may be of help in future research. The overall objective is to look backward in order to see ways forward. It is noted that two distinct methods of imaging or modeling the growth of an organism were inspired over 70 years ago by Thompson's (1915, "XXVII Morphology and Mathematics," Trans. - R. Soc. Edinbrgh, 50, pp. 857-895; 1942, On Growth and Form, Cambridge University Press, Cambridge, UK) method of coordinate transformations to study the growth and form of organisms. One is based on the solid mechanics concept of the deformation of an object, and the other is based on the fluid mechanics concept of the velocity field of a fluid. The solid mechanics model is called the distributed continuous growth (DCG) model by Skalak (1981, "Growth as a Finite Displacement Field," Proceedings of the IUTAM Symposium on Finite Elasticity, D. E. Carlson and R. T. Shield, eds., Nijhoff, The Hague, pp. 348-355) and Skalak et al. (1982, "Analytical Description of Growth," J. Theor. Biol., 94, pp. 555-577), and the fluid mechanics model is called the graphical growth velocity field representation (GVFR) by Cowin (2010, "Continuum Kinematical Modeling of Mass Increasing Biological Growth," Int. J. Eng. Sci., 48, pp. 1137-1145). The GVFR is a minimum or simple model based only on the assumption that a velocity field may be used effectively to illustrate experimental results concerning the temporal evolution of the size and shape of the organism that reveals the centers of growth and growth gradients first described by Huxley (1924, "Constant Differential Growth-Ratios and Their Significance," Nature (London), 114, pp. 895-896; 1972, Problems of Relative Growth, 2nd ed., L. MacVeagh, ed., Dover, New York). It is the method with an independent future that

  17. Integrin-extracellular matrix interactions in connective tissue remodeling and osteoblast differentiation

    NASA Technical Reports Server (NTRS)

    Globus, R. K.; Moursi, A.; Zimmerman, D.; Lull, J.; Damsky, C.

    1995-01-01

    The differentiaton of bone cells is a complex multistep process. Bone is somewhat unusual in that it is very actively and continually remodeled in the adult and that maintenance of its mass in the mature organism is exquisitely sensitive to mechanical as well as chemical signals. Bone is also unique because it consists of a very large amount of extracellular matrix (ECM) that is mineralized. The integrin family of ECM receptors has been shown to play an important role in tissue morphogenesis in several systems. Our studies on the regulation of matrix remodeling enzymes by integrins in rabbit synovial fibroblasts show that two b1 integrin fibronectin (FN) receptor complexes (alpha 5 beta 1 and alpha 4 beta 1) cooperate in detecting subtle changes in the composition of the ECM. As a result of signal transduction by these integrins, the levels of mRNA and protein for several members of the metalloproteinase family are regulated in these cells. We have also used antibody and RGD peptide perturbation studies to determine the significance of cell/ECM interactions to normal osteogenesis. We found that interactions between the cell binding domain of FN and integrins are required for both normal morphogenesis and gene expression in cultured osteoblasts that differentiate to form bone-like tissue in culture. These data lead us to propose that beta 1 integrins play an important role in osteoblast differentiation as well as in bone remodeling.

  18. Contribution of collagen and elastin fibers to the mechanical behavior of an abdominal connective tissue.

    PubMed

    Levillain, A; Orhant, M; Turquier, F; Hoc, T

    2016-08-01

    The linea alba is a complex structure commonly involved in hernia formation. Knowledge of its mechanical behavior is essential to design suitable meshes and reduce the risk of recurrence. The aim of this study was to investigate the relationships between the mechanical properties of the linea alba and the organization of collagen and elastin fibers. For that purpose, longitudinal and transversal samples were removed from four porcine and three human linea alba, to perform tensile tests under a biphotonic confocal microscope, in each direction. Microscopic observation revealed a tissue composed of two layers, made of transversal collagen fibers in the dorsal side and oblique collagen fibers in the ventral side. This particular architecture led to an anisotropic mechanical behavior, with higher stress in the transversal direction. During loading, oblique fibers of the ventral layer reoriented toward the tensile axis in both directions, while fibers of the dorsal layer remained in the transversal direction. This rotation of oblique fibers progressively increased the stiffness of the tissue and induced a non-linear stress-stretch relation. Elastin fibers formed a layer covering the collagen fibers and followed their movement, suggesting that they ensure their elastic recoil. All of these results demonstrated the strong relationships between the microstructure and the mechanical behavior of the linea alba. PMID:27100469

  19. Immune physiology in tissue regeneration and aging, tumor growth, and regenerative medicine

    PubMed Central

    Bukovsky, Antonin; Caudle, Michael R.; Carson, Ray J.; Gaytán, Francisco; Huleihel, Mahmoud; Kruse, Andrea; Schatten, Heide; Telleria, Carlos M.

    2009-01-01

    The immune system plays an important role in immunity (immune surveillance), but also in the regulation of tissue homeostasis (immune physiology). Lessons from the female reproductive tract indicate that immune system related cells, such as intraepithelial T cells and monocyte-derived cells (MDC) in stratified epithelium, interact amongst themselves and degenerate whereas epithelial cells proliferate and differentiate. In adult ovaries, MDC and T cells are present during oocyte renewal from ovarian stem cells. Activated MDC are also associated with follicular development and atresia, and corpus luteum differentiation. Corpus luteum demise resembles rejection of a graft since it is attended by a massive influx of MDC and T cells resulting in parenchymal and vascular regression. Vascular pericytes play important roles in immune physiology, and their activities (including secretion of the Thy-1 differentiation protein) can be regulated by vascular autonomic innervation. In tumors, MDC regulate proliferation of neoplastic cells and angiogenesis. Tumor infiltrating T cells die among malignant cells. Alterations of immune physiology can result in pathology, such as autoimmune, metabolic, and degenerative diseases, but also in infertility and intrauterine growth retardation, fetal morbidity and mortality. Animal experiments indicate that modification of tissue differentiation (retardation or acceleration) during immune adaptation can cause malfunction (persistent immaturity or premature aging) of such tissue during adulthood. Thus successful stem cell therapy will depend on immune physiology in targeted tissues. From this point of view, regenerative medicine is more likely to be successful in acute rather than chronic tissue disorders. PMID:20195382

  20. Methods of Monitoring Cell Fate and Tissue Growth in Three-Dimensional Scaffold-Based Strategies for In Vitro Tissue Engineering.

    PubMed

    Leferink, Anne M; van Blitterswijk, Clemens A; Moroni, Lorenzo

    2016-08-01

    In the field of tissue engineering, there is a need for methods that allow assessing the performance of tissue-engineered constructs noninvasively in vitro and in vivo. To date, histological analysis is the golden standard to retrieve information on tissue growth, cellular distribution, and cell fate on tissue-engineered constructs after in vitro cell culture or on explanted specimens after in vivo applications. Yet, many advances have been made to optimize imaging techniques for monitoring tissue-engineered constructs with a sub-mm or μm resolution. Many imaging modalities have first been developed for clinical applications, in which a high penetration depth has been often more important than lateral resolution. In this study, we have reviewed the current state of the art in several imaging approaches that have shown to be promising in monitoring cell fate and tissue growth upon in vitro culture. Depending on the aimed tissue type and scaffold properties, some imaging methods are more applicable than others. Optical methods are mostly suited for transparent materials such as hydrogels, whereas magnetic resonance-based methods are mostly applied to obtain contrast between hard and soft tissues regardless of their transparency. Overall, this review shows that the field of imaging in scaffold-based tissue engineering is developing at a fast pace and has the potential to overcome the limitations of destructive endpoint analysis. PMID:26825610

  1. Assessment of three types of spaceflight hardware for tissue culture studies: Comparison of skeletal tissue growth and differentiation

    SciTech Connect

    Klement, B.J.; Spooner, B.S.

    1997-01-01

    Three different types of spaceflight hardware, the BioProcessing Module (BPM), the Materials Dispersion Apparatus (MDA), and the Fluid Processing Apparatus (FPA), were assessed for their ability to support pre-metatarsal growth and differentiation in experiments conducted on five space shuttle flights. BPM-cultured pre-metatarsal tissue showed no difference in flight and ground control lengths. Flight and ground controls cultured in the MDA grew 135 {mu}m and 141 {mu}m, respectively, in an 11 day experiment. Only five control rods and three flight rods mineralized. In another MDA experiment, pre-metatarsals were cultured at 4{degree}C (277K) or 20{degree}C (293K) for the 16 day mission, then cultured an additional 16 days in laboratory dishes at 37{degree}C (310K). The 20{degree}C (293K) cultures died post-flight. The 4{degree}C (277K) flight pre-metatarsals grew 417 {mu}m more than the 4{degree}C (277K) ground controls post-flight. In 5 and 6 day experiments done in FPAs, flight rods grew longer than ground control rods. In a 14 day experiment, ground control and flight rods also expanded in length, but there was no difference between them. The pre-metatarsals cultured in the FPAs did not mineralize, or terminally differentiate. These experiments demonstrate, that while supporting pre-metatarsal growth in length, the three types of hardware are not suitable to support routine differentiation. {copyright} {ital 1997 American Institute of Physics.}

  2. The neuroimmune connection interferes with tissue regeneration and chronic inflammatory disease in the skin.

    PubMed

    Peters, Eva M J; Liezmann, Christiane; Klapp, Burghard F; Kruse, Johannes

    2012-07-01

    Research over the past decades has revealed close interactions between the nervous and immune systems that regulate peripheral inflammation and link psychosocial stress with chronic somatic disease. Besides activation of the sympathetic and the hypothalamus-pituitary-adrenal axis, stress leads to increased neurotrophin and neuropeptide production in organs at the self-environment interface. The scope of this short review is to discuss key functions of these stress mediators in the skin, an exemplary stress-targeted and stress-sensitive organ. We will focus on the skin's response to acute and chronic stress in tissue regeneration and pathogenesis of allergic inflammation, psoriasis, and skin cancer to illustrate the impact of local stress-induced neuroimmune interaction on chronic inflammation. PMID:22823443

  3. Bioinformatic identification of connective tissue growth factor as an osteogenic protein within skeletal muscle

    PubMed Central

    Forrester, Steven J.; Kawata, Keisuke; Lee, Hojun; Kim, Ji‐Seok; Sebzda, Kelly; Butler, Tiffiny; Yingling, Vanessa R.; Park, Joon‐Young

    2014-01-01

    Abstract Aging is associated with increasing incidence of osteoporosis; a skeletal disorder characterized by compromised bone strength that may predispose patients to an increased risk of fracture. It is imperative to identify novel ways in which to attenuate such declines in the functional properties of bone. The purpose of this study was to identify, through in silico, in vitro, and in vivo approaches, a protein secreted from skeletal muscle that is putatively involved in bone formation. We performed a functional annotation bioinformatic analysis of human skeletal muscle‐derived secretomes (n = 319) using DAVID software. Cross‐referencing was conducted using OMIM, Unigene, UniProt, GEO, and CGAP databases. Signal peptides and transmembrane residues were analyzed using SignalP and TMHMM software. To further investigate functionality of the identified protein, L6 and C2C12 myotubes were grown for in vitro analysis. C2C12 myotubes were subjected to 16 h of glucose deprivation (GD) prior to analysis. In vivo experiments included analysis of 6‐week calorie restricted (CR) rat muscle samples. Bioinformatic analysis yielded 15 genes of interest. GEO dataset analysis identified BMP5, COL1A2, CTGF, MGP, MMP2, and SPARC as potential targets for further processing. Following TMHMM and SignalP processing, CTGF was chosen as a candidate gene. CTGF expression level was increased during L6 myoblast differentiation (P <0.01). C2C12 myotubes showed no change in response to GD. Rat soleus muscle samples exhibited an increase in CTGF expression (n = 16) in response to CR (35%) (P <0.05). CTGF was identified as a skeletal muscle expressed protein through bioinformatic analysis of skeletal muscle‐derived secretomes and in vitro/in vivo analysis. Future study is needed to determine the role of muscle‐derived CTGF in bone formation and remodeling processes. PMID:25539834

  4. The GTPase regulatory proteins Pix and Git control tissue growth via the Hippo pathway.

    PubMed

    Dent, Lucas G; Poon, Carole L C; Zhang, Xiaomeng; Degoutin, Joffrey L; Tipping, Marla; Veraksa, Alexey; Harvey, Kieran F

    2015-01-01

    The Salvador-Warts-Hippo (Hippo) pathway is a conserved regulator of organ size and is deregulated in human cancers. In epithelial tissues, the Hippo pathway is regulated by fundamental cell biological properties, such as polarity and adhesion, and coordinates these with tissue growth. Despite its importance in disease, development, and regeneration, the complete set of proteins that regulate Hippo signaling remain undefined. To address this, we used proteomics to identify proteins that bind to the Hippo (Hpo) kinase. Prominent among these were PAK-interacting exchange factor (known as Pix or RtGEF) and G-protein-coupled receptor kinase-interacting protein (Git). Pix is a conserved Rho-type guanine nucleotide exchange factor (Rho-GEF) homologous to Beta-PIX and Alpha-PIX in mammals. Git is the single Drosophila melanogaster homolog of the mammalian GIT1 and GIT2 proteins, which were originally identified in the search for molecules that interact with G-protein-coupled receptor kinases. Pix and Git form an oligomeric scaffold to facilitate sterile 20-like kinase activation and have also been linked to GTPase regulation. We show that Pix and Git regulate Hippo-pathway-dependent tissue growth in D. melanogaster and that they do this in parallel to the known upstream regulator Fat cadherin. Pix and Git influence activity of the Hpo kinase by acting as a scaffold complex, rather than enzymes, and promote Hpo dimerization and autophosphorylation of Hpo's activation loop. Therefore, we provide important new insights into an ancient signaling network that controls the growth of metazoan tissues. PMID:25484297

  5. Tissue growth into three-dimensional composite scaffolds with controlled micro-features and nanotopographical surfaces.

    PubMed

    Tamjid, Elnaz; Simchi, Arash; Dunlop, John W C; Fratzl, Peter; Bagheri, Reza; Vossoughi, Manouchehr

    2013-10-01

    Controlling topographic features at all length scales is of great importance for the interaction of cells with tissue regenerative materials. We utilized an indirect three-dimensional printing method to fabricate polymeric scaffolds with pre-defined and controlled external and internal architecture that had an interconnected structure with macro- (400-500 μm) and micro- (∼25 μm) porosity. Polycaprolactone (PCL) was used as model system to study the kinetics of tissue growth within porous scaffolds. The surface of the scaffolds was decorated with TiO2 and bioactive glass (BG) nanoparticles to the better match to nanoarchitecture of extracellular matrix (ECM). Micrometric BG particles were also used to reveal the effect of particle size on the cell behavior. Observation of tissue growth and enzyme activity on two-dimensional (2D) films and three-dimensional (3D) scaffolds showed effects of nanoparticle inclusion and of surface curvature on the cellular adhesion, proliferation, and kinetics of preosteoblastic cells (MC3T3-E1) tissue growth into the pore channels. It was found that the presence of nanoparticles in the substrate impaired cellular adhesion and proliferation in 3D structures. Evaluation of alkaline phosphate activity showed that the presence of the hard particles affects differentiation of the cells on 2D films. Notwithstanding, the effect of particles on cell differentiation was not as strong as that seen by the curvature of the substrate. We observed different effects of nanofeatures on 2D structures with those of 3D scaffolds, which influence the cell proliferation and differentiation for non-load-bearing applications in bone regenerative medicine. PMID:23463703

  6. Growth Factor-Free Pre-vascularization of Cell Sheets for Tissue Engineering.

    PubMed

    Costa, Marina; Pirraco, Rogério P; Cerqueira, Mariana T; Reis, Rui L; Marques, Alexandra P

    2016-01-01

    The therapeutic efficacy of tissue-engineered constructs is often compromised by inadequate inosculation and neo-vascularization. This problem is considered one of the biggest hurdles in the field and finding a solution is currently the focus of a great fraction of the research community. Many of the methodologies designed to address this issue propose the use of endothelial cells and angiogenic growth factors, or combinations of both, to accelerate neo-vascularization after transplantation. However, an adequate solution is still elusive. In this context, we describe a methodology that combines the use of the stromal vascular fraction (SVF) isolated from adipose tissue with low oxygen culture to produce pre-vascularized cell sheets as angiogenic tools for Tissue Engineering. The herein proposed approach takes advantage of the SVF angiogenic nature conferred by adipose stem cells, endothelial progenitors, endothelial and hematopoietic cells, and pericytes and further potentiates it using low oxygen, or hypoxic, culture. Freshly isolated nucleated SVF cells are cultured in hyperconfluent conditions under hypoxia (pO2 = 5 %) for up to 5 days in medium without extrinsic growth factors enabling the generation of contiguous sheets as described by the cell sheet engineering technique. Flow cytometry and immunocytochemistry allow confirming the phenotype of the different cell types composing the cell-sheets as well the organization of the CD31(+) cells in branched and highly complex tube-like structures. Overall, a simple and flexible approach to promote growth factor-free pre-vascularization of cell sheets for tissue engineering (TE) applications is described. PMID:27250706

  7. Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: Report of a case and review of the literature

    PubMed Central

    Woo, Victoria L.; Landesberg, Regina; Imel, Erik A.; Singer, Steven R.; Folpe, Andrew L.; Econs, Michael J.; Kim, Taeyun; Harik, Lara R.; Jacobs, Thomas P.

    2009-01-01

    Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results in renal phosphate wasting with hypophosphatemia. In most cases, the underlying cause of TIO is a small mesenchymal neoplasm that is often difficult to detect, resulting in delayed diagnosis. One such neoplasm is the phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT), an unusual entity with unique morphologic and biochemical features. The majority of these tumors are found at appendicular sites with only rare cases reported in the jaws. We describe a PMTMCT involving the mandible in a patient with a protracted history of osteomalacia. A review of the current literature is provided with emphasis on the clinical and histologic features, etiopathogenesis, and management of PMTMCT in the setting of TIO. PMID:19828339

  8. Development of diagnostic and treatment strategies for glaucoma through understanding and modification of scleral and lamina cribrosa connective tissue

    PubMed Central

    Quigley, Harry A.; Cone, Frances E.

    2013-01-01

    There is considerable evidence that the state of ocular connective tissues and their response in glaucomatous disease affects the degree of glaucoma damage. Both experimental and clinical data suggest that improved diagnostic and prognostic information could be derived from assessment of the mechanical responsiveness of the sclera and lamina cribrosa to intraocular pressure (IOP). Controlled mutagenesis of the sclera has produced a mouse strain that is relatively resistant to increased IOP. Alteration of the baseline scleral state could be accomplished through either increased cross-linking of fibrillar components or their reduction. The sclera is a dynamic structure, altering its structure and behavior in response to IOP change. The biochemical pathways that control these responses are fertile areas for new glaucoma treatments. PMID:23535950

  9. Development of mixed connective tissue disease and Sjögren's syndrome in a patient with trisomy X.

    PubMed

    Fujimoto, M; Ikeda, K; Nakamura, T; Iwamoto, T; Furuta, S; Nakajima, H

    2015-10-01

    Increased risk of developing systemic lupus erythematosus (SLE) has been reported in patients with Klinefelter syndrome. Here, we describe a 16-year-old Japanese patient with trisomy X (47,XXX) who developed mixed connective tissue disease (MCTD) and Sjögren's syndrome. She had polyarthritis, edematous fingers with Raynaud's phenomenon, sicca syndrome, interstitial lung disease, possible myositis, and was positive for anti-nuclear antibody, anti-nRNP antibody and rheumatoid factor. This is the first report in the literature of a case of MCTD with female polysomy X, which further supports the link between the presence of extra X chromosome(s) and the development of autoimmune diseases. PMID:25854827

  10. Growth-Related Neural Reorganization and the Autism Phenotype: A Test of the Hypothesis that Altered Brain Growth Leads to Altered Connectivity

    ERIC Educational Resources Information Center

    Lewis, John D.; Elman, Jeffrey L.

    2008-01-01

    Theoretical considerations, and findings from computational modeling, comparative neuroanatomy and developmental neuroscience, motivate the hypothesis that a deviant brain growth trajectory will lead to deviant patterns of change in cortico-cortical connectivity. Differences in brain size during development will alter the relative cost and…

  11. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion.

    PubMed

    Gorin, Caroline; Rochefort, Gael Y; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Muller, Laurent; Chaussain, Catherine; Germain, Stéphane

    2016-03-01

    Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF. PMID:26798059

  12. β2-Adrenoceptor is involved in connective tissue remodeling in regenerating muscles by decreasing the activity of MMP-9.

    PubMed

    Silva, Meiricris T; Nascimento, Tábata L; Pereira, Marcelo G; Siqueira, Adriane S; Brum, Patrícia C; Jaeger, Ruy G; Miyabara, Elen H

    2016-07-01

    We investigated the role of β2-adrenoceptors in the connective tissue remodeling of regenerating muscles from β2-adrenoceptor knockout (β2KO) mice. Tibialis anterior muscles from β2KO mice were cryolesioned and analyzed after 3, 10, and 21 days. Regenerating muscles from β2KO mice showed a significant increase in the area density of the connective tissue and in the amount of collagen at 10 days compared with wild-type (WT) mice. A greater increase occurred in the expression levels of collagen I, III, and IV in regenerating muscles from β2KO mice evaluated at 10 days compared with WT mice; this increase continued at 21 days, except for collagen III. Matrix metalloproteinase (MMP-2) activity increased to a similar extent in regenerating muscles from both β2KO and WT mice at 3 and 10 days. This was also the case for MMP-9 activity in regenerating muscles from both β2KO and WT mice at 3 days; however, at 10 days post-cryolesion, this activity returned to baseline levels only in WT mice. MMP-3 activity was unaltered in regenerating muscles at 10 days. mRNA levels of tumor necrosis factor-α increased in regenerating muscles from WT and β2KO mice at 3 days and, at 10 days post-cryolesion, returned to baseline only in WT mice. mRNA levels of interleukin-6 increased in muscles from WT mice at 3 days post-cryolesion and returned to baseline at 10 days post-cryolesion but were unchanged in β2KO mice. Our results suggest that the β2-adrenoceptor contributes to collagen remodeling during muscle regeneration by decreasing MMP-9 activity. PMID:26896238

  13. Tensilin-like stiffening protein from Holothuria leucospilota does not induce the stiffest state of catch connective tissue.

    PubMed

    Tamori, Masaki; Yamada, Akira; Nishida, Naoto; Motobayashi, Yumiko; Oiwa, Kazuhiro; Motokawa, Tatsuo

    2006-05-01

    The dermis of sea cucumbers is a catch connective tissue or mutable connective tissue that exhibits large changes in mechanical properties. A stiffening protein, tensilin, has been isolated from the sea cucumber Cucumaria frondosa. We purified a similar protein, H-tensilin, from Holothuria leucospilota, which belongs to a different family to C. frondosa. H-tensilin appeared as a single band with an apparent molecular mass of 34 kDa on SDS-PAGE. No sugar chain was detected. Tryptic fragments of the protein had homology to known tensilin. H-tensilin aggregated isolated collagen fibrils in vitro in a buffer containing 0.5 mol l(-1) NaCl with or without 10 mmol l(-1) Ca(2+). The activity of H-tensilin was quantitatively studied by dynamic mechanical tests on the isolated dermis. H-tensilin increased stiffness of the dermis in the soft state, induced by Ca(2+)-free artificial seawater, to a level comparable to that of the standard state, which was the state found in the dermis rested in artificial seawater with normal ionic condition. H-tensilin decreased the energy dissipation ratio of the soft dermis to a level comparable to that of the standard state. When H-tensilin was applied on the dermis in the standard state, it did not alter stiffness nor dissipation ratio. The subsequent application of artificial seawater in which the potassium concentration was raised to 100 mmol l(-1) increased stiffness by one order of magnitude. These findings suggest that H-tensilin is involved in the changes from the soft state to the standard state and that some stiffening factors other than tensilin are necessary for the changes from the standard to the stiff state. PMID:16621940

  14. Connecting galaxy and supermassive black hole growth during the last 8 billion years

    NASA Astrophysics Data System (ADS)

    Juneau, Stephanie

    It has become increasingly clear that a complete picture of galaxy evolution requires a better understanding of the role of Active Galactic Nuclei (AGN). In particular, they could be responsible for regulating star formation and galaxy growth via feedback processes. There are also competing views about the main modes of stellar growth and supermassive black hole growth in galaxies that need to be resolved. With high infrared luminosities (thus star formation rates) and a frequent occurrence of AGN, galaxies selected in the far-infrared wavebands form an ideal sample to search for a connection between AGN and star formation. The first part of this thesis contains a detailed analysis of the molecular gas properties of nearby infrared luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs). We find that the enhanced molecular gas density in the most IR-luminous systems can be explained by major galaxy mergers, and that AGN are more likely to reside in higher-density systems. While the frequent concurrence of AGN and galaxy mergers in ULIRGs was already established, this work provides a coherent framework that explains trends observed with five molecular gas tracers with a broad range of critical densities, and a comparison with simulations that reproduce observed molecular line ratios without invoking AGN-induced chemistry. The second part of the thesis presents an analysis of the AGN content of intermediate redshift galaxies (0.3 < z < 1). However, identifying complete AGN samples at these redshift is challenging because it is difficult to find X-ray weak or absorbed AGN. To alleviate this problem, we developed the Mass-Excitation (MEx) diagram, which is applicable out to redshift of ˜ 1 with existing optical spectra. It improves the overall AGN census by detecting AGN that are missed in even the most sensitive X-ray surveys. The new diagnostic was used to study the concurrence of star formation and AGN in 70 micron-selected galaxies from the Far

  15. Methotrexate inhibits neutrophil function by stimulating adenosine release from connective tissue cells

    SciTech Connect

    Cronstein, B.N.; Eberle, M.A.; Levin, R.I. ); Gruber, H.E. )

    1991-03-15

    Although commonly used to control a variety of inflammatory diseases, the mechanism of action of a low dose of methotrexate remains a mystery. Methotrexate accumulates intracellularly where it may interfere with purine metabolism. Therefore, the authors determined whether a 48-hr pretreatment with methotrexate affected adenosine release from ({sup 14}C)adenine-labeled human fibroblasts and umbilical vein endothelial cells. Methotrexate significantly increased adenosine release by fibroblasts. The effect of methotrexate on adenosine release was not due to cytotoxicity since cells treated with maximal concentrations of methotrexate took up ({sup 14}C)adenine and released {sup 14}C-labeled purine (a measure of cell injury) in a manner identical to control cells. Methotrexate treatment of fibroblasts dramatically inhibited adherence to fibroblasts by both unstimulated neutrophils and stimulated neutrophils. One hypothesis that explains the effect of methotrexate on adenosine release is that, by inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, methotrexate induces the accumulation of AICAR, the nucleoside precursor of which has previously been shown to cause adenosine release from ischemic cardiac tissue. The observation that the antiinflammatory actions of methotrexate are due to the capacity of methotrexate to induce adenosine release may form the basis for the development of an additional class of antiinflammatory drugs.

  16. Connecting brains to robots: an artificial body for studying the computational properties of neural tissues.

    PubMed

    Reger, B D; Fleming, K M; Sanguineti, V; Alford, S; Mussa-Ivaldi, F A

    2000-01-01

    We have created a hybrid neuro-robotic system that establishes two-way communication between the brain of a lamprey and a small mobile robot. The purpose of this system is to offer a new paradigm for investigating the behavioral, computational, and neurobiological mechanisms of sensory-motor learning in a unified context. The mobile robot acts as an artificial body that delivers sensory information to the neural tissue and receives command signals from it. The sensory information encodes the intensity of light generated by a fixed source. The closed-loop interaction between brain and robot generates autonomous behaviors whose features are strictly related to the structure and operation of the neural preparation. We provide a detailed description of the hybrid system, and we present experimental findings on its performance. In particular, we found (a) that the hybrid system generates stable behaviors, (b) that different preparations display different but systematic responses to the presentation of an optical stimulus, and (c) that alteration of the sensory input leads to short- and long-term adaptive changes in the robot responses. The comparison of the behaviors generated by the lamprey's brain stem with the behaviors generated by network models of the same neural system provides us with a new tool for investigating the computational properties of synaptic plasticity. PMID:11348584

  17. Changes in bone tissue under conditions of hypokinesia and in connection with age

    NASA Technical Reports Server (NTRS)

    Podrushnyak, E. P.; Suslov, E. I.

    1980-01-01

    X-ray micrography was used to study the optical density of the blackening of X-ray photographs made of five bones in 9 young people (ages 24 to 29) before and after strict bed rest for 16 to 37 days. Photometric studies of the X-ray film determined the relative concentration of bone structure before and after hypokinesia. In addition, the bone tissues of 25 cadavers of practically healthy individuals (aged 18 to 70) who died from injuries were investigated using X-ray structural analysis. Results show that the reaction to the state of hypokinesia is not uniform in different individuals and is quite often directly reversed. It was established that pronounced osteoporosis can be found in a relatively short time after conditions of hypokinesia in healthy young individuals. Results show that the stabilization of the crystalline structure of hydroxyapatite, especially its crystal formation, is finished by the age of 20 to 25. From 25 to 60, the crystal lattice remains in stable condition but X-ray analysis shows a reduction in the hydroxyapatite density.

  18. Immediate placement and provisionalization of maxillary anterior single implant with guided bone regeneration, connective tissue graft, and coronally positioned flap procedures.

    PubMed

    Waki, Tomonori; Kan, Joseph Y K

    2016-01-01

    Immediate implant placement and provisionalization in the esthetic zone have been documented with success. The benefit of immediate implant placement and provisionalization is the preservation of papillary mucosa. However, in cases with osseous defects presenting on the facial bony plate, immediate implant placement procedures have resulted in facial gingival recession. Subepithelial connective tissue grafts for immediate implant placement and provisionalization procedures have been reported with a good esthetic outcome. Biotype conversion around implants with subepithelial connective tissue grafts have been advocated, and the resulting tissues appear to be more resistant to recession. The dimensions of peri-implant mucosa in a thick biotype were significantly greater than in a thin biotype. Connective tissue graft with coronally positioned flap procedures on natural teeth has also been documented with success. This article describes a technique combining immediate implant placement, provisionalization, guided bone regeneration (GBR), connective tissue graft, and a coronally positioned flap in order to achieve more stable peri-implant tissue in facial osseous defect situations. PMID:27092345

  19. The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways

    PubMed Central

    Shimoda, Shinji; Mishima, Kenji; Higashiyama, Hiroyuki; Idaira, Yayoi; Asada, Yoshinobu; Kitamura, Hiroshi; Yamasaki, Satoru; Hojyo, Shintaro; Nakayama, Manabu; Ohara, Osamu; Koseki, Haruhiko; dos Santos, Heloisa G.; Bonafe, Luisa; Ha-Vinh, Russia; Zankl, Andreas; Unger, Sheila; Kraenzlin, Marius E.; Beckmann, Jacques S.; Saito, Ichiro; Rivolta, Carlo; Ikegawa, Shiro; Superti-Furga, Andrea; Hirano, Toshio

    2008-01-01

    Background Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Methodology/Principal Findings Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-β signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. Conclusions/Significance Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-β signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-β signaling and connective tissue dysfunction. PMID:18985159

  20. Intrinsic variability in shell and soft tissue growth of the freshwater mussel Lampsilis siliquoidea

    USGS Publications Warehouse

    Larson, James H.; Eckert, Nathan L.; Bartsch, Michelle

    2014-01-01

    Freshwater mussels are ecologically and economically important members of many aquatic ecosystems, but are globally among the most imperiled taxa. Propagation techniques for mussels have been developed and used to boost declining and restore extirpated populations. Here we use a cohort of propagated mussels to estimate the intrinsic variability in size and growth rate of Lampsilis siliquoidea (a commonly propagated species). Understanding the magnitude and pattern of variation in data is critical to determining whether effects observed in nature or experimental treatments are likely to be important. The coefficient of variation (CV) of L. siliquoidea soft tissues (6.0%) was less than the CV of linear shell dimensions (25.1-66.9%). Size-weight relationships were best when mussel width (the maximum left-right dimension with both valves appressed) was used as a predictor, but 95% credible intervals on these predictions for soft tissues were ~145 mg wide (about 50% of the mean soft tissue mass). Mussels in this study were treated identically, raised from a single cohort and yet variation in soft tissue mass at a particular size class (as determined by shell dimensions) was still high. High variability in mussel size is often acknowledged, but seldom discussed in the context of mussel conservation. High variability will influence the survival of stocked juvenile cohorts, may affect the ability to experimentally detect sublethal stressors and may lead to incongruities between the effects that mussels have on structure (via hard shells) and biogeochemical cycles (via soft tissue metabolism). Given their imperiled status and longevity, there is often reluctance to destructively sample unionid mussel soft tissues even in metabolic studies (e.g., studies of nutrient cycling). High intrinsic variability suggests that using shell dimensions (particularly shell length) as a response variable in studies of sublethal stressors or metabolic processes will make confident

  1. Intrinsic Variability in Shell and Soft Tissue Growth of the Freshwater Mussel Lampsilis siliquoidea

    PubMed Central

    Larson, James H.; Eckert, Nathan L.; Bartsch, Michelle R.

    2014-01-01

    Freshwater mussels are ecologically and economically important members of many aquatic ecosystems, but are globally among the most imperiled taxa. Propagation techniques for mussels have been developed and used to boost declining and restore extirpated populations. Here we use a cohort of propagated mussels to estimate the intrinsic variability in size and growth rate of Lampsilis siliquoidea (a commonly propagated species). Understanding the magnitude and pattern of variation in data is critical to determining whether effects observed in nature or experimental treatments are likely to be important. The coefficient of variation (CV) of L. siliquoidea soft tissues (6.0%) was less than the CV of linear shell dimensions (25.1–66.9%). Size-weight relationships were best when mussel width (the maximum left-right dimension with both valves appressed) was used as a predictor, but 95% credible intervals on these predictions for soft tissues were ∼145 mg wide (about 50% of the mean soft tissue mass). Mussels in this study were treated identically, raised from a single cohort and yet variation in soft tissue mass at a particular size class (as determined by shell dimensions) was still high. High variability in mussel size is often acknowledged, but seldom discussed in the context of mussel conservation. High variability will influence the survival of stocked juvenile cohorts, may affect the ability to experimentally detect sublethal stressors and may lead to incongruities between the effects that mussels have on structure (via hard shells) and biogeochemical cycles (via soft tissue metabolism). Given their imperiled status and longevity, there is often reluctance to destructively sample unionid mussel soft tissues even in metabolic studies (e.g., studies of nutrient cycling). High intrinsic variability suggests that using shell dimensions (particularly shell length) as a response variable in studies of sublethal stressors or metabolic processes will make confident

  2. In vivo inhibition of polyamine biosynthesis and growth in tobacco ovary tissues

    NASA Technical Reports Server (NTRS)

    Slocum, R. D.; Galston, A. W.

    1985-01-01

    Post fertilization growth of tobacco ovary tissues treated with inhibitors of polyamine (PA) biosynthesis was examined in relation to endogenous PA titers and the activities of arginine decarboxylase (ADC, EC 4.1.1.19) and ornithine decarboxylase (ODC, EC 4.1.1.17). DL-alpha-Difluoromethylornithine (DFMO) and DL-alpha-difluoromethylarginine (DFMA), specific, irreversible ("suicide") inhibitors of ODC and ADC in vitro, were used to modulate PA biosynthesis in excised flowers. ODC represented >99% of the total decarboxylase activity in tobacco ovaries. In vivo inhibition of ODC with DFMO resulted in a significant decrease in PA titers, ovary fresh weight and protein content. Simultaneous inhibition of both decarboxylases by DFMO and DFMA produced only a marginally greater depression in growth and PA titers, indicating that ODC activity is rate-limiting for PA biosynthesis in these tissues. Paradoxically, DFMA alone inhibited PA biosynthesis, not as a result of a specific inhibition of ADC, but primarily through the inactivation of ODC. In vivo inhibition of ODC by DFMA appears to result from arginase-mediated hydrolysis of this inhibitor to urea and DFMO, the suicide substrate for ODC. Putrescine conjugates in tobacco appear to function as a storage form of this amine which, upon hydrolysis, may contribute to Put homeostasis during growth.

  3. Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: A review

    PubMed Central

    Bose, Susmita; Tarafder, Solaiman

    2012-01-01

    Calcium phosphates (CaPs) are the most widely used bone substitutes in bone tissue engineering due to their compositional similarities to bone mineral and excellent biocompatibility. In recent years, CaPs, especially hydroxyapatite and tricalcium phosphate, have attracted significant interest in simultaneous use as bone substitute and drug delivery vehicle, adding a new dimension to their application. CaPs are more biocompatible than many other ceramic and inorganic nanoparticles. Their biocompatibility and variable stoichiometry, thus surface charge density, functionality, and dissolution properties, make them suitable for both drug and growth factor delivery. CaP matrices and scaffolds have been reported to act as delivery vehicles for growth factors and drugs in bone tissue engineering. Local drug delivery in musculoskeletal disorder treatments can address some of the critical issues more effectively and efficiently than the systemic delivery. CaPs are used as coatings on metallic implants, CaP cements, and custom designed scaffolds to treat musculoskeletal disorders. This review highlights some of the current drug and growth factor delivery approaches and critical issues using CaP particles, coatings, cements, and scaffolds towards orthopedic and dental applications. PMID:22127225

  4. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth.

    PubMed

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  5. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  6. Evaluation of corneal cell growth on tissue engineering materials as artificial cornea scaffolds

    PubMed Central

    Wang, Hai-Yan; Wei, Rui-Hua; Zhao, Shao-Zhen

    2013-01-01

    The keratoprosthesis (KPro; artificial cornea) is a special refractive device to replace human cornea by using heterogeneous forming materials for the implantation into the damaged eyes in order to obtain a certain vision. The main problems of artificial cornea are the biocompatibility and stability of the tissue particularly in penetrating keratoplasty. The current studies of tissue-engineered scaffold materials through comprising composites of natural and synthetic biopolymers together have developed a new way to artificial cornea. Although a wide agreement that the long-term stability of these devices would be greatly improved by the presence of cornea cells, modification of keratoprosthesis to support cornea cells remains elusive. Most of the studies on corneal substrate materials and surface modification of composites have tried to improve the growth and biocompatibility of cornea cells which can not only reduce the stimulus of heterogeneous materials, but also more importantly continuous and stable cornea cells can prevent the destruction of collagenase. The necrosis of stroma and spontaneous extrusion of the device, allow for maintenance of a precorneal tear layer, and play the role of ensuring a good optical surface and resisting bacterial infection. As a result, improvement in corneal cells has been the main aim of several recent investigations; some effort has focused on biomaterial for its well biological properties such as promoting the growth of cornea cells. The purpose of this review is to summary the growth status of the corneal cells after the implantation of several artificial corneas. PMID:24392340

  7. Hair growth promoting potential of phospholipids purified from porcine lung tissues.

    PubMed

    Choi, Seong-Hyun; Moon, Jeong-Su; Jeon, Byung-Suk; Jeon, Yeon-Jeong; Yoon, Byung-Il; Lim, Chang-Jin

    2015-03-01

    BP201, porcine lung tissue-derived phospholipids, consists of phosphatidylcholine as a major phospholipid species. BP201 promoted hair growth after application onto the shaved backs of BALB/c and C3H mice. Its effect was enhanced when applied together with minoxidil (MNX) in C3H mice. When the tissue specimens prepared from the shaved skins of BP201-treated and control mice were microscopically examined, the total numbers of hair follicles in both anagen and telogen phases of BP201-treated mice were significantly higher than those of control mice. The numbers of hair follicles in the anagen phase of BP201-treated mice were also higher than those of control mice. In combination with MNX, BP201 further increased the total number of hair follicles, but did not alter the percentage of hair follicles in the anagenic phase. BP201 also increased the proliferation of human hair follicle dermal papilla cells. Collectively, BP201 possesses hair growth promoting potential, which would suggest its use singly or in combination for hair growth products. PMID:25767686

  8. Hair Growth Promoting Potential of Phospholipids Purified from Porcine Lung Tissues

    PubMed Central

    Choi, Seong-Hyun; Moon, Jeong-Su; Jeon, Byung-Suk; Jeon, Yeon-Jeong; Yoon, Byung-Il; Lim, Chang-Jin

    2015-01-01

    BP201, porcine lung tissue-derived phospholipids, consists of phosphatidylcholine as a major phospholipid species. BP201 promoted hair growth after application onto the shaved backs of BALB/c and C3H mice. Its effect was enhanced when applied together with minoxidil (MNX) in C3H mice. When the tissue specimens prepared from the shaved skins of BP201-treated and control mice were microscopically examined, the total numbers of hair follicles in both anagen and telogen phases of BP201-treated mice were significantly higher than those of control mice. The numbers of hair follicles in the anagen phase of BP201-treated mice were also higher than those of control mice. In combination with MNX, BP201 further increased the total number of hair follicles, but did not alter the percentage of hair follicles in the anagenic phase. BP201 also increased the proliferation of human hair follicle dermal papilla cells. Collectively, BP201 possesses hair growth promoting potential, which would suggest its use singly or in combination for hair growth products. PMID:25767686

  9. Platelet-derived growth factor and transforming growth factor-beta enhance tissue repair activities by unique mechanisms.

    PubMed

    Pierce, G F; Mustoe, T A; Lingelbach, J; Masakowski, V R; Griffin, G L; Senior, R M; Deuel, T F

    1989-07-01

    Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) markedly potentiate tissue repair in vivo. In the present experiments, both in vitro and in vivo responses to PDGF and TGF-beta were tested to identify mechanisms whereby these growth factors might each enhance the wound-healing response. Recombinant human PDGF B-chain homodimers (PDGF-BB) and TGF-beta 1 had identical dose-response curves in chemotactic assays with monocytes and fibroblasts as the natural proteins from platelets. Single applications of PDGF-BB (2 micrograms, 80 pmol) and TGF-beta 1 (20 micrograms, 600 pmol) were next applied to linear incisions in rats and each enhanced the strength required to disrupt the wounds at 5 d up to 212% of paired control wounds. Histological analysis of treated wounds demonstrated an in vivo chemotactic response of macrophages and fibroblasts to both PDGF-BB and to TGF-beta 1 but the response to TGF-beta 1 was significantly less than that observed with PDGF-BB. Marked increases of procollagen type I were observed by immunohistochemical staining in fibroblasts in treated wounds during the first week. The augmented breaking strength of TGF-beta 1 was not observed 2 and 3 wk after wounding. However, the positive influence of PDGF-BB on wound breaking strength persisted through the 7 wk of testing. Furthermore, PDGF-BB-treated wounds had persistently increased numbers of fibroblasts and granulation tissue through day 21, whereas the enhanced cellular influx in TGF-beta 1-treated wounds was not detectable beyond day 7. Wound macrophages and fibroblasts from PDGF-BB-treated wounds contained sharply increased levels of immunohistochemically detectable intracellular TGF-beta. Furthermore, PDGF-BB in vitro induced a marked, time-dependent stimulation of TGF-beta mRNA levels in cultured normal rat kidney fibroblasts. The results suggest that TGF-beta transiently attracts fibroblasts into the wound and may stimulate collagen synthesis directly. In

  10. The Influence of Input on Connective Acquisition: A Growth Curve Analysis of English "Because" and German "Weil"

    ERIC Educational Resources Information Center

    van Veen, Rosie; Evers-Vermeul, Jacqueline; Sanders, Ted; van den Bergh, Huub

    2013-01-01

    The current study used growth curve analysis to study the role of input during the acquisition of the English causal connective "because" and its German counterpart "weil." The corpora of five German and five English children and their adult caretakers (age range 0;10-4;3) were analyzed for the amount as well as for the type of…

  11. Experiment K-7-29: Connective Tissue Studies. Part 1; Rat Skin, Normal and Repair

    NASA Technical Reports Server (NTRS)

    Vailas, A. C.; Grindeland, R.; Ashman, R.; Choy, V.; Durnova, G.; Graf, B.; Griffith, P.; Kaplansky, A. S.; Kolis, S.; Martinez, D.; Rao, J. S.; Rayford, A. R.; Reddy, B. R.; Sears, J.; Thielke, R.; Ulm, M.; Vanderby, R.

    1994-01-01

    The skin repair studies started to be problematic for the following reasons: (1) It was very difficult to locate the wound and many lesions were not of the same dimensions. A considerable amount of time was devoted to the identification of the wound using polarized light. We understand that this experiment was added on to the overall project. Marking of the wound site and standard dimensions should be recommended for the next flight experiment. (2) The tissue was frozen, therefore thawing and fixation caused problems with some of the immunocytochemical staining for obtaining better special resolution with light microscopy image processing. Despite these problems, we were unable to detect any significant qualitative differences for the following wound markers: (1) Collagen Type 3, (2) Hematotoxylin and Eosin, and (3) Macrophage Factor 13. All protein markers were isolated from rat sources and antibodies prepared and tested for cross reactivity with other molecules at the University of Wisconsin Hybridoma Facility. However, rat skin from the non lesioned site 'normal' showed interesting biochemical results. Skin was prepared for the following measurements: (1) DNA content, (2) Collagen content by hydroxyproline, and (3) uronic acid content and estimation of ground substance. The results indicated there was a non-significant increase (10%) in the DNA concentration of skin from flight animals. However, the data expressed as a ratio DNA/Collagen estimates the cell or nuclear density that supports a given quantity of collagen showed a dramatic increase in the flight group (33%). This means flight conditions may have slowed down collagen secretion and/or increased cell proliferation in adult rat skin. Further biochemical tests are being done to determine the crosslinking of elastin which will enhance the insight to assessing changes in skin turnover.

  12. Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor.

    PubMed Central

    Lesa, G M; Sternberg, P W

    1997-01-01

    The major determinants of receptor tissue tyrosine kinase (RTK) signaling specificity have been proposed to be Src homology 2 (SH2) binding sites, phosphotyrosine-containing oligopeptides in the cytoplasmic domain of the receptor. The Caenorhabditis elegans epidermal growth factor receptor homologue LET-23 has multiple functions during development and has eight potential SH2-binding sites in a region carboxyl terminal to its kinase domain. By analyzing transgenic nematodes for three distinct LET-23 functions, we show that six of eight potential sites function in vivo and that they are required for most, but not all, of LET-23 activity. A single site is necessary and sufficient to promote wild-type fertility. Three other sites activate the RAS pathway and are involved only in viability and vulval differentiation. A fifth site is promiscuous and can mediate all three LET-23 functions. An additional site mediates tissue-specific negative regulation. Putative SH2 binding sites are thus key effectors of both cell-specific and negative regulation in an intact organism. We suggest two distinct mechanisms for tissue-specific RTK-mediated signaling. A positive mechanism would promote RTK function through effectors present only in certain cell types. A negative mechanism would inhibit RTK function through tissue-specific negative regulators. Images PMID:9168466

  13. Evidence that cyclosporin A administration induces the formation of new cementum-like islets inside the gingival connective tissue.

    PubMed

    Ayanoglou, C M

    1998-04-01

    Two groups of 3 male Sprague-Dawley rats were given orally 30 mg/kg/d of vehicle (control group) or cyclosporin-A (experimental group) solution for 14 wk. The rats were anesthetized, tissues fixed by intracardiac perfusion of fixative solution and jaws dissected, demineralized, processed for Epon inclusion and cut by semi-thin serial sections. Histological examination revealed the presence of several islets located paravascularly inside the gingival connective tissue in the proximity of the root surfaces. The structure of these new cementum-like islets (NCLIs) was either compact and homogeneous or heterogeneous, but identical to that of the adjacent new cementum (NC) deposits. Histomorphometric evaluation indicated that the volume and the external surface of the NCLIs varied from 2354 to 679,497 micron 3 and from 465 to 47,517 micron 2, respectively. These observations (a) suggest that CsA stimulates possibly paravascular progenitor cells which secrete in situ a NC-like material and (b) provides further evidence about the high potential of CsA to induce NC formation. PMID:9651878

  14. Differences in irradiation susceptibility and turnover between mucosal and connective tissue-type mast cells of mice

    SciTech Connect

    Fukuzumi, T.; Waki, N.; Kanakura, Y.; Nagoshi, J.; Hirota, S.; Yoshikawa, K.; Kitamura, Y. )

    1990-08-01

    Although precursors of mast cells are derived from the bone marrow, phenotypes of mast cells are influenced by the tissues in which final differentiation occurs. Connective tissue-type mast cells (CTMC) and mucosal mast cells (MMC) are different in morphological, biochemical, immunological, and functional criteria. The purpose of the present study was to obtain information about the differentiation process of MMC. First, we compared changes in irradiation susceptibility in mice during the differentiation process of CTMC and MMC. The decrease in irradiation susceptibility was remarkable in the CTMC differentiation process, but it was moderate in that of MMC. Some morphologically identifiable CTMC in the peritoneal cavity had proliferative potential and were highly radioresistant, whereas such a radioresistant population of MMC was not detectable in the gastric mucosa. Second, we estimated the turnover of CTMC and MMC by determining the proportion of mast cells that were labeled with continuously administered bromodeoxyuridine. The turnover of MMC was significantly faster than that of CTMC. The absence of the radioresistant mast cell population in the gastric mucosa appeared to be related to the short life span of MMC.

  15. Alterations in the biosynthesis of extracellular matrix molecules in connective tissues by electric and magnetic fields

    SciTech Connect

    Ciombor, D.M.

    1992-01-01

    Pulsed electromagnetic fields (PEMFs) of certain configurations have been shown to be effective clinically in promoting the healing of fracture non-unions and are believed to enhance calcification of extracellular matrix. In vitro studies have suggested that PEMFs may also have the effect of modifying the extracellular matrix by promoting the synthesis of matrix molecules. This study examines the effect of one particular type of PEMF and a sinusoidal continuous wave upon the extracellular matrix and calcification of endochondral ossification in vivo. The pulsed magnetic field (SS-22) utilized in these studies is being used clinically for the treatment of fracture non-unions, a condition in which the bone is not restored to form or function. The sinusoidal continuous wave was designed to provide a 5 Gauss amplitude at a 15 Hz. rate. The synthesis of cartilage molecules is enhanced by this type of PEMF and since wave and subsequent endochondral calcification is stimulated. Histomorphometric studies indicate that the maturation of bone trabeculae is also promoted by this type of PEMF stimulation. These results indicate that a specific PEMF or continuous waveform can change the composition of cartilage extracellular matrix in vivo and raises the possibility that the effects on other processes of endochondral ossification (e.g., fracture healing and growth plates) may occur through a similar mechanism.

  16. Statistical Properties of Cell Topology and Geometry in a Tissue-Growth Model

    NASA Astrophysics Data System (ADS)

    Sahlin, Patrik; Hamant, Olivier; Jönsson, Henrik

    Statistical properties of cell topologies in two-dimensional tissues have recently been suggested to be a consequence of cell divisions. Different rules for the positioning of new walls in plants have been proposed, where e.g. Errara’s rule state that new walls are added with the shortest possible path dividing the mother cell’s volume into two equal parts. Here, we show that for an isotropically growing tissue Errara’s rule results in the correct distributions of number of cell neighbors as well as cellular geometries, in contrast to a random division rule. Further we show that wall mechanics constrain the isotropic growth such that the resulting cell shape distributions more closely agree with experimental data extracted from the shoot apex of Arabidopsis thaliana.

  17. Restricting dietary magnesium accelerates ectopic connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-) ).

    PubMed

    Jiang, Qiujie; Uitto, Jouni

    2012-09-01

    Ectopic mineralization, linked to a number of diseases, is a major cause of morbidity and mortality in humans. Pseudoxanthoma elasticum (PXE) is a heritable multisystem disorder characterized by calcium phosphate deposition in various tissues. The mineral content of diet has been suggested to modify the disease severity in PXE. The aim of this study is to explore the role of diet with reduced magnesium in modifying tissue mineralization in a mouse model of PXE. Abcc6(-/-) mice were placed on either standard rodent diet (control) or an experimental diet low in magnesium at weaning (4 weeks) and examined for mineralization in the skin and internal organs at the ages of 1.5, 2 or 6 months by computerized morphometric analysis of histopathological sections and by chemical assay of calcium and phosphate. Abcc6(-/-) mice on experimental diet demonstrated an accelerated, early-onset mineralization of connective tissues, as compared to control mice. Wild-type or heterozygous mice on experimental diet did not show evidence of mineralization up to 6 months of age. All mice on experimental diet showed decreased urinary calcium, increased urinary phosphate and elevated parathyroid serum levels. However, no difference in bone density at 6 months of age was noted. Our findings indicate that the mineral content, particularly magnesium, can modify the extent and the onset of mineralization in Abcc6(-/-) mice and suggest that dietary magnesium levels may contribute to the phenotypic variability of PXE. The control of mineralization by dietary magnesium may have broader implications in general population in the context of vascular mineralization. PMID:22897576

  18. Mineralization of the connective tissue: a complex molecular process leading to age-related loss of function.

    PubMed

    Shindyapina, Anastasia V; Mkrtchyan, Garik V; Gneteeva, Tatiana; Buiucli, Sveatoslav; Tancowny, B; Kulka, M; Aliper, Alexander; Zhavoronkov, Alexander

    2014-04-01

    Age-related metastatic mineralization of soft tissues has been considered a passive and spontaneous process. Recent data have demonstrated that calcium salt deposition in soft tissues could be a highly regulated process. Although calcification occurs in any tissue type, vascular calcification has been of particular interest due to association with atherosclerosis, chronic kidney disease (CKD), and osteoporosis. Different mechanisms underlying calcium apatite accumulation are explored with these age-related disorders. In the case of atherosclerotic plaques, oxy-lipids trigger release of the pro-inflammatory cytokines and inflammation that activate calcification processes in aorta intimae. In CKD patients, renal failure alters the balance between calcium and phosphate levels usually regulated by fibroblast growth factor-23 (FGF23), Klotho, and vitamin D, and vascular smooth muscle cells (VSMCs) begin to explore an osteoblastosteoblast-like phenotype. Calcification could affect extracellular matrix along with VSMCs. Collagen is a major component of extracellular matrix and its modifications accumulate with age. The formation of cross-links between collagen fibers is regulated by the action of lysine hydroxylases and lysyl oxidase and could occur spontaneously. Oxidation-induced advanced glycation end products (AGEs) are a major type of spontaneous cross-links that accelerate with age and may result in tissue stiffness, problems with recycling, and potential accumulation of calcium apatite. Applying strategies for clearing the AGEs proposed by de Grey may be more difficult in the highly mineralized extracellular matrix. We performed bioinformatic analysis of the molecular pathways underlying calcification in atherosclerotic and CKD patients, signaling pathways of collagen cross-links formation, and bone mineralization, and we propose new potential targets and review drugs for calcification treatment. PMID:23902273

  19. The Relationship between Frontotemporal Effective Connectivity during Picture Naming, Behavior, and Preserved Cortical Tissue in Chronic Aphasia.

    PubMed

    Meier, Erin L; Kapse, Kushal J; Kiran, Swathi

    2016-01-01

    While several studies of task-based effective connectivity of normal language processing exist, little is known about the functional reorganization of language networks in patients with stroke-induced chronic aphasia. During oral picture naming, activation in neurologically intact individuals is found in "classic" language regions involved with retrieval of lexical concepts [e.g., left middle temporal gyrus (LMTG)], word form encoding [e.g., left posterior superior temporal gyrus, (LpSTG)], and controlled retrieval of semantic and phonological information [e.g., left inferior frontal gyrus (LIFG)] as well as domain-general regions within the multiple demands network [e.g., left middle frontal gyrus (LMFG)]. After stroke, lesions to specific parts of the left hemisphere language network force reorganization of this system. While individuals with aphasia have been found to recruit similar regions for language tasks as healthy controls, the relationship between the dynamic functioning of the language network and individual differences in underlying neural structure and behavioral performance is still unknown. Therefore, in the present study, we used dynamic causal modeling (DCM) to investigate differences between individuals with aphasia and healthy controls in terms of task-induced regional interactions between three regions (i.e., LIFG, LMFG, and LMTG) vital for picture naming. The DCM model space was organized according to exogenous input to these regions and partitioned into separate families. At the model level, random effects family wise Bayesian Model Selection revealed that models with driving input to LIFG best fit the control data whereas models with driving input to LMFG best fit the patient data. At the parameter level, a significant between-group difference in the connection strength from LMTG to LIFG was seen. Within the patient group, several significant relationships between network connectivity parameters, spared cortical tissue, and behavior were

  20. The Relationship between Frontotemporal Effective Connectivity during Picture Naming, Behavior, and Preserved Cortical Tissue in Chronic Aphasia

    PubMed Central

    Meier, Erin L.; Kapse, Kushal J.; Kiran, Swathi

    2016-01-01

    While several studies of task-based effective connectivity of normal language processing exist, little is known about the functional reorganization of language networks in patients with stroke-induced chronic aphasia. During oral picture naming, activation in neurologically intact individuals is found in “classic” language regions involved with retrieval of lexical concepts [e.g., left middle temporal gyrus (LMTG)], word form encoding [e.g., left posterior superior temporal gyrus, (LpSTG)], and controlled retrieval of semantic and phonological information [e.g., left inferior frontal gyrus (LIFG)] as well as domain-general regions within the multiple demands network [e.g., left middle frontal gyrus (LMFG)]. After stroke, lesions to specific parts of the left hemisphere language network force reorganization of this system. While individuals with aphasia have been found to recruit similar regions for language tasks as healthy controls, the relationship between the dynamic functioning of the language network and individual differences in underlying neural structure and behavioral performance is still unknown. Therefore, in the present study, we used dynamic causal modeling (DCM) to investigate differences between individuals with aphasia and healthy controls in terms of task-induced regional interactions between three regions (i.e., LIFG, LMFG, and LMTG) vital for picture naming. The DCM model space was organized according to exogenous input to these regions and partitioned into separate families. At the model level, random effects family wise Bayesian Model Selection revealed that models with driving input to LIFG best fit the control data whereas models with driving input to LMFG best fit the patient data. At the parameter level, a significant between-group difference in the connection strength from LMTG to LIFG was seen. Within the patient group, several significant relationships between network connectivity parameters, spared cortical tissue, and behavior were

  1. Immunohistochemical detection of active transforming growth factor-beta in situ using engineered tissue

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Ehrhart, E. J.; Kalia, M.; Jirtle, R.; Flanders, K.; Tsang, M. L.; Chatterjee, A. (Principal Investigator)

    1995-01-01

    The biological activity of transforming growth factor-beta 1 (TGF-beta) is governed by dissociation from its latent complex. Immunohistochemical discrimination of active and latent TGF-beta could provide insight into TGF-beta activation in physiological and pathological processes. However, evaluation of immunoreactivity specificity in situ has been hindered by the lack of tissue in which TGF-beta status is known. To provide in situ analysis of antibodies to differentiate between these functional forms, we used xenografts of human tumor cells modified by transfection to overexpress latent TGF-beta or constitutively active TGF-beta. This comparison revealed that, whereas most antibodies did not differentiate between TGF-beta activation status, the immunoreactivity of some antibodies was activation dependent. Two widely used peptide antibodies to the amino-terminus of TGF-beta, LC(1-30) and CC(1-30) showed marked preferential immunoreactivity with active TGF-beta versus latent TGF-beta in cryosections. However, in formalin-fixed, paraffin-embedded tissue, discrimination of active TGF-beta by CC(1-30) was lost and immunoreactivity was distinctly extracellular, as previously reported for this antibody. Similar processing-dependent extracellular localization was found with a neutralizing antibody raised to recombinant TGF-beta. Antigen retrieval recovered cell-associated immunoreactivity of both antibodies. Two antibodies to peptides 78-109 showed mild to moderate preferential immunoreactivity with active TGF-beta only in paraffin sections. LC(1-30) was the only antibody tested that discriminated active from latent TGF-beta in both frozen and paraffin-embedded tissue. Thus, in situ discrimination of active versus latent TGF-beta depends on both the antibody and tissue preparation. We propose that tissues engineered to express a specific form of a given protein provide a physiological setting in which to evaluate antibody reactivity with specific functional forms of a

  2. Mixture theory-based poroelasticity as a model of interstitial tissue growth.

    PubMed

    Cowin, Stephen C; Cardoso, Luis

    2012-01-01

    This contribution presents an alternative approach to mixture theory-based poroelasticity by transferring some poroelastic concepts developed by Maurice Biot to mixture theory. These concepts are a larger RVE and the subRVE-RVE velocity average tensor, which Biot called the micro-macro velocity average tensor. This velocity average tensor is assumed here to depend upon the pore structure fabric. The formulation of mixture theory presented is directed toward the modeling of interstitial growth, that is to say changing mass and changing density of an organism. Traditional mixture theory considers constituents to be open systems, but the entire mixture is a closed system. In this development the mixture is also considered to be an open system as an alternative method of modeling growth. Growth is slow and accelerations are neglected in the applications. The velocity of a solid constituent is employed as the main reference velocity in preference to the mean velocity concept from the original formulation of mixture theory. The standard development of statements of the conservation principles and entropy inequality employed in mixture theory are modified to account for these kinematic changes and to allow for supplies of mass, momentum and energy to each constituent and to the mixture as a whole. The objective is to establish a basis for the development of constitutive equations for growth of tissues. PMID:22184481

  3. Modeling the coupled mechanics, transport, and growth processes in collagen tissues.

    SciTech Connect

    Holdych, David J.; Nguyen, Thao D.; Klein, Patrick A.; in't Veld, Pieter J.; Stevens, Mark Jackson

    2006-11-01

    The purpose of this project is to develop tools to model and simulate the processes of self-assembly and growth in biological systems from the molecular to the continuum length scales. The model biological system chosen for the study is the tendon fiber which is composed mainly of Type I collagen fibrils. The macroscopic processes of self-assembly and growth at the fiber scale arise from microscopic processes at the fibrillar and molecular length scales. At these nano-scopic length scales, we employed molecular modeling and simulation method to characterize the mechanical behavior and stability of the collagen triple helix and the collagen fibril. To obtain the physical parameters governing mass transport in the tendon fiber we performed direct numerical simulations of fluid flow and solute transport through an idealized fibrillar microstructure. At the continuum scale, we developed a mixture theory approach for modeling the coupled processes of mechanical deformation, transport, and species inter-conversion involved in growth. In the mixture theory approach, the microstructure of the tissue is represented by the species concentration and transport and material parameters, obtained from fibril and molecular scale calculations, while the mechanical deformation, transport, and growth processes are governed by balance laws and constitutive relations developed within a thermodynamically consistent framework.

  4. Mixture theory-based poroelasticity as a model of interstitial tissue growth

    PubMed Central

    Cowin, Stephen C.; Cardoso, Luis

    2011-01-01

    This contribution presents an alternative approach to mixture theory-based poroelasticity by transferring some poroelastic concepts developed by Maurice Biot to mixture theory. These concepts are a larger RVE and the subRVE-RVE velocity average tensor, which Biot called the micro-macro velocity average tensor. This velocity average tensor is assumed here to depend upon the pore structure fabric. The formulation of mixture theory presented is directed toward the modeling of interstitial growth, that is to say changing mass and changing density of an organism. Traditional mixture theory considers constituents to be open systems, but the entire mixture is a closed system. In this development the mixture is also considered to be an open system as an alternative method of modeling growth. Growth is slow and accelerations are neglected in the applications. The velocity of a solid constituent is employed as the main reference velocity in preference to the mean velocity concept from the original formulation of mixture theory. The standard development of statements of the conservation principles and entropy inequality employed in mixture theory are modified to account for these kinematic changes and to allow for supplies of mass, momentum and energy to each constituent and to the mixture as a whole. The objective is to establish a basis for the development of constitutive equations for growth of tissues. PMID:22184481

  5. Growth differentiation factor 6 derived from mesenchymal stem/stromal cells reduces age-related functional deterioration in multiple tissues

    PubMed Central

    Hisamatsu, Daisuke; Ohno-Oishi, Michiko; Nakamura, Shiho; Mabuchi, Yo; Naka-Kaneda, Hayato

    2016-01-01

    The senescence-associated secretory phenotype (SASP) has attracted attention as a mechanism that connects cellular senescence to tissue dysfunction, and specific SASP factors have been identified as systemic pro-aging factors. However, little is known about the age-dependent changes in the secretory properties of stem cells. Young, but not old, mesenchymal stem/stromal cells (MSCs) are a well-known source of critical regenerative factors, but the identity of these factors remains elusive. In this study, we identified growth differentiation factor 6 (Gdf6; also known as Bmp13 and CDMP-2) as a regenerative factor secreted from young MSCs. The expression of specific secretory factors, including Gdf6, was regulated by the microRNA (miRNA) miR-17, whose expression declined with age. Upregulation of Gdf6 restored the osteogenic capacity of old MSCs in vitro and exerted positive effects in vivo on aging-associated pathologies such as reduced lymphopoiesis, insufficient muscle repair, reduced numbers of neural progenitors in the brain, and chronic inflammation. Our results suggest that manipulation of miRNA could enable control of the SASP, and that regenerative factors derived from certain types of young cells could be used to treat geriatric diseases. PMID:27311402

  6. Identification of Genes Related to Growth and Lipid Deposition from Transcriptome Profiles of Pig Muscle Tissue

    PubMed Central

    Chamba, Yangzom; Zhang, Bo; Shang, Peng; Zhang, Hao; Wu, Changxin

    2015-01-01

    Transcriptome profiles established using high-throughput sequencing can be effectively used for screening genome-wide differentially expressed genes (DEGs). RNA sequences (from RNA-seq) and microRNA sequences (from miRNA-seq) from the tissues of longissimus dorsi muscle of two indigenous Chinese pig breeds (Diannan Small-ear pig [DSP] and Tibetan pig [TP]) and two introduced pig breeds (Landrace [LL] and Yorkshire [YY]) were examined using HiSeq 2000 to identify and compare the differential expression of functional genes related to muscle growth and lipid deposition. We obtained 27.18 G clean data through the RNA-seq and detected that 18,208 genes were positively expressed and 14,633 of them were co-expressed in the muscle tissues of the four samples. In all, 315 DEGs were found between the Chinese pig group and the introduced pig group, 240 of which were enriched with functional annotations from the David database and significantly enriched in 27 Gene Ontology (GO) terms that were mainly associated with muscle fiber contraction, cadmium ion binding, response to organic substance and contractile fiber part. Based on functional annotation, we identified 85 DEGs related to growth traits that were mainly involved in muscle tissue development, muscle system process, regulation of cell development, and growth factor binding, and 27 DEGs related to lipid deposition that were mainly involved in lipid metabolic process and fatty acid biosynthetic process. With miRNA-seq, we obtained 23.78 M reads and 320 positively expressed miRNAs from muscle tissues, including 271 known pig miRNAs and 49 novel miRNAs. In those 271 known miRNAs, 20 were higher and 10 lower expressed in DSP-TP than in LL-YY. The target genes of the 30 miRNAs were mainly participated in MAPK, GnRH, insulin and Calcium signaling pathway and others involved cell development, growth and proliferation, etc. Combining the DEGs and the differentially expressed (DE) miRNAs, we drafted a network of 46 genes and 18

  7. Wbp2 cooperates with Yorkie to drive tissue growth downstream of the Salvador–Warts–Hippo pathway

    PubMed Central

    Zhang, X; Milton, C C; Poon, C L C; Hong, W; Harvey, K F

    2011-01-01

    The Salvador–Warts–Hippo (SWH) pathway is a key controller of tissue growth in both flies and mammals, and deregulation of pathway activity contributes to tumour formation. The SWH pathway regulates cell growth, proliferation and apoptosis by restricting activity of the Yorkie transcriptional co-activator protein. The proteins that function together with Yorkie to drive transcription and tissue growth are beginning to be revealed and include the Scalloped (Sd), Teashirt (Tsh) and Homothorax (Hth) transcription factors. In this study, we define Wbp2 as a promoter of Yorkie-dependent growth of Drosophila melanogaster tissues. Mammalian WBP2 was previously identified as a protein that interacts with the mammalian Yorkie homologue, Yes-associated protein. WBP2 has been shown to enhance steroid hormone-dependent transcription in cultured cells but its in vivo function has remained obscure. We show that D. melanogaster Wbp2 interacts with Yorkie in a WW domain- and PY motif-dependent manner and that Wbp2 can enhance Yorkie's transcriptional co-activator properties. In vivo, Wbp2 is required for growth of the D. melanogaster wing, and reduction of Wbp2 expression suppresses overgrowth of tissues that lack the warts growth-suppressive gene. Collectively, these studies define an important role for Wbp2 as a downstream component of the SWH tissue growth-control pathway. PMID:21311569

  8. Root coverage using subepithelial connective tissue graft with platelet-rich plasma in the treatment of gingival recession: A clinical study

    PubMed Central

    Srinivas, B. V. V.; Rupa, N.; Halini Kumari, K. V.; Prasad, S. S. V.; Varalakshmi, U.; Sudhakar, K.

    2015-01-01

    Introduction: The presence of gingival recession associated with an insufficient amount of keratinized tissue may indicate gingival augmentation procedure. It is a multifaceted problem for which several treatment options are available. The most predictable technique used for gingival augmentation is the subepithelial connective tissue graft (SCTG). Platelet-rich plasma (PRP) is an enhanced source of growth factors and helps in accelerated periodontal repair and regeneration. Aims: The aim of this study was to evaluate the efficacy of SCTG along with PRP in the treatment of Miller's class I and II gingival recessions. Materials and Methods: Eleven subjects with Miller's class I and II gingival recessions were treated using SCTG with PRP. Clinical variables, including plaque index, gingival index, recession depth (RD), Recession width (RW), width of the keratinized gingiva, probing pocket depth (PD) and clinical attachment level (CAL) were recorded. Patients were recalled at baseline, 3 months, 6 months and 1-year after surgery and clinical recordings were taken. Root coverage percentage (%) was measured at the end of 1-year. Results: The clinical parameters were analyzed during the follow-up period by repeated measures ANOVA test. Twelve months follow-up results showed significant improvements in all the clinical parameters. Reduction of recession resulted in a significant decrease in CAL, PD, RW and RD at the end of 12 months. A statistically significant gain in width of keratinized gingiva and a mean root coverage of 84.72 ± 19.10 was obtained at the end of 12 months. Conclusion: From the results of this study, it may be concluded that SCTG with PRP is an effective and predictable method to treat miller's class I and II gingival recession. PMID:26538912

  9. Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth

    PubMed Central

    Nakazawa, Michael S.; Eisinger-Mathason, T. S. Karin; Sadri, Navid; Ochocki, Joshua D.; Gade, Terence P. F.; Amin, Ruchi K.; Simon, M. Celeste

    2016-01-01

    In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1α mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2α protein is unknown. Surprisingly, here we show that HIF-2α inhibits high-grade STS cell growth in vivo, as loss of HIF-2α promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. We find that most human STS have lower levels of EPAS1 (the gene encoding HIF-2α) expression relative to normal tissue. Many cancers, including STS, contain altered epigenetics, and our findings define an epigenetic mechanism whereby EPAS1 is silenced during sarcoma progression. The clinically approved HDAC inhibitor Vorinostat specifically increases HIF-2α, but not HIF-1α, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2α deletion, implicating HIF-2α as a biomarker for Vorinostat efficacy in STS. PMID:26837714

  10. Suppression of Rous Sarcoma Virus Growth in Tissue Cultures by Mycoplasma orale

    PubMed Central

    Somerson, Norman L.; Cook, M. K.

    1965-01-01

    Somerson, Norman L. (National Institute of Allergy and Infectious Diseases, Bethesda, Md.), and M. K. Cook. Suppression of Rous sarcoma virus growth in tissue cultures by Mycoplasma orale. J. Bacteriol. 90:534–540. 1965.—An agent which produced cell destruction in human diploid and chick-embryo fibroblasts was isolated from WI-26 strain of human diploid fibroblasts and shown to be a mycoplasma. The multiplication of Rous sarcoma virus (RSV) and Rous associated virus (RAV) was inhibited in WI-26, WI-38, and chick-embryo fibroblasts infected with this mycoplasma. The mycoplasma isolate, designated strain 941, reacted strongly in the complement-fixation test with antiserum to Mycoplasma orale CH19299, an isolate obtained from the human oral cavity. The cytopathic effect of mycoplasma strain 941 could be eliminated by growing the mycoplasma on an artificial agar medium before inoculation into chick-embryo fibroblasts. Serial passage in chick-embryo fibroblasts restored the cytopathogenicity of the agar-grown mycoplasma. However, growth of RSV and RAV was inhibited by both the tissue culture-grown and the agar-grown 941 strain, and also by the CH19299 strain which did not produce any cytopathic effect. Images PMID:14329470

  11. Epigenetic re-expression of HIF-2α suppresses soft tissue sarcoma growth.

    PubMed

    Nakazawa, Michael S; Eisinger-Mathason, T S Karin; Sadri, Navid; Ochocki, Joshua D; Gade, Terence P F; Amin, Ruchi K; Simon, M Celeste

    2016-01-01

    In soft tissue sarcomas (STS), low intratumoural O2 (hypoxia) is a poor prognostic indicator. HIF-1α mediates key transcriptional responses to hypoxia, and promotes STS metastasis; however, the role of the related HIF-2α protein is unknown. Surprisingly, here we show that HIF-2α inhibits high-grade STS cell growth in vivo, as loss of HIF-2α promotes sarcoma proliferation and increases calcium and mTORC1 signalling in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. We find that most human STS have lower levels of EPAS1 (the gene encoding HIF-2α) expression relative to normal tissue. Many cancers, including STS, contain altered epigenetics, and our findings define an epigenetic mechanism whereby EPAS1 is silenced during sarcoma progression. The clinically approved HDAC inhibitor Vorinostat specifically increases HIF-2α, but not HIF-1α, accumulation in multiple STS subtypes. Vorinostat inhibits STS tumour growth, an effect ameliorated by HIF-2α deletion, implicating HIF-2α as a biomarker for Vorinostat efficacy in STS. PMID:26837714

  12. Development of luminescent pH sensor films for monitoring bacterial growth through tissue

    PubMed Central

    Wang, Fenglin; Raval, Yash; Chen, Hongyu; Tzeng, Tzuen-Rong J.; DesJardins, John D.

    2014-01-01

    Although implanted medical devices (IMDs) offer many benefits, they are susceptible to bacterial colonization and infections. Such infections are difficult to treat because bacteria could form biofilms on the implant surface, which reduce antibiotics penetration and generate local dormant regions with low pH and low oxygen. In addition, these infections are hard to detect early because biofilms are often localized on the surface. Herein, an optical sensor film is developed to detect local acidosis on an implanted surface. The film contains both upconverting particles (UCPs) that serve as a light source and a pH indicator that alters the luminescence spectrum. When irradiated with 980 nm light, the UCPs produce deeply penetrating red light emission, while generating negligible autofluorescence in the tissue. The basic form of the pH indicator absorbs more of upconversion luminescence at 661 nm than at 671 nm and consequently the spectral ratio indicates pH. Implanting this pH sensor film beneath 6-7 mm of porcine tissue does not substantially affect the calibration curve because the peaks are closely spaced. Furthermore, growth of Staphylococcus epidermidis on the sensor surface causes a local pH decrease that can be detected non-invasively through the tissue. PMID:23832869

  13. Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling

    PubMed Central

    Kamimoto, Kenji; Kaneko, Kota; Kok, Cindy Yuet-Yin; Okada, Hajime; Miyajima, Atsushi; Itoh, Tohru

    2016-01-01

    Dynamic remodeling of the intrahepatic biliary epithelial tissue plays key roles in liver regeneration, yet the cellular basis for this process remains unclear. We took an unbiased approach based on in vivo clonal labeling and tracking of biliary epithelial cells in the three-dimensional landscape, in combination with mathematical simulation, to understand their mode of proliferation in a mouse liver injury model where the nascent biliary structure formed in a tissue-intrinsic manner. An apparent heterogeneity among biliary epithelial cells was observed: whereas most of the responders that entered the cell cycle upon injury exhibited a limited and tapering growth potential, a select population continued to proliferate, making a major contribution in sustaining the biliary expansion. Our study has highlighted a unique mode of epithelial tissue dynamics, which depends not on a hierarchical system driven by fixated stem cells, but rather, on a stochastically maintained progenitor population with persistent proliferative activity. DOI: http://dx.doi.org/10.7554/eLife.15034.001 PMID:27431614

  14. Advances in the use of growth factors for treatment of disorders of soft tissues.

    PubMed

    Halper, Jaroslava

    2014-01-01

    Repair and healing of injured and diseased tendons have been traditionally fraught with apprehension and difficulties, and often lead to rather unsatisfactory results. The burgeoning research field of growth factors has opened new venues for treatment of tendon disorders and injuries, and possibly for treatment of disorders of the aorta and major arteries as well. Several chapters in this volume elucidate the role of transforming growth factor β in pathogenesis of several heritable disorders affecting soft tissues, such as aorta, cardiac valves, and tendons and ligaments. Several members of the bone morphogenetic group either have been approved by the FDA for treatment of non-healing fractures or have been undergoing intensive clinical and experimental testing for use in healing of bone fractures and tendon injuries. Because FGFs are involved in embryonic development of tendons and muscles among other tissues and organs the hope is that their testing would lead to the development of some new treatment strategies providing that we can control angiogenicity of these growth factors. The problem, or rather question regarding practical use of IGF-I in tendon repair is whether IGF-I acts independently or under the guidance of growth hormone. FGF2 or PDGF alone or in combination with IGF-I stimulated regeneration of periodontal ligament, a matter of importance in Marfan patients with periodontitis. In contrast, VEGF appears to have rather deleterious effect on experimental tendon healing, perhaps because of its angiogenic activity and stimulation of matrix metalloproteinases, proteases whose increased expression has been documented in a variety of ruptured tendons. Other modalities, such as local administration of platelet-rich plasma (PRP) and/or of mesenchymal stem cells have been explored extensively in tendon healing. Though treatment with PRP and mesenchymal stem cells has met with some success in horses (who experience a lot of tendon injuries and other tendon

  15. Vitamin D Status and Bone and Connective Tissue Turnover in Brown Bears (Ursus arctos) during Hibernation and the Active State

    PubMed Central

    Vestergaard, Peter; Støen, Ole-Gunnar; Swenson, Jon E.; Mosekilde, Leif; Heickendorff, Lene; Fröbert, Ole

    2011-01-01

    Background Extended physical inactivity causes disuse osteoporosis in humans. In contrast, brown bears (Ursus arctos) are highly immobilised for half of the year during hibernation without signs of bone loss and therefore may serve as a model for prevention of osteoporosis. Aim To study 25-hydroxy-vitamin D (25OHD) levels and bone turnover markers in brown bears during the hibernating state in winter and during the active state in summer. We measured vitamin D subtypes (D2 and D3), calcitropic hormones (parathyroid hormone [PTH], 1,25-dihydroxy-vitamin D [1,25(OH)2D]) and bone turnover parameters (osteocalcin, ICTP, CTX-I), PTH, serum calcium and PIIINP. Material and Methods We drew blood from seven immobilised wild brown bears during hibernation in February and in the same bears while active in June. Results Serum 25-hydroxy-cholecalciferol (25OHD3) was significantly higher in the summer than in the winter (22.8±4.6 vs. 8.8±2.1 nmol/l, two tailed p - 2p = 0.02), whereas 25-hydroxy-ergocalciferol (25OHD2) was higher in winter (54.2±8.3 vs. 18.7±1.7 nmol/l, 2p<0.01). Total serum calcium and PTH levels did not differ between winter and summer. Activated 1,25(OH)2D demonstrated a statistically insignificant trend towards higher summer levels. Osteocalcin levels were higher in summer than winter, whereas other markers of bone turnover (ICTP and CTX-I) were unchanged. Serum PIIINP, which is a marker of connective tissue and to some degree muscle turnover, was significantly higher during summer than during winter. Conclusions Dramatic changes were documented in the vitamin D3/D2 ratio and in markers of bone and connective tissue turnover in brown bears between hibernation and the active state. Because hibernating brown bears do not develop disuse osteoporosis, despite extensive physical inactivity we suggest that they may serve as a model for the prevention of this disease. PMID:21731765

  16. Heart rate recovery is an important predictor of outcomes in patients with connective tissue disease-associated pulmonary hypertension.

    PubMed

    Minai, Omar A; Nguyen, Quyen; Mummadi, Srinivas; Walker, Esteban; McCarthy, Kevin; Dweik, Raed A

    2015-09-01

    Reduced heart rate recovery (HRR) after exercise is associated with increased mortality in cardiac and pulmonary diseases. We sought to evaluate the association between HRR after the 6-minute walk test (6MWT) and outcomes in patients with connective tissue disease-associated pulmonary hypertension (CTD-PH). Data were obtained by review of the medical records. HRR was defined as the difference in heart rate at the end of the 6MWT and after 1 minute (HRR1), 2 minutes (HRR2), and 3 minutes (HRR3) of rest. All patients with pulmonary hypertension and a diagnosis of systemic sclerosis, systemic lupus erythematosus, or mixed connective tissue disease who underwent the 6MWT between August 1, 2009, and October 30, 2011, were included (n = 66). By Kaplan-Meier analysis, HRR1, HRR2, and HRR3 at different cutoff points were all good predictors, with HRR1 of <16 being the best predictor of time to clinical worsening (log-rank P < 0.0001), hospitalization (log-rank P = 0.0001), and survival (log-rank P < 0.003). By proportional hazards regression, patients with HRR1 of <16 were at increased risk of clinical worsening (hazard ratio [HR]: 6.4 [95% confidence interval (CI): 2.6-19.2]; P < 0.0001], hospitalization (HR: 6.6 [95% CI: 2.4-23]; P < 0.0001), and death (HR: 4.5 [95% CI: 1.6-15.7]; P = 0.003). Patients in the highest tercile (HRR1 of ≥19) were unlikely to have a clinical worsening event (HR: 0.1 [95% CI: 0.04-0.5]; P = 0.001], to be hospitalized (HR: 0.1 [95% CI: 0.02-0.5]; P = 0.001), or to die (HR: 0.3 [95% CI: 0.07-0.9]; P = 0.04]. In conclusion, in patients with CTD-PH, abnormal HRR1 (defined as HRR1 of <16) after the 6MWT is a strong predictor of clinical worsening, time to clinical worsening, survival, and hospitalization. PMID:26401258

  17. Clinical evaluation of expanded mesh connective tissue graft in the treatment for multiple adjacent gingival recessions in the esthetic zone

    PubMed Central

    Shanmugam, M.; Shivakumar, B.; Meenapriya, B.; Anitha, V.; Ashwath, B.

    2015-01-01

    Background: Multiple approaches have been used to replace lost, damaged or diseased gingival tissues. The connective tissue graft (CTG) procedure is the golden standard method for root coverage. Although multiple sites often need grafting, the palatal mucosa supplies only a limited area of grafting material. To overcome this limitation, expanded mesh graft provides a method whereby a graft can be stretched to cover a large area. The aim of this study was to evaluate the effectiveness and the predictability of expanded mesh CTG (e-MCTG) in the treatment of adjacent multiple gingival recessions. Materials and Methods: Sixteen patients aged 20–50 years contributed to 55 sites, each site falling into at least three adjacent Miller's Class 1 or Class 2 gingival recession. The CTG obtained from the palatal mucosa was expanded to cover the recipient bed, which was 1.5 times larger than the graft. Clinical measurements were recorded at baseline and 3 months, 12 months postoperatively. Results: A mean coverage of 1.96 mm ± 0.66 mm and 2.22 mm ± 0.68 mm was obtained at the end of 3rd and 12th month, respectively. Twelve months after surgery a statistically significant increase in CAL (2.2 mm ± 0.68 mm, P < 0.001) and increasing WKT (1.75 ± 0.78, P < 0.001) were obtained. In 80% of the treated sites, 100% root coverage was achieved (mean 93.5%). Conclusions: The results of this study demonstrated that multiple adjacent recessions were treated by using e-MCTG technique can be applied and highly predictable root coverage can be achieved. PMID:26321829

  18. Growth factor treated tensioned synoviocyte neotissues: towards meniscal bioscaffold tissue engineering.

    PubMed

    Warnock, J J; Bobe, G; Duesterdieck-Zellmer, K F; Spina, J; Ott, J; Baltzer, W I; Bay, B K

    2014-04-01

    Meniscal injury is a common cause of osteoarthritis, pain, and disability in dogs and humans, but tissue-engineered bioscaffolds could be a treatment option for meniscal deficiency. The objective of this study was to compare meniscus-like matrix histology, composition, and biomechanical properties of autologous tensioned synoviocyte neotissues (TSN) treated with fetal bovine serum (TSNfbs) or three chondrogenic growth factors (TSNgf). Fourth passage canine synoviocytes from 10 dogs were grown in hyperconfluent monolayer culture, formed into TSN, and then cultured for 3 weeks with 17.7% FBS or three human recombinant TSNgf (bFGF, TGF-β1, and IGF-1). Cell viability was determined with laser microscopy. Histological architecture and the composition of fibrocartilage matrix were evaluated in TSN by staining tissues for glycosaminoglycan (GAG), α-smooth muscle actin, and collagen 1 and 2; quantifying the content of GAG, DNA, and hydroxyproline; and measuring the gene expression of collagens type 1α and 2α, the GAG aggrecan, and transcription factor Sry-type Homeobox Protein-9 (SOX9). Biomechanical properties were determined by materials testing force-deformation curves. The TSN contained components and histological features of mensical fibrocartilage extracellular matrix. Growth factor-treated TSN had higher DNA content but lower cell viability than TSNfbs. TSNgf had greater fibrocartilage-like matrix content (collagen 2 and GAG content with increased collagen 2α and SOX9 gene expression). Additionally, TSNgf collagen was more organized histologically and so had greater tensile biomechanical properties. The results indicate the potential of TSN when cultured with growth factors as implantable bioscaffolds for the treatment of canine meniscal deficiency. PMID:24559744

  19. Epidermal growth factor receptor is overexpressed in neuroblastoma tissues and cells.

    PubMed

    Zheng, Chao; Shen, Ruling; Li, Kai; Zheng, Na; Zong, Yuqing; Ye, Danrong; Wang, Qingcheng; Wang, Zuopeng; Chen, Lian; Ma, Yangyang

    2016-08-01

    Neuroblastoma is the most common abdominal malignant tumor in childhood. Immunotoxin (IT) that targets the tumor cell surface receptor is a new supplementary therapeutic treatment approach. The purpose of this study is to detect the expression of epidermal growth factor receptor (EGFR) in neuroblastoma cell lines and tissues, and to explore if IT therapy can be used to treat refractory neuroblastoma. The EGFR expression in human neuroblastoma tissue samples was detected by immunohistochemistry staining. The positive rate of EGFR expression was 81.0% in neuroblastoma tissue and 50.0% in gangliocytoma, respectively, but without statistical significance between them (P > 0.05). The positive rate of EGFR expression in favorable type and unfavorable type was 62.5% and 92.3%, respectively, but they were not statistically different (P > 0.05). Results from pre-chemotherapy and post-chemotherapy samples showed that there was no significant statistical difference (P > 0.05) between them in the EGFR expression. Furthermore, the EGFR expression levels in five neuroblastoma cell lines were measured using cell-based ELISA assay and western blot analysis. The results showed that the expression of EGFR was higher in KP-N-NS and BE(2)-C than those in other cell lines. Our results revealed that there are consistent and widespread expressions of EGFR in neuroblastoma tissues as well as in neuroblastoma cell lines, suggesting that it is possible to develop future treatment strategies of neuroblastoma by targeting at the EGFR. PMID:27353319

  20. Effects of perchlorate on growth of four wetland plants and its accumulation in plant tissues.