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Sample records for connective tissue disease

  1. 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 ...

  2. 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

  3. [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

  4. 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

  5. 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

  6. 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

  7. [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

  8. [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

  9. 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

  10. 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

  11. 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

  12. [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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. [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

  20. 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

  1. 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

  2. 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

  3. Esophageal disorders in mixed connective tissue diseases.

    PubMed

    Nica, A E; Alexa, L M; Ionescu, A O; Andronic, O; Păduraru, D N

    2016-01-01

    Extra Musculoskeletal manifestations are a distinct clinical entity that refers to a combination of clinical features, which are found in multiple rheumatic diseases. Besides the standard manifestations, other organs can be damaged such as the vascular system, skin, gastrointestinal tract, musculoskeletal system, cardiopulmonary system, hematologic system, kidneys, and the central nervous system. Among the gastrointestinal MCTD symptoms, the most frequent are the esophageal ones. Treatment of patients with MCTD must be performed by both medical and surgical multidisciplinary teams in order to provide a management suitable for the patients' needs. All authors have contributed significantly and have been involved in the writing of the manuscript in draft and any revision stages, and have read and approved its final version. PMID:27453743

  4. [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

  5. 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

  6. 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

  7. 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

  8. 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

  9. [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

  10. 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

  11. 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

  12. 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

  13. 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

  14. [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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  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. Salivary secretion and connective tissue disease in man.

    PubMed Central

    Matthews, R W; Bhoola, K D; Rasker, J J; Jayson, M I

    1985-01-01

    Parotid and submandibular gland secretions collected from patients with rheumatoid arthritis or systemic sclerosis have been analysed and the results compared with those obtained from a matched group of healthy individuals. Flow rates were measured and the saliva samples assayed for amylase, kallikrein, protein, and salivary IgA concentration. The results showed that only patients with rheumatoid arthritis had a reduced salivary flow, especially parotid flow, with a significantly increased concentration of salivary IgA in both parotid and submandibular saliva. Patients with systemic sclerosis did not show significantly altered salivary flow rates, but there was a marked depletion of salivary IgA content in both parotid and submandibular saliva. Neither disease states appeared to alter the kallikrein or amylase content of saliva. The possible clinical value of these findings is discussed. Images PMID:2578776

  7. 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

  8. 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

  9. 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.

  10. 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 ...

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. [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

  3. 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

  4. [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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. [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

  10. [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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  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. 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

  1. 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

  2. [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

  3. 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.

  4. 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

  5. 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

  6. 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

  7. Autoantibodies to type II collagen: occurrence in rheumatoid arthritis, other arthritides, autoimmune connective tissue diseases, and chronic inflammatory syndromes.

    PubMed Central

    Choi, E K; Gatenby, P A; McGill, N W; Bateman, J F; Cole, W G; York, J R

    1988-01-01

    Serum IgG antibodies to native and denatured human type II collagen (Col II) were measured using an enzyme linked immunosorbent assay (ELISA). One hundred and thirty one patients with various forms of arthritis such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PSA). Reiter's Syndrome (RS), osteoarthritis (OA), and gout, 60 with autoimmune connective tissue disease, and 37 with the chronic inflammatory conditions--graft versus host disease and leprosy--were studied. With the exception of RS, PSA, OA, and gout, significant levels of Col II antibodies were detected in each disease group. Blocking studies with types I and II collagen on selected serum samples confirmed the specificity to native Col II, though some cross reactivity was apparent with denatured collagen. The patients with RA who were Col II antibody positive tended to fall into stage III of disease progression. There was, however, no correlation with rheumatoid factor, erythrocyte sedimentation rate, or disease duration and this, together with the finding that Col II antibodies are present in a wide array of diseases, makes their role in the pathogenesis of RA questionable. They may arise as a secondary disease perpetuating mechanism in some patients, or in turn may be an epiphenomenon secondary to generalised disturbed immunoregulation or B cell hyperreactivity, or both, that characterises these clinical conditions. PMID:3365030

  8. Reconciling Healthcare Professional and Patient Perspectives in the Development of Disease Activity and Response Criteria in Connective Tissue Disease Related Interstitial Lung Diseases

    PubMed Central

    Saketkoo, LA; Mittoo, S; Frankel, S; LeSage, D; Sarver, C; Phillips, K; Strand, V; Matteson, EL

    2015-01-01

    Interstitial lung diseases (ILD), including connective tissue disease (CTD) related and idiopathic pulmonary fibrosis (IPF), carry a high morbidity and mortality. Great efforts are underway to develop and investigate meaningful treatments in the context of clinical trials. However, these efforts have been challenged by the lack of validated outcome measures and inconsistent use of measures in the context of clinical trials. This lack of consensus has fragmented effective use of investigative in CTD-ILD and IPF with a history of resultant difficulties in agency approval of treatment interventions. Patient perspective in determination of domains and outcome measures in CTD-ILD and IPF, prior to this effort, has never occurred. These efforts demonstrate unequivocally the value and impact of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/co-morbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF. PMID:24488412

  9. Clinical and Immunologic Manifestations of Mixed Connective Tissue Disease in a Miami Population Compared to a Midwestern US Caucasian Population

    PubMed Central

    Maldonado, Marcos E.; Perez, Magdalena; Pignac-Kobinger, Judith; Marx, Emily Triana; Tozman, Elaine M.; Greidinger, Eric L.; Hoffman, Robert W.

    2010-01-01

    Objective A cross-sectional study of mixed connective tissue disease (MCTD) was performed to determine if there were identifiable differences in the clinical expression of MCTD associated with race or ethnicity. Methods Miami, Florida, and Midwestern US (Missouri) Caucasian MCTD cohorts were studied. Clinical and laboratory features of the 2 MCTD cohorts were compared. A concurrently collected cohort of Sm-positive patients with systemic lupus erythematosus (SLE) was studied as a control. Disease activity and severity and functional status were measured. CD4+CD25high-expressing T-regulatory cells were enumerated and serum soluble L selectin was measured as biomarkers of disease activity. Results The Miami and Missouri Caucasian MCTD groups, while differing from the SLE group, were largely similar; however, gastroesophageal reflux, sclerodactyly, and malar rash were significantly more frequent in the Missouri MCTD group and alopecia was more frequent in the Miami MCTD group. Significant clinical and laboratory differences were found between the Miami MCTD and Miami SLE groups despite similar disease duration, activity, severity and functional status. Raynaud's phenomenon (RP), hand swelling, synovitis, myositis, and sclerodactyly were all significantly more common in RNP-positive MCTD versus Sm-positive SLE subjects. Conclusion Ethnic differences were observed in the frequency of end-organ involvement in the Miami MCTD versus the Missouri Caucasian MCTD groups. Clinical and laboratory features of all MCTD groups were clearly different from the SLE group, despite similar disease activity, disease severity, and functional status. Disease activity measures appeared to behave similarly as valid measures of disease activity in SLE and MCTD. PMID:18260175

  10. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

    PubMed Central

    Saketkoo, Lesley Ann; Mittoo, Shikha; Huscher, Dörte; Khanna, Dinesh; Dellaripa, Paul F; Distler, Oliver; Flaherty, Kevin R; Frankel, Sid; Oddis, Chester V; Denton, Christopher P; Fischer, Aryeh; Kowal-Bielecka, Otylia M; LeSage, Daphne; Merkel, Peter A; Phillips, Kristine; Pittrow, David; Swigris, Jeffrey; Antoniou, Katerina; Baughman, Robert P; Castelino, Flavia V; Christmann, Romy B; Christopher-Stine, Lisa; Collard, Harold R; Cottin, Vincent; Danoff, Sonye; Highland, Kristin B; Hummers, Laura; Shah, Ami A; Kim, Dong Soon; Lynch, David A; Miller, Frederick W; Proudman, Susanna M; Richeldi, Luca; Ryu, Jay H; Sandorfi, Nora; Sarver, Catherine; Wells, Athol U; Strand, Vibeke; Matteson, Eric L; Brown, Kevin K; Seibold, James R

    2014-01-01

    Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field. PMID:24368713

  11. Connective tissue disease-associated interstitial pneumonia and idiopathic interstitial pneumonia: similarity and difference.

    PubMed

    Bryson, Thomas; Sundaram, Baskaran; Khanna, Dinesh; Kazerooni, Ella A

    2014-02-01

    Interstitial lung diseases (ILDs) are increasingly recognized in patients with systemic diseases. Patients with early ILD changes may be asymptomatic. Features of ILD overlap among systemic diseases and with idiopathic variety. High-resolution computed tomography plays a central role in diagnosing ILDs. Imaging features are often nonspecific. Therapy- and complication-related lung changes would pose difficulty in diagnosing and classifying an ILD. Biology and prognosis of secondary ILDs may differ between different disease-related ILDs and idiopathic variety. Combination of clinical features, serological tests, pulmonary and extrapulmonary imaging findings, and pathology findings may help to diagnose ILDs. PMID:24480141

  12. 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

  13. The Prevalence of Atherosclerosis in Those with Inflammatory Connective Tissue Disease by Race, Age, and Traditional Risk Factors

    PubMed Central

    Alenghat, Francis J.

    2016-01-01

    Systemic inflammation promotes cardiovascular disease. Inflammatory connective tissue diseases (CTD) like lupus and rheumatoid arthritis associate with cardiovascular risk, but it is unknown whether particular groups of patients have enhanced propensity for atherosclerotic cardiovascular disease (ASCVD) associated with their CTD. Analysis of aggregate health record data at a large U.S. academic center identified CTD and ASCVD status for 287,467 African American and white adults. ASCVD prevalence in those with CTD was 29.7% for African Americans and 14.7% for white patients with prevalence ratios, compared to those without CTD, of 3.1 and 1.8, respectively. When different types of CTD were analyzed individually (rheumatoid arthritis; lupus; scleroderma; Sjögren Syndrome; dermatomyositis/polymyositis; unspecified/mixed CTD; other inflammatory arthropathy), increased ASCVD rates were found in nearly all subsets, always with higher prevalence ratios in African Americans. The prevalence ratio of ASCVD was particularly high in young African Americans. Furthermore, individuals lacking traditional cardiovascular risk factors had more ASCVD if they had CTD (prevalence ratio 2.9). Multivariate analysis confirmed a positive interaction between CTD and African-American race and a negative interaction between CTD and age. The factors driving the observed disproportionate CTD-associated ASCVD in African Americans, young adults, and those without traditional risk factors warrant further study. PMID:26842423

  14. The Prevalence of Atherosclerosis in Those with Inflammatory Connective Tissue Disease by Race, Age, and Traditional Risk Factors.

    PubMed

    Alenghat, Francis J

    2016-01-01

    Systemic inflammation promotes cardiovascular disease. Inflammatory connective tissue diseases (CTD) like lupus and rheumatoid arthritis associate with cardiovascular risk, but it is unknown whether particular groups of patients have enhanced propensity for atherosclerotic cardiovascular disease (ASCVD) associated with their CTD. Analysis of aggregate health record data at a large U.S. academic center identified CTD and ASCVD status for 287,467 African American and white adults. ASCVD prevalence in those with CTD was 29.7% for African Americans and 14.7% for white patients with prevalence ratios, compared to those without CTD, of 3.1 and 1.8, respectively. When different types of CTD were analyzed individually (rheumatoid arthritis; lupus; scleroderma; Sjögren Syndrome; dermatomyositis/polymyositis; unspecified/mixed CTD; other inflammatory arthropathy), increased ASCVD rates were found in nearly all subsets, always with higher prevalence ratios in African Americans. The prevalence ratio of ASCVD was particularly high in young African Americans. Furthermore, individuals lacking traditional cardiovascular risk factors had more ASCVD if they had CTD (prevalence ratio 2.9). Multivariate analysis confirmed a positive interaction between CTD and African-American race and a negative interaction between CTD and age. The factors driving the observed disproportionate CTD-associated ASCVD in African Americans, young adults, and those without traditional risk factors warrant further study. PMID:26842423

  15. 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

  16. Mitochondrial antibodies in chronic liver diseases and connective tissue disorders: further characterization of the autoantigens.

    PubMed Central

    Meek, F; Khoury, E L; Doniach, D; Baum, H

    1980-01-01

    The heterogeneity of mitochrondrial autoantibodies in a variety of diseases states has been critically re-examined by a combination of immunofluorescence staining (IFL) and complement fixation tests (CFT). The different mitochondrial IFL patterns described by other workers were confirmed and extra criteria using new substrates are presented for their differential recognition. Biochemically defined mitochondrial subfractions were used in the CFT to confirm and extend the IFL classifications. The 'M1' cardiolipin antibodies of syphilis did not react with the ATPase fraction but the antigen was present in all membrane preparations and found to be chemically resistant. The major antibody specificity of the 'M3' pattern associated with drug-induced pseudolupus syndrome is a firmly bound, outer membrane component; and a second, minor reactivity is apparently to a mercurial-insensitive antigen present in the chloroform-released ATPase preparation. The 'M5' antibody pattern correlates with a digitonin-sensitive outer membrane component. Although it was not possible to differentiate within the group of liver diseases between the 'M2' antibodies of primary biliary cirrhosis and the previously described 'M4' antibodies of other chronic liver diseases, several antibody specificities were demonstrated. All sera from liver disease patients contain the antibody directed against a mercurial-sensitive protein found in the chloroform-released ATPase preparation, and, in addition, varying titres of antibodies against two or more mercurial-resistant membrane components, of which at least one is on the inner membrane and one on the outer membrane. Images Fig. 3 PMID:6449333

  17. 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

  18. Personal Authentication Analysis Using Finger-Vein Patterns in Patients with Connective Tissue Diseases—Possible Association with Vascular Disease and Seasonal Change -

    PubMed Central

    Kono, Miyuki; Miura, Naoto; Fujii, Takao; Ohmura, Koichiro; Yoshifuji, Hajime; Yukawa, Naoichiro; Imura, Yoshitaka; Nakashima, Ran; Ikeda, Takaharu; Umemura, Shin-ichiro; Miyatake, Takafumi; Mimori, Tsuneyo

    2015-01-01

    Objective To examine how connective tissue diseases affect finger-vein pattern authentication. Methods The finger-vein patterns of 68 patients with connective tissue diseases and 24 healthy volunteers were acquired. Captured as CCD (charge-coupled device) images by transmitting near-infrared light through fingers, they were followed up in once in each season for one year. The similarity of the follow-up patterns and the initial one was evaluated in terms of their normalized cross-correlation C. Results The mean C values calculated for patients tended to be lower than those calculated for healthy volunteers. In midwinter (February in Japan) they showed statistically significant reduction both as compared with patients in other seasons and as compared with season-matched healthy controls, whereas the values calculated for healthy controls showed no significant seasonal changes. Values calculated for patients with systemic sclerosis (SSc) or mixed connective tissue disease (MCTD) showed major reductions in November and, especially, February. Patients with rheumatoid arthritis (RA) and patients with dermatomyositis or polymyositis (DM/PM) did not show statistically significant seasonal changes in C values. Conclusions Finger-vein patterns can be used throughout the year to identify patients with connective tissue diseases, but some attention is needed for patients with advanced disease such as SSc. PMID:26701644

  19. Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study.

    PubMed

    Oguz, Ekin Oktay; Kucuksahin, Orhan; Turgay, Murat; Yildizgoren, Mustafa Turgut; Ates, Askin; Demir, Nalan; Kumbasar, Ozlem Ozdemir; Kinikli, Gulay; Duzgun, Nursen

    2016-03-01

    It was aimed to evaluate KL-6 glycoprotein levels to determine if it may be a diagnostic marker for the connective tissue diseases (CTDs) predicting CTD-related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between patients and healthy controls. The study included 113 patients with CTD (45 CTD without lung involvement, 68 CTD-ILD) and 45 healthy control subjects. KL-6 glycoprotein levels were analyzed with ELISA in patients and the control group. The relationship between KL-6 glycoprotein levels and CTD-ILD was assessed. In the comparison of all the groups in the study, significantly higher levels of KL-6 were determined in the CTD-ILD group than in either the CTD without pulmonary involvement group or the healthy control group (p < 0.008 and p < 0.001, respectively). There was no statistically significant difference between the KL-6 levels in the healthy control group and the CTD without pulmonary involvement group (p = 0.289). The KL-6 levels did not differ significantly according to the connective tissue diseases in the diagnostic groups (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease, scleroderma, polymyositis/ dermatomyositis). In the healthy control group, there was a statistically significant difference between KL-6 levels in smokers and non-smokers. Smokers had significantly higher serum KL-6 levels compared with non-smokers (p < 0.05). There was no statistically significant difference between smoking status (pack-year) and serum KL-6 levels. There was no statistically significant correlation between serum KL-6 levels and time since diagnosis of CTD and CTD-ILD. The level of KL-6 as a predictive factor could be used to identify the clinical development of ILD before it is detected on imaging modality. Further prospective clinical studies are needed to define whether levels of KL-6 might have prognostic value or might predict

  20. Thrombotic thrombocytopenic purpura in the presence of connective tissue disease and HIV infection: A diagnostic and therapeutic challenge in a resource- constrained setting.

    PubMed

    Perumal, Rubeshan; Marais, Johannes Alexander; Brown, Susan

    2016-01-01

    Thrombotic thrombocytopenic purpura is a catastrophic disease and may occur in the presence of other confounding diseases. We present a case of TTP in a patient with connective tissue disease and HIV infection, in whom the diagnosis and management of TTP was challenging. It is important to understand the various underlying mechanisms that drive TTP in the presence of these comorbid diseases, so that an appropriate treatment strategy can be initiated. Our patient failed an initial trial of plasma infusion alone, but responded well to plasma exchange. PMID:27245723

  1. Assessment of the level of vaccine-induced anti-HBs antibodies in children with inflammatory systemic connective tissue diseases treated with immunosuppression

    PubMed Central

    Hernik, Elżbieta; Kwiatkowska, Małgorzata; Rutkowska-Sak, Lidia; Kołodziejczyk, Beata; Gazda, Agnieszka

    2015-01-01

    Objectives Protective vaccinations are the most effective method of prevention of type B virus hepatitis. The aim of the study was to determine whether in children receiving immunosuppressive therapy due to inflammatory systemic connective tissue diseases the protective concentration of the anti-HBs antibodies produced after vaccination against type B virus hepatitis in infancy is maintained. Material and methods The concentration of anti-HBs antibodies was assessed in the sera of 50 children with inflammatory connective tissue diseases – 37 girls (74%) and 13 boys (26%), aged 1.5–17.5 years – during the immunosuppressive treatment, which lasted at least 6 months. The control group consisted of 50 healthy children – 28 girls (56%) and 22 boys (44%) aged 2–17 years. All children were vaccinated in infancy with Engerix B vaccine according to the 0–1–6 months schedule. The antibody concentration of ≥ 10 mIU/ml in patients is regarded as protective. Results No protective antibody concentrations were found in 25 cases (50%) in the group of diseased children and only in 2 children in the control group (4%). Conclusions The concentration of vaccine-induced antibodies should be assessed in children with inflammatory systemic connective tissue diseases and, in case of the absence of a protective concentration, revaccination should be started. The use of glucocorticosteroids, synthetic and biological disease-modifying antirheumatic drugs is no contraindication to vaccination against hepatitis B. PMID:27407228

  2. 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

  3. Patient Perspectives in OMERACT Provide an Anchor for Future Metric Development and Improved Approaches to Healthcare Delivery in Connective Tissue Disease Related Interstitial Lung Disease (CTD-ILD)

    PubMed Central

    Mittoo, Shikha; Frankel, Sid; LeSage, Daphne; Strand, Vibeke; Shah, Ami A.; Christopher-Stine, Lisa; Danoff, Sonye; Hummers, Laura K.; Swigris, Jeffery J.; Huscher, Dörte; Christensen, Angela M.; Cenac, Sophia L.; Erbil, Jen K.; Ferguson, Sancia; Garcia-Valladares, Ignacio; Grewal, Harmanjot K.; Orbai, Ana-Maria; Smith, Katherine Clegg; Tran, Maithy; Bingham, Clifton O.; Castelino, Flavia V.; Fischer, Aryeh; Saketkoo, Lesley Ann

    2015-01-01

    Objective The impact and natural history of connective tissue disease related interstitial lung disease (CTD-ILD) are poorly understood; and have not been previously described from the patient’s perspective. This investigation sought insight into CTD-ILD from the patients’ perspective to add to our knowledge of CTD-ILD, identify disease-specific areas of unmet need and gather potentially meaningful information towards development of disease-specific patient-reported outcome measures (PROMs). Methods A mixed methods design incorporating patient focus groups (FGs) querying disease progression and life impact followed by questionnaires with items of importance generated by >250 ILD specialists were implemented among CTD-ILD patients with rheumatoid arthritis, idiopathic inflammatory myopathies, systemic sclerosis, and other CTD subtypes. FG data were analyzed through inductive analysis with five independent analysts, including a patient research partner. Questionnaires were analyzed through Fisher’s Exact tests and hierarchal cluster analysis. Results Six multicenter FGs included 45 patients. Biophysiologic themes were cough and dyspnea, both pervasively impacting health related quality of life (HRQoL). Language indicating dyspnea was unexpected, unique and contextual. Psycho-social themes were Living with Uncertainty, Struggle over Self-Identity, and Self-Efficacy - with education and clinician communication strongly emphasised. All questionnaire items were rated ‘moderately’ to ‘extremely’ important with 10 items of highest importance identified by cluster analysis. Conclusion Patients with CTD-ILD informed our understanding of symptoms and impact on HRQoL. Cough and dyspnea are central to the CTD-ILD experience. Initial FGs have provided disease-specific content, context and language essential for reliable PROM development with questionnaires adding value in recognition of patients’ concerns. PMID:26568747

  4. Lupus erythematosus and localized scleroderma coexistent at the same sites: a rare presentation of overlap syndrome of connective-tissue diseases.

    PubMed

    Pascucci, Anabella; Lynch, Peter J; Fazel, Nasim

    2016-05-01

    Overlap syndromes are known to occur with connective-tissue diseases (CTDs). Rarely, the overlap occurs at the same tissue site. We report the case of a patient with clinical and histopathologic findings consistent with the presence of discoid lupus erythematosus (DLE) and localized scleroderma within the same lesions. Based on our case and other reported cases in the literature, the following features are common in patients with an overlap of lupus erythematosus (LE) and localized scleroderma: predilection for young women, photodistributed lesions, DLE, linear morphology clinically, and positivity along the dermoepidermal junction on direct immunofluorescence. Most patients showed good response to antimalarials, topical steroids, or systemic steroids. PMID:27274545

  5. Increased serum concentration of BAFF/APRIL and IgA2 subclass in patients with mixed connective tissue disease complicated by interstitial lung disease.

    PubMed

    Kaneko, Toshiyuki; Amano, Hirofumi; Kawano, Shinya; Minowa, Kentaro; Ando, Seiichiro; Watanabe, Takashi; Nakano, Soichiro; Suzuki, Jun; Morimoto, Shinji; Tokano, Yoshiaki; Takasaki, Yoshinari

    2014-03-01

    B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are known to be crucial for B cell maturation and survival, and increased expression of these factors in various autoimmune diseases has been reported. Human B cells produce two IgA subclasses: IgA1 and IgA2, the latter being abundant in the distal intestine, saliva, colostrum and bronchial fluid. We investigated these parameters in patients with mixed connective tissue disease (MCTD) complicated by interstitial lung disease (ILD+), and compared them with those in MCTD patients without ILD (ILD-). Sixty-three MCTD patients were divided into two groups: 21 ILD+ patients and 42 ILD- patients. In each patient group we analyzed soluble BAFF/APRIL using ELISA, and IgA1 and IgA2 using double immunodiffusion. Furthermore, we analyzed BAFF-APRIL receptors, BCMA, BAFF-R and TACI, using flow cytometry. The ILD+ patients had significantly higher levels of BAFF/APRIL than the ILD- patients. There were significant correlations between BAFF/APRIL, BAFF/KL-6 and APRIL/KL-6. Although there was no significant inter-group difference in the serum IgA1 level, ILD+ patients had a significantly elevated IgA2 level in comparison with ILD- patients. Moreover, although there were no significant inter-group differences in the expression of BCMA, BAFF-R and TACI on B cells, the expression of BAFF-R was significantly decreased in the ILD+ patients. In recent years, relationships between BAFF/APRIL and IgA subclass have been reported. Our results suggest that an elevated level of BAFF/APRIL drives the maturation of B cells, subsequently leading to IgA2 class switching, and possibly to the development of ILD in patients with MCTD. PMID:24252051

  6. 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

  7. Spectrum of diffuse parenchymal lung diseases with special reference to idiopathic pulmonary fibrosis and connective tissue disease: An eastern India experience

    PubMed Central

    Kundu, Somenath; Mitra, Subhra; Ganguly, Joydeep; Mukherjee, Subhasis; Ray, Souvik; Mitra, Ritabrata

    2014-01-01

    Objective: To evaluate the clinical spectrum of diffuse parenchymal lung diseases (DPLD) encountered in the Indian setting and to compare idiopathic pulmonary fibrosis (IPF) and connective tissue disease associated DPLD (CTD-DPLD), the two commonest aetiologies. Materials and Methods: A prospective study of clinical, imaging and laboratory parameters of patients diagnosed as DPLD and followed up in the Pulmonary Medicine Department of a tertiary-care teaching institution in eastern India was conducted over a period of one year. Results: 92 patients of DPLD were diagnosed in the study period with IPF (n = 35, 38.04%), CTD-DPLD (n = 29, 31.5%), hypersensitivity pneumonitis (n = 10, 10.9%), sarcoidosis (n = 5, 5.4%) and silicosis (n = 5, 5.4%) being the common causes. The CTD-DPLD group had a lower mean age (39.5 ± 1.86 vs 56.9 ± 1.12 years), a longer duration of symptoms (3.5 ± 0.27 vs 2.5 ± 0.26 years), more extra pulmonary manifestations, significantly more base line FVC and 6-minute-walk-distance than the IPF patients. 19 patients of IPF (54%) opted for treatment. All the IPF patients had a significant fall in FVC after six months (mean change -0.203 ± 0.01 litres) compared to the CTD-DPLD group (mean change - 0.05 ± 0.04 litres.) Conclusion: CTD-DPLD patients belong to a younger age group, with longer duration of symptoms, more extrapulmonary features, better physiological parameters and better response to therapy than IPF patients. Larger prospective epidemiological studies and enrolment in clinical trials are necessary for better understanding of the spectrum of diffuse parenchymal lung disorders and their therapeutic options. PMID:25378843

  8. Assessment of T Regulatory Cells and Expanded Profiling of Autoantibodies May Offer Novel Biomarkers for the Clinical Management of Systemic Sclerosis and Undifferentiated Connective Tissue Disease

    PubMed Central

    Cordiali-Fei, Paola; Mussi, Anna; D'Agosto, Giovanna; Trento, Elisabetta; Bordignon, Valentina; Trincone, Silvana; Vento, Antonella; Sperduti, Isabella; Cristaudo, Antonio; Ensoli, Fabrizio

    2013-01-01

    In order to identify disease biomarkers for the clinical and therapeutic management of autoimmune diseases such as systemic sclerosis (SSc) and undifferentiated connective tissue disease (UCTD), we have explored the setting of peripheral T regulatory (T reg) cells and assessed an expanded profile of autoantibodies in patients with SSc, including either limited (lcSSc) or diffuse (dcSSc) disease, and in patients presenting with clinical signs and symptoms of UCTD. A large panel of serum antibodies directed towards nuclear, nucleolar, and cytoplasmic antigens, including well-recognized molecules as well as less frequently tested antigens, was assessed in order to determine whether different antibody profiles might be associated with distinct clinical settings. Beside the well-recognized association between lcSSc and anti-centromeric or dcSSC and anti-topoisomerase-I antibodies, we found a significative association between dcSSc and anti-SRP or anti-PL-7/12 antibodies. In addition, two distinct groups emerged on the basis of anti-RNP or anti-PM-Scl 75/100 antibody production among UCTD patients. The levels of T reg cells were significantly lower in patients with SSc as compared to patients with UCTD or to healthy controls; in patients with lcSSc, T reg cells were inversely correlated to disease duration, suggesting that their levels may represent a marker of disease progression. PMID:23818915

  9. 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

  10. Tetramers reveal IL-17-secreting CD4+ T cells that are specific for U1-70 in lupus and mixed connective tissue disease.

    PubMed

    Kattah, Nicole H; Newell, Evan W; Jarrell, Justin Ansel; Chu, Alvina D; Xie, Jianming; Kattah, Michael G; Goldberger, Ofir; Ye, Jessica; Chakravarty, Eliza F; Davis, Mark M; Utz, Paul J

    2015-03-10

    Antigen-specific CD4(+) T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E(k)-containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4(+) T-cell populations in MRL/lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine(140). The frequency of CD4(+) T cells specific for U1-70(131-150):I-E(k) (without phosphorylation) correlates with disease severity and anti-U1-70 autoantibody production. These T cells also express RORγt and produce IL-17A. Furthermore, the U1-70-specific CD4(+) T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen-specific CD4(+) T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease. PMID:25713364

  11. 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

  12. 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

  13. 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

  14. 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

  15. A Rare Case of Mixed Connective Tissue Disease (MCTD) with Intricate Features of Lupus, Polymyositis and Rheumatoid Arthritis Presenting with Severe Myositis.

    PubMed

    S, Lokesh; Tony, Kadavanu; Raghupathy; V, Suresh; Malepati, Balakrishna

    2015-03-01

    Mixed connective tissue disease (MCTD) includes clinical and laboratorial manifestations of systemic lupus erythematosus, scleroderma and polymyositis along with high titres of anti-U1RNP antibodies. In the initial phases of the disease, muscle enzyme levels increase but the disease remains generally subclinical. Presentation with myositis is uncommon. Our objective is to report a rare case of a patient who presented with a severe onset of myositis characterized by dysphagia, an increase in myopathy and joint involvement suggestive of RA. The patient was initiated on pulse corticosteroid therapy along with methotrexate in view of her elevated Creatine Kinase levels and biopsy findings that were suggestive of severe myositis. The patient showed clinical and laboratory improvement with this regimen. Though severe myositis and arthritis can occur in overlap syndrome, MCTD evolved as a separate disease entity due to presence of high titres of Anti U1-RNP antibodies. The authors emphasize that this is an extremely rare presentation of MCTD with only two previous cases seen in literature, one of a 13 year old child and the other being an adult female both of whom had evidence of myositis on presentation. PMID:25954655

  16. 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

  17. 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

  18. 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

  19. 351 Prevalence of Thyroid Peroxidase Autoantibodies (ANTI-TPO) in Women with Autoimmune Connective Tissue Diseases (ACTD)

    PubMed Central

    Papadopoulos, Georgios; Vakaloudi, Anastasia; Koutsika, Eirene; Anastasiou, Ekarerini; Koteli, Asimoula

    2012-01-01

    Background Chronic autoimmune thyroiditis, manifested by positive test for antithyroid antibodies, is common in the general population, occurring in 10 to 20 percent of women. The aim of the study was to determine whether Anti-TPO is more prevalent in women with ACTD, compared to the general population. Methods Anti-TPO was determined in 290 women diagnosed with ACTD based on ACR (American College of Rheumatology) criteria and in 50 healthy women (control group). Among ACTD patients, 121 were diagnosed with Rheumatoid Arthritis (RA), 44 Systemic Lupus Erythematosus (SLE), 43 Sjοgren's Syndrome (SS), 42 Systemic Scleroderma (SScl) and 40 Psoriatic Arthritis (PsA). Anti-TPO was measured by Chemiluminescent Microparticle Immunoassay (CMIA) on Architect i2000SR (ABBOT Laboratories). Results The prevalence of Anti-TPO in separate groups of patients had as follow: RA 28.93%, SLE 29.55%, SS 27.91%, SScl 23.81%, PsA 30% and control group 12%. Conclusions ACTD and thyroid autoimmune diseases often overlap with each other. Increased Anti-TPO may be most common among women patients with ACTD. On the other hand, these systemic diseases are often present in Hasimoto's thyroiditis subjects. Therefore it is clinically important to screen women patients with ACTD for the co-existence of thyroid disorders.

  20. Preliminary Report of Endovascular Treatment for Critical Limb Ischemia Patients with Connective Tissue Disease: Cases Series and Review of the Literature.

    PubMed

    Obara, Hideaki; Matsubara, Kentaro; Fujimura, Naoki; Sekimoto, Yasuhito; Kitagawa, Yuko

    2015-06-01

    Only few studies have addressed the surgical revascularization in patients with both connective tissue disease (CTD) and critical limb ischemia (CLI), and the evidence for the endovascular treatment (EVT) is lacking in such patients. The main purpose of this study is to assess our outcome of EVT in patients with CTD and ischemic leg ulcers and review the current situation of the revascularization in such patients. Medical records of 10 consecutive patients with coexistent CTD and CLI-related leg ulcers (in 11 limbs) treated endovascularly at our institution between 2009 and 2013 were reviewed retrospectively. The patients had rheumatoid arthritis (n = 5), systemic lupus erythematosus (n = 1), progressive systemic scleroderma (n = 3), or polyarteritis nodosa (n = 1). EVT was technically successful in all the cases. No procedure-related morbidity or mortality occurred. During the mean follow-up period of 26 months, there were no major amputations, and sustained clinical improvement (ulcer healing and reduction in Rutherford category) was observed in eight limbs. The overall 1-year rates of amputation-free survival and freedom from reintervention were 89 and 81%, respectively. In our series of patients with CTD and ischemic leg ulcers, EVT had acceptable outcomes and may be recommended as a safe and reasonably effective initial treatment option for such patients. PMID:26060386

  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. Local amino acid sequence patterns dominate the heterogeneous phenotype for the collagen connective tissue disease Osteogenesis Imperfecta resulting from Gly mutations.

    PubMed

    Xiao, Jianxi; Yang, Zhangfu; Sun, Xiuxia; Addabbo, Rayna; Baum, Jean

    2015-10-01

    Osteogenesis Imperfecta (OI), a hereditary connective tissue disease in collagen that arises from a single Gly → X mutation in the collagen chain, varies widely in phenotype from perinatal lethal to mild. It is unclear why there is such a large variation in the severity of the disease considering the repeating (Gly-X-Y)n sequence and the uniform rod-like structure of collagen. We systematically evaluate the effect of local (Gly-X-Y)n sequence around the mutation site on OI phenotype using integrated bio-statistical approaches, including odds ratio analysis and decision tree modeling. We show that different Gly → X mutations have different local sequence patterns that are correlated with lethal and nonlethal phenotypes providing a mechanism for understanding the sensitivity of local context in defining lethal and non-lethal OI. A number of important trends about which factors are related to OI phenotypes are revealed by the bio-statistical analyses; most striking is the complementary relationship between the placement of Pro residues and small residues and their correlation to OI phenotype. When Pro is present or small flexible residues are absent nearby a mutation site, the OI case tends to be lethal; when Pro is present or small flexible residues are absent further away from the mutation site, the OI case tends to be nonlethal. The analysis also reveals the dominant role of local sequence around mutation sites in the Major Ligand Binding Regions that are primarily responsible for collagen binding to its receptors and shows that non-lethal mutations are highly predicted by local sequence considerations alone whereas lethal mutations are not as easily predicted and may be a result of more complex interactions. Understanding the sequence determinants of OI mutations will enhance genetic counseling and help establish which steps in the collagen hierarchy to target for drug therapy. PMID:25980613

  3. A case of idiopathic portal hypertension associated with nodular regenerative hyperplasia-like nodule of the liver and mixed connective tissue disease.

    PubMed

    Hayano, Shunsuke; Naganuma, Atsushi; Okano, Yudai; Suzuki, Yuhei; Shiina, Keisuke; Yoshida, Haruka; Hayashi, Eri; Uehara, Sanae; Hoshino, Takashi; Miyamae, Naomi; Kudo, Tomohiro; Ishihara, Hiroshi; Ogawa, Akira; Sato, Ken; Kakizaki, Satoru

    2016-05-01

    A 51-year-old woman was diagnosed with mixed connective tissue disease (MCTD) in 2011. She underwent treatment with prednisolone. Her hepatobiliary enzyme level increased, and multiple nodules were found in both liver lobes in abdominal imaging studies. Ultrasonography revealed large and small hyperechoic lesions with indistinct or well-defined borders. No findings of classic hepatocellular carcinoma or liver cirrhosis were observed on contrast-enhanced computed tomography, but some nodules showed an enhanced effect of the central lesion that was characteristic of focal nodular hyperplasia (FNH) in an arterial phase. On gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging, slightly high-intensity nodules, 10-40mm in size, were observed on T1- and T2-weighted images. The nodules showed highest intensities in the hepatocyte phase and were enhanced with the uptake of Gd-EOB-DTPA as compared with the background liver. FNH was suspected based on the imaging findings, but we performed a liver tumor biopsy for differential diagnosis of the malignant lesion. Based on the immunohistopathological examination results, the final diagnosis was idiopathic portal hypertension associated with nodular regenerative hyperplasia (NRH)-like nodule of the liver. Benign nodular hepatocellular lesions are caused by abnormal hepatic circulation and were previously known as anomalous portal tract syndrome. Our case of atypical NRH with large nodules may be included in this disease entity. Here, we report a rare case of MCTD with NRH-like nodules and idiopathic portal hypertension with a review of literature. PMID:27151480

  4. 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

  5. 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

  6. Adipocytes in both brown and white adipose tissue of adult mice are functionally connected via gap junctions: implications for Chagas disease.

    PubMed

    Burke, Shoshana; Nagajyothi, Fnu; Thi, Mia M; Hanani, Menachem; Scherer, Philipp E; Tanowitz, Herbert B; Spray, David C

    2014-11-01

    Adipose tissue serves as a host reservoir for the protozoan Trypanosoma cruzi, the causative organism in Chagas disease. Gap junctions interconnect cells of most tissues, serving to synchronize cell activities including secretion in glandular tissue, and we have previously demonstrated that gap junctions are altered in various tissues and cells infected with T. cruzi. Herein, we examined the gap junction protein connexin 43 (Cx43) expression in infected adipose tissues. Adipose tissue is the largest endocrine organ of the body and is also involved in other physiological functions. In mammals, it is primarily composed of white adipocytes. Although gap junctions are a prominent feature of brown adipocytes, they have not been explored extensively in white adipocytes, especially in the setting of infection. Thus, we examined functional coupling in both white and brown adipocytes in mice. Injection of electrical current or the dye Lucifer Yellow into adipocytes within fat tissue spread to adjacent cells, which was reduced by treatment with agents known to block gap junctions. Moreover, Cx43 was detected in both brown and white fat tissue. At thirty and ninety days post-infection, Cx43 was downregulated in brown adipocytes and upregulated in white adipocytes. Gap junction-mediated intercellular communication likely contributes to hormone secretion and other functions in white adipose tissue and to nonshivering thermogenesis in brown fat, and modulation of the coupling by T. cruzi infection is expected to impact these functions. PMID:25150689

  7. Adipocytes in both brown and white adipose tissue of adult mice are functionally connected via gap junctions: implications for Chagas disease

    PubMed Central

    Burke, Shoshana; Nagajyothi, Fnu; Thi, Mia M.; Hanani, Menachem; Scherer, Philipp E.; Tanowitz, Herbert B.; Spray, David C.

    2015-01-01

    Adipose tissue serves as a host reservoir for the protozoan Trypanosoma cruzi, the causative organism in Chagas disease. Gap junctions interconnect cells of most tissues, serving to synchronize cell activities including secretion in glandular tissue, and we have previously demonstrated that gap junctions are altered in various tissues and cells infected with T. cruzi. Herein, we examined the gap junction protein connexin 43 (Cx43) expression in infected adipose tissues. Adipose tissue is the largest endocrine organ of the body and is also involved in other physiological functions. In mammals, it is primarily composed of white adipocytes. Although gap junctions are a prominent feature of brown adipocytes, they have not been explored extensively in white adipocytes, especially in the setting of infection. Thus, we examined functional coupling in both white and brown adipocytes in mice. Injection of electrical current or the dye Lucifer Yellow into adipocytes within fat tissue spread to adjacent cells, which was reduced by treatment with agents known to block gap junctions. Moreover, Cx43 was detected in both brown and white fat tissue. At thirty and ninety days post-infection, Cx43 was downregulated in brown adipocytes and upregulated in white adipocytes. Gap junction-mediated intercellular communication likely contributes to hormone secretion and other functions in white adipose tissue and to nonshivering thermogenesis in brown fat, and modulation of the coupling by T. cruzi infection is expected to impact these functions. PMID:25150689

  8. [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

  9. 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

  10. DiseaseConnect: a comprehensive web server for mechanism-based disease-disease connections.

    PubMed

    Liu, Chun-Chi; Tseng, Yu-Ting; Li, Wenyuan; Wu, Chia-Yu; Mayzus, Ilya; Rzhetsky, Andrey; Sun, Fengzhu; Waterman, Michael; Chen, Jeremy J W; Chaudhary, Preet M; Loscalzo, Joseph; Crandall, Edward; Zhou, Xianghong Jasmine

    2014-07-01

    The DiseaseConnect (http://disease-connect.org) is a web server for analysis and visualization of a comprehensive knowledge on mechanism-based disease connectivity. The traditional disease classification system groups diseases with similar clinical symptoms and phenotypic traits. Thus, diseases with entirely different pathologies could be grouped together, leading to a similar treatment design. Such problems could be avoided if diseases were classified based on their molecular mechanisms. Connecting diseases with similar pathological mechanisms could inspire novel strategies on the effective repositioning of existing drugs and therapies. Although there have been several studies attempting to generate disease connectivity networks, they have not yet utilized the enormous and rapidly growing public repositories of disease-related omics data and literature, two primary resources capable of providing insights into disease connections at an unprecedented level of detail. Our DiseaseConnect, the first public web server, integrates comprehensive omics and literature data, including a large amount of gene expression data, Genome-Wide Association Studies catalog, and text-mined knowledge, to discover disease-disease connectivity via common molecular mechanisms. Moreover, the clinical comorbidity data and a comprehensive compilation of known drug-disease relationships are additionally utilized for advancing the understanding of the disease landscape and for facilitating the mechanism-based development of new drug treatments. PMID:24895436

  11. The high incidence of anti-Ro/SSA and anti-p200 antibodies in female patients with connective tissue diseases confirms the importance of screening for congenital heart block-associated autoantibodies during pregnancy.

    PubMed

    Cozzani, E; Agnoletti, Arianna Fay; Pappalardo, F; Schiavetti, I; Torino, A; Parodi, A

    2016-03-01

    It is known that anti-Ro/SSA positivity leads to higher risk of miscarriage and fetal cardiac malformations. Particularly, anti-p200 antibodies against a finer specificity of the Ro/SSA antigen, have been associated with congenital heart block. The aim of the study was to assess the frequency of anti-p200 among female patients with different connective tissue diseases and, among these, the relevance of anti-p200 values in patients with cutaneous diseases compared to systemic diseases. Anti-p200 were investigated in 110 anti-Ro/SSA positive female sera, sent to our laboratory between 2008 and 2014 with suspect of connective disease, by using ELISA testing. Positivity was found in 40.9 % samples, 34 of them showed a strong positivity (values ≥ 1.0, cut off = 0.7). Patients with systemic diseases were anti-p200 positive in the 45.9 % of cases while patients with cutaneous diseases were positive in the 24.0 % of cases. Positivity for anti-p200 antibodies was revealed in 24.0 % of patients with discoid lupus erythematosus; 100 % of patients with dermatomyositis; 40.0 % of patients with mixed connective tissue disease; 25.0 % of patients with rheumatoid arthritis; 100 % of patients with Sjögren's syndrome; 33.3 % of patients with subacute cutaneous lupus erythematosus; 42.9 % of patients with systemic lupus erythematosus; 80.0 % of patients with systemic sclerosis. No significant difference in anti-p200 prevalence was found between systemic and cutaneous involvement, nevertheless, considering only positive sera, the antibody titer was higher in systemic diseases rather than in cutaneous diseases (2.6 ± 1.7 and 1.7 ± 1.9; p = 0.041). The authors think screenings for anti-Ro/SSA and anti-p200 antibodies should be included in the laboratory checklist for pregnancy. PMID:26830903

  12. 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

  13. Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

    PubMed Central

    Nielsen, Mette J.; Sand, Jannie M.; Henriksen, Kim; Genovese, Federica; Bay-Jensen, Anne-Christine; Smith, Victoria; Adamkewicz, Joanne I.; Christiansen, Claus; Leeming, Diana J.

    2013-01-01

    Abstract Increased attention is paid to the structural components of tissues. These components are mostly collagens and various proteoglycans. Emerging evidence suggests that altered components and noncoded modifications of the matrix may be both initiators and drivers of disease, exemplified by excessive tissue remodeling leading to tissue stiffness, as well as by changes in the signaling potential of both intact matrix and fragments thereof. Although tissue structure until recently was viewed as a simple architecture anchoring cells and proteins, this complex grid may contain essential information enabling the maintenance of the structure and normal functioning of tissue. The aims of this review are to (1) discuss the structural components of the matrix and the relevance of their mutations to the pathology of diseases such as fibrosis and cancer, (2) introduce the possibility that post-translational modifications (PTMs), such as protease cleavage, citrullination, cross-linking, nitrosylation, glycosylation, and isomerization, generated during pathology, may be unique, disease-specific biochemical markers, (3) list and review the range of simple enzyme-linked immunosorbent assays (ELISAs) that have been developed for assessing the extracellular matrix (ECM) and detecting abnormal ECM remodeling, and (4) discuss whether some PTMs are the cause or consequence of disease. New evidence clearly suggests that the ECM at some point in the pathogenesis becomes a driver of disease. These pathological modified ECM proteins may allow insights into complicated pathologies in which the end stage is excessive tissue remodeling, and provide unique and more pathology-specific biochemical markers. PMID:23046407

  14. 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

  15. 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.

  16. 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

  17. Connectivity Changes in Parkinson's Disease.

    PubMed

    Cerasa, Antonio; Novellino, Fabiana; Quattrone, Aldo

    2016-10-01

    Parkinson's disease (PD) is a chronic and progressive movement disorder of the central nervous system characterized by widespread alterations in several non-motor aspects such as mood, sleep, olfactory, and cognition in addition to motor dysfunctions. Advanced neuroimaging using functional connectivity reconstruction of the human brain has provided a vast knowledge on the pathophysiological mechanisms underlying this disorder, but this, however, does not cover the overall inter-/intra-individual variability of PD phenotypes. The present review is aimed at discussing to what extent the evidence provided by group-based neuroimaging analysis in this field of study (using seed-based, network-based, or graph theory approaches) may be generalized. In particular, we summarized the literature on the application of resting-state functional connectivity studies to explore different neural correlates of motor and non-motor symptoms of PD and the neural mechanisms involved in treatment effects: effects of levodopa or deep brain stimulation. The lesson learnt from one decade of studies provides consistent evidence on the role of the altered communication between the striato-frontal pathways as a marker of PD-related motor degeneration, whereas in the non-motor domain, several missing pieces of a complex puzzle are provided. However, the main target is to present a new era of intelligent neuroimaging applications, where automated multivariate analysis of functional connectivity data may be used for moving from group-level statistical results to personalized predictions in a clinical setting. Although in its relative infancy, the evidence gathered so far suggests a new era of clinical neuroimaging is starting. PMID:27568202

  18. 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

  19. 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

  20. Kidney diseases and tissue engineering.

    PubMed

    Moon, Kyung Hyun; Ko, In Kap; Yoo, James J; Atala, Anthony

    2016-04-15

    Kidney disease is a worldwide public health problem. Renal failure follows several disease stages including acute and chronic kidney symptoms. Acute kidney injury (AKI) may lead to chronic kidney disease (CKD), which can progress to end-stage renal disease (ESRD) with a mortality rate. Current treatment options are limited to dialysis and kidney transplantation; however, problems such as donor organ shortage, graft failure and numerous complications remain a concern. To address this issue, cell-based approaches using tissue engineering (TE) and regenerative medicine (RM) may provide attractive approaches to replace the damaged kidney cells with functional renal specific cells, leading to restoration of normal kidney functions. While development of renal tissue engineering is in a steady state due to the complex composition and highly regulated functionality of the kidney, cell therapy using stem cells and primary kidney cells has demonstrated promising therapeutic outcomes in terms of restoration of renal functions in AKI and CKD. In this review, basic components needed for successful renal kidney engineering are discussed, and recent TE and RM approaches to treatment of specific kidney diseases will be presented. PMID:26134528

  1. A musculoskeletal model of low grade connective tissue inflammation in patients with thyroid associated ophthalmopathy (TAO): the WOMED concept of lateral tension and its general implications in disease

    PubMed Central

    Moncayo, Roy; Moncayo, Helga

    2007-01-01

    Background Low level connective tissue inflammation has been proposed to play a role in thyroid associated ophthalmopathy (TAO). The aim of this study was to investigate this postulate by a musculoskeletal approach together with biochemical parameters. Methods 13 patients with TAO and 16 controls were examined. Erythrocyte levels of Zn, Cu, Ca2+, Mg, and Fe were determined. The musculoskeletal evaluation included observational data on body posture with emphasis on the orbit-head region. The angular foot position in the frontal plane was quantified following gait observation. The axial orientation of the legs and feet was evaluated in an unloaded supine position. Functional propioceptive tests based on stretch stimuli were done by using foot inversion and foot rotation. Results Alterations in the control group included neck tilt in 3 cases, asymmetrical foot angle during gait in 2, and a reaction to foot inversion in 5 cases. TAO patients presented facial asymmetry with displaced eye fissure inclination (mean 9.1°) as well as tilted head-on-neck position (mean 5.7°). A further asymmetry feature was external rotation of the legs and feet (mean 27°). Both foot inversion as well as foot rotation induced a condition of neuromuscular deficit. This condition could be regulated by gentle acupressure either on the lateral abdomen or the lateral ankle at the acupuncture points gall bladder 26 or bladder 62, respectively. In 5 patients, foot rotation produced a phenomenon of moving toes in the contra lateral foot. In addition foot rotation was accompanied by an audible tendon snapping. Lower erythrocyte Zn levels and altered correlations between Ca2+, Mg, and Fe were found in TAO. Conclusion This whole body observational study has revealed axial deviations and body asymmetry as well as the phenomenon of moving toes in TAO. The most common finding was an arch-like displacement of the body, i.e. eccentric position, with foot inversion and head tilt to the contra lateral side

  2. 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

    Silicon may be important for bone and connective tissue health. Higher concentrations of silicon are suggested to be associated with bone and the connective tissues, compared with the non-connective soft tissues. Moreover, in connective tissues it has been suggested that silicon levels may decrease with age based upon analyses of human aorta. These claims, however, have not been tested under controlled conditions. Here connective and non-connective tissues were collected and analysed for silicon levels from female Sprague-Dawley rats of different ages (namely, 3, 5, 8, 12, 26 and 43 weeks; n=8-10 per age group), all maintained on the same feed source and drinking water, and kept in the same environment from weaning to adulthood. Tissues (696 samples) were digested in nitric acid and analysed by inductively coupled plasma optical emission spectrometry for total silicon content. Fasting serum samples were also collected, diluted and analysed for silicon. Higher concentrations of silicon (up to 50-fold) were found associated with bone and the connective tissues compared with the non-connective tissues. Although total silicon content increased with age in all tissues, the highest connective tissue silicon concentrations (up to 9.98 μg/g wet weight) were found in young weanling rats, decreasing thereafter with age (by 2-6 fold). Fasting serum silicon concentrations reflected the pattern of connective tissue silicon concentrations and, both measures, when compared to collagen data from a prior experiment in Sprague-Dawley rats, mirrored type I collagen turnover with age. Our findings confirm the link between silicon and connective tissues and would imply that young growing rats have proportionally higher requirements for dietary silicon than mature adults, for bone and connective tissue development, although this was not formally investigated here. However, estimation of total body silicon content suggested that actual Si requirements may be substantially lower than

  3. 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

    Silicon may be important for bone and connective tissue health. Higher concentrations of silicon are suggested to be associated with bone and the connective tissues, compared with the non-connective soft tissues. Moreover, in connective tissues it has been suggested that silicon levels may decrease with age based upon analyses of human aorta. These claims, however, have not been tested under controlled conditions. Here connective and non-connective tissues were collected and analysed for silicon levels from female Sprague–Dawley rats of different ages (namely, 3, 5, 8, 12, 26 and 43 weeks; n = 8–10 per age group), all maintained on the same feed source and drinking water, and kept in the same environment from weaning to adulthood. Tissues (696 samples) were digested in nitric acid and analysed by inductively coupled plasma optical emission spectrometry for total silicon content. Fasting serum samples were also collected, diluted and analysed for silicon. Higher concentrations of silicon (up to 50-fold) were found associated with bone and the connective tissues compared with the non-connective tissues. Although total silicon content increased with age in all tissues, the highest connective tissue silicon concentrations (up to 9.98 μg/g wet weight) were found in young weanling rats, decreasing thereafter with age (by 2–6 fold). Fasting serum silicon concentrations reflected the pattern of connective tissue silicon concentrations and, both measures, when compared to collagen data from a prior experiment in Sprague–Dawley rats, mirrored type I collagen turnover with age. Our findings confirm the link between silicon and connective tissues and would imply that young growing rats have proportionally higher requirements for dietary silicon than mature adults, for bone and connective tissue development, although this was not formally investigated here. However, estimation of total body silicon content suggested that actual Si requirements may be substantially

  4. 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

  5. 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.

  6. 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.

  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. 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

  10. [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

  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. 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

  13. [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

  14. 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

  15. 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.

  16. [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

  17. 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

  18. 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

  19. 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

  20. [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

  1. Tissue engineering in the rheumatic diseases

    PubMed Central

    Ringe, Jochen; Sittinger, Michael

    2009-01-01

    Diseases such as degenerative or rheumatoid arthritis are accompanied by joint destruction. Clinically applied tissue engineering technologies like autologous chondrocyte implantation, matrix-assisted chondrocyte implantation, or in situ recruitment of bone marrow mesenchymal stem cells target the treatment of traumatic defects or of early osteoarthritis. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Here, most likely, cartilage formation is impaired and engineered neocartilage will be degraded. Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases. Tissue engineering also provides highly organized three-dimensional in vitro culture models of human cells and their extracellular matrix for arthritis research. PMID:19232063

  2. 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.

  3. Tissue engineering therapy for cardiovascular disease.

    PubMed

    Nugent, Helen M; Edelman, Elazer R

    2003-05-30

    The present treatments for the loss or failure of cardiovascular function include organ transplantation, surgical reconstruction, mechanical or synthetic devices, or the administration of metabolic products. Although routinely used, these treatments are not without constraints and complications. The emerging and interdisciplinary field of tissue engineering has evolved to provide solutions to tissue creation and repair. Tissue engineering applies the principles of engineering, material science, and biology toward the development of biological substitutes that restore, maintain, or improve tissue function. Progress has been made in engineering the various components of the cardiovascular system, including blood vessels, heart valves, and cardiac muscle. Many pivotal studies have been performed in recent years that may support the move toward the widespread application of tissue-engineered therapy for cardiovascular diseases. The studies discussed include endothelial cell seeding of vascular grafts, tissue-engineered vascular conduits, generation of heart valve leaflets, cardiomyoplasty, genetic manipulation, and in vitro conditions for optimizing tissue-engineered cardiovascular constructs. PMID:12775655

  4. 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

  5. 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

  6. 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

  7. Tissue-Engineered Kidney Disease Models

    PubMed Central

    DesRochers, Teresa M.; Palma, Erica; Kaplan, David L.

    2014-01-01

    Renal disease represents a major health problem that often results in end-stage renal failure necessitating dialysis and eventually transplantation. Historically these diseases have been studied with patient observation and screening, animal models, and two-dimensional cell culture. In this review, we focus on recent advances in tissue engineered kidney disease models that have the capacity to compensate for the limitations of traditional modalities. The cells and materials utilized to develop these models are discussed and tissue engineered models of polycystic kidney disease, drug-induced nephrotoxicity, and the glomerulus are examined in detail. The application of these models has the potential to direct future disease treatments and preclinical drug development. PMID:24361391

  8. Raman spectroscopy of Alzheimer's diseased tissue

    NASA Astrophysics Data System (ADS)

    Sudworth, Caroline D.; Krasner, Neville

    2004-07-01

    Alzheimer's disease is one of the most common forms of dementia, and causes steady memory loss and mental regression. It is also accompanied by severe atrophy of the brain. However, the pathological biomarkers of the disease can only be confirmed and examined upon the death of the patient. A commercial (Renishaw PLC, UK) Raman system with an 830 nm NIR diode laser was used to analyse brain samples, which were flash frozen at post-mortem. Ethical approval was sought for these samples. The Alzheimer's diseased samples contained a number of biomarkers, including neuritic plaques and tangles. The Raman spectra were examined by order to differentiate between normal and Alzheimer's diseased brain tissues. Preliminary results indicate that Alzheimer's diseased tissues can be differentiated from control tissues using Raman spectroscopy. The Raman spectra differ in terms of peak intensity, and the presence of a stronger amide I band in the 1667 cm-1 region which occurs more prominently in the Alzheimer's diseased tissue. These preliminary results indicate that the beta-amyloid protein originating from neuritic plaques can be identified with Raman spectroscopy.

  9. Ulcerative colitis and Crohn's disease tissue cytotoxins

    SciTech Connect

    McLaren, L.C.; Gitnick, G.

    1982-06-01

    Bowel-wall tissue filtrates from patients with inflammatory bowel disease produce cytopathic effects in tissue culture. The cytopathic effects inducers have been reported to have the characteristics of a small RNA virus. Clostridium difficile toxin also produces cytopathic effects and has been found in the stools of patients with Crohn's disease and ulcerative colitis. The present study concerns the further characterization of the cytopathic inducers in tissues of inflammatory bowel disease patients. It was found that they are nonsedimentable at 148,000 g for 2 h and resistant to inactivation by UV light. They are proteins that are distinct from C. difficile toxin and are unique cytotoxins which are associated with the early cytopathic effects observed in Riff-free chick embryo and rabbit ileum cell cultures. These results suggest that the early cytopathic effects previously described are not produced by a virus. They do not explain the delayed cytopathic effects seen in rabbit ileum or WI-38 cells.

  10. 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

  11. Chronic Wasting Disease Positive Tissue Bank

    USGS Publications Warehouse

    Wright, Scott D.

    2007-01-01

    In 2005, the USGS National Wildlife Health Center entered into an agreement with the Wyoming Game and Fish Department and the Department of Veterinary Sciences at the University of Wyoming to produce a collection of positive tissues from cervids intentionally infected with chronic wasting disease. This agreement was facilitated through the University of Wyoming Cooperative Fish and Wildlife Unit. Also, the investigators on this project sampled the animals incrementally over 2 years to show changes over time, and examined tissues from the animals by immunohistochemistry. CWD positive tissues are catalogued by species, sample site and time of infection. These data and more will soon be published.

  12. 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.

  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. 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

  15. Tissue refractive index as marker of disease

    NASA Astrophysics Data System (ADS)

    Wang, Zhuo; Tangella, Krishnarao; Balla, Andre; Popescu, Gabriel

    2011-11-01

    The gold standard in histopathology relies on manual investigation of stained tissue biopsies. A sensitive and quantitative method for in situ tissue specimen inspection is highly desirable, as it would allow early disease diagnosis and automatic screening. Here we demonstrate that quantitative phase imaging of entire unstained biopsies has the potential to fulfill this requirement. Our data indicates that the refractive index distribution of histopathology slides, which contains information about the molecular scale organization of tissue, reveals prostate tumors and breast calcifications. These optical maps report on subtle, nanoscale morphological properties of tissues and cells that cannot be recovered by common stains, including hematoxylin and eosin. We found that cancer progression significantly alters the tissue organization, as exhibited by consistently higher refractive index variance in prostate tumors versus normal regions. Furthermore, using the quantitative phase information, we obtained the spatially resolved scattering mean free path and anisotropy factor g for entire biopsies and demonstrated their direct correlation with tumor presence. In essence, our results show that the tissue refractive index reports on the nanoscale tissue architecture and, in principle, can be used as an intrinsic marker for cancer diagnosis.

  16. 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

  17. 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

  18. Airway tissue engineering for congenital laryngotracheal disease.

    PubMed

    Maughan, Elizabeth; Lesage, Flore; Butler, Colin R; Hynds, Robert E; Hewitt, Richard; Janes, Sam M; Deprest, Jan A; Coppi, Paolo De

    2016-06-01

    Regenerative medicine offers hope of a sustainable solution for severe airway disease by the creation of functional, immunocompatible organ replacements. When considering fetuses and newborns, there is a specific spectrum of airway pathologies that could benefit from cell therapy and tissue engineering applications. While hypoplastic lungs associated with congenital diaphragmatic hernia (CDH) could benefit from cellular based treatments aimed at ameliorating lung function, patients with upper airway obstruction could take advantage from a de novo tissue engineering approach. Moreover, the international acceptance of the EXIT procedure as a means of securing the precarious neonatal airway, together with the advent of fetal surgery as a method of heading off postnatal co-morbidities, offers the revolutionary possibility of extending the clinical indication for tissue-engineered airway transplantation to infants affected by diverse severe congenital laryngotracheal malformations. This article outlines the necessary basic components for regenerative medicine solutions in this potential clinical niche. PMID:27301606

  19. Cell and Tissue Engineering for Liver Disease

    PubMed Central

    Bhatia, Sangeeta N.; Underhill, Gregory H.; Zaret, Kenneth S.; Fox, Ira J.

    2015-01-01

    Despite the tremendous hurdles presented by the complexity of the liver’s structure and function, advances in liver physiology, stem cell biology and reprogramming, and the engineering of tissues and devices are accelerating the development of cell-based therapies for treating liver disease and liver failure. This State of the Art Review discusses both the near and long-term prospects for such cell-based therapies and the unique challenges for clinical translation. PMID:25031271

  20. Mucosal tissue transglutaminase expression in celiac disease

    PubMed Central

    Villanacci, Vincenzo; Not, Tarcisio; Sblattero, Daniele; Gaiotto, Tiziano; Chirdo, Fernando; Galletti, Anna; Bassotti, Gabrio

    2009-01-01

    Abstract Tissue transglutaminase (tTG) plays an important role in celiac disease pathogenesis and antibodies to tTG are a diagnostic marker of gluten-sensitive enteropathy. The aim of this study was to investigate the localization of tTG in the duodenal mucosa in control tissues and in different histological stages of celiac disease by using a commercial and a novel set of anti-tTG monoclonal antibodies, to see whether this assessment can be useful for diagnostic purpose. The distribution of tTG was firstly evaluated in 18 untreated celiac patients by using a commercial monoclonal antibody (CUB7402) against tissue transglutaminase enzyme and directed against the loop-core region of the enzyme. Thereafter, in further 30 untreated celiac patients we employed three newly characterized anti-tTG monoclonal antibodies produced against recombinant human-tTG. The epitopes recognized are located in three distinct domains of the protein corresponding to the core, C1 and C2 protein structure. Eleven age- and sex-matched patients with chronic duodenitis acted as controls. All subjects underwent upper endoscopy to obtain biopsy samples from the duodenum. Overall, we found that (i) tTG is equally expressed in CD at different stages of disease; (ii) tTG is expressed, at similar level, in CD and controls with duodenitis. Assessment of tTG level in biopsy samples by immunohistochemical methods is not useful in the clinical diagnostic work-up of CD. PMID:18373732

  1. Retroperitoneal Castleman's disease mimicking soft tissue tumour.

    PubMed

    Pandya, B; Ghosh, S K; Chude, G; Rajmohan, M V; Narang, R

    2007-08-01

    Castleman's disease is a type of non-neoplastic lymphoproliferative disease having lymph nodal hyperplasia. It has two distinct microscopic types: hyaline-vascular type and plasma cell type. Clinically, it may present either as a solitary mass, most commonly in the mediastinum, or as a multicentric form whose features are generalized lymph-adenopathy, splenomegaly and involvement of other organs like the lungs and kidneys. Here we report a case of isolated retroperitoneal Castleman's disease, which presented as a lump in the iliac fossa in a young female. A clinico-radio-logical diagnosis of retroperitoneal soft tissue tumour was made and the patient underwent complete surgical excision. The exact diagnosis was only obtained at histopathology and there is no evidence of recurrence at six months follow-up. PMID:23132970

  2. 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.

  3. 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

  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. 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

  6. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.

    PubMed

    Lamb, Justin; Crawford, Emily D; Peck, David; Modell, Joshua W; Blat, Irene C; Wrobel, Matthew J; Lerner, Jim; Brunet, Jean-Philippe; Subramanian, Aravind; Ross, Kenneth N; Reich, Michael; Hieronymus, Haley; Wei, Guo; Armstrong, Scott A; Haggarty, Stephen J; Clemons, Paul A; Wei, Ru; Carr, Steven A; Lander, Eric S; Golub, Todd R

    2006-09-29

    To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project. PMID:17008526

  7. 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

  8. Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases.

    PubMed

    Marbach, Daniel; Lamparter, David; Quon, Gerald; Kellis, Manolis; Kutalik, Zoltán; Bergmann, Sven

    2016-04-01

    Mapping perturbed molecular circuits that underlie complex diseases remains a great challenge. We developed a comprehensive resource of 394 cell type- and tissue-specific gene regulatory networks for human, each specifying the genome-wide connectivity among transcription factors, enhancers, promoters and genes. Integration with 37 genome-wide association studies (GWASs) showed that disease-associated genetic variants-including variants that do not reach genome-wide significance-often perturb regulatory modules that are highly specific to disease-relevant cell types or tissues. Our resource opens the door to systematic analysis of regulatory programs across hundreds of human cell types and tissues (http://regulatorycircuits.org). PMID:26950747

  9. 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

  10. 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

  11. [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

  12. 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

  13. Combating plant diseases--the Darwin connection.

    PubMed

    Hollomon, Derek W; Brent, Keith J

    2009-11-01

    Although Darwin knew of plant diseases, he did not study them as part of his analysis of natural selection. Effective plant disease control has only been developed after his death. This article explores the relevance of Darwin's ideas to three problem areas with respect to diseases caused by fungi: emergence of new diseases, loss of disease resistance bred into plants and development of fungicide resistance. Darwin's concept of change through natural or artificial selection relied on selection of many small changes, but subsequent genetic research has shown that change can also occur through large steps. Appearance of new diseases can involve gene duplication, transfer or recombination, but all evidence points to both host plant resistance and fungicide susceptibility being overcome through point mutations. Because the population size of diseases such as rusts and powdery and downy mildews is so large, all possible point mutations are likely to occur daily, even during moderate epidemics. Overcoming control measures therefore reflects the overall fitness of these mutants, and much resource effort is being directed towards assessment of their fitness, both in the presence and in the absence of selection. While recent developments in comparative genomics have caused some revision of Darwin's ideas, experience in managing plant disease control measures clearly demonstrates the relevance of concepts he introduced 150 years ago. It also reveals the remarkable speed and the practical impact of adaptation in wild microorganism populations to changes in their environment, and the difficulty of stopping or delaying such adaptation. PMID:19771541

  14. Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases

    NASA Astrophysics Data System (ADS)

    Park, Solip; Yang, Jae-Seong; Kim, Jinho; Shin, Young-Eun; Hwang, Jihye; Park, Juyong; Jang, Sung Key; Kim, Sanguk

    2012-10-01

    The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

  15. 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.

  16. Refugia and connectivity sustain amphibian metapopulations afflicted by disease.

    PubMed

    Heard, Geoffrey W; Thomas, Chris D; Hodgson, Jenny A; Scroggie, Michael P; Ramsey, David S L; Clemann, Nick

    2015-08-01

    Metapopulation persistence in fragmented landscapes depends on habitat patches that can support resilient local populations and sufficient connectivity between patches. Yet epidemiological theory for metapopulations has largely overlooked the capacity of particular patches to act as refuges from disease, and has suggested that connectivity can undermine persistence. Here, we show that relatively warm and saline wetlands are environmental refuges from chytridiomycosis for an endangered Australian frog, and act jointly with connectivity to sustain frog metapopulations. We coupled models of microclimate and infection probability to map chytrid prevalence, and demonstrate a strong negative relationship between chytrid prevalence and the persistence of frog populations. Simulations confirm that frog metapopulations are likely to go extinct when they lack environmental refuges from disease and lose connectivity between patches. This study demonstrates that environmental heterogeneity can mediate host-pathogen interactions in fragmented landscapes, and provides evidence that connectivity principally supports host metapopulations afflicted by facultative pathogens. PMID:26108261

  17. Achalasia and thyroid disease: possible autoimmune connection?

    PubMed

    Quidute, Ana Rosa P; Freitas, Eduardo Vasconcelos de; Lima, Tadeu Gonçalves de; Feitosa, Ana Márcia Lima; Santos, Joyce Paiva dos; Correia, José Walter

    2012-12-01

    Many cases have been published showing a co-existence of autoimmune thyroid diseases (AITDs) and other autoimmune diseases. About a quarter of patients with achalasia have a concurrent thyroid disease, most commonly associated with hypothyroidism. Although relatively rare, the association of achalasia and hyperthyroidism requires attention. The physiopathology of Grave's Disease (GD) involves B- and T-mediator lymphocytes, which have an affinity for known thyroid antigens: thyroglobulin, thyroid-peroxidase, and thyrotrophin receptor. Currently, however, the real physiopathogenesis of achalasia continues to be unknown. Some important findings are suggestive of an autoimmune mechanism: significant infiltration of the myoenteric plexus by monocytes, presence of the class II-Human Histocompatibility Complex DQwl antigen and antibodies to myoenteric neurons. The present case reports a patient who, despite testing negative for Chagas' disease, had achalasia, progressed to developing significant wasting and worsening of his quality of life, was later diagnosed with hyperthyroidism. After endoscopic esophageal dilatation and radioiodine ablation of the thyroid gland, there was great improvement in the patient clinical condition. PMID:23329193

  18. Hyper-connectivity of functional networks for brain disease diagnosis.

    PubMed

    Jie, Biao; Wee, Chong-Yaw; Shen, Dinggang; Zhang, Daoqiang

    2016-08-01

    Exploring structural and functional interactions among various brain regions enables better understanding of pathological underpinnings of neurological disorders. Brain connectivity network, as a simplified representation of those structural and functional interactions, has been widely used for diagnosis and classification of neurodegenerative diseases, especially for Alzheimer's disease (AD) and its early stage - mild cognitive impairment (MCI). However, the conventional functional connectivity network is usually constructed based on the pairwise correlation among different brain regions and thus ignores their higher-order relationships. Such loss of high-order information could be important for disease diagnosis, since neurologically a brain region predominantly interacts with more than one other brain regions. Accordingly, in this paper, we propose a novel framework for estimating the hyper-connectivity network of brain functions and then use this hyper-network for brain disease diagnosis. Here, the functional connectivity hyper-network denotes a network where each of its edges representing the interactions among multiple brain regions (i.e., an edge can connect with more than two brain regions), which can be naturally represented by a hyper-graph. Specifically, we first construct connectivity hyper-networks from the resting-state fMRI (R-fMRI) time series by using sparse representation. Then, we extract three sets of brain-region specific features from the connectivity hyper-networks, and further exploit a manifold regularized multi-task feature selection method to jointly select the most discriminative features. Finally, we use multi-kernel support vector machine (SVM) for classification. The experimental results on both MCI dataset and attention deficit hyperactivity disorder (ADHD) dataset demonstrate that, compared with the conventional connectivity network-based methods, the proposed method can not only improve the classification performance, but also help

  19. [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

  20. 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

  1. 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

  2. Translation of disease associated gene signatures across tissues.

    PubMed

    Kasim, Adetayo; Shkedy, Ziv; Lin, Dan; Van Sanden, Suzy; Abrahantes, Josè Cortiñas; Göhlmann, Hinrich W H; Bijnens, Luc; Yekutieli, Dani; Camilleri, Michael; Aerssens, Jeroen; Talloen, Willem

    2015-01-01

    It has recently been shown that disease associated gene signatures can be identified by profiling tissue other than the disease related tissue. In this paper, we investigate gene signatures for Irritable Bowel Syndrome (IBS) using gene expression profiling of both disease related tissue (colon) and surrogate tissue (rectum). Gene specific joint ANOVA models were used to investigate differentially expressed genes between the IBS patients and the healthy controls taken into account both intra and inter tissue dependencies among expression levels of the same gene. Classification algorithms in combination with feature selection methods were used to investigate the predictive power of gene expression levels from the surrogate and the target tissues. We conclude based on the analyses that expression profiles of the colon and the rectum tissue could result in better predictive accuracy if the disease associated genes are known. PMID:26333264

  3. Nuclear membrane diversity: underlying tissue-specific pathologies in disease?

    PubMed Central

    Worman, Howard J.; Schirmer, Eric C.

    2015-01-01

    Human ‘laminopathy’ diseases result from mutations in genes encoding nuclear lamins or nuclear envelope (NE) transmembrane proteins (NETs). These diseases present a seeming paradox: the mutated proteins are widely expressed yet pathology is limited to specific tissues. New findings suggest tissue-specific pathologies arise because these widely expressed proteins act in various complexes that include tissue-specific components. Diverse mechanisms to achieve NE tissue-specificity include tissue-specific regulation of the expression, mRNA splicing, signaling, NE-localization and interactions of potentially hundreds of tissue-specific NETs. New findings suggest these NETs underlie tissue-specific NE roles in cytoskeletal mechanics, cell-cycle regulation, signaling, gene expression and genome organization. This view of the NE as ‘specialized’ in each cell type is important to understand the tissue-specific pathology of NE-linked diseases. PMID:26115475

  4. Abnormal fronto-striatal functional connectivity in Parkinson's disease.

    PubMed

    Xu, Jinping; Zhang, Jiuquan; Wang, Jiaojian; Li, Guanglin; Hu, Qingmao; Zhang, Yuanchao

    2016-02-01

    Parkinson's disease (PD) is characterized by the relatively selective depletion of dopamine in the striatum, which consequently leads to dysfunctions in cortico-striatal-thalamic-cortical circuitries. It has been shown that the most common cognitive deficits in PD patients are related to the fronto-striatal circuits. In PD, most previous functional connectivity studies have been performed using seed-based methods to identify the brain regions that are abnormally connected to one or more seeds, but these cannot be used to quantify the interactions between one region and all other regions in a particular network. Functional connectivity degree, which is a measurement that can be used to quantify the functional or structural connectivity of a complex brain network, was adopted in this study to assess the interactions of the fronto-striatal network. Compared to healthy controls, PD patients had significantly decreased total functional connectivity degree for the left putamen and the right globus pallidum in fronto-striatal networks. Additionally, negative correlations between the fronto-pallial functional connectivity degree (i.e., the right globus pallidum with the left middle frontal gyrus, and with the right triangular part of inferior frontal gyrus) and disease duration were observed in PD patients. The results of this study demonstrate that fronto-striatal functional connectivity is abnormal in patients with PD and indicate that these deficits might be the result of motor and cognitive dysfunctions in PD patients. PMID:26724369

  5. Microglial dysfunction connects depression and Alzheimer's disease.

    PubMed

    Santos, Luís Eduardo; Beckman, Danielle; Ferreira, Sergio T

    2016-07-01

    Alzheimer's disease (AD) and major depressive disorder (MDD) are highly prevalent neuropsychiatric conditions with intriguing epidemiological overlaps. Depressed patients are at increased risk of developing late-onset AD, and around one in four AD patients are co-diagnosed with MDD. Microglia are the main cellular effectors of innate immunity in the brain, and their activation is central to neuroinflammation - a ubiquitous process in brain pathology, thought to be a causal factor of both AD and MDD. Microglia serve several physiological functions, including roles in synaptic plasticity and neurogenesis, which may be disrupted in neuroinflammation. Following early work on the 'sickness behavior' of humans and other animals, microglia-derived inflammatory cytokines have been shown to produce depressive-like symptoms when administered exogenously or released in response to infection. MDD patients consistently show increased circulating levels of pro-inflammatory cytokines, and anti-inflammatory drugs show promise for treating depression. Activated microglia are abundant in the AD brain, and concentrate around senile plaques, hallmark lesions composed of aggregated amyloid-β peptide (Aβ). The Aβ burden in affected brains is regulated largely by microglial clearance, and the complex activation state of microglia may be crucial for AD progression. Intriguingly, recent reports have linked soluble Aβ oligomers, toxins that accumulate in AD brains and are thought to cause memory impairment, to increased brain cytokine production and depressive-like behavior in mice. Here, we review recent findings supporting the inflammatory hypotheses of AD and MDD, focusing on microglia as a common player and therapeutic target linking these devastating disorders. PMID:26612494

  6. 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.

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Brain connectivity and novel network measures for Alzheimer's disease classification.

    PubMed

    Prasad, Gautam; Joshi, Shantanu H; Nir, Talia M; Toga, Arthur W; Thompson, Paul M

    2015-01-01

    We compare a variety of different anatomic connectivity measures, including several novel ones, that may help in distinguishing Alzheimer's disease (AD) patients from controls. We studied diffusion-weighted magnetic resonance imaging from 200 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative. We first evaluated measures derived from connectivity matrices based on whole-brain tractography; next, we studied additional network measures based on a novel flow-based measure of brain connectivity, computed on a dense 3-dimensional lattice. Based on these 2 kinds of connectivity matrices, we computed a variety of network measures. We evaluated the measures' ability to discriminate disease with a repeated, stratified 10-fold cross-validated classifier, using support vector machines, a supervised learning algorithm. We tested the relative importance of different combinations of features based on the accuracy, sensitivity, specificity, and feature ranking of the classification of 200 people into normal healthy controls and people with early or late mild cognitive impairment or AD. PMID:25264345

  16. EEG functional connectivity, axon delays and white matter disease

    PubMed Central

    Nunez, Paul L.; Srinivasan, Ramesh; Fields, R. Douglas

    2016-01-01

    Objective Both structural and functional brain connectivities are closely linked to white matter disease. We discuss several such links of potential interest to neurologists, neurosurgeons, radiologists, and non-clinical neuroscientists. Methods Treatment of brains as genuine complex systems suggests major emphasis on the multi-scale nature of brain connectivity and dynamic behavior. Cross-scale interactions of local, regional, and global networks are apparently responsible for much of EEG's oscillatory behaviors. Finite axon propagation speed, often assumed to be infinite in local network models, is central to our conceptual framework. Results Myelin controls axon speed, and the synchrony of impulse traffic between distant cortical regions appears to be critical for optimal mental performance and learning. Results Several experiments suggest that axon conduction speed is plastic, thereby altering the regional and global white matter connections that facilitate binding of remote local networks. Conclusions Combined EEG and high resolution EEG can provide distinct multi-scale estimates of functional connectivity in both healthy and diseased brains with measures like frequency and phase spectra, covariance, and coherence. Significance White matter disease may profoundly disrupt normal EEG coherence patterns, but currently these kinds of studies are rare in scientific labs and essentially missing from clinical environments. PMID:24815984

  17. Cartilage tissue engineering for degenerative joint disease.

    PubMed

    Nesic, Dobrila; Whiteside, Robert; Brittberg, Mats; Wendt, David; Martin, Ivan; Mainil-Varlet, Pierre

    2006-05-20

    Pain in the joint is often due to cartilage degeneration and represents a serious medical problem affecting people of all ages. Although many, mostly surgical techniques, are currently employed to treat cartilage lesions, none has given satisfactory results in the long term. Recent advances in biology and material science have brought tissue engineering to the forefront of new cartilage repair techniques. The combination of autologous cells, specifically designed scaffolds, bioreactors, mechanical stimulations and growth factors together with the knowledge that underlies the principles of cell biology offers promising avenues for cartilage tissue regeneration. The present review explores basic biology mechanisms for cartilage reconstruction and summarizes the advances in the tissue engineering approaches. Furthermore, the limits of the new methods and their potential application in the osteoarthritic conditions are discussed. PMID:16574268

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. Perivascular adipose tissue in vascular function and disease: a review of current research and animal models

    PubMed Central

    Brown, Nicholas K.; Zhou, Zhou; Zhang, Jifeng; Zeng, Rong; Wu, Jiarui; Eitzman, Daniel T.; Chen, Y. Eugene; Chang, Lin

    2014-01-01

    Perivascular adipose tissue (PVAT), long assumed to be nothing more than vessel-supporting connective tissue, is now understood to be an important, active component of the vasculature, with integral roles in vascular health and disease. PVAT is an adipose tissue with similarities to both brown and white adipose tissue, although recent evidence suggests that PVAT develops from its own precursors. Like other adipose tissue depots, PVAT secretes numerous biologically active substances that can act in both autocrine and paracrine fashion. PVAT has also proven to be involved in vascular inflammation. While PVAT can support inflammation during atherosclerosis via macrophage accumulation, emerging evidence suggests that PVAT also has anti-atherosclerotic properties related to its abilities to induce non-shivering thermogenesis and metabolize fatty acids. We here discuss the accumulated knowledge of PVAT biology, and related research on models of hypertension and atherosclerosis. PMID:24833795

  3. 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

  4. Thrombomodulin Expression in Tissues From Dogs With Systemic Inflammatory Disease.

    PubMed

    Kim, S D; Baker, P; DeLay, J; Wood, R D

    2016-07-01

    Thrombomodulin (TM) is a membrane glycoprotein expressed on endothelial cells, which plays a major role in the protein C anticoagulation pathway. In people with inflammation, TM expression can be down-regulated on endothelial cells and a soluble form released into circulation, resulting in increased risk of thrombosis and disseminated intravascular coagulation. TM is present in dogs; however, there has been minimal investigation of its expression in canine tissues, and the effects of inflammation on TM expression in canine tissues have not been investigated. The objective of this study was to evaluate endothelial TM expression in tissues from dogs with systemic inflammatory diseases. A retrospective evaluation of tissue samples of lung, spleen, and liver from dogs with and without systemic inflammatory diseases was performed using immunohistochemistry (IHC) and a modified manual IHC scoring system. TM expression was significantly reduced in all examined tissues in dogs diagnosed with septic peritonitis or acute pancreatitis. PMID:26926084

  5. Wnt pathway in Dupuytren disease: connecting profibrotic signals.

    PubMed

    van Beuge, Marike M; Ten Dam, Evert-Jan P M; Werker, Paul M N; Bank, Ruud A

    2015-12-01

    A role of Wnt signaling in Dupuytren disease, a fibroproliferative disease of the hand and fingers, has not been fully elucidated. We examined a large set of Wnt pathway components and signaling targets and found significant dysregulation of 41 Wnt-related genes in tissue from the Dupuytren nodules compared with patient-matched control tissue. A large proportion of genes coding for Wnt proteins themselves was downregulated. However, both canonical Wnt targets and components of the noncanonical signaling pathway were upregulated. Immunohistochemical analysis revealed that protein expression of Wnt1-inducible secreted protein 1 (WISP1), a known Wnt target, was increased in nodules compared with control tissue, but knockdown of WISP1 using small interfering RNA (siRNA) in the Dupuytren myofibroblasts did not confirm a functional role. The protein expression of noncanonical pathway components Wnt5A and VANGL2 as well as noncanonical coreceptors Ror2 and Ryk was increased in nodules. On the contrary, the strongest downregulated genes in this study were 4 antagonists of Wnt signaling (DKK1, FRZB, SFRP1, and WIF1). Downregulation of these genes in the Dupuytren tissue was mimicked in vitro by treating normal fibroblasts with transforming growth factor β1 (TGF-β1), suggesting cross talk between different profibrotic pathways. Furthermore, siRNA-mediated knockdown of these antagonists in normal fibroblasts led to increased nuclear translocation of Wnt target β-catenin in response to TGF-β1 treatment. In conclusion, we have shown extensive dysregulation of Wnt signaling in affected tissue from Dupuytren disease patients. Components of both the canonical and the noncanonical pathways are upregulated, whereas endogenous antagonists are downregulated, possibly via interaction with other profibrotic pathways. PMID:26470681

  6. 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

  7. 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

  8. Increased monocyte tissue factor expression in coronary disease.

    PubMed Central

    Leatham, E. W.; Bath, P. M.; Tooze, J. A.; Camm, A. J.

    1995-01-01

    OBJECTIVE--To investigate whether monocyte expression of tissue factor is increased in patients with acute coronary syndromes and chronic stable angina. DESIGN--Cross sectional study of monocyte tissue factor expression in patients with ischaemic heart disease and control subjects. BACKGROUND--Unstable angina and myocardial infarction are associated with enhanced mononuclear cell procoagulant activity. Procoagulant activity of blood monocytes is principally mediated by tissue factor expression. Tissue factor initiates the coagulation cascade and monocyte tissue factor expression may therefore be increased in these syndromes. METHODS--Monocyte tissue factor expression was measured cytometrically in whole blood flow using a polyclonal rabbit antihuman tissue factor antibody. PATIENTS--30 patients with acute myocardial infarction, 17 with unstable angina, 13 with chronic stable angina, and 11 normal control subjects. RESULTS--Increased proportions of monocytes expressing tissue factor (> 2.5%) were found in none of 11 (0%) normal subjects, five 13 (38%) patients with stable angina, 11 of 17 (64%) patients with unstable angina, and 16 of 30 (53%) patients with myocardial infarction (2P = 0.006). Blood from all subjects showed similar monocyte tissue factor expression similar monocyte tissue factor expression (46.1 (15.1)%) after lipopolysaccharide stimulation. CONCLUSION--Hypercoagulability associated with acute myocardial infarction, unstable angina, and chronic stable angina may be induced by tissue factor expressed on circulating monocytes. PMID:7888247

  9. Mathematical Analysis of Biomolecular Network Reveals Connections Between Diseases

    NASA Astrophysics Data System (ADS)

    Wang, Guanyu

    2012-02-01

    Connections between cancer and metabolic diseases may consist in the complex network of interactions among a common set of biomolecules. By applying singularity and bifurcation analysis, the phenotypes constrained by the AKT signaling pathway are identified and mapped onto the parameter space, which include cancer and certain metabolic diseases. By considering physiologic properties (sensitivity, robustness and adaptivity) the AKT pathway must possess in order to efficiently sense growth factors and nutrients, the region of normal responses is located. The analysis illuminates the parameter space and reveals system-level mechanisms in regulating biological functions (cell growth, survival, proliferation and metabolism) and how their deregulation may lead to the development of diseases. The analytical expressions summarize the synergistic interactions among many molecules, which provides valuable insights into therapeutic interventions.

  10. Decreased coherence and functional connectivity of electroencephalograph in Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Wang, Ruofan; Wang, Jiang; Yu, Haitao; Wei, Xile; Yang, Chen; Deng, Bin

    2014-09-01

    In this paper, we investigate the abnormalities of electroencephalograph (EEG) signals in the Alzheimer's disease (AD) by analyzing 16-scalp electrodes EEG signals and make a comparison with the normal controls. Coherence is introduced to measure the pair-wise normalized linear synchrony and functional correlations between two EEG signals in different frequency domains, and graph analysis is further used to investigate the influence of AD on the functional connectivity of human brain. Data analysis results show that, compared with the control group, the pair-wise coherence of AD group is significantly decreased, especially for the theta and alpha frequency bands in the frontal and parieto-occipital regions. Furthermore, functional connectivity among different brain regions is reconstructed based on EEG, which exhibit obvious small-world properties. Graph analysis demonstrates that the local functional connections between regions for AD decrease. In addition, it is found that small-world properties of AD networks are largely weakened, by calculating its average path lengths, clustering coefficients, global efficiency, local efficiency, and small-worldness. The obtained results show that both pair-wise coherence and functional network can be taken as effective measures to distinguish AD patients from the normal, which may benefit our understanding of the disease.

  11. 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...

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. External globus pallidus stimulation modulates brain connectivity in Huntington's disease.

    PubMed

    Ligot, Noémie; Krystkowiak, Pierre; Simonin, Clémence; Goldman, Serge; Peigneux, Philippe; Van Naemen, John; Monclus, Michel; Lacroix, Simon Frédéric; Devos, David; Dujardin, Kathy; Delmaire, Christine; Bardinet, Eric; Delval, Arnaud; Delliaux, Marie; Defebvre, Luc; Yelnik, Jerome; Blond, Serge; Destée, Alain; De Tiège, Xavier

    2011-01-01

    Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model. PMID:20959850

  19. External globus pallidus stimulation modulates brain connectivity in Huntington's disease

    PubMed Central

    Ligot, Noémie; Krystkowiak, Pierre; Simonin, Clémence; Goldman, Serge; Peigneux, Philippe; Van Naemen, John; Monclus, Michel; Lacroix, Simon Frédéric; Devos, David; Dujardin, Kathy; Delmaire, Christine; Bardinet, Eric; Delval, Arnaud; Delliaux, Marie; Defebvre, Luc; Yelnik, Jerome; Blond, Serge; Destée, Alain; De Tiège, Xavier

    2011-01-01

    Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model. PMID:20959850

  20. CARS microscopy of Alzheimer's diseased brain tissue

    NASA Astrophysics Data System (ADS)

    Enejder, Annika; Kiskis, Juris; Fink, Helen; Nyberg, Lena; Thyr, Jakob; Li, Jia-Yi

    2014-02-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder currently without cure, characterized by the presence of extracellular plaques surrounded by dystrophic neurites. In an effort to understand the underlying mechanisms, biochemical analysis (protein immunoblot) of plaque extracts reveals that they consist of amyloid-beta (Aβ) peptides assembled as oligomers, protofibrils and aggregates. Their spatial distribution has been confirmed by Thioflavin-S or immuno-staining with fluorescence microscopy. However, it is increasingly understood that the protein aggregation is only one of several mechanism that causes neuronal dysfunction and death. This raises the need for a more complete biochemical analysis. In this study, we have complemented 2-photon fluorescence microscopy of Thioflavin-S and Aβ immuno-stained human AD plaques with CARS microscopy. We show that the chemical build-up of AD plaques is more complex and that Aβ staining does not provide the complete picture of the spatial distribution or the molecular composition of AD plaques. CARS images provide important complementary information to that obtained by fluorescence microscopy, motivating a broader introduction of CARS microscopy in the AD research field.

  1. Tissue stiffness dictates development, homeostasis, and disease progression.

    PubMed

    Handorf, Andrew M; Zhou, Yaxian; Halanski, Matthew A; Li, Wan-Ju

    2015-01-01

    Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression. PMID:25915734

  2. Inflammation Biomarkers of Advanced Disease in Nongingival Tissues of Chronic Periodontitis Patients

    PubMed Central

    da Costa, Thiago Alvares; Silva, Marcelo José Barbosa; Alves, Polyanna Miranda; Chica, Javier Emílio Lazo; Barcelos, Emilio Zorzo; Giani, Max Antonio Alves; Garlet, Gustavo Pompermaier; da Silva, João Santana; Rodrigues Júnior, Virmondes; Rodrigues, Denise Bertulucci Rocha; Cardoso, Cristina Ribeiro de Barros

    2015-01-01

    Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17+ and TRAP+ cells. The levels of TNF-α and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-α and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression. PMID:26063981

  3. 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

  4. 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

  5. Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease.

    PubMed

    Borchert, Robin J; Rittman, Timothy; Passamonti, Luca; Ye, Zheng; Sami, Saber; Jones, Simon P; Nombela, Cristina; Vázquez Rodríguez, Patricia; Vatansever, Deniz; Rae, Charlotte L; Hughes, Laura E; Robbins, Trevor W; Rowe, James B

    2016-07-01

    Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest ('task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems. PMID:26837463

  6. Atomoxetine Enhances Connectivity of Prefrontal Networks in Parkinson's Disease

    PubMed Central

    Borchert, Robin J; Rittman, Timothy; Passamonti, Luca; Ye, Zheng; Sami, Saber; Jones, Simon P; Nombela, Cristina; Vázquez Rodríguez, Patricia; Vatansever, Deniz; Rae, Charlotte L; Hughes, Laura E; Robbins, Trevor W; Rowe, James B

    2016-01-01

    Cognitive impairment is common in Parkinson's disease (PD), but often not improved by dopaminergic treatment. New treatment strategies targeting other neurotransmitter deficits are therefore of growing interest. Imaging the brain at rest (‘task-free') provides the opportunity to examine the impact of a candidate drug on many of the brain networks that underpin cognition, while minimizing task-related performance confounds. We test this approach using atomoxetine, a selective noradrenaline reuptake inhibitor that modulates the prefrontal cortical activity and can facilitate some executive functions and response inhibition. Thirty-three patients with idiopathic PD underwent task-free fMRI. Patients were scanned twice in a double-blind, placebo-controlled crossover design, following either placebo or 40-mg oral atomoxetine. Seventy-six controls were scanned once without medication to provide normative data. Seed-based correlation analyses were used to measure changes in functional connectivity, with the right inferior frontal gyrus (IFG) a critical region for executive function. Patients on placebo had reduced connectivity relative to controls from right IFG to dorsal anterior cingulate cortex and to left IFG and dorsolateral prefrontal cortex. Atomoxetine increased connectivity from the right IFG to the dorsal anterior cingulate. In addition, the atomoxetine-induced change in connectivity from right IFG to dorsolateral prefrontal cortex was proportional to the change in verbal fluency, a simple index of executive function. The results support the hypothesis that atomoxetine may restore prefrontal networks related to executive functions. We suggest that task-free imaging can support translational pharmacological studies of new drug therapies and provide evidence for engagement of the relevant neurocognitive systems. PMID:26837463

  7. 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

  8. 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

  9. 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

  10. 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 .

  11. 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

  12. 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

  13. Adipose tissue-liver axis in alcoholic liver disease.

    PubMed

    Wang, Zhi-Gang; Dou, Xiao-Bing; Zhou, Zhan-Xiang; Song, Zhen-Yuan

    2016-02-15

    Alcoholic liver disease (ALD) remains an important health problem worldwide. The disease spectrum is featured by early steatosis, steatohepatitis (steatosis with inflammatory cells infiltration and necrosis), with some individuals ultimately progressing to fibrosis/cirrhosis. Although the disease progression is well characterized, no effective therapies are currently available for the treatment in humans. The mechanisms underlying the initiation and progression of ALD are multifactorial and complex. Emerging evidence supports that adipose tissue dysfunction contributes to the pathogenesis of ALD. In the first part of this review, we discuss the mechanisms whereby chronic alcohol exposure contributed to adipose tissue dysfunction, including cell death, inflammation and insulin resistance. It has been long known that aberrant hepatic methionine metabolism is a major metabolic abnormality induced by chronic alcohol exposure and plays an etiological role in the pathogenesis of ALD. The recent studies in our group documented the similar metabolic effect of chronic alcohol drinking on methionine in adipose tissue. In the second part of this review, we also briefly discuss the recent research progress in the field with a focus on how abnormal methionine metabolism in adipose tissue contributes to adipose tissue dysfunction and liver damage. PMID:26909225

  14. Adipose tissue-liver axis in alcoholic liver disease

    PubMed Central

    Wang, Zhi-Gang; Dou, Xiao-Bing; Zhou, Zhan-Xiang; Song, Zhen-Yuan

    2016-01-01

    Alcoholic liver disease (ALD) remains an important health problem worldwide. The disease spectrum is featured by early steatosis, steatohepatitis (steatosis with inflammatory cells infiltration and necrosis), with some individuals ultimately progressing to fibrosis/cirrhosis. Although the disease progression is well characterized, no effective therapies are currently available for the treatment in humans. The mechanisms underlying the initiation and progression of ALD are multifactorial and complex. Emerging evidence supports that adipose tissue dysfunction contributes to the pathogenesis of ALD. In the first part of this review, we discuss the mechanisms whereby chronic alcohol exposure contributed to adipose tissue dysfunction, including cell death, inflammation and insulin resistance. It has been long known that aberrant hepatic methionine metabolism is a major metabolic abnormality induced by chronic alcohol exposure and plays an etiological role in the pathogenesis of ALD. The recent studies in our group documented the similar metabolic effect of chronic alcohol drinking on methionine in adipose tissue. In the second part of this review, we also briefly discuss the recent research progress in the field with a focus on how abnormal methionine metabolism in adipose tissue contributes to adipose tissue dysfunction and liver damage. PMID:26909225

  15. Periodontal disease and the oral-systemic connection: "is it all the RAGE?".

    PubMed

    Katz, Joseph; Wallet, Shannon; Cha, Seunghee

    2010-03-01

    Ample studies have reported on the association between periodontal diseases, a persistent inflammatory process, and other chronic ailments such as cardiovascular diseases, diabetes mellitus, Alzheimer disease, and cancer. Other conditions such as low birth weight and premature delivery due to chorioamnionitis are also known to be linked to poor periodontal health. Although much epidemiologic data support these associations, a cause-and-effect relationship has not been established. The receptor for advanced glycation end products (RAGE) is a multiligand receptor expressed on various cell membranes, including immune, endothelial, and epithelial, and cells of the central nervous system. This receptor, which is frequently associated with proinflammatory responses, has been shown to be activated by various ligands such as high mobility group box-1 (HMGB1/amphoterin), amyloid fibrils, transthyrein, Mac-1 (Integrin Mac-1), as well as advanced glycation end products (AGEs). Recent studies indicate that signaling through RAGE has been implicated as an underlying condition in diverse pathologies including periodontal disease, cardiovascular diseases, diabetes mellitus, Alzheimer disease, cancer, and neurologic conditions. Review of the literature supports the hypothesis that activation of RAGE by ligands in a variety of cell types and tissues may play a role in oral systemic associations. In addition, the ligand cell source and timing of RAGE stimulation may determine the disease produced by this axis. Understanding the distribution and functions of RAGE and its ligands would enhance clinicians' knowledge on pathogenesis of the oral-systemic connection. PMID:20213024

  16. 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

  17. 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

  18. Quiet connections: Reduced fronto-temporal connectivity in nondemented Parkinson's Disease during working memory encoding.

    PubMed

    Wiesman, Alex I; Heinrichs-Graham, Elizabeth; McDermott, Timothy J; Santamaria, Pamela M; Gendelman, Howard E; Wilson, Tony W

    2016-09-01

    Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor symptoms such as bradykinesia, muscle rigidity, and resting tremor. It is now broadly accepted that these motor symptoms frequently co-occur with cognitive impairments, with deficits in working memory and attention being among the most common cognitive sequelae associated with PD. While these cognitive impairments are now recognized, the underlying neural dynamics and precise regions involved remain largely unknown. To this end, we examined the oscillatory dynamics and interregional functional connectivity that serve working memory processing in a group of unmedicated adults with PD and a matched group without PD. Each participant completed a high-load, Sternberg-type working memory task during magnetoencephalography (MEG), and we focused on the encoding and maintenance phases. All data were transformed into the time-frequency domain and significant oscillatory activity was imaged using a beamforming approach. Phase-coherence (connectivity) was also computed among the brain subregions exhibiting the strongest responses. Our most important findings were that unmedicated patients with PD had significantly diminished working memory performance (i.e., accuracy), and reduced functional connectivity between left inferior frontal cortices and left supramarginal-superior temporal cortices compared to participants without PD during the encoding phase of working memory processing. We conclude that patients with PD have reduced neural interactions between left prefrontal executive circuits and temporary verbal storage centers in the left supramarginal/superior temporal cortices during the stimulus encoding phase, which may underlie their diminished working memory function. Hum Brain Mapp 37:3224-3235, 2016. © 2016 Wiley Periodicals, Inc. PMID:27151624

  19. Decreased interhemispheric functional connectivity in subtypes of Parkinson's disease.

    PubMed

    Hu, Xiaofei; Zhang, Jiuquan; Jiang, Xiaomei; Zhou, Chaoyang; Wei, Luqing; Yin, Xuntao; Wu, Ya; Li, Jing; Zhang, Yanling; Wang, Jian

    2015-03-01

    Parkinson's disease (PD) can be classified into tremor-dominant (TD) subtype and akinetic-rigid (AR) subtype, which exhibit different clinical courses and prognoses. However, the neural mechanisms underlying different subtypes of PD are not well understood. Using voxel-mirrored homotopic connectivity (VMHC), we examined the homotopic resting-state functional connectivity patterns in akinetic-rigid PD (AR-PD) and tremor-dominant PD (TD-PD) to study the neural basis for these disparate manifestations of PD. Twenty-one TD-PD patients, 29 AR-PD patients and 26 normal control subjects participated in this study. Resting-state fMRI data were analyzed using VMHC. Correlations between VMHC values and each clinical characteristic were also calculated. Compared with normal control subjects and subjects with AR-PD, subjects with TD-PD exhibited significantly lower VMHC values in the posterior lobe of the cerebellum. Moreover, tremor scores and VMHC values for the cerebellum were found to be significantly negatively correlated in TD-PD patients. By contrast, subjects with AR-PD exhibited lower VMHC values in the precentral gyrus compared with normal control subjects. These findings suggest that functional coordination between homotopic brain regions is impaired in AR-PD and TD-PD patients. This study provides evidence of both cerebellum-related connectivity deficits in TD-PD. The finding that VMHC values and tremor scores were significantly correlated suggests that VMHC measurements may be of potential clinical relevance in TD-PD. PMID:25577177

  20. 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

  1. 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

  2. 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

  3. [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

  4. Midcingulate cortex: Structure, connections, homologies, functions and diseases.

    PubMed

    Vogt, Brent A

    2016-07-01

    Midcingulate cortex (MCC) has risen in prominence as human imaging identifies unique structural and functional activity therein and this is the first review of its structure, connections, functions and disease vulnerabilities. The MCC has two divisions (anterior, aMCC and posterior, pMCC) that represent functional units and the cytoarchitecture, connections and neurocytology of each is shown with immunohistochemistry and receptor binding. The MCC is not a division of anterior cingulate cortex (ACC) and the "dorsal ACC" designation is a misnomer as it incorrectly implies that MCC is a division of ACC. Interpretation of findings among species and developing models of human diseases requires detailed comparative studies which is shown here for five species with flat maps and immunohistochemistry (human, monkey, rabbit, rat, mouse). The largest neurons in human cingulate cortex are in layer Vb of area 24 d in pMCC which project to the spinal cord. This area is part of the caudal cingulate premotor area which is involved in multisensory orientation of the head and body in space and neuron responses are tuned for the force and direction of movement. In contrast, the rostral cingulate premotor area in aMCC is involved in action-reinforcement associations and selection based on the amount of reward or aversive properties of a potential movement. The aMCC is activated by nociceptive information from the midline, mediodorsal and intralaminar thalamic nuclei which evoke fear and mediates nocifensive behaviors. This subregion also has high dopaminergic afferents and high dopamine-1 receptor binding and is engaged in reward processes. Opposing pain/avoidance and reward/approach functions are selected by assessment of potential outcomes and error detection according to feedback-mediated, decision making. Parietal afferents differentially terminate in MCC and provide for multisensory control in an eye- and head-centric manner. Finally, MCC vulnerability in human disease confirms

  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. 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

  8. Functional connectivity and graph theory in preclinical Alzheimer's disease.

    PubMed

    Brier, Matthew R; Thomas, Jewell B; Fagan, Anne M; Hassenstab, Jason; Holtzman, David M; Benzinger, Tammie L; Morris, John C; Ances, Beau M

    2014-04-01

    Alzheimer's disease (AD) has a long preclinical phase in which amyloid and tau cerebral pathology accumulate without producing cognitive symptoms. Resting state functional connectivity magnetic resonance imaging has demonstrated that brain networks degrade during symptomatic AD. It is unclear to what extent these degradations exist before symptomatic onset. In this study, we investigated graph theory metrics of functional integration (path length), functional segregation (clustering coefficient), and functional distinctness (modularity) as a function of disease severity. Further, we assessed whether these graph metrics were affected in cognitively normal participants with cerebrospinal fluid evidence of preclinical AD. Clustering coefficient and modularity, but not path length, were reduced in AD. Cognitively normal participants who harbored AD biomarker pathology also showed reduced values in these graph measures, demonstrating brain changes similar to, but smaller than, symptomatic AD. Only modularity was significantly affected by age. We also demonstrate that AD has a particular effect on hub-like regions in the brain. We conclude that AD causes large-scale disconnection that is present before onset of symptoms. PMID:24216223

  9. Morpho-chemistry and functionality of diseased biological tissues

    NASA Astrophysics Data System (ADS)

    Lange, Marta; Cicchi, Riccardo; Pavone, Francesco

    2014-09-01

    Heart and cardiovascular diseases are one of the most common in the world, in particular - arthrosclerosis. The aim of the research is to distinguish pathological and healthy tissue regions in biological samples, in this case - to distinguish collagen and lipid rich regions within the arterial wall. In the work a specific combination of such methods are used: FLIM and SHG in order to evaluate the biological tissue morphology and functionality, so that this research could give a contribution for creating a new biological tissue imaging standard in the closest future. During the study the most appropriate parameter for fluorescence lifetime decay was chosen in order to evaluate lifetime decay parameters and the isotropy of the arterial wall and deposition, using statistical methods FFT and GLCM. The research gives a contribution or the future investigations for evaluating lipid properties when it can de-attach from the arterial wall and cause clotting in the blood vessel or even a stroke.

  10. Creating a global dialogue on infectious disease surveillance: connecting organizations for regional disease surveillance (CORDS).

    PubMed

    Gresham, Louise S; Smolinski, Mark S; Suphanchaimat, Rapeepong; Kimball, Ann Marie; Wibulpolprasert, Suwit

    2013-01-01

    Connecting Organizations for Regional Disease Surveillance (CORDS) is an international non-governmental organization focused on information exchange between disease surveillance networks in different areas of the world. By linking regional disease surveillance networks, CORDS builds a trust-based social fabric of experts who share best practices, surveillance tools and strategies, training courses, and innovations. CORDS exemplifies the shifting patterns of international collaboration needed to prevent, detect, and counter all types of biological dangers - not just naturally occurring infectious diseases, but also terrorist threats. Representing a network-of-networks approach, the mission of CORDS is to link regional disease surveillance networks to improve global capacity to respond to infectious diseases. CORDS is an informal governance cooperative with six founding regional disease surveillance networks, with plans to expand; it works in complement and cooperatively with the World Health Organization (WHO), the World Organization for Animal Health (OIE), and the Food and Animal Organization of the United Nations (FAO). As described in detail elsewhere in this special issue of Emerging Health Threats, each regional network is an alliance of a small number of neighboring countries working across national borders to tackle emerging infectious diseases that require unified regional efforts. Here we describe the history, culture and commitment of CORDS; and the novel and necessary role that CORDS serves in the existing international infectious disease surveillance framework. PMID:23362412

  11. Creating a Global Dialogue on Infectious Disease Surveillance: Connecting Organizations for Regional Disease Surveillance (CORDS)

    PubMed Central

    Gresham, Louise S.; Smolinski, Mark S.; Suphanchaimat, Rapeepong; Kimball, Ann Marie; Wibulpolprasert, Suwit

    2013-01-01

    Connecting Organizations for Regional Disease Surveillance (CORDS) is an international non-governmental organization focused on information exchange between disease surveillance networks in different areas of the world. By linking regional disease surveillance networks, CORDS builds a trust-based social fabric of experts who share best practices, surveillance tools and strategies, training courses, and innovations. CORDS exemplifies the shifting patterns of international collaboration needed to prevent, detect, and counter all types of biological dangers – not just naturally occurring infectious diseases, but also terrorist threats. Representing a network-of-networks approach, the mission of CORDS is to link regional disease surveillance networks to improve global capacity to respond to infectious diseases. CORDS is an informal governance cooperative with six founding regional disease surveillance networks, with plans to expand; it works in complement and cooperatively with the World Health Organization (WHO), the World Organization for Animal Health (OIE), and the Food and Animal Organization of the United Nations (FAO). As described in detail elsewhere in this special issue of Emerging Health Threats, each regional network is an alliance of a small number of neighboring countries working across national borders to tackle emerging infectious diseases that require unified regional efforts. Here we describe the history, culture and commitment of CORDS; and the novel and necessary role that CORDS serves in the existing international infectious disease surveillance framework. PMID:23362412

  12. 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

  13. 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

  14. 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

  15. Nanomedicine: Addressing Cardiovascular Disease and Cardiovascular Tissue Regeneration

    PubMed Central

    Botchwey, Edward A.

    2016-01-01

    Cardiovascular disease is becoming an increasingly significant problem. In attempts to overcome many of the traditional hurdles of cardiovascular disease treatment, therapeutic approaches have been gradually moving beyond an exclusive focus on orally delivered drugs towards the development of nanoscale applications. These technologies exploit molecular scale events to improve drug and gene delivery applications, enhance preventative medicine and diagnostic strategies, and create biomimicking substrates for vascular tissue engineering. As nanoscale treatments enter the arena of clinical medicine, new ways of thinking about and routes for applying nanomedicine to cardiovascular health issues are emerging. With focuses on drug delivery, gene therapy, and biomimetics, this article will provide a comprehensive review of various nanomedicine applications for combating atherosclerosis and for improving upon current vascular tissue engineering designs.

  16. 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

  17. Perspectives on Tissue Interactions in Development and Disease

    PubMed Central

    Strand, D.W.; Franco, O.E.; Basanta, D.; Anderson, A.R.A.; Hayward, S.W.

    2014-01-01

    From the morphogenetic movements of the three germ layers during development to the reactive stromal microenvironment in cancer, tissue interactions are vital to maintaining healthy organ morphologic architecture and function. The stromal compartment is thought to be complicit in tumor progression and, as such, represents an opportune target for disease therapies. However, recent developments in our understanding of the diversity of the stromal compartment and the lack of appropriate models to study its relevance in human disease have limited our further understanding of the role of tissue interactions in tumor progression. The failure of any model to fully recapitulate the complexities of systemic biology continues to create a higher imperative for incorporating various perspectives into a broader understanding for the ultimate goal of designing interventional therapies. Understanding this potential, this review examines the biological models used to study stromal-epithelial interactions and includes an attempt to incorporate behavioral terminology to define and mathematically model ecological relationships in stromal-epithelial interactions. In addition, the current attempt to incorporate these diverse ecological perspectives into in silico mathematical models through cross-disciplinary coordination is reviewed, which will provide a fresh perspective on defining cell group behavior and tissue ecology in disease and hopefully lead to the generation of new hypotheses to be empirically validated. PMID:20205682

  18. 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

  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. 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

  3. Network topology and functional connectivity disturbances precede the onset of Huntington's disease.

    PubMed

    Harrington, Deborah L; Rubinov, Mikail; Durgerian, Sally; Mourany, Lyla; Reece, Christine; Koenig, Katherine; Bullmore, Ed; Long, Jeffrey D; Paulsen, Jane S; Rao, Stephen M

    2015-08-01

    Cognitive, motor and psychiatric changes in prodromal Huntington's disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntington's disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene-negative controls (n = 16) and prodromal Huntington's disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal-posterior connections that evolved as disease

  4. The metabolic syndrome as a concept of adipose tissue disease.

    PubMed

    Oda, Eiji

    2008-07-01

    The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to directly promote the development of diabetes and cardiovascular disease. However, in 2005, the American Diabetes Association and the European Association for the Study of Diabetes jointly stated that no existing definition of the metabolic syndrome meets the criteria of a syndrome, and there have been endless debates on the pros and cons of using the concept of this syndrome. The controversy may stem from confusion between the syndrome and obesity. Obesity is an epidemic, essentially contagious disease caused by an environment of excess nutritional energy and reinforced by deeply rooted social norms. The epidemic of obesity should be prevented or controlled by social and political means, similar to the approaches now being taken to combat global warming. The diagnosis of metabolic syndrome is useless for this public purpose. The purpose of establishing criteria for diagnosing metabolic syndrome is to find individuals who are at increased risk of diabetes and cardiovascular disease and who require specific therapy including diet and exercise. The syndrome may be an adipose tissue disease different from obesity; in that case, it would be characterized by inflammation clinically detected through systemic inflammatory markers such as high-sensitivity C-reactive protein and insulin resistance reflecting histological changes in adipose tissue. However, many problems in defining the optimal diagnostic criteria remain unresolved. PMID:18957797

  5. Brain tissue modifications induced by cholinergic therapy in Alzheimer's disease.

    PubMed

    Bozzali, Marco; Parker, Geoff J M; Spanò, Barbara; Serra, Laura; Giulietti, Giovanni; Perri, Roberta; Magnani, Giuseppe; Marra, Camillo; G Vita, Maria; Caltagirone, Carlo; Cercignani, Mara

    2013-12-01

    A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement. PMID:22711258

  6. RD-Connect: an integrated platform connecting databases, registries, biobanks and clinical bioinformatics for rare disease research.

    PubMed

    Thompson, Rachel; Johnston, Louise; Taruscio, Domenica; Monaco, Lucia; Béroud, Christophe; Gut, Ivo G; Hansson, Mats G; 't Hoen, Peter-Bram A; Patrinos, George P; Dawkins, Hugh; Ensini, Monica; Zatloukal, Kurt; Koubi, David; Heslop, Emma; Paschall, Justin E; Posada, Manuel; Robinson, Peter N; Bushby, Kate; Lochmüller, Hanns

    2014-08-01

    Research into rare diseases is typically fragmented by data type and disease. Individual efforts often have poor interoperability and do not systematically connect data across clinical phenotype, genomic data, biomaterial availability, and research/trial data sets. Such data must be linked at both an individual-patient and whole-cohort level to enable researchers to gain a complete view of their disease and patient population of interest. Data access and authorization procedures are required to allow researchers in multiple institutions to securely compare results and gain new insights. Funded by the European Union's Seventh Framework Programme under the International Rare Diseases Research Consortium (IRDiRC), RD-Connect is a global infrastructure project initiated in November 2012 that links genomic data with registries, biobanks, and clinical bioinformatics tools to produce a central research resource for rare diseases. PMID:25029978

  7. Microbiome Heterogeneity Characterizing Intestinal Tissue and Inflammatory Bowel Disease Phenotype.

    PubMed

    Tyler, Andrea D; Kirsch, Richard; Milgrom, Raquel; Stempak, Joanne M; Kabakchiev, Boyko; Silverberg, Mark S

    2016-04-01

    Inflammatory bowel disease has been associated with differential abundance of numerous organisms when compared to healthy controls (HCs); however, few studies have investigated variability in the microbiome across intestinal locations and how this variability might be related to disease location and phenotype. In this study, we have analyzed the microbiome of a large cohort of individuals recruited at Mount Sinai Hospital in Toronto, Canada. Biopsies were taken from subjects with Crohn's disease, ulcerative colitis, and HC, and also individuals having undergone ileal pouch-anal anastomosis for treatment of ulcerative colitis or familial adenomatous polyposis. Microbial 16S rRNA was sequenced using the Illumina MiSeq platform. We observed a great deal of variability in the microbiome characterizing different sampling locations. Samples from pouch and afferent limb were comparable in microbial composition. When comparing sigmoid and terminal ileum samples, more differences were observed. The greatest number of differentially abundant microbes was observed when comparing either pouch or afferent limb samples to sigmoid or terminal ileum. Despite these differences, we were able to observe modest microbial variability between inflammatory bowel disease phenotypes and HCs, even when controlling for sampling location and additional experimental factors. Most detected associations were observed between HCs and Crohn's disease, with decreases in specific genera in the families Ruminococcaceae and Lachnospiraceae characterizing tissue samples from individuals with Crohn's disease. This study highlights important considerations when analyzing the composition of the microbiome and also provides useful insight into differences in the microbiome characterizing these seemingly related phenotypes. PMID:26954709

  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. 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

  13. Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection.

    PubMed

    Cohen, P G

    2001-06-01

    In males, aging, health and disease are processes that occur over physiologic time and involve a cascade of hormonal, biochemical and physiological changes that accompany the down-regulation of the hypothalamic-anterior pituitary-testicular axis. As aging progresses there are relative increases of body fat and decreases in muscle mass. The increased adipose tissue mass is associated with the production of a number of newly generated factors. These include aromatase, leptin, PAI-1, insulin resistance, and the dyslipidemias, all of which can lead to tissue damage. Fatty tissue becomes the focal point for study as it represents the intersection between energy storage and mobilization. The increase in adipose tissue is associated with an increase in the enzyme aromatase that converts testosterone to estradiol and leads to diminished testosterone levels that favor the preferential deposition of visceral fat. As the total body fat mass increases, hormone resistance develops for leptin and insulin. Increasing leptin fails to prevent weight gain and the hypogonadal-obesity cycle ensues causing further visceral obesity and insulin resistance. The progressive insulin resistance leads to a high triglyceride-low HDL pattern of dyslipidemia and increased cardiovascular risk. All of these factors eventually contribute to the CHAOS Complex: coronary disease, hypertension, adult-onset diabetes mellitus, obesity and/or stroke as permanent changes unfold. Other consequences of the chronic hypogonadal state include osteopenia, extreme fatigue, depression, insomnia, loss of aggressiveness and erectile dysfunction all of which develop over variable periods of time. PMID:11399122

  14. 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

  15. Pyrosequencing revealed shifts of prokaryotic communities between healthy and disease-like tissues of the Red Sea sponge Crella cyathophora

    PubMed Central

    Gao, Zhao-Ming; Wang, Yong; Tian, Ren-Mao; Lee, On On; Wong, Yue Him; Batang, Zenon B.; Al-Suwailem, Abdulaziz; Lafi, Feras F.; Bajic, Vladimir B.

    2015-01-01

    Sponge diseases have been widely reported, yet the causal factors and major pathogenic microbes remain elusive. In this study, two individuals of the sponge Crella cyathophora in total that showed similar disease-like characteristics were collected from two different locations along the Red Sea coast separated by more than 30 kilometers. The disease-like parts of the two individuals were both covered by green surfaces, and the body size was much smaller compared with adjacent healthy regions. Here, using high-throughput pyrosequencing technology, we investigated the prokaryotic communities in healthy and disease-like sponge tissues as well as adjacent seawater. Microbes in healthy tissues belonged mainly to the Proteobacteria, Cyanobacteria and Bacteroidetes, and were much more diverse at the phylum level than reported previously. Interestingly, the disease-like tissues from the two sponge individuals underwent shifts of prokaryotic communities and were both enriched with a novel clade affiliated with the phylum Verrucomicrobia, implying its intimate connection with the disease-like Red Sea sponge C. cyathophora. Enrichment of the phylum Verrucomicrobia was also considered to be correlated with the presence of algae assemblages forming the green surface of the disease-like sponge tissues. This finding represents an interesting case of sponge disease and is valuable for further study. PMID:26082867

  16. 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

  17. 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

  18. 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.

  19. 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

  20. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in sera and tissue of patients with Dupuytren's disease.

    PubMed

    Ulrich, Dietmar; Hrynyschyn, Klaus; Pallua, Norbert

    2003-10-01

    Dupuytren's contracture is a fibroproliferative disorder characterized by progressive deposition of mature collagen fibers. In other fibrotic diseases affecting organs such as the liver, lung, heart, and skin, matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), play an important role. In this study, serum concentrations of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined in 22 patients (five women and 17 men; average age, 67 +/- 11 years) with Dupuytren's disease using an enzyme-linked immunosorbent assay. Tissue samples were obtained for standard histological and immunohistochemical analyses. Sera and samples of palmar fascia from 20 patients (13 women and seven men; average age, 60 +/- 15 years) who had undergone hand surgery for carpal tunnel syndrome were used as the control group. Statistical analysis was performed using the Mann-Whitney test. Patients with Dupuytren's contracture presented with a TIMP-1 concentration of 437 +/- 160 ng/ml, a significantly higher TIMP-1 concentration than that seen in the control patients, who had a concentration of 321 +/- 70 ng/ml (p < 0.05). Patients with a proliferative active disease (n = 14) had a significantly higher TIMP-1 concentration (525 +/- 136 ng/ml) than patients (n = 8) with a contracture in the late involutional and residual phase (286 +/- 41 ng/ml; p < 0.05). There were no significant differences in the TIMP-2, MMP-1, MMP-2, and MMP-9 serum concentrations between patients with palmar fibromatosis and the control group. Patients with Dupuytren's disease had a significantly lower MMP-to-TIMP ratio (1.1 +/- 0.3; p < 0.05) than the control group (1.5 +/- 0.35). Patients with an active palmar fibromatosis presented a significantly (p < 0.05) reduced ratio (1 +/- 0.2) compared with those in later phases (1.4 +/- 0.3). TIMP-1 and TIMP-2 could be detected in tissue of patients with Dupuytren's contracture, with an accumulation in proliferative

  1. Network Analysis of Intrinsic Functional Brain Connectivity in Alzheimer's Disease

    PubMed Central

    Supekar, Kaustubh; Menon, Vinod; Rubin, Daniel; Musen, Mark; Greicius, Michael D.

    2008-01-01

    Functional brain networks detected in task-free (“resting-state”) functional magnetic resonance imaging (fMRI) have a small-world architecture that reflects a robust functional organization of the brain. Here, we examined whether this functional organization is disrupted in Alzheimer's disease (AD). Task-free fMRI data from 21 AD subjects and 18 age-matched controls were obtained. Wavelet analysis was applied to the fMRI data to compute frequency-dependent correlation matrices. Correlation matrices were thresholded to create 90-node undirected-graphs of functional brain networks. Small-world metrics (characteristic path length and clustering coefficient) were computed using graph analytical methods. In the low frequency interval 0.01 to 0.05 Hz, functional brain networks in controls showed small-world organization of brain activity, characterized by a high clustering coefficient and a low characteristic path length. In contrast, functional brain networks in AD showed loss of small-world properties, characterized by a significantly lower clustering coefficient (p<0.01), indicative of disrupted local connectivity. Clustering coefficients for the left and right hippocampus were significantly lower (p<0.01) in the AD group compared to the control group. Furthermore, the clustering coefficient distinguished AD participants from the controls with a sensitivity of 72% and specificity of 78%. Our study provides new evidence that there is disrupted organization of functional brain networks in AD. Small-world metrics can characterize the functional organization of the brain in AD, and our findings further suggest that these network measures may be useful as an imaging-based biomarker to distinguish AD from healthy aging. PMID:18584043

  2. Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomaslies not linked to the Fibrillin genes

    SciTech Connect

    Boileau, C.; Coulon, M.; Alexandre, J.-A.; Junien, C. ); Jondeau, G.; Delorme, G.; Dubourg, O.; Bourdarias, J.-P. ); Babron, M.-C.; Bonaieti-Pellie, C. ); Sakai, L. ); Melki, J. )

    1993-07-01

    The authors describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly), respectively. To test whether one of these genes was also implicated in this French family, the authors performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fib15) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of [minus]11.39 (for Fib15) and [minus]13.34 (for Fib5), at 0 = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome. 33 refs., 1 fig. 2 tabs.

  3. 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

  4. 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

  5. Degradation of connective tissue matrices by macrophages. II. Influence of matrix composition on proteolysis of glycoproteins, elastin, and collagen by macrophages in culture

    SciTech Connect

    Jones, P.A.; Werb, Z.

    1980-12-01

    Thioglycollate-elicited mouse peritoneal macrophages were cultured in contact with the mixture of extracellular matrix proteins produced by rat smooth muscle cells in culture. Both live macrophages and their conditioned media hydrolyzed glycoproteins, elastin, and collagen. Live macrophages also degraded extracellular connective tissue proteins secreted by endothelial cells and fibroblasts. The glycoproteins in the matrix markedly inhibited the rate of digestion of the other macromolecules, particularly elastin. When plasminogen was added to the matrix, activation of plasminogen to plasmin resulted in the hydrolysis of the glycoprotein components, which then allowed the macrophage elastase easier access to its substrate, elastin. Thus, although plasmin has no direct elastinolytic activity, its presence accelerated the rate of hydrolysis of elastin and therefore the rate of matrix degradation. These findings may be important in an understanding of disease states, such as emphysema and atherosclerosis, that are characterized by the destruction of connective tissue.

  6. 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

  7. 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

  8. Platelet-derived serotonin links vascular disease and tissue fibrosis

    PubMed Central

    Dees, Clara; Akhmetshina, Alfiya; Zerr, Pawel; Reich, Nicole; Palumbo, Katrin; Horn, Angelika; Jüngel, Astrid; Beyer, Christian; Krönke, Gerhard; Zwerina, Jochen; Reiter, Rudolf; Alenina, Natalia; Maroteaux, Luc; Gay, Steffen; Schett, Georg

    2011-01-01

    Vascular damage and platelet activation are associated with tissue remodeling in diseases such as systemic sclerosis, but the molecular mechanisms underlying this association have not been identified. In this study, we show that serotonin (5-hydroxytryptamine [5-HT]) stored in platelets strongly induces extracellular matrix synthesis in interstitial fibroblasts via activation of 5-HT2B receptors (5-HT2B) in a transforming growth factor β (TGF-β)–dependent manner. Dermal fibrosis was reduced in 5-HT2B−/− mice using both inducible and genetic models of fibrosis. Pharmacologic inactivation of 5-HT2B also effectively prevented the onset of experimental fibrosis and ameliorated established fibrosis. Moreover, inhibition of platelet activation prevented fibrosis in different models of skin fibrosis. Consistently, mice deficient for TPH1, the rate-limiting enzyme for 5-HT production outside the central nervous system, showed reduced experimental skin fibrosis. These findings suggest that 5-HT/5-HT2B signaling links vascular damage and platelet activation to tissue remodeling and identify 5-HT2B as a novel therapeutic target to treat fibrotic diseases. PMID:21518801

  9. Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease.

    PubMed

    Talukdar, Husain A; Foroughi Asl, Hassan; Jain, Rajeev K; Ermel, Raili; Ruusalepp, Arno; Franzén, Oscar; Kidd, Brian A; Readhead, Ben; Giannarelli, Chiara; Kovacic, Jason C; Ivert, Torbjörn; Dudley, Joel T; Civelek, Mete; Lusis, Aldons J; Schadt, Eric E; Skogsberg, Josefin; Michoel, Tom; Björkegren, Johan L M

    2016-03-23

    Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine. PMID:27135365

  10. 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

  11. 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

  12. 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

  13. [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

  14. 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

  15. The Lung Tissue Microbiome in Chronic Obstructive Pulmonary Disease

    PubMed Central

    Sze, Marc A.; Dimitriu, Pedro A.; Hayashi, Shizu; Elliott, W. Mark; McDonough, John E.; Gosselink, John V.; Cooper, Joel; Sin, Don D.; Mohn, William W.

    2012-01-01

    Rationale: Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), which have now been confirmed by others. Objectives: To extend these findings to human lung tissue samples. Methods: DNA from lung tissue samples was obtained from nonsmokers (n = 8); smokers without COPD (n = 8); patients with very severe COPD (Global Initiative for COPD [GOLD] 4) (n = 8); and patients with cystic fibrosis (CF) (n = 8). The latter served as a positive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying 16S rRNA gene fragments. Total bacterial populations were measured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing. Measurement and Main Results: Total bacterial populations within lung tissue were small (20–1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P < 0.001). Terminal restriction fragment length polymorphism analysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, a second to the GOLD 4 group, and the third to the CF-positive control group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD 4 patients versus all other groups (P < 0.003) attributable to an increase in the Lactobacillus genus (P < 0.0007). Conclusions: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD. PMID:22427533

  16. 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

  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 use of platelet rich plasma with guided tissue regeneration in defects caused by periodontal diseases.

    PubMed

    Holly, D; Mracna, J

    2009-01-01

    The goal of periodontal treatment in not only the stabilization of disease but also the regeneration of the destructed tissue. In the past few years various procedures have been created to achieve this. The guided tissue regeneration is a surgical procedure developed on the basis of experimental studies. It enables the creation of periodontal tissues affected by periodontitis, the so called reattachment. It stands for formation of new attachment--meaning the regeneration of cementum, alveolar bone and periodontal ligament. This surgical procedure of the treatment of periodontitis is based on the principle of exclusion of the epithelium and also the gingival connective tissue from the root surface so the precursor cells (desmodontal cells) can occupy the defect and pursue their differentiation. Periodontal ligament containing cells with regenerative potential are the exclusive ones to have the ability to regenerate structures affected by periodontitis. The use of growth factors offer new aspects to the therapy (Fig. 7, Ref. 11). Full Text (Free, PDF) www.bmj.sk. PMID:20017463

  19. 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

  20. Disease emergence and resurgence: the wildlife-human connection

    USGS Publications Warehouse

    Friend, Milton

    2006-01-01

    In 2000, the Global Outbreak Alert and Response Network (GOARN) was organized as a global disease watchdog group to coordinate disease outbreak information and health crisis response. The World Health Organization (WHO) is the headquarters for this network.2 Understandably, the primary focus for WHO is human health. However, diseases such as the H5N1 avian influenza epizootic in Asian bird populations demonstrate the need for integrating knowledge about disease emergence in animals and in humans.

  1. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease

    PubMed Central

    Zhou, Juan; Greicius, Michael D.; Gennatas, Efstathios D.; Growdon, Matthew E.; Jang, Jung Y.; Rabinovici, Gil D.; Kramer, Joel H.; Weiner, Michael; Miller, Bruce L.

    2010-01-01

    Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Discover the network mechanisms underlying the connections between aging and age-related diseases

    PubMed Central

    Yang, Jialiang; Huang, Tao; Song, Won-min; Petralia, Francesca; Mobbs, Charles V.; Zhang, Bin; Zhao, Yong; Schadt, Eric E.; Zhu, Jun; Tu, Zhidong

    2016-01-01

    Although our knowledge of aging has greatly expanded in the past decades, it remains elusive why and how aging contributes to the development of age-related diseases (ARDs). In particular, a global mechanistic understanding of the connections between aging and ARDs is yet to be established. We rely on a network modelling named “GeroNet” to study the connections between aging and more than a hundred diseases. By evaluating topological connections between aging genes and disease genes in over three thousand subnetworks corresponding to various biological processes, we show that aging has stronger connections with ARD genes compared to non-ARD genes in subnetworks corresponding to “response to decreased oxygen levels”, “insulin signalling pathway”, “cell cycle”, etc. Based on subnetwork connectivity, we can correctly “predict” if a disease is age-related and prioritize the biological processes that are involved in connecting to multiple ARDs. Using Alzheimer’s disease (AD) as an example, GeroNet identifies meaningful genes that may play key roles in connecting aging and ARDs. The top modules identified by GeroNet in AD significantly overlap with modules identified from a large scale AD brain gene expression experiment, supporting that GeroNet indeed reveals the underlying biological processes involved in the disease. PMID:27582315

  12. Discover the network mechanisms underlying the connections between aging and age-related diseases.

    PubMed

    Yang, Jialiang; Huang, Tao; Song, Won-Min; Petralia, Francesca; Mobbs, Charles V; Zhang, Bin; Zhao, Yong; Schadt, Eric E; Zhu, Jun; Tu, Zhidong

    2016-01-01

    Although our knowledge of aging has greatly expanded in the past decades, it remains elusive why and how aging contributes to the development of age-related diseases (ARDs). In particular, a global mechanistic understanding of the connections between aging and ARDs is yet to be established. We rely on a network modelling named "GeroNet" to study the connections between aging and more than a hundred diseases. By evaluating topological connections between aging genes and disease genes in over three thousand subnetworks corresponding to various biological processes, we show that aging has stronger connections with ARD genes compared to non-ARD genes in subnetworks corresponding to "response to decreased oxygen levels", "insulin signalling pathway", "cell cycle", etc. Based on subnetwork connectivity, we can correctly "predict" if a disease is age-related and prioritize the biological processes that are involved in connecting to multiple ARDs. Using Alzheimer's disease (AD) as an example, GeroNet identifies meaningful genes that may play key roles in connecting aging and ARDs. The top modules identified by GeroNet in AD significantly overlap with modules identified from a large scale AD brain gene expression experiment, supporting that GeroNet indeed reveals the underlying biological processes involved in the disease. PMID:27582315

  13. Mineral density volume gradients in normal and diseased human tissues

    SciTech Connect

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.; Aikawa, Elena

    2015-04-09

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.

  14. Mineral density volume gradients in normal and diseased human tissues

    DOE PAGESBeta

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.; Aikawa, Elena

    2015-04-09

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-raymore » fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.« less

  15. Mineral Density Volume Gradients in Normal and Diseased Human Tissues

    PubMed Central

    Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.

    2015-01-01

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations. PMID:25856386

  16. Mineral density volume gradients in normal and diseased human tissues.

    PubMed

    Djomehri, Sabra I; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W; Yun, Wenbing; Lau, S H; Webb, Samuel; Ho, Sunita P

    2015-01-01

    Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095 mg/cc, bone: 570-1415 mg/cc, cementum: 1240-1340 mg/cc, dentin: 1480-1590 mg/cc, cementum affected by periodontitis: 1100-1220 mg/cc, hypomineralized carious dentin: 345-1450 mg/cc, hypermineralized carious dentin: 1815-2740 mg/cc, and dental calculus: 1290-1770 mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations. PMID:25856386

  17. 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.…

  18. Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease

    PubMed Central

    Thomas, Jewell B; Brier, Matthew R; Bateman, Randall J; Snyder, Abraham Z; Benzinger, Tammie L; Xiong, Chengjie; Raichle, Marcus; Holtzman, David M; Sperling, Reisa A; Mayeux, Richard; Ghetti, Bernardino; Ringman, John M; Salloway, Stephen; McDade, Eric; Rossor, Martin N; Ourselin, Sebastien; Schofield, Peter R; Masters, Colin L; Martins, Ralph N; Weiner, Michael W; Thompson, Paul M; Fox, Nick C; Koeppe, Robert A; Jack, Clifford R; Mathis, Chester A; Oliver, Angela; Blazey, Tyler M; Moulder, Krista; Buckles, Virginia; Hornbeck, Russ; Chhatwal, Jasmeer; Schultz, Aaron P; Goate, Alison M; Fagan, Anne M; Cairns, Nigel J; Marcus, Daniel S; Morris, John C; Ances, Beau M

    2014-01-01

    Importance Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile. Design, Setting, and Participants We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites. Main Outcomes and Measures For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs. Results Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers. Conclusions and Relevance rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process. PMID:25069482

  19. Functional Connectivity Measured with Magnetoencephalography Identifies Persons with HIV Disease

    PubMed Central

    Becker, James T.; Bajo, Ricardo; Fabrizio, Melissa; Sudre, Gustavo; Cuesta, Pablo; Aizenstein, Howard J.; Lopez, Oscar L.; Wolk, David; Parkkonen, Lauri; Maestu, Fernando; Bagic, Anto

    2012-01-01

    There is need for a valid and reliable biomarker for HIV Associated Neurocognitive Disorder (HAND). The purpose of the present study was to provide preliminary evidence of the potential utility of neuronal functional connectivity measures obtained using magnetoencephalography (MEG) to identify HIV-associated changes in brain function. Resting state, eyes closed, MEG data from 10 HIV-infected individuals and 8 seronegative controls were analyzed using mutual information (MI) between all pairs of MEG sensors to determine whether there were functional brain networks that distinguished between subject groups based on cognition (global and learning) or on serostatus. Three networks were identified across all subjects, but after permutation testing (at α < .005) only the one related to HIV serostatus was significant. The network included MEG sensors (planar gradiometers) above the right anterior region connecting to sensors above the left posterior region. A mean MI value was calculated across all connections from the anterior to the posterior groupings; that score distinguished between the serostatus groups with only one error (sensitivity = 1.00, specificity = .88 (X2 = 15.4, df = 1, p < .01, Relative Risk = .11). There were no significant associations between the MI value and the neuropsychological Global Impairment rating, substance abuse, mood disorder, age, education, CD4+ cell counts or HIV viral load. We conclude that using a measure of functional connectivity, it may be possible to distinguish between HIV-infected and uninfected individuals, suggesting that MEG may have the potential to serve as a sensitive, non-invasive biomarker for HAND. PMID:22328062

  20. 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.

  1. Network topology and functional connectivity disturbances precede the onset of Huntington’s disease

    PubMed Central

    Harrington, Deborah L.; Rubinov, Mikail; Durgerian, Sally; Mourany, Lyla; Reece, Christine; Koenig, Katherine; Bullmore, Ed; Long, Jeffrey D.; Paulsen, Jane S.

    2015-01-01

    Cognitive, motor and psychiatric changes in prodromal Huntington’s disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntington’s disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntington’s disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntington’s disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene-negative controls (n = 16) and prodromal Huntington’s disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal-posterior connections that evolved

  2. 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

  3. 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

  4. 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

  5. Multi-resolution statistical analysis of brain connectivity graphs in preclinical Alzheimer's disease.

    PubMed

    Kim, Won Hwa; Adluru, Nagesh; Chung, Moo K; Okonkwo, Ozioma C; Johnson, Sterling C; B Bendlin, Barbara; Singh, Vikas

    2015-09-01

    There is significant interest, both from basic and applied research perspectives, in understanding how structural/functional connectivity changes can explain behavioral symptoms and predict decline in neurodegenerative diseases such as Alzheimer's disease (AD). The first step in most such analyses is to encode the connectivity information as a graph; then, one may perform statistical inference on various 'global' graph theoretic summary measures (e.g., modularity, graph diameter) and/or at the level of individual edges (or connections). For AD in particular, clear differences in connectivity at the dementia stage of the disease (relative to healthy controls) have been identified. Despite such findings, AD-related connectivity changes in preclinical disease remain poorly characterized. Such preclinical datasets are typically smaller and group differences are weaker. In this paper, we propose a new multi-resolution method for performing statistical analysis of connectivity networks/graphs derived from neuroimaging data. At the high level, the method occupies the middle ground between the two contrasts - that is, to analyze global graph summary measures (global) or connectivity strengths or correlations for individual edges similar to voxel based analysis (local). Instead, our strategy derives a Wavelet representation at each primitive (connection edge) which captures the graph context at multiple resolutions. We provide extensive empirical evidence of how this framework offers improved statistical power by analyzing two distinct AD datasets. Here, connectivity is derived from diffusion tensor magnetic resonance images by running a tractography routine. We first present results showing significant connectivity differences between AD patients and controls that were not evident using standard approaches. Later, we show results on populations that are not diagnosed with AD but have a positive family history risk of AD where our algorithm helps in identifying potentially

  6. 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

  7. 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

  8. 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

  9. 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 ...

  10. Identifying and Mapping Connectivity Patterns of Brain Network Hubs in Alzheimer's Disease.

    PubMed

    Dai, Zhengjia; Yan, Chaogan; Li, Kuncheng; Wang, Zhiqun; Wang, Jinhui; Cao, Miao; Lin, Qixiang; Shu, Ni; Xia, Mingrui; Bi, Yanchao; He, Yong

    2015-10-01

    Alzheimer's disease (AD) is associated not only with regional gray matter damages, but also with abnormalities in functional integration between brain regions. Here, we employed resting-state functional magnetic resonance imaging data and voxel-based graph-theory analysis to systematically investigate intrinsic functional connectivity patterns of whole-brain networks in 32 AD patients and 38 healthy controls (HCs). We found that AD selectively targeted highly connected hub regions (in terms of nodal functional connectivity strength) of brain networks, involving the medial and lateral prefrontal and parietal cortices, insula, and thalamus. This impairment was connectivity distance-dependent (Euclidean), with the most prominent disruptions appearing in the long-range connections (e.g., 100-130 mm). Moreover, AD also disrupted functional connections within the default-mode, salience and executive-control modules, and connections between the salience and executive-control modules. These disruptions of hub connectivity and modular integrity significantly correlated with the patients' cognitive performance. Finally, the nodal connectivity strength in the posteromedial cortex exhibited a highly discriminative power in distinguishing individuals with AD from HCs. Taken together, our results emphasize AD-related degeneration of specific brain hubs, thus providing novel insights into the pathophysiological mechanisms of connectivity dysfunction in AD and suggesting the potential of using network hub connectivity as a diagnostic biomarker. PMID:25331602

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. [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

  18. Compensatory striatal–cerebellar connectivity in mild–moderate Parkinson's disease

    PubMed Central

    Simioni, Alison C.; Dagher, Alain; Fellows, Lesley K.

    2015-01-01

    Dopamine depletion in the putamen is associated with altered motor network functional connectivity in people with Parkinson's disease (PD), but the functional significance of these changes remains unclear, attributed to either pathological or compensatory mechanisms in different studies. Here, we examined the effects of PD on dorsal caudal putamen functional connectivity, off and on dopamine replacement therapy (DRT), using resting state fMRI. Motor performance was assessed with the Purdue pegboard task. Twenty-one patients with mild–moderate Parkinson's disease were studied twice, once after an overnight DRT washout and once after the administration of a standard dose of levodopa (Sinemet), and compared to 20 demographically-matched healthy control participants. PD patients off DRT showed increased putamen functional connectivity with both the cerebellum (lobule V) and primary motor cortex (M1), relative to healthy controls. Greater putamen–cerebellar functional connectivity was significantly correlated with better motor performance, whereas greater putamen–M1 functional connectivity was predictive of poorer motor performance. The administration of levodopa improved motor performance in the PD group, as expected, and reduced putamen–cerebellar connectivity to levels comparable to the healthy control group. The strength of putamen–cerebellar functional connectivity continued to predict motor performance in the PD group while on levodopa. These findings argue that increased putamen–M1 functional connectivity reflects a pathological change, deleterious to motor performance. In contrast, increased putamen–cerebellar connectivity reflects a compensatory mechanism. PMID:26702396

  19. Compensatory striatal-cerebellar connectivity in mild-moderate Parkinson's disease.

    PubMed

    Simioni, Alison C; Dagher, Alain; Fellows, Lesley K

    2016-01-01

    Dopamine depletion in the putamen is associated with altered motor network functional connectivity in people with Parkinson's disease (PD), but the functional significance of these changes remains unclear, attributed to either pathological or compensatory mechanisms in different studies. Here, we examined the effects of PD on dorsal caudal putamen functional connectivity, off and on dopamine replacement therapy (DRT), using resting state fMRI. Motor performance was assessed with the Purdue pegboard task. Twenty-one patients with mild-moderate Parkinson's disease were studied twice, once after an overnight DRT washout and once after the administration of a standard dose of levodopa (Sinemet), and compared to 20 demographically-matched healthy control participants. PD patients off DRT showed increased putamen functional connectivity with both the cerebellum (lobule V) and primary motor cortex (M1), relative to healthy controls. Greater putamen-cerebellar functional connectivity was significantly correlated with better motor performance, whereas greater putamen-M1 functional connectivity was predictive of poorer motor performance. The administration of levodopa improved motor performance in the PD group, as expected, and reduced putamen-cerebellar connectivity to levels comparable to the healthy control group. The strength of putamen-cerebellar functional connectivity continued to predict motor performance in the PD group while on levodopa. These findings argue that increased putamen-M1 functional connectivity reflects a pathological change, deleterious to motor performance. In contrast, increased putamen-cerebellar connectivity reflects a compensatory mechanism. PMID:26702396

  20. A Winding Road: Alzheimer’s Disease Increases Circuitous Functional Connectivity Pathways

    PubMed Central

    Suckling, John; Simas, Tiago; Chattopadhyay, Shayanti; Tait, Roger; Su, Li; Williams, Guy; Rowe, James B.; O’Brien, John T.

    2015-01-01

    Neuroimaging has been successful in characterizing the pattern of cerebral atrophy that accompanies the progression of Alzheimer’s disease (AD). Examination of functional connectivity, the strength of signal synchronicity between brain regions, has gathered pace as another way of understanding changes to the brain that are associated with AD. It appears to have good sensitivity and detect effects that precede cognitive decline, and thus offers the possibility to understand the neurobiology of the disease in its earliest phases. However, functional connectivity analyzes to date generally consider only the strongest connections, with weaker links ignored. This proof-of-concept study compared patients with mild-to-moderate AD (N = 11) and matched control individuals (N = 12) based on functional connectivities derived from blood-oxygenation level dependent (BOLD) sensitive functional MRI acquired during resting wakefulness. All positive connectivities irrespective of their strength were included. Transitive closures of the resulting connectome were calculated that classified connections as either direct or indirect. Between-group differences in the proportion of indirect paths were observed. In AD, there was broadly increased indirect connectivity across greater spatial distances. Furthermore, the indirect pathways in AD had greater between-subject topological variance than controls. The prevailing characterization of AD as being a disconnection syndrome is refined by the observation that direct links between regions that are impaired are perhaps replaced by an increase in indirect functional pathways that is only detectable through inclusion of connections across the entire range of connection strengths. PMID:26635593

  1. Quantum pharmacology for infectious diseases: a molecular connectivity approach.

    PubMed

    Singh, Shailza

    2012-09-01

    Infectious diseases are a major cause of global health, economic and social problems. Relationship between the infectious diseases and drugs designed to combat them can be understood by the Quantum Pharmacology approach. Quantum pharmacology which is an amalgamation of chemistry, quantum mechanics and computer modeling aims to understand the structure activity relationship of a drug. As compared to the classical MM, the hybrid QM/MM approach which takes into account the quantum mechanics along with the molecular mechanics facilitates the simulation of biological structures with greater accuracy and speed. This review highlights the importance of quantum mechanics for a better understanding of molecular systems and QSAR studies. PMID:22738083

  2. Assessment of genetic damage in healthy and diseased tissue.

    PubMed

    Shuga, Joe; Hainaut, Pierre; Smith, Martyn T

    2011-01-01

    DNA, along with other cellular components, is under constant attack by chemical, physical, and infectious agents present in the human environment, as well as by reactive metabolites generated by physiological processes. Mutations occur as the consequence of this damage, but may also be caused by improper DNA repair of alterations occurring during normal DNA replication and transcription. Genetic damage can occur at the level of the gene (e.g. point mutations, insertions, and deletions) or at the level of the chromosome (e.g. aneuploidy, translocations). Further, mutations can also take place in mitochondrial DNA. Another form of DNA modification is epigenetic methylation of CpG islands, which affects the dynamics of chromatin as well as the expression of a large panel of genes. Recent technical advances have improved the capacity to detect and quantify genetic and epigenetic changes. This chapter summarizes current knowledge on mechanisms of DNA damage and mutagenesis, laying out the concepts for interpreting mutations as biomarkers in investigating the causes and consequences of cancer. It also outlines both established and novel methods for detecting genetic and epigenetic changes in normal and diseased tissues, and then discusses their application in the realm of molecular epidemiology. PMID:22997857

  3. 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

  4. Human adipose CD34+ CD90+ stem cells and collagen scaffold constructs grafted in vivo fabricate loose connective and adipose tissues.

    PubMed

    Ferraro, Giuseppe A; De Francesco, Francesco; Nicoletti, Gianfranco; Paino, Francesca; Desiderio, Vincenzo; Tirino, Virginia; D'Andrea, Francesco

    2013-05-01

    Stem cell based therapies for the repair and regeneration of various tissues are of great interest for a high number of diseases. Adult stem cells, instead, are more available, abundant and harvested with minimally invasive procedures. In particular, mesenchymal stem cells (MSCs) are multi-potent progenitors, able to differentiate into bone, cartilage, and adipose tissues. Human adult adipose tissue seems to be the most abundant source of MSCs and, due to its easy accessibility; it is able to give a considerable amount of stem cells. In this study, we selected MSCs co-expressing CD34 and CD90 from adipose tissue. This stem cell population displayed higher proliferative capacity than CD34(-) CD90(-) cells and was able to differentiate in vitro into adipocytes (PPARγ(+) and adiponectin(+)) and endothelial cells (CD31(+) VEGF(+) Flk1(+)). In addition, in methylcellulose without VEGF, it formed a vascular network. The aim of this study was to investigate differentiation potential of human adipose CD34(+) /CD90(+) stem cells loaded onto commercial collagen sponges already used in clinical practice (Gingistat) both in vitro and in vivo. The results of this study clearly demonstrate that human adult adipose and loose connective tissues can be obtained in vivo, highlighting that CD34(+) /CD90 ASCs are extremely useful for regenerative medicine. PMID:23129214

  5. Dry Eye Disease and Microbial Keratitis: Is There a Connection?

    PubMed Central

    Narayanan, Srihari; Redfern, Rachel L.; Miller, William L.; Nichols, Kelly K.; McDermott, Alison M.

    2013-01-01

    Dry eye is a common ocular surface disease of multifactorial etiology characterized by elevated tear osmolality and inflammation leading to a disrupted ocular surface. The latter is a risk factor for ocular surface infection, yet overt infection is not commonly seen clinically in the typical dry eye patient. This suggests that important innate mechanisms operate to protect the dry eye from invading pathogens. This article reviews the current literature on epidemiology of ocular surface infection in dry eye patients and laboratory-based studies on innate immune mechanisms operating at the ocular surface and their alterations in human dry eye and animal models. The review highlights current understanding of innate immunity in dry eye and identifies gaps in our knowledge to help direct future studies to further unravel the complexities of dry eye disease and its sequelae. PMID:23583043

  6. mRNP granules. Assembly, function, and connections with disease.

    PubMed

    Buchan, J Ross

    2014-01-01

    Messenger ribonucleoprotein (mRNP) granules are dynamic, self-assembling structures that harbor non-translating mRNAs bound by various proteins that regulate mRNA translation, localization, and turnover. Their importance in gene expression regulation is far reaching, ranging from precise spatial-temporal control of mRNAs that drive developmental programs in oocytes and embryos, to similarly exquisite control of mRNAs in neurons that underpin synaptic plasticity, and thus, memory formation. Analysis of mRNP granules in their various contexts has revealed common themes of assembly, disassembly, and modes of mRNA regulation, yet new studies continue to reveal unexpected and important findings, such as links between aberrant mRNP granule assembly and neurodegenerative disease. Continued study of these enigmatic structures thus promises fascinating new insights into cellular function, and may also suggest novel therapeutic strategies in various disease states. PMID:25531407

  7. Heme Deficiency in Alzheimer's Disease: A Possible Connection to Porphyria

    PubMed Central

    Dwyer, Barney E.; Stone, Meghan L.; Zhu, Xiongwei; Perry, George; Smith, Mark A.

    2006-01-01

    Mechanisms that cause Alzheimer's disease (AD), an invariably fatal neurodegenerative disease, are unknown. Important recent data indicate that neuronal heme deficiency may contribute to AD pathogenesis. If true, factors that contribute to the intracellular heme deficiency could potentially alter the course of AD. The porphyrias are metabolic disorders characterized by enzyme deficiencies in the heme biosynthetic pathway. We hypothesize that AD may differ significantly in individuals possessing the genetic trait for an acute hepatic porphyria. We elaborate on this hypothesis and briefly review the characteristics of the acute hepatic porphyrias that may be relevant to AD. We note the proximity of genes encoding enzymes of the heme biosynthesis pathway to genetic loci linked to sporadic, late-onset AD. In addition, we suggest that identification of individuals carrying the genetic trait for acute porphyria may provide a unique resource for investigating AD pathogenesis and inform treatment and management decisions. PMID:17047301

  8. The Role of Tissue Factor in Atherothrombosis and Coronary Artery Disease: Insights into Platelet Tissue Factor.

    PubMed

    Camera, Marina; Toschi, Vincenzo; Brambilla, Marta; Lettino, Maddalena; Rossetti, Laura; Canzano, Paola; Di Minno, Alessandro; Tremoli, Elena

    2015-10-01

    The contribution of vessel wall-derived tissue factor (TF) to atherothrombosis is well established, whereas the pathophysiological relevance of the blood-borne TF is still a matter of debate, and controversies on the presence of platelet-associated TF still exist. In the past 15 years, several studies have documented the presence of TF in human platelets, the capacity of human platelets to use TF mRNA to make de novo protein synthesis, and the increase in the percentage of TF positive platelets in pathological conditions such as coronary artery disease (CAD). The exposure of vessel wall-derived TF at the site of vascular injury would play its main role in the initiation phase, whereas the blood-borne TF carried by platelets would be involved in the propagation phase of thrombus formation. More recent data indicate that megakaryocytes are committed to release into the bloodstream a well-defined number of TF-carrying platelets, which represents only a fraction of the whole platelet population. These findings are in line with the evidence that platelets are heterogeneous in their functions and only a subset of them is involved in the hemostatic process. In this review we summarize the existing knowledge on platelet associated TF and speculate on its relevance to physiology and to atherothrombosis and CAD. PMID:26408918

  9. A literature based method for identifying gene-disease connections.

    PubMed

    Adamic, Lada A; Wilkinson, Dennis; Huberman, Bernardo A; Adar, Eytan

    2002-01-01

    We present a statistical method that can swiftly identify, from the literature, sets of genes known to be associated with given diseases. It offers a comprehensive way to treat alias symbols, a statistical method for computing the relevance of the gene to the query, and a novel way to disambiguate gene symbols from other abbreviations. The method is illustrated by finding genes related to breast cancer. PMID:15838128

  10. Gut Microbiome and Kidney Disease in Pediatrics: Does Connection Exist?

    PubMed Central

    Vasylyeva, Tetyana L.; Singh, Ruchi

    2016-01-01

    Child development is a unique and continuous process that is impacted by genetics and environmental factors. Gut microbiome changes with development and depends on the stage of gut maturation, nutrition, and overall health. In spite of emerging data and active study in adults, the gut-renal axis in pediatrics has not been well considered and investigated. This review will focus on the current knowledge of gut microbiota impacts on kidney disease with extrapolation to the pediatric population. PMID:26973613

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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

  19. Infectious Disease: Connecting Innate Immunity to Biocidal Polymers

    PubMed Central

    Gabriel, Gregory J.; Som, Abhigyan; Madkour, Ahmad E.; Eren, Tarik; Tew, Gregory N.

    2007-01-01

    Infectious disease is a critically important global healthcare issue. In the U.S. alone there are 2 million new cases of hospital-acquired infections annually leading to 90,000 deaths and 5 billion dollars of added healthcare costs. Couple these numbers with the appearance of new antibiotic resistant bacterial strains and the increasing occurrences of community-type outbreaks, and clearly this is an important problem. Our review attempts to bridge the research areas of natural host defense peptides (HDPs), a component of the innate immune system, and biocidal cationic polymers. Recently discovered peptidomimetics and other synthetic mimics of HDPs, that can be short oligomers as well as polymeric macromolecules, provide a unique link between these two areas. An emerging class of these mimics are the facially amphiphilic polymers that aim to emulate the physicochemical properties of HDPs but take advantage of the synthetic ease of polymers. These mimics have been designed with antimicrobial activity and, importantly, selectivity that rivals natural HDPs. In addition to providing some perspective on HDPs, selective mimics, and biocidal polymers, focus is given to the arsenal of biophysical techniques available to study their mode of action and interactions with phospholipid membranes. The issue of lipid type is highlighted and the important role of negative curvature lipids is illustrated. Finally, materials applications (for instance, in the development of permanently antibacterial surfaces) are discussed as this is an important part of controlling the spread of infectious disease. PMID:18160969

  20. 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

  1. 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

  2. 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.

  3. 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

  4. Alzheimer disease and amyotrophic lateral sclerosis: An etiopathogenic connection

    PubMed Central

    Wang, Xiaochuan; Blanchard, Julie; Grundke-Iqbal, Inge; Wegiel, Jerzy; Deng, Han-Xiang; Siddique, Teepu; Iqbal, Khalid

    2013-01-01

    The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) are well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I2PP2A. In AD brain PP2A activity is compromised, probably because I2PP2A is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I2CTF, and both fragments inhibit PP2A. Here we analyzed the spinal cords from ALS and control cases for I2PP2A cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I2PP2A into I2NTF and I2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I2PP2A, we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I2CTF. AAV1- I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5–8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10–14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I2PP2A and the potential of I2PP2A-based therapeutics for these diseases. PMID:24136402

  5. Cerebellar atrophy in Parkinson's disease and its implication for network connectivity.

    PubMed

    O'Callaghan, Claire; Hornberger, Michael; Balsters, Joshua H; Halliday, Glenda M; Lewis, Simon J G; Shine, James M

    2016-03-01

    Pathophysiological and atrophic changes in the cerebellum are documented in Parkinson's disease. Without compensatory activity, such abnormalities could potentially have more widespread effects on both motor and non-motor symptoms. We examined how atrophic change in the cerebellum impacts functional connectivity patterns within the cerebellum and between cerebellar-cortical networks in 42 patients with Parkinson's disease and 29 control subjects. Voxel-based morphometry confirmed grey matter loss across the motor and cognitive cerebellar territories in the patient cohort. The extent of cerebellar atrophy correlated with decreased resting-state connectivity between the cerebellum and large-scale cortical networks, including the sensorimotor, dorsal attention and default networks, but with increased connectivity between the cerebellum and frontoparietal networks. The severity of patients' motor impairment was predicted by a combination of cerebellar atrophy and decreased cerebellar-sensorimotor connectivity. These findings demonstrate that cerebellar atrophy is related to both increases and decreases in cerebellar-cortical connectivity in Parkinson's disease, identifying potential cerebellar driven functional changes associated with sensorimotor deficits. A post hoc analysis exploring the effect of atrophy in the subthalamic nucleus, a cerebellar input source, confirmed that a significant negative relationship between grey matter volume and intrinsic cerebellar connectivity seen in controls was absent in the patients. This suggests that the modulatory relationship of the subthalamic nucleus on intracerebellar connectivity is lost in Parkinson's disease, which may contribute to pathological activation within the cerebellum. The results confirm significant changes in cerebellar network activity in Parkinson's disease and reveal that such changes occur in association with atrophy of the cerebellum. PMID:26794597

  6. 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.

  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. 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.

  8. 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.

  9. Regulation of lysyl oxidase mRNA in dermal fibroblasts from normal donors and patients with inherited connective tissue disorders.

    PubMed

    Yeowell, H N; Marshall, M K; Walker, L C; Ha, V; Pinnell, S R

    1994-01-01

    Lysyl oxidase (LO) is an extracellular copper-dependent enzyme that catalyzes the initial reaction in the formation of lysine or hydroxylysine-derived crosslinks during collagen biosynthesis. We have isolated a cDNA for human LO from skin fibroblast poly(A+)RNA by PCR using primers based on the recently published sequence of human LO. This cDNA probe detects a major mRNA of 4.2 kb on Northern blots of RNA from normal fibroblasts. The level of LO mRNA was not significantly affected by cell density or by ascorbate treatment. Treatment of skin fibroblasts with hydralazine (50 microM), which increases the mRNAs for both the alpha and the beta subunits of prolyl hydroxylase (PH) and the mRNAs for lysyl hydroxylase, also increased LO mRNA by fourfold over a 72-h time course. In contrast, hydralazine dramatically decreased the mRNAs for alpha 1(I) collagen. Administration of minoxidil (500 microM), which specifically decreases LH activity without affecting PH activity or collagen biosynthesis in skin fibroblasts, stimulated the level of LO mRNA. Neither the administration of penicillamine (100 microM), which interferes with collagen cross-linking, nor the administration of beta-aminopropionitrile, which is a strong irreversible inhibitor of LO, to fibroblasts significantly changed the levels of LO mRNA over a 72-h time course. However, bleomycin (0.6 microgram/ml) significantly decreased the 4.2-kb LO mRNA in contrast to the levels of the alpha 1(I) collagen mRNAs, which were unchanged. No significant change was observed in the steady-state levels of LO mRNAs in fibroblasts isolated from patients with certain connective tissue disorders, including Marfan syndrome, Menkes disease, cutis laxa, and pseudoxanthoma elasticum. PMID:7508709

  10. Dilution versus facilitation: Impact of connectivity on disease risk in metapopulations.

    PubMed

    Huang, Zheng Y X; van Langevelde, Frank; Prins, Herbert H T; de Boer, Willem F

    2015-07-01

    Epidemiological studies have suggested that increasing connectivity in metapopulations usually facilitates pathogen transmission. However, these studies focusing on single-host systems usually neglect that increasing connectivity can increase species diversity which might reduce pathogen transmission via the 'dilution effect', a hypothesis whose generality is still disputed. On the other hand, studies investigating the generality of the dilution effect were usually conducted without considering habitat structure, which is surprising as species loss is often driven by habitat fragmentation. Using a simple general model to link fragmentation to the dilution effect, we determined the effect of connectivity on disease risk and explored when the dilution effect can be detected. We showed that landscape structure can largely modify the diversity-disease relationship. The net impact of connectivity on disease risk can be either positive or negative, depending on the relative importance of the facilitation effect (through increasing contact rates among patches) versus the dilution effect (via increasing species richness). We also demonstrated that different risk indices (i.e. infection prevalence and abundance of infected hosts) react differently to increasing connectivity and species richness. Our study may contribute to the current debate on the dilution effect, and a better understanding of the impacts of fragmentation on disease risks. PMID:25882748

  11. Everything is connected: social determinants of pediatric health and disease.

    PubMed

    Tarazi, Carine; Skeer, Margie; Fiscella, Kevin; Dean, Stephanie; Dammann, Olaf

    2016-01-01

    Carine Tarazi, MA, is an Assistant Editor for Pediatric Research in Boston, Massachusetts, USA. Margie Skeer, ScD, MPH, MSW, served as a Guest Editor for this special issue. Dr. Skeer is Assistant Professor of Public Health and Community Medicine at Tufts University. Her research focuses on adolescent substance misuse and sexual risk prevention, both from epidemiologic and intervention-development perspectives. Kevin Fiscella, MD, MPH, served as a Guest Editor for this special issue. Dr. Fiscella is Tenured Professor of Family Medicine, Public Health Sciences and Community Health at the University of Rochester Medical Center. Dr. Fiscella's research focuses on health and health care disparities, particularly practical strategies to improve health equity. Stephanie Dean, MBA, is Managing Editor of Pediatric Research and is based out of editorial office in The Woodlands, Texas. Olaf Dammann, MD, served as a Guest Editor for this special issue. Dr. Dammann is a Professor of Public Health and Community Medicine, Pediatrics, and Ophthalmology at Tufts University School of Medicine in Boston, Massachusetts, USA, as well as Professor of Perinatal Neuroepidemiology at Hannover Medical School, Hannover, Germany. His research interests include the elucidation of risk factors for brain damage and retinopathy in preterm newborns, the theory of risk and causation in biomedical and public health research, and the development of computational chronic disease models. PMID:26841091

  12. Disease epidemics: Lessons for resilience in an increasingly connected world

    USGS Publications Warehouse

    Allen, Craig R.; DeWitte, S.N.; Kurth, M.H.; Linkov, I.

    2016-01-01

    In public health, the term resilience often refers to the personality traits that individuals possess which help them endure and recover from stressors. However, resilience as a system characteristic, especially in regards to complex social-ecological systems, can be informative for public health at scales larger than the individual. Acute shocks to systems occur against a background of existing conditions, which are crucial determinants of the eventual public health outcomes of those shocks, and in the context of complex dependencies among and between ecological and societal elements. Many components of a system's baseline condition are chronic public health concerns themselves and diminish the capacity of the system to perform in the face of acute shocks. The emerging field of resilience management is concerned with holistically assessing and improving a system's ability to prepare for and absorb disruption, and then recover and adapt across physical, information, environmental and social domains. Integrating resilience considerations into current risk- and evidence-based approaches to disease control and prevention1 can move public health efforts toward more proactive and comprehensive solutions for protecting and improving the health of communities. Here, we look to the case of the Black Death as an illustrative case of a dramatic transformation in human history, an acute shock to a system that was underlain by chronic social maladies, to derive lessons about resilience management for public health in contemporary systems.

  13. Climate-disease connections: Rift Valley Fever in Kenya

    NASA Technical Reports Server (NTRS)

    Anyamba, A.; Linthicum, K. J.; Tucker, C. J.

    2001-01-01

    All known Rift Valley fever(RVF) outbreaks in Kenya from 1950 to 1998 followed periods of abnormally high rainfall. On an interannual scale, periods of above normal rainfall in East Africa are associated with the warm phase of the El Nino/Southern Oscillation (ENSO) phenomenon. Anomalous rainfall floods mosquito-breeding habitats called dambos, which contain transovarially infected mosquito eggs. The eggs hatch Aedes mosquitoes that transmit the RVF virus preferentially to livestock and to humans as well. Analysis of historical data on RVF outbreaks and indicators of ENSO (including Pacific and Indian Ocean sea surface temperatures and the Southern Oscillation Index) indicates that more than three quarters of the RVF outbreaks have occurred during warm ENSO event periods. Mapping of ecological conditions using satellite normalized difference vegetation index (NDVI) data show that areas where outbreaks have occurred during the satellite recording period (1981-1998) show anomalous positive departures in vegetation greenness, an indicator of above-normal precipitation. This is particularly observed in arid areas of East Africa, which are predominantly impacted by this disease. These results indicate a close association between interannual climate variability and RVF outbreaks in Kenya.

  14. Helicobacter pylori vs coronary heart disease - searching for connections

    PubMed Central

    Chmiela, Magdalena; Gajewski, Adrian; Rudnicka, Karolina

    2015-01-01

    In this review, we discussed the findings and concepts underlying the potential role of Helicobacter pylori (H. pylori) infections in the initiation, development or persistence of atherosclerosis and coronary heart disease (CHD). This Gram-negative bacterium was described by Marshall and Warren in 1984. The majority of infected subjects carries and transmits H. pylori with no symptoms; however, in some individuals these bacteria may cause peptic ulcers, and even gastric cancers. The widespread prevalence of H. pylori infections and the fact that frequently they remain asymptomatic may suggest that, similarly to intestinal microflora, H. pylori may deliver antigens that stimulate not only local, but also systemic inflammatory response. Recently, possible association between H. pylori infection and extragastric disorders has been suggested. Knowledge on the etiology of atherosclerosis together with current findings in the area of H. pylori infections constitute the background for the newly proposed hypothesis that those two processes may be related. Many research studies confirm the indirect association between the prevalence of H. pylori and the occurrence of CHD. According to majority of findings the involvement of H. pylori in this process is based on the chronic inflammation which might facilitate the CHD-related pathologies. It needs to be elucidated, if the infection initiate or just accelerate the formation of atheromatous plaque. PMID:25914788

  15. 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

  16. 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

  17. Mesenchymal stem cells from umbilical cord tissue as potential therapeutics for cardiomyodegenerative diseases – a review

    PubMed Central

    Hollweck, Trixi; Hagl, Christian; Eissner, Günther

    2012-01-01

    Heart failure is one of the leading causes of death worldwide. End stage disease often requires heart transplantation, which is hampered by donor organ shortage. Tissue engineering represents a promising alternative approach for cardiac repair. For the generation of artificial heart muscle tissue several cell types, scaffold materials and bioreactor designs are under investigation. In this review, the use of mesenchymal stem cells derived from human umbilical cord tissue (UCMSC) for cardiac tissue engineering will be discussed. PMID:24551768

  18. 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

  19. 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

  20. Small vessel disease and cognitive impairment: The relevance of central network connections.

    PubMed

    Reijmer, Yael D; Fotiadis, Panagiotis; Piantoni, Giovanni; Boulouis, Gregoire; Kelly, Kathleen E; Gurol, Mahmut E; Leemans, Alexander; O'Sullivan, Michael J; Greenberg, Steven M; Viswanathan, Anand

    2016-07-01

    Central brain network connections greatly contribute to overall network efficiency. Here we examined whether small vessel disease (SVD) related white matter alterations in central brain network connections have a greater impact on executive functioning than alterations in non-central brain network connections. Brain networks were reconstructed from diffusion-weighted MRI scans in 72 individuals (75 ± 8 years) with cognitive impairment and SVD on MRI. The centrality of white matter connections in the network was defined using graph theory. The association between the fractional anisotropy (FA) of central versus non-central connections, executive functioning, and markers of SVD was evaluated with linear regression and mediation analysis. Lower FA in central network connections was more strongly associated with impairment in executive functioning than FA in non-central network connections (r = 0.41 vs. r = 0.27; P < 0.05). Results were consistent across varying thresholds to define the central subnetwork (>50%-10% connections). Higher SVD burden was associated with lower FA in central as well as non-central network connections. However, only central network FA mediated the relationship between white matter hyperintensity volume and executive functioning [change in regression coefficient after mediation (95% CI): -0.15 (-0.35 to -0.02)]. The mediation effect was not observed for FA alterations in non-central network connections [-0.03 (-0.19 to 0.04)]. These findings suggest that the centrality of network connections, and thus their contribution to global network efficiency, appears to be relevant for understanding the relationship between SVD and cognitive impairment. Hum Brain Mapp 37:2446-2454, 2016. © 2016 Wiley Periodicals, Inc. PMID:27004840

  1. Task-rest modulation of basal ganglia connectivity in mild to moderate Parkinson's disease.

    PubMed

    Müller-Oehring, Eva M; Sullivan, Edith V; Pfefferbaum, Adolf; Huang, Neng C; Poston, Kathleen L; Bronte-Stewart, Helen M; Schulte, Tilman

    2015-09-01

    Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance. PMID:25280970

  2. 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

  3. Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer's disease

    PubMed Central

    Hafkemeijer, Anne; Möller, Christiane; Dopper, Elise G. P.; Jiskoot, Lize C.; Schouten, Tijn M.; van Swieten, John C.; van der Flier, Wiesje M.; Vrenken, Hugo; Pijnenburg, Yolande A. L.; Barkhof, Frederik; Scheltens, Philip; van der Grond, Jeroen; Rombouts, Serge A. R. B.

    2015-01-01

    Introduction: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are the most common types of early-onset dementia. Early differentiation between both types of dementia may be challenging due to heterogeneity and overlap of symptoms. Here, we apply resting state functional magnetic resonance imaging (fMRI) to study functional brain connectivity differences between AD and bvFTD. Methods: We used resting state fMRI data of 31 AD patients, 25 bvFTD patients, and 29 controls from two centers specialized in dementia. We studied functional connectivity throughout the entire brain, applying two different analysis techniques, studying network-to-region and region-to-region connectivity. A general linear model approach was used to study group differences, while controlling for physiological noise, age, gender, study center, and regional gray matter volume. Results: Given gray matter differences, we observed decreased network-to-region connectivity in bvFTD between (a) lateral visual cortical network and lateral occipital and cuneal cortex, and (b) auditory system network and angular gyrus. In AD, we found decreased network-to-region connectivity between the dorsal visual stream network and lateral occipital and parietal opercular cortex. Region-to-region connectivity was decreased in bvFTD between superior temporal gyrus and cuneal, supracalcarine, intracalcarine cortex, and lingual gyrus. Conclusion: We showed that the pathophysiology of functional brain connectivity is different between AD and bvFTD. Our findings support the hypothesis that resting state fMRI shows disease-specific functional connectivity differences and is useful to elucidate the pathophysiology of AD and bvFTD. However, the group differences in functional connectivity are less abundant than has been shown in previous studies. PMID:26441584

  4. 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

  5. Tissue resident regulatory T cells: novel therapeutic targets for human disease

    PubMed Central

    Zhou, Xiaohui; Tang, Jiayou; Cao, Hao; Fan, Huimin; Li, Bin

    2015-01-01

    Over the past decade, the ability of regulatory T cells (Tregs) to suppress multiple types of immune cells has received tremendous attention. Mounting evidence has revealed that tissue resident Tregs control non-immunological processes of their target tissues and contribute to a plethora of human diseases. The identification of novel tissue-specific Tregs has highlighted their heterogeneity and complexity. This review summarizes the recent findings for visceral adipose tissue CD4+Foxp3+ regulatory T cells (VAT Tregs), muscle Tregs, bone Tregs and skin memory Tregs, with a focus on their unique functions in local tissues. This interpretation of the roles of tissue-specific Tregs and of their involvement in disease progression provides new insight into the discovery of potential therapeutic targets of human diseases. PMID:25891216

  6. 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

  7. Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer's disease: preliminary report.

    PubMed

    Zaidel, Liam; Allen, Greg; Cullum, C Munro; Briggs, Richard W; Hynan, Linda S; Weiner, Myron F; McColl, Roderick; Gopinath, Kaundinya S; McDonald, Elizabeth; Rubin, Craig D

    2012-01-01

    We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer's disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls. PMID:22886013

  8. Understanding multicellular function and disease with human tissue-specific networks

    PubMed Central

    Greene, Casey S.; Krishnan, Arjun; Wong, Aaron K.; Ricciotti, Emanuela; Zelaya, Rene A.; Himmelstein, Daniel S.; Zhang, Ran; Hartmann, Boris M.; Zaslavsky, Elena; Sealfon, Stuart C.; Chasman, Daniel I.; FitzGerald, Garret A.; Dolinski, Kara; Grosser, Tilo; Troyanskaya, Olga G.

    2016-01-01

    Tissue and cell-type identity lie at the core of human physiology and disease. Understanding the genetic underpinnings of complex tissues and individual cell lineages is crucial for developing improved diagnostics and therapeutics. We present genome-wide functional interaction networks for 144 human tissues and cell types developed using a data-driven Bayesian methodology that integrates thousands of diverse experiments spanning tissue and disease states. Tissue-specific networks predict lineage-specific responses to perturbation, reveal genes’ changing functional roles across tissues, and illuminate disease-disease relationships. We introduce NetWAS, which combines genes with nominally significant GWAS p-values and tissue-specific networks to identify disease-gene associations more accurately than GWAS alone. Our webserver, GIANT, provides an interface to human tissue networks through multi-gene queries, network visualization, analysis tools including NetWAS, and downloadable networks. GIANT enables systematic exploration of the landscape of interacting genes that shape specialized cellular functions across more than one hundred human tissues and cell types. PMID:25915600

  9. Edge effects, not connectivity, determine the incidence and development of a foliar fungal plant disease.

    SciTech Connect

    Johnson, Brenda, L.; Haddad, Nick, M.

    2011-08-01

    Using a model plant-pathogen system in a large-scale habitat corridor experiment, we found that corridors do not facilitate the movement of wind-dispersed plant pathogens, that connectivity of patches does not enhance levels of foliar fungal plant disease, and that edge effects are the key drivers of plant disease dynamics. Increased spread of infectious disease is often cited as a potential negative effect of habitat corridors used in conservation, but the impacts of corridors on pathogen movement have never been tested empirically. Using sweet corn (Zea mays) and southern corn leaf blight (Cochliobolus heterostrophus) as a model plant-pathogen system, we tested the impacts of connectivity and habitat fragmentation on pathogen movement and disease development at the Savannah River Site, South Carolina, USA. Over time, less edgy patches had higher proportions of diseased plants, and distance of host plants to habitat edges was the greatest determinant of disease development. Variation in average daytime temperatures provided a possible mechanism for these disease patterns. Our results show that worries over the potentially harmful effects of conservation corridors on disease dynamics are misplaced, and that, in a conservation context, many diseases can be better managed by mitigating edge effects.

  10. Functional Brain Connectivity using fMRI in Aging and Alzheimer’s Disease

    PubMed Central

    Dennis, Emily L.; Thompson, Paul M.

    2014-01-01

    Normal aging and Alzheimer’s disease cause profound changes in the brain’s structure and function. AD in particular is accompanied by widespread cortical neuronal loss, and loss of connections between brain systems. This degeneration of neural pathways disrupts the functional coherence of brain activation. Recent innovations in brain imaging have detected characteristic disruptions in functional networks. Here we review studies examining changes in functional connectivity, measured through fMRI (functional magnetic resonance imaging), starting with healthy aging and then Alzheimer’s disease (AD). We cover studies that employ the three primary methods to analyze functional connectivity – seed-based, ICA (independent components analysis), and graph theory. At the end we include a brief discussion of other methodologies, such as EEG (electroencephalography), MEG (magnetoencephalography), and PET (positron emission tomography). We also describe multi-modal studies that combine rsfMRI (resting state fMRI) with PET imaging, as well as studies examining the effects of medications. Overall, connectivity and network integrity appear to decrease in healthy aging, but this decrease is accelerated in AD, with specific systems hit hardest, such as the default mode network (DMN). Functional connectivity is a relatively new topic of research, but it holds great promise in revealing how brain network dynamics change across the lifespan and in disease. PMID:24562737

  11. Dopaminergic modulation of resting-state functional connectivity in de novo patients with Parkinson's disease.

    PubMed

    Baik, KyoungWon; Cha, Jungho; Ham, Jee Hyun; Baek, Gwang-Min; Sunwoo, Mun Kyung; Hong, Jin Yong; Shin, Na-Young; Kim, Jae Seung; Lee, Jong-Min; Lee, Seung-Koo; Sohn, Young Ho; Lee, Phil Hyu

    2014-11-01

    Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine-dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP-CIT positron emission tomography imaging and resting-state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine-dependent functional networks. The major finding is that the patterns of dopamine-dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine-dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine-dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine-dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine-dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian-related motor and cognitive performance. PMID:24938993

  12. Academic and molecular matrices: A study of the transformations of connective tissue research at the University of Manchester (1947–1996)☆

    PubMed Central

    García-Sancho, Miguel

    2011-01-01

    This paper explores the different identities adopted by connective tissue research at the University of Manchester during the second half of the 20th century. By looking at the long-term redefinition of a research programme, it sheds new light on the interactions between different and conflicting levels in the study of biomedicine, such as the local and the global, or the medical and the biological. It also addresses the gap in the literature between the first biomedical complexes after World War II and the emergence of biotechnology. Connective tissue research in Manchester emerged as a field focused on new treatments for rheumatic diseases. During the 1950s and 60s, it absorbed a number of laboratory techniques from biology, namely cell culture and electron microscopy. The transformations in scientific policy during the late 70s and the migration of Manchester researchers to the US led them to adopt recombinant DNA methods, which were borrowed from human genetics. This resulted in the emergence of cell matrix biology, a new field which had one of its reference centres in Manchester. The Manchester story shows the potential of detailed and chronologically wide local studies of patterns of work to understand the mechanisms by which new biomedical tools and institutions interact with long-standing problems and existing affiliations. PMID:21486662

  13. Voxelwise spectral diffusional connectivity and its applications to Alzheimer's disease and intelligence prediction.

    PubMed

    Li, Junning; Jin, Yan; Shi, Yonggang; Dinov, Ivo D; Wang, Danny J; Toga, Arthur W; Thompson, Paul M

    2013-01-01

    Human brain connectivity can be studied using graph theory. Many connectivity studies parcellate the brain into regions and count fibres extracted between them. The resulting network analyses require validation of the tractography, as well as region and parameter selection. Here we investigate whole brain connectivity from a different perspective. We propose a mathematical formulation based on studying the eigenvalues of the Laplacian matrix of the diffusion tensor field at the voxel level. This voxelwise matrix has over a million parameters, but we derive the Kirchhoff complexity and eigen-spectrum through elegant mathematical theorems, without heavy computation. We use these novel measures to accurately estimate the voxelwise connectivity in multiple biomedical applications such as Alzheimer's disease and intelligence prediction. PMID:24505723

  14. Decreased Effective Connectivity from Cortices to the Right Parahippocampal Gyrus in Alzheimer's Disease Subjects

    PubMed Central

    Chen, Guangyu; Ward, B. Douglas; Chen, Gang

    2014-01-01

    Abstract The purpose of this study was to detect effective connectivity (EC) changes in the default mode network and hippocampus network in 20 patients with Alzheimer's disease (AD) and 20 cognitively normal (CN) subjects, using multivariate Granger causality. The authors used the maximum coefficients in the multivariate autoregression model to quantitatively measure the different EC strength levels between the CN and AD groups. It was demonstrated that the EC strength difference can classify AD from CN subjects. Further, the right parahippocampal gyrus (PHP_R) showed imbalanced bidirectional EC connections. The PHP_R received weaker input connections from the neocortices, but its output connections were significantly increased in AD. These findings may provide neural physiological mechanisms for interpreting AD subjects' memory deficits during the encoding processes. PMID:25132215

  15. On the central role of brain connectivity in neurodegenerative disease progression

    PubMed Central

    Iturria-Medina, Yasser; Evans, Alan C.

    2015-01-01

    Increased brain connectivity, in all its variants, is often considered an evolutionary advantage by mediating complex sensorimotor function and higher cognitive faculties. Interaction among components at all spatial scales, including genes, proteins, neurons, local neuronal circuits and macroscopic brain regions, are indispensable for such vital functions. However, a growing body of evidence suggests that, from the microscopic to the macroscopic levels, such connections might also be a conduit for in intra-brain disease spreading. For instance, cell-to-cell misfolded proteins (MP) transmission and neuronal toxicity are prominent connectivity-mediated factors in aging and neurodegeneration. This article offers an overview of connectivity dysfunctions associated with neurodegeneration, with a specific focus on how these may be central to both normal aging and the neuropathologic degenerative progression. PMID:26052284

  16. Discriminative Analysis of Parkinson’s Disease Based on Whole-Brain Functional Connectivity

    PubMed Central

    Chen, Yongbin; Yang, Wanqun; Long, Jinyi; Zhang, Yuhu; Feng, Jieying; Li, Yuanqing; Huang, Biao

    2015-01-01

    Recently, there has been an increasing emphasis on applications of pattern recognition and neuroimaging techniques in the effective and accurate diagnosis of psychiatric or neurological disorders. In the present study, we investigated the whole-brain resting-state functional connectivity patterns of Parkinson's disease (PD), which are expected to provide additional information for the clinical diagnosis and treatment of this disease. First, we computed the functional connectivity between each pair of 116 regions of interest derived from a prior atlas. The most discriminative features based on Kendall tau correlation coefficient were then selected. A support vector machine classifier was employed to classify 21 PD patients with 26 demographically matched healthy controls. This method achieved a classification accuracy of 93.62% using leave-one-out cross-validation, with a sensitivity of 90.47% and a specificity of 96.15%. The majority of the most discriminative functional connections were located within or across the default mode, cingulo-opercular and frontal-parietal networks and the cerebellum. These disease-related resting-state network alterations might play important roles in the pathophysiology of this disease. Our results suggest that analyses of whole-brain resting-state functional connectivity patterns have the potential to improve the clinical diagnosis and treatment evaluation of PD. PMID:25885059

  17. A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease

    PubMed Central

    Freer, Rosie; Sormanni, Pietro; Vecchi, Giulia; Ciryam, Prajwal; Dobson, Christopher M.; Vendruscolo, Michele

    2016-01-01

    In Alzheimer’s disease, aggregates of Aβ and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts—at ages well before the typical onset—the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aβ and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer’s disease. PMID:27532054

  18. A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease.

    PubMed

    Freer, Rosie; Sormanni, Pietro; Vecchi, Giulia; Ciryam, Prajwal; Dobson, Christopher M; Vendruscolo, Michele

    2016-08-01

    In Alzheimer's disease, aggregates of Aβ and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts-at ages well before the typical onset-the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aβ and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer's disease. PMID:27532054

  19. Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network.

    PubMed

    Balthazar, Marcio L F; Pereira, Fabrício R S; Lopes, Tátila M; da Silva, Elvis L; Coan, Ana Carolina; Campos, Brunno M; Duncan, Niall W; Stella, Florindo; Northoff, Georg; Damasceno, Benito P; Cendes, Fernando

    2014-04-01

    Neuropsychiatric syndromes are highly prevalent in Alzheimer's disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or "resting-state" analysis, may help to clarify this issue. Using such approaches, alterations in the default-mode and salience networks (SNs) have been described in Alzheimer's, although their relationship with specific symptoms remains unclear. We therefore carried out resting-state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimer's patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default-mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy. PMID:23418130

  20. Impaired long distance functional connectivity and weighted network architecture in Alzheimer's disease.

    PubMed

    Liu, Yong; Yu, Chunshui; Zhang, Xinqing; Liu, Jieqiong; Duan, Yunyun; Alexander-Bloch, Aaron F; Liu, Bing; Jiang, Tianzi; Bullmore, Ed

    2014-06-01

    Alzheimer's disease (AD) is increasingly recognized as a disconnection syndrome, which leads to cognitive impairment due to the disruption of functional activity across large networks or systems of interconnected brain regions. We explored abnormal functional magnetic resonance imaging (fMRI) resting-state dynamics, functional connectivity, and weighted functional networks, in a sample of patients with severe AD (N = 18) and age-matched healthy volunteers (N = 21). We found that patients had reduced amplitude and regional homogeneity of low-frequency fMRI oscillations, and reduced the strength of functional connectivity, in several regions previously described as components of the default mode network, for example, medial posterior parietal cortex and dorsal medial prefrontal cortex. In patients with severe AD, functional connectivity was particularly attenuated between regions that were separated by a greater physical distance; and loss of long distance connectivity was associated with less efficient global and nodal network topology. This profile of functional abnormality in severe AD was consistent with the results of a comparable analysis of data on 2 additional groups of patients with mild AD (N = 17) and amnestic mild cognitive impairment (MCI; N = 18). A greater degree of cognitive impairment, measured by the mini-mental state examination across all patient groups, was correlated with greater attenuation of functional connectivity, particularly over long connection distances, for example, between anterior and posterior components of the default mode network, and greater reduction of global and nodal network efficiency. These results indicate that neurodegenerative disruption of fMRI oscillations and connectivity in AD affects long-distance connections to hub nodes, with the consequent loss of network efficiency. This profile was evident also to a lesser degree in the patients with less severe cognitive impairment, indicating that the potential of resting

  1. Resting-State Network Disruption and APOE Genotype in Alzheimer's Disease: A lagged Functional Connectivity Study

    PubMed Central

    Canuet, Leonides; Tellado, Ivan; Couceiro, Veronica; Fraile, Carmen; Fernandez-Novoa, Lucia; Ishii, Ryouhei; Takeda, Masatoshi; Cacabelos, Ramon

    2012-01-01

    Background The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called “lagged phase synchronization”. Methodology/Principal Findings Resting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions. Conclusions/Significance In addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent

  2. 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

  3. Organ-wide Telomeric Status in Diseased and Disease-free Prostatic Tissues

    PubMed Central

    Heaphy, Christopher M.; Fleet, Trisha M.; Treat, Eric G.; Lee, Sang-Joon; Smith, Anthony Y.; Davis, Michael S.; Griffith, Jeffrey K.; Fischer, Edgar G.; Bisoffi, Marco

    2012-01-01

    BACKGROUND Telomere attrition occurs early in the development of prostatic adenocarcinoma. However, little is known about either telomere status in benign prostatic hyperplasia (BPH), or the spatial and organ-wide distribution of potential telomere aberrations throughout all areas of prostatic glands affected by cancer or BPH. METHODS Slot blot titration assay was used to determine telomere DNA content (TC), a proxy for telomere length, in macrodissected tissue consisting of 54 normal samples from 5 disease-free prostates, 128 BPH samples from 4 non-cancerous prostates, and 45 tumor, 73 BPH, and 4 prostatic intraepithelial neoplasia (PIN) samples from 5 cancerous prostates. RESULTS Compared to TC in normal prostate samples (n=54; TC mean=0.98), tumor samples displayed telomere attrition (n=45; TC mean=0.67). TC in PIN samples was similar to tumors. BPH samples from cancerous prostates were similar to TC in tumors and also displayed telomere shortening (n=73; TC mean=0.76), whereas BPH samples from non-cancerous prostates displayed longer telomeres (n=128; TC mean=1.06). In prostates affected by adenocarcinoma, areas of potential telomere attrition occurred in histologically normal tissues through the entire gland. However, three-dimensional zoning revealed a pattern of increasing TC as a function of distance from the primary (index) tumor. CONCLUSIONS Spatial distributions of TC in prostate specimens indicate a complex “field effect” with varying contributions from both cancer and BPH. The observation that telomere length variations occur in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it may have implications for the diagnosis and focal therapy of prostate cancer. PMID:20687220

  4. Tissue Renin–Angiotensin Systems: A Unifying Hypothesis of Metabolic Disease

    PubMed Central

    Skov, Jeppe; Persson, Frederik; Frøkiær, Jørgen; Christiansen, Jens Sandahl

    2014-01-01

    The actions of angiotensin peptides are diverse and locally acting tissue renin–angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans. Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease. Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications. Based on these observations, we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control. PMID:24592256

  5. Proteomics analyses for the global proteins in the brain tissues of different human prion diseases.

    PubMed

    Shi, Qi; Chen, Li-Na; Zhang, Bao-Yun; Xiao, Kang; Zhou, Wei; Chen, Cao; Zhang, Xiao-Mei; Tian, Chan; Gao, Chen; Wang, Jing; Han, Jun; Dong, Xiao-Ping

    2015-04-01

    Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases. PMID:25616867

  6. 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

  7. Distinction and connection between contact network, social network, and disease transmission network.

    PubMed

    Chen, Shi; Lanzas, Cristina

    2016-09-01

    In this paper we discuss the distinction and connection between three closely related networks in animal ecology and epidemiology studies: the contact, social, and disease transmission networks. We provide a robust theoretical definition and interpretation of these three networks, demonstrate that social and disease transmission networks can be derived as spanning subgraphs of contact network, and show examples based on real-world high-resolution cattle contact structure data. Furthermore, we establish a modeling framework to track potential disease transmission dynamics and construct transmission network based on the observed animal contact network. PMID:27544246

  8. Quantification of Regional Interstitial Lung Disease from CT-derived Fractional Tissue Volume: A Lung Tissue Research Consortium Study

    PubMed Central

    Yilmaz, Cuneyt; Watharkar, Snehal S.; de Leon, Alberto Diaz; Garcia, Christine K.; Patel, Nova C.; Jordan, Kirk G.; Hsia, Connie C.W.

    2011-01-01

    Rationale and Objectives Evaluation of chest CT is usually qualitative or semi-quantitative, resulting in subjective descriptions often by different observers over time and imprecise determinations of disease severity within distorted lobes. There is a need for standardized imaging biomarkers to quantify regional disease, maximize diagnostic yield, and facilitate multi-center comparisons. We applied lobe-based voxelwise image analysis to derive regional air (Vair) and tissue (Vtissue) volumes and fractional tissue volume (FTV=tissue/[tissue+air] volume) as internally standardized parameter for assessing interstitial lung disease (ILD). Materials and Methods High-resolution CT was obtained at supine and prone end-inspiration and supine end-expiration in 29 patients with ILD and 20 normal subjects. Lobar Vair, Vtissue, and FTV were expressed along standard coordinate axes. Results In normal subjects from end-inspiration to end-expiration, total Vair declined 43%, FTV increased ~80% while Vtissue remained unchanged. With increasing ILD, Vair declined and Vtissue rose in all lobes; FTV increased with a peripheral-to-central progression inversely correlated to spirometry and lung diffusing capacity (R2=0.57–0.75, prone end-inspiration). Inter- and intra-lobar coefficients of variation (CVs) of FTV increased 84–148% in mild-to-moderate ILD, indicating greater spatial heterogeneity, then normalized in severe ILD. Analysis of discontinuous images incurs <3% error compared to consecutive images. Conclusions These regional attenuation-based biomarkers could quantify heterogeneous parenchymal disease in distorted lobes, detect mild ILD involvement in all lobes and describe the pattern of disease progression. The next step would be to study a larger series, examine reproducibility and follow longitudinal changes in correlation with clinical and functional indices. PMID:21596593

  9. Using Tractography to Distinguish SWEDD from Parkinson's Disease Patients Based on Connectivity

    PubMed Central

    Kim, Mansu

    2016-01-01

    Background. It is critical to distinguish between Parkinson's disease (PD) and scans without evidence of dopaminergic deficit (SWEDD), because the two groups are different and require different therapeutic approaches. Objective. The aim of this study was to distinguish SWEDD patients from PD patients using connectivity information derived from diffusion tensor imaging tractography. Methods. Diffusion magnetic resonance images of SWEDD (n = 37) and PD (n = 40) were obtained from a research database. Tractography, the process of obtaining neural fiber information, was performed using custom software. Group-wise differences between PD and SWEDD patients were quantified using the number of connected fibers between two regions, and correlation analyses were performed based on clinical scores. A support vector machine classifier (SVM) was applied to distinguish PD and SWEDD based on group-wise differences. Results. Four connections showed significant group-wise differences and correlated with the Unified Parkinson's Disease Rating Scale sponsored by the Movement Disorder Society. The SVM classifier attained 77.92% accuracy in distinguishing between SWEDD and PD using these identified connections. Conclusions. The connections and regions identified represent candidates for future research investigations. PMID:27034889

  10. Pathological manifestations in murine Lyme disease: association with tissue invasion and spirochete persistence.

    PubMed

    Weis, J J; Yang, L; Seiler, K P; Silver, R M

    1997-07-01

    The clinical manifestations of human Lyme disease present with a spectrum of tissue or organ involvement and severity of symptoms. The murine model of Lyme disease has proved to be an accurate reflection of many of the human symptoms of disease and has been particularly useful for studying development of subacute arthritis and tendonitis. Direct tissue invasion by Borrelia burgdorferi and persistence of high levels of spirochetes in tissues are important components of arthritis development. The outer-surface lipoproteins contain a biologically active lipid-modified moiety with potent ability to stimulate inflammatory cytokine production and other inflammatory mediators such as nitric oxide. Localized inflammation stimulated by these lipoproteins may be the trigger for neutrophil infiltration, synovial proliferation, and other events associated with this arthritis. Invasion of maternal uterine tissue, but not direct invasion of fetal tissue, is associated with low levels of pregnancy loss in mice infected during gestation, consistent with the detrimental effect of inflammatory cytokines on pregnancy. PMID:9233659

  11. Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease.

    PubMed

    Fuster, José J; Ouchi, Noriyuki; Gokce, Noyan; Walsh, Kenneth

    2016-05-27

    Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the collateral damage of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of proinflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines. PMID:27230642

  12. Arthritis, a complex connective and synovial joint destructive autoimmune disease: animal models of arthritis with varied etiopathology and their significance.

    PubMed

    Naik, S R; Wala, S M

    2014-01-01

    Animal models play a vital role in simplifying the complexity of pathogenesis and understanding the indefinable processes and diverse mechanisms involved in the progression of disease, and in providing new knowledge that may facilitate the drug development program. Selection of the animal models has to be carefully done, so that there is morphologic similarity to human arthritic conditions that may predict as well as augment the effective screening of novel antiarthritic agents. The review describes exclusively animal models of rheumatoid arthritis (RA) and osteoarthritis (OA). The development of RA has been vividly described using a wide variety of animal models with diverse insults (viz. collagen, Freund's adjuvant, proteoglycan, pristane, avridine, formaldehyde, etc.) that are able to simulate/trigger the cellular, biochemical, immunological, and histologic alterations, which perhaps mimic, to a great extent, the pathologic conditions of human RA. Similarly, numerous methods of inducing animal models with OA have also been described (such as spontaneous, surgical, chemical, and physical methods including genetically manipulated animals) which may give an insight into the events of alteration in connective tissues and their metabolism (synovial membrane/tissues along with cartilage) and bone erosion. The development of such arthritic animal models may throw light for better understanding of the etiopathogenic mechanisms of human arthritis and give new impetus for the drug development program on arthritis, a crippling disease. PMID:25121375

  13. Functional connectivity and information flow of the respiratory neural network in chronic obstructive pulmonary disease.

    PubMed

    Yu, Lianchun; De Mazancourt, Marine; Hess, Agathe; Ashadi, Fakhrul R; Klein, Isabelle; Mal, Hervé; Courbage, Maurice; Mangin, Laurence

    2016-08-01

    Breathing involves a complex interplay between the brainstem automatic network and cortical voluntary command. How these brain regions communicate at rest or during inspiratory loading is unknown. This issue is crucial for several reasons: (i) increased respiratory loading is a major feature of several respiratory diseases, (ii) failure of the voluntary motor and cortical sensory processing drives is among the mechanisms that precede acute respiratory failure, (iii) several cerebral structures involved in responding to inspiratory loading participate in the perception of dyspnea, a distressing symptom in many disease. We studied functional connectivity and Granger causality of the respiratory network in controls and patients with chronic obstructive pulmonary disease (COPD), at rest and during inspiratory loading. Compared with those of controls, the motor cortex area of patients exhibited decreased connectivity with their contralateral counterparts and no connectivity with the brainstem. In the patients, the information flow was reversed at rest with the source of the network shifted from the medulla towards the motor cortex. During inspiratory loading, the system was overwhelmed and the motor cortex became the sink of the network. This major finding may help to understand why some patients with COPD are prone to acute respiratory failure. Network connectivity and causality were related to lung function and illness severity. We validated our connectivity and causality results with a mathematical model of neural network. Our findings suggest a new therapeutic strategy involving the modulation of brain activity to increase motor cortex functional connectivity and improve respiratory muscles performance in patients. Hum Brain Mapp 37:2736-2754, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:27059277

  14. Brain excitability and connectivity of neuronal assemblies in Alzheimer's disease: from animal models to human findings.

    PubMed

    D'Amelio, Marcello; Rossini, Paolo Maria

    2012-10-01

    The human brain contains about 100 billion neurons forming an intricate network of innumerable connections, which continuously adapt and rewire themselves following inputs from external and internal environments as well as the physiological synaptic, dendritic and axonal sculpture during brain maturation and throughout the life span. Growing evidence supports the idea that Alzheimer's disease (AD) targets selected and functionally connected neuronal networks and, specifically, their synaptic terminals, affecting brain connectivity well before producing neuronal loss and compartmental atrophy. The understanding of the molecular mechanisms underlying the dismantling of neuronal circuits and the implementation of 'clinically oriented' methods to map-out the dynamic interactions amongst neuronal assemblies will enhance early/pre-symptomatic diagnosis and monitoring of disease progression. More important, this will open the avenues to innovative treatments, bridging the gap between molecular mechanisms and the variety of symptoms forming disease phenotype. In the present review a set of evidence supports the idea that altered brain connectivity, exhausted neural plasticity and aberrant neuronal activity are facets of the same coin linked to age-related neurodegenerative dementia of Alzheimer type. Investigating their respective roles in AD pathophysiology will help in translating findings from basic research to clinical applications. PMID:22789698

  15. The formation and management of middle ear granulation tissue in chronic ear disease.

    PubMed

    Roland, Peter S

    2004-01-01

    Granulation tissue is an important pathogenic feature of all types of chronic ear disease, and it can be controlled and treated with good aural toilet, appropriate antibiotic therapy, topical steroids, and chemical cautery or surgical debridement. PMID:14986396

  16. Brain functional connectivity patterns for emotional state classification in Parkinson's disease patients without dementia.

    PubMed

    Yuvaraj, R; Murugappan, M; Acharya, U Rajendra; Adeli, Hojjat; Ibrahim, Norlinah Mohamed; Mesquita, Edgar

    2016-02-01

    Successful emotional communication is crucial for social interactions and social relationships. Parkinson's Disease (PD) patients have shown deficits in emotional recognition abilities although the research findings are inconclusive. This paper presents an investigation of six emotions (happiness, sadness, fear, anger, surprise, and disgust) of twenty non-demented (Mini-Mental State Examination score >24) PD patients and twenty Healthy Controls (HCs) using Electroencephalogram (EEG)-based Brain Functional Connectivity (BFC) patterns. The functional connectivity index feature in EEG signals is computed using three different methods: Correlation (COR), Coherence (COH), and Phase Synchronization Index (PSI). Further, a new functional connectivity index feature is proposed using bispectral analysis. The experimental results indicate that the BFC change is significantly different among emotional states of PD patients compared with HC. Also, the emotional connectivity pattern classified using Support Vector Machine (SVM) classifier yielded the highest accuracy for the new bispectral functional connectivity index. The PD patients showed emotional impairments as demonstrated by a poor classification performance. This finding suggests that decrease in the functional connectivity indices during emotional stimulation in PD, indicating functional disconnections between cortical areas. PMID:26515932

  17. CSF proteins and resting-state functional connectivity in Parkinson disease

    PubMed Central

    Koller, Jonathan M.; Snyder, Abraham Z.; Buddhala, Chandana; Kotzbauer, Paul T.; Perlmutter, Joel S.

    2015-01-01

    Objective: The purpose of this study was to investigate the relationship between disruption of MRI-measured resting-state functional connectivity (rs-fcMRI) brain networks and CSF levels of potentially pathogenic proteins that reflect brain pathology in Parkinson disease (PD). Methods: PD participants without dementia (n = 43) and age-matched controls (n = 22) had lumbar punctures to measure CSF protein levels, Pittsburgh compound B (PiB)–PET imaging, and rs-fcMRI while off medication. Imaging analyses focused on 5 major resting-state networks as well as the striatum. Results: Participants with PD had significantly reduced sensorimotor functional connectivity, which correlated with reduced CSF levels of α-synuclein. The PD group also had significantly stronger default mode network functional connectivity that did not correlate with CSF β-amyloid (Aβ)42 or PiB uptake. In contrast, default mode network functional connectivity in the control group did correlate with CSF Aβ42 levels. Functional connectivity was similar between groups in the dorsal attention, control, and salience networks. Conclusion: These results suggest that abnormal α-synuclein accumulation, but not Aβ, contributes to the disruption of motor-related functional connectivity in PD. Furthermore, correlating CSF protein measures with the strength of resting-state networks provides a direct link between abnormal α-synuclein metabolism and disrupted brain function in PD. PMID:25979701

  18. Presumptive service connection for disease associated with exposure to certain herbicide agents: AL amyloidosis. Final rule.

    PubMed

    2009-05-01

    This document amends the Department of Veterans Affairs (VA) adjudication regulations concerning presumptive service connection for a certain disease based on the most recent National Academy of Sciences (NAS) Institute of Medicine committee report, "Veterans and Agent Orange: Update 2006" (Update 2006). This amendment is necessary to implement a decision of the Secretary of Veterans Affairs that there is a positive association between exposure to herbicides used in the Republic of Vietnam during the Vietnam era and the subsequent development of AL amyloidosis. The intended effect of this amendment is to establish presumptive service connection for AL amyloidosis based on herbicide exposure. PMID:19507326

  19. 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

  20. Inorganic particles in human tissues and their association with neoplastic disease

    PubMed Central

    Langer, Arthur M.

    1974-01-01

    An increased gastrointestinal cancer risk is associated with occupational exposure to asbestos fiber. Examination of tissues obtained from extrapulmonary organs of exposed workmen demonstrates the presence of asbestos fibers and bodies. The amount of fiber present in these tissues is many magnitudes less than encountered in the lung tissues from the same individuals. Ingestion of asbestos fiber in some environmental instances may approach in magnitude the amount resulting from occupational exposure. Disease factors are discussed. PMID:4470940

  1. 38 CFR 3.310 - Disabilities that are proximately due to, or aggravated by, service-connected disease or injury.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... determine the baseline and current levels of severity under the Schedule for Rating Disabilities (38 CFR... proximately due to, or aggravated by, service-connected disease or injury. 3.310 Section 3.310 Pensions... are proximately due to, or aggravated by, service-connected disease or injury. (a) General. Except...

  2. 38 CFR 3.371 - Presumptive service connection for tuberculous disease; wartime and service on or after January 1...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... connection for tuberculous disease; wartime and service on or after January 1, 1947. 3.371 Section 3.371... Presumptive service connection for tuberculous disease; wartime and service on or after January 1, 1947. (a... of clinical activity. (2) A notation of inactive tuberculosis of the reinfection type at induction...

  3. 38 CFR 3.371 - Presumptive service connection for tuberculous disease; wartime and service on or after January 1...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... connection for tuberculous disease; wartime and service on or after January 1, 1947. 3.371 Section 3.371... Presumptive service connection for tuberculous disease; wartime and service on or after January 1, 1947. (a... of clinical activity. (2) A notation of inactive tuberculosis of the reinfection type at induction...

  4. 38 CFR 3.371 - Presumptive service connection for tuberculous disease; wartime and service on or after January 1...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... connection for tuberculous disease; wartime and service on or after January 1, 1947. 3.371 Section 3.371... Presumptive service connection for tuberculous disease; wartime and service on or after January 1, 1947. (a... of clinical activity. (2) A notation of inactive tuberculosis of the reinfection type at induction...

  5. 38 CFR 3.371 - Presumptive service connection for tuberculous disease; wartime and service on or after January 1...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... connection for tuberculous disease; wartime and service on or after January 1, 1947. 3.371 Section 3.371... Presumptive service connection for tuberculous disease; wartime and service on or after January 1, 1947. (a... of clinical activity. (2) A notation of inactive tuberculosis of the reinfection type at induction...

  6. 38 CFR 3.371 - Presumptive service connection for tuberculous disease; wartime and service on or after January 1...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... connection for tuberculous disease; wartime and service on or after January 1, 1947. 3.371 Section 3.371... Presumptive service connection for tuberculous disease; wartime and service on or after January 1, 1947. (a... of clinical activity. (2) A notation of inactive tuberculosis of the reinfection type at induction...

  7. 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

  8. 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

  9. Mechanisms of foot-and-mouth disease virus tropism inferred from differential tissue gene expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Foot-and-Mouth Disease virus (FMDV) has a characteristic tropism in terms of primary, secondary, and persistent infection and vesicular lesion sites. The virus targets specific tissues for primary replication. From these tissues, the virus spreads via the blood stream to a few preferred secondary in...

  10. Differentially disrupted functional connectivity of the subregions of the amygdala in Alzheimer's disease.

    PubMed

    Wang, Zhiqun; Zhang, Min; Han, Ying; Song, Haiqing; Guo, Rongjuan; Li, Kuncheng

    2016-01-01

    The amygdala is an important brain area involved in cognitive procession and emotional regulation. Previous studies have typically considered the amygdala as a single structure, which likely masks contribution of individual amygdala subdivisions. Actually, the amygdala is heterogeneous and composed of structurally and functionally distinct nuclei, which may present different connectivity patterns and predict to relevant cognitive deficits in Alzheimer's disease (AD). However, little is known about functional connectivity of amygdala subregions in the resting state in AD subjects. Here, we employed resting-state functional MRI (fMRI) to examine functional connectivity changes of subregions comparing the AD patients with the age-matched control subjects. Thirty-two AD and 38 control subjects were analyzed. We defined three subregions of the amygdala according to probabilistic cytoarchitectonic atlases and mapped the whole-brain resting-state functional connectivity for each subregion: The central medial nucleus (CM) of amygdala exhibited connections with the lentiform nucleus, parahippocampus and lateral temporal gyrus; the lateral basal nucleus (LB) of amygdala functionally connected with the parahippocampus, lateral temporal gyrus, middle occipital gyrus and medial prefrontal cortex; and the superficial nucleus (SF) of amygdala had connection with the parahippocampus, lentiform nucleus, lateral temporal gyrus, insula, middle occipital gyrus, precentral and postcentral gyrus. Comparing with the controls, the AD patients presented disrupted connectivity patterns in the LB of amygdala, which predicted disconnection with the left uncus, right insula, right precentral gyrus, the left superior temporal gyrus and right claustrum. These findings in a large part supported our hypothesis and provided a new insight in understanding the pathophysiological mechanisms of AD. PMID:27002909

  11. Magnesium carbonate-containing phosphate binder prevents connective tissue mineralization in Abcc6(-/-) mice-potential for treatment of pseudoxanthoma elasticum.

    PubMed

    Li, Qiaoli; Larusso, Jennifer; Grand-Pierre, Alix E; Uitto, Jouni

    2009-12-01

    the calcium and phosphate content of the femurs by chemical assay, in comparison to mice on control diet. Similar experiments with another experimental diet supplemented with lanthanum carbonate did not interfere with the mineralization process in Abcc6(-/-) mice. These results suggest that magnesium carbonate may offer a potential treatment modality for PXE, a currently intractable disease, as well as for other conditions characterized by ectopic mineralization of connective tissues. PMID:20443931

  12. 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.

  13. 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

  14. Structural mass spectrometry of tissue extracts to distinguish cancerous and non-cancerous breast diseases

    PubMed Central

    Hines, K. M.; Ballard, B. R.

    2014-01-01

    Breast cancer is well-known to broadly impact cellular metabolism and aberrant metabolism in breast cancer tumors has been widely studied by both targeted and untargeted analyses to characterize the affected metabolic pathways. In this work, we utilize ultra-performance liquid chromatography (UPLC) in tandem with ion mobility-mass spectrometry (IM-MS), which provides chromatographic, structural, and mass information, to characterize the aberrant metabolism associated with breast diseases such as cancer. In a double-blind analysis of matched control (n=3) and disease tissues (n=3), tissues were homogenized, polar metabolites were extracted, and the extracts were characterized by UPLC-IM-MS/MS. Principle component analysis revealed a strong separation between disease tissues, with one diseased tissue clustering with the control tissues along PC1 and two others separated along PC2. Using postion mobility MS/MS spectra acquired by data-independent acquisition, the features giving rise to the observed grouping were determined to be biomolecules associated with aggressive breast cancer tumors, including glutathione, oxidized glutathione, thymosins β4 and β10, and choline-containing species. Pathology reports revealed the outlier of the disease tissues to be a benign fibroadenoma, whereas the other disease tissues represented highly metabolic benign and aggressive tumors. This IM-MS-based workflow bridges the transition from untargeted metabolomic profiling to tentative identifications of key descriptive molecular features using data acquired in one analysis, with additional experiments performed only for validation. The ability to resolve cancerous and non-cancerous tissues at the biomolecular level demonstrates UPLC-IM-MS/MS as a robust and sensitive platform for metabolomic profiling of tissues. PMID:25212505

  15. 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

  16. 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

  17. Functional connectivity in a rat model of Alzheimer's disease during a working memory task.

    PubMed

    Liu, Tiaotiao; Bai, Wenwen; Yi, Hu; Tan, Tao; Wei, Jing; Wang, Ju; Tian, Xin

    2014-01-01

    Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of memory. Impairment of working memory was typically observed in AD. The concept of brain functional connectivity plays an important role in neuroscience as a useful tool to understand the organized behavior of brain. Hence, the purpose of this study is to investigate the possible mechanism of working memory deficits in AD from a new perspective of functional connectivity. Rats were randomly divided into 2 groups: Aβ injection group (Aβ₁₋₄₂-induced toxicity rat model) and control group. Multi-channel local field potentials (LFPs) were obtained from rat prefrontal cortex with implanted microelectrode arrays while the rats performed a Y-maze working memory task. The short-time Fourier transform was utilized to analyze the power changes in LFPs and sub-bands (in particular theta and low gamma bands) were extracted via band filtering. Then the Directed transfer function (DTF) method was applied to calculate the functional connections among LFPs. From the DTF calculation, the causal networks in the sub-bands were identified. DTFmean (mean of connectivity matrix elements) was used to quantify connection strength as well as global efficiency (Eglob) was calculated to quantitatively describe the efficient of information transfer in the network. Our results showed that both connection strength and efficient of information transfer increased during the working memory task in the control group; by contrast, there was no significantly change in the Aβ injection group. These findings could lead to improve the understanding of the mechanism of working memory deficits in AD. PMID:25387338

  18. Potential role of gut microbiota and tissue barriers in Parkinson's disease and amyotrophic lateral sclerosis.

    PubMed

    Fang, Xin

    2016-09-01

    Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with pathophysiology that may be related to the gastrointestinal tract. It is well established that tissue barriers maintain homeostasis and health. Furthermore, gut microbiota may have an impact on brain activity through the gut-microbiota-brain axis under both physiological and pathological conditions. In this review, we highlight the current knowledge regarding the role of gut microbiota and tissue barriers in PD and ALS. To our knowledge, this is the first review of the key issues involving both the altered gut microbiota and impaired tissue barriers in the pathophysiology of PD and ALS. PMID:26381230

  19. Deciphering the genetic and modular connections between coronary heart disease, idiopathic pulmonary arterial hypertension and pulmonary heart disease.

    PubMed

    Yuan, Ye; Zhang, Yingying; Zhang, Xiaoxu; Yu, Yanan; Li, Bing; Wang, Pengqian; Li, Haixia; Zhao, Yijun; Shen, Chunti; Wang, Zhong

    2016-07-01

    Coronary heart disease (CHD), idiopathic pulmonary arterial hypertension (IPAH) and pulmonary heart disease (PHD) are circulatory system diseases that may simultaneously emerge in a patient and they are often treated together in clinical practice. However, the molecular mechanisms connecting these three diseases remain unclear. In order to determine the multidimensional characteristic correlations between these three diseases based on genomic networks to aid in medical decision-making, genes from the Online Mendelian Inheritance in Man database were obtained, and applied network construction and modularized analysis were conducted. Functional enrichment analysis was conducted to explore the associations between overlapping genes, modules and pathways. A total of 29 overlapping genes and 3 common modules were identifed for the 3 diseases. Glycosphingolipid biosynthesis and the arachidonic acid metabolism are common pathways, and the biosynthetic process is suggested to be the major function involved in the three diseases. The current study reported, to the best of our knowledge for the first time, the role of glycosphingolipid biosynthesis in IPAH and PHD. The present study provided an improved understanding of the pathological mechanisms underlying CHD, IPAH and PHD. The overlapping genes, modules and pathways suggest novel areas for further research, and drug targets. The observations of the current study additionally suggest that drug indications can be broadened because of the presence of common targets. PMID:27221156

  20. Deciphering the genetic and modular connections between coronary heart disease, idiopathic pulmonary arterial hypertension and pulmonary heart disease

    PubMed Central

    YUAN, YE; ZHANG, YINGYING; ZHANG, XIAOXU; YU, YANAN; LI, BING; WANG, PENGQIAN; LI, HAIXIA; ZHAO, YIJUN; SHEN, CHUNTI; WANG, ZHONG

    2016-01-01

    Coronary heart disease (CHD), idiopathic pulmonary arterial hypertension (IPAH) and pulmonary heart disease (PHD) are circulatory system diseases that may simultaneously emerge in a patient and they are often treated together in clinical practice. However, the molecular mechanisms connecting these three diseases remain unclear. In order to determine the multidimensional characteristic correlations between these three diseases based on genomic networks to aid in medical decision-making, genes from the Online Mendelian Inheritance in Man database were obtained, and applied network construction and modularized analysis were conducted. Functional enrichment analysis was conducted to explore the associations between overlapping genes, modules and pathways. A total of 29 overlapping genes and 3 common modules were identifed for the 3 diseases. Glycosphingolipid biosynthesis and the arachidonic acid metabolism are common pathways, and the biosynthetic process is suggested to be the major function involved in the three diseases. The current study reported, to the best of our knowledge for the first time, the role of glycosphingolipid biosynthesis in IPAH and PHD. The present study provided an improved understanding of the pathological mechanisms underlying CHD, IPAH and PHD. The overlapping genes, modules and pathways suggest novel areas for further research, and drug targets. The observations of the current study additionally suggest that drug indications can be broadened because of the presence of common targets. PMID:27221156

  1. A spectral graph regression model for learning brain connectivity of Alzheimer's disease.

    PubMed

    Hu, Chenhui; Cheng, Lin; Sepulcre, Jorge; Johnson, Keith A; Fakhri, Georges E; Lu, Yue M; Li, Quanzheng

    2015-01-01

    Understanding network features of brain pathology is essential to reveal underpinnings of neurodegenerative diseases. In this paper, we introduce a novel graph regression model (GRM) for learning structural brain connectivity of Alzheimer's disease (AD) measured by amyloid-β deposits. The proposed GRM regards 11C-labeled Pittsburgh Compound-B (PiB) positron emission tomography (PET) imaging data as smooth signals defined on an unknown graph. This graph is then estimated through an optimization framework, which fits the graph to the data with an adjustable level of uniformity of the connection weights. Under the assumed data model, results based on simulated data illustrate that our approach can accurately reconstruct the underlying network, often with better reconstruction than those obtained by both sample correlation and ℓ1-regularized partial correlation estimation. Evaluations performed upon PiB-PET imaging data of 30 AD and 40 elderly normal control (NC) subjects demonstrate that the connectivity patterns revealed by the GRM are easy to interpret and consistent with known pathology. Moreover, the hubs of the reconstructed networks match the cortical hubs given by functional MRI. The discriminative network features including both global connectivity measurements and degree statistics of specific nodes discovered from the AD and NC amyloid-beta networks provide new potential biomarkers for preclinical and clinical AD. PMID:26024224

  2. A Spectral Graph Regression Model for Learning Brain Connectivity of Alzheimer’s Disease

    PubMed Central

    Hu, Chenhui; Cheng, Lin; Sepulcre, Jorge; Johnson, Keith A.; Fakhri, Georges E.; Lu, Yue M.; Li, Quanzheng

    2015-01-01

    Understanding network features of brain pathology is essential to reveal underpinnings of neurodegenerative diseases. In this paper, we introduce a novel graph regression model (GRM) for learning structural brain connectivity of Alzheimer's disease (AD) measured by amyloid-β deposits. The proposed GRM regards 11C-labeled Pittsburgh Compound-B (PiB) positron emission tomography (PET) imaging data as smooth signals defined on an unknown graph. This graph is then estimated through an optimization framework, which fits the graph to the data with an adjustable level of uniformity of the connection weights. Under the assumed data model, results based on simulated data illustrate that our approach can accurately reconstruct the underlying network, often with better reconstruction than those obtained by both sample correlation and ℓ1-regularized partial correlation estimation. Evaluations performed upon PiB-PET imaging data of 30 AD and 40 elderly normal control (NC) subjects demonstrate that the connectivity patterns revealed by the GRM are easy to interpret and consistent with known pathology. Moreover, the hubs of the reconstructed networks match the cortical hubs given by functional MRI. The discriminative network features including both global connectivity measurements and degree statistics of specific nodes discovered from the AD and NC amyloid-beta networks provide new potential biomarkers for preclinical and clinical AD. PMID:26024224