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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.

  3. Undiagnosed connective tissue diseases

    PubMed Central

    Cavagna, Lorenzo; Codullo, Veronica; Ghio, Stefano; Scirè, Carlo Alberto; Guzzafame, Eleonora; Scelsi, Laura; Rossi, Silvia; Montecucco, Carlomaurizio; Caporali, Roberto

    2016-01-01

    Abstract Among different subgroups of pulmonary arterial hypertension (PAH), those associated with connective tissue diseases (CTDs) have distinct hemodynamic and prognostic features; a correct etiologic diagnosis is thus mandatory. To estimate frequency and prognosis of previously undiagnosed CTDs in a suspect idiopathic (i) PAH cohort. Consecutive patients with PAH confirmed by right heart catheterization referred at the Cardiology Division of our Hospital without a previous rheumatological assessment or the occurrence of other conditions explaining PAH were checked for CTD by a clinical, laboratory, and instrumental evaluation. Survival in each group has also been analyzed. In our study 17 of 49 patients were classified as CTD-PAH, corresponding to a prevalence (95% CI) of 34.7% (21.7–49.6%). ANA positivity had 94% (71.3–99.9%) sensitivity and 78.1% (60–90.7%) specificity for a diagnosis of CTD-PAH; Raynaud phenomenon (RP) showed 83.3% (51.6–97.9%) sensitivity and 100% (90.5–100%) specificity for the diagnosis of Systemic Sclerosis (SSc)-PAH. At diagnosis, SSc patients were older and had a lower creatinine clearance compared with iPAH and other CTD-PAH. After a median follow-up of 44 (2–132) months, 18 of 49 (36.7%) patients died: 31.2% in the iPAH group, 20% in the CTD-, and 58.3% in the SSc-PAH group. Mortality was significantly higher in SSc-PAH (HR 3.32, 1.11–9.95, P <0.05) versus iPAH. We show a high prevalence of undiagnosed CTDs in patients with iPAH without a previous rheumatological assessment. All patients with RP were diagnosed with SSc. Our data stress the importance of a rheumatological assessment in PAH, especially because of the unfavorable prognostic impact of an associated SSc. PMID:27684814

  4. Autoimmune connective tissue diseases.

    PubMed

    Østensen, Monika; Cetin, Irene

    2015-07-01

    Rheumatic diseases (RDs) occur preferentially in women, often during the childbearing age. The interaction of pregnancy and the RD is varied, ranging from spontaneous improvement to aggravation of disease symptoms or life-threatening flares. Risks for the mother with RD and the child differ in regard to the presence of organ manifestations, organ damage, disease activity, presence of specific autoantibodies, and therapy. Pregnancy complications comprise hypertension, preeclampsia, premature delivery, and side effects of therapy. Adverse pregnancy outcomes include recurrent miscarriage, intrauterine growth restriction, and fetal demise, and they are frequently encountered in RD with organ manifestations and harmful autoantibodies. Because of the difference in the prevalence of RDs, knowledge on the gestational course of disease and pregnancy outcome is limited to the fairly common RDs such as rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Pregnancies in RD are connected with increased risks for mother and child and need interdisciplinary care and management.

  5. [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.

  6. Undifferentiated Connective Tissue Disease

    MedlinePlus

    ... Professionals Treatment & Programs Health Information Doctors ... disease (UCTD) is a systemic autoimmune disease. This means the body's natural immune system does not behave normally. Instead of ...

  7. Adipokines in connective tissue diseases.

    PubMed

    Sawicka, Karolina; Krasowska, Dorota

    2016-01-01

    Adipokines, pleiotropic molecules produced by white adipose tissue (WAT) have attracted the attention of scientists since 1994. The role of adipokines in metabolic syndrome is known and fixed. Adipokines exerting a variety of metabolic activities have contributed to the ethiopathogenesis and the consequences of metabolic syndrome. Furthermore, adipokines are involved in the regulation of inflammatory processes and autoimmunity in the light of pathogenesis of connective tissue diseases. Given some evidence for the influence of adipokines in metabolic syndrome, there may be a link between CVDs and rheumatic diseases. This review provides an overview of the literature focusing on the role of adipokines in rheumatic diseases by putting special emphasis on the potential role of leptin, resistin, adiponectin, chemerin, visfatin and novel adipokines in connective tissue diseases.

  8. 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.

  9. Radiotherapy in patients with connective tissue diseases.

    PubMed

    Giaj-Levra, Niccolò; Sciascia, Savino; Fiorentino, Alba; Fersino, Sergio; Mazzola, Rosario; Ricchetti, Francesco; Roccatello, Dario; Alongi, Filippo

    2016-03-01

    The decision to offer radiotherapy in patients with connective tissue diseases continues to be challenging. Radiotherapy might trigger the onset of connective tissue diseases by increasing the expression of self-antigens, diminishing regulatory T-cell activity, and activating effectors of innate immunity (dendritic cells) through Toll-like receptor-dependent mechanisms, all of which could potentially lead to breaks of immune tolerance. This potential risk has raised some debate among radiation oncologists about whether patients with connective tissue diseases can tolerate radiation as well as people without connective tissue diseases. Because the number of patients with cancer and connective tissue diseases needing radiotherapy will probably increase due to improvements in medical treatment and longer life expectancy, the issue of interactions between radiotherapy and connective tissue diseases needs to be clearer. In this Review, we discuss available data and evidence for patients with connective tissue diseases treated with radiotherapy.

  10. [Gastroenterologic aspects of connective tissue diseases].

    PubMed

    Altomonte, L; Zoli, A; Alessi, F; Ghirlanda, G; Greco, A V; Magarò, M

    1985-07-14

    The connective tissue disorders are a protean group of acquired diseases which have in common widespread immunologic and inflammatory alterations of connective tissue. The acquired connective tissue diseases generally include the following clinical entities: rheumatoid arthritis, systemic lupus erythematosus, polymyositis, polyarteritis nodosa, scleroderma, mixed connective tissue disease, Sjögren's and Behcet's sindromes. These entities have certain features in common which include sinovitis, pleuritis, myocarditis, endocarditis, pericarditis, peritonitis, vasculitis, myositis, changes in skin, alteration of connective tissue and nephritis. Gastrointestinal and hepatic involvement in connective tissue disorders are not the most important features, nevertheless appear almost regularly. Anorexia, nausea, vomiting, abdominal pain, malabsorption may affect patients suffering by rheumatoid arthritis, systemic lupus erythematosus and other collagenophaties. In some cases mesenteric vasculitis may cause intestinal ischemia which may result in bowel infarction, mucosal ulceration, hemorrhage, perforation. After an extensive review of the existing literature the Authors make an accurate evaluation of gastrointestinal and hepatic alterations in connective tissue diseases.

  11. Cutaneous mucinosis in mixed connective tissue disease.

    PubMed

    Favarato, Maria Helena Sampaio; Miranda, Sofia Silveira de Castro; Caleiro, Maria Teresa Correia; Assad, Ana Paula Luppino; Halpern, Ilana; Fuller, Ricardo

    2013-01-01

    Cutaneous mucinosis is a group of conditions involving an accumulation of mucin or glycosaminoglycan in the skin and its annexes. It is described in some connective tissue diseases but never in association with mixed connective tissue disease. This report concerns two cases of cutaneous mucinosis in patients with mixed connective tissue disease in remission; one patient presented the papular form, and the other reticular erythematous mucinosis. These are the first cases of mucinosis described in mixed connective tissue disease. Both cases had skin lesions with no other clinical or laboratorial manifestations, with clinical response to azathioprine in one, and to an association of chloroquine and prednisone in the other.

  12. Cutaneous mucinosis in mixed connective tissue disease*

    PubMed Central

    Favarato, Maria Helena Sampaio; Assad, Ana Paula Luppino; Miranda, Sofia Silveira de Castro; Halpern, Ilana; Caleiro, Maria Teresa Correia; Fuller, Ricardo

    2013-01-01

    Cutaneous mucinosis is a group of conditions involving an accumulation of mucin or glycosaminoglycan in the skin and its annexes. It is described in some connective tissue diseases but never in association with mixed connective tissue disease. This report concerns two cases of cutaneous mucinosis in patients with mixed connective tissue disease in remission; one patient presented the papular form, and the other reticular erythematous mucinosis. These are the first cases of mucinosis described in mixed connective tissue disease. Both cases had skin lesions with no other clinical or laboratorial manifestations, with clinical response to azathioprine in one, and to an association of chloroquine and prednisone in the other. PMID:24068142

  13. Pulmonary hypertension associated with connective tissue disease.

    PubMed

    Fagan, Karen A; Badesch, David B

    2002-01-01

    Pulmonary arterial hypertension is a life threatening complication of several connective tissue diseases including scleroderma (both diffuse and limited scleroderma, or the CREST syndrome--calcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangectasia), systemic lupus erythomatosis (SLE), mixed connective tissue disease (MCTD), and less commonly, rheumatoid arthritis (RA) and dermatomyositis/polymyositis. This report reviews the occurrence of this complication, potential etiologies, clinical presentation, and treatment options.

  14. [Pulmonary arterial hypertension in connective tissue diseases].

    PubMed

    Cordier, Jean-François

    2009-11-01

    Among connective tissue diseases, pulmonary arterial hypertension (PAH) is frequently associated with systemic sclerosis and systemic lupus erythematosus. PAH is less common in mixed connective tissue diseases and Sjögren's syndrome, and rare in rheumatoid arthritis. PAH in systemic sclerosis may be either isolated (prevalence about 8%) or associated with interstitial lung disease. Echocardiographic screening for PAH is worthwhile in patients with systemic sclerosis, especially as treatments for idiopathic PAH (endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostanoids) are effective in this setting. The prevalence of PAH among patients with systemic lupus erythematosus is poorly known; immunosuppressive treatment is sometimes effective by itself but most patients benefit from PAH treatment. PAH associated with connective tissue diseases has a worse prognosis than idiopathic PAH.

  15. 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.

  16. [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.

  17. 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.

  18. Mixed connective tissue disorder and Castleman's disease.

    PubMed

    Chrispal, Anugrah; Vasuki, Zoya; Thomas, Elsa Mary; Boorugu, Hari Kishan

    2010-08-01

    We present a 16-year-old girl who presented with polyarthritis in association with Raynaud's phenomenon, malar rash, oral ulcers, photosensitivity and alopecia of 6 months duration. On evaluation, it emerged that she had a mixed connective tissue disorder with a mesangio-proliferative glomerulonephritis. Her Chest radiograph revealed a well defined left mid and lower zone opacity with evidence of a hilar mass on CT Thorax. Histopathological examination following CT guided biopsy of the mass revealed a hyaline vascular type of Castleman's disease. Mixed Connective Tissue Disorder with Castleman's Disease is a rare association; the patient presenting with varied and interesting manifestations. It is important to understand this association in view of management. The exact etio-pathogenesis of the autoimmune manifestations in patients with Castleman's disease is not clear. Treatment with immunosuppression can suppress both immune manifestations and result in tumour regression as well.

  19. Vasculitis associated with connective tissue diseases.

    PubMed

    Cozzani, E; Gasparini, G; Papini, M; Burlando, M; Drago, F; Parodi, A

    2015-04-01

    Vasculitis in connective tissue disease (CTD) is quite rare, it is reported in approximately 10% of patients with CTD; systemic lupus erythematosus (SLE) shows the highest association rate. Vessels of any size may be involved, but mainly small vessels vasculitis is reported. At present the classification of these vasculitis is unsatisfactory. According to the 2012 revised International Chapel Hill Consensus Conference, vasculitides secondary to CTD are a well identified entity and are classified under the category of "vasculitis associated with systemic disease". However only lupus vasculitis and rheumatoid vasculitis are explicitly listed, while the remaining are generically included under the heading "others". Petechiae, purpura, gangrene and ulcers are the most frequent cutaneous manifestations that should investigated in order to rule out potentially dangerous systemic involvement, especially if cryoglobulinemic or necrotizing vasculitis are suspected. This review will focus on the cutaneous involvement in CTD associated vasculitis.

  20. [Autoimmune connective tissue diseases and vaccination].

    PubMed

    Więsik-Szewczyk, Ewa; Jahnz-Różyk, Karina

    2015-12-31

    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.

  1. 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

  2. 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.

  3. Antiphospholipid syndrome in systemic connective tissue diseases.

    PubMed

    Mitrović, D; Popović, M; Stefanović, D; Cirković, M; Glisić, B; Pavlica, L; Popović, R; Pejnović, N

    1998-01-01

    Clinical manifestation and immunoserological features of secondary antiphospholipid syndrome (SAPS) were analyzed in this paper in 107 patients with systemic connective tissue diseases. In the group of patients with confirmed systemic lupus erythematosus (SLE), antiphospholipid antibodies (aPL) were positive in 43/93 (46.23%), while in 50/93 (53.76%) they were negative. Among aPL positive patients, 33/43 (76.74%) had clinical manifestations of SAPS, while 10 patients (23.26%) were without any clinical manifestations. The most frequent manifestations of SAPS associated with SLE were: arteriovenous thrombosis in 20/43 (46.51%), thrombocitopenia in 15/43 (34.88%) and autoimmune hemolytic anemia in 7/43 (16.27%). In our patients, rare manifestations of SAPS associated with SLE were recurrent fetal loss (1 case), livedo reticularis (1 case), transversal myelitis (2 cases), neuropathy (2 cases) and aseptic endocarditis (Libman-Sacks) (5 cases). Among 7 patients, with Sjögren's syndrome, clinically manifested SAPS was observed in 2, while in other 5 only increased aPL levels were found, as well as in patients with systemic vasculitis-3, MCTD-2 and Sy. Sjögren with vasculitis-1. One RA patient had thrombosis of v. cava inferior. In majority of patients with clinically present SAPS the levels of both examined immunoglobulin isotypes (IgG + IgM) were decreased-21/40 or 52.5%, while isolated increase of IgG was found in 14 (35%) and isolated increase of IgM in 5 (19.22%) patients. In three out of five patients with Libman-Sacks only LA test was positive. This investigation have shown that arterial and venous thromboses are the most common manifestations of SAPS in SLE. Every blood vessel may be involved (from arteriolae to the aorta and from postcapilar venules to the v. cava).

  4. [Relation between autoimmune thyroid diseases and connective tissue diseases].

    PubMed

    Barragán-Garfias, Jorge Alberto; Zárate, Arturo

    2013-01-01

    The main physiological function of the immune system consists in the defense against infectious micro-organisms. Sometimes there is a loss of immunological tolerance with the consequence of ignorance of self-antibodies. Some thyroid diseases are related to autoimmune diseases associated with the most common exocrine glands between them. There are also the autoimmune thyroid organ specific diseases, such as Graves-Basedow and the Hashimoto thyroiditis. It has been shown that there is a higher prevalence of autoimmune thyroid diseases in patients with connective tissue diseases (systemic autoimmune) such as Sjögren syndrome, rheumatoid arthritis, systemic lupus erithmatosis and systemic myopathic diseases. In the same way a higher prevalence of antinuclear antibodies against antigens extracted from the nucleus in patients with a thyroid autoimmune disease has been identified. There is a high percentage of patients with subclinical thyroid diseases, and it is recommended for patients with connective tissue diseases with hypo- or hyperthyroidism to have thyroid globulin and peroxide antibodies measured.

  5. Imaging of Pulmonary Manifestations of Connective Tissue Diseases.

    PubMed

    Ahuja, Jitesh; Arora, Deepika; Kanne, Jeffrey P; Henry, Travis S; Godwin, J David

    2016-11-01

    Connective tissue diseases (CTDs) are a heterogeneous group of conditions characterized by circulating autoantibodies and autoimmune-mediated organ damage. Common CTDs with lung manifestations are rheumatoid arthritis, scleroderma or systemic sclerosis, Sjögren syndrome, polymyositis/dermatomyositis, systemic lupus erythematosis, mixed connective tissue disease, and undifferentiated connective tissue disease. The most common histopathologic patterns of CTD-related interstitial lung disease are nonspecific interstitial pneumonia, usual interstitial pneumonia, organizing pneumonia, and lymphoid interstitial pneumonia. Drug treatment of CTDs can cause complications, including opportunistic infection.

  6. Perioperative Management of Patients with Connective Tissue Disease

    PubMed Central

    Goodman, Susan M.; Figgie, Mark P.

    2010-01-01

    Diseases of the connective tissue are a varied group of disorders with major musculoskeletal manifestations such as joint pain and loss of function. As a consequence of the accompanying inflammatory joint disease, such patients often require surgery. Due to the protean organ-related consequences of these conditions, patients who suffer from chronic connective tissue disease are a highly challenging population in the perioperative context. This paper reviews the management of such patients in this clinical setting. PMID:22294961

  7. Biomarkers of connective tissue disease in patients with intracranial aneurysms.

    PubMed

    Yurt, Alaattin; Vardar, Enver; Selçuki, Mehmet; Ertürk, Ali Riza; Ozbek, Gülriz; Atçi, Burak

    2010-09-01

    Connective tissue defects may play a significant role in the development of intracranial aneurysms (IAs). Multiorgan connective tissue disorders may, therefore, indicate a risk of IA development. We investigated biomarkers of connective tissue disease in patients with IAs. A series of 62 patients with IAs was studied by physical examination, echocardiography, ultrasound examination of the kidneys and abdomen, and microscopic examination of skin tissue (temporal area) and superficial temporal artery taken at operation. Patients with IAs had a higher incidence of biomarkers of systemic connective tissue disease than controls and identification of these markers may be important for screening for IAs. Microscopic investigation of biopsies of the skin and superficial temporal artery from patients and their relatives may become valuable for clinical diagnosis, identification of people at risk and basic studies of the pathogenesis of this vascular disease.

  8. Pulmonary vascular manifestations of mixed connective tissue disease.

    PubMed

    Bull, Todd M; Fagan, Karen A; Badesch, David B

    2005-08-01

    Mixed connective tissue disease (MCTD) refers to a disease process with combined clinical features characteristic of systemic lupus erythematous, scleroderma, and polymyositis-dermatomyositis. This article focuses on the pulmonary vasculature manifestations of MCTD. We briefly discuss associations between MCTD and interstitial lung disease, pleural disease, and alveolar hemorrhage.

  9. Hypocomplementemic urticarial vasculitis in mixed connective tissue disease.

    PubMed

    Calistru, Ana Maria; Lisboa, Carmen; Cruz, Maria João; Delgado, Luis; Poças, Licínio; Azevedo, Filomena

    2010-12-15

    Urticarial vasculitis is characterized clinically by urticaria-like skin lesions and histologically by leukocytoclastic vasculitis. It may be idiopathic or associated with various conditions such as infections, hematologic disorders, drugs, and connective tissue diseases, primarily systemic lupus erythematosus; an association with mixed connective tissue disease (MCTD) has rarely been reported. We present a case of hypocomplementemic urticarial vasculitis in a patient with MCTD that responded to hydroxychloroquine after a period of corticosteroid dependence.

  10. Connective Tissue Disease-associated Interstitial Lung Disease: A review

    PubMed Central

    Gutsche, Markus; Rosen, Glenn D.; Swigris, Jeffrey J.

    2012-01-01

    Interstitial lung disease (ILD) is commonly encountered in patients with connective tissue diseases (CTD). Besides the lung parenchyma, the airways, pulmonary vasculature and structures of the chest wall may all be involved, depending on the type of CTD. As a result of this so-called multi-compartment involvement, airflow limitation, pulmonary hypertension, vasculitis and extrapulmonary restriction can occur alongside fibro-inflammatory parenchymal abnormalities in CTD. Rheumatoid arthritis (RA), systemic sclerosis (SSc), poly-/dermatomyositis (PM/DM), Sjögren’s syndrome (SjS), systemic lupus erythematosus (SLE), and undifferentiated (UCTD) as well as mixed connective tissue disease (MCTD) can all be associated with the development of ILD. Non-specific interstitial pneumonia (NSIP) is the most commonly observed histopathological pattern in CTD-ILD, but other patterns including usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP) may occur. Although the majority of patients with CTD-ILD experience stable or slowly advancing ILD, a small yet significant group exhibits a more severe and progressive course. Randomized placebo-controlled trials evaluating the efficacy of immunomodulatory treatments have been conducted only in SSc-associated ILD. However, clinical experience suggests that a handful of immunosuppressive medications are potentially effective in a sizeable portion of patients with ILD caused by other CTDs. In this manuscript, we review the clinical characteristics and management of the most common CTD-ILDs. PMID:23125954

  11. 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.

  12. Mixed connective tissue disease-enigma variations?

    PubMed

    Ciang, Natalia C O; Pereira, Nídia; Isenberg, David A

    2017-03-01

    In 1972, Sharp et al. described a new autoimmune rheumatic disease that they called MCTD, characterized by overlapping features of SSc, SLE, PM/DM, high levels of anti-U1snRNP and low steroid requirements with good prognosis. MCTD was proposed as a distinct disease. However, soon after the original description, questions about the existence of such a syndrome as well as disputes over the features initially described began to surface. The conundrum of whether MCTD is a distinct disease entity remains controversial. We undertook a literature review, focusing on the articles reporting new data about MCTD published in the last decade, to determine whether any new observations help to answer the conundrum of MCTD. After reviewing recent data, we question whether the term MCTD is appropriately retained, preferring to use the term undifferentiated autoimmune rheumatic disease.

  13. Infrared thermal imaging in connective tissue diseases

    PubMed Central

    2017-01-01

    Infrared thermal imaging (IRT) is a non-invasive, non-contact technique which allows one to measure and visualize infrared radiation. In medicine, thermal imaging has been used for more than 50 years in various clinical settings, including Raynaud’s phenomenon and systemic sclerosis. Imaging and quantification of surface body temperature provides an indirect measure of the microcirculation’s overall performance. As such, IRT is capable of confirming the diagnosis of Raynaud’s phenomenon, and, with additional cold or heat challenge, of differentiating between the primary and secondary condition. In systemic sclerosis IRT has a potential role in assessing disease activity and monitoring treatment response. Despite certain limitations, thermal imaging can find a place in clinical practice, and with the introduction of small, low-cost infrared cameras, possibly become a part of routine rheumatological evaluation. PMID:28386141

  14. Infrared thermal imaging in connective tissue diseases.

    PubMed

    Chojnowski, Marek

    2017-01-01

    Infrared thermal imaging (IRT) is a non-invasive, non-contact technique which allows one to measure and visualize infrared radiation. In medicine, thermal imaging has been used for more than 50 years in various clinical settings, including Raynaud's phenomenon and systemic sclerosis. Imaging and quantification of surface body temperature provides an indirect measure of the microcirculation's overall performance. As such, IRT is capable of confirming the diagnosis of Raynaud's phenomenon, and, with additional cold or heat challenge, of differentiating between the primary and secondary condition. In systemic sclerosis IRT has a potential role in assessing disease activity and monitoring treatment response. Despite certain limitations, thermal imaging can find a place in clinical practice, and with the introduction of small, low-cost infrared cameras, possibly become a part of routine rheumatological evaluation.

  15. Connective Tissue Degeneration: Mechanisms of Palmar Fascia Degeneration (Dupuytren's Disease).

    PubMed

    Karkampouna, S; Kreulen, M; Obdeijn, M C; Kloen, P; Dorjée, A L; Rivellese, F; Chojnowski, A; Clark, I; Kruithof-de Julio, Marianna

    Dupuytren's disease is a connective tissue disorder of the hand causing excessive palmar fascial fibrosis with associated finger contracture and disability. The aetiology of the disease is heterogeneous, with both genetic and environmental components. The connective tissue is abnormally infiltrated by myofibroblasts that deposit collagen and other extracellular matrix proteins. We describe the clinical profile of Dupuytren's disease along with current therapeutic schemes. Recent findings on molecular and cellular parameters that are dysregulated in Dupuytren's disease, which may contribute to the onset of the disease, and the role of resident inflammation promoting fibrosis, are highlighted. We review recent literature focusing on non-myofibroblast cell types (stem cell-like cells), their pro-inflammatory and pro-fibrotic role that may account for abnormal wound healing response.

  16. The diagnosis and classification of undifferentiated connective tissue diseases.

    PubMed

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

    2014-01-01

    The term undifferentiated connective tissue disease (UCTD) refers to unclassifiable systemic autoimmune diseases which share clinical and serological manifestations with definite connective tissue diseases (CTDs) but not fulfilling any of the existing classification criteria. In this review we will go through the more recent evidence on UCTD and we will discuss in what extent the availability of new criteria for the CTDs could interfere with the "UCTD concept". The development of criteria able to identify early phases of defined CTD, may help in the differentiation of stable UCTD form their early stages and may offer a valuable guide to the treating physician to set up appropriate follow up schedules as well as therapeutic protocols. This simplified subset of CTD could offer a model to study clinic pathological correlations as well as the role of possible environmental factors in the development of autoimmunity.

  17. 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

  18. Collapsing glomerulopathy in a patient with mixed connective tissue disease.

    PubMed

    Rifkin, S I; Gutta, H; Nair, R; McFarren, C; Wheeler, D E

    2011-02-01

    Collapsing glomerulopathy (CG) is a distinct clinicopathological entity characterized by glomerular capillary collapse, podocyte proliferation, diffuse mesangial sclerosis, and podocyte maturation arrest. Initially noted primarily in HIV infected patients, a number of other diseases have now been associated with CG. Mixed connective tissue disease (MCTD) is a disease with overlapping features of systemic lupus erythematosus, progressive systemic sclerosis, and polymyositis. It was originally thought that renal involvement was a rare complication of MCTD. However, over the years, it has become clearer that renal involvement, although not always clinically apparent, is frequent. In this report we present a patient with MCTD who developed CG.

  19. [Cardiovascular manifestations in mixed connective tissue disease in adults].

    PubMed

    Badui, E; Robles Saavedra, E; García Rubí, D; Mintz Spiro, G

    1984-01-01

    Twenty two patients with mixed connective tissue disease (MCTD) were studied with noninvasive cardiovascular techniques. Fifty percent of the cases presented cardiovascular abnormalities which in order of importance were: pericarditis with effusion (28%), myocarditis (14%) and one case; myocardial infarction. Complications of less importance were: supraventricular and ventricular premature beats, enlargement of left and right cardiac chambers, septal hypertrophy and type A paradoxical septal movement. We consider that patients with MCTD should have a routine cardiological evaluation.

  20. Review of Primary Cutaneous Mucinoses in Nonlupus Connective Tissue Diseases.

    PubMed

    Wong, Russell X; Chia, Justin C; Haber, Richard M

    2017-07-01

    Lichen myxedematosus is an idiopathic, cutaneous mucinosis with 2 clinicopathologic subsets. There is the generalised papular and sclerodermoid form, more properly termed scleromyxedema, and the localised papular form. We report the first case, to our knowledge, of lichen myxedematosus in association with rheumatoid arthritis as well as a case in association with dermatomyositis. An up-to-date literature review on cutaneous mucinoses and connective tissue diseases, excluding the common association of primary and secondary mucinoses with systemic lupus erythematosus, was also performed.

  1. 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

  2. Topical review-connective tissue diseases: orofacial manifestations including pain.

    PubMed

    Klasser, Gary D; Balasubramaniam, Ramesh; Epstein, Joel

    2007-01-01

    This topical review presents an overview of orofacial manifestations associated with the more common connective tissue diseases affecting multiple organs. The orofacial manifestations associated with these autoimmune disorders include oral mucosa alterations, salivary gland pathosis, sensory neuropathies, headaches, and temporomandibular disorders. Since many of these orofacial manifestations may be painful, the practitioner managing pain patients should be familiar with them. An understanding of the orofacial manifestations associated with these systemic diseases will enable the pain practitioner to establish an appropriate diagnosis within the context of the underlying systemic disease. This will allow the practitioner the opportunity to contribute and collaborate as a member of a multidisciplinary health-care team in the management of these systemic autoimmune diseases.

  3. Current concepts in the classification of connective tissue diseases. Overlap syndromes and mixed connective tissue disease (MCTD).

    PubMed

    Sharp, G C; Anderson, P C

    1980-04-01

    New principles are discussed for the classification of the diffuse collagen diseases, particularly the mixed connective tissue disease (MCTD), with clinical and historical explanation. Emphasis in classification has shifted from a concern with tissue pathology to serologic anomalies, which may involve eleven different antigens, many from human cell nuclei. New serologic tests, such as the ribonucleoprotein (RNP) antibody test, may be superior to the well-known fluorescent antinuclear antibody (ANA) studies for diagnosis and follow-up of diffuse collagen diseases. Functional clinical studies, such as esophageal motility, gas exchange in the lung, and major joint mobility, which may appear early in MCTD, are more important to diagnosis than anatomic studies of late-developing lesions.

  4. Pulmonary hypertension in connective tissue diseases: an update.

    PubMed

    Aithala, Ramya; Alex, Anoop G; Danda, Debashish

    2017-02-16

    Pulmonary hypertension (PH) is a relatively commoner complication of systemic sclerosis (SSc) with estimated prevalence ranging between 8% and 12% as compared to much lower figures in other connective tissue diseases (CTD). It is a major cause of morbidity and mortality in CTDs. PH is classified into five major groups. CTD-associated PH belongs to group 1 PH, also known as pulmonary arterial hypertension (PAH). Around 30% of scleroderma-related deaths are due to PAH. Underlying pathogenesis is related to pulmonary vasculopathy involving small vessels. The Evidence-based Detection of Pulmonary Arterial Hypertension in Systemic sclerosis (DETECT) algorithm outperforms the current European Society of Cardiology/European Respiratory Society guidelines as a screening tool in SSc-PAH; it can, therefore, suggest when to refer a patient for right heart catheterization. CTD-PAH patients constitute at least 20% of patients included in all major trials of PH-specific therapy and the results are comparable to those of idiopathic PAH. The role of anticoagulation in CTD-PAH is associated with a high risk-benefit ratio with the caveat of its potential role in those with severe disease. There appears to be no role of immunosuppression in scleroderma-PAH; however, immunosuppressive agents, namely the combination of glucocorticoids and pulse cyclophosphamide / possibly mycophenolate, may result in clinical improvement in a subset of patients with systemic lupus erythematosus and mixed connective tissue disease-related PAH.

  5. 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.

  6. [Septic arthritis in connective tissue diseases and other chronic arthropathies].

    PubMed

    Stecher, D R; Gusis, S E; Maldonado Cocco, J A

    1991-01-01

    In order to describe the features of septic arthritis (SA) in patients with connective tissue diseases (CTDs), a series of 17 CTD cases with SA episodes were studied retrospectively. The most common CTDs were systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Involvement was oligoarticular in 64% of cases and mono-articular in the remainder. Clinical, radiological and laboratory findings proved insufficient to allow differential diagnosis between SA and an underlying arthritic flare-up, which could only be carried out by bacterial isolation from synovial fluid. The most frequent etiological agent was Staphylococcus aureus (Table 1). Throughout, patients were treated by needle drainage together with antibiotics, first by parenteral (average 17 days) and later by oral route (average 46 days). Cases with greater diagnostic delay and initiation of therapy were those requiring arthrotomy and those who presented more complications mainly osteomyelitis and permanent disability (Table 2).

  7. Antinuclear antibody profile in Italian patients with connective tissue diseases.

    PubMed

    Neri, R; Tavoni, A; Cristofani, R; Levanti, C; Sodini, G; d'Ascanio, A; Vitali, C; Ferri, C; Bombardieri, S

    1992-08-01

    In the present work we report data on the specificity of antinuclear antibodies (ANA) in a large series of Italian patients suffering from a broad spectrum of connective tissue diseases (CTD), by using a series of homogeneous and validated techniques. The present study confirms, on the one hand, generally accepted concepts, i.e. that certain autoantibodies are strictly associated to certain disease states (such as anti-PCNA and anti-Sm in systemic lupus erythematosus, Jo 1 in polymyositis, and ACA and Scl-70 in scleroderma); the presence of 'marker' antibodies is, however, restricted to a relative minority of CTD patients. The application of a new methodological approach that considers the entire profile of ANA can greatly augment their diagnostic relevance and may provide useful indications for their interpretation, allowing us to establish for the first time the diagnostic usefulness not only of marker autoantibodies but also of certain associations between non-marker autoantibodies. Finally, the application of a more appropriate and powerful statistical tool (multiple correspondence analysis) has further emphasized the clear relationship existing between antibody specificities and certain disease states.

  8. Vitamin D deficiency in undifferentiated connective tissue disease

    PubMed Central

    Zold, Eva; Szodoray, Peter; Gaal, Janos; Kappelmayer, János; Csathy, Laszlo; Gyimesi, Edit; Zeher, Margit; Szegedi, Gyula; Bodolay, Edit

    2008-01-01

    Introduction Both experimental and clinical data provide evidence that vitamin D is one of those important environmental factors that can increase the prevalence of certain autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes mellitus, and inflammatory bowel disease. The aim of the present study was to investigate the prevalence of vitamin D insufficiency in patients with undifferentiated connective tissue disease (UCTD). Methods Plasma 25(OH)D3 levels in 161 UCTD patients were measured in both summer and winter periods. Autoantibody profiles (antinuclear antibody, anti-U1-ribonucleoprotein, anti-SSA, anti-SSB, anti-Jo1, anti-Scl70, anti-double-stranded DNA, anti-centromere, anti-cardiolipin, rheumatoid factor, and anti-cyclic citrullinated peptide) and clinical symptoms of the patients were assessed. Results Plasma levels of 25(OH)D3 in UCTD patients were significantly lower compared with controls in both summer and winter periods (UCTD summer: 33 ± 13.4 ng/mL versus control: 39.9 ± 11.7 ng/mL, P = 0.01; UCTD winter: 27.8 ± 12.48 ng/mL versus control: 37.8 ± 12.3 ng/mL, P = 0.0001). The presence of dermatological symptoms (photosensitivity, erythema, and chronic discoid rash) and pleuritis was associated with low levels of vitamin D. During the average follow-up period of 2.3 years, 35 out of 161 patients (21.7%) with UCTD further developed into well-established connective tissue disease (CTD). Patients who progressed into CTDs had lower vitamin D levels than those who remained in the UCTD stage (vitamin D levels: CTD: 14.7 ± 6.45 ng/mL versus UCTD: 33.0 ± 13.4 ng/mL, P = 0.0001). Conclusions In patients with UCTD, a seasonal variance in levels of 25(OH)D3 was identified and showed that these levels were significantly lower than in controls during the corresponding seasons. Our results suggest that vitamin D deficiency in UCTD patients may play a role in the subsequent progression into well-defined CTDs

  9. [Discontinuation of immunosuppressive and immunomodulatory drugs in connective tissue diseases].

    PubMed

    Targońska-Stępniak, Bożena

    2015-01-01

    Remission in connective tissue diseases became a realistic goal of therapy nowadays. However, there is lack of recommendations on the management after achieving a remission. Chronic exposure to immunosuppressive or immunomodulatory drugs may be associated with adverse events, that is why temporal withdrawal or discontinuation of treatment is advisable. In patients with rheumatoid arthritis (RA) who achieve sustained remission lasting for 6-12 months, an attempt to withdraw biological disease modifying antirheumatic drugs (bDMARDs) may be considered. In most patients with established RA discontinuation of bDMARDs is accompanied by a disease flare, butthe risk of loss of good therapeutic response is lower in case of slowly tapering by expanding the interval between doses or reducing the dose of bDMARDs. Patients with early RA are more likely to have successful discontinuation of therapy. Discontinuation of conventional DMARDs (cDMARDs) is usually associated with a disease flare, that is why tapering of doses is advised rather than stopping cDMARDs. DMARDs free remission occurs relatively rare, more often in patients with seronegative RA and with early onset of modifying treatment. In lupus nephritis (LN) patients with persistent, long-term remission, progressive tapering of doses of immunosuppressive drugs and glucocorticoids is recommended, with treatment discontinuation as a goal. An attempt of treatment withdrawal may be taken in patients remaining in LN complete remission as a consequence of maintenance therapy for 3 years.The process of slow tapering of doses preceding discontinuation of drugs, may last several months. The therapy with antimalarial drugs may be helpful to maintain remission after the treatment discontinuation. There is few data on treatment discontinuation in patients with systemic lupus erythematosus (SLE) without kidney involvement. Immunosuppressive drugs withdrawal is usually performed in patients with stable serological and clinically

  10. Neurological manifestations of connective tissue diseases mimicking multiple sclerosis.

    PubMed

    Pelidou, Sigliti-Henrietta; Giannopoulos, Sotiris; Tzavidi, Sotiria; Tsifetaki, Niki; Kitsos, Georgios; Stefanou, Dimitrios; Kostadima, Vassiliki; Drosos, Alexandros A; Kyritsis, Athanassios P

    2007-11-01

    The objective of the study was to analyze retrospectively the clinical, laboratory and imaging findings of multiple sclerosis (MS), such as the manifestations in a cohort of 132 patients referred to the neurology in and outpatient clinic. The proposed clinical and laboratory diagnostic criteria for MS and connective tissue disorders were systematically assessed in 132 consecutive patients. Cerebrospinal fluid serology and brain or spinal cord MRI were studied in all cases. In patients suspected for connective tissue disorder, schirmer test, rose bengal staining and biopsy of minor salivary glands were performed. A total of 115 (87%) patients were diagnosed to have definite MS, while 17 (13%) were diagnosed to have connective tissue disorder. Positive neurological and MRI findings were observed in both groups. The majority of patients with connective tissue disorder demonstrated extra-neurological manifestations like Raynaud's phenomenon, arthritis, livedo reticularis, purpura and presence of multiple autoantibodies in their sera. All patients with MS should be screened systematically for connective tissue disorder. In the absence of pathognomonic clinical and laboratory findings, the diagnosis of MS is a diagnosis of exclusion.

  11. Idiopathic interstitial pneumonias with connective tissue diseases features: A review.

    PubMed

    Cottin, Vincent

    2016-02-01

    A systematic approach is recommended to search for clinical and biological features of connective tissue disease (CTD) in any patient with interstitial lung disease (ILD). In the diagnostic approach to ILD, a diagnosis of CTD should be considered particularly in women and subjects younger than 50 years, and in those with an imaging and/or pathological pattern of non-specific interstitial pneumonia. However, the diagnosis of CTD may be difficult when ILD is the presenting or the dominant manifestation of CTD. A proportion of patients with ILD present symptoms that belong to the spectrum of CTD and/or biological autoimmune features, but do not fulfil diagnostic criteria for a given CTD. Some imaging and histopathological patterns may also suggest the presence of an underlying CTD. Although studies published to date used heterogeneous definitions and terminology for this condition, evidence is accumulating that even limited CTD features are relevant regarding symptoms, imaging features, pathological pattern and possibly evolution to overt CTD, whereas the impact on prognosis needs confirmation. Conversely, autoantibodies alone do not seem to impact the prognosis or management in patients with otherwise typical idiopathic pulmonary fibrosis and no extra-pulmonary manifestation. A collective international multidisciplinary effort has proposed a uniform definition and criteria for 'interstitial pneumonia with autoimmune features', a condition characterized by limited CTD features occurring in the setting of ILD, with the aim of fostering future clinical studies. Referral of ILD patients suspect to have CTD to a rheumatologist and possibly multidisciplinary discussion may contribute to a better management.

  12. 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

  13. Distinct phenotypes in mixed connective tissue disease: subgroups and survival.

    PubMed

    Szodoray, P; Hajas, A; Kardos, L; Dezso, B; Soos, G; Zold, E; Vegh, J; Csipo, I; Nakken, B; Zeher, M; Szegedi, G; Bodolay, E

    2012-11-01

    The aim of the present study was to assess the autoantibody profile, dominant clinical symptoms and cluster characteristics of different mixed connective tissue disease (MCTD phenotypes. Two-hundred-and-one patients with MCTD were followed-up longitudinally. Five clinical parameters, Raynaud's phenomenon, pulmonary artery hypertension (PAH), myositis, interstitial lung disease (ILD), erosive arthritis and five auto-antibodies besides anti-U1RNP, antiendothelial cell antibodies (AECA), anti-CCP, anti-cardiolipin (anti-CL), anti-SSA/SSB and IgM rheumatoid factor (RF) were selected for cluster analysis. The mean age of patients was 52.9 ± 12.4 years and the mean follow-up of the disease was 12.5 ± 7.2 years. Patients were classified into three cluster groups. Cluster 1 with 77 patients, cluster 2 with 79 patients and cluster 3 with 45 patients. In cluster 1 the prevalence of PAH (55.8%; p < 0.001), Raynaud's phenomenon (92.2%; p < 0.001) and livedo reticularis (24.6%, p < 0.001) was significantly greater than in cluster 2 and 3. In cluster 2, the incidence of ILD (98.7%; p < 0.001), myositis (77.2%; p < 0.001), and esophageal dysmotility (89.8%; p < 0.001) was significantly greater than that in cluster 1 and 3. In cluster 3, anti-CCP antibodies were present in 31 of 45 patients (68.8%) with erosions. Anti-CCP antibodies were present in 37 of 42 patients (88.0%) with erosions. PAH, angina, venous thrombosis was observed in cluster 1 and pulmonary fibrosis in cluster 2, musculosceletal damage, gastrointestinal symptoms and osteoporotic fractures were most frequent in cluster 3. Cumulative survival assessment indicated cluster 1 patients having the worst prognosis. Cluster analysis is valuable to differentiate among various subsets of MCTD and useful prognostic factor regarding the disease course.

  14. Maternal Mixed Connective Tissue Disease and Offspring with Chondrodysplasia Punctata

    PubMed Central

    Schulz, Steffan W.; Bober, Michael; Johnson, Caitlyn; Braverman, Nancy; Jimenez, Sergio A.

    2009-01-01

    Chondrodysplasia punctata (CDP) comprises a heterogeneous group of disorders that result in abnormal development of the fetal skeleton. The hallmark of the condition is radiographic presence of abnormal islands of calcification in areas of endochondral bone formation associated with premature closure of growth plates. Recently, several cases have been described in infants born to mothers with systemic lupus erythematosus (SLE). Objectives To describe the case of a mother with mixed connective tissue disease (MCTD) whose male and female offspring from two successive pregnancies had CDP in the absence of identifiable biochemical or genetic abnormalities or teratogen exposure. Methods Description of a male and female offspring from a mother with MCTD harboring high titer anti-RNP antibodies. Maternal autoantibody assays were performed employing quantitative multiplex suspension arrays and flow cytometry, and autoantibody titer and pattern were determined by indirect immunofluorescence. Assays of phytanic acid, plasmalogen and very long chain fatty acids were performed employing commercially available reagents. Chromosomal analysis was performed on both offspring employing standard cytogenetic analysis. Review of the relevant literature was performed (PubMed search 1966 through July 2008). Results Two children with CDP born to a mother with MCTD who harbored anti-RNP autoantibodies at high titer are described. Genetic and chromosomal studies, and biochemical analysis of peroxisome function and very long chain fatty acids excluded known biochemical or genetic defects or mutations as the cause of CDP in these children. Furthermore, detailed review of the clinical history failed to disclose any evidence of maternal teratogen exposure during the two pregnancies. Conclusions Maternal MCTD is the most likely explanation for the occurrence of CDP in the two children reported here. Review of previously published cases of CDP associated with autoimmune disease suggests that

  15. 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.

  16. Addison's disease secondary to connective tissue diseases: a report of six cases.

    PubMed

    Zhang, Zhuo-li; Wang, Yu; Zhou, Wei; Hao, Yan-jie

    2009-04-01

    Addison's disease is an autoimmune process. However, Addison's disease associated with connective tissue diseases (CTD) is only occasionally reported. Here, we report six cases of Addison's disease secondary to a variety of CTD, which include systemic lupus erythematosus, Takayasu arteritis, systemic sclerosis, ankylosing spondylitis (AS) and antiphospholipid antibody syndrome. The association of Addison's disease with Takayasu arteritis and AS is reported for the first time. We also found high prevalence of hypothyroidism as concomitant autoimmune disorder. Our case series highlight the autoimmune features of Addison's disease. Therefore, we suggest considering adrenal dysfunction in patients with CTD.

  17. Interstitial lung disease in connective tissue diseases: evolving concepts of pathogenesis and management

    PubMed Central

    2010-01-01

    Interstitial lung disease (ILD) is a challenging clinical entity associated with multiple connective tissue diseases, and is a significant cause of morbidity and mortality. Effective therapies for connective tissue disease-associated interstitial lung disease (CTD-ILD) are still lacking. Multidisciplinary clinics dedicated to the early diagnosis and improved management of patients with CTD-ILD are now being established. There is rapid progress in understanding and identifying the effector cells, the proinflammatory and profibrotic mediators, and the pathways involved in the pathogenesis of CTD-ILD. Serum biomarkers may provide new insights as risk factors for pulmonary fibrosis and as measures of disease progression. Despite these recent advances, the management of patients with CTD-ILD remains suboptimal. Further studies are therefore urgently needed to better understand these conditions, and to develop effective therapeutic interventions. PMID:20735863

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

    PubMed

    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.

  19. 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

  20. Evaluation of an automated connective tissue disease screening assay in Korean patients with systemic rheumatic diseases.

    PubMed

    Jeong, Seri; Yang, Heeyoung; Hwang, Hyunyong

    2017-01-01

    This study aimed to evaluate the diagnostic utilities of the automated connective tissues disease screening assay, CTD screen, in patients with systemic rheumatic diseases. A total of 1093 serum samples were assayed using CTD screen and indirect immunofluorescent (IIF) methods. Among them, 162 were diagnosed with systemic rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCT). The remaining 931 with non-systemic rheumatic disease were assigned to the control group. The median ratios of CTD screen tests were significantly higher in the systemic rheumatic disease group than in the control group. The positive likelihood ratios of the CTD screen were higher than those of IIF in patients with total rheumatic diseases (4.1 vs. 1.6), including SLE (24.3 vs. 10.7). The areas under the receiver operating characteristic curves (ROC-AUCs) of the CTD screen for discriminating total rheumatic diseases, RA, SLE, and MCT from controls were 0.68, 0.56, 0.92 and 0.80, respectively. The ROC-AUCs of the combinations with IIF were significantly higher in patients with total rheumatic diseases (0.72) and MCT (0.85) than in those of the CTD screen alone. Multivariate analysis indicated that both the CTD screen and IIF were independent variables for predicting systemic rheumatic disease. CTD screen alone and in combination with IIF were a valuable diagnostic tool for predicting systemic rheumatic diseases, particularly for SLE.

  1. Evaluation of an automated connective tissue disease screening assay in Korean patients with systemic rheumatic diseases

    PubMed Central

    Jeong, Seri; Yang, Heeyoung; Hwang, Hyunyong

    2017-01-01

    This study aimed to evaluate the diagnostic utilities of the automated connective tissues disease screening assay, CTD screen, in patients with systemic rheumatic diseases. A total of 1093 serum samples were assayed using CTD screen and indirect immunofluorescent (IIF) methods. Among them, 162 were diagnosed with systemic rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCT). The remaining 931 with non-systemic rheumatic disease were assigned to the control group. The median ratios of CTD screen tests were significantly higher in the systemic rheumatic disease group than in the control group. The positive likelihood ratios of the CTD screen were higher than those of IIF in patients with total rheumatic diseases (4.1 vs. 1.6), including SLE (24.3 vs. 10.7). The areas under the receiver operating characteristic curves (ROC-AUCs) of the CTD screen for discriminating total rheumatic diseases, RA, SLE, and MCT from controls were 0.68, 0.56, 0.92 and 0.80, respectively. The ROC-AUCs of the combinations with IIF were significantly higher in patients with total rheumatic diseases (0.72) and MCT (0.85) than in those of the CTD screen alone. Multivariate analysis indicated that both the CTD screen and IIF were independent variables for predicting systemic rheumatic disease. CTD screen alone and in combination with IIF were a valuable diagnostic tool for predicting systemic rheumatic diseases, particularly for SLE. PMID:28273146

  2. 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.

  3. Recurrent case of ibuprofen-induced aseptic meningitis in mixed connective tissue disease.

    PubMed

    Karmacharya, Paras; Mainali, Naba Raj; Aryal, Madan Raj; Lloyd, Benjamin

    2013-04-30

    Although relatively uncommon, the incidence of non-steroidal anti-inflammatory drug-induced aseptic meningitis appears to be increasing among patients with connective tissue disease and also among the healthy population. Ibuprofen is the most common culprit identified. We report a case of a 28-year-old woman with mixed connective tissue disease and recent intake of ibuprofen, presenting with a recurrent episode of ibuprofen-induced aseptic meningitis.

  4. [Nailfold capillaroscopy in the evaluation of Raynaud's phenomenon and undifferentiated connective tissue disease].

    PubMed

    Cortes, Sara; Clemente-Coelho, Paulo

    2008-01-01

    Microvascular abnormalities involved in the pathogenic mechanism of several connective tissue disorders can be detected by nailfold capillaroscopy. Evaluation of the interest of nailfold capillaroscopy results in patients with Raynaud s phenomenon or undifferentiated connective tissue disease and their correlation with diagnostic and therapeutical evolution. Selection of capillaroscopic and laboratory results of patients with the diagnosis of Raynaud s phenomenon (without defined connective tissue disease) or undifferentiated connective tissue disease. Evaluation of the present diagnosis and treatment comparing with the ones existed at the time of capillaroscopy performance. 80 patients were enrolled with an age of 51.4+/-14.3 years (mean+/-SD) 78 females (97.5%) with Raynaud s phenomenon and undifferentiated connective tissue disease 27 patients (33.8%); Raynaud s Phenomenon 46 patients (57.5%); undifferentiated connective tissue disease 7 patients (8.7%). The capillaroscopic results were normal 30 patients (37.5%); minor changes tortuosity enlargement 16 patients (20.0%) major changes 34 patients (42.5%) hemorrhages 25 patients (31.3%) megacapillaries 26 patients (32.5%) avascular areas 3 patients (3.8%). The introduction of new treatments after the capillaroscopy occurred in 32 patients (40.0%) and a new diagnosis was done in 39 patients (48.8%). Major changes in capillaroscopy correlated with the change of diagnosis and the introduction of a new treatment (p<0.0001). Nailfold capillaroscopy performed in patients with isolated Raynaud s phenomenon or undifferentiated connective tissue disease has a role in the prognostic evaluation related to the possibility of an evolution of the diagnosis or to the need of the introduction of new treatments.

  5. Hereditary Connective Tissue Diseases in Young Adult Stroke: A Comprehensive Synthesis

    PubMed Central

    Vanakker, Olivier M.; Hemelsoet, Dimitri; De Paepe, Anne

    2011-01-01

    Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis. PMID:21331163

  6. 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 ...

  7. 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

  8. Diagnostic and management problems in a complex case of connective tissue disease.

    PubMed

    Yeap, S S; Deighton, C M; Powell, R J; Read, R C; Finch, R G

    1995-12-01

    A 28-year-old Nigerian woman presented with persistent pyrexia, marked pruritus, eosinophilia, myalgias, flitting arthralgias, serositis and massive splenomegaly. Intensive investigation for an infective or neoplastic aetiology proved negative. Empirical treatment for helminthic infections and tuberculosis was unhelpful. Although there were no specific clues to suggest an underlying connective tissue disease, a trial of steriods and azathioprine was introduced, with no obvious response. Her condition deteriorated to a point where it was decided that intravenous immunosuppressive therapy was needed and subsequently, her condition improved remarkably. This patient illustrates the problems in the diagnosis and management of complex disorders, particularly when classical tests for connective tissue diseases are absent. Also, we would like to report that marked pruritus can be associated with connective tissue disease.

  9. Diagnostic and management problems in a complex case of connective tissue disease.

    PubMed Central

    Yeap, S. S.; Deighton, C. M.; Powell, R. J.; Read, R. C.; Finch, R. G.

    1995-01-01

    A 28-year-old Nigerian woman presented with persistent pyrexia, marked pruritis, eosinophilia, myalgias, flitting arthralgias, serositis and massive splenomegaly. Intensive investigation for an infective or neoplastic aetiology proved negative. Empirical treatment for helminthic infections and tuberculosis was unhelpful. Although there were no specific clues to suggest an underlying connective tissue disease, a trial of steriods and azathioprine was introduced, with no obvious response. Her condition deteriorated to a point where it was decided that intravenous immunosuppressive therapy was needed and subsequently, her condition improved remarkably. This patient illustrates the problems in the diagnosis and management of complex disorders, particularly when classical tests for connective tissue diseases are absent. Also, we would like to report that marked pruritis can be associated with connective tissue disease. PMID:8552544

  10. [Klinefelter's syndrome associated with mixed connective tissue disease (Sharp's syndrome) and thrombophilia with postthrombotic syndrome].

    PubMed

    Kasten, Robert; Pfirrmann, Gudrun; Voigtländer, Volker

    2005-08-01

    A 43-year-old male with eunuchoid body proportions and a history of deep venous thromboses in the right leg presented with recurrent ulcers in the right perimalleolar region for 6 years. Karyotyping revealed a 47 XXY Klinefelter's syndrome, while serologic testing showed protein S deficiency, hyperhomocysteinemia and positive lupus anticoagulant. He also had mixed connective tissue disease (Sharp's syndrome) with acrosclerosis, proximal finger edema, Raynaud's phenomenon, and high titers of ANA and U1-RNP-antibodies, as well as osteoporosis. There is evidence that patients with Klinefelter's syndrome are prone to develop connective tissue diseases and thrombophilia as a result of low androgen levels. Substitution of testosterone in Klinefelter's syndrome can have a favorable therapeutic effect on the associated connective tissue disease, thrombophilia and osteoporosis.

  11. Congenic autoimmune murine models of central nervous system disease in connective tissue disorders.

    PubMed

    Alexander, E L; Murphy, E D; Roths, J B; Alexander, G E

    1983-08-01

    Congenic mice of the MRL/Mp strain spontaneously develop an autoimmune connective tissue disease that shares immunological and histopathological features with systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome. The autoimmune disorder in these mice is accelerated markedly by the recessive gene lpr. By 6 months of age, MRL/Mp-lpr/lpr mice developed prominent mononuclear cell infiltrates restricted to the choroid plexus and meninges, whereas congeneric MRL/Mp- +/+ mice (which lack the lpr gene) showed delayed but widespread inflammatory infiltrates involving cerebral vessels and meninges, with sparing of the choroid plexus. These distinctive patterns of cerebral inflammation, which are comparable in many respects to those seen in human connective tissue disease, provide some of the first animal models of relevant central nervous system histopathological processes associated with underlying connective tissue disease.

  12. Mixed connective tissue disease characterized by speckled epidermal nuclear IgG deposition in normal skin.

    PubMed

    Bentley-Phillips, C B; Geake, T M

    1980-05-01

    Four African female patients are described, who presented with the features of systemic sclerosis. Overlapping features of lupus erythematosus or dermatomyositis were present in three cases but were not prominent. Direct immunofluorescence of uninvolved skin revealed a particulate (or speckled) epidermal nuclear staining, with specificity for IgG. In view of the reported association between this finding and mixed connective tissue disease, these patients were treated with corticosteroids and marked improvment occurred in all cases. The usefulness of this investigation in making the distinction between systemic sclerosis and mixed connective tissue disease and in indicating a potentially effective form of therapy is discussed.

  13. Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children.

    PubMed

    Cabrera, Natalia; Duquesne, Agnes; Desjonquères, Marine; Larbre, Jean-Paul; Lega, Jean-Christophe; Fabien, Nicole; Belot, Alexandre

    2016-01-01

    Arthritis is one of the main manifestations of mixed connective tissue disease (MCTD) and overlap syndrome in children and can be responsible for functional disability. We report on 2 children with arthritis that were dramatically improved by a treatment with interleukin-6 (IL-6) blockers in the context of connective tissue disease. However, in both cases, other systemic autoimmune symptoms were not modified by the treatment and autoantibodies tend to increase, suggesting a differential effect of IL-6 inhibition on articular inflammation and systemic autoimmunity.

  14. Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children

    PubMed Central

    Cabrera, Natalia; Duquesne, Agnes; Desjonquères, Marine; Larbre, Jean-Paul; Lega, Jean-Christophe; Fabien, Nicole; Belot, Alexandre

    2016-01-01

    Arthritis is one of the main manifestations of mixed connective tissue disease (MCTD) and overlap syndrome in children and can be responsible for functional disability. We report on 2 children with arthritis that were dramatically improved by a treatment with interleukin-6 (IL-6) blockers in the context of connective tissue disease. However, in both cases, other systemic autoimmune symptoms were not modified by the treatment and autoantibodies tend to increase, suggesting a differential effect of IL-6 inhibition on articular inflammation and systemic autoimmunity. PMID:27738519

  15. Undifferentiated connective tissue disease and interstitial lung disease: Trying to define patterns.

    PubMed

    Alberti, María Laura; Paulin, Francisco; Toledo, Heidegger Mateos; Fernández, Martín Eduardo; Caro, Fabián Matías; Rojas-Serrano, Jorge; Mejía, Mayra Edith

    2016-12-12

    To identify clinical or immunological features in patients with undifferentiated connective tissue disease (UCTD) associated interstitial lung disease (ILD), in order to group them and recognize different functional and high resolution computed tomography (HRCT) behavior. Retrospective cohort study. Patients meeting Kinder criteria for UCTD were included. We defined the following predictive variables: 'highly specific' connective tissue disease (CTD) manifestations (Raynaud's phenomenon, dry eyes or arthritis), high antinuclear antibody (ANA) titer (above 1: 320), and 'specific' ANA staining patterns (centromere, cytoplasmic and nucleolar patterns). We evaluated the following outcomes: change in the percentage of the predicted forced vital capacity (FVC%) during the follow-up period, and HRCT pattern. Sixty-six patients were included. Twenty-nine (43.94%) showed at least one 'highly specific' CTD manifestation, 16 (28.57%) had a 'specific' ANA staining pattern and 29 (43.94%) high ANA titer. Patients with 'highly specific' CTD manifestations were younger (mean [SD] 52 years [14.58] vs 62.08 years [9.46], P<.001), were more likely men (10.34% vs 48.65%, P<.001) and showed a smaller decline of the FVC% (median [interquartile range] 1% [-1 to 10] vs -6% [-16 to -4], P<.006). In the multivariate analysis, the presence of highly specific manifestations was associated with improvement in the FVC% (B coefficient of 13.25 [95% confidence interval, 2.41 to 24.09]). No association was observed in relation to the HRCT pattern. The presence of 'highly specific' CTD manifestations was associated with female sex, younger age and better functional behavior. These findings highlight the impact of the clinical features in the outcome of patients with UCTD ILD. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  16. Interstitial lung disease in connective tissue disease--mechanisms and management.

    PubMed

    Wells, Athol U; Denton, Christopher P

    2014-12-01

    Pulmonary complications are an important extra-articular feature of autoimmune rheumatic diseases and a major cause of mortality. The underlying pathogenesis probably involves multiple cellular compartments, including the epithelium, lung fibroblasts, and the innate and adaptive immune system. Heterogeneity in the extent and progression of lung fibrosis probably reflects differences in underlying pathogenic mechanisms. Growing understanding of the key pathogenic drivers of lung fibrosis might lead to the development of more effective targeted therapies to replicate the treatment advances in other aspects of these diseases. Interstitial lung disease (ILD) in connective tissue disease (CTD) is characterized using the classification of the idiopathic interstitial pneumonias. Systemic sclerosis is most frequently associated with ILD and, in most of these patients, ILD manifests as a histological pattern of nonspecific interstitial pneumonia. Conversely, in rheumatoid arthritis, the pattern of ILD is most often usual interstitial pneumonia. The key goals of clinical assessment of patients with both ILD and CTD are the detection of ILD and prognostic evaluation to determine which patients should be treated. Data from treatment trials in systemic sclerosis support the use of immunosuppressive therapy, with the treatment benefit largely relating to the prevention of progression of lung disease.

  17. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases.

    PubMed

    Flåm, Siri Tennebø; Gunnarsson, Ragnar; Garen, Torhild; Lie, Benedicte Alexandra; Molberg, Øyvind

    2015-03-01

    The Norwegian nationwide MCTD cohort was established to obtain unbiased data on key disease issues, and thereby reappraise the concept of MCTD. In the current study, the aims were to obtain detailed HLA profile data on the large Norwegian MCTD cohort and compare these with the HLA profiles of ethnically matched healthy controls and related CTD controls. HLA profiles, determined by sequence-based typing of HLA-B* and DRB1*, were compared between four control groups of Norwegian ancestry, SLE (n = 96), SSc (n = 95), PM/DM (n = 84), healthy individuals (n = 282), the complete MCTD cohort (n = 155) and MCTD subsets defined by key clinical parameters. HLA-B*08 [odds ratio (OR) 2.05, P = 1.31 × 10(-4)) and DRB1*04:01 (OR 2.82, P = 3.64 × 10(-8)) were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE and PM/DM were B*08 and DRB1*03:01. SSc risk was associated with DRB1*08:01. Analyses of MCTD subsets identified B*18 [OR 3.32 (95% CI 1.38, 8.01)] and DRB1*03:01 [OR 1.83 (95% CI 1.03, 3.25)] as independent risk factors for lung fibrosis. Novel HLA alleles associated with MCTD and disease subsets were identified and DRB1*04:01 was confirmed as a major risk allele. Altogether, the data reinforce the notion of MCTD as a disease entity distinct from SLE, SSc and PM/DM. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. 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

  19. Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease

    PubMed Central

    Fischer, Aryeh; Solomon, Joshua J.; du Bois, Roland M.; Deane, Kevin D.; Olson, Amy L.; Fernandez-Perez, Evans R.; Huie, Tristan J.; Stevens, Allen D.; Gill, Mary B.; Rabinovitch, Avi M.; Lynch, David A.; Burns, David A.; Pineiro, Isabel S.; Groshong, Steve D.; Duarte Achcar, Rosane D.; Brown, Kevin K.; Martin, Richard J.; Swigris, Jeffrey J.

    2013-01-01

    Summary Objective We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD). Methods The study sample included 74 subjects with respiratory symptoms, evaluated January 2008–January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation. Results The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days. Conclusion We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation. PMID:22503074

  20. Efficacy and Safety of Rituximab in Connective Tissue Disease related Interstitial Lung Disease.

    PubMed

    Fitzgerald, Deirdre Brigid; Moloney, Fiachra; Twomey, Maria; O'Connell, John Oisin; Cronin, Owen; Harty, Len; Harney, Sinead; Henry, Michael T

    2015-09-14

    Pulmonary complications of connective tissue disease are being identified more frequently with the advent of more sophisticated radiological investigations. Limited previous studies have suggested Rituximab (RTX), a chimeric monoclonal antibody with activity against CD-20, may benefit connective tissue disease patients with pulmonary complications. We performed a retrospective analysis of the efficacy and safety of RTX in patients attending a tertiary referral centre. Ten patients treated with RTX for pulmonary complications of CTD in our institution were identified. Baseline demographics, pre- and post-treatment investigations and adverse events were documented with an average follow up time-frame of 12.3 months (range: 3 - 27). Statistical analysis was performed using the Wilcoxan Signed-Rank test in SPSS. There was a statistically significant improvement in pulmonary function, with a mean increase of 19% in DLCO (median DLCO (ml/min/mmHg) pre-treatment vs. post-treatment: 13.94 vs. 19.34, p=0.028) and a mean increase of 13% in FVC (median FVC (L) pre-treatment vs. post-treatment: 3.47 vs.3.6, p=0.28). For patients with pulmonary fibrosis (n=7), CT severity was improved on post-treatment scan, though this did not reach statistical significance. There was a reduction in the number of nodules seen on the follow-up scans of two patients without fibrosis. No patient had a severe adverse reaction to RTX. Treatment with RTX resulted in an objective, measurable improvement in pulmonary function and/or radiological severity for the majority of patients included in the series. This was statistically significant despite the small numbers included. These results indicate a positive response to RTX with few complications of treatment.  

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

    PubMed Central

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

    2016-01-01

    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 20.3mg ± 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

  2. Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist's point of view.

    PubMed

    Koo, So-My; Uh, Soo-Taek

    2017-07-01

    Interstitial lung disease (ILD) occurs in 15% of patients with collagen vascular disease (CVD), referred to as connective tissue disease (CTD). Despite advances in management strategies, ILD continues to be a significant cause of mortality in patients with CVD-associated ILD (CTD-ILD). There is a lack of randomized, clinical trials assessing pharmacological agents for CTD-ILD, except in cases of ILD-associated systemic sclerosis (SSc). This may be due to the lack of CTD cases available, the difficulty of histological confirmation of ILD, and the various types of CTD and ILD. As a result, evidence-based pharmacological treatment of CTD-ILD is not yet well established. CTD-ILD presents with varying degrees of histology, from inflammation to fibrosis, and a wide spectrum of clinical manifestations, from minimal symptoms to respiratory failure. This renders it difficult for clinicians to make decisions regarding treatment options, observational strategies, optimal timing for interventions, and the appropriateness of pharmacological agents for treatment. There is no specific treatment for reversing fibrosis-like idiopathic pulmonary fibrosis in a clinical setting. This review describes pharmacological interventions for SSc-ILD described in randomized control trials, and presents an overview of recent advances of CTD-ILD-dependent treatments based on the types of CTD.

  3. Serum B cell-activating factor (BAFF) level in connective tissue disease associated interstitial lung disease.

    PubMed

    Hamada, Tsutomu; Samukawa, Takuya; Kumamoto, Tomohiro; Hatanaka, Kazuhito; Tsukuya, Go; Yamamoto, Masuki; Machida, Kentaro; Watanabe, Masaki; Mizuno, Keiko; Higashimoto, Ikkou; Inoue, Yoshikazu; Inoue, Hiromasa

    2015-09-30

    Interstitial lung diseases (ILDs) are common in patients with connective tissue diseases (CTDs). Although the diagnosis of an underlying CTD in ILD (CTD-ILD) affects both prognosis and treatment, it is sometimes difficult to distinguish CTD-ILD from chronic fibrosing interstitial pneumonia (CFIP). B cell-activating factor belonging to the tumour necrosis factor family (BAFF) plays a crucial role in B cell development, survival, and antibody production. We examined serum levels of BAFF, surfactant protein D (SP-D), and Krebs von den Lungen-6 (KL-6) in 33 patients with CTD-ILD, 16 patients with undifferentiated CTD-ILD, 19 patients with CFIP, and 26 healthy volunteers. And we analysed the relationship between serum BAFF levels and pulmonary function, as well as the expression of BAFF in the lung tissue of patients with CTD-ILD. Serum levels of BAFF were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. However, there were no significant differences in serum levels of SP-D and KL-6. Furthermore, serum BAFF levels in CTD-ILD patients were inversely correlated with pulmonary function. BAFF was strongly expressed in the lungs of CTD-ILD patients, but weakly in normal lungs. This is the first study to demonstrate that serum BAFF levels were significantly higher in CTD-ILD patients compared to healthy subjects and CFIP patients. Furthermore, serum BAFF levels were correlated with pulmonary function. We consider that serum BAFF levels in patients with CTD-ILD reflect the presence of ILDs disease activity and severity. These finding suggest that BAFF may be a useful marker for distinguishing CTD-ILD from CFIP.

  4. Mixed connective tissue disease presenting with progressive scleroderma symptoms in a 10-year-old girl.

    PubMed

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

    2013-10-01

    Mixed connective tissue disease (MCTD) is a systemic inflammatory disease affecting connective tissue with the underlying autoimmunological mechanism. The core of MCTD is an appearance of symptoms of several other inflammatory diseases of connective tissue - systemic lupus erythematosus, systemic scleroderma, poly- or dermatomyositis, rheumatoid arthritis at the same time, accompanied by a high level of anti-ribonucleoprotein antibodies (anti-U1RNP). The disease was described more than 40 years ago by Sharp et al. During recent years, many efforts to better understand clinical and serological features of MCTD have been made. Diagnosis of MCTD can be difficult. Obligatory international diagnostic criteria are required to be fulfilled. Several versions of such criteria have been proposed, but the most widely used one was described by Kasukawa. There is no consensus about treatment - a choice of drugs depends on symptoms. We present a case of a 10-year-old girl with sclerodactyly and trophic damages of fingers accompanied by symptoms of Raynaud's phenomenon. After an almost 2-year course of the disease, a diagnosis of MCTD has been established.

  5. Isolated Ro52 Antibodies as Immunological Marker of a Mild Phenotype of Undifferentiated Connective Tissue Diseases

    PubMed Central

    Navarro-Gonzálvez, José Antonio; Rodríguez-Lozano, Beatriz

    2017-01-01

    The term undifferentiated connective tissue disease (UCTD) is used to describe undiagnosed patients that do not fulfill classification criteria for definite connective tissue disease (Systemic Lupus, Systemic Sclerosis, Sjögren Syndrome, and Dermatomyositis/Polymyositis). It is important to find serological markers as predictors of the evolution or severity of these diseases. The objective of this retrospective study was to investigate if there was a milder subgroup of UCTD with a special clinical profile consisting only in the presence of anti-Ro52 autoantibodies. Immunological and clinical records of 62 patients attending the hospital during 30 months were studied. Results showed a target population formed by mostly women, aged between 40 and 80 years at the moment of the study, with a registered age of onset between 40 and 60 years. Speckled pattern was the most frequent pattern found by indirect immunofluorescence. Given the obtained results and keeping in mind possible limitations because of sample size, isolated positive anti-Ro52 autoantibodies seem to lead to a benign effect in terms of evolution of the disease. As a future objective, the follow-up of these patients should be necessary to investigate new clinical symptoms, serological markers, or development of a definite connective tissue disease over time. PMID:28210273

  6. Nailfold digital capillaroscopy in 447 patients with connective tissue disease and Raynaud's disease.

    PubMed

    Nagy, Z; Czirják, L

    2004-01-01

    The presence of megacapillaries and a decreased capillary density are the hallmarks of the scleroderma capillary pattern, which can be detected by nailfold capillarmicroscopy. One hundred and eighty-six patients with Raynaud's phenomenon, 65 cases with undifferentiated connective tissue disease (UCTD), 47 patients with systemic lupus erythematosus (SLE), 26 patients with dermato/polymyositis, 14 with rheumatoid arthritis, seven cases with primary Sjögren's syndrome and 102 patients with systemic sclerosis (SSc) were investigated. Of the 16 patients with diffuse cutaneous SSc and the 86 limited cutaneous SSc cases, 14 (87.5%) and 53 (61.6%) showed the scleroderma capillary pattern, respectively. Nine of the 65 (13.8%) cases with UCTD and 24 of the 186 (12.9%) cases with Raynaud's phenomenon also exhibited the same pattern. Four of the 47 (8.5%) with SLE and seven of the 26 (26.9%) with dermato/polymyositis, and no patients with rheumatoid arthritis or Sjögren's syndrome, exhibited the scleroderma capillary pattern. The conclusion is that the scleroderma capillary pattern is often present in SSc and dermato/polymyositis. Furthermore, patients with Raynaud's phenomenon and UCTD may also occasionally exhibit this pattern. Therefore, capillarmicroscopy seems to be a useful tool for the early selection of those patients who are potential candidates for developing scleroderma spectrum disorders.

  7. Scleroderma renal crisis in a case of mixed connective tissue disease.

    PubMed

    Vij, Mukul; Agrawal, Vinita; Jain, Manoj

    2014-07-01

    Mixed connective tissue disease (MCTD) is an overlap syndrome first defined in 1972 by Sharp et al. In this original study, the portrait emerged of a connective tissue disorder sharing features of systemic lupus erythematosus, systemic sclerosis (scleroderma) and polymyositis. Scleroderma renal crisis (SRC) is an extremely infrequent but serious complication that can occur in MCTD. The histologic picture of SRC is that of a thrombotic micro-angiopathic process. Renal biopsy plays an important role in confirming the clinical diagnosis, excluding overlapping/superimposed diseases that might lead to acute renal failure in MCTD patients, helping to predict the clinical outcome and optimizing patient management. We herewith report a rare case of SRC in a patient with MCTD and review the relevant literature.

  8. Peripheral nervous system lesion syndromes and the mechanisms of their formation in connective tissue diseases.

    PubMed

    Spirin, N N; Bulanova, V A; Pizova, N V; Shilkina, N P

    2007-01-01

    Systemic rheumatological diseases are often accompanied by the development of central and peripheral nervous system pathology. Data providing evidence of the high incidence of peripheral nervous system lesions in systemic lupus erythematosus and systemic scleroderma are presented. These diseases in particular are characterized by polyneuropathies and tunnel syndromes. Our own observations, along with published data, revealed the following major pathogenetic mechanisms of peripheral nervous system lesions in diffuse connective tissue diseases - ischemic, immunological, and metabolic. Consideration of these mechanisms will lead to pathogenetically based treatment and improved therapeutic outcomes.

  9. 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

  10. Mycophenolate Mofetil Improves Lung Function in Connective Tissue Disease-associated Interstitial Lung Disease

    PubMed Central

    Fischer, Aryeh; Brown, Kevin K.; Du Bois, Roland M.; Frankel, Stephen K.; Cosgrove, Gregory P.; Fernandez-Perez, Evans R.; Huie, Tristan J.; Krishnamoorthy, Mahalakshmi; Meehan, Richard T.; Olson, Amy L.; Solomon, Joshua J.; Swigris, Jeffrey J.

    2013-01-01

    Objective Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF. Methods We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF. Results We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% ± 1.9%, p = 0.01; 6.1% ± 1.8%, p = 0.0008; and 7.3% ± 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% ± 2.8%, p = 0.02; 7.1% ± 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%. Conclusion In a large diverse cohort of CTD-ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD. PMID:23457378

  11. Rituximab for the treatment of connective tissue disease-associated interstitial lung disease.

    PubMed

    Chartrand, Sandra; Swigris, Jeffrey J; Peykova, Lina; Fischer, Aryeh

    2016-01-15

    To describe our experience with rituximab (RTX) as treatment for a diverse spectrum of chronic connective tissue disease-associated interstitial lung disease (CTD-ILD). Twenty-four subjects with CTD-ILD were included. All had pulmonary function testing before and after their first RTX infusion. Each subject was evaluated in a multidisciplinary autoimmune and ILD outpatient clinic. Data were extracted by retrospective review of complete medical records. Most subjects were middle-aged white women with rheumatoid arthritis (RA) (n=15) and a nonspecific interstitial pneumonia (NSIP) pattern on high-resolution chest computed tomography scans (n=17). Sixteen subjects received a corticosteroid-sparing agent at the time of RTX initiation; mostly mycophenolate mofetil (n=8). RTX administration was not associated with corticosteroid-sparing effects: 13 subjects were on prednisone at the time of the initial RTX cycle, and 9 remained on prednisone at 6 months after (mean daily dosage 10.2±16.2 mg before vs. 5.6±11.0 mg after, p=0.27). RTX had no appreciable effect on pulmonary physiology; however, individual trajectories for percentage predicted forced vital capacity (FVC%) were highly variable. The underlying CTD (RA vs. non-RA) and ILD pattern did not appear to affect response to RTX. Among 14 subjects who received multiple RTX cycles, FVC% trajectories were variable: FVC% increased in eight and declined in six. Respiratory infections were the most common post-RTX adverse event. In this small, retrospective study of chronic CTD-ILD, RTX was not associated with changes in FVC% or corticosteroid-sparing effects. Controlled, prospective studies are needed to more confidently define the effects of RTX in CTD-ILD.

  12. Cardiovascular Involvement in Connective Tissue Disease: The Role of Interstitial Lung Disease

    PubMed Central

    Wang, XiaoBing; Lou, MeiNa; Li, Yongji; Ye, WenJing; Zhang, ZhiYong; Jia, Xiufen; Shi, HongYing; Zhu, XiaoChun; Wang, LiangXing

    2015-01-01

    Objective The aim of this study was to assess cardiovascular involvement in patients with connective tissue disease (CTD), and determine whether interstitial lung disease (ILD) in these patients is associated with elevated cardiovascular risk. Methods This study evaluated a retrospective cohort of 436 CTD patients admitted to a large teaching hospital in Zhejiang province, China, along with an additional 436 participants of an annual community health screening conducted in the physical examination center who served as age- and gender-matched controls. Demographic, clinical, serologic and imaging characteristics, as well as medications used by each participant were recorded. Cardiovascular involvement was defined by uniform criteria. Correlations between clinical/serologic factors and cardiovascular involvement were determined by univariate and multivariate analyses. Results CTD patients had a significantly higher cardiovascular involvement rate than controls (64.7% vs 23.4%), with higher rates of diabetes, hypertension, and hyperlipidemia, elevated systolic and diastolic pressures, C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol, and lower albumin and high-density lipoprotein cholesterol (all p < 0.05). Furthermore, CTP patients with cardiovascular involvement were significantly older, had higher systolic and diastolic pressures, C-reactive protein, glucose, and uric acid, higher rates of diabetes, hypertension, and use of moderate- to high-dose glucocorticoids, and longer disease duration compared to patients without involvement (all p < 0.05). Moreover, CTD in patients with cardiovascular involvement was more likely to be complicated by ILD (p < 0.01), which manifested as a higher alveolar inflammation score (p < 0.05). In the multivariate analysis, cardiovascular involvement in CTD patients was associated with age, systolic pressure, body mass index, uric acid, disease duration > 2 years, use of moderate- to high

  13. Cardiovascular involvement in connective tissue disease: the role of interstitial lung disease.

    PubMed

    Wang, XiaoBing; Lou, MeiNa; Li, Yongji; Ye, WenJing; Zhang, ZhiYong; Jia, Xiufen; Shi, HongYing; Zhu, XiaoChun; Wang, LiangXing

    2015-01-01

    The aim of this study was to assess cardiovascular involvement in patients with connective tissue disease (CTD), and determine whether interstitial lung disease (ILD) in these patients is associated with elevated cardiovascular risk. This study evaluated a retrospective cohort of 436 CTD patients admitted to a large teaching hospital in Zhejiang province, China, along with an additional 436 participants of an annual community health screening conducted in the physical examination center who served as age- and gender-matched controls. Demographic, clinical, serologic and imaging characteristics, as well as medications used by each participant were recorded. Cardiovascular involvement was defined by uniform criteria. Correlations between clinical/serologic factors and cardiovascular involvement were determined by univariate and multivariate analyses. CTD patients had a significantly higher cardiovascular involvement rate than controls (64.7% vs 23.4%), with higher rates of diabetes, hypertension, and hyperlipidemia, elevated systolic and diastolic pressures, C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol, and lower albumin and high-density lipoprotein cholesterol (all p < 0.05). Furthermore, CTP patients with cardiovascular involvement were significantly older, had higher systolic and diastolic pressures, C-reactive protein, glucose, and uric acid, higher rates of diabetes, hypertension, and use of moderate- to high-dose glucocorticoids, and longer disease duration compared to patients without involvement (all p < 0.05). Moreover, CTD in patients with cardiovascular involvement was more likely to be complicated by ILD (p < 0.01), which manifested as a higher alveolar inflammation score (p < 0.05). In the multivariate analysis, cardiovascular involvement in CTD patients was associated with age, systolic pressure, body mass index, uric acid, disease duration > 2 years, use of moderate- to high-dose glucocorticoids, and ILD with a high

  14. ANCA-associated vasculitis with dual ANCA positivity in coexistence with mixed connective tissue disease.

    PubMed

    Murakami, Masanori; Shimane, Kenichi; Takahashi, Hiroshi; Tomiyama, Junji; Nagashima, Masakazu

    2013-01-01

    We here report a rare case of dual antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a 38-year-old Japanese woman previously diagnosed with mixed connective tissue disease. The patient was found to be positive for myeloperoxidase- and proteinase 3-ANCA, and was diagnosed with AAV following admission to hospital with fervescence, polyarthralgia, purpura, and asymmetric numbness of the extremities. Examination of her genetic background revealed that she carried HLA-DR9, which confers risk of both diseases in Japanese populations.

  15. Antinuclear antibodies in scleroderma, mixed connective tissue disease and "primary" Raynaud's phenomenon.

    PubMed

    Cruz, M; Mejia, G; Lavalle, C; Cortes, J J; Reyes, P A

    1988-03-01

    The diversity of antibodies in patients with scleroderma, mixed connective tissue disease or "primary" Raynaud's phenomenon could be used as a laboratory aid in the clinical diagnosis. In serum samples of 75 patients we screened for antinuclear antibodies (HEp 2 cells), anti DNA, soluble nucleoprotein and extractable nuclear antigens (Sm, rRNP, U1-nRNP, SSA/Ro, SSB/La and Scl-70). Distinctive antinuclear antibodies pattern was identified in each group of patients. This immunologic profile is valuable for clinical diagnosis and the preferential association of certain autoantibodies with some diseases and not with others, suggest an antigen-driven stimulus for its production.

  16. A Rasch analysis for classification of systemic lupus erythematosus and mixed connective tissue disease.

    PubMed

    Perkins, Kyle; Hoffman, Robert W; Bezruczko, Nikolaus

    2008-01-01

    The classification of rheumatic diseases is challenging because these diseases have protean and frequently overlapping clinical and laboratory manifestations. This problem is typified by the difficulty of classification and differentiation of two prototypic multi-system autoimmune diseases, Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease (MCTD). The researchers submitted medical risk factor data represented by instrument or laboratory measures and physician judgments (12 key features for SLE) from 43 patients diagnosed with SLE and 12 key features for MCTD from 51 patients diagnosed with MCTD to the WINSTEPS Rasch analysis program. Using Rasch model parameterization, and fit and residuals analyses, the researchers identified separate dimensions for MCTD and SLE, thereby lending support to the position that MCTD is its own separate disease, distinct from SLE.

  17. Fifteen-year experience of pediatric-onset mixed connective tissue disease.

    PubMed

    Tsai, Yi-Ying; Yang, Yao-Hsu; Yu, Hsin-Hui; Wang, Li-Chieh; Lee, Jyh-Hong; Chiang, Bor-Luen

    2010-01-01

    The aim of this study was to investigate the initial clinical manifestations, laboratory data, complications, and outcomes of patients with pediatric-onset mixed connective tissue disease (MCTD) in Taiwan. We reviewed medical charts of patients younger than 18 years with a diagnosis of mixed connective tissue disease based on the criteria of Kasukawa (1) at the pediatric department of National Taiwan University Hospital from 1993 to 2008. A total of 12 patients were included. All of the patients were female. The mean age at disease onset was 10.7 years (range 6.5 to 14 years). The most common symptoms at disease onset were polyarthritis (7/12 patients) and Raynaud's phenomenon (7/12 patients). The clinical symptoms changed with time, and other symptoms encompassing the criteria for MCTD developed sequentially. Inflammatory manifestations (arthritis, fever, and skin rash) improved following treatment, whereas sclerodermatous features (sclerodactyly, esophageal disease, and vasculopathy) persisted and were often unresponsive to therapy. The organ involvement-free rates at 2 years, 5 years, and 10 years were 91.7%, 78.6%, and 52.4%, respectively. In this retrospective study, sclerodermatous changes of internal organs were a poor prognostic factor in our population, and we emphasize that long-term follow-up is necessary, and appropriate treatment should be applied to improve the outcomes.

  18. [Fungal invasion of connective tissue in patients with gingival-periodontal disease].

    PubMed

    Rubio, Nicolás Agustín; Puia, Sebastian; Toranzo, Silvia; Brusca, María Isabel

    2015-01-01

    In the last few years unusual microorganisms have been isolated from subgingival biofilm, as possible initiators or contributors to periodontal disease, especially in patients who show no improvement during treatment. To study the Candida invasion of the connective tissue in relation to subgingival biofilm presence. A total of 55 immunocompetent patients of both sexes, between 21 and 55 years of age, non-smokers, without previous antimicrobial treatment, suffering periodontal diseases, were studied. Soft tissues, supragingival and subgingival plaque samples, and periodontal pocket biopsies were taken. Microscopic studies, cultures, assimilation profiles, and DNA amplifications were performed. In 35% of the samples, different species of Candida were isolated in cultures, especially Candida albicans. Hyphae invasions in the connective tissue were observed, in association with anaerobic microorganisms (Porphyromonas gingivalis, Prevotella intermedia and Aggregatibacter actinomycetemcomitans) in patients with periodontitis. Different species of Candida could be part of the periodontal plaque and could play an important role in the adherence to soft tissues, allowing deep invasion. They also could infect gingival pockets in patients with gingivitis, even in healthy locations, playing a commensal or opportunist role. Copyright © 2011 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

  19. Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD).

    PubMed

    Uzuki, Miwa; Kamataki, Akihisa; Watanabe, Mika; Sasaki, Nobuhito; Miura, Yasuhiro; Sawai, Takashi

    2011-06-15

    Esophageal symptoms in mixed connective tissue disease (MCTD) have been investigated radiologically. We investigated the esophageal lesions in MCTD histopathologically, and analyzed relationships between these lesions and autoantibodies extracted from the serum of MCTD patients. Esophageal tissues from 27 MCTD patients submitted to autopsy were examined. We compared histopathological features of the esophagus in different wall layers from the mucosa, submucosa, and muscular layer to the adventitia, and in the upper, middle, and lower portions of esophagus. The most striking change observed was severe atrophy and occasional loss of smooth muscle cells in the muscular layer, followed by fibrosis. These muscular changes were particularly prominent in the inner layer of the lower esophagus. Immunohistochemically, degenerated muscular tissues of the esophagus were positive for anti-IgG and anti-C3 antibodies, but not for anti-IgM antibodies. IgG fractions extracted from three MCTD patients were immunohistochemically used to examine whether some antibodies in MCTD patients showed reactivity for esophageal components. The IgG fractions isolated from MCTD patients reacted with smooth muscle from non-connective tissue disease cases, suggesting that some serum antibodies may trigger esophageal changes. These findings suggest that esophageal lesions associated with clinical dysphagia in MCTD may be related to autoantibodies.

  20. Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease.

    PubMed

    Yakova, Maria; Lézin, Agnès; Dantin, Fabienne; Lagathu, Gisèle; Olindo, Stéphane; Jean-Baptiste, Georges; Arfi, Serge; Césaire, Raymond

    2005-02-01

    Human T-lymphotropic virus type 1 (HTLV-1) proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load.

  1. 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.

  2. Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases

    PubMed Central

    Mavrogeni, Sophie; Markousis-Mavrogenis, George; Koutsogeorgopoulou, Loukia; Kolovou, Genovefa

    2017-01-01

    Cardiovascular magnetic resonance imaging is a recently developed noninvasive, nonradiating, operator-independent technique that has been successfully used for the evaluation of congenital heart disease, valvular and pericardial diseases, iron overload, cardiomyopathies, great and coronary vessel diseases, cardiac inflammation, stress–rest myocardial perfusion, and fibrosis. Rheumatoid arthritis and other spondyloarthropathies, systemic lupus erythematosus, inflammatory myopathies, mixed connective tissue diseases (CTDs), systemic sclerosis, vasculitis, and sarcoidosis are among CTDs with serious cardiovascular involvement; this is due to multiple causative factors such as myopericarditis, micro/macrovascular disease, coronary artery disease, myocardial fibrosis, pulmonary hypertension, and finally heart failure. The complicated pathophysiology and the high cardiovascular morbidity and mortality of CTDs demand a versatile, noninvasive, nonradiative diagnostic tool for early cardiovascular diagnosis, risk stratification, and treatment follow-up. Cardiovascular magnetic resonance imaging can detect early silent cardiovascular lesions, assess disease acuteness, and reliably evaluate the effect of both cardiac and rheumatic medication in the cardiovascular system, due to its capability to perform tissue characterization and its high spatial resolution. However, until now, high cost; lack of interaction between cardiologists, radiologists, and rheumatologists; lack of availability; and lack of experts in the field have limited its wider adoption in the clinical practice. PMID:28546762

  3. Mixed connective tissue disease developing into MPO-ANCA-positive polyangiitis.

    PubMed

    Murakami, Taichi; Endo, Shuichiro; Moriki, Toshiaki; Doi, Toshio; Matsumoto, Yoshihiro

    2011-01-01

    Renal involvement of mixed connective tissue disease (MCTD) shows systemic lupus erythematosus (SLE)-like immune complex glomerulonephritis. The prognosis of this condition is generally good. We report the case of an elderly female patient with MCTD who developed autoimmune pleurisy and rapidly progressive glomerulonephritis. Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) was positive with a titer of 59.0 EU. Anti-DNA antibody and complement levels were normal. Renal biopsy revealed crescentic glomerulonephritis and mild mesangial proliferation. However, immunofluorescence examination revealed immune-complex glomerulonephritis. These findings suggest that the renal involvement of MCTD developed concurrently with MPO-ANCA-related glomerulonephritis.

  4. Autoantibodies to DNA topoisomerase II in cryptogenic fibrosing alveolitis and connective tissue disease.

    PubMed Central

    Meliconi, R; Bestagno, M; Sturani, C; Negri, C; Galavotti, V; Sala, C; Facchini, A; Ciarrocchi, G; Gasbarrini, G; Astaldi Ricotti, G C

    1989-01-01

    Sera from patients with autoimmune lung and connective tissue diseases were investigated for antibodies to topoisomerase II. Anti-topoisomerase II antibodies were detected by ELISA in 37% of sera from patients with cryptogenic fibrosing alveolitis (CFA), in one (8%) case of sarcoidosis and in 31% of sera from systemic lupus erythematosus (SLE) patients. Sera from rheumatoid arthritis, juvenile rheumatoid arthritis, progressive systemic sclerosis, Sjögren's syndrome and undifferentiated connective tissue disease were negative. CFA and sarcoidosis sera strongly reacted in immunoblotting with a 170 kD protein, also recognized by rabbit antiserum to recombinant topoisomerase II, while SLE sera presented a weak reaction. Pre-adsorption with dsDNA dramatically decreased the topoisomerase II binding in ELISA by the most positive SLE serum, but did not affect the binding by the most positive CFA serum, thus indicating that anti-topoisomerase II reactivity of SLE sera is probably due either to cross-reacting antibodies or, in part, to minor DNA contamination of our enzyme preparation. The determination of DNA topoisomerase II relaxation activity, performed after incubation with antibody-positive sera, showed that only CFA sera precipitate enzymatic activity. The finding that CFA presents antibodies to an enzyme essential to cell survival stresses the role of autoimmunity in the pathogenesis of idiopathic pulmonary fibrosis. This may offer further insight into the cause of autoimmune disease and prove a valuable tool in the study of enzyme molecular biology. Images Fig. 3 PMID:2547538

  5. 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.

  6. Clinical applicability of quantitative nailfold capillaroscopy in differential diagnosis of connective tissue diseases with Raynaud's phenomenon.

    PubMed

    Wu, Po-Chang; Huang, Min-Nung; Kuo, Yu-Min; Hsieh, Song-Chou; Yu, Chia-Li

    2013-08-01

    Nailfold capillaroscopy is a useful tool to distinguish primary from secondary Raynaud's phenomenon (RP) by examining the morphology of nailfold capillaries but its role in disease diagnosis is not clearly established. The purpose of this study was to evaluate the roles of quantitative nailfold capillaroscopy in differential diagnosis of connective tissue diseases (CTDs) with RP. The data between the year 2005 and 2009 were retrieved from the nailfold capillaroscopic database of National Taiwan University Hospital (NTUH). Only the data from the patients with RP were analyzed. The criteria for interpretation of capillaroscopic findings were predefined. The final diagnoses of the patients were based on the American College of Rheumatology classification criteria for individual diseases, independent of nailfold capillaroscopic findings. The sensitivity and the specificity of each capillaroscopic pattern to the diseases were determined. The data from a total of 67 patients were qualified for the current study. We found the sensitivity and specificity of scleroderma pattern for systemic sclerosis (SSc) were 89.47% and 80%, and the specificity of the early, active, and late scleroderma patterns for SSc reached 87.5%, 97.5%, and 95%, respectively. The sensitivity/specificity of systemic lupus erythematosus (SLE) pattern for SLE and polymyositis/dermatomyositis (PM/DM) pattern for PM/DM were 33.33%/95.45% and 60%/96.3%, respectively. The sensitivity/specificity of mixed connective tissue disease (MCTD) pattern for MCTD were 20%/100%. The nailfold capillaroscopic (NC) patterns may be useful in the differential diagnosis of CTDs with RP. The NC patterns for SSc and PM/DM are both sensitive and specific to the diseases, while the SLE and MCTD patterns exhibit high specificity but relatively low sensitivity. Copyright © 2012. Published by Elsevier B.V.

  7. [Connective tissue and inflammation].

    PubMed

    Jakab, Lajos

    2014-03-23

    The author summarizes the structure of the connective tissues, the increasing motion of the constituents, which determine the role in establishing the structure and function of that. The structure and function of the connective tissue are related to each other in the resting as well as inflammatory states. It is emphasized that cellular events in the connective tissue are part of the defence of the organism, the localisation of the damage and, if possible, the maintenance of restitutio ad integrum. The organism responds to damage with inflammation, the non specific immune response, as well as specific, adaptive immunity. These processes are located in the connective tissue. Sterile and pathogenic inflammation are relatively similar processes, but inevitable differences are present, too. Sialic acids and glycoproteins containing sialic acids have important roles, and the role of Siglecs is also highlighted. Also, similarities and differences in damages caused by pathogens and sterile agents are briefly summarized. In addition, the roles of adhesion molecules linked to each other, and the whole event of inflammatory processes are presented. When considering practical consequences it is stressed that the structure (building up) of the organism and the defending function of inflammation both have fundamental importance. Inflammation has a crucial role in maintaining the integrity and the unimpaired somato-psychological state of the organism. Thus, inflammation serves as a tool of organism identical with the natural immune response, inseparably connected with the specific, adaptive immune response. The main events of the inflammatory processes take place in the connective tissue.

  8. 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.

  9. Efficacy and safety of liposomal amphotericin B for deep mycosis in patients with connective tissue disease.

    PubMed

    Kotani, Takuya; Takeuchi, Tohru; Makino, Shigeki; Hata, Kenichiro; Yoshida, Shuzo; Nagai, Koji; Wakura, Daisuke; Isoda, Kentaro; Hanafusa, Toshiaki

    2013-08-01

    The efficacy and safety of liposomal amphotericin B (L-AMB) in the treatment of invasive fungal infections (IFIs) were retrospectively evaluated for patients with connective tissue diseases (CTDs) during treatment with immunosuppressive therapy. Subjects were 13 patients with CTDs complicated by IFI, on the basis of clinical symptoms, imaging findings, and microbiological and histological examinations. All patients were treated with L-AMB. Efficacy and safety were evaluated before and after administration of L-AMB. Underlying diseases were systemic lupus erythematosus for 4 patients, rheumatoid arthritis for 3, microscopic polyangiitis for 2, adult-onset Still disease for 1, dermatomyositis for 1, and mixed connective tissue disease for 1. Eight patients were resistant to other antifungal drugs. Prednisolone was given to 11 patients and the median dose was 10 mg/day. Immunosuppressants were used for 8 patients. The median duration of administration of L-AMB was 8.5 days (range 4-38 days). In proven and probable diagnosis patients (n = 5), the treatment was effective for 3 patients and ineffective for 2 (efficacy rate 60 %). Serum 1,3-β-D-glucan antigenemia (BG) levels decreased after treatment in the 2 patients who were positive for BG. Serum Aspergillus galactomannan antigen levels decreased in 3 of 4 patients with Aspergillus infection. No patient died of IFI. Regarding potential adverse reactions, there were no significant changes in serum creatinine and potassium levels. L-AMB is effective and well-tolerated for treatment of IFI in patients with CTDs.

  10. Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness.

    PubMed

    Ramirez, Francesco; Caescu, Cristina; Wondimu, Elisabeth; Galatioto, Josephine

    2017-08-04

    Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients. Copyright © 2017 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

  11. Association between previously unknown connective tissue disease and subclinical hypothyroidism diagnosed during first trimester of pregnancy.

    PubMed

    Beneventi, Fausta; Locatelli, Elena; Alpini, Claudia; Lovati, Elisabetta; Ramoni, Véronique; Simonetta, Margherita; Cavagnoli, Chiara; Spinillo, Arsenio

    2015-11-01

    To investigate the presence of autoimmune rheumatic disorders among women with autoimmune thyroid disorders diagnosed during the first trimester of pregnancy and subsequent pregnancy outcomes. Case-control study. Tertiary obstetric and gynecologic center. Pregnant women in the first trimester of pregnancy. Clinical, laboratory, ultrasonographic evaluations. Thyroid-stimulating hormone (TSH) level; antibodies against thyroperoxidase, thyroid globulin and TSH receptor detection; screening for rheumatic symptoms and antinuclear antibodies (ANA); uterine artery pulsatility index evaluation; pregnancy complication onset. Out of 3,450 women enrolled, 106 (3%) were diagnosed with autoimmune thyroid disorders. ANA were present in 18 (16.9%) of 106 cases and 26 (12.6%) of 206 controls. Of the cases, 28 (26.4%) of 106 reported rheumatic symptoms, 5 of these were diagnosed with Sjögren syndrome or with undefined connective tissue disease. Autoimmune thyroid diseases are statistically significantly associated with a higher risk of preeclampsia, fetal growth restriction, and overall pregnancy complications compared with controls, with a higher uterine artery pulsatility index, suggesting a defective placentation in thyroid disorders. The effect of ANA-positivity on moderate/severe adverse pregnancy outcomes was statistically significant among the patients with thyroid disorders (9 of 18 as compared to 8 of 88, odds ratio 9.65; 95% confidence interval, 2.613-7.81). Connective tissue diseases are frequently associated with autoimmune thyroid disorders diagnosed during the first trimester of pregnancy. Thyroid autoimmunity and ANA positivity independently increased the risk of adverse pregnancy outcomes. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  12. [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.

  13. The beneficial effect of plasmapheresis in mixed connective tissue disease with coexisting antiphospholipid syndrome.

    PubMed

    Szodoray, P; Hajas, A; Toth, L; Szakall, S; Nakken, B; Soltesz, P; Bodolay, E

    2014-09-01

    The authors report a rare case of a female patient with mixed connective tissue disease (MCTD) with coexisting antiphospholipid syndrome (APS). Five years after the diagnosis of MCTD high concentrations of anticardiolipin (anti-CL) and anti-β2-glycoprotein (anti-β2GPI) autoantibodies were present in the patient's serum without thrombotic events. Epstein-Barr virus (EBV) reactivation provoked APS, with the clinical manifestations of livedo reticularis, digital gangrene and leg ulcers. Skin biopsy from the necrotic area showed multiple fibrin microthrombi in the superficial vessels. Corticosteroid pulse therapy, and plasma exchange in combination with synchronized cyclophosphamide was administered, which led to improvement of the digital gangrenes, while no new lesions developed. The number of CD27high plasma cells decreased, and the previous high levels of autoantibodies also normalized in the peripheral blood. In the case of MCTD with coexisting APS combination therapy, including plasmapheresis has beneficial effects.

  14. 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

  15. Adhesive arachnoiditis in mixed connective tissue disease: a rare neurological manifestation.

    PubMed

    Khan, Maria Usman; Devlin, James Anthony Joseph; Fraser, Alexander

    2016-12-16

    The overall incidence of neurological manifestations is relatively low among patients with mixed connective tissue disease (MCTD). We recently encountered a case of autoimmune adhesive arachnoiditis in a young woman with 7 years history of MCTD who presented with severe back pain and myeloradiculopathic symptoms of lower limbs. To the best of our knowledge, adhesive arachnoiditis in an MCTD patient has never been previously reported. We report here this rare case, with the clinical picture and supportive ancillary data, including serology, cerebral spinal fluid analysis, electrophysiological evaluation and spinal neuroimaging, that is, MRI and CT (CT scan) of thoracic and lumbar spine. Her neurological deficit improved after augmenting her immunosuppressant therapy. Our case suggests that adhesive arachnoiditis can contribute to significant neurological deficits in MCTD and therefore requires ongoing surveillance.

  16. Adhesive arachnoiditis in mixed connective tissue disease: a rare neurological manifestation

    PubMed Central

    Devlin, James Anthony Joseph; Fraser, Alexander

    2016-01-01

    The overall incidence of neurological manifestations is relatively low among patients with mixed connective tissue disease (MCTD). We recently encountered a case of autoimmune adhesive arachnoiditis in a young woman with 7 years history of MCTD who presented with severe back pain and myeloradiculopathic symptoms of lower limbs. To the best of our knowledge, adhesive arachnoiditis in an MCTD patient has never been previously reported. We report here this rare case, with the clinical picture and supportive ancillary data, including serology, cerebral spinal fluid analysis, electrophysiological evaluation and spinal neuroimaging, that is, MRI and CT (CT scan) of thoracic and lumbar spine. Her neurological deficit improved after augmenting her immunosuppressant therapy. Our case suggests that adhesive arachnoiditis can contribute to significant neurological deficits in MCTD and therefore requires ongoing surveillance. PMID:27986694

  17. 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.

  18. Sarcoidosis in patients with mixed connective tissue disease: clinical, genetic, serological and histological observations.

    PubMed

    Szodoray, Peter; Szollosi, Zoltan; Gyimesi, Edit; Takacs, Istvan; Mekkel, Gabriella; Vegh, Judit; Szilagyi, Anna; Zeher, Margit; Szegedi, Gyula; Bodolay, Edit

    2008-06-01

    The objective of this study was to investigate how the development of sarcoidosis influences the disease course of mixed connective tissue disease (MCTD). The cellular composition of MCTD-associated sarcoidosis granulomas was evaluated and also the disease-accompanying T-cell activation and alterations of the serum cytokine levels were measured before and after the therapy. The HLA-DR specific alleles were also assessed. We present two cases with MCTD coexisting sarcoidosis. Serum concentrations of Th1 and Th2 cytokines were assessed by ELISA. Peripheral blood CD3+ total T-cell numbers, CD4+ and CD8+ T-cell subset were determined by flow cytometry. Furthermore, hematoxylin-eosin staining and immunhistochemistry were performed for histological assessment. HLA-DR specific alleles were determined by using PCR-SSP. Elevated number of activated T-cells and high Th1 cytokine levels were detected, mainly IFN-gamma and TNF-alpha. Histologically, CD4+ and CD8+ T-cells were present in the sarcoidosis infiltrations. The haplotypes were to some extent dissimilar from the HLA-DR genotype from patients with MCTD, or sarcoidosis alone. Sarcoidosis enhances the activation of MCTD, based on the laboratory and clinical findings. Our results show that the inflammation is mainly in the effector phase, while granuloma formation is characteristic of the resolution phase of the disease. The assessment of the cytokine network in sarcoidosis-associated MCTD enables us to select the most effective, individualized therapy protocol for these patients.

  19. Lung involvement in "stable" undifferentiated connective tissue diseases: a rheumatology perspective.

    PubMed

    Riccardi, Antonella; Irace, Rosaria; Di Stefano, Ilaria; Iudici, Michele; Fasano, Serena; Bocchino, Marialuisa; Capaccio, Annalisa; Sanduzzi, Alessandro; Valentini, Gabriele

    2017-08-01

    Previous studies of the occurrence of interstitial lung disease (ILD) in undifferentiated connective tissue diseases (UCTD) were conducted in patients admitted to Respiratory Medicine Units. The aim of the present prospective study was to investigate lung involvement in UCTD patients admitted to a Rheumatology Unit. Eighty-one consecutive UCTD patients were enrolled in the study. Each patient underwent history and physical examination, routine laboratory investigations, antinuclear antibody (ANA) profiling, B-mode echocardiography, and lung function study according to previously reported methods. Lung high resolution computed tomography (HRCT) was performed in patients who provided informed consent. Six patients (7.4%) had a history of grade II dyspnea. Three of them had a DLCO ranging from 42 to 55% of the predicted value; and a HRCT-documented ILD with a non-specific interstitial pneumonia (NSIP) pattern. Symptoms in the other three patients were due to cardiac disease. None of the 75 asymptomatic patients, had relevant findings at physical examination, 26/75 had a DLCO <80% (<70% in 10 cases). Of these, 3 of the 30 patients who underwent lung HRCT were affected by NSIP-ILD. Six of the 81 enrolled were affected by ILD, which was symptomatic in three patients. A higher percentage of patients had a reduced DLCO. The latter finding may reflect a preradiographic ILD or a preechocardiographic pulmonary vascular disease.

  20. Recommendations for Screening and Detection of Connective-Tissue Disease Associated Pulmonary Arterial Hypertension

    PubMed Central

    Khanna, Dinesh; Gladue, Heather; Channick, Richard; Chung, Lorinda; Distler, Oliver; Furst, Daniel E.; Hachulla, Eric; Humbert, Marc; Langleben, David; Mathai, Stephen C.; Saggar, Rajeev; Visovatti, Scott; Altorok, Nezam; Townsend, Whitney; FitzGerald, John; McLaughlin, Vallerie

    2013-01-01

    Objectives Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTD). Previous recommendations developed as part of larger efforts in PAH did not provide detailed recommendations for patients with CTD-PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-PAH. Methods We performed a systematic review for the screening and diagnosis of PAH in CTD by searching the literature. Using the RAND/UCLA methodology, we developed case scenarios followed by 2 stages of voting—first international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario and then the experts met in a face-to-face meeting to discuss and resolve discrepant votes to arrive at consensus recommendations. Results The key recommendations state that patients with systemic sclerosis (SSc) should be screened for PAH. In addition, mixed connective tissue diseases (MCTD) or other CTD’s with scleroderma features should also be screened for PAH (scleroderma-spectrum disorder). Initial screening evaluation in patients with SSc and scleroderma-spectrum disorders include pulmonary function test (PFT) including diffusion capacity carbon monoxide (DLCO), transthoracic echocardiogram (TTE), and NT- Pro BNP. In SSc and spectrum disorders, TTE and PFT should be performed on annual basis. The full screening panel (TTE, PFT, and NT-ProBNP) should be performed as soon as any new signs or symptoms are present. Conclusion We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-PAH. It is our hope that these recommendations will lead to earlier detection of CTD-PAH and ultimately improve patient outcomes. PMID:24022584

  1. Neonatal lupus in triplet pregnancy of a patient with undifferentiated connective tissue disease evolving to systemic lupus erythematosus.

    PubMed

    Demaestri, M; Sciascia, S; Kuzenko, A; Bergia, R; Barberis, L; Lanza, M G; Bertero, M T

    2009-04-01

    Pregnancy in patients suffering from undifferentiated connective tissue disease (UCTD) represents a risk situation for both the mother and the child. SSA/SSB autoantibodies can determine neonatal lupus (NL) in the foetus, regardless of the maternal disease. Furthermore, pregnancy increases the risk of flares and evolution to differentiated connective tissue disease (CTD). We report an uncommon case in which these complications occurred in a mother and in her foetuses. A 37-year-old woman affected by UCTD developed systemic lupus erythematosus (SLE) after her triplet pregnancy. The only manifestation of neonatal lupus we observed in the three newborns was SSA positivity associated with asymptomatic transient neutropenia.

  2. Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL

    PubMed Central

    Liu, Juliana; Parsons, Lori; Hassoun, Paul M.; McGoon, Michael; Badesch, David B.; Miller, Dave P.; Nicolls, Mark R.; Zamanian, Roham T.

    2010-01-01

    Background: REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH). Methods: All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA). Results: Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH). Conclusions: Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco

  3. Nailfold Capillaroscopy Within and Beyond the Scope of Connective Tissue Diseases.

    PubMed

    Lambova, Sevdalina; Müller-Ladner, Ulf

    2017-06-14

    Nailfold capillaroscopy is a noninvasive instrumental method for morphological analysis of the nutritive capillaries in the nailfold area. In rheumatology, it is a method of choice among instrumental modalities for differentiation of primary and secondary Raynaud's phenomenon (RP) in rheumatic diseases. RP is a common diagnostic problem in rheumatology. Defining the proper diagnosis is a prerequisite for administration of the appropriate treatment. Thus, nailfold capillaroscopic examination is of crucial importance for the every-day practice of the rheumatologists and is currently gaining increasing attention. The most specific capillaroscopic changes are observed in systemic sclerosis (SSc). Due to the high prevalence of the capillaroscopic changes in this clinical entity and their early appearance, they could be used for early and very early diagnosis of the disease. More recently, "scleroderma" type capillaroscopic changes have been defined as diagnostic criterion in the new EULAR/ACR classification criteria for SSc together with the presence of scleroderma-related autoantibodies, RP, telangiectasia and other clinical signs. In addition, capillaroscopic changes in other connective tissue disease and in different rheumatic-like conditions, which are characterized with microvascular pathology should be interpreted properly in order to obtain precise diagnosis in the shortest possible differential diagnostic process. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Connective Tissue Reflex Massage for Type 2 Diabetic Patients with Peripheral Arterial Disease: Randomized Controlled Trial

    PubMed Central

    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

  5. 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

    Paradowska-Gorycka, Agnieszka

    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.

  6. Invasive pulmonary fungal infections in patients with connective tissue disease: a retrospective study from northern China

    PubMed Central

    Ge, H.F.; Liu, X.Q.; Zhu, Y.Q.; Chen, H.Q.; Chen, G.Z.

    2016-01-01

    Invasive pulmonary fungal infection (IPFI) is a potentially fatal complication in patients with connective tissue disease (CTD). The current study aimed to uncover the clinical characteristics and risk factors of patients with IPFI-CTD. The files of 2186 CTD patients admitted to a single center in northern China between January 2011 and December 2013 were retrospectively reviewed. A total of 47 CTD patients with IPFI were enrolled into this study and assigned to the CTD-IPFI group, while 47 uninfected CTD patients were assigned to the control group. Clinical manifestations were recorded, and risk factors of IPFI were calculated by stepwise logistical regression analysis. Forty-seven (2.15%) CTD patients developed IPFI. Systemic lupus erythematosus patients were responsible for the highest proportion (36.17%) of cases with IPFI. Candida albicans (72.3%) accounted for the most common fungal species. CTD-IPFI patients had significantly elevated white blood cell count, erythrocyte sedimentation rate, C-reactive protein and fasting glucose values compared to controls (P<0.05). Cough, sputum and blood in phlegm were the most common symptoms. Risk factors of IPFI in CTD included maximum prednisone dose ≥30 mg/day within 3 months prior to infection, anti-microbial drug therapy, and interstitial pneumonia. CTD patients who have underlying interstitial pneumonia, prior prednisone or multiple antibiotics, were more likely to develop IPFI. PMID:27683823

  7. [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.

  8. [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.

  9. Derailed B cell homeostasis in patients with mixed connective tissue disease.

    PubMed

    Hajas, A; Barath, S; Szodoray, P; Nakken, B; Gogolak, P; Szekanecz, Z; Zold, E; Zeher, M; Szegedi, G; Bodolay, E

    2013-07-01

    Mixed connective tissue disease (MCTD) is a systemic autoimmune disorder, characterized by the presence of antibodies to U1-RNP protein. We aimed to determine phenotypic abnormalities of peripheral B cell subsets in MCTD. Blood samples were obtained from 46 MCTD patients, and 20 controls. Using anti-CD19, anti-CD27, anti-IgD and anti-CD38 monoclonal antibodies, the following B cell subsets were identified by flow cytometry: (1) transitional B cells (CD19+CD27-IgD+CD38(high)); (2) naive B cells (CD19+CD27-IgD+CD38(low)); (3) non-switched memory B cells (CD19+CD27+IgD+); (4) switched memory B cells (CD19+CD27+IgD-); (5) double negative (DN) memory B cells (CD19+CD27-IgD-) and (6) plasma cells (CD19+CD27(high)IgD-). The proportion of transitional B cells, naive B cells and DN B lymphocytes was higher in MCTD than in controls. The DN B cells were positive for CD95 surface marker. This memory B cells population showed a close correlation with disease activity. The number of plasma cells was also increased, and there was an association between the number of plasma cells and the anti-U1RNP levels. Cyclophosphamide, methotrexate, and corticosteroid treatment decreased the number of DN and CD27(high) B cells. In conclusion, several abnormalities were found in the peripheral B-cell subsets in MCTD, which reinforces the role of derailed humoral autoimmune processes in the pathogenesis.

  10. Pneumorrhachis and pneumomediastinum in connective tissue disease-related interstitial lung disease: case series from a tertiary care teaching hospital in South India.

    PubMed

    Sandhya, P; Keshava, Shyamkumar Nidugala; Danda, Debashish; Padhan, Prasanta; Mathew, John; Gibikote, Sridhar

    2012-05-01

    Pneumomediastinum has been described as a rare complication of connective tissue diseases. Here, we report four cases of pneumomediastinum: three of which are associated with dermatomyositis and one with mixed connective tissue disease. All our patients had interstitial lung disease. The first case of dermatomyositis described below was complicated by epidural emphysema (pneumorrhachis) in addition to pneumomediastinum. Pneumorrhachis is reported in many isolated case reports and series in the setting of asthma, pneumothorax, blunt chest trauma, etc. Less than 10% of pneumomediastinum cases develop this complication and vast majority of cases resolve spontaneously. The mechanism behind this has been postulated to be the passage of air through the intervertebral foramen. Others suggest entrapment of air which dissects between paraspinal soft tissues and along the vascular and nerve sheaths into the epidural space. This is the first ever reported case of epidural emphysema in connective tissue disease to the best of our knowledge.

  11. Increased frequency of delayed type hypersensitivity to metals in patients with connective tissue disease.

    PubMed

    Stejskal, Vera; Reynolds, Tim; Bjørklund, Geir

    2015-01-01

    Connective tissue disease (CTD) is a group of inflammatory disorders of unknown aetiology. Patients with CTD often report hypersensitivity to nickel. We examined the frequency of delayed type hypersensitivity (DTH) (Type IV allergy) to metals in patients with CTD. Thirty-eight patients; 9 with systemic lupus erythematosus (SLE), 16 with rheumatoid arthritis (RA), and 13 with Sjögren's syndrome (SS) and a control group of 43 healthy age- and sex-matched subjects were included in the study. A detailed metal exposure history was collected by questionnaire. Metal hypersensitivity was evaluated using the optimised lymphocyte transformation test LTT-MELISA(®) (Memory Lymphocyte Immuno Stimulation Assay). In all subjects, the main source of metal exposure was dental metal restorations. The majority of patients (87%) had a positive lymphocyte reaction to at least one metal and 63% reacted to two or more metals tested. Within the control group, 43% of healthy subjects reacted to one metal and only 18% reacted to two or more metals. The increased metal reactivity in the patient group compared with the control group was statistically significant (P<0.0001). The most frequent allergens were nickel, mercury, gold and palladium. Patients with SLE, RA and SS have an increased frequency of metal DTH. Metals such as nickel, mercury and gold are present in dental restorative materials, and many adults are therefore continually exposed to metal ions through corrosion of dental alloys. Metal-related DTH will cause inflammation. Since inflammation is a key process in CTDs, it is possible that metal-specific T cell reactivity is an etiological factor in their development. The role of metal-specific lymphocytes in autoimmunity remains an exciting challenge for future studies. Copyright © 2015 Elsevier GmbH. All rights reserved.

  12. Treatment of connective tissue disease-associated interstitial lung disease: the pulmonologist’s point of view

    PubMed Central

    Koo, So-My; Uh, Soo-Taek

    2017-01-01

    Interstitial lung disease (ILD) occurs in 15% of patients with collagen vascular disease (CVD), referred to as connective tissue disease (CTD). Despite advances in management strategies, ILD continues to be a significant cause of mortality in patients with CVD-associated ILD (CTD-ILD). There is a lack of randomized, clinical trials assessing pharmacological agents for CTD-ILD, except in cases of ILD-associated systemic sclerosis (SSc). This may be due to the lack of CTD cases available, the difficulty of histological confirmation of ILD, and the various types of CTD and ILD. As a result, evidence-based pharmacological treatment of CTD-ILD is not yet well established. CTD-ILD presents with varying degrees of histology, from inflammation to fibrosis, and a wide spectrum of clinical manifestations, from minimal symptoms to respiratory failure. This renders it difficult for clinicians to make decisions regarding treatment options, observational strategies, optimal timing for interventions, and the appropriateness of pharmacological agents for treatment. There is no specific treatment for reversing fibrosis-like idiopathic pulmonary fibrosis in a clinical setting. This review describes pharmacological interventions for SSc-ILD described in randomized control trials, and presents an overview of recent advances of CTD-ILD-dependent treatments based on the types of CTD. PMID:28704913

  13. Connective tissue disorders and the mouth.

    PubMed

    Porter, Stephen; Scully, Crispian

    2008-06-01

    The connective tissue disorders frequently give rise to orofacial manifestations, especially dry mouth because of Sjögren's syndrome. In addition, the systemic complications of such diseases may impact upon the provision of oral health care. The present article reviews the consequences of connective tissue disorders of relevance to oral health care providers. Connective tissue disorders can give rise to oral manifestations and systemic complications that may occasionally compromise primary oral health care.

  14. Longitudinal analysis of quality of life in patients with undifferentiated connective tissue diseases

    PubMed Central

    Iudici, Michele; Irace, Rosaria; Riccardi, Antonella; Cuomo, Giovanna; Vettori, Serena; Valentini, Gabriele

    2017-01-01

    Introduction/objectives To prospectively assess the quality of life (QoL) of patients affected by undifferentiated connective tissue diseases (UCTDs) and to identify factors associated with changes over time. Patients and methods A total of 46 consecutive UCTD patients completed the Short-Form 36 (SF-36) questionnaire at presentation and then yearly. At each 6-month visit, all patients underwent a detailed history taking and a laboratory and physical assessment, in order to follow the evolution of the disease over time and to assess the the co-existence of fibromyalgia. Results At presentation, scores lower than the average of the general population were detected in 34 (74%) and 41 (89%) patients in the physical and mental domains, respectively. No difference between patients with and without Raynaud’s phenomenon was detected. Fibromyalgia was the only independent variable associated with an impaired physical component summary score (p = 0.0009). No patient feature was found to be associated with the basal mental component summary score. During 24 months of follow-up, a significant improvement (ie, a change ≥5 from baseline) in physical component summary and mental component summary scores was observed in 14 (33.3%) and 20 (43.4%) patients, respectively. Patients who significantly improved in the physical domain more frequently had a history of glucocorticoids intake (p<0.001), while those who improved in the mental component more frequently had a history of either glucocorticoids (p = 0.043) or immunosuppressors (p = 0.037) intake during follow-up. Conclusion UCTD patients perceive a worse QoL, regardless of Raynaud’s phenomenon Fibromyalgia is one of the major contributors of physical QoL, whereas no factor influencing mental component has been identified. An improvement in QoL can be observed in less than half of patients over a 2-year follow-up. Larger studies are needed to identify factors influencing QoL and to define the role of pharmacological

  15. [Prevalence and specificity of antineutrophil cytoplasmic antibodies (ANCA) in connective tissue diseases].

    PubMed

    Puszczewicz, Mariusz; Zimmermann-Górska, Irena; Białkowska-Puszczewicz, Grazyna; Tuchocka, Aleksandra

    2003-01-01

    Antineutrophil cytoplasmic antibodies (ANCA) have specificity for constituents of neutrophil granules. There are two different types of ANCA identifiable by indirect immunofluorescence method. One type produces the cytoplasmic staining pattern (C-ANCA) and the second-perinuclear (P-ANCA). The aim of the study was to evaluate the frequency of ANCA in patients with connective tissue diseases (CTD). Serum samples were obtained from 394 patients suffering from CTD. The patients group consisted of 86 patients with lupus erythematosus systemic (LES) (including 30 with LES accompanied with glomerulonephritis), 136 cases with rheumatoid arthritis (RA) (including 18 patients with RA and vasculitis), 42 patients with systemic sclerosis (SSc), 76 cases of Sjögren's syndrome (SS), 30 with Wegener's granulomatosis (WG), and 24 patients with polyarteritis nodosa (PAN). All patients fulfilled ARA criteria for the classification of CTD. The control group consisted of 42 healthy individuals. ANCA were detected by immunofluorescence method according to Wiik, and by an antigen-specific--enzyme-linked immunosorbent assay (ELISA). Proteinase 3 (PR-3), myeloperoxidase (MPO), elastase (ELA), lactoferrin (LC) and lysozyme (LZ), as well as cathepsin G were used as antigens in ELISA method. ANCA were detected in sera of 86 (21.8%) patients with CTD. C-ANCA pattern was observed in 28 (7.1%) cases, and p-ANCA in 58 (14.7%). C-ANCA were detected in sera of 28 (93%) patients with WG. P-ANCA were showed in 12 (13.9%) patients with LES, in 12 (50%) cases with PAN, in 20 (14.7%) with RA, in sera of 4 (9.5%) patients with SSc and in 10 (13.1%) with SS. No ANCAs were detected in healthy individuals. Ani-PR-3 antibodies were showed in sera of 26 patients, anti MPO in 30 cases, anti-ELA in sera of 12 patients, and anti-LC in 14 cases, but anti-LZ in 4 patients with CTD. The presence of ANCA in CTD patients may indicate the vascular inflammatory process during the course of the disease. It is a very

  16. Connective tissue diseases in primary biliary cirrhosis: A population-based cohort study

    PubMed Central

    Wang, Li; Zhang, Feng-Chun; Chen, Hua; Zhang, Xuan; Xu, Dong; Li, Yong-Zhe; Wang, Qian; Gao, Li-Xia; Yang, Yun-Jiao; Kong, Fang; Wang, Ke

    2013-01-01

    AIM: To establish the frequency and clinical features of connective tissue diseases (CTDs) in a cohort of Chinese patients with primary biliary cirrhosis (PBC). METHODS: Three-hundred and twenty-two Chinese PBC patients were screened for the presence of CTD, and the systemic involvement was assessed. The differences in clinical features and laboratory findings between PBC patients with and without CTD were documented. The diversity of incidence of CTDs in PBC of different countries and areas was discussed. For the comparison of normally distributed data, Student’s t test was used, while non-parametric test (Wilcoxon test) for the non-normally distributed data and 2 × 2 χ2 or Fisher’s exact tests for the ratio. RESULTS: One-hundred and fifty (46.6%) PBC patients had one or more CTDs. The most common CTD was Sjögren’s syndrome (SS, 121 cases, 36.2%). There were nine cases of systemic sclerosis (SSc, 2.8%), 12 of systemic lupus erythematosus (SLE, 3.7%), nine of rheumatoid arthritis (RA, 2.8%), and 10 of polymyositis (PM, 3.1%) in this cohort. Compared to patients with PBC only, the PBC + SS patients were more likely to have fever and elevated erythrocyte sedimentation rate (ESR), higher serum immunoglobulin G (IgG) levels and more frequent rheumatoid factor (RF) and interstitial lung disease (ILD) incidences; PBC + SSc patients had higher frequency of ILD; PBC + SLE patients had lower white blood cell (WBC) count, hemoglobin (Hb), platelet count, γ-glutamyl transpeptidase and immunoglobulin M levels, but higher frequency of renal involvement; PBC + RA patients had lower Hb, higher serum IgG, alkaline phosphatase, faster ESR and a higher ratio of RF positivity; PBC + PM patients had higher WBC count and a tendency towards myocardial involvement. CONCLUSION: Besides the common liver manifestation of PBC, systemic involvement and overlaps with other CTDs are not infrequent in Chinese patients. When overlapping with other CTDs, PBC patients manifested some

  17. Lung cancer development in patients with connective tissue disease–related interstitial lung disease

    PubMed Central

    Enomoto, Yasunori; Inui, Naoki; Yoshimura, Katsuhiro; Nishimoto, Koji; Mori, Kazutaka; Kono, Masato; Fujisawa, Tomoyuki; Enomoto, Noriyuki; Nakamura, Yutaro; Iwashita, Toshihide; Suda, Takafumi

    2016-01-01

    Abstract Previous studies have reported that patients with idiopathic pulmonary fibrosis occasionally develop lung cancer (LC). However, in connective tissue disease (CTD)-related interstitial lung disease (ILD), there are few data regarding the LC development. The aim of the present study was to evaluate the clinical significance of LC development in patients with CTD-ILD. A retrospective review of our database of 562 patients with ILD between 2000 and 2014 identified 127 patients diagnosed with CTD-ILD. The overall and cumulative incidences of LC were calculated. In addition, the risk factors and prognostic impact of LC development were evaluated. The median age at the ILD diagnosis was 63 years (range 37–84 years), and 73 patients (57.5%) were female. The median follow-up period from the ILD diagnosis was 67.4 months (range 10.4–322.1 months). During the period, 7 out of the 127 patients developed LC (overall incidence 5.5%). The cumulative incidences at 1, 3, and 5 years were 0.0%, 1.8%, and 2.9%, respectively. The risk of LC development was significantly higher in patients with higher smoking pack-year (odds ratio [OR] 1.028; 95% confidence interval [CI] 1.008–1.049; P = 0.007) and emphysema on chest high-resolution computed tomography (OR 14.667; 95% CI 2.871–74.926; P = 0.001). The median overall survival time after developing LC was 7.0 months (95% CI 4.9–9.1 months), and the most common cause of death was LC, not ILD. According to the Cox proportional hazard model analysis with time-dependent covariates, patients who developed LC showed significantly poorer prognosis than those who did not (hazard ratio 87.86; 95% CI 19.56–394.67; P < 0.001). In CTD-ILD, clinicians should be careful with the risk of LC development in patients with a heavy smoking history and subsequent emphysema. Although not so frequent, the complication could be a poor prognostic determinant. PMID:27977621

  18. 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

  19. Connective Tissue Disease-associated Interstitial Lung Diseases (CTD-ILD) - Report from OMERACT CTD-ILD Working Group.

    PubMed

    Khanna, Dinesh; Mittoo, Shikha; Aggarwal, Rohit; Proudman, Susanna M; Dalbeth, Nicola; Matteson, Eric L; Brown, Kevin; Flaherty, Kevin; Wells, Athol U; Seibold, James R; Strand, Vibeke

    2015-11-01

    Interstitial lung disease (ILD) is common in connective tissue disease (CTD) and is the leading cause of mortality. Investigators have used certain outcome measures in randomized controlled trials (RCT) in CTD-ILD, but the lack of a systematically developed, CTD-specific index that captures all measures relevant and meaningful to patients with CTD-ILD has left a large and conspicuous gap in CTD-ILD research. The CTD-ILD working group, under the aegis of the Outcome Measures in Rheumatology (OMERACT) initiative, has completed a consensus group exercise to reach harmony on core domains and items for inclusion in RCT in CTD-ILD. During the OMERACT 12 meeting, consensus was sought on domains and core items for inclusion in RCT. In addition, consensus was pursued on a definition of response in RCT. Consensus was defined as ≥ 75% agreement among the participants. OMERACT 12 participants endorsed the domains with minimal modifications. Clinically meaningful progression for CTD-ILD was proposed as ≥ 10% relative decline in forced vital capacity (FVC) or ≥ 5% to < 10% relative decline in FVC and ≥ 15% relative decline in DLCO. There is consensus on domains for inclusion in RCT in CTD-ILD and on a definition of clinically meaningful progression. Data-driven approaches to validate these results in different cohorts and RCT are needed.

  20. 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.

  1. 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.

  2. 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

    2015-11-09

    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.

  3. 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.

  4. Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment.

    PubMed

    Ortega-Hernandez, Oscar-Danilo; Shoenfeld, Yehuda

    2012-02-01

    The most common clinical manifestations of mixed connective disease are Raynaud's phenomenon, arthralgias, swollen joints, esophageal dysfunction, muscle weakness and fingers sausage-like appearance together with the presence of anti-ribonucleoprotein (RNP) antibodies. However, organ involvement is more extensive than first descriptions reported. The disease can be serious with development of pulmonary, kidney, cardiovascular, gastrointestinal and central nervous system manifestations. The worst prognosis and high mortality are associated with the presence of pulmonary disease. Although a different set of clinical criteria have been proposed, there is no consensus about the most accurate. There is no full agreement about treatment and the initial impression of a satisfactory response to low doses of steroids is not always the rule. Herein, we review available evidence to a better approach to all previous topics.

  5. 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

  6. Diagnostic Exome Sequencing Identifies a Novel Gene, EMILIN1, Associated with Autosomal-Dominant Hereditary Connective Tissue Disease.

    PubMed

    Capuano, Alessandra; Bucciotti, Francesco; Farwell, Kelly D; Tippin Davis, Brigette; Mroske, Cameron; Hulick, Peter J; Weissman, Scott M; Gao, Qingshen; Spessotto, Paola; Colombatti, Alfonso; Doliana, Roberto

    2016-01-01

    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.

  7. Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide

    PubMed Central

    Sugawara, Eri; Kato, Masaru; Hisada, Ryo; Oku, Kenji; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Atsumi, Tatsuya

    2017-01-01

    Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH. PMID:28202869

  8. Sustained remission of antineutrophil cytoplasmic antibody-mediated glomerulonephritis and nephrotic syndrome in mixed connective tissue disease.

    PubMed

    Konstantinov, Konstantin N; Harris, Alexis A; Barry, Marc; Murata, Glen H; Tzamaloukas, Antonios H

    2013-08-01

    A woman diagnosed with mixed connective tissue disease (MCTD) developed an anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) and nephrotic syndrome with normal serum creatinine. Percutaneous kidney biopsy showed pauci-immune glomerulonephritis with superimposed immune complex deposition. After treatment with cyclophophamide and prednisone, proteinuria decreased progressively to a level of 0.4 g/g creatinine, ANCA became undetectable, while serum creatinine remained normal seven years after the beginning of treatment. Sustained remission of nephrotic proteinuria with preserved renal function may follow treatment of ANCA-mediated disease developing in patients with MCTD.

  9. Treatment of Vasodilator-resistant Mixed Connective Tissue Disease-associated Pulmonary Arterial Hypertension with Glucocorticoid and Cyclophosphamide.

    PubMed

    Sugawara, Eri; Kato, Masaru; Hisada, Ryo; Oku, Kenji; Bohgaki, Toshiyuki; Horita, Tetsuya; Yasuda, Shinsuke; Atsumi, Tatsuya

    2017-01-01

    Pulmonary arterial hypertension (PAH) associated with systemic lupus erythematosus (SLE) or mixed connective tissue disease (MTCD), in contrast to other types of PAH, may respond to immunosuppressive therapy. Most PAH cases with an immunosuppressant response were in the early stages of the disease (WHO functional class III or less). The present case was a 34-year-old woman with MCTD-associated PAH (WHO functional class IV) who was resistant to a combination of three vasodilators. Afterwards, she was treated with glucocorticoid and cyclophosphamide. This case suggested the potential benefit of immunosuppressants in patients with severe MCTD-associated PAH.

  10. IgA and IgG tissue transglutaminase antibody prevalence and clinical significance in connective tissue diseases, inflammatory bowel disease, and primary biliary cirrhosis.

    PubMed

    Bizzaro, N; Villalta, D; Tonutti, E; Doria, A; Tampoia, M; Bassetti, D; Tozzoli, R

    2003-12-01

    An association between celiac disease (CD) and other autoimmune diseases such as connective tissue diseases (CTD), inflammatory bowel diseases (IBD), and primary biliary cirrhosis (PBC) has been reported in several studies. However, a high rate of false positives in autoantibody testing was noted, especially when tissue transglutaminase (tTG) from guinea pig liver was used. Thus, the real prevalence of CD in CTD, IBD, and PBC is unclear. In a case-control study, 400 patients with CTD, 170 with IBD, 48 with PBC, and 120 healthy subjects were investigated for CD by the analysis of IgA and IgG tTG antibodies using the more specific human recombinant tTG immunoenzymatic assay. Patients and controls with positive findings were further tested for antiendomysial antibodies by indirect immunofluorescence and HLA typing, and those found positive by either of these tests underwent duodenal biopsy to confirm a possible diagnosis of CD. Twelve patients were positive for IgA or IgG tTG antibodies, showing an overall prevalence of 1.9%. Only 1 healthy subject (0.8%) had a low level positive reaction for IgA anti-tTG. Among the 12 patients and the healthy subject, only 2 (1 SLE and 1 ulcerative colitis patient) were subsequently confirmed to be affected with CD by positive EMA, HLA, and small bowel biopsy findings. The highest rate of false positives was found in PBC patients (10.4%). For these reasons, serological screening testing for CD is not recommended in CTD patients or in subjects affected with IBD or PBC, unless there is a relevant clinical suspicion of CD.

  11. Pulmonary arterial hypertension associated with connective tissue disease: meta-analysis of clinical trials

    PubMed Central

    Kuwana, Masataka; Watanabe, Hiroshi; Matsuoka, Nobushige; Sugiyama, Naonobu

    2013-01-01

    Objectives Few studies have focused on pulmonary arterial hypertension (PAH) associated with connective tissue diseases (CTDs). The optimal treatment for CTD-PAH has yet to be established. Design Meta-analysis of the data from evaluations of treatment for PAH generally (19 studies) and CTD-PAH specifically (nine studies) to compare the effects of pulmonary vasodilative PAH agents. MEDLINE, EMBASE and BIOSIS were searched. English-language full-text articles published between January 1990 and August 2012 were eligible. Setting International. Participants Patients with PAH generally (n=3073) and CTD-PAH specifically (n=678). Primary outcome measure Exercise capacity (6 min walk distance, 6 MWD). Results Patients with PAH (all forms) had mean age 32–55 years (women, 61–87%); CTD-PAH patients had mean age 45–55 years (women, 74–95%). Overall estimate of mean change in 6 MWD from baseline (95% CI) for the active treatment group versus the control group in all patients with PAH was 34.6 m (27.4–41.9 m). Pooled mean differences from the results for patients receiving placebo by subgroup of patients receiving phosphodiesterase (PDE)-5 inhibitors, endothelin receptor antagonists (ERAs) and prostacyclin (PGI2) analogues were 22.4–45.5, 39.5–44.2 and 12.4–64.9 m, respectively. Overall estimate of mean difference between changes in 6 MWD in patients with CTD-PAH was 34.2 m (23.3–45.0 m). Pooled mean differences by subgroup of patients receiving PDE-5 inhibitors, ERAs and PGI2 analogues in patients with CTD-PAH were 37.0–47.1, 14.1–21.7 and 21.0–108.0 m, respectively. ERAs were less effective in patients with CTD-PAH than all-form patients with PAH: 14.1 m (−4.4–32.6 m) vs 39.5 m (19.5–59.6 m) for bosentan and 21.7 m (2.2–41.3 m) vs 44.2 m (30.2–58.2 m) for ambrisentan. Conclusions All three types of PAH agent are effective. However, ERAs may be a less effective choice against CTD-PAH; further studies are

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

    PubMed

    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

    To examine how connective tissue diseases affect finger-vein pattern authentication. 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. 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. 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.

  13. An external validation study of a classification of mixed connective tissue disease and systemic lupus erythematosus patients.

    PubMed

    Hoffman, Robert W; Bezruczko, Nikolaus; Perkins, Kyle

    2012-01-01

    Mixed Connective Tissue Disease (MCTD) and Systemic Lupus Erythematosus (SLE) are autoimmune rheumatic diseases that are difficult for physicians to diagnose and to distinguish for a variety of reasons. The correct classification of these two diseases is a crucial issue for clinicians who treat autoimmune rheumatic diseases. In prior research, medical risk factors represented by instrument or laboratory measures and physician judgments (12 key features for MCTD and 12 key features for SLE) were parameterized with a one parameter logistic function in a Rasch model. Those results identified separate diagnostic dimensions for MCTD and SLE. This procedure was replicated in the present research with a sample of largely African American and Hispanic patients. Results verified separate dimensions for MCTD and SLE, which suggests MCTD is a separate disease from SLE.

  14. 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

    Paradowska-Gorycka, Agnieszka

    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.

  15. [Muscles and connective tissue: histology].

    PubMed

    Delage, J-P

    2012-10-01

    Here, we give some comments about the DVD movies "Muscle Attitudes" from Endovivo productions, the movies up lighting some loss in the attention given to studies on the connective tissue, and especially them into muscles. The main characteristics of the different components in the intra-muscular connective tissue (perimysium, endomysium, epimysium) are shown here with special references to their ordered architecture and special references to their spatial distributions. This connective tissue is abundant into the muscles and is in continuity with the muscles in vicinity, with their tendons and their sheath, sticking the whole on skin. This connective tissue has also very abundant connections on the muscles fibres. It is then assumed that the connective tissue sticks every organs or cells of the locomotion system. Considering the elastic properties of the collagen fibres which are the most abundant component of connective tissue, it is possible to up light a panel of connective tissue associated functions such as the transmission of muscle contractions or the regulation of protein and energetic muscles metabolism.

  16. Immunity and early atherosclerosis in the course of systemic lupus erythematosus, mixed connective tissue disease and antiphospholipid syndrome

    PubMed Central

    Paradowska-Gorycka, Agnieszka; Felis-Giemza, Anna; Olesińska, Marzena

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease of the arteries associated with various risk factors that promote lipid abnormalities, development and progression of atherosclerotic lesions, plaque rupture, and vascular thrombosis. Atherosclerosis is accelerated in autoimmune diseases. Non-invasive investigations showed increased intima-media thickness (IMT), carotid plaque, and coronary artery calcifications in patients with antiphospholipid syndrome, systemic lupus erythematosus and mixed connective tissue disease compared to controls. The balance between the proinflammatory and anti-inflammatory cytokines allows the immune equilibrium to be maintained. In autoimmune diseases the prevalence of proinflammatory factors leads to premature atherosclerosis. This review presents complementary knowledge on innate and adaptive immunity, cytokines and the role of inflammasomes in progression of early atherosclerosis. PMID:27826173

  17. Immunity and early atherosclerosis in the course of systemic lupus erythematosus, mixed connective tissue disease and antiphospholipid syndrome.

    PubMed

    Haładyj, Ewa; Paradowska-Gorycka, Agnieszka; Felis-Giemza, Anna; Olesińska, Marzena

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease of the arteries associated with various risk factors that promote lipid abnormalities, development and progression of atherosclerotic lesions, plaque rupture, and vascular thrombosis. Atherosclerosis is accelerated in autoimmune diseases. Non-invasive investigations showed increased intima-media thickness (IMT), carotid plaque, and coronary artery calcifications in patients with antiphospholipid syndrome, systemic lupus erythematosus and mixed connective tissue disease compared to controls. The balance between the proinflammatory and anti-inflammatory cytokines allows the immune equilibrium to be maintained. In autoimmune diseases the prevalence of proinflammatory factors leads to premature atherosclerosis. This review presents complementary knowledge on innate and adaptive immunity, cytokines and the role of inflammasomes in progression of early atherosclerosis.

  18. Radionuclide imaging for the assessment of esophageal motility disorders in mixed connective tissue disease patients: relation to pulmonary impairment.

    PubMed

    Caleiro, M T C; Lage, L V; Navarro-Rodriguez, T; Bresser, A; da Costa, P A; Yoshinari, N H

    2006-01-01

    Esophageal functional abnormalities may lead to regurgitation, chronic esophagitis and life-threatening conditions such as aspiration pneumonia. In mixed connective tissue disease patients, previous reports showed that esophageal dysfunction varies according to the method employed for investigation. Our study was conceived to: (i) assess esophageal motility and mucosal aspects in patients with mixed connective tissue disease by endoscopy, cine-esophogram and scintigraphy focusing on the prevalence of each exam; and (ii) verify the association between pulmonary and esophageal dysfunctions. Twenty-four mixed connective tissue disease patients were enrolled for this study. Cine-esophogram and upper digestive endoscopy with mucosal biopsy were performed according to previous standardization. Radionuclide esophageal scintigraphy was performed with a semisolid meal with (99m)Tc. Eleven healthy individuals voluntarily submitted to scintigraphy as controls. Cine-esophogram showed esophageal delayed emptying in 90% of patients. At scintigraphy there was a significant delay in total esophageal transit time in the group of patients when compared to healthy controls (35.3 +/- 8.2 s. vs. 13.6 +/- 9.5 s.; P < 0.0001). The whole esophageal body showed dysmotility in 96% of patients. The cine-esophogram detected functional esophageal impairment similar to scintigraphic findings. Histopathologic examination found esophagitis in 95% of studied patients. Reduced lung volumes were associated with esophagitis and delayed esophageal clearance at scintigraphy, observed at the distal portion of the esophagus. Esophageal scintigraphy is easy to perform, with good acceptance by patients with low radiation exposition. It is a useful non-invasive test for follow-up and interventional studies concerning esophagus dysfunction.

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

    PubMed

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

    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).

  20. 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.

  1. Serum IgG levels demonstrate seasonal change in connective tissue diseases: a large-scale, 4-year analysis in Japanese.

    PubMed

    Terao, Chikashi; Ohmura, Koichiro; Yamamoto, Keiichi; Yukawa, Naoichiro; Kawabata, Daisuke; Nojima, Takaki; Fujii, Takao; Mimori, Tsuneyo

    2012-06-01

    Hypergammaglobulinemia is often found in patients with autoimmune diseases, such as systemic lupus erythematosus (SLE), and its level may correlate with disease activity. However, it is unclear whether immunoglobulin G (IgG) displays seasonal changes. We analyzed the seasonal change in serum IgG by assessing 450 patients with connective tissue disease. The serum IgG levels in summer were compared with those in winter from 2006 to 2009. Independent samples from 355 patients were analyzed to confirm results in the first set. The differences in the IgG levels between the two seasons were analyzed in each disease and compared with disease activity. 488 patients without connective tissue disease were analyzed as reference instead of healthy people as control. We found that connective tissue disease patients tended to show higher levels of serum IgG in summer than in winter every year from 2006 to 2009, whereas patients without connective tissue disease did not demonstrate such a tendency. We observed this seasonal tendency in each disease. Seasonal changes weakly correlated with those of anti-DNA antibody in SLE patients and those of disease activity score in rheumatoid arthritis (RA) patients. Serum IgG levels of patients with connective tissue diseases display seasonal variations. Biological and clinical significance of these variations should be elucidated.

  2. Long-term effects of intermittent Iloprost infusion on pulmonary arterial pressure in connective tissue disease.

    PubMed

    Caravita, Sergio; Wu, Sheng Chin; Secchi, Maria Beatrice; Dadone, Viola; Bencini, Chiara; Pierini, Simona

    2011-10-01

    Intravenous periodic Iloprost is proven effective in the treatment of Raynaud phenomenon (RP) related to connective tissue disorder (CTD). It's well known that synthetic prostaglandins are effective drugs for the treatment of pulmonary arterial hypertension (PAH), and that PAH is frequently associated with CTD. The aim of the study is to evaluate in the chronic effect of cyclic intravenous Iloprost on pulmonary arterial pressure. We studied 17 consecutive patients with CTD (14 systemic sclerosis, 3 mixed CTD) and RP, at the entry and after at least 6months of treatment of RP with cyclic Iloprost. On both occasions, in all patients we performed transthoracic Doppler echocardiography and we determined NT-proBNP plasma levels, NYHA functional class, 6 Minute-Walk Distance (6MWD). At follow-up (8.2±1.9months; range 6-12) mean values of pulmonary arterial systolic pressure (PASP) significantly decreased (from 32.2±9.2 to 29.2±7.6mmHg, p<0.04) and mean values of 6MWD significantly increased (from 407.5±101.5 to 448.3±89.9m, p<0.01). Moreover, we observed a significant direct correlation between PASP and NT-proBNP values and a significant inverse correlation both between NT-proBNP and 6MWD values and between PASP and 6MWD values. Our results suggest that cyclic intravenous Iloprost may protect against the development or worsening of PAH in patients with CTD and RP. Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

  3. Heritable Disorders of Connective Tissue

    MedlinePlus

    ... syndrome. In most cases, the genetic defect involves collagen, the major protein-building material of bone. Epidermolysis ... play a role in how the body makes collagen, the main component of connective tissue. What Is ...

  4. Risk of connective tissue disease and related disorders among women with breast implants: a nation-wide retrospective cohort study in Sweden.

    PubMed Central

    Nyrén, O.; Yin, L.; Josefsson, S.; McLaughlin, J. K.; Blot, W. J.; Engqvist, M.; Hakelius, L.; Boice, J. D.; Adami, H. O.

    1998-01-01

    OBJECTIVE: To examine the relation between connective tissue disease and related conditions and breast implants. DESIGN: Retrospective cohort study of all women in the Swedish national inpatient registry who underwent breast augmentation surgery with artificial implants during 1964-93, compared with women who underwent breast reduction surgery during the same period. SETTING: Sweden. SUBJECTS: 7442 women with implants for cosmetic reasons or for reconstruction after breast cancer surgery and 3353 women with breast reduction surgery. MAIN OUTCOME MEASURES: Subsequent hospitalisation for definite connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, and Sjögren's syndrome) or related disorders. RESULTS: 29 women with implants were hospitalised for definite connective tissue disease compared with 25.5 expected based on general population rates (standardised hospitalisation ratio 1.1 (95% confidence interval 0.8 to 1.6)). There were no diagnoses of systemic sclerosis, and no significant excess in risk for polymyalgia rheumatica, fibromyalgia, and several related disorders. Among women who underwent breast reduction surgery, 14 were hospitalised for definite connective tissue disease compared with 10.5 expected (standardised hospitalisation ratio 1.3 (0.7 to 2.2)). Compared with the breast reduction group, women with breast implants showed a slight reduction for all definite connective tissue disease (relative risk 0.8 (95% confidence interval 0.5 to 1.4)). CONCLUSIONS: This large nationwide cohort study shows no evidence of association between breast implants and connective tissue disease. PMID:9492663

  5. Rapid progression to pulmonary arterial hypertension crisis associated with mixed connective tissue disease in an 11-year-old girl.

    PubMed

    Okura, Yuka; Takezaki, Shunichiro; Yamazaki, Yasuhiro; Yamada, Masafumi; Kobayashi, Ichiro; Ariga, Tadashi

    2013-09-01

    Mixed connective tissue disease (MCTD) is rare in pediatric rheumatic diseases. Pulmonary arterial hypertension (PAH) associated with MCTD usually progresses gradually and is difficult to note at the asymptomatic phase. We report a 11-year-old girl with MCTD complicated with rapidly progressive PAH. Although PAH was not detected by echocardiogram or chest CT scan at the initial examination, it became clear in 1 year and suddenly came to cardiac arrest during an invasive procedure. She was successfully treated with extracorporeal assist and both vasodilative and immunosuppressive medication. A combination of echocardiogram and plasma BNP levels could be a useful marker for the follow-up of such cases. PAH could develop early in the course of pediatric MCTD and needs attention to unexpected acute exacerbation, especially under emotional stress.

  6. Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases.

    PubMed

    Saketkoo, Lesley Ann; Mittoo, Shikha; Frankel, Sid; LeSage, Daphne; Sarver, Catherine; Phillips, Kristine; Strand, Vibeke; Matteson, Eric L

    2014-04-01

    Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity 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.

  7. 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

  8. Detection of anti-extractable nuclear antigens in connective tissue diseases: comparison between passive hemagglutination, counterimmunoelectrophoresis and double immunodiffusion.

    PubMed

    Siracusano, A; Agelli, M; Ioppolo, S; Quintieri, F; Bombardieri, S

    1985-01-01

    Antibodies to the three major components of the complex called soluble extractable nuclear antigen (ENA) were detected by passive hemagglutination (HA), counterimmunoelectrophoresis (CIE) and double immunodiffusion (DI) in 256 patients with connective tissue diseases. Anti-ENA antibodies were demonstrated by all the three employed methods in only 44.9% of the cases. These methods were not able to detect all antibodies to these antigens or any single specificity; CIE was however the most sensitive method for anti-RNP and HA for anti-Sm antibodies, while DI was the most suitable technique for serum samples with multiple anti-ENA specificities. Only in less than 50% of the cases the specificity detected by HA was comparable with that given by CIE or DI. Hence, for detecting anti-ENA antibodies a combination of these methods should be maintained, at least until more precise and reliable methods will become available.

  9. Mixed connective tissue disease associated with antineutrophil cytoplasmic antibodies against proteinase-3 and systemic atherosclerosis: a case report.

    PubMed

    Kanazawa, Masato; Wada, Yoko; Ohno, Tsukasa; In, Hian; Yahata, Kazuaki; Izumi, Junko; Tanaka, Hisao; Ito, Satoshi; Ueno, Mitsuhiro; Nakano, Masaaki; Gejyo, Fumitake

    2004-10-01

    A 47-year-old woman presented with facial spasm, swollen fingers and Raynaud's phenomenon due to cerebrovascular disorder and mixed connective tissue disease (MCTD). Although she was positive for both antineutrophil cytoplasmic antibodies against proteinase-3 (PR3-ANCA) and anti-U1 RNP antibodies, she did not meet the American College of Rheumatology classification criteria for Wegener's granulomatosis (WG). Physical and histopathological examinations revealed severe systemic atherosclerosis without any of the traditional risk factors. Elevated levels of malondialdehyde-modified LDL and antioxidized LDL autoantibodies, which are considered to be key factors in the pathogenesis of atherosclerosis, were also detected in the serum of this patient. In this case, systemic atherosclerosis might have been linked to these autoimmune reactions.

  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

    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

    2014-05-01

    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. 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). 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. 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.

  11. 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

  12. 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

  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. 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

  15. Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle

    PubMed Central

    Poggiogalle, Eleonora; Donini, Lorenzo Maria; Lenzi, Andrea; Chiesa, Claudio; Pacifico, Lucia

    2017-01-01

    The estimates of global incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) are worrisome, due to the parallel burden of obesity and its metabolic complications. Indeed, excess adiposity and insulin resistance represent two of the major risk factors for NAFLD; interestingly, in the last years a growing body of evidence tended to support a novel mechanistic perspective, in which the liver is at the center of a complex interplay involving organs and systems, other than adipose tissue and glucose homeostasis. Bone and the skeletal muscle are fat- free tissues which appeared to be independently associated with NAFLD in several cross-sectional studies. The deterioration of bone mineral density and lean body mass, leading to osteoporosis and sarcopenia, respectively, are age-related processes. The prevalence of NAFLD also increases with age. Beyond physiological aging, the three conditions share some common underlying mechanisms, and their elucidations could be of paramount importance to design more effective treatment strategies for the management of NAFLD. In this review, we provide an overview on epidemiological data as well as on potential contributors to the connections of NAFLD with bone and skeletal muscle. PMID:28348479

  16. Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle.

    PubMed

    Poggiogalle, Eleonora; Donini, Lorenzo Maria; Lenzi, Andrea; Chiesa, Claudio; Pacifico, Lucia

    2017-03-14

    The estimates of global incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) are worrisome, due to the parallel burden of obesity and its metabolic complications. Indeed, excess adiposity and insulin resistance represent two of the major risk factors for NAFLD; interestingly, in the last years a growing body of evidence tended to support a novel mechanistic perspective, in which the liver is at the center of a complex interplay involving organs and systems, other than adipose tissue and glucose homeostasis. Bone and the skeletal muscle are fat- free tissues which appeared to be independently associated with NAFLD in several cross-sectional studies. The deterioration of bone mineral density and lean body mass, leading to osteoporosis and sarcopenia, respectively, are age-related processes. The prevalence of NAFLD also increases with age. Beyond physiological aging, the three conditions share some common underlying mechanisms, and their elucidations could be of paramount importance to design more effective treatment strategies for the management of NAFLD. In this review, we provide an overview on epidemiological data as well as on potential contributors to the connections of NAFLD with bone and skeletal muscle.

  17. Mixed Connective Tissue Disease

    MedlinePlus

    ... often involve the hands. Fingers might swell like sausages, and the fingertips become white and numb. In ... swelling to the point where the fingers resemble sausages. Muscle and joint pain. Joints may become deformed, ...

  18. [Preliminary study of the expression of connective tissue growth factor in papillary muscles of the patients with rheumatic heart disease].

    PubMed

    Wang, Y N; Li, T; Gu, J R; Yu, B Y

    2016-04-19

    To investigate the expression and the effect of connective tissue growth factor (CTGF) on rheumatic myocardial fibrosis of rheumatic heart disease (RHD). The papillary muscles samples were obtained from patients with RHD during mitral valve replacement.The expression of TGF-β1, CTGF mRNA and CTGF protein were detected with semiquantitative RT-PCR technique and immunohistochemistry technologyin the papillary muscles cell from 41RHD patients and 20 normal papillary muscles samples.The area of myocardial fibrosis was measured by imaging analysis system. SPSS package was used to analyze the relationship between the expression of CTGF and the area of myocardial fibrosis. Compared with normal controls (PU 2.4±0.9), the mean level of CTGF protein expression in the papillary muscles samples of the RHD patients (PU 44.7±6.0) was significantly increased(P<0.01). The expression of CTGF protein in papillary muscles of RHD was positivelycorrelated with the expression of CTGFmRNA (r=0.862, P<0.01) and the area of myocardial fibrosis (r=0.856, P<0.01). Compared with normal controls, CTGF expression in the papillary muscles of the RHD patients is significantly increased, which suggests CTGF may play animportant role in myocardial fibrosis of RHD.

  19. Pneumocystis jirovecii pneumonia in mycophenolate mofetil-treated patients with connective tissue disease: analysis of 17 cases.

    PubMed

    Zhang, Yongfeng; Zheng, Yi

    2014-12-01

    The association of Pneumocystis jirovecii pneumonia (PJP) with connective tissue disease (CTD) and mycophenolate mofetil's (MMF) potent activity against PJP have been separately reported. Until now, there have been no papers describing the occurrence of PJP following MMF treatment in CTD patients. The objective of this study was to describe the clinical features, risk factors, outcomes of PJP in patients with CTD and investigates the effects of MMF on the occurrence of PJP in China. In this retrospective cohort study, we performed a chart review, analyzing clinical features, treatment, and outcomes of PJP in patients with CTD in a single hospital. A total of 17 cases met the inclusion criteria of having PJP and a CTD diagnosis: systemic lupus erythematosus; polymyositis; dermatomyositis; rheumatoid arthritis; Wegener's granulomatosis; and microscopic polyangiitis. Sixteen patients were treated with glucocorticoids (GCs) plus immunosuppressive drugs. Only one patient had GCs without immunosuppressive drugs. Ten subjects (62.5 %) received MMF (1-1.5 g/day), and all ten had lymphopenia. The mortality rates of MMF and non-MMF patients were 50 and 14 %, respectively. This study is the first report of PJP following MMF plus GC treatment in patients with CTD. CTD itself may be a risk factor for PJP. When CTD patients receiving MMF therapy have low lymphocyte counts and/or CD4 lymphocyte counts <250/µL, we should be care of occurrence of PJP.

  20. Successful laparoscopic Nissen fundoplication in a patient with mixed connective tissue disease with a short esophagus: report of a case.

    PubMed

    Nakajima, Kiyokazu; Takahashi, Tsuyoshi; Takiguchi, Shuji; Miyata, Hiroshi; Yamasaki, Makoto; Kurokawa, Yukinori; Mori, Masaki; Doki, Yuichiro

    2013-11-01

    A 51-year-old female with esophageal stricture was referred to our hospital. She was diagnosed to have mixed connective tissue disease and had been placed on steroid and immunosuppressant treatment. She presented with passage disturbance and free reflux of the gastric contents when in the supine position. Pneumatic dilatation and medication resulted in partial relief of her symptoms. Preoperative imaging studies demonstrated a shortened esophagus with severe stricture of the esophagogastric junction and a moderate hiatal hernia. A DeMeester's score of 140.1 was noted on 24-h pH monitoring. Under a diagnosis of stricturing reflux esophagitis, surgical treatment was indicated. Laparoscopic transhiatal mediastinal dissection with crural repair and fundoplication was offered instead of thoracotomy and/or laparotomy, since she had a high risk due to immunosuppression. The esophagus was extensively dissected through the hiatus up to the level of the tracheal bifurcation, and fundoplication was completed without Collis gastroplasty. Her postoperative course was rapid and uneventful. Postoperatively, her clinical symptoms were resolved with anatomical/functional improvement.

  1. High sensitivity, specificity and predictive value of the Connective Tissue Disease Screening Questionnaire among urban African-American women.

    PubMed

    Karlson, E W; Costenbader, K H; McAlindon, T E; Massarotti, E M; Fitzgerald, L M; Jajoo, R; Husni, E; Wright, E A; Pankey, H; Fraser, P A

    2005-01-01

    The Connective Tissue Disease Screening Questionnaire (CSQ), developed to screen populations for SLE and other CTDs, has been validated in a predominantly Caucasian population with hospital-based controls. We aimed to test the performance characteristics of the CSQ in an urban, predominantly African-American population. The CSQ was administered by interview to women recruited for a study of environmental risk factors and SLE, including 99 cases with SLE validated by medical record review and 202 healthy controls recruited from the community. Overall, 88% of subjects had African heritage, 6% were Hispanic and 4% were non-Hispanic Caucasian. Controls were more likely to report African heritage than cases (91% versus 82%, P = 0.001). Sensitivity for detecting SLE was 88% and specificity was 91%. In this study, where the prevalence of SLE was 33%, predictive value of a positive CSQ was 82% and predictive value of a negative CSQ was 94%. The CSQ has slightly lower sensitivity but greater specificity for SLE in an urban, predominantly African-American population with community-based controls compared with a Caucasian population with hospital-based controls. These results suggest that the CSQ has adequate sensitivity and specificity and could be used in population studies to screen African-American women for SLE.

  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. 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

  4. Hematopoietic stem cell origin of connective tissues.

    PubMed

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications.

  5. Prediction of Future Overt Pulmonary Hypertension by 6-Min Walk Stress Echocardiography in Patients With Connective Tissue Disease.

    PubMed

    Kusunose, Kenya; Yamada, Hirotsugu; Hotchi, Junko; Bando, Mika; Nishio, Susumu; Hirata, Yukina; Ise, Takayuki; Yamaguchi, Koji; Yagi, Shusuke; Soeki, Takeshi; Wakatsuki, Tetsuzo; Kishi, Jun; Sata, Masataka

    2015-07-28

    Early detection of pulmonary hypertension (PH) in connective tissue disease (CTD) is crucial to ensuring that patients receive timely treatment for this progressive disease. Exercise stress tests have been used to screen patients in an attempt to identify early-stage PH. Recent studies have described abnormal mean pulmonary artery pressure (mPAP)-cardiac output (Q) responses as having the potential to assess the disease state. This study hypothesized that pulmonary circulation pressure-flow relationships obtained by 6-min walk (6MW) stress echocardiography would better delineate differential progression of PH and predict development of PH during follow-up. We prospectively performed 6MW stress echocardiographic studies in 78 CTD patients (age 58 ± 12 years; 9% male) at baseline and follow-up. All patients underwent yearly echocardiographic follow-up studies for up to 5 years. During a median period of 32 months (range: 15 to 62 months), 16 patients reached the clinical endpoint of development of PH and none died during follow-up. PH was confirmed by right heart catheterization in all 16 patients (mPAP ≥25 mm Hg and pulmonary capillary wedge pressure ≤15 mm Hg). In a Cox proportional-hazards survival model, 6MW distance (hazard ratio [HR]: 0.99; p = 0.010), early diastolic tricuspid annulus motion velocity (HR: 0.79; p = 0.025), and ΔmPAP/ΔQ by 6MW stress (HR: 1.10; p = 0.005) were associated with development of PH. In sequential Cox models, a model on the basis of 6MW distance (chi-square, 6.6) was improved by ΔmPAP/ΔQ (chi-square: 14.4; p = 0.019). Using a receiver-operating characteristic curve, we found that the best cutoff value of ΔmPAP/ΔQ for predicting development of pulmonary hypertension was >3.3 mm Hg/l/min. The 6MW stress echocardiography noninvasively provides an incremental prognostic value of PH development in CTD. This is a single-center prospective cohort study. Larger multicenter studies are warranted to confirm this result

  6. Plasma ADAMTS13, von Willebrand Factor (VWF), and VWF Propeptide Profiles in Patients With Connective Tissue Diseases and Antiphospholipid Syndrome.

    PubMed

    Habe, Koji; Wada, Hideo; Matsumoto, Takeshi; Ohishi, Kohshi; Ikejiri, Makoto; Tsuda, Kenshiro; Kondo, Makoto; Kamimoto, Yuki; Ikeda, Tomoaki; Katayama, Naoyuki; Mizutani, Hitoshi

    2016-01-11

    Thrombotic thrombocytopenic purpura (TTP) frequently develops in patients with connective tissue diseases (CTDs). ADAMTS13 and von Willebrand factor (VWF) are closely related to the onset of TTP. We investigated the roles of ADAMTS13 and VWF in thrombotic events of patients with CTD. ADAMTS13 activity and VWF and VWF propeptide (VWFpp) levels in CTD, primary antiphospholipid antibody syndrome (pAPS), and controls were measured to examine their relationship with thrombosis. ADAMTS13 activity levels were significantly low in the patients with CTD but not in the patients with pAPS. No significant difference in the ADAMTS13 activity levels among the various CTD subgroups was found. The levels of VWF and VWFpp were significantly elevated in the patients with pAPS and CTD compared with that of control groups. Eleven patients with CTD developed TTP, and their ADAMTS13 activity levels were significantly lower than patients having CTD without TTP. However, the ADAMTS13 activity levels showed no difference between the patients having CTD with and without thrombotic events. The VWF antigen levels were significantly high in the patients having CTD with TTP. There were no significant differences in the VWF levels of the patients having CTD with TTP and thrombosis. The VWFpp levels were significantly high in the patients having CTD with TTP and thrombosis. The VWF and VWFpp levels were significantly high in the patients with pAPS. Decreased ADAMTS13 activity and elevated VWF and VWFpp levels were observed in patients with CTD. These abnormalities in patients with CTD may represent the increased risk of thrombosis in CTD.

  7. The use of Tween 20 in immunoblotting assays for the detection of autoantibodies in connective tissue diseases.

    PubMed

    Zampieri, S; Ghirardello, A; Doria, A; Tonello, M; Bendo, R; Rossini, K; Gambari, P F

    2000-05-26

    Autoantibodies directed against intracellular antigens can be detected by immunoblotting (IB). Due to its high sensitivity this technique has many advantages, but it can give misleading results when the specific bands are weak or blurred against the background staining. To decrease background staining, non-ionic detergents (Tween 20, Triton X-100, Nonidet P-40) are generally used as blocking agents. Moreover, these agents appear to have a renaturating action towards proteins and antigens. Tween 20 has a more pronounced renaturating effect on proteins than other detergents and thereby improves antigen-antibody binding. To evaluate the effect of Tween 20 on specific autoantibody detection by IB, we tested the sera of 162 patients with connective tissue diseases (CTDs) by adding this detergent at certain steps of the IB assay. We found that the use of Tween 20 in the IB procedure significantly improved the binding of autoantibodies to Jo-1, Scl70, (U1)RNP 68 kDa and C, Sm B/B' and D. Moreover, it increased the sensitivity for the detection of anti-Sm D peptide in systemic lupus erythematosus (SLE) sera with no decrease in specificity. In contrast, the addition of Tween 20 significantly decreased the binding of autoantibodies specific for ribosomal P proteins, La/SSB, Ro/SSA, but not the overall sensitivity and specificity of the method. We conclude that the addition of Tween 20 to standard IB is advantageous for anti-nuclear antigen antibody detection and improves the sensitivity of the method in revealing anti-Sm-positive sera in SLE. However, Tween 20 is not recommended for the detection of anti-cytoplasmic antibodies.

  8. Clinical characteristics and survival of pulmonary arterial hypertension associated with three major connective tissue diseases: A cohort study in China.

    PubMed

    Zhao, Jiuliang; Wang, Qian; Liu, Yongtai; Tian, Zhuang; Guo, Xiaoxiao; Wang, Hui; Lai, Jinzhi; Huang, Can; Yang, Xiaoxi; Li, Mengtao; Zeng, Xiaofeng

    2017-06-01

    Pulmonary arterial hypertension (PAH) is a major cause of death in connective tissue disease patients. This study investigated the clinical characteristics and survival of CTD-PAH in Chinese patients. This cohort study enrolled 190 consecutive PAH patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), or primary Sjögren's syndrome (pSS) who visited our referral center between May 2006 and December 2014. Baseline demographics, clinical features, laboratory results, and hemodynamic assessments were analyzed. Cox proportional hazards regression analysis was used to identify independent factors associated with increased risk of mortality. The PAH patients were more likely to have SLE (58.4%) as the underlying CTD than SSc (26.3%) or pSS (15.3%). Mean age was 37.8±10.4years, and patients with SLE were youngest at the time of PAH diagnosis. The most prevalent autoantibody was anti-U1RNP antibody (55.8%). The three groups did not differ significantly regarding World Health Organization functional class or hemodynamic results. The overall 1-, 3-, and 5-year survival rates were 87.1%, 79.1%, and 62.9%, respectively. The 3-year survival rate of 81.3% for those with SLE-PAH was significantly better than that for patients with SSc-PAH (63.6%, P<0.05). Independent predictors of mortality were 6-minute walk distance (6MWD) ≤380m (HR 3.222, 95% CI 1.485-6.987, P=0.003) and underlying CTD (HR 1.684; 95CI% 1.082-2.622, P=0.021). Independent predictors of mortality for CTD-PAH were 6MWD <380m and SSc as the underlying CTD. Increased awareness of pSS-PAH is needed because of its worse prognosis compared to SLE-PAH. Copyright © 2016. Published by Elsevier B.V.

  9. Endothelial cell-binding activity of anti-U1-ribonucleoprotein antibodies in patients with connective tissue diseases

    PubMed Central

    Okawa-Takatsuji, M; Aotsuka, S; Uwatoko, S; Takaono, M; Iwasaki, K; Kinoshita, M; Sumiya, M

    2001-01-01

    In order to elucidate the immunological properties of anti-U1-ribonucleoprotein (RNP) antibody, one of the autoantibodies detected in patients with connective tissue diseases (CTDs), we tested the endothelial cell-binding by anti-U1-RNP antibodies and epitopes on human pulmonary artery endothelial cells (HPAECs) to which the autoantibody bound. IgG fractions positive for anti-U1-RNP from patients with CTDs bound to the HPAECs. Furthermore, intact and F(ab′)2 IgG anti-U1-RNP purified by affinity chromatography also bound to endothelial cells. The binding activity of IgG fractions positive for anti-U1-RNP to the endothelial cells could be effectively absorbed by U1-RNP-Sepharose. An immunoblotting assay of purified IgG anti-U1-RNP antibodies showed that these antibodies could bind to various membrane proteins of NP40-treated HPAECs such as 68, 48, 43, 38, 33, 29, 28 and 24 kDa. Some bands, 68, 33, 28 and 24 kDa, seemed to correspond to components of U1-RNP, i.e. 68 kDa, A, B′ and C peptides, respectively. We confirmed that the anti-U1-RNP antibody from patients with CTDs can directly recognize a variety of antigens on the endothelial surface of the pulmonary artery, including the components of U1-RNP or other unknown polypeptides. These results suggest that binding to pulmonary artery endothelial cells of this autoantibody may be one of the triggers of endothelial cell inflammation in CTDs. PMID:11703381

  10. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2.

    PubMed

    Humbert, Marc; Coghlan, J Gerry; Ghofrani, Hossein-Ardeschir; Grimminger, Friedrich; He, Jian-Guo; Riemekasten, Gabriela; Vizza, Carmine Dario; Boeckenhoff, Annette; Meier, Christian; de Oliveira Pena, Janethe; Denton, Christopher P

    2017-02-01

    The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD). Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5 mg three times daily); the primary endpoint was safety and tolerability. In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2 years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2 years in patients with PAH-CTD. PATENT-1 (NCT00810693), PATENT-2 (NCT00863681). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  11. Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease

    PubMed Central

    Girgis, Reda E; Frost, Adaani E; Hill, Nicholas S; Horn, Evelyn M; Langleben, David; McLaughlin, Vallerie V; Oudiz, Ronald J; Robbins, Ivan M; Seibold, James R; Shapiro, Shelley; Tapson, Victor F; Barst, Robyn J

    2007-01-01

    Introduction Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the ETA receptor, in a cohort of patients with PAH and CTD. Short‐term clinical and haemodynamic effects and longer‐term follow‐up data are presented. Methods A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD, out of a group of 178 patients enrolled in a 12‐week, double‐blind, randomised clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo‐treated patients. There were 41 patients entered into the blinded extension study, in which all patients received either 100 mg or 300 mg sitaxsentan once daily. Results Patients treated with sitaxsentan had a mean (SD) increase in 6 minute walk distance of 20 (5) m from baseline to week 12 (p = 0.037), whereas the placebo group had a decrease of 38 (84) m, resulting in a placebo‐subtracted treatment effect of 58 m (p = 0.027). Parallel improvements in quality of life and haemodynamics were also observed. No patient discontinued their drug during the 12‐week trial. In the blinded extension study (median treatment duration 26 weeks), more patients were in functional class I–II than in III–IV (p<0.001) at the end of the study compared with the start of active therapy. Elevation of hepatic transaminase levels occurred in two patients. Conclusions Sitaxsentan appears to be efficacious in patients with PAH associated with CTD. PMID:17472992

  12. Chondrodysplasia punctata associated with maternal autoimmune diseases: expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases.

    PubMed

    Chitayat, David; Keating, Sarah; Zand, Dina J; Costa, Teresa; Zackai, Elaine H; Silverman, Earl; Tiller, George; Unger, Sheila; Miller, Stephen; Kingdom, John; Toi, Ants; Curry, Cynthia J R

    2008-12-01

    Chondrodysplasia punctata (CDP) is etiologically a heterogeneous condition and has been associated with single gene disorders, chromosome abnormalities and teratogenic exposures. The first publication of the association between CDP and maternal autoimmune connective tissue disorder was by Curry et al. 1993]. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and subsequently, other cases have been reported. We report on eight cases of maternal collagen vascular disease associated with fetal CDP and included the cases reported by Curry et al. 1993. Chondrodysplasia punctata associated with maternal collagen vascular disease. A new etiology? Presented at the David W. Smith Workshop on Morphogenesis and Malformations, Mont Tremblant, Quebec, August 1993] and Costa et al. [1993]. Maternal systemic lupus erythematosis (SLE) and chondrodysplasia punctata in two infants. Coincidence or association? 1st Meeting of Bone Dysplasia Society, Chicago, June 1993] which were reported in an abstract form. We suggest that maternal autoimmune diseases should be part of the differential diagnosis and investigation in newborns/fetuses with CDP. Thus, in addition to cardiac evaluation, fetuses/newborn to mothers with autoimmune diseases should have fetal ultrasound/newborn examination and if indicated, X-rays, looking for absent/hypoplastic nasal bone, brachydactyly, shortened long bones and epiphyseal stippling. Copyright (c) 2008 Wiley-Liss, Inc.

  13. 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.

  14. 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

  15. Elevated IL-1β levels in anti-Ro/SSA connective tissue diseases patients with prolonged corrected QTc interval.

    PubMed

    Pisoni, Cecilia N; Reina, Silvia; Arakaki, Diego; Eimon, Alicia; Carrizo, Carolina; Borda, Enri

    2015-01-01

    Patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) have increased IL-1β levels. IL-1β and other pro-inflammatory cytokines have a modulating activity on cardiac ion channels and have been associated with increased arrhythmic risk in rheumatoid arthritis patients. Likewise, adult patients with connective tissue diseases (CTDs) may have prolonged QTc intervals associated with the presence of anti-Ro/SSA antibodies. Our objective was to evaluate the presence of serum IL-1β in subjects with CTDs, in relation to the presence of anti-Ro/SSA antibodies and QTc interval duration. 12-lead electrocardiograms (ECG) were performed and blood was withdrawn, measuring electrolytes, IL-1β anti-Ro/SSA antibodies by ELISA in 73 patients with CTDs. 55 patients were anti-Ro/SSA positive and 18 were anti-Ro/SSA negative. Patients with anti-Ro/SSA positive antibodies had a significantly greater median IL-1β serum level: 7.29 (range: 0.17-17.3 pg/ml) compared to patients with anti-Ro/SSA negative antibodies whose median was: 1.67 (range 0.55-4.12 pg/ml) p<0.001. The mean QTc interval values obtained in both groups were not significantly different (417.7±23.1 vs. 414.7±21.2, p=0.63). The QTc interval was prolonged in 11 (20%) patients, who were all anti-Ro/SSA positive versus 0 (0 %) in anti-Ro/SSA negative patients p=0.05. Median IL-1β levels were: 8.7 (range: 2.69-15.1 pg/ml) in patients with prolonged QTc interval versus median: 5.0 (range: 0.17-17.3 pg/ml) in those with normal QTc interval values (<440ms) p=0.006. IL-1β is elevated in patients with CTDs that have both anti-Ro/SSA antibodies and prolonged QTc intervals.

  16. 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.

  17. Two histopathologic types of inflammatory vascular disease in MRL/Mp autoimmune mice. Model for human vasculitis in connective tissue disease.

    PubMed

    Alexander, E L; Moyer, C; Travlos, G S; Roths, J B; Murphy, E D

    1985-10-01

    We have recently described 2 histopathologic types of inflammatory vascular disease (IVD) in patients with Sjögren's syndrome (SS): neutrophilic IVD (NIVD) and mononuclear IVD (MIVD). Autoimmune MRL/Mp mice, which have many features of SS, spontaneously develop IVD which is histopathologically indistinguishable from that observed in human SS patients. Both MRL/Mp-+/+ and MRL/Mp-lpr/lpr mice develop MIVD which evolves into NIVD and results in decreased survival; the transition to NIVD is accelerated by the lpr gene. The presence of the lpr gene on other genetic backgrounds does not result in a similar acceleration of IVD and associated decreased survival. Thus, the spontaneous autosomal recessive mutation lpr appears to modulate the development of IVD in a strain of mice with an underlying propensity for vasculitis. Based on our observations on IVD in SS patients and MRL/Mp mice, we propose a new model which may enhance our understanding of the immunopathogenesis of IVD in connective tissue disease.

  18. Aberrant expression of cytokine interleukin 9 along with interleukin 4 and interferon γ in connective tissue disease-associated interstitial lung disease: association with severity of pulmonary fibrosis.

    PubMed

    Jiang, Shan; Wang, Zhi; Ouyang, Han; Liu, Zhichun; Li, Lingyun; Shi, Yongbing

    2016-02-01

    Connective tissues diseases (CTDs) are a heterogeneous group of disorders that share certain clinical characteristics and disturbed immunoregulation. Interstitial lung diseases (ILDs), also known as diffuse parenchymal lung diseases, are among the most serious pulmonary complications associated with CTDs. Interleukin 9 (IL-9), IL-4 and interferon γ (IFN-γ) - cytokines with important roles in autoimmune disease - were studied in CTD patients and CTD-ILD patients. Sixty-one hospitalized untreated CTD patients were recruited, and 20 healthy volunteers were enrolled as controls. The 61 CTD patients were divided into a simple CTD group and a CTD-ILD group, and the plasma protein IL-9, IL-4 and IFN-γ levels were measured by enzyme-linked immunosorbent assay (ELISA). The results indicate that the serum IL-9 levels were significantly higher in CTD-ILD and simple CTD patients than they were in healthy controls (each p < 0.05) and that the levels were elevated in CTD-ILD patients compared with simple CTD patients (p < 0.05). The IL-4 levels were higher in CTD-ILD patients than they were in the simple CTD patients (p < 0.05) and healthy controls (p < 0.01). In addition, the serum IL-9 levels were negatively correlated with the level of IFN-γ (r (2) = 0.34, p = 0.01), the estimated percentage of predicted forced vital capacity (FVC%) (r (2) = 0.36, p = 0.00) and the estimated percentage of predicted diffusing capacity (DLCO%) (r (2) = 0.27, p = 0.04) and were positively correlated with the IL-4 level (r (2) = 0.31, p = 0.01). Interleukin-9 may play an important role in the pathogenesis of CTD and may contribute to the progression of interstitial lung injury in CTD patients.

  19. Lung Ultrasonography in the Evaluation of Interstitial Lung Disease in Systemic Connective Tissue Diseases: Criteria and Severity of Pulmonary Fibrosis - Analysis of 52 Patients.

    PubMed

    Buda, N; Piskunowicz, M; Porzezińska, M; Kosiak, W; Zdrojewski, Z

    2016-08-01

    Patients with a diagnosed systemic connective tissue disease require regular monitoring from the point of view of interstitial lung disease. The main aim of this work is a description of the criteria for pulmonary fibrosis and the degree of the severity of the fibrosis during the course of interstitial lung disease through the TLU (transthoracic lung ultrasound). 52 patients with diagnosed diffuse interstitial lung disease were qualified for this research, together with 50 volunteers in the control group. The patients in both groups were over 18 years of age and were of both sexes. The results of the TLU of the patients underwent statistical analysis and were compared to High-Resolution Computed Tomography (HRCT) results. As a consequence of the statistical analysis, we defined our own criteria for pulmonary fibrosis in TLU: irregularity of the pleura line, tightening of the pleura line, the fragmentary nature of the pleura line, blurring of the pleura line, thickening of the pleura line, artifacts of line B ≤ 3 and ≥ 4, artifacts of Am line and subpleural consolidations < 5 mm. As a result of the conducted research, a scale of severity of pulmonary fibrosis in TLU was devised (UFI - Ultrasound Fibrosis Index), enabling a division to be made into mild, moderate and severe cases. Transthoracic Lung Ultrasonography (TLU) gives a new outlook on the diagnostic possibilities, non-invasive and devoid of ionising radiation, of pulmonary fibrosis. This research work has allowed to discover two new ultrasound symptoms of pulmonary fibrosis (blurred pleural line and Am lines). © Georg Thieme Verlag KG Stuttgart · New York.

  20. Serum KL-6 and surfactant protein-D as monitoring and predictive markers of interstitial lung disease in patients with systemic sclerosis and mixed connective tissue disease

    PubMed Central

    Hagiwara, Eri; Kitamura, Hideya; Yamanaka, Yumie; Ikeda, Satoshi; Sekine, Akimasa; Baba, Tomohisa; Okudela, Koji; Iwasawa, Tae; Takemura, Tamiko; Kuwano, Kazuyoshi; Ogura, Takashi

    2017-01-01

    Background Interstitial lung disease (ILD) is frequent complication of systemic sclerosis (SSc) and mixed connective tissue disease (MCTD). The disease is heterogeneous, and its outcome is unpredictable. Some patients have severe and progressive deterioration of ILD, which is the leading cause of mortality. We aimed to determine whether serum levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) correlate with SSc/MCTD-associated ILD activity. Methods We retrospectively analyzed the medical records of 40 patients with SSc/MCTD-associated ILD: 29 patients with SSc and 11 patients with MCTD. Measurement of serum KL-6 and SP-D levels, pulmonary function tests, and high-resolution computed tomography (HRCT) performed in parallel were reviewed. Results Serum KL-6 correlated positively with diffusing capacity of the lung for carbon monoxide (DLCO) (% predicted) and disease extent on HRCT, and the changes in serum levels of KL-6 were significantly related to the changes in forced vital capacity (FVC) in SSc/MCTD-associated ILD. On the other hand, multivariate logistic regression analyses with calculation of the area under the curve of the receiver-operating characteristic curve suggested that a higher serum level of SP-D was a significant predictor of FVC decline in SSc/MCTD-associated ILD. Conclusions Our study suggests that serum KL-6 can be a useful monitoring tool of SSc/MCTD-associated ILD activity. In contrast, serum SP-D may be a significant predictor of potential FVC decline in the short term. PMID:28275485

  1. IgG and IgM anti-snRNP reactivity in sequentially obtained serum samples from patients with connective tissue diseases.

    PubMed Central

    Nyman, U; Lundberg, I; Hedfors, E; Wahren, M; Pettersson, I

    1992-01-01

    Sequentially obtained serum samples from 30 patients with connective tissue disease positive for antibody to ribonucleoprotein (RNP) were examined to determine the specificities of IgG and IgM antibodies to snRNP during the disease course using immunoblotting of nuclear extracts. The antibody patterns were correlated with disease activity. The patterns of antibody to snRNP of individual patients were mainly stable during the study but changes in levels of antibody to snRNP were seen corresponding to changes in clinical activity. These results indicate that increased reactivity of serum IgM antibodies against the B/B' proteins seems to precede a clinically evident exacerbation of disease whereas IgG antibody reactivity to the 70 K protein peaks at the time of a disease flare. Images PMID:1485812

  2. 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.

  3. [Connective tissue dysplasia, magnesium, and nucleotide polymorphisms].

    PubMed

    Torshin, I Iu; Gromova, O A

    2008-01-01

    Undifferentiated connective tissue dysplasia (UCTD) is one of most common diseases of the connective tissue. High frequency of UCTD in population along with the fact that it can provoke a number of other diseases make UCTD an important object of the modern biomedical research in the areas of cardiology, neurology, rheumatology and pulmonology. Modern diagnostics and determination of the predisposition to UCTD allow elaboration of personalized therapy. In particular, Mg-containing supplements and medications can be effectively used in the therapy of UCTD. In one of our previous works we have analyzed possible molecular mechanisms of UCTD etiology as well as therapeutic action of magnesium. The use of data on nucleotide polymorphisms as complementation of standard medical diagnostics is one of perspective trends of the post-genomic medical research. The present work suggest a number of nucleotide polymorphisms that can be used in genetic association analyses of the UCTD as of well as therapeutic efficiency of magnesium treatment. Selection and analysis of the polymorphisms was done on the base of molecular mechanisms we had proposed earlier, comprehensive analysis of published data and also with the use of an integral approach to analysis of the functional effects of the nucleotide polymorphisms and corresponding amino acid substitutions.

  4. [Human lung connective tissue in postnatal ontogeny].

    PubMed

    Kasimtsev, A A; Nikolaev, V G

    1993-01-01

    Changes of the connective tissue structures, appearing during all postnatal ontogenesis stages were studied in 147 human lung specimens of different age groups (from newborns up to 82-year-olds). Qualitative and quantitative composition of connective tissue structures changes with the age which leads to the lateral aggregation of the fibers and growth of the general mass of the connective tissue. Heterochronia of the age variability manifestations in different regions of the lung framework was demonstrated. The original age transformations of connective tissue structures are characteristic for the basal lung regions. With the exception of perivasal connective tissue, similar changes in the region of the lung apexes appear 3-5 years later. This gives an opportunity to distinguish three anatomic zones in the lungs in an apico-basal direction, characterising the local nature of the age changes manifestations.

  5. Acupuncture, connective tissue, and peripheral sensory modulation.

    PubMed

    Langevin, Helene M

    2014-01-01

    Although considerable controversy surrounds the legitimacy of acupuncture as a treatment, a growing literature on the physiological effects of acupuncture needling in animals and humans is providing new insights into basic cellular mechanisms including connective tissue mechanotransduction and purinergic signaling. This review summarizes these findings and proposes a model combining connective tissue plasticity and peripheral sensory modulation in response to the sustained stretching of tissue that results from acupuncture needle manipulation.

  6. The prognostic value of nailfold capillary changes for the development of connective tissue disease in children and adolescents with primary raynaud phenomenon: a follow-up study of 250 patients.

    PubMed

    Pavlov-Dolijanović, Slavica; Damjanov, Nemanja; Ostojić, Predrag; Susić, Gordana; Stojanović, Roksanda; Gacić, Dragica; Grdinić, Aleksandra

    2006-01-01

    To assess the prognostic value of capillaroscopy findings for the development of connective tissue disease in children and adolescents with Raynaud phenomenon, we followed up a group of 250 (mean age 15 years) for 1 to 6 years after the first capillaroscopy was performed. Every 6 months they were screened for signs and symptoms of connective tissue disease. Analysis was performed on capillary changes registered 6 months before the development of connective tissue disease. Capillary changes were classified into three types: normal, nonspecific, and sclerodermatous. At the end of the follow-up period, 191 (76%) subjects had primary Raynaud phenomenon, 27 (10.8%) were diagnosed as having undifferentiated connective tissue disease, and 32 (12.8%) fulfilled the criteria for a diagnosis of a specific connective tissue disease. Systemic lupus erythematosus was found in nine (3.6%) patients, rheumatoid arthritis in 10 (4%) patients (six of them with juvenile onset rheumatoid arthritis), and scleroderma spectrum disorders in 13 (5.2%). The mean time for the evolution of Raynaud phenomenon into undifferentiated connective tissue disease or a form of the disease was 2 years. Most of the subjects with primary Raynaud phenomenon (173/191, 91%), undifferentiated connective tissue disease (22/27, 81%), juvenile onset rheumatoid arthritis/rheumatoid arthritis (7/10, 70%), and systemic lupus erythematosus (6/9, 67%) had normal capillary findings. Nonspecific capillary changes occurred in 3 of 10 (30%) patients with rheumatoid arthritis, 2 of 9 (22%) with systemic lupus erythematosus, 4 of 27 (15%) with undifferentiated connective tissue disease, and 18 of 191 (9%) with primary Raynaud phenomenon. Of all the subjects, only 10 (4%) showed sclerodermatous disease type capillary changes 6 months before the expression of a particular disease: eight (62%) of these developed scleroderma spectrum disorders, one expressed systemic lupus erythematosus, and one had undifferentiated connective

  7. Increased levels of anti-heat-shock protein 60 (anti-Hsp60) indicate endothelial dysfunction, atherosclerosis and cardiovascular diseases in patients with mixed connective tissue disease.

    PubMed

    Bodolay, Edit; Prohászka, Zoltan; Paragh, Gyorgy; Csipő, Istvan; Nagy, Gabor; Laczik, Renata; Demeter, Nora; Zöld, Eva; Nakken, Britt; Szegedi, Gyula; Szodoray, Peter

    2014-10-01

    Heat-shock protein 60 (Hsp60) has been shown to provoke inflammation, and anti-Hsp60 may facilitate the development of atherosclerosis. In this study, we have investigated 30 patients with mixed connective tissue disease (MCTD) and assessed anti-Hsp60 and their relationship to cardiovascular diseases (CVD). Out of 30 patients with MCTD, 15 had CVDs. Anti-Hsp60 antibody was determined by enzyme-linked immunosorbent assay. Since endothelial dysfunction and accelerated atherosclerosis are characteristic to MCTD, a wide array of MCTD-, endothelial dysfunction- and CVD-associated parameters was investigated: serum lipid levels, paraoxonase activity (PON1), rich nuclear ribonucleoprotein U1 (anti-U1RNP), anti-endothelial cell antibodies, anti-cardiolipin and anti-β2-glycoprotein I antibody isotypes (anti-CL and anti-β2GPI), endothelin-1 (ET-1) levels, also intima-media thickness (IMT), a quantitative indicator of atherosclerosis. In MCTD, anti-Hsp60 antibody levels were significantly higher than in healthy individuals (p < 0.02). MCTD patients with CVD had significantly higher levels of anti-Hsp60 compared to MCTD without CVD (p = 0.001). Patients with MCTD had significantly lower high-density lipoprotein cholesterol (p = 0.02) and PON activity (p < 0.001), and significantly increased systolic (p < 0.0002) and diastolic (p < 0.001) blood pressure compared to healthy individuals. Anti-U1RNP levels (p < 0.002) and IMT were higher in patients compared to controls (p = 0.002). The CVD-positive MCTD patients had increased anti-Hsp60 (p < 0.0013), anti-CL IgG (p = 0.0005), ET-1 serum concentration (p < 0.05) and IMT levels (p < 0.001) compared to MCTD patients without CVD. Anti-Hsp60 showed a strong correlation with anti-oxLDL (r = 0.36, p = 0.01) and serum ET-1 (r = 0.62, p < 0.001) and negative correlation with PON activity (r = -0.47, p = 0.01). Anti-Hsp60 indicates endothelial injury, CVD, and can function as a novel atherosclerotic

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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.

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

    PubMed Central

    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.

    2015-01-01

    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-Ek–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 serine140. The frequency of CD4+ T cells specific for U1-70(131-150):I-Ek (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

  14. 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.

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

    PubMed Central

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

    2015-01-01

    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. 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.

  17. Aortic Disease in the Young: Genetic Aneurysm Syndromes, Connective Tissue Disorders, and Familial Aortic Aneurysms and Dissections

    PubMed Central

    Cury, Marcelo; Zeidan, Fernanda; Lobato, Armando C.

    2013-01-01

    There are many genetic syndromes associated with the aortic aneurysmal disease which include Marfan syndrome (MFS), Ehlers-Danlos syndrome (EDS), Loeys-Dietz syndrome (LDS), familial thoracic aortic aneurysms and dissections (TAAD), bicuspid aortic valve disease (BAV), and autosomal dominant polycystic kidney disease (ADPKD). In the absence of familial history and other clinical findings, the proportion of thoracic and abdominal aortic aneurysms and dissections resulting from a genetic predisposition is still unknown. In this study, we propose the review of the current genetic knowledge in the aortic disease, observing, in the results that the causative genes and molecular pathways involved in the pathophysiology of aortic aneurysm disease remain undiscovered and continue to be an area of intensive research. PMID:23401778

  18. Microgravity Stress: Bone and Connective Tissue.

    PubMed

    Bloomfield, Susan A; Martinez, Daniel A; Boudreaux, Ramon D; Mantri, Anita V

    2016-03-15

    The major alterations in bone and the dense connective tissues in humans and animals exposed to microgravity illustrate the dependency of these tissues' function on normal gravitational loading. Whether these alterations depend solely on the reduced mechanical loading of zero g or are compounded by fluid shifts, altered tissue blood flow, radiation exposure, and altered nutritional status is not yet well defined. Changes in the dense connective tissues and intervertebral disks are generally smaller in magnitude but occur more rapidly than those in mineralized bone with transitions to 0 g and during recovery once back to the loading provided by 1 g conditions. However, joint injuries are projected to occur much more often than the more catastrophic bone fracture during exploration class missions, so protecting the integrity of both tissues is important. This review focuses on the research performed over the last 20 years in humans and animals exposed to actual spaceflight, as well as on knowledge gained from pertinent ground-based models such as bed rest in humans and hindlimb unloading in rodents. Significant progress has been made in our understanding of the mechanisms for alterations in bone and connective tissues with exposure to microgravity, but intriguing questions remain to be solved, particularly with reference to biomedical risks associated with prolonged exploration missions. Copyright © 2016 John Wiley & Sons, Inc.

  19. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.

    PubMed

    Ganesh, Santhi K; Morissette, Rachel; 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

    2014-08-01

    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.

  20. The illness experience of youth with lupus/mixed connective tissue disease: a mixed methods analysis of patient and parent perspectives.

    PubMed

    Knight, A; Vickery, M; Fiks, A G; Barg, F K

    2016-08-01

    We aimed to develop a model of the illness experience for youth with systemic lupus erythematosus (SLE)/mixed connective tissue disease (MCTD). We conducted 32 semi-structured interviews with 16 outpatient youth with SLE/MCTD, age 11 to 22 years, and their parents. We qualitatively defined key features of illness for families and distinguished profiles of youth adapting well vs poorly to SLE/MCTD. We then related these profiles to features of illness, patient-level attributes and outcomes. Experiences with SLE/MCTD grouped into five themes: managing disease, limitations, stigma, illness uncertainty and psychological coping. Youth adapting well experienced minimal challenges in these areas. Youth adapting poorly (4/16) experienced significant challenges in >1 thematic area, and were older with lower socioeconomic status, quality of life and psychosocial functioning, and increased disease-related morbidity. They also described suboptimal treatment adherence, healthcare utilization and transition to adult care. These findings support a dynamic model in which illness adaptation and outcomes are shaped by patient characteristics and five central illness-related challenges. Further testing of our model of illness experience may help guide comprehensive and personalized care of youth with SLE/MCTD, with targeted supports for youth at risk for negative adaptation to illness and poor outcomes. © The Author(s) 2016.

  1. A novel anti-microfilament antibody, anti-135 kD, is associated with Raynaud's disease, undifferentiated connective tissue disease and systemic autoimmune diseases.

    PubMed

    Girard, D; Senécal, J L

    1996-01-01

    We report herein the characterization of a human IgG antibody reactive with a nonmuscle 135 kD microfilament-associated protein, anti-135 kD. Using nonmuscle epithelial PtK2 cells as substrate in indirect immunofluorescence, we identified a distinctive pattern of reactivity with microfilaments in sera from 12 of 165 (7.3%) patients investigated for systemic autoimmune diseases and in only 2 of 171 (1.2%) normal and rheumatic disease controls (P < 0.006, 95% Cl 1.46 to 30.1). An association between anti-135 kD and Raynaud's phenomenon (n = 12/14, 85.7%) with or without an associated systemic autoimmune disease was noted. The anti-135 kD specificity was established by several criteria. (1) The fluorescence was periodically distributed along microfilaments and concentrated at focal adhesions for all sera (n = 14). (2) On immunoblots, the 14 sera reacted with a PtK2 polypeptide of 135 kD. (3) IgG purified by blot-affinity from the 135 kD band (alpha-135) reproduced the fluorescent pattern of the original sera while IgG purified from other bands did not. (4) Double immunofluorescence with alpha-135 and anti-alpha-actinin mAb indicated absence of antibody fluorescence at ruffling membranes where a-actinin was distributed. (5) IgG subclass analysis of anti-135 kD revealed that 12 (85.7%) sera are of IgG3 isotype and 2 (14.3%) are of IgG1 isotype while the light chain expression was kappa restricted. This is the first report of an antibody to a 135 kD microfilament protein. Anti-135 kD expand the repertoire of anti-microfilament and anticytoskeletal antibodies in human sera.

  2. 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.

  3. STRETCHING IMPACTS INFLAMMATION RESOLUTION IN CONNECTIVE TISSUE

    PubMed Central

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

    2016-01-01

    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 minutes twice daily reduced inflammation and improved pain, two 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 vs. no stretch for 48 hours, 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

  4. Carotid artery intima-media thickness in patients with autoimmune connective tissue diseases: a case-control study.

    PubMed

    Bruzzese, Vincenzo; Marrese, Cinzia; Zullo, Angelo; Hassan, Cesare; Ridola, Lorenzo; Izzo, Annamaria; Riccioni, Camillo

    2013-12-01

    Patients with autoimmune rheumatic disorders have an increased incidence of cardiovascular (CV) events and mortality. Despite this being related to a high prevalence of the traditional CV risk factors, systemic inflammation has been postulated to be an independent CV risk factor, particularly in patients with rheumatoid arthritis (RA). However, data are still controversial. We designed a case-control study, in which patients with autoimmune rheumatic disorders were matched with age-, sex-matched controls. Prevalence of early atherosclerosis was assessed by carotid artery intima-media thickness (IMT) measurement. IMT values were considered normal (IMT ≤ 0.9 mm) or abnormal (IMT > 0.9). Multivariate analysis was performed to identify predictors of pathological IMT. Overall, 152 patients and 140 matched controls were enrolled. Prevalence of >0.9 mm IMT values did not significantly differ between patients with autoimmune rheumatic disorders and controls (61 vs. 69%, p = 0.1). In detail, a similar IMT distribution between the 69 RA patients and controls was observed. Cases with a CV risk factor showed a higher prevalence of pathological IMT as compared to those without any risk factor, both in patients (77.1 vs. 38.6%; p < 0.0001) and controls (84.6 vs. 25%; p < 0.0001). At multivariate analysis, age and presence of CV risk factors were found to be independent predictors of >0.9 mm IMT, while RA as well as any other considered rheumatic disease were not. Our data found a similar prevalence of preclinical arterial wall atherosclerotic damage in patients with autoimmune rheumatic diseases and matched controls. Presence of traditional CV risk factors and patient age remain the main factors involved in preclinical atherosclerosis in patients with autoimmune rheumatic disorders, including RA.

  5. Connective tissue growth factor (CTGF) expression in the brain is a downstream effector of insulin resistance- associated promotion of Alzheimer's disease beta-amyloid neuropathology.

    PubMed

    Zhao, Zhong; Ho, Lap; Wang, Jun; Qin, Weiping; Festa, Eugene D; Mobbs, Charles; Hof, Patrick; Rocher, Anne; Masur, Sandra; Haroutunian, Vahram; Pasinetti, Giulio Maria

    2005-12-01

    The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD). Using genome-wide array technology, we found that connective tissue growth factor (CTGF), a gene product described previously for its involvement in diabetic fibrosis, is elevated in brain tissue in an established mouse model of diet-induced IR. With this evidence we continued to explore the regulation of CTGF in postmortem AD brain tissue and found that CTGF expression correlated with the progression of AD clinical dementia and amyloid neuritic plaque (NP) neuropathology, but not neurofibrillary tangle (NFT) deposition. Consistent with this evidence, we also found that exposure of Tg2576 mice (a model AD-type amyloid neuropathology) to a diabetogenic diet that promotes IR results in a ~2-fold elevation in CTGF steady-state levels in the brain, coincident with a commensurate promotion of AD-type amyloid plaque burden. Finally, using in vitro cellular models of amyloid precursor protein (APP)-processing and Abeta generation/clearance, we confirmed that human recombinant (hr)CTGF may increase Abeta1-40 and Abeta1-42 peptide steady-state levels, possibly through a mechanism that involves gamma-secretase activation and decreased insulin-degrading enzyme (IDE) steady-state levels in a MAP kinase (MAPK)/ phosphatidylinositol 3-kinase (PI-3K)/protein kinase-B (AKT)1-dependent manner. The findings in this study tentatively suggest that increased CTGF expression in the brain might be a novel biological predicative factor of AD clinical progression and neuropathology in response to dietary regimens promoting IR conditions.

  6. Some connective tissue disorders of the lung.

    PubMed Central

    Turner-Warwick, M.

    1988-01-01

    Many connective tissue disorders involve the lungs. The same clinical syndrome may be associated with several distinctive types of pathology in different patients. Fibrosing alveolitis is a common feature of a number of different syndromes. An hypothesis is set out in schematic form which may help to account for some of these differences and emphasizes the potential importance of the pulmonary vasculature in pathogenesis. Images Figure 3 Figure 4 Figure 5 Figure 8 Figure 9 PMID:3074281

  7. Altered Th17 cells and Th17/regulatory T-cell ratios indicate the subsequent conversion from undifferentiated connective tissue disease to definitive systemic autoimmune disorders.

    PubMed

    Szodoray, Peter; Nakken, Britt; Barath, Sandor; Csipo, Istvan; Nagy, Gabor; El-Hage, Fadi; Osnes, Liv T; Szegedi, Gyula; Bodolay, Edit

    2013-12-01

    A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker.

  8. Isotype switching and titer variation of anti-Ro/SSA antibodies over time in 100 patients with undifferentiated connective tissue disease (UCTD).

    PubMed

    Ceribelli, A; Cavazzana, I; Franceschini, F; Quinzanini, M; Rizzini, F Lodi; Cattaneo, R

    2008-01-01

    To correlate the clinical course of the disease with the titer, the isotype profile and the switch of the anti-Ro/SSA antibodies in a cohort of patients affected by UCTD. One hundred selected patients with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis (CIE), and affected by UCTD with a mean follow-up of 7.6 years (SD 4.8 yrs.), were studied. The titer of IgA, IgG and IgM anti-Ro/SSA antibodies was determined in two different sera, obtained at the time of diagnosis and at the last visit, by ELISA with Ro/SSA recombinant proteins as substrate. Thirty-five patients evolved from UCTD to a different connective tissue disease, while 65 showed a stable disease. Anti-Ro/SSA antibodies were detected in 91% and 97% of the patients, at baseline and during follow-up, respectively. IgG dominates the anti-Ro response. The titer of IgA, IgM and IgG anti-Ro/SSA did not differ significantly between the two groups of patients with UCTD. An increasing trend of IgG and IgA anti-Ro/SSA titer could be detected in patients evolving in primary Sjögren's Syndrome (pSS), but only the increase of IgG anti-Ro/SSA was significant (p=0.0235). IgG dominates the anti-Ro/SSA response in patients with UCTD. No substantial change of the antibody isotype against Ro/SSA peptides could be observed during follow-up. The titer of IgG anti-Ro/SSA significantly raised in the group of patients evolving in pSS.

  9. Prevalence of Mixed Connective Tissue Disease in a Population-Based Registry of American Indian/Alaska Native People in 2007.

    PubMed

    Ferucci, Elizabeth D; Johnston, Janet M; Gordon, Caroline; Helmick, Charles G; Lim, S Sam

    2017-08-01

    To determine the prevalence of mixed connective tissue disease (MCTD) in 2007 in the Indian Health Service (IHS) active clinical population from 3 regions of the US. The IHS Lupus Registry was designed to identify possible MCTD cases in addition to systemic lupus erythematosus cases. The population denominator for this report includes American Indian or Alaska Native adults within the IHS active clinical population in 2007, residing in select communities in 3 regions of the US. Potential MCTD cases were identified using a broad range of diagnostic codes and were confirmed by detailed medical record abstraction. Classification as MCTD for this analysis required both rheumatologist diagnosis of MCTD without diagnosis of other CTD, and documentation of the Alarcón-Segovia MCTD criteria in the medical record. Prevalence was also calculated using 2 alternate definitions of MCTD. The age-adjusted prevalence of MCTD using our primary definition was 6.4 per 100,000 (95% confidence interval 2.8-12.8). The prevalence was higher in women than in men using all 3 definitions of MCTD, and no men met the criteria for the primary definition of MCTD. The first population-based estimates of the prevalence of MCTD in the US American Indian/Alaska Native population show that the prevalence appears to be higher than in other populations. Additional population-based estimates are needed to better understand the epidemiology of MCTD. © 2016, American College of Rheumatology.

  10. Antibody penetration into living cells. I. Intranuclear immunoglobulin in peripheral blood mononuclear cells in mixed connective tissue disease and systemic lupus erythematosus.

    PubMed

    Alarcón-Segovia, D; Ruíz-Argüelles, A; Fishbein, E

    1979-03-01

    We have shown recently (Alarcón-Segovia, Ruíz-Argüelles & Fishbein, 1978) that an IgG anti-RNP antibody obtained from a patient with mixed connective tissue disease (MCTD) can penetrate viable mononuclear cells (MNC) from normal donors via their Fc receptors. Live MNC from twelve MCTD patients incubated with goat anti-Ig antibody had intranuclear antibody with a speckled pattern in a mean of 5.5% of all MNC and 57.3% of all Fc receptor-bearing MNC. We found intranuclear immunoglobulins in all twelve patients with MCTD which were present only in cells with Fc receptors. Only three out of twenty-one patients with systemic lupus erythematosus (SLE) were found to have intranuclear antibody in a mean of 17.2% of their Fc receptor-bearing cells. Further experiments with MNC from SLE patients revealed a partial blocking of penetration of antibody via Fc receptors. MNC from ten scleroderma, ten rheumatoid arthritis patients and eleven normal controls did not have intranuclear immunoglobulin. In vivo penetration of autoantibodies into Fc receptor-bearing cells in MCTD, and probably in SLE as well, may represent an important pathogenetic mechanism.

  11. Antibody penetration into living cells. I. Intranuclear immunoglobulin in peripheral blood mononuclear cells in mixed connective tissue disease and systemic lupus erythematosus.

    PubMed Central

    Alarcón-Segovia, D; Ruíz-Argüelles, A; Fishbein, E

    1979-01-01

    We have shown recently (Alarcón-Segovia, Ruíz-Argüelles & Fishbein, 1978) that an IgG anti-RNP antibody obtained from a patient with mixed connective tissue disease (MCTD) can penetrate viable mononuclear cells (MNC) from normal donors via their Fc receptors. Live MNC from twelve MCTD patients incubated with goat anti-Ig antibody had intranuclear antibody with a speckled pattern in a mean of 5.5% of all MNC and 57.3% of all Fc receptor-bearing MNC. We found intranuclear immunoglobulins in all twelve patients with MCTD which were present only in cells with Fc receptors. Only three out of twenty-one patients with systemic lupus erythematosus (SLE) were found to have intranuclear antibody in a mean of 17.2% of their Fc receptor-bearing cells. Further experiments with MNC from SLE patients revealed a partial blocking of penetration of antibody via Fc receptors. MNC from ten scleroderma, ten rheumatoid arthritis patients and eleven normal controls did not have intranuclear immunoglobulin. In vivo penetration of autoantibodies into Fc receptor-bearing cells in MCTD, and probably in SLE as well, may represent an important pathogenetic mechanism. Images FIG. 1 PMID:378481

  12. Soft tissue engineering with micronized-gingival connective tissues.

    PubMed

    Noda, Sawako; Sumita, Yoshinori; Ohba, Seigo; Yamamoto, Hideyuki; Asahina, Izumi

    2017-02-24

    The free gingival graft (FGG) and connective tissue graft (CTG) are currently considered to be the gold standards for keratinized gingival tissue reconstruction and augmentation. However, these procedures have some disadvantages in harvesting large grafts, such as donor-site morbidity as well as insufficient gingival width and thickness at the recipient site post-treatment. To solve these problems, we focused on an alternative strategy using micronized tissue transplantation (micro-graft). In this study, we first investigated whether transplantation of micronized gingival connective tissues (MGCTs) promotes skin wound healing. MGCTs (≤100 µm) were obtained by mincing a small piece (8 mm(3) ) of porcine keratinized gingiva using the RIGENERA system. The MGCTs were then transplanted to a full skin defect (5 mm in diameter) on the dorsal surface of immunodeficient mice after seeding to an atelocollagen matrix. Transplantations of atelocollagen matrixes with and without micronized dermis were employed as experimental controls. The results indicated that MGCTs markedly promote the vascularization and epithelialization of the defect area 14 days after transplantation compared to the experimental controls. After 21 days, complete wound closure with low contraction was obtained only in the MGCT grafts. Tracking analysis of transplanted MGCTs revealed that some mesenchymal cells derived from MGCTs can survive during healing and may function to assist in wound healing. We propose here that micro-grafting with MGCTs represents an alternative strategy for keratinized tissue reconstruction that is characterized by low morbidity and ready availability. © 2017 Wiley Periodicals, Inc.

  13. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-β1-connective tissue growth factor signalling cascade.

    PubMed

    Huang, Jiqian; Matavelli, Luis C; Siragy, Helmy M

    2011-04-01

    1. Transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) are expressed in renal glomeruli, and contribute to the development of diabetic nephropathy. Recently, we showed that (pro)renin receptor (PRR) is upregulated in the kidneys of the streptozocin (STZ)-induced diabetes rat model. We hypothesized that in the presence of hyperglycaemia, increased renal PRR expression contributes to enhanced TGF-β1-CTGF signalling activity, leading to the development of diabetic kidney disease. 2. In vivo and in vitro studies were carried out in Sprague-Dawley rats and rat mesangial cells (RMC). PRR blockade was achieved in vivo by treating STZ induced diabetes rats with the handle region peptide (HRP) of prorenin and in vitro by HRP or PRR siRNA in RMC. Angiotensin AT1 receptor blockade was achieved by valsartan treatment. 3. Results showed that expression of PRR, TGF-β1 and CTGF were upregulated in diabetic kidneys and RMC exposed to high glucose. Glucose exposure also induced PRR phosphorylation, a process that was inhibited by HRP, valsartan or PRR siRNA. HRP and valsartan significantly attenuated renal TGF-β1 and CTGF expression in diabetic animals and high glucose treated RMC. Similar results were observed in high glucose exposed RMC in response to PRR siRNA. TGF-β receptor blockade decreased CTGF expression in RMC. Combined administration of valsartan and PRR siRNA showed further reduction of TGF-β1 and CTGF expression in RMC. 4. In conclusion, PRR contributes to kidney disease in diabetes through an enhanced TGF-β1-CTGF signalling cascade.

  15. 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.

  16. New coupled-particle light-scattering assay for detection of Ro/SSA (52 and 60 kilodaltons) and La/SSB autoantibodies in connective tissue diseases.

    PubMed

    Bizzaro, N; Bonelli, F; Tonutti, E; Tozzoli, R; Villalta, D

    2001-09-01

    The diagnostic and analytical performance of the coupled-particle light-scattering assay in detecting anti-Ro/SSA autoantibodies (the 60-kDa [Ro60] and the 52-kDa [Ro52] antibodies) and anti-La/SSB autoantibodies was evaluated. The antigens were obtained by recombinant DNA procedures to include the most immunogenic epitopes for each protein by using a prokaryotic expression system. Serum samples from 151 patients with connective tissue diseases and 52 control subjects (including patients with viral infections, patients with Lyme disease, and healthy subjects) were studied. Sensitivities for detection of anti-Ro/SSA and anti-La/SSB were 88.2 and 95.2%, respectively; specificities were 97.6 and 98.1%, respectively. The intra-assay coefficient of variation (CV) ranged from 4.3 to 10.9% for anti-Ro/SSA and from 2.8 to 12.5% for anti-La/SSB; interassay CVs ranged from 6.5 to 13.2% and from 8.2 to 14.5%, respectively. Among the anti-Ro/SSA-positive samples, Ro60 was recognized by 66% of the test sera and Ro52 was recognized by 95% of the test sera. Thirty-four percent of the Ro/SSA-positive sera were reactive only with the Ro52 antigen, indicating that anti-Ro52 is the most common antibody specificity recognized by anti-Ro/SSA autoantibodies. No differences were found between the prevalences of anti-Ro60 and anti-Ro52 in relation to systemic lupus erythematosus or Sjögren's syndrome. The results of the present study indicate that this new immunoassay is an efficient diagnostic tool for the detection of anti-Ro/SSA and anti-La/SSB antibodies in patients with autoimmune disorders.

  17. New Coupled-Particle Light-Scattering Assay for Detection of Ro/SSA (52 and 60 Kilodaltons) and La/SSB Autoantibodies in Connective Tissue Diseases

    PubMed Central

    Bizzaro, Nicola; Bonelli, Fabrizio; Tonutti, Elio; Tozzoli, Renato; Villalta, Danilo

    2001-01-01

    The diagnostic and analytical performance of the coupled-particle light-scattering assay in detecting anti-Ro/SSA autoantibodies (the 60-kDa [Ro60] and the 52-kDa [Ro52] antibodies) and anti-La/SSB autoantibodies was evaluated. The antigens were obtained by recombinant DNA procedures to include the most immunogenic epitopes for each protein by using a prokaryotic expression system. Serum samples from 151 patients with connective tissue diseases and 52 control subjects (including patients with viral infections, patients with Lyme disease, and healthy subjects) were studied. Sensitivities for detection of anti-Ro/SSA and anti-La/SSB were 88.2 and 95.2%, respectively; specificities were 97.6 and 98.1%, respectively. The intra-assay coefficient of variation (CV) ranged from 4.3 to 10.9% for anti-Ro/SSA and from 2.8 to 12.5% for anti-La/SSB; interassay CVs ranged from 6.5 to 13.2% and from 8.2 to 14.5%, respectively. Among the anti-Ro/SSA-positive samples, Ro60 was recognized by 66% of the test sera and Ro52 was recognized by 95% of the test sera. Thirty-four percent of the Ro/SSA-positive sera were reactive only with the Ro52 antigen, indicating that anti-Ro52 is the most common antibody specificity recognized by anti-Ro/SSA autoantibodies. No differences were found between the prevalences of anti-Ro60 and anti-Ro52 in relation to systemic lupus erythematosus or Sjögren's syndrome. The results of the present study indicate that this new immunoassay is an efficient diagnostic tool for the detection of anti-Ro/SSA and anti-La/SSB antibodies in patients with autoimmune disorders. PMID:11527804

  18. Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial

    PubMed Central

    Coghlan, John Gerry; Galiè, Nazzareno; Barberà, Joan Albert; Frost, Adaani E; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M; Kuwana, Masataka; McLaughlin, Vallerie V; Peacock, Andrew J; Simonneau, Gérald; Vachiéry, Jean-Luc; Blair, Christiana; Gillies, Hunter; Miller, Karen L; Harris, Julia H N; Langley, Jonathan; Rubin, Lewis J

    2017-01-01

    Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results. PMID:28039187

  19. Occurrence of organ-specific and systemic autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases: report of data obtained through direct patient interviews.

    PubMed

    Mosca, Marta; Carli, Linda; d'Ascanio, Anna; Tani, Chiara; Talarico, Rosaria; Baldini, Chiara; Bazzichi, Laura; Tavoni, Antonio; Migliorini, Paola; Bombardieri, Stefano

    2008-08-01

    Studies have demonstrated a familial aggregation of systemic and organ-specific autoimmune diseases. The aim of the present survey was to obtain, by patient interviews, a preliminary estimate of the prevalence of systemic and organ-specific autoimmune diseases among the first- and second-degree relatives of Caucasian patients with connective tissue diseases (CTD) or inflammatory arthritis followed at our unit. Between June 2007 and January 2008, 626 patients and 85 controls (patients with osteoarthritis, osteoporosis, or fibromyalgia) were interviewed. Three hundred ten patients (50%) versus 21 controls (25%) were found to have at least one relative affected with an autoimmune condition (p < 0.0001). The most common conditions were organ-specific autoimmune diseases: 160 (34%) autoimmune thyroid (AT) disease, 112 (24%) psoriasis, 21 vitiligo, and 19 insulin-dependent diabetes mellitus. Systemic autoimmune diseases were reported in 126 relatives: rheumatoid arthritis (66 cases, 14%), 16 sacroileitis, and CTD (43 cases). A significant difference was observed in the prevalence of AT disease between the relatives of the patients and controls (3% versus 0.5%). In conclusion, these data confirm the high prevalence of autoimmune conditions, particularly of AT disease, among the relatives of patients.

  20. [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.

  1. 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

  2. Barriers and facilitators for mental healthcare in pediatric lupus and mixed connective tissue disease: a qualitative study of youth and parent perspectives.

    PubMed

    Knight, Andrea M; Vickery, Michelle E; Fiks, Alexander G; Barg, Frances K

    2015-11-24

    Untreated mental health problems may result in poor outcomes for youth with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). We investigated perceptions, barriers and facilitators for mental healthcare of these youth. We conducted 32 semi-structured interviews with 16 outpatient youth with SLE/MCTD, ages 11-22 years, and their parents. We used purposive sampling to deliberately obtain the experiences of youth screened during a previous study for depression and anxiety with the Patient Health Questionnaire 9 and the Screen for Childhood Anxiety and Related Disorders, respectively. We recruited 6 youth with previous positive screens and 10 with negative screens. We assessed interim mental health history, and qualitatively examined perceptions, barriers and facilitators for mental healthcare. Youth with a mental health history increased from 6 (38%) at initial screening to 9 (56%) at interview (mean follow-up = 2.1 years). Youth receiving mental health treatment increased from 33 to 67%. Youth and parents identified rheumatologists as primary physicians and found mental health screening in rheumatology acceptable. Barriers to mental healthcare included: stigma; fear; uncertainty about getting help; parental emotional burden; minimization by doctors; and limited mental healthcare access. Facilitators included: strong clinician relationships; clinician initiative, sincerity and normalization in discussing mental health; and increased patient/family awareness of mental health issues in SLE/MCTD. Youth with SLE/MCTD and their parents perceive pediatric rheumatologists as a preferred source for mental health screening, guidance and referral. Interventions addressing barriers and enhancing facilitators may improve mental healthcare for youth with SLE/MCTD.

  3. Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - A subgroup analysis of the ARIES-E clinical trial.

    PubMed

    Fischer, Aryeh; Denton, Christopher P; Matucci-Cerinic, Marco; Gillies, Hunter; Blair, Christiana; Tislow, James; Nathan, Steven D

    2016-08-01

    Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD ≥30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Late appearance and exacerbation of primary Raynaud's phenomenon attacks can predict future development of connective tissue disease: a retrospective chart review of 3,035 patients.

    PubMed

    Pavlov-Dolijanovic, Slavica; Damjanov, Nemanja S; Vujasinovic Stupar, Nada Z; Radunovic, Goran L; Stojanovic, Roksanda M; Babic, Dragan

    2013-04-01

    To assess the prognostic value of the age at onset of Raynaud's (RP) and of a history of exacerbation of RP attacks for the development of connective tissue disease (CTD) in patients initially found to have primary Raynaud's. 3,035 patients with primary RP (2,702 women and 333 men) were followed for an average of 4.8 years (range from 1 to 10 years). At baseline and every 6 months, they were screened for signs and symptoms of CTD. At 4.8 years of follow-up, 54.7 % patients remained as primary RP, 8.1 % had developed suspected secondary RP, and 37.2 % had developed a definite CTD. Primary RP patients had an earlier onset of RP (mean age of 32.2 years) than those with suspected (mean age 36.5 years, P = .007) or definite secondary RP associated with CTD (mean age of 39.8 years, P = .004). RP beginning before the age of forty was not significantly associated with the development of CTD. Conversely, the appearance of RP after the age of 40 was significantly associated with the development of CTD (P = .00001). Worsening of RP attacks predicted the development of CTD, especially systemic sclerosis (relative risk [RR] of 1.42), scleroderma overlap syndrome (RR of 1.18), and mixed CTD (RR of 1.18). Patients whose onset of RP occurred past 40 years of age and those with worsening RP attacks were at risk for the future development of CTD.

  5. 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. Copyright © 2014. Published by Elsevier Masson SAS.

  6. 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

  7. Connective tissue alterations in Fkbp10-/- mice.

    PubMed

    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

    2014-09-15

    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. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile.

    PubMed

    Longhi, Maria Serena; Ma, Yun; Grant, Charlotte R; Samyn, Marianne; Gordon, Patrick; Mieli-Vergani, Giorgina; Vergani, Diego

    2013-03-01

    Autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinaemia, autoantibodies and interface hepatitis, is occasionally associated with systemic autoimmune manifestations [systemic lupus erythematosus (SLE); mixed connective tissue disease (MCTD)]. In both AIH and SLE/MCTD numerical and/or functional impairment of regulatory T-cells (T-regs) is believed to favour autoimmunity. To investigate whether immune-tolerance breakdown profiles differ in patients with AIH and SLE/MCTD, isolated AIH or systemic autoimmunity, we studied phenotypic and functional features of T-regs in 10 patients with AIH-SLE/MCTD, 22 with AIH, 12 with SLE and 20 healthy subjects. Compared to health, CD4(pos)CD25(pos) cells were decreased in number and expressed high levels of the CD127 activation marker in all three disease groups; in AIH-SLE/MCTD and in SLE they displayed low levels of FOXP3. In AIH-SLE/MCTD, they also contained a high proportion of IFNγ positive cells, indicating a Th1 profile. Similarly, in AIH-SLE/MCTD, CD4(pos)CD25(pos)CD25(high) T-regs were reduced in number and contained an increased proportion of activated CD127(pos) and IFNγ(pos) cells. Such skewing towards a Th1 profile was also present at effector level, as a high frequency of IFNγ-producing cells was observed within AIH-SLE/MCTD CD4(pos)CD25(neg) responder cells. Impairment in suppressor function both of CD4(pos)CD25(pos) cells and CD4(pos)CD25(pos)CD127(neg) T-regs was observed in all three autoimmune conditions, but while addition of CD4(pos)CD25(pos)CD127(neg) T-regs decreased CD4(pos)CD25(neg) responder cell proliferation in healthy subjects and partially in AIH patients, it had no effect in AIH-SLE/MCTD and SLE patients. In conclusion, in AIH-SLE/MCTD T-regs display a distinctive phenotypic and functional signature, characterized by marked activation, elevated IFNγ production and by a profound impairment of suppressive function, suggesting that multiple autoimmune manifestations

  9. Cell-cell connectivity: desmosomes and disease.

    PubMed

    Brooke, Matthew A; Nitoiu, Daniela; Kelsell, David P

    2012-01-01

    Cell-cell connectivity is an absolute requirement for the correct functioning of cells, tissues and entire organisms. At the level of the individual cell, direct cell-cell adherence and communication is mediated by the intercellular junction complexes: desmosomes, adherens, tight and gap junctions. A broad spectrum of inherited, infectious and auto-immune diseases can affect the proper function of intercellular junctions and result in either diseases affecting specific individual tissues or widespread syndromic conditions. A particularly diverse group of diseases result from direct or indirect disruption of desmosomes--a consequence of their importance in tissue integrity, their extensive distribution, complex structure, and the wide variety of functions their components accomplish. As a consequence, disruption of desmosomal assembly, structure or integrity disrupts not only their intercellular adhesive function but also their functions in cell communication and regulation, leading to such diverse pathologies as cardiomyopathy, epidermal and mucosal blistering, palmoplantar keratoderma, woolly hair, keratosis, epidermolysis bullosa, ectodermal dysplasia and alopecia. Here, as well as describing the importance of the other intercellular junctions, we focus primarily on the desmosome, its structure and its role in disease. We will examine the various pathologies that result from impairment of desmosome function and thereby demonstrate the importance of desmosomes to tissues and to the organism as a whole.

  10. 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.

  11. Systemic Connective Tissue Features in Women with Fibromuscular Dysplasia

    PubMed Central

    O’Connor, Sarah; Kim, Esther S. H.; Brinza, Ellen; Moran, Rocio; Fendrikova-Mahlay, Natalia; Wolski, Kathy; Gornik, Heather L.

    2016-01-01

    Background Fibromuscular Dysplasia (FMD) is an 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. Methods and Results 142 FMD patients were consecutively enrolled at a single referral center (97.9% female, 92.3% 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. 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. History of spontaneous pneumothorax (5.9% high risk vs. 0% standard risk) and atrophic scarring (17.3% 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 vs. 27.3% in the standard risk group, p=0.055. Conclusions 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

  12. [Marfan syndrome and related connective tissue disorders].

    PubMed

    Steindl, Katharina

    2013-11-27

    Marfan syndrome is an autosomal dominantly inherited connective tissue disorder with a prevalence of approximately 1:5000 people. Typical manifestations affect the cardiovascular system, eyes, skeleton, lungs, skin and dura mater. Most patients have a so-called marfanoid habitus with tall stature, long and narrow limbs, a long and narrow head shape and other skeletal abnormalities. Of particular medical importance are the possible complications such as severe scoliosis or pectus excavatum, spontaneous pneumothorax, retinal detachment, or an acute glaucoma evoked by lens luxation. However, the most dangerous complication is acute dissection of the ascending aorta, which is usually the result of a slowly progressive aortic dilatation. With the introduction of therapies the average life expectancy of previously just 32 years could be raised to above 60 years.

  13. 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

  14. 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. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  15. Assessment of risks of pulmonary infection during 12 months following immunosuppressive treatment for active connective tissue diseases: a large-scale prospective cohort study.

    PubMed

    Yamazaki, Hayato; Sakai, Ryoko; Koike, Ryuji; Miyazaki, Yasunari; Tanaka, Michi; Nanki, Toshihiro; Watanabe, Kaori; Yasuda, Shinsuke; Kurita, Takashi; Kaneko, Yuko; Tanaka, Yoshiya; Nishioka, Yasuhiko; Takasaki, Yoshinari; Nagasaka, Kenji; Nagasawa, Hayato; Tohma, Shigeto; Dohi, Makoto; Sugihara, Takahiko; Sugiyama, Haruhito; Kawaguchi, Yasushi; Inase, Naohiko; Ochi, Sae; Hagiyama, Hiroyuki; Kohsaka, Hitoshi; Miyasaka, Nobuyuki; Harigai, Masayoshi

    2015-04-01

    Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.

  16. Non-myogenic Contribution to Muscle Development and Homeostasis: The Role of Connective Tissues.

    PubMed

    Nassari, Sonya; Duprez, Delphine; Fournier-Thibault, Claire

    2017-01-01

    Skeletal muscles belong to the musculoskeletal system, which is composed of bone, tendon, ligament and irregular connective tissue, and closely associated with motor nerves and blood vessels. The intrinsic molecular signals regulating myogenesis have been extensively investigated. However, muscle development, homeostasis and regeneration require interactions with surrounding tissues and the cellular and molecular aspects of this dialogue have not been completely elucidated. During development and adult life, myogenic cells are closely associated with the different types of connective tissue. Connective tissues are defined as specialized (bone and cartilage), dense regular (tendon and ligament) and dense irregular connective tissue. The role of connective tissue in muscle morphogenesis has been investigated, thanks to the identification of transcription factors that characterize the different types of connective tissues. Here, we review the development of the various connective tissues in the context of the musculoskeletal system and highlight their important role in delivering information necessary for correct muscle morphogenesis, from the early step of myoblast differentiation to the late stage of muscle maturation. Interactions between muscle and connective tissue are also critical in the adult during muscle regeneration, as impairment of the regenerative potential after injury or in neuromuscular diseases results in the progressive replacement of the muscle mass by fibrotic tissue. We conclude that bi-directional communication between muscle and connective tissue is critical for a correct assembly of the musculoskeletal system during development as well as to maintain its homeostasis in the adult.

  17. Non-myogenic Contribution to Muscle Development and Homeostasis: The Role of Connective Tissues

    PubMed Central

    Nassari, Sonya; Duprez, Delphine; Fournier-Thibault, Claire

    2017-01-01

    Skeletal muscles belong to the musculoskeletal system, which is composed of bone, tendon, ligament and irregular connective tissue, and closely associated with motor nerves and blood vessels. The intrinsic molecular signals regulating myogenesis have been extensively investigated. However, muscle development, homeostasis and regeneration require interactions with surrounding tissues and the cellular and molecular aspects of this dialogue have not been completely elucidated. During development and adult life, myogenic cells are closely associated with the different types of connective tissue. Connective tissues are defined as specialized (bone and cartilage), dense regular (tendon and ligament) and dense irregular connective tissue. The role of connective tissue in muscle morphogenesis has been investigated, thanks to the identification of transcription factors that characterize the different types of connective tissues. Here, we review the development of the various connective tissues in the context of the musculoskeletal system and highlight their important role in delivering information necessary for correct muscle morphogenesis, from the early step of myoblast differentiation to the late stage of muscle maturation. Interactions between muscle and connective tissue are also critical in the adult during muscle regeneration, as impairment of the regenerative potential after injury or in neuromuscular diseases results in the progressive replacement of the muscle mass by fibrotic tissue. We conclude that bi-directional communication between muscle and connective tissue is critical for a correct assembly of the musculoskeletal system during development as well as to maintain its homeostasis in the adult. PMID:28386539

  18. 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.

  19. Assessment of the 'no eosinophils' rule: are eosinophils truly absent in pityriasis lichenoides, connective tissue disease, and graft-vs.-host disease?

    PubMed

    Sharon, Victoria R; Konia, Thomas H; Barr, Keira L; Fung, Maxwell A

    2012-04-01

    Eosinophils are often present in the inflammatory infiltrate of an interface dermatitis, but the diagnostic specificity of eosinophils in interface dermatitis has not been formally evaluated. We retrospectively identified 97 examples of interface dermatitis with clinically confirmed diagnoses, including lupus erythematosus (LE), lichen planus, pityriasis lichenoides (PL), graft-vs.-host disease (GVHD), dermatomyositis (DM) and drug reaction. Diagnoses were clinically confirmed by at least two dermatologists. Slides were reviewed in a blinded fashion by at least two dermatopathologists. The average eosinophil count per 10 ×200 (×20 objective) fields was lowest for PL (0.2), DM (0.3), GVHD (0.4), and LE (0.5) [defined as Group 1] and was higher for lichen planus, drug reactions, erythema multiforme (major and minor) and viral exanthems [defined as Group 2]. Distinction between Group 1 and Group 2 was maximized using an eosinophil count cutoff of 1.1. In conclusion, eosinophils are usually rare to absent in PL, DM, most forms of LE and GVHD. While final interpretation requires a composite assessment of all features, our results suggest that the presence of even a single eosinophil within nine or ten ×20 fields argues against a diagnosis of PL, DM or LE. Copyright © 2012 John Wiley & Sons A/S.

  20. Identifying Differences in Risk Factors for Depression and Anxiety in Pediatric Chronic Disease: A Matched Cross-Sectional Study of Youth with Lupus/Mixed Connective Tissue Disease and Their Peers with Diabetes.

    PubMed

    Knight, Andrea; Weiss, Pamela; Morales, Knashawn; Gerdes, Marsha; Rearson, Melissa; Vickery, Michelle; Keren, Ron

    2015-12-01

    To investigate differences in risk factors for depression and anxiety, such as central nervous system involvement in systemic lupus erythematosus (SLE)/mixed connective tissue disease (MCTD), by comparing youth with SLE/MCTD to peers with type 1 diabetes mellitus (T1D). We conducted a cross-sectional study of 50 outpatient pairs, ages 8 years and above, matching subjects with SLE/MCTD and T1D by sex and age group. We screened for depression, suicidal ideation, and anxiety using the Patient Health Questionnaire-9 and the Screen for Childhood Anxiety Related Emotional Disorders, respectively. We collected parent-reported mental health treatment data. We compared prevalence and treatment rates between subjects with SLE/MCTD and T1D, and identified disease-specific risk factors using logistic regression. Depression symptoms were present in 23%, suicidal ideation in 15%, and anxiety in 27% of participants. Compared with subjects with T1D, subjects with SLE/MCTD had lower adjusted rates of depression and suicidal ideation, yet poorer rates of mental health treatment (24% vs 53%). Non-White race/ethnicity and longer disease duration were independent risk factors for depression and suicidal ideation. Depression was associated with poor disease control in both groups, and anxiety with insulin pump use in subjects with T1D. Depression and anxiety are high and undertreated in youth with SLE/MCTD and T1D. Focusing on risk factors such as race/ethnicity and disease duration may improve their mental health care. Further study of central nervous system and other disease-related factors may identify targets for intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure.

    PubMed

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

    2013-03-01

    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.

  2. [The survival and treatment of patients with systemic connective tissue diseases (research based on data from the II Internal Medicine Department of the Main Community Hospital in Stara Zagora for 1976-1986)].

    PubMed

    Mineva, S; Georgiev, N

    1988-01-01

    The experience of the district hospital in Stara Zagora in the treatment of patients with systemic connective tissue diseases for the period 1976-1986 is presented. The study includes 47 patients with systemic connective tissue diseases: 22 patients with systemic lupus erythematodes (19 alive, 3 deceased); 18 patients with systemic progressive sclerodermia (16 alive, 2 deceased); 5 patients with dermatomyositis (4 alive, I deceased); 2 patients with nodal polyarteriitis (I alive, I deceased). The characteristic of the course of the disease is discussed--acute, subacute and chronic. The treatment applied and the cause of death are analyzed. The mean duration of the disease from the first clinical signs for the alive and the deceased is as follows: systemic lupus erythematodes--13.7 years for the alive and 12.5 years for the deceased patients; systemic progressive sclerodermia--16.6 years for the alive and 3.0 years for the deceased patients; dermatomyositis--3.7 years for the alive, 1.5 years for the deceased patients; polyarteritis nodosa--5 years for the alive, 2 years for the deceased patients. The conclusion is reached that the contemporary treatment can lead to a remission even in severe cases and life-threatening forms of the disease.

  3. Connective tissue panniculitis: lupus panniculitis, dermatomyositis, morphea/scleroderma.

    PubMed

    Hansen, Christopher B; Callen, Jeffrey P

    2010-01-01

    Panniculitis is an uncommon cutaneous manifestation of connective tissue diseases. Our discussion will include panniculitis occurring in the setting of lupus erythematosus, dermatomyositis, and scleroderma/morphea. These subtypes of panniculitis are unified by an active inflammatory stage of the disease that can progress to develop scarring, atrophy, and calcifications. Treatment is most effective if initiated during the active phase of the disease and often requires systemic therapy because of the location of the inflammation. Antimalarials are the initial treatment of choice for most cases of lupus erythematosus panniculitis, whereas corticosteroids in combination with other steroid-sparing immunosuppressive agents are the first-line treatment for panniculitis in patients with dermatomyositis. The appropriate treatment for panniculitis in the setting of morphea/scleroderma varies based on clinical severity.

  4. Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties

    PubMed Central

    Carroll, Chad C.

    2015-01-01

    Exercising individuals commonly consume analgesics but these medications alter tendon and skeletal muscle connective tissue properties, possibly limiting a person from realizing the full benefits of exercise training. I detail the novel hypothesis that analgesic medications alter connective tissue structure and mechanical properties by modifying fibroblast production of growth factors and matrix enzymes, which are responsible for extracellular matrix remodeling. PMID:26509485

  5. Analgesic Drugs Alter Connective Tissue Remodeling and Mechanical Properties.

    PubMed

    Carroll, Chad C

    2016-01-01

    Exercising individuals commonly consume analgesics, but these medications alter tendon and skeletal muscle connective tissue properties, possibly limiting a person from realizing the full benefits of exercise training. I detail the novel hypothesis that analgesic medications alter connective tissue structure and mechanical properties by modifying fibroblast production of growth factors and matrix enzymes, which are responsible for extracellular matrix remodeling.

  6. Pectus excavatum and heritable disorders of the connective tissue.

    PubMed

    Tocchioni, Francesca; Ghionzoli, Marco; Messineo, Antonio; Romagnoli, Paolo

    2013-09-24

    Pectus excavatum, the most frequent congenital chest wall deformity, may be rarely observed as a sole deformity or as a sign of an underlying connective tissue disorder. To date, only few studies have described correlations between this deformity and heritable connective tissue disorders such as Marfan, Ehlers-Danlos, Poland, MASS (Mitral valve prolapse, not progressive Aortic enlargement, Skeletal and Skin alterations) phenotype among others. When concurring with connective tissue disorder, cardiopulmonary and vascular involvement may be associated to the thoracic defect. Ruling out the concomitance of pectus excavatum and connective tissue disorders, therefore, may have a direct implication both on surgical outcome and long term prognosis. In this review we focused on biological bases of connective tissue disorders which may be relevant to the pathogenesis of pectus excavatum, portraying surgical and clinical implication of their concurrence.

  7. Pectus Excavatum and Heritable Disorders of the Connective Tissue

    PubMed Central

    Tocchioni, Francesca; Ghionzoli, Marco; Messineo, Antonio; Romagnoli, Paolo

    2013-01-01

    Pectus excavatum, the most frequent congenital chest wall deformity, may be rarely observed as a sole deformity or as a sign of an underlying connective tissue disorder. To date, only few studies have described correlations between this deformity and heritable connective tissue disorders such as Marfan, Ehlers-Danlos, Poland, MASS (Mitral valve prolapse, not progressive Aortic enlargement, Skeletal and Skin alterations) phenotype among others. When concurring with connective tissue disorder, cardiopulmonary and vascular involvement may be associated to the thoracic defect. Ruling out the concomitance of pectus excavatum and connective tissue disorders, therefore, may have a direct implication both on surgical outcome and long term prognosis. In this review we focused on biological bases of connective tissue disorders which may be relevant to the pathogenesis of pectus excavatum, portraying surgical and clinical implication of their concurrence. PMID:24198927

  8. Electrospun nanofibrous scaffolds for engineering soft connective tissues.

    PubMed

    James, Roshan; Toti, Udaya S; Laurencin, Cato T; Kumbar, Sangamesh G

    2011-01-01

    Tissue-engineered medical implants, such as polymeric nanofiber scaffolds, are potential alternatives to autografts and allografts, which are short in supply and carry risks of disease transmission. These scaffolds have been used to engineer various soft connective tissues such as skin, ligament, muscle, and tendon, as well as vascular and neural tissue. Bioactive versions of these materials have been produced by encapsulating molecules such as drugs and growth factors during fabrication. The fibers comprising these scaffolds can be designed to match the structure of the native extracellular matrix (ECM) closely by mimicking the dimensions of the collagen fiber bundles evident in soft connective tissues. These nanostructured implants show improved biological performance over the bulk materials in aspects of cellular infiltration and in vivo integration, and the topography of such scaffolds has been shown to dictate cellular attachment, migration, proliferation, and differentiation, which are critical steps in engineering complex functional tissues and crucial to improved biocompatibility and functional performance. Nanofiber matrices can be fabricated using a variety of techniques, including drawing, molecular self-assembly, freeze-drying, phase separation, and electrospinning. Among these processes, electrospinning has emerged as a simple, elegant, scalable, continuous, and reproducible technique to produce polymeric nanofiber matrices from solutions and their melts. We have shown the ability of this technique to be used to fabricate matrices composed of fibers from a few hundred nanometers to several microns in diameter by simply altering the polymer solution concentration. This chapter will discuss the use of the electrospinning technique in the fabrication of ECM-mimicking scaffolds. Furthermore, selected scaffolds will be seeded with primary adipose-derived stromal cells, imaged using scanning electron microscopy and confocal microscopy, and evaluated in terms

  9. 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

  10. 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

  11. Unique Gene Expression and MR T2 Relaxometry Patterns Define Chronic Murine Dextran Sodium Sulphate Colitis as a Model for Connective Tissue Changes in Human Crohn’s Disease

    PubMed Central

    Breynaert, Christine; Dresselaers, Tom; Perrier, Clémentine; Arijs, Ingrid; Cremer, Jonathan; Van Lommel, Leentje; Van Steen, Kristel; Ferrante, Marc; Schuit, Frans; Vermeire, Séverine; Rutgeerts, Paul; Himmelreich, Uwe; Ceuppens, Jan L.; Geboes, Karel; Van Assche, Gert

    2013-01-01

    Introduction Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. Materials and Methods C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. Results Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn’s colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. Conclusions Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn’s disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis

  12. 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

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

    PubMed Central

    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

    2014-01-01

    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

  14. Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes.

    PubMed

    Recchia, Anna Grazia; Filice, Elisabetta; Pellegrino, Daniela; Dobrina, Aldo; Cerra, Maria Carmela; Maggiolini, Marcello

    2009-03-01

    Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction, and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis, osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.

  15. 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.

  16. 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.

  17. Micromechanical modeling of rate-dependent behavior of Connective tissues.

    PubMed

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

    2017-03-07

    In this paper, a constitutive and micromechanical model for prediction of rate-dependent behavior of connective tissues (CTs) is presented. Connective tissues are considered as nonlinear viscoelastic material. The rate-dependent behavior of CTs is incorporated into model using the well-known quasi-linear viscoelasticity (QLV) theory. A planar wavy representative volume element (RVE) is considered based on the tissue microstructure histological evidences. The presented model parameters are identified based on the available experiments in the literature. The presented constitutive model introduced to ABAQUS by means of UMAT subroutine. Results show that, monotonic uniaxial test predictions of the presented model at different strain rates for rat tail tendon (RTT) and human patellar tendon (HPT) are in good agreement with experimental data. Results of incremental stress-relaxation test are also presented to investigate both instantaneous and viscoelastic behavior of connective tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. CONNECTIVE TISSUE SYNTHESIS BY SCLERODERMA SKIN FIBROBLASTS IN CELL CULTURE

    PubMed Central

    Leroy, E. Carwile

    1972-01-01

    Skin fibroblasts from subjects with scleroderma and control subjects were grown in tissue culture to compare the characteristics of connective tissue metabolism. A striking increase in soluble collagen (media hydroxyproline) was observed in eight of nine scleroderma cultures when they were compared with identically handled control cultures matched for the age and sex of the donor and the anatomic site of the donor skin. Glycoprotein content as estimated by hexosamine and sialic acid was also significantly increased in the scleroderma cultures. Estimations of protein-polysaccharide content by uronic acid determinations were low in all cultures and not significantly increased in scleroderma cultures. This report demonstrates the feasibility of using fibroblast cell cultures to study chronic rheumatic and connective tissue disorders. The initial results suggest a net increase in collagen and glycoprotein synthesis in scleroderma fibroblast cultures. The implications of an abnormality of connective tissue metabolism by skin fibroblasts propagated in vitro in the acquired disorder scleroderma are discussed. PMID:4260235

  19. Joint hypermobility and skin elasticity: the hereditary disorders of connective tissue.

    PubMed

    Hakim, Alan J; Sahota, Anshoo

    2006-01-01

    The hereditary disorders of connective tissues (HDCTs) encompass a spectrum of conditions linked pathophysiologically by abnormalities of collagen, fibrillin, and matrix proteins. The clinical picture ranges from morbidity because of musculoskeletal, skin, ocular and visceral pathologies to mortality from acute vascular collapse. For many of the conditions, there is a considerable overlap in clinical features, although severity varies; appreciating the subtle differences in presentation is vital to the clinician in determining the diagnosis. Though conditions associated with severe vascular pathology are rare, other hereditary disorders of connective tissues such as the joint hypermobility syndrome and Stickler's disease are common and probably underrecognized. Abnormal skin elasticity and scaring, joint hypermobility, and chronic arthralgia are important clues that should trigger the clinician to search for underlying hereditary disorders of connective tissues. In this article, we discuss the spectrum of clinical findings, management, and genetic screening of the more common hereditary disorders of connective tissues, highlighting their diagnostic criteria and their differences.

  20. Invited review: mesenchymal progenitor cells in intramuscular connective tissue development.

    PubMed

    Miao, Z G; Zhang, L P; Fu, X; Yang, Q Y; Zhu, M J; Dodson, M V; Du, M

    2016-01-01

    The abundance and cross-linking of intramuscular connective tissue contributes to the background toughness of meat, and is thus undesirable. Connective tissue is mainly synthesized by intramuscular fibroblasts. Myocytes, adipocytes and fibroblasts are derived from a common pool of progenitor cells during the early embryonic development. It appears that multipotent mesenchymal stem cells first diverge into either myogenic or non-myogenic lineages; non-myogenic mesenchymal progenitors then develop into the stromal-vascular fraction of skeletal muscle wherein adipocytes, fibroblasts and derived mesenchymal progenitors reside. Because non-myogenic mesenchymal progenitors mainly undergo adipogenic or fibrogenic differentiation during muscle development, strengthening progenitor proliferation enhances the potential for both intramuscular adipogenesis and fibrogenesis, leading to the elevation of both marbling and connective tissue content in the resulting meat product. Furthermore, given the bipotent developmental potential of progenitor cells, enhancing their conversion to adipogenesis reduces fibrogenesis, which likely results in the overall improvement of marbling (more intramuscular adipocytes) and tenderness (less connective tissue) of meat. Fibrogenesis is mainly regulated by the transforming growth factor (TGF) β signaling pathway and its regulatory cascade. In addition, extracellular matrix, a part of the intramuscular connective tissue, provides a niche environment for regulating myogenic differentiation of satellite cells and muscle growth. Despite rapid progress, many questions remain in the role of extracellular matrix on muscle development, and factors determining the early differentiation of myogenic, adipogenic and fibrogenic cells, which warrant further studies.

  1. Scleroderma pattern of nailfold capillary changes as predictive value for the development of a connective tissue disease: a follow-up study of 3,029 patients with primary Raynaud's phenomenon.

    PubMed

    Pavlov-Dolijanovic, Slavica; Damjanov, Nemanja S; Stojanovic, Roksanda M; Vujasinovic Stupar, Nada Z; Stanisavljevic, Dejana M

    2012-10-01

    To assess the prognostic value of scleroderma pattern of nailfold capillary changes for the development of connective tissue diseases (CTD) in subjects with primary Raynaud's phenomenon (RP). The study included 3,029 consecutive patients with primary RP who had been followed at 6-month intervals during the mean of 4.8 years. The pathological features of nailfold capillaroscopy were recorded in all patients who had neither clinical nor serological signs of a CTD. In patients who developed CTD, capillary changes obtained 6 months prior to diagnosis were analyzed. A possible relationship between capillary changes and the presence of associated CTD was assessed. At the end of follow-up, 1,660 (54,8%) patients have still the primary RP, 246 (8,1%) had suspected secondary RP, and 1,123 (37,1%) patients developed CTD (363 undifferentiated CTD, 263 systemic sclerosis, 143 systemic lupus erythematosus, 106 rheumatoid arthritis, 102 Sjögren's syndrome, 61 overlap syndrome, 30 vasculitides, 24 mixed CTD, 19 polymyositis, 7 dermatomyositis, and 5 primary antiphospholipid syndrome). Scleroderma pattern were significantly associated with the development of systemic sclerosis [P = .00001, sensitivity 94%, specificity 92%, positive predictive value 52%, negative predictive value 99%, and odds ratio 163 (95% CI, 97,9-271,5)], as well as dermatomyositis (P = .0004), overlap syndrome with signs of systemic sclerosis (P = .0001), and mixed connective tissue disease (P = .007). Capillary microscopy is effective method for differentiation between primary and secondary RP and useful tool for the prediction of scleroderma spectrum disorders in RP patients.

  2. 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

  3. [50 years of connective tissue research: from the French Connective Tissue Club to the French Society of Extracellular Matrix Biology].

    PubMed

    Maquart, François-Xavier; Borel, Jacques-Paul

    2012-01-01

    The history of connective tissue research began in the late 18th century. However, it is only 50 years later that the concept of connective tissue was shaped. It took another fifty years before biochemical knowledge of extracellular matrix macromolecules began to emerge in the first half of the 20th century. In 1962, thanks to Ladislas and Barbara Robert, back from the US, the first society called "French Connective Tissue Club" was created in Paris. The first board was constituted of Albert Delaunay, Suzanne Bazin and Ladislas Robert. Very quickly, under the influence of these pioneers, national and international meetings were organized and, in 1967, a "Federation of the European Connective Tissue Clubs" was created at the initiative of Ladislas Robert (Paris) and John Scott (Manchester). It spread rapidly to the major European nations. In 1982 the transformation of "Clubs" in "Societies" occurred, a name more in line with the requirements of the time. In 2008, the "French Connective Tissue Society" became the "French Society of Extracellular Matrix Biology" ("Société Française de Biologie de la Matrice Extracellulaire", SFBMEc), to better highlight the importance of the extracellular matrix in the biology of living organisms. The SFBMEc's mission today is to promote and develop scientific exchanges between academic, industrial, and hospital laboratories involved in research on the extracellular matrix. SFBMEc organizes or subsidizes scientific meetings and awards scholarships to Ph.D. students or post-docs to participate in international conferences. It includes 200 to 250 members from different disciplines, developing strong interactions between scientists, clinicians and pathologists. It is present all around the French territory in many research laboratories. During these last 50 years, the extraordinary advances made possible by the development of new investigation techniques, in particular molecular biology, cell and tissue imaging, molecular modeling

  4. [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. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  5. Animals, disease, and man: making connections.

    PubMed

    Hardy, Anne

    2003-01-01

    The intricate causal relationships between disease in man and disease in animals first began to be elucidated in the mid-19th century. Although the connections between animal and human disease are now generally understood, individuals as well as societies remain slow to act on this knowledge. This paper examines the gradual recognition of these disease connections and explores the parallel theme of man's reluctance to appreciate the implications of these connections. It identifies factors that have inhibited the realization of the links between disease in man and animals, and discusses several milestones in the scientific elucidation of these links. Beginning with emerging concerns over the relationship between bovine and human tuberculosis in the 1860s, it follows the discovery of insect vectors, animal reservoirs, and the links between animals, influenza, and man. Despite warnings of the potential significance for human disease of patterns of changes in the relationship with animals and the natural world, scientists have continued to treat human and animal health as largely independent disciplines, while historians too have neglected this important aspect of human disease.

  6. Sustained deep-tissue pain alters functional brain connectivity.

    PubMed

    Kim, Jieun; Loggia, Marco L; Edwards, Robert R; Wasan, Ajay D; Gollub, Randy L; Napadow, Vitaly

    2013-08-01

    Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, frontoparietal control, and default mode networks: SMN, SLN, DAN, FCN, and DMN) was evaluated with functional-connectivity magnetic resonance imaging, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable, with no significant changes of subjects' pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula, and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to interindividual differences in pain sensitivity.

  7. Sustained deep-tissue pain alters functional brain connectivity

    PubMed Central

    Kim, Jieun; Loggia, Marco L.; Edwards, Robert; Wasan, Ajay D.; Gollub, Randy L.; Napadow, Vitaly

    2013-01-01

    Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically-relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, fronto-parietal control and default mode networks; SMN, SLN, DAN, FCN and DMN) was evaluated with functional-connectivity MRI, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable with no significant changes of subjects’ pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala, was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to inter-individual differences in pain sensitivity. PMID:23718988

  8. 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

  9. PDGFRα plays a crucial role in connective tissue remodeling.

    PubMed

    Horikawa, Shinjiro; Ishii, Yoko; Hamashima, Takeru; Yamamoto, Seiji; Mori, Hisashi; Fujimori, Toshihiko; Shen, Jie; Inoue, Ran; Nishizono, Hirofumi; Itoh, Hiroshi; Majima, Masataka; Abraham, David; Miyawaki, Toshio; Sasahara, Masakiyo

    2015-12-07

    Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

  10. [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.

  11. Mueller matrix approach for probing multifractality in the underlying anisotropic connective tissue

    NASA Astrophysics Data System (ADS)

    Das, Nandan Kumar; Dey, Rajib; Ghosh, Nirmalya

    2016-09-01

    Spatial variation of refractive index (RI) in connective tissues exhibits multifractality, which encodes useful morphological and ultrastructural information about the disease. We present a spectral Mueller matrix (MM)-based approach in combination with multifractal detrended fluctuation analysis (MFDFA) to exclusively pick out the signature of the underlying connective tissue multifractality through the superficial epithelium layer. The method is based on inverse analysis on selected spectral scattering MM elements encoding the birefringence information on the anisotropic connective tissue. The light scattering spectra corresponding to the birefringence carrying MM elements are then subjected to the Born approximation-based Fourier domain preprocessing to extract ultrastructural RI fluctuations of anisotropic tissue. The extracted RI fluctuations are subsequently analyzed via MFDFA to yield the multifractal tissue parameters. The approach was experimentally validated on a simple tissue model comprising of TiO2 as scatterers of the superficial isotropic layer and rat tail collagen as an underlying anisotropic layer. Finally, the method enabled probing of precancer-related subtle alterations in underlying connective tissue ultrastructural multifractality from intact tissues.

  12. 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.

  13. 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.

  14. Cysteine-rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy.

    PubMed

    Yan, Lulu; Chaqour, Brahim

    2013-12-01

    The vasculature forms a highly branched network investing every organ of vertebrate organisms. The retinal circulation, in particular, is supported by a central retinal artery branching into superficial arteries, which dive into the retina to form a dense network of capillaries in the deeper retinal layers. The function of the retina is highly dependent on the integrity and proper functioning of its vascular network and numerous ocular diseases including diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity are caused by vascular abnormalities culminating in total and sometimes irreversible loss of vision. CCN1 and CCN2 are inducible extracellular matrix (ECM) proteins which play a major role in normal and aberrant formation of blood vessels as their expression is associated with developmental and pathological angiogenesis. Both CCN1 and CCN2 achieve disparate cell-type and context-dependent activities through modulation of the angiogenic and synthetic phenotype of vascular and mesenchymal cells respectively. At the molecular level, CCN1 and CCN2 may control capillary growth and vascular cell differentiation by altering the composition or function of the constitutive ECM proteins, potentiating or interfering with the activity of various ligands and/or their receptors, physically interfering with the ECM-cell surface interconnections, and/or reprogramming gene expression driving cells toward new phenotypes. As such, these proteins emerged as important prognostic markers and potential therapeutic targets in neovascular and fibrovascular diseases of the eye. The purpose of this review is to highlight our current knowledge and understanding of the most recent data linking CCN1 and CCN2 signaling to ocular neovascularization bolstering the potential value of targeting these proteins in a therapeutic context.

  15. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting.

    PubMed Central

    Kallenberg, C G; Wouda, A A; Hoet, M H; van Venrooij, W J

    1988-01-01

    Eighty five patients referred because of Raynaud's phenomenon (RP) were followed up for six years. Every two years they were screened for signs and symptoms of connective tissue disease (CTD) according to a protocol, and serum was stored. Initially, 30 patients had primary RP, 16 had one symptom of CTD ('possible CTD'), 18 had two or more symptoms ('probable CTD'), and 21 had definite CTD (14 of whom had scleroderma). Most of the symptoms were related to scleroderma. There was an insidious progression to scleroderma or CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, telangiectasia): 11 of 46 patients with primary RP or possible CTD developed probable scleroderma (two or more symptoms but not fulfilling all criteria), and seven of 13 patients with probable scleroderma developed definite scleroderma or CRST. The presence of distinct antinuclear antibodies (ANAs) as detected by immunoblotting in patients with primary RP and possible CTD at the start of the study was associated with the evolution of symptoms of CTD (chi 2 = 5.7, p less than 0.01). In patients initially with primary RP or possible CTD the antibody specificities of ANAs as determined by immunoblotting had prognostic value for the development of certain disease entities: anticentromere (CR-19) for CRST (sensitivity 60%, specificity 98%) and antitopoisomerase I (Scl-70 or Scl-86) for scleroderma or probable scleroderma (sensitivity 38%, specificity 100%). PMID:3261966

  16. EQ-5D studies in musculoskeletal and connective tissue diseases in eight Central and Eastern European countries: a systematic literature review and meta-analysis.

    PubMed

    Zrubka, Zsombor; Rencz, Fanni; Závada, Jakub; Golicki, Dominik; Rupel, Valentina Prevolnik; Simon, Judit; Brodszky, Valentin; Baji, Petra; Petrova, Guenka; Rotar, Alexandru; Gulácsi, László; Péntek, Márta

    2017-08-28

    EQ-5D is becoming the preferred instrument to measure health-state utilities involved in health technology assessment. The objective of this study is to assess the state of EQ-5D research in musculoskeletal disorders in 8 Central and Eastern European countries and to provide a meta-analysis of EQ-5D index scores. Original research articles published in any language between Jan 2000 and Sept 2016 were included, if they reported any EQ-5D outcome from at least two musculoskeletal patients from Austria, Bulgaria, the Czech Republic, Hungary, Poland, Romania, Slovakia, or Slovenia. Risk of bias was assessed with the Cochrane Collaboration's tool. Twenty-nine articles (5992 patients) were included on rheumatoid arthritis (n = 7), osteoporosis (n = 5), chronic pain (n = 5), osteoarthritis (n = 4), ankylosing spondylitis (n = 2), psoriatic arthritis (n = 2), total hip replacement (n = 2), and scleroderma (n = 2). Low back pain was under-represented, while studies in neck pain, systemic lupus erythematosus, gout, and childhood disorders were lacking. EQ-5D index scores were reported in 24 studies, while the version of the instrument and the value-set was not specified in 41% and 46% of the articles, respectively. Meta-analysis was performed on 24 disease states involving 6876 observation points. Intervention effect was reported in 22 subgroups, out of which risk of bias was low in 41%. This review provides recommendations to improve reporting standards of EQ-5D results and highlights potential areas for future research. Coordinated research in conditions with greatest public health impact as well as a development of a regional value-set could provide locally relevant health-state utilities that are transferable among countries within the region.

  17. Bioactive glass and connective tissue graft used to treat intrabony periodontal defects.

    PubMed

    Deliberador, Tatiana Miranda; Trotta, Daniel Rizzo; Klug, Luis Gustavo; Zielak, Joao Cesar; Giovanini, Allan Fernando

    2013-07-01

    Different techniques and materials can be used to treat intrabony periodontal defects caused by periodontal diseases. This case report presents an intrabony periodontal defect with bioactive glass and connective tissue graft used as a barrier. Probing depth and clinical attachment gain were reduced at 6 and 12 months post-treatment.

  18. 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.

  19. Role of PTPα in the destruction of periodontal connective tissues.

    PubMed

    Rajshankar, Dhaarmini; Sima, Corneliu; Wang, Qin; Goldberg, Stephanie R; Kazembe, Mwayi; Wang, Yongqiang; Glogauer, Michael; Downey, Gregory P; McCulloch, Christopher A

    2013-01-01

    IL-1β contributes to connective tissue destruction in part by up-regulating stromelysin-1 (MMP-3), which in fibroblasts is a focal adhesion-dependent process. Protein tyrosine phosphatase-α (PTPα) is enriched in and regulates the formation of focal adhesions, but the role of PTPα in connective tissue destruction is not defined. We first examined destruction of periodontal connective tissues in adult PTPα(+/+) and PTPα(-/-) mice subjected to ligature-induced periodontitis, which increases the levels of multiple cytokines, including IL-1β. Three weeks after ligation, maxillae were processed for morphometry, micro-computed tomography and histomorphometry. Compared with unligated controls, there was ∼1.5-3 times greater bone loss as well as 3-fold reduction of the thickness of the gingival lamina propria and 20-fold reduction of the amount of collagen fibers in WT than PTPα(-/-) mice. Immunohistochemical staining of periodontal tissue showed elevated expression of MMP-3 at ligated sites. Second, to examine mechanisms by which PTPα may regulate matrix degradation, human MMP arrays were used to screen conditioned media from human gingival fibroblasts treated with vehicle, IL-1β or TNFα. Although MMP-3 was upregulated by both cytokines, only IL-1β stimulated ERK activation in human gingival fibroblasts plated on fibronectin. TIRF microscopy and immunoblotting analyses of cells depleted of PTPα activity with the use of various mutated constructs or with siRNA or PTPα(KO) and matched wild type fibroblasts were plated on fibronectin to enable focal adhesion formation and stimulated with IL-1β. These data showed that the catalytic and adaptor functions of PTPα were required for IL-1β-induced focal adhesion formation, ERK activation and MMP-3 release. We conclude that inflammation-induced connective tissue degradation involving fibroblasts requires functionally active PTPα and in part is mediated by IL-1β signaling through focal adhesions.

  20. 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.

  1. Radiotherapy of spontaneous fibrous connective-tissue sarcomas in animals.

    PubMed

    Hilmas, D E; Gillette, E L

    1976-02-01

    The clinical records and follow-up data obtained over 13 years on the results of radiotherapy of spontaneous fibrous connective-tissue sarcomas in dogs, cats, and horses were reviewed. The results obtained from the treatment of fibrosarcomas and sarcoids of horses indicated that radiation administered with 60Co is important in the medical and surgical management of these tumors. Fibrous connective-tissue sarcomas in horses were radioresponsive. When radiotherapy was applied postoperatively, the probability of a 2-year cure approached 50% for all prescribed radiation doses of less than 2,000 to greater than 4,000 rads. If radiation doses of 4,500-6,000 rads were used, a 2-year cure rate may approach or exceed 60%.

  2. Anisotropic tissue motion induced by acupuncture needling along intermuscular connective tissue planes.

    PubMed

    Fox, James R; Gray, Weili; Koptiuch, Cathryn; Badger, Gary J; Langevin, Helene M

    2014-04-01

    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. 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. 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. The anisotropic tissue motion observed in this study may influence the spatial distribution of local connective tissue cellular responses following acupuncture needle manipulation.

  3. Uniphasic Blanching of the Fingers, Abnormal Capillaroscopy in Nonsymptomatic Digits, and Autoantibodies: Expanding Options to Increase the Level of Suspicion of Connective Tissue Diseases beyond the Classification of Raynaud's Phenomenon

    PubMed Central

    Gualtierotti, Roberta; Orenti, Annalisa; Schioppo, Tommaso; Marfia, Giovanni; Campanella, Rolando; Mastaglio, Claudio; Meroni, Pier Luigi; Boracchi, Patrizia

    2015-01-01

    In patients with Raynaud's phenomenon (RP), the role of medical history, capillaroscopy, and autoantibodies in order to provide an early diagnosis of connective tissue disease (CTD) were examined. 115 consecutive adults with uni-, bi-, or triphasic colour changes of the fingers were studied. RP was bilateral in 92.7% of patients. The middle finger was significantly more affected. A lack of association between fingers affected by RP and fingers with capillary abnormalities was observed OR = 0.75 (0.34–1.66). RP with the cyanotic phase had a higher risk at capillaroscopy to have hemorrhages OR = 4.46 (1.50–13.30) and giant capillaries OR = 24.85 (1.48–417.44). The thumb and triphasic involvement have an OR of 1.477 and 1.845, respectively. RP secondary to systemic sclerosis (SSc) had greater value of VAS pain (p = 0.011). The presence of anti-centromere antibodies was significantly associated with a higher risk of SSc (p < 0.001). 44.3% of subjects had uniphasic blanching of the fingers, and among these, 27% was diagnosed as having an overt or suspected CTD. Markers of a potential development of CTDs include severe RP symptoms, positive autoantibodies, and capillary abnormalities. These data support the proposal to not discharge patients with uniphasic blanching of the fingers to avoid missing the opportunity of an early diagnosis. PMID:26075287

  4. Clinical association of mixed connective tissue disease and granulomatosis with polyangiitis: a case report and systematic screening of anti-U1RNP and anti-PR3 auto-antibody double positivity in ten European hospitals.

    PubMed

    Tubery, Amandine; Fortenfant, Françoise; Combe, Bernard; Abreu, Isabelle; Bossuyt, Xavier; Chretien, Pascale; Desplat-Jégo, Sophie; Fabien, Nicole; Hue, Sophie; Johanet, Catherine; Lakomy, Daniela; Vincent, Thierry; Daïen, Claire I

    2016-12-01

    We report here the case of a 50-years-old man treated for mixed connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein (U1RNP) antibodies who secondarily developed a granulomatosis with polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of the association between anti-U1RNP and anti-PR3-ANCA antibodies by a systematic retrospective study in ten European hospitals. Overall, out of 11,921 samples analyzed for both auto-antibodies, 18 cases of anti-U1RNP and anti-PR3-ANCA double positivity were found and only one patient presented with both MCTD and GPA symptoms. Our retrospective analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double positivity is infrequent and very rarely associated with both MTCD and GPA. Our observation describes for the first time the coexistence of MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP and ANCA antibodies was rarely reported in the literature. Eleven cases of MCTD and ANCA vasculitis have been reported to date, with only two cases with anti-PR3-ANCA association, and only one vasculitis. The seven other cases reported in the literature presented with an association of MCTD and microscopic polyangiitis which appears to be a more frequent presentation than MTCD associated with GPA.

  5. ARTIFICIAL ACTIVATION OF THE GROWTH IN VITRO OF CONNECTIVE TISSUE

    PubMed Central

    Carrel, Alexis

    1913-01-01

    The experiments have shown that extracts of tissues and tissue juices, under certain conditions, accelerate the growth in intro of the connective tissue from about three to forty times. This activating power was found in many tissues. It was much more marked, however, with the extracts of embryos, of adult spleen, and of the Rous sarcoma. The power diminished directly with the dilution of the extracts, and appeared not to apply to the tissues of a heterologous animal. The power was reduced when heated at 56° C., and removed when heated at 70° C. It was diminished markedly by filtration through a Berkefield filter and was completely suppressed by filtration through a Chamberland filter. Possibly the finding of the activating power of tissue extracts will have no immediate practical application. Nevertheless, it may be indirectly useful by leading to the discovery of some of the factors determining the growth of tissues and of the unknown laws of cell dynamics, and may ultimately throw light on the mechanism of the cicatrization of wounds. PMID:19867620

  6. FOXO1 expression in keratinocytes promotes connective tissue healing

    PubMed Central

    Zhang, Chenying; Lim, Jason; Liu, Jian; Ponugoti, Bhaskar; Alsadun, Sarah; Tian, Chen; Vafa, Rameen; Graves, Dana T.

    2017-01-01

    Wound healing is complex and highly orchestrated. It is well appreciated that leukocytes, particularly macrophages, are essential for inducing the formation of new connective tissue, which requires the generation of signals that stimulate mesenchymal stem cells (MSC), myofibroblasts and fibroblasts. A key role for keratinocytes in this complex process has yet to be established. To this end, we investigated possible involvement of keratinocytes in connective tissue healing. By lineage-specific deletion of the forkhead box-O 1 (FOXO1) transcription factor, we demonstrate for the first time that keratinocytes regulate proliferation of fibroblasts and MSCs, formation of myofibroblasts and production of collagen matrix in wound healing. This stimulation is mediated by a FOXO1 induced TGFβ1/CTGF axis. The results provide direct evidence that epithelial cells play a key role in stimulating connective tissue healing through a FOXO1-dependent mechanism. Thus, FOXO1 and keratinocytes may be an important therapeutic target where healing is deficient or compromised by a fibrotic outcome. PMID:28220813

  7. Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling.

    PubMed Central

    Ashworth, J L; Murphy, G; Rock, M J; Sherratt, M J; Shapiro, S D; Shuttleworth, C A; Kielty, C M

    1999-01-01

    Fibrillin is the principal structural component of the 10-12 nm diameter elastic microfibrils of the extracellular matrix. We have previously shown that both fibrillin molecules and assembled microfibrils are susceptible to degradation by serine proteases. In this study, we have investigated the potential catabolic effects of six matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-12, MMP-13 and MMP-14) on fibrillin molecules and on intact fibrillin-rich microfibrils isolated from ciliary zonules. Using newly synthesized recombinant fibrillin molecules, major cleavage sites within fibrillin-1 were identified. In particular, the six different MMPs generated a major degradation product of approximately 45 kDa from the N-terminal region of the molecule, whereas treatment of truncated, unprocessed and furin-processed C-termini also generated large degradation products. Introduction of a single ectopia lentis-causing amino acid substitution (E2447K; one-letter symbols for amino acids) in a calcium-binding epidermal growth factor-like domain, predicted to disrupt calcium binding, markedly altered the pattern of C-terminal fibrillin-1 degradation. However, the fragmentation pattern of a mutant fibrillin-1 with a comparable E-->K substitution in an upstream calcium-binding epidermal growth factor-like domain was indistinguishable from wild-type molecules. Ultrastructural examination highlighted that fibrillin-rich microfibrils isolated from ciliary zonules were grossly disrupted by MMPs. This is the first demonstration that fibrillin molecules and fibrillin-rich microfibrils are degraded by MMPs and that certain amino acid substitutions change the fragmentation patterns. These studies have important implications for physiological and pathological fibrillin catabolism and for loss of connective tissue elasticity in ageing and disease. PMID:10229672

  8. Spontaneous coronary artery dissection and its association with heritable connective tissue disorders.

    PubMed

    Henkin, Stanislav; Negrotto, Sara M; Tweet, Marysia S; Kirmani, Salman; Deyle, David R; Gulati, Rajiv; Olson, Timothy M; Hayes, Sharonne N

    2016-06-01

    Spontaneous coronary artery dissection (SCAD) is an under-recognised but important cause of myocardial infarction and sudden cardiac death. We sought to determine the role of medical and molecular genetic screening for connective tissue disorders in patients with SCAD. We performed a single-centre retrospective descriptive analysis of patients with spontaneous coronary artery disease who had undergone medical genetics evaluation 1984-2014 (n=116). The presence or absence of traits suggestive of heritable connective tissue disease was extracted. Genetic testing for connective tissue disorders and/or aortopathies, if performed, is also reported. Of the 116 patients (mean age 44.2 years, 94.8% women and 41.4% with non-coronary fibromuscular dysplasia (FMD)), 59 patients underwent genetic testing, of whom 3 (5.1%) received a diagnosis of connective tissue disorder: a 50-year-old man with Marfan syndrome; a 43-year-old woman with vascular Ehlers-Danlos syndrome and FMD; and a 45-year-old woman with vascular Ehlers-Danlos syndrome. An additional 12 patients (20.3%) had variants of unknown significance, none of which was thought to be a definite disease-causing mutation based on in silico analyses. Only a minority of patients with SCAD who undergo genetic evaluation have a likely pathogenic mutation identified on gene panel testing. Even fewer exhibit clinical features of connective tissue disorder. These findings underscore the need for further studies to elucidate the molecular mechanisms of SCAD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. Cell-cell connection to cardiac disease.

    PubMed

    Sheikh, Farah; Ross, Robert S; Chen, Ju

    2009-08-01

    Intercalated disks (ICDs) are highly organized cell-cell adhesion structures, which connect cardiomyocytes to one another. They are composed of three major complexes: desmosomes, fascia adherens, and gap junctions. Desmosomes and fascia adherens junction are necessary for mechanically coupling and reinforcing cardiomyocytes, whereas gap junctions are essential for rapid electrical transmission between cells. Because human genetics and mouse models have revealed that mutations and/or deficiencies in various ICD components can lead to cardiomyopathies and arrhythmias, considerable attention has focused on the biologic function of the ICD. This review will discuss recent scientific developments related to the ICD and focus on its role in regulating cardiac muscle structure, signaling, and disease.

  10. The connective tissue phenotype of glaucomatous cupping in the monkey eye - Clinical and research implications.

    PubMed

    Yang, Hongli; Reynaud, Juan; Lockwood, Howard; Williams, Galen; Hardin, Christy; Reyes, Luke; Stowell, Cheri; Gardiner, Stuart K; Burgoyne, Claude F

    2017-03-12

    In a series of previous publications we have proposed a framework for conceptualizing the optic nerve head (ONH) as a biomechanical structure. That framework proposes important roles for intraocular pressure (IOP), IOP-related stress and strain, cerebrospinal fluid pressure (CSFp), systemic and ocular determinants of blood flow, inflammation, auto-immunity, genetics, and other non-IOP related risk factors in the physiology of ONH aging and the pathophysiology of glaucomatous damage to the ONH. The present report summarizes 20 years of technique development and study results pertinent to the characterization of ONH connective tissue deformation and remodeling in the unilateral monkey experimental glaucoma (EG) model. In it we propose that the defining pathophysiology of a glaucomatous optic neuropathy involves deformation, remodeling, and mechanical failure of the ONH connective tissues. We view this as an active process, driven by astrocyte, microglial, fibroblast and oligodendrocyte mechanobiology. These cells, and the connective tissue phenomena they propagate, have primary and secondary effects on retinal ganglion cell (RGC) axon, laminar beam and retrolaminar capillary homeostasis that may initially be "protective" but eventually lead to RGC axonal injury, repair and/or cell death. The primary goal of this report is to summarize our 3D histomorphometric and optical coherence tomography (OCT)-based evidence for the early onset and progression of ONH connective tissue deformation and remodeling in monkey EG. A second goal is to explain the importance of including ONH connective tissue processes in characterizing the phenotype of a glaucomatous optic neuropathy in all species. A third goal is to summarize our current efforts to move from ONH morphology to the cell biology of connective tissue remodeling and axonal insult early in the disease. A final goal is to facilitate the translation of our findings and ideas into neuroprotective interventions that target

  11. Influence of intercellular tissue connections on airway muscle mechanics.

    PubMed

    Meiss, R A

    1999-01-01

    Contraction of smooth muscle in visceral organs is modified by structures external to the muscle. Within muscle tissue itself, connective tissue plays an important role in force transference among the contractile cells. Connections arranged radially can affect contractile mechanics by limiting tissue expansion at short lengths. Previous work suggests that increased stiffness at extreme shortening is due to such radial constraints. Two approaches to further study of these effects are reported. To increase radial constraints, very thin Silastic bands were placed loosely about strips of canine trachealis muscle at rest length. The strips were allowed to shorten under light afterloads, expanding until restrained by the bands. Subsequent removal of the bands allowed increased shortening, with less increase in stiffness at short lengths. Related isometric effects were observed. To reduce constraints, muscle strips were partially digested with collagenase. Compared with control conditions, this treatment permitted further shortening, with less increase in stiffness at short lengths. These results emphasize the role of extracellular structures in determining mechanical function of smooth muscle.

  12. [New data on the histogenesis of connective tissue tumors].

    PubMed

    Smol'iannikov, A V; Sarkisov, D S; Pal'tsyn, A A

    1984-01-01

    The normal skin and adipose subcutaneous tissue, desmoid fibroma, lipomas with varying proliferative activity, fibrosarcoma, malignant fibrous histiocytoma, epithelioid leiomyoma are studied by means of electron microscopy and electron microscopical radioautography. It was found that the walls of the smallest vessels contain cells which are the source of a permanent physiological renewal of a different type of the connective tissue. In proportion to differentiation and gradual removal of these cells from the vascular wall their proliferative and metabolic activity is more and more decreasing. Thus, the vessels represent not only the transport-nutritive system but the central generative structure of the connective tissue as well. Pluripotential mesenchymal cell of the vascular wall which under physiological conditions is differentiating in the direction of fibro-, angio-, lipo- or osteogenesis, due to the influence of oncogenic factors gives rise to the development of benign and malignant tumours of fibrous, vascular (angiomas), smooth muscle, adipose and bone structure. This can be most demonstratively checked using electron-radioautography of tumourlike conditions and relatively slow growing tumours.

  13. 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.

  14. Epstein-Barr virus-negative, CD5-positive diffuse large B-cell lymphoma developing after treatment with oral tacrolimus for mixed connective tissue disease : a case report and review of the literature.

    PubMed

    Sekiguchi, Yasunobu; Shimada, Asami; Imai, Hidenori; Wakabayashi, Mutsumi; Sugimoto, Keiji; Nakamura, Noriko; Sawada, Tomonori; Komatsu, Norio; Noguchi, Masaaki

    2012-01-01

    A 69-year-old woman, who had been diagnosed as having Sjögren's syndrome at 37 years old and mixed connective tissue disease at 42 years old, was under treatment with oral prednisolone. In 2009, she was diagnosed as having active systemic lupus erythematosus, and started on treatment with tacrolimus at 3 mg/day. In 2010, para-aortic lymphadenopathy and superficial multiple lymphadenopathy were detected. Tacrolimus was discontinued. Axillary lymph node biopsy revealed Epstein-Barr (EB) virus-negative CD5-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified into clinical stage IIIA and as being at high risk according to the international prognostic index. After the discontinuation of tacrolimus, the lymph nodes reduced temporarily in size. In January 2011, the lymphadenopathy increased again, and the patient received a total of 8 courses of therapy with rituximab, pirarubicin, vincristine, cyclophosphamide and prednisolone, followed by intrathecal injection to prevent central nervous system infiltration, which was followed by complete remission. In February 2012, fluorodeoxyglucose positron emission tomography showed relapse in multiple lymph nodes and central nervous system infiltration. The patient was considered to have iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" by the WHO, and this is the first reported case of CD5-positive DLBCL and central nervous system infiltration following administration of the drug. The patient was considered to have a poor prognosis as EB virus was negative, discontinuation of tacrolimus was ineffective and there was evidence of central nervous system infiltration.

  15. Tissue Specificity of Human Disease Module

    PubMed Central

    Kitsak, Maksim; Sharma, Amitabh; Menche, Jörg; Guney, Emre; Ghiassian, Susan Dina; Loscalzo, Joseph; Barabási, Albert-László

    2016-01-01

    Genes carrying mutations associated with genetic diseases are present in all human cells; yet, clinical manifestations of genetic diseases are usually highly tissue-specific. Although some disease genes are expressed only in selected tissues, the expression patterns of disease genes alone cannot explain the observed tissue specificity of human diseases. Here we hypothesize that for a disease to manifest itself in a particular tissue, a whole functional subnetwork of genes (disease module) needs to be expressed in that tissue. Driven by this hypothesis, we conducted a systematic study of the expression patterns of disease genes within the human interactome. We find that genes expressed in a specific tissue tend to be localized in the same neighborhood of the interactome. By contrast, genes expressed in different tissues are segregated in distinct network neighborhoods. Most important, we show that it is the integrity and the completeness of the expression of the disease module that determines disease manifestation in selected tissues. This approach allows us to construct a disease-tissue network that confirms known and predicts unexpected disease-tissue associations. PMID:27748412

  16. Hair follicle nevi and accessory tragi: variable quantity of adipose tissue in connective tissue framework.

    PubMed

    Ban, M; Kamiya, H; Yamada, T; Kitajima, Y

    1997-01-01

    Controversy exists about the histologic differences between hair follicle nevi and accessory tragi. We examined 10 congenital lesions histologically, possible diagnoses of which were hair follicle nevi or accessory tragi. Two specimens out of the 10 had tiny, mature hair follicles surrounded by thick fibrous root sheaths, a few fat cells, and no cartilage. The subcutaneous fat cells of their bases were segmented by a connective tissue framework. They had histologic features of hair follicle nevi. One specimen had cartilage and abundant fat cells with a connective tissue framework in the nodule, as well as a conglomeration of numerous well-differentiated hair follicles. It possessed both elements of a hair follicle nevus and an accessory tragus. Seven specimens had abundant subcutaneous fat and showed a prominent connective tissue framework. These were typical accessory tragi. The present study suggests that the number of fat cells in the nodule or papule differs between these two conditions. All the lesions studied revealed a connective tissue framework in the subcutaneous fat. Histologic features of both hair follicle nevi and accessory tragi can coexist in a single lesion. Hair follicle nevi may represent incomplete accessory tragi with scant fat cells.

  17. Affine kinematics in planar fibrous connective tissues: an experimental investigation.

    PubMed

    Jayyosi, C; Affagard, J-S; Ducourthial, G; Bonod-Bidaud, C; Lynch, B; Bancelin, S; Ruggiero, F; Schanne-Klein, M-C; Allain, J-M; Bruyère-Garnier, K; Coret, M

    2017-03-29

    The affine transformation hypothesis is usually adopted in order to link the tissue scale with the fibers scale in structural constitutive models of fibrous tissues. Thanks to the recent advances in imaging techniques, such as multiphoton microscopy, the microstructural behavior and kinematics of fibrous tissues can now be monitored at different stretching within the same sample. Therefore, the validity of the affine hypothesis can be investigated. In this paper, the fiber reorientation predicted by the affine assumption is compared to experimental data obtained during mechanical tests on skin and liver capsule coupled with microstructural imaging using multiphoton microscopy. The values of local strains and the collagen fibers orientation measured at increasing loading levels are used to compute a theoretical estimation of the affine reorientation of collagen fibers. The experimentally measured reorientation of collagen fibers during loading could not be successfully reproduced with this simple affine model. It suggests that other phenomena occur in the stretching process of planar fibrous connective tissues, which should be included in structural constitutive modeling approaches.

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

    PubMed

    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.

  19. Myoarchitecture and connective tissue in hearts with tricuspid atresia

    PubMed Central

    Sanchez-Quintana, D; Climent, V; Ho, S; Anderson, R

    1999-01-01

    Objective—To compare the atrial and ventricular myoarchitecture in the normal heart and the heart with tricuspid atresia, and to investigate changes in the three dimensional arrangement of collagen fibrils.
Methods—Blunt dissection and cell maceration with scanning electron microscopy were used to study the architecture of the atrial and ventricular musculature and the arrangement of collagen fibrils in three specimens with tricuspid atresia and six normal human hearts.
Results—There were significant modifications in the myoarchitecture of the right atrium and the left ventricle, both being noticeably hypertrophied. The middle layer of the ventricle in the abnormal hearts was thicker than in the normal hearts. The orientation of the superficial layer in the left ventricle in hearts with tricuspid atresia was irregular compared with the normal hearts. Scanning electron microscopy showed coarser endomysial sheaths and denser perimysial septa in hearts with tricuspid atresia than in normal hearts.
Conclusions—The overall architecture of the muscle fibres and its connective tissue matrix in hearts with tricuspid atresia differed from normal, probably reflecting modelling of the myocardium that is inherent to the malformation. This is in concordance with clinical observations showing deterioration in pump function of the dominant left ventricle from very early in life.

 Keywords: tricuspid atresia; congenital heart defects; connective tissue; fibrosis PMID:9922357

  20. 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.

  1. 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

  2. Tbx4 and Tbx5 acting in connective tissue are required for limb muscle and tendon patterning

    PubMed Central

    Hasson, Peleg; DeLaurier, April; Bennett, Michael; Grigorieva, Elena; Naiche, L. A.; Papaioannou, Virginia E.; Mohun, Timothy J.; Logan, Malcolm P.O.

    2010-01-01

    Summary Proper functioning of the musculo-skeletal system requires the precise integration of bones, muscles and tendons. Complex morphogenetic events ensure that these elements are linked together in the appropriate 3D configuration. It has been difficult, however, to tease apart the mechanisms that regulate tissue morphogenesis. We find that deletion of Tbx5 in forelimb (or Tbx4 in hindlimbs) specifically affects muscle and tendon patterning without disrupting skeletal development thus suggesting that distinct cues regulate these processes. We identify muscle connective tissue as the site of action of these transcription factors and show that N-Cadherin and β-Catenin are key downstream effectors acting in muscle connective tissue regulating soft-tissue morphogenesis. In humans, TBX5 mutations lead to Holt-Oram syndrome, which is characterised by forelimb musculo-skeletal defects. Our results suggest that a focus on connective tissue is required to understand the aetiology of diseases affecting soft tissue formation. PMID:20152185

  3. Graph Theory and Brain Connectivity in Alzheimer's Disease.

    PubMed

    delEtoile, Jon; Adeli, Hojjat

    2017-04-01

    This article presents a review of recent advances in neuroscience research in the specific area of brain connectivity as a potential biomarker of Alzheimer's disease with a focus on the application of graph theory. The review will begin with a brief overview of connectivity and graph theory. Then resent advances in connectivity as a biomarker for Alzheimer's disease will be presented and analyzed.

  4. Mechanisms of action of cyclosporine and effects on connective tissues.

    PubMed

    Russell, G; Graveley, R; Seid, J; al-Humidan, A K; Skjodt, H

    1992-06-01

    Cyclosporine is a potent immunomodulatory agent with an increasing number of clinical applications. Its major mode of action is inhibition of the production of cytokines involved in the regulation of T-cell activation. In particular, cyclosporine inhibits the transcription of interleukin 2. Although cyclosporine's major actions are on T cells, there is some evidence that it produces direct effects on other cell types. Its immunosuppressive action is closely linked to its binding of cyclophilin, a member of a family of high-affinity cyclosporine-binding proteins widely distributed in different cell types and in different species. The cyclophilins have been shown to have peptidyl-prolyl cis-trans isomerase enzyme activity that is blocked by cyclosporine. Although this may be a factor in cyclosporine's selective inhibition of cytokine gene transcription, it is still unclear whether inhibition of this activity is the mechanism through which cyclosporine exerts its effects on target cells. The ubiquitous presence of cyclophilins raises the question of why cyclosporine has major effects on T cells. Perhaps the critical proteins affected are transcriptional regulators restricted in their tissue distribution. The effects of cyclosporine on T cells and, directly or indirectly, on connective tissue cells, all of which can produce a range of cytokines, are of interest in relation to the tissue changes that occur in such inflammatory conditions as rheumatoid arthritis.

  5. 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.

  6. Digital cushions in horses comprise coarse connective tissue, myxoid tissue, and cartilage but only little unilocular fat tissue.

    PubMed

    Egerbacher, M; Helmreich, M; Probst, A; König, H; Böck, P

    2005-04-01

    Digital cushions were studied in horses with particular reference to vascularization, tissue constituents and matrix components. The cushions mainly resembled a network of coarse collagen bundles. The areas inbetween the bundles were replenished with loosely woven interstitial connective tissue, myxoid tissue, and fibrocartilage. Expected masses of fat lobules were missing: only solitary adipocytes or small groups of adipocytes were seen. Vascular supply to the cushions was remarkably poor. The mucinous myxoid matrix largely consisted of hyaluronan with little sulphated glycosaminoglycans. Myxoid cells were stellate or ramified in shape and showed a tendency to store glycogen and lipid droplets. Myxoid cells reacted for vimentin and stained for S-100 protein. Moreover, myxoid cells often reacted for neuron specific enolase and glial fibrillary acidic protein. Myxoid tissue continuously transformed into loosely organized interstitial connective tissue with fibroblasts, which remained unreactive when tested for neuroectodermal markers. Myxoid tissue also was not clearly demarcated against irregularly interspersed islets of fibrocartilage or hyaline cartilage. Chondrocytes did not stain for neuron specific enolase but reactivity for S-100 protein and glial fibrillary acidic protein was noted in peripheral regions of fibrocartilage. Single or grouped unilocular fat cells were rarely placed into myxoid areas. Unilocular fat cells stained for vimentin, S-100 protein, and occasionally for glial fibrillary acidic protein but not for neuron specific enolase. Continuous transformation of myxoid tissue into cartilage together with corresponding reactivity for neuroectodermal marker proteins of myxoid cells and peripherally located chondrocytes suggest close relationship between myxoid cells and chondrocytes. The same criteria indicate relationship between myxoid cells and adipocytes. Coarse connective tissue, myxoid tissue, fibrous cartilage, and fat cells are functionally

  7. Connective tissue representation for detection of microcalcifications in digital mammograms

    NASA Astrophysics Data System (ADS)

    McLoughlin, Kristin J.; Bones, Philip J.; Kovesi, Peter

    2002-05-01

    Microcalcification clusters appear as an early sign of breast cancer and play an important role in interpreting mammograms. Progress is reported towards an automated computer aided detection system for clustered microcalcifications utilizing two image feature parameters: local contrast and shape. The use of a shape parameter is necessary to distinguish thin patches of connective tissue from microcalcifications. Two shape parameter techniques are compared in the segmentation of 15 digital mammogram images. The first technique implements the linear Hough transform, while the second uses image phase information in the Fourier domain. In both cases labeling of the image is performed by a deterministic relaxation scheme, in which both image data dn prior beliefs are weighted simultaneously. Similar segmentation results are obtained for each shape parameter technique however the execution time for the phase method is approximately one quarter that for the Hough method. Both techniques offer an improvement over segmentation results obtained without the shape parameter.

  8. 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.

  9. Genetic Dissection of Marfan Syndrome and Related Connective Tissue Disorders: An Update 2012

    PubMed Central

    Hoffjan, S.

    2012-01-01

    Marfan syndrome (MFS) is an autosomal dominant disorder of the connective tissue characterized by early development of thoracic aortic aneurysms/dissections together with symptoms of the ocular and skeletal systems. While most patients/families with a classic phenotypic expression of MFS harbour mutations in the gene encoding fibrillin-1 (FBN1), genetic studies of the recent years revealed that the clinical features, as well as the mutated genes, show a high degree of overlap between MFS and other connective tissue diseases (e.g. Loeys-Dietz syndrome, Ehlers-Danlos syndrome, familial thoracic aneurysms and dissections and others). We summarize herein the current knowledge about the wide spectrum of differential diagnoses and their genetic background as well as novel therapeutic approaches in order to provide appropriate counselling and clinical follow-up for the patients. PMID:23326250

  10. Muscle and tendon connective tissue adaptation to unloading, exercise and NSAID.

    PubMed

    Dideriksen, Kasper

    2014-04-01

    The extracellular matrix network of skeletal muscle and tendon connective tissue is primarily composed of collagen and connects the muscle contractile protein to the bones in the human body. The mechanical properties of the connective tissue are important for the effectiveness of which the muscle force is transformed into movement. Periods of unloading and exercise affect the synthesis rate of connective tissue collagen protein, whereas only sparse information exits regarding collagen protein degradation. It is likely, though, that changes in both collagen protein synthesis and degradation are required for remodeling of the connective tissue internal structure that ultimately results in altered mechanical properties of the connective tissue. Both unloading and exercise lead to increased production of growth factors and inflammatory mediators that are involved in connective tissue remodeling. Despite the fact that non-steroidal anti-inflammatory drugs seem to inhibit the healing process of connective tissue and the stimulating effect of exercise on connective tissue protein synthesis, these drugs are often consumed in relation to connective tissue injury and soreness. However, the potential effect of non-steroidal anti-inflammatory drugs on connective tissue needs further investigation.

  11. Connective tissue progenitor cell growth characteristics on textured substrates

    PubMed Central

    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 μm high and 5, 10, 20, and 40 μm diameter, respectively, and channel micro-textures (CHANNELS) with curved cross-sections that were 11 μm high, 45 μm wide, and separated by 5 μm 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 μm-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 μm POSTS), and significantly more so compared to those on SMOOTH (104%). PMID:18019838

  12. Long-term effects of connective tissue cancer treatment.

    PubMed

    Mankin, Henry J; Gunnoe, Jaime; Farid, Yasser; Hornicek, Francis J; Gebhardt, Mark C

    2004-09-01

    In 1999, we began a study to assess the long-term effect of connective tissue cancer treatment on clinical, social, and psychologic aspects of the lives of surviving patients. A specially designed computer program generated an 85-item questionnaire, which was sent to more than 2000 patients with malignant bone and soft tissue neoplasms. Twelve hundred forty-four patients responded. The data were entered into a computer system and were correlated with the clinical information already contained in the system for the individual patients. Although there are many possible uses for these data, we chose to do a study comparing the lifestyle and physical and sociologic problems for 144 patients treated with chemotherapy and surgery for high-grade osteosarcoma against a control population consisting of 61 patients treated surgically for benign giant cell tumors of bone. The data show a remarkable degree of compensation on the part of the patients with the malignant tumors in terms of some problems but some significant differences particularly in physical status and functional limitations.

  13. Growth of connective tissue progenitor cells on microtextured polydimethylsiloxane surfaces.

    PubMed

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

    2002-12-15

    Growth of human connective tissue progenitor cells (CTPs) was characterized on smooth and microtextured polydimethylsiloxane (PDMS) surfaces. Human bone-marrow-derived cells were cultured for 9 days under conditions promoting osteoblastic differentiation on smooth PDMS surfaces and on PDMS post microtextures that were 6 microm high and 5, 10, 20, and 40 microm in diameter, respectively. Glass tissue-culture dishes were used as controls. The number of viable cells was determined, and an alkaline phosphatase stain was used as a marker for osteoblastic phenotype. CTPs attached, proliferated, and differentiated on all surfaces. Cells on the smooth PDMS and control surfaces spread and proliferated as colonies in proximity to other cells and migrated in random directions, with cell process lengths of up to 80 microm. In contrast, cells on the PDMS post microtextures grew as sparsely distributed networks of cells, with processes, occasionally up to 300 microm, that appeared to interact with the posts. Cell counts revealed that there were fewer (50%) CTPs on the smooth PDMS surface than were on the glass control surfaces. However, there were consistently more (>144%) CTPs on the PDMS post textures than on the controls. In particular, the 10-microm-in-diameter posts (268%) exhibited a significantly (p < 0.05) greater cell number than did the smooth PDMS.

  14. [Oral rehabilitation with metalloceramic restorations in patients with non-differentiated systemic connective tissue dysplasia].

    PubMed

    Stafeev, A A

    2015-01-01

    False formation of connective tissues have a great influence on structure and function of organs and tissues of the human body. In prosthodontics, the changes in connective tissues greatly occur during clinical stages of preparing metal ceramic dentures. The algorithm of treatment patients with connective tissue dysplasia during metal ceramic dentures was developed and introduced into practical dentistry based on studying the morphology and functionality of dentition and clinical experience.

  15. Connective tissue in gut development: a key player in motility and in intestinal desmosis.

    PubMed

    Bruhin-Feichter, Sonja; Meier-Ruge, William; Martucciello, Giuseppe; Bruder, Elisabeth

    2012-12-01

    Efficient intestinal peristalsis is a function of intact enteric nervous system, muscle, and connective muscularis propria tissue. Malfunction of any component results in impaired peristalsis. Hirschsprung disease (HD) as prototypic enteric neural migration disorder is increasingly well characterized. More recently, intestinal myopathies and particularly defects of myenteric collagenization have entered the focus of attention. However, detailed development of muscularis propria connective tissue is not well known. The aim of this study was to morphologically characterize intestinal connective tissue in fetal and postnatal development and intestinal pseudo-obstruction. In this study, 130 archival specimens of fetal autopsies, intestinal resections, and biopsies were analyzed. Patients' age was 10th gestational week (gw) to 70 years. Muscularis mucosae, muscle layers, collagen tissue, and enteric plexus were analyzed. Picrosirius red stains, enzyme histochemistry, and immunohistochemistry for collagens I, III, and IV were performed. Total 89 normal intestinal specimens were from fetal autopsies or intestinal resections; 41 patients showed a primary structural colon wall defect (HD, desmosis). Our results showed a constant increase in tunica muscularis propria thickness with age. Separation into circular and longitudinal muscle layer first occurred in the 11th gw. A tendinous collagen plexus layer first arose in the 10th gw and showed a steady caliber increase. Muscularis mucosae first appeared in the 10th gw and grew independent of any primary gastrointestinal disease. In the 11th gw, enteric ganglia were fully developed. In desmosis, a collagen plexus layer was absent. In contrast, in HD, muscularis mucosae showed hypertrophy, but the collagen plexus layer was intact in the aganglionic segment. In intestinal neuronal dysplasia and hypoganglionosis, nerve cell development was disturbed; connective tissue and muscle layers were well developed. Our comprehensive study

  16. White matter predicts functional connectivity in premanifest Huntington's disease.

    PubMed

    McColgan, Peter; Gregory, Sarah; Razi, Adeel; Seunarine, Kiran K; Gargouri, Fatma; Durr, Alexandra; Roos, Raymund A C; Leavitt, Blair R; Scahill, Rachael I; Clark, Chris A; Tabrizi, Sarah J; Rees, Geraint; Coleman, A; Decolongon, J; Fan, M; Petkau, T; Jauffret, C; Justo, D; Lehericy, S; Nigaud, K; Valabrègue, R; Choonderbeek, A; Hart, E P T; Hensman Moss, D J; Crawford, H; Johnson, E; Papoutsi, M; Berna, C; Reilmann, R; Weber, N; Stout, J; Labuschagne, I; Landwehrmeyer, B; Orth, M; Johnson, H

    2017-02-01

    The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero-posterior dissociation that is in keeping with the caudo-rostral gradient of striatal pathology in HD.

  17. Epithelial-connective tissue boundary in the oral part of the human soft palate

    PubMed Central

    PAULSEN, FRIEDRICH; THALE, ANDREAS

    1998-01-01

    The papillary layer of the oral part of the human soft palate was studied in 31 subjects of different age by means of histological, immunohistochemical and scanning electron microscopical methods. For scanning electron microscopy a new maceration method was introduced. Results determine epithelial thickness, height and density of connective tissue papillae and their 3-dimensional architecture inside the lining epithelium as well as the collagenous arrangement of the openings of the glandular ducts. The individual connective tissue papillae of the soft palate are compared with the connective tissue boundary on the other side of the oral cavity. The connective tissue plateaux carrying a variable number of connective tissue papillae were found to be the basic structural units of the papillary body. The function of the epithelial-connective tissue interface and the extracellular matrix arrangement in the lamina propria are discussed in order to promote the comparability of normal with pathologically altered human soft palates. PMID:9877301

  18. Myoarchitecture and connective tissue in hearts with tricuspid atresia.

    PubMed

    Sanchez-Quintana, D; Climent, V; Ho, S Y; Anderson, R H

    1999-02-01

    To compare the atrial and ventricular myoarchitecture in the normal heart and the heart with tricuspid atresia, and to investigate changes in the three dimensional arrangement of collagen fibrils. Blunt dissection and cell maceration with scanning electron microscopy were used to study the architecture of the atrial and ventricular musculature and the arrangement of collagen fibrils in three specimens with tricuspid atresia and six normal human hearts. There were significant modifications in the myoarchitecture of the right atrium and the left ventricle, both being noticeably hypertrophied. The middle layer of the ventricle in the abnormal hearts was thicker than in the normal hearts. The orientation of the superficial layer in the left ventricle in hearts with tricuspid atresia was irregular compared with the normal hearts. Scanning electron microscopy showed coarser endomysial sheaths and denser perimysial septa in hearts with tricuspid atresia than in normal hearts. The overall architecture of the muscle fibres and its connective tissue matrix in hearts with tricuspid atresia differed from normal, probably reflecting modelling of the myocardium that is inherent to the malformation. This is in concordance with clinical observations showing deterioration in pump function of the dominant left ventricle from very early in life.

  19. Mechanical mutability in connective tissue of starfish body wall.

    PubMed

    Motokawa, Tatsuo

    2011-12-01

    Stiffness changes in response to mechanical and chemical stimulation were studied in muscle-free dermal samples from the body wall of the starfish Linckia laevigata. The ultrastructural study showed that the dermis was packed with collagen fibrils between which only a small number of cells were observed. Muscles were found only in the walls of coelomic extensions leading to papulae. Stress-strain tests were performed on isolated dermis containing no muscles. The tangent modulus was 27.5 MPa at 0.04% strain rate in the stress-strain tests. It was increased to 40.7 MPa by mechanical stimulation, which also increased the tensile strength and breaking-strain energy density. Dynamic mechanical tests showed that the increase in stiffness in response to mechanical stimulation was transient. Acetylcholine (10(-6)-10(-3) mol l(-1)) and artificial seawater with an elevated potassium concentration (KASW) stiffened the dermis. Mechanical stimulation caused a 12% mass loss. KASW also caused mass loss, which was inhibited by anesthesia. These results clearly showed that the stiffness changes in the starfish dermis were based on a non-muscular mechanism that was similar to that of other echinoderm connective tissues with mechanical mutability.

  20. 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.

  1. Qualitative assessment of connective tissue graft with epithelial component. A microsurgical periodontal plastic surgical technique for soft tissue esthetics.

    PubMed

    Rossi, Roberto; Pilloni, Andrea; Morales, Regina Santos

    2009-01-01

    Connective tissue grafts have been used successfully in the treatment of gingival recession. In the mid 80s and late 90s, the periodontal literature presented various techniques such as free gingival grafts, pedicle flaps, subepithelial connective tissue grafts, acellular dermal matrix grafts, and guided tissue regeneration to cover denuded root surfaces. Currently, connective tissue grafting is a reliable treatment for esthetic root coverage. This paper presents a qualitative assessment of a surgical technique that uses a connective tissue graft, including a portion of epithelium in the shape of the defect. This procedure enhances the healing of the covered root surface, increases the thickness of the soft tissue and improves esthetics. The criteria used for evaluation were: color, volume, texture, and blending. This evaluation demonstrated encouraging results from an esthetic viewpoint.

  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. [Syndromes of peripheral nervous system lesions and mechanisms of their formation in disorders of connective tissue].

    PubMed

    Spirin, N N; Bulanova, V A; Pizova, N V; Shilkina, N P

    2005-01-01

    Systemic rheumatoid diseases are often concomitant with the development of central and peripheral systems pathologies. Presented are the results revealing high frequency of peripheral nervous system lesions (lupus erythematosus and systemic scleroderma), which characterized by polyneuropathy and tunnel syndromes. Based on the results of literature and own studies, pathological mechanisms of peripheral nervous system lesions in diffusion disorders of connective tissue were singled out as follows: ischemic, immunological and metabolic. Taking these mechanisms into account will permit to conduct pathogenetically valid therapy and to improve its results.

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

    PubMed

    Yoo, Lawrence; Gupta, Vijay; Lee, Choongyeop; Kavehpore, Pirouz; Demer, Joseph L

    2011-12-01

    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 multi-mode 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.

  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. 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.

  7. [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.

  8. Molecular regulation of CCN2 in the intervertebral disc: lessons learned from other connective tissues.

    PubMed

    Tran, Cassie M; Shapiro, Irving M; Risbud, Makarand V

    2013-08-08

    Connective tissue growth factor (CCN2/CTGF) plays an important role in extracellular matrix synthesis, especially in skeletal tissues such as cartilage, bone, and the intervertebral disc. As a result there is a growing interest in examining the function and regulation of this important molecule in the disc. This review discusses the regulation of CCN2 by TGF-β and hypoxia, two critical determinants that characterize the disc microenvironment, and discusses known functions of CCN2 in the disc. The almost ubiquitous regulation of CCN2 by TGF-β, including that seen in the disc, emphasizes the importance of the TGF-β-CCN2 relationship, especially in terms of extracellular matrix synthesis. Likewise, the unique cross-talk between CCN2 and HIF-1 in the disc highlights the tissue and niche specific mode of regulation. Taken together the current literature supports an anabolic role for CCN2 in the disc and its involvement in the maintenance of tissue homeostasis during both health and disease. Further studies of CCN2 in this tissue may reveal valuable targets for the biological therapy of disc degeneration.

  9. Basal ganglia-cortical structural connectivity in Huntington's disease.

    PubMed

    Novak, Marianne J U; Seunarine, Kiran K; Gibbard, Clare R; McColgan, Peter; Draganski, Bogdan; Friston, Karl; Clark, Chris A; Tabrizi, Sarah J

    2015-05-01

    Huntington's disease is an incurable neurodegenerative disease caused by inheritance of an expanded cytosine-adenine-guanine (CAG) trinucleotide repeat within the Huntingtin gene. Extensive volume loss and altered diffusion metrics in the basal ganglia, cortex and white matter are seen when patients with Huntington's disease (HD) undergo structural imaging, suggesting that changes in basal ganglia-cortical structural connectivity occur. The aims of this study were to characterise altered patterns of basal ganglia-cortical structural connectivity with high anatomical precision in premanifest and early manifest HD, and to identify associations between structural connectivity and genetic or clinical markers of HD. 3-Tesla diffusion tensor magnetic resonance images were acquired from 14 early manifest HD subjects, 17 premanifest HD subjects and 18 controls. Voxel-based analyses of probabilistic tractography were used to quantify basal ganglia-cortical structural connections. Canonical variate analysis was used to demonstrate disease-associated patterns of altered connectivity and to test for associations between connectivity and genetic and clinical markers of HD; this is the first study in which such analyses have been used. Widespread changes were seen in basal ganglia-cortical structural connectivity in early manifest HD subjects; this has relevance for development of therapies targeting the striatum. Premanifest HD subjects had a pattern of connectivity more similar to that of controls, suggesting progressive change in connections over time. Associations between structural connectivity patterns and motor and cognitive markers of disease severity were present in early manifest subjects. Our data suggest the clinical phenotype in manifest HD may be at least partly a result of altered connectivity.

  10. [The effect of the biopolymer chondroitin sulfate on reparative regeneration of connective tissue].

    PubMed

    Belova, S V; Norkin, I A; Puchinyan, D M

    2015-01-01

    The research objective is a study of an intra-articular method of introduction of the preparation "mukosat" for stimulation of reparative regeneration of connective tissue of knee joints in rabbits with an experimental arthritis. It is ascertained that intra-articular maintenance of chondroitin sulfate (the preparation "mukosat") acts as a stimulus for reparative regeneration of connective tissue thus showing up positive changes in the status of connective tissue elements of joints: decrease in glycosaminoglycan content in blood serum and normalization of the composition of glycosaminoglycan carbohydrate component. It probably depends on stimulation of biosynthesis of autologous normal glycosaminoglycans in tissues of animal knee joints.

  11. 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. (c) 2009 Society of Chemical Industry.

  12. 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

  13. 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.

  14. 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.

  15. Modeling disease progression using dynamics of pathway connectivity.

    PubMed

    Ma, Xiaoke; Gao, Long; Tan, Kai

    2014-08-15

    Disease progression is driven by dynamic changes in both the activity and connectivity of molecular pathways. Understanding these dynamic events is critical for disease prognosis and effective treatment. Compared with activity dynamics, connectivity dynamics is poorly explored. We describe the M-module algorithm to identify gene modules with common members but varied connectivity across multiple gene co-expression networks (aka M-modules). We introduce a novel metric to capture the connectivity dynamics of an entire M-module. We find that M-modules with dynamic connectivity have distinct topological and biochemical properties compared with static M-modules and hub genes. We demonstrate that incorporation of module connectivity dynamics significantly improves disease stage prediction. We identify different sets of M-modules that are important for specific disease stage transitions and offer new insights into the molecular events underlying disease progression. Besides modeling disease progression, the algorithm and metric introduced here are broadly applicable to modeling dynamics of molecular pathways. M-module is implemented in R. The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/M-module.zip. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Familial occurrence and heritable connective tissue disorders in cervical artery dissection

    PubMed Central

    Goeggel Simonetti, Barbara; Schilling, Sabrina; Martin, Juan José; Kloss, Manja; Sarikaya, Hakan; Hausser, Ingrid; Engelter, Stefan; Metso, Tiina M.; Pezzini, Alessandro; Thijs, Vincent; Touzé, Emmanuel; Paolucci, Stefano; Costa, Paolo; Sessa, Maria; Samson, Yves; Béjot, Yannick; Altintas, Ayse; Metso, Antti J.; Hervé, Dominique; Lichy, Christoph; Jung, Simon; Fischer, Urs; Lamy, Chantal; Grau, Armin; Chabriat, Hugues; Caso, Valeria; Lyrer, Philippe A.; Stapf, Christian; Tatlisumak, Turgut; Brandt, Tobias; Tournier-Lasserve, Elisabeth; Germain, Dominique P.; Frank, Michael; Baumgartner, Ralf W.; Grond-Ginsbach, Caspar; Bousser, Marie-Germaine; Leys, Didier; Dallongeville, Jean; Bersano, Anna

    2014-01-01

    Objective: In a large series of patients with cervical artery dissection (CeAD), a major cause of ischemic stroke in young and middle-aged adults, we aimed to examine frequencies and correlates of family history of CeAD and of inherited connective tissue disorders. Methods: We combined data from 2 large international multicenter cohorts of consecutive patients with CeAD in 23 neurologic departments participating in the CADISP-plus consortium, following a standardized protocol. Frequency of reported family history of CeAD and of inherited connective tissue disorders was assessed. Putative risk factors, baseline features, and 3-month outcome were compared between groups. Results: Among 1,934 consecutive patients with CeAD, 20 patients (1.0%, 95% confidence interval: 0.6%–1.5%) from 17 families (0.9%, 0.5%–1.3%) had a family history of CeAD. Family history of CeAD was significantly more frequent in patients with carotid location of the dissection and elevated cholesterol levels. Two patients without a family history of CeAD had vascular Ehlers-Danlos syndrome with a mutation in COL3A1. This diagnosis was suspected in 2 additional patients, but COL3A1 sequencing was negative. Two patients were diagnosed with classic and hypermobile Ehlers-Danlos syndrome, one patient with Marfan syndrome, and one with osteogenesis imperfecta, based on clinical criteria only. Conclusions: In this largest series of patients with CeAD to date, family history of symptomatic CeAD was rare and inherited connective tissue disorders seemed exceptional. This finding supports the notion that CeAD is a multifactorial disease in the vast majority of cases. PMID:25355833

  17. 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.

  18. 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.

  19. Connective tissue and bacterial deposits on rubber dam sheet and ePTFE barrier membranes in guided periodontal tissue regeneration.

    PubMed

    Apinhasmit, Wandee; Swasdison, Somporn; Tamsailom, Suphot; Suppipat, Nophadol

    2002-01-01

    The aim of this study was to compare the connective tissue and bacterial deposits on rubber dam sheets and expanded polytetrafluoroethylene membranes used as barrier membranes in guided tissue regeneration for periodontal treatment. Twenty patients having intrabony defects and/or furcation defects were surgically treated by guided tissue regeneration employing either rubber dam sheets (10 patients) or expanded polytetrafluoroethylene membranes (10 patients) as barrier membranes. Four to six weeks after the first operation, membranes were retrieved from the lesion sites and processed for scanning electron microscopy. The lesion-facing surfaces of membranes were examined for the presence of connective tissue and bacterial deposits. The differences between the numbers of fields and the distributions of connective tissue and bacteria on both types of membranes were analysed by the Chi-square test at the level of 0.05 significance. The results showed a lot of fibroblasts with their secreted extracellular matrices, known as components of the connective tissue on rubber dam sheets and expanded polytetrafluoroethylene membranes. There was no significant difference in the total number of connective tissue on both types of membranes (P = 0.456). Many bacterial forms including cocci, bacilli, filaments and spirochetes with the interbacterial matrices were identified. The total number of bacteria on rubber dam sheets was statistically less than that on expanded polytetrafluoroethylene membranes (P < 0.001). The comparable number of connective tissue on both types of membranes suggests that the healing process under both types of membranes was also comparable. Therefore, the rubber dam sheet might be used as a barrier membrane in guided tissue regeneration.

  20. 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.

  1. A new experimental method for hiatal reinforcement using connective tissue patch transfer.

    PubMed

    Vereczkei, A; Varga, G; Tornoczky, T; Papp, A; Horvath, Ö P

    2012-07-01

    The closure of a large hiatal hernia still represents a challenge for the surgeon. Mesh reinforcement of a hiatoplasty generally decreases recurrence rate. An artificial mesh is cheaper compared with a biologic one, but has a higher complication rate. Our aim was to introduce a new biologic reinforcement method with less expenses. During organ donation for transplantation, tissue islets from pericardium and fascia lata were cryopreserved in a tissue bank. Later, the grafts were transplanted on the diaphragm of mongrel dogs. After 1, 3, and 6 months, the animals were sacrificed, and the transplanted patches were macroscopically and microscopically examined. There were no macroscopic signs of inflammation, abcedation, or significant adhesion formation. The grafts were well recognizable, with palpable thickening and moderate shrinkage. Microscopically, an organization process with fibrosis, neovascularization, and peritoneal integration could be observed. Reinforcement of a hiatoplasty with connective tissue transfer either with cryopreserved or autologous tissue is a good option. This is a cheap and easy method, which should also be tested in human interventions. © 2011 Copyright the Authors. Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.

  2. Ectopic mineralization disorders of the extracellular matrix of connective tissue: molecular genetics and pathomechanisms of aberrant calcification.

    PubMed

    Li, Qiaoli; Jiang, Qiujie; Uitto, Jouni

    2014-01-01

    Ectopic mineralization of connective tissues is a complex process leading to deposition of calcium phosphate complexes in the extracellular matrix, particularly affecting the skin and the arterial blood vessels and common in age-associated disorders. A number of initiating and contributing metabolic and environmental factors are linked to aberrant mineralization in these diseases, making the identification of precise pathomechanistic pathways exceedingly difficult. However, there has been significant recent progress in understanding the ectopic mineralization processes through study of heritable single-gene disorders, which have allowed identification of discrete pathways and contributing factors leading to aberrant connective tissue mineralization. These studies have provided support for the concept of an intricate mineralization/anti-mineralization network present in peripheral connective tissues, providing a perspective to development of pharmacologic approaches to limit the phenotypic consequences of ectopic mineralization. This overview summarizes the current knowledge of ectopic heritable mineralization disorders, with accompanying animal models, focusing on pseudoxanthoma elasticum and generalized arterial calcification of infancy, two autosomal recessive diseases manifesting with extensive connective tissue mineralization in the skin and the cardiovascular system.

  3. Ectopic mineralization disorders of the extracellular matrix of connective tissue: Molecular genetics and pathomechanisms of aberrant calcification

    PubMed Central

    Li, Qiaoli; Jiang, Qiujie; Uitto, Jouni

    2013-01-01

    Ectopic mineralization of connective tissues is a complex process leading to deposition of calcium phosphate complexes in the extracellular matrix, particularly affecting the skin and the arterial blood vessels and common in age-associated disorders. A number of initiating and contributing metabolic and environmental factors are linked to aberrant mineralization in these diseases, making the identification of precise pathomechanistic pathways exceedingly difficult. However, there has been significant recent progress in understanding the ectopic mineralization processes through study of heritable single-gene disorders, which have allowed identification of discreet pathways and contributing factors leading to aberrant connective tissue mineralization. These studies have provided support for the concept of an intricate mineralization/anti-mineralization network present in peripheral connective tissues, providing a perspective to development of pharmacologic approaches to limit the phenotypic consequences of ectopic mineralization. This overview summarizes the current knowledge of ectopic heritable mineralization disorders, with accompanying animal models, focusing on pseudoxanthoma elasticum and generalized arterial calcification of infancy, two autosomal recessive diseases manifesting with extensive connective tissue mineralization in the skin and the cardiovascular system. PMID:23891698

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

    PubMed Central

    Jie, Biao; Wee, Chong-Yaw

    2017-01-01

    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

  5. 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

  6. 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

    2014-09-29

    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.

  7. Corticostriatal connectivity and its role in disease

    PubMed Central

    Shepherd, Gordon M. G.

    2014-01-01

    Corticostriatal projections are essential components of forebrain circuits widely involved in motivated behavior. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) type neurons. Convergent evidence points to IT/PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signaling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an etiological factor in neurodevelopmental, neuropsychiatric, and movement disorders – autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington’s and Parkinson’s diseases, and major depression are highlighted here. PMID:23511908

  8. Removal of an amalgam tattoo using a subepithelial connective tissue graft and laser deepithelialization.

    PubMed

    Campbell, Casey M; Deas, David E

    2009-05-01

    A 56-year-old female presented for periodontal treatment with a large amalgam tattoo located in alveolar mucosa on the facial aspect of her maxillary central incisors. The lesion had been present for 42 years since having endodontic surgery at teeth #8 and #9 after a traumatic childhood incident. A two-stage surgical approach was used to eliminate the lesion, beginning with a subepithelial connective tissue graft to increase tissue thickness subjacent to the amalgam tattoo. After 6 weeks of healing, the overlying pigmented tissue was removed using laser surgery to expose the underlying grafted connective tissue. After 2 months of healing following laser surgery, the amalgam pigmentation was completely removed, with good color match and an increased width of keratinized tissue at the surgical site. A relatively large amalgam tattoo in the esthetic zone can be adequately removed by a two-stage procedure using grafted palatal connective tissue and laser deepithelialization.

  9. Functional connectivity disruptions correlate with cognitive phenotypes in Parkinson's disease.

    PubMed

    Hassan, M; Chaton, L; Benquet, P; Delval, A; Leroy, C; Plomhause, L; Moonen, A J H; Duits, A A; Leentjens, A F G; van Kranen-Mastenbroek, V; Defebvre, L; Derambure, P; Wendling, F; Dujardin, K

    2017-01-01

    Cognitive deficits in Parkinson's disease are thought to be related to altered functional brain connectivity. To date, cognitive-related changes in Parkinson's disease have never been explored with dense-EEG with the aim of establishing a relationship between the degree of cognitive impairment, on the one hand, and alterations in the functional connectivity of brain networks, on the other hand. This study was aimed at identifying altered brain networks associated with cognitive phenotypes in Parkinson's disease using dense-EEG data recorded during rest with eyes closed. Three groups of Parkinson's disease patients (N = 124) with different cognitive phenotypes coming from a data-driven cluster analysis, were studied: G1) cognitively intact patients (63), G2) patients with mild cognitive deficits (46) and G3) patients with severe cognitive deficits (15). Functional brain networks were identified using a dense-EEG source connectivity method. Pairwise functional connectivity was computed for 68 brain regions in different EEG frequency bands. Network statistics were assessed at both global (network topology) and local (inter-regional connections) level. Results revealed progressive disruptions in functional connectivity between the three patient groups, typically in the alpha band. Differences between G1 and G2 (p < 0.001, corrected using permutation test) were mainly frontotemporal alterations. A statistically significant correlation (ρ = 0.49, p < 0.001) was also obtained between a proposed network-based index and the patients' cognitive score. Global properties of network topology in patients were relatively intact. These findings indicate that functional connectivity decreases with the worsening of cognitive performance and loss of frontotemporal connectivity may be a promising neuromarker of cognitive impairment in Parkinson's disease.

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

    PubMed

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

    2012-01-01

    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.

  11. Stretching of the back improves gait, mechanical sensitivity and connective tissue inflammation in a rodent model.

    PubMed

    Corey, Sarah M; Vizzard, Margaret A; Bouffard, Nicole A; Badger, Gary J; Langevin, Helene M

    2012-01-01

    The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.

  12. Sonographic measurements of subsynovial connective tissue thickness in patients with carpal tunnel syndrome.

    PubMed

    van Doesburg, Margriet H M; Mink van der Molen, Aebele; Henderson, Jacqueline; Cha, Stephen S; An, Kai Nan; Amadio, Peter C

    2012-01-01

    A major pathologic finding in patients with idiopathic carpal tunnel syndrome is noninflammatory fibrosis and thickening of the subsynovial connective tissue. The objective of this study was to determine the ability of sonography to depict this thickening by comparing subsynovial connective tissue thickness in patients with carpal tunnel syndrome and healthy control participants. Longitudinal sonograms of the middle finger superficial flexor tendon and subsynovial connective tissue were obtained at 3 levels: at the wrist crease (proximal tunnel), at the hook of the hamate (mid tunnel), and at the distal edge of the transverse carpal ligament (distal tunnel). The thickness of the subsynovial connective tissue perpendicular to the direction of the tendon and the diameter of the flexor digitorum superficialis tendon at the same level were measured. Then, a thickness ratio was created. At all 3 levels, the subsynovial connective tissue was thicker in patients than in controls (P < .0001) with a thickness ranging from 0.60 to 0.63 mm in patients and 0.46 to 0.50 mm in controls. The thickness ratio was significantly greater in patients at the hamate and distal levels (P = .018 and .013, respectively). With this study, we have shown that it is possible to measure subsynovial connective tissue thickness with sonography, and the tissue is thicker in patients with carpal tunnel syndrome than in healthy controls.

  13. Aminoacyl tRNA synthetases and their connections to disease.

    PubMed

    Park, Sang Gyu; Schimmel, Paul; Kim, Sunghoon

    2008-08-12

    Aminoacylation of transfer RNAs establishes the rules of the genetic code. The reactions are catalyzed by an ancient group of 20 enzymes (one for each amino acid) known as aminoacyl tRNA synthetases (AARSs). Surprisingly, the etiology of specific diseases-including cancer, neuronal pathologies, autoimmune disorders, and disrupted metabolic conditions-is connected to specific aminoacyl tRNA synthetases. These connections include heritable mutations in the genes for tRNA synthetases that are causally linked to disease, with both dominant and recessive disease-causing mutations being annotated. Because some disease-causing mutations do not affect aminoacylation activity or apparent enzyme stability, the mutations are believed to affect functions that are distinct from aminoacylation. Examples include enzymes that are secreted as procytokines that, after activation, operate in pathways connected to the immune system or angiogenesis. In addition, within cells, synthetases form multiprotein complexes with each other or with other regulatory factors and in that way control diverse signaling pathways. Although much has been uncovered in recent years, many novel functions, disease connections, and interpathway connections of tRNA synthetases have yet to be worked out.

  14. [Impaired endometrial receptivity in primary infertility in women with undifferentiated connective tissue dysplasia and hereditary thrombophilia].

    PubMed

    Zanozin, A S; Demura, T A; Kolosovsky, D Yu; Faizullina, N M; Kogan, E A

    2016-01-01

    The concurrence of undifferentiated connective tissue dysplasia (uCTD) and hereditary thrombophilia (HT) often accompanies female infertility, in the pathogenesis of which impaired endometrial receptivity plays an important role.

  15. Connective Tissue Disorders and Cardiovascular Complications: The indomitable role of Transforming Growth Factor-beta signaling

    PubMed Central

    Wheeler, Jason B.; Ikonomidis, John S.; Jones, Jeffrey A.

    2015-01-01

    Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system. PMID:24443024

  16. 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.

  17. Voluntary exercise improves murine dermal connective tissue status in high-fat diet-induced obesity.

    PubMed

    Lőrincz, Kende; Haluszka, Dóra; Kiss, Norbert; Gyöngyösi, Nóra; Bánvölgyi, András; Szipőcs, Róbert; Wikonkál, Norbert M

    2017-04-01

    Obesity is a risk factor for several cardiovascular and metabolic diseases. Its influence on the skin is less obvious, yet certain negative effects of adipose tissue inflammation on the dermis have been suggested. Excess weight is closely associated with sedentary behavior, so any increase in physical activity is considered beneficial against obesity. To investigate the effects of obesity and physical exercise on the skin, we established a mouse model in which mice were kept either on a high-fat diet or received standard chow. After the two groups achieved a significant weight difference, physical exercise was introduced to both. Animals were given the opportunity to perform voluntary exercise for 40 min daily in a hamster wheel for a period of 8 weeks. We evaluated the status of the dermis at the beginning and at the end of the exercise period by in vivo nonlinear microscopy. Obese mice kept on high-fat diet lost weight steadily after they started to exercise. In the high-fat diet group, we could detect significantly larger adipocytes and a thicker layer of subcutaneous tissue; both changes started to normalize after exercise. Nonlinear microscopy revealed an impaired collagen structure in obese mice that improved considerably after physical activity was introduced. With the ability to detect damage on collagen structure, we set out to address the question whether this process is reversible. With the use of a novel imaging method, we were able to show the reversibility of connective tissue deterioration as a benefit of physical exercise.

  18. Relative resistance of long junctional epithelial adhesions and connective tissue attachments to plaque-induced inflammation.

    PubMed

    Beaumont, R H; O'Leary, T J; Kafrawy, A H

    1984-04-01

    . Under the conditions of this study, there appeared to be no appreciable difference in resistance to disease between a long junctional epithelial adhesion and a true connective tissue attachment.

  19. Applications of Resting-State Functional Connectivity to Neurodegenerative Disease.

    PubMed

    Zhou, Juan; Liu, Siwei; Ng, Kwun Kei; Wang, Juan

    2017-11-01

    Neurodegenerative diseases target specific large-scale neuronal networks, leading to distinct behavioral and cognitive dysfunctions. Resting-state functional magnetic resonance imaging (rsfMR imaging)-based functional connectivity method maps symptoms-associated functional network deterioration in vivo. This article summarizes accumulating functional connectivity findings supporting the network-based neurodegeneration hypothesis. Understanding of disease mechanism can further guide early detection and predictions of disease progression and inform development of more effective treatment. With better clinical phenotyping and larger samples across multiple sites, we discuss several possible future directions to further develop rsfMR imaging-based functional connectivity methods into scientifically and clinically useful assays for neurodegenerative disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Increased connectivity between sensorimotor and attentional areas in Parkinson's disease.

    PubMed

    Onu, Mihaela; Badea, Liviu; Roceanu, Adina; Tivarus, Madalina; Bajenaru, Ovidiu

    2015-09-01

    Our study is using Independent Component Analysis (ICA) to evaluate functional connectivity changes in Parkinson's disease (PD) in an unbiased manner. Resting-state functional magnetic resonance imaging (rs-fMRI) data was collected for 27 PD patients and 16 healthy subjects. Differences for intra- and inter-network connectivity between healthy subjects and patients were investigated using FMRIB Software Library (FSL) tools (Melodic ICA, dual regression, FSLNets). Twenty-three ICA maps were identified as components of neuronal origin. For intra-network connectivity changes, eight components showed a significant connectivity increase in patients (p < 0.05); these were correlated with clinical scores and were largest for (sensori)motor networks. For inter-network connectivity changes, we found higher connectivity between the sensorimotor network and the spatial attention network (p = 0.0098) and lower connectivity between anterior and posterior default mode networks (DMN) (p =  0.024), anterior DMN and visual recognition networks (p = 0.026), as well as between visual attention and main dorsal attention networks (p = 0.03), for patients as compared to healthy subjects. The area under the Receiver Operating Characteristics (ROC) curve for the best predictor (partial correlation between sensorimotor and spatial attention networks) was 0.772. These functional alterations were not associated with any gray or white matter structural changes. Our results show higher connectivity between sensorimotor and spatial attention areas in patients that may be related to the reduced movement automaticity in PD.

  1. Elevated plasma hydroxyproline. A possible risk factor associated with connective tissue injuries during overuse.

    PubMed

    Murguia, M J; Vailas, A; Mandelbaum, B; Norton, J; Hodgdon, J; Goforth, H; Riedy, M

    1988-01-01

    Basal plasma hydroxyproline was measured in 104 male Navy Seal candidates 1 week into their intense physical training program, which lasted 7 weeks, and correlated to the incidence of connective tissue injuries incurred later in the training program. Eleven subjects (10.6%) were diagnosed as having connective tissue injuries. Those subjects with connective tissue injuries had a significantly higher (P less than 0.05) mean plasma hydroxyproline value (4.02 micrograms/ml) than subjects without injury (3.10 micrograms/ml). The majority of graduates (75%) had plasma hydroxyproline values less than 3.3 micrograms/ml. These graduates represented the strongest and most enduring injury-free subjects. Of the subject pool who incurred connective tissue injuries, only 27% had plasma hydroxyproline values less than 3.3 micrograms/ml. The majority of the injured subjects (73%) had plasma hydroxyproline values greater than or equal to 3.3 micrograms/ml. In conclusion, there is a relationship between initial training basal plasma hydroxyproline levels and connective tissue injuries later incurred in an intense physical training program. These data suggest that elevated plasma hydroxyproline levels may represent a risk factor associated with connective tissue injuries.

  2. Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.

    PubMed

    Reinstein, Eyal; Pariani, Mitchel; Bannykh, Serguei; Rimoin, David L; Schievink, Wouter I

    2013-04-01

    We aimed to assess the frequency of connective tissue abnormalities among patients with cerebrospinal fluid (CSF) leaks in a prospective study using a large cohort of patients. We enrolled a consecutive group of 50 patients, referred for consultation because of CSF leak. All patients have been carefully examined for the presence of connective tissue abnormalities, and based on findings, patients underwent genetic testing. Ancillary diagnostic studies included echocardiography, eye exam, and histopathological examinations of skin and dura biopsies in selected patients. We identified nine patients with heritable connective tissue disorders, including Marfan syndrome, Ehlers-Danlos syndrome and other unclassified forms. In seven patients, spontaneous CSF leak was the first noted manifestation of the genetic disorder. We conclude that spontaneous CSF leaks are associated with a spectrum of connective tissue abnormalities and may be the first noted clinical presentation of the genetic disorder. We propose that there is a clinical basis for considering spontaneous CSF leak as a clinical manifestation of heritable connective tissue disorders, and we suggest that patients with CSF leaks should be screened for connective tissue and vascular abnormalities.

  3. Transcriptomes in healthy and diseased gingival tissues.

    PubMed

    Demmer, Ryan T; Behle, Jan H; Wolf, Dana L; Handfield, Martin; Kebschull, Moritz; Celenti, Romanita; Pavlidis, Paul; Papapanou, Panos N

    2008-11-01

    Clinical and radiographic measures are gold standards for diagnosing periodontitis but offer little information regarding the pathogenesis of the disease. We hypothesized that a comparison of gene expression signatures between healthy and diseased gingival tissues would provide novel insights in the pathobiology of periodontitis and would inform the design of future studies. Ninety systemically healthy non-smokers with moderate to advanced periodontitis (63 with chronic periodontitis and 27 with aggressive periodontitis) each contributed at least two diseased interproximal papillae (with bleeding on probing [BOP], probing depth [PD] > or =4 mm, and attachment loss [AL] > or =3 mm) and a healthy papilla, if available (no BOP, PD < or =4 mm, and AL < or =2 mm). RNA was extracted, amplified, reverse-transcribed, labeled, and hybridized with whole genome microarrays. Differential expression was assayed in 247 individual tissue samples (183 from diseased sites and 64 from healthy sites) using a standard mixed-effects linear model approach, with patient effects considered random with a normal distribution and gingival tissue status considered a two-level fixed effect. Gene ontology analysis classified the expression patterns into biologically relevant categories. Transcriptome analysis revealed that 12,744 probe sets were differentially expressed after adjusting for multiple comparisons (P <9.15 x 10(7)). Of those, 5,295 were upregulated and 7,449 were downregulated in disease compared to health. Gene ontology analysis identified 61 differentially expressed groups (adjusted P <0.05), including apoptosis, antimicrobial humoral response, antigen presentation, regulation of metabolic processes, signal transduction, and angiogenesis. Gingival tissue transcriptomes provide a valuable scientific tool for further hypothesis-driven studies of the pathobiology of periodontitis.

  4. Identification of tumor cells infiltrating into connective tissue in esophageal cancer by multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Xu, Jian; Jiang, Liwei; Kang, Deyong; Wu, Xuejing; Xu, Meifang; Zhuo, Shuangmu; Zhu, Xiaoqin; Lin, Jiangbo; Chen, Jianxin

    2016-10-01

    Esophageal cancer is one of the most common malignancies of the gastrointestinal cancers and carries poorer prognosis than other gastrointestinal cancers. In general practice, the depth of tumor infiltration in esophageal wall is crucial to establishing appropriate treatment plan which is established by detecting the tumor infiltration depth. Connective tissue is one of the main structures that form the esophageal wall. So, identification of tumor cells infiltrating into connective tissue is helping for detecting the tumor infiltration depth. Our aim is to evaluate whether multiphoton microscopy (MPM) can be used to detect tumor cells infiltrating into connective tissue in the esophageal cancer. MPM is well-suited for real-time detecting morphologic and cellular changes in fresh tissues since many endogenous fluorophores of fresh tissues are excited through two-photon excited fluorescence (TPEF) and second harmonic generation (SHG). In this work, microstructure of tumor cells and connective tissue are first studied. Then, morphological changes of collagen fibers after the infiltration of tumor cells are shown. These results show that MPM has the ability to detect tumor cells infiltrating into connective tissue in the esophageal cancer. In the future, MPM may be a promising imaging technique for detecting tumor cells in esophageal cancer.

  5. [Morphometric evaluation of connective tissue reaction to cartilage implants].

    PubMed

    Bumber, Z; Pezerovic Panian, R; Vukoja, M; Markov, D

    1993-03-01

    In this paper, besides already investigated cartilage implants, we studied morphologically and histometrically possibilities to use human thyroid cartilage in reconstructive surgery, especially in nasal septum and pyramid reconstructions. Preserved human thyroid and rib cartilage as well as rabbit preserved rib cartilage were implanted under the back skin of 12 New Zealand rabbits. Animals were divided into two groups with 6 specimens in each group followed 6 and 12 weeks after implantation. Beside morphological investigation we measured histometrically the thickness of connective capsule around implants. Results obtained by our morphological and histometric studies indicate that preserved human thyroid cartilage could be used in reconstructive surgery with the same success as other cartilage implants already used.

  6. 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. Copyright © 2016. Published by Elsevier Inc.

  7. Cell and tissue engineering for liver disease.

    PubMed

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

    2014-07-16

    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.

  8. 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

  9. Transcriptomes in Healthy and Diseased Gingival Tissues

    PubMed Central

    Demmer, Ryan; Behle, Jan H.; Wolf, Dana L.; Handfield, Martin; Kebschull, Moritz; Celenti, Romanita; Pavlidis, Paul; Papapanou, Panos N.

    2009-01-01

    Objectives Clinical and radiographic measures are gold standards for diagnosing periodontitis but offer little information regarding the pathogenesis of the disease. We hypothesized that a comparison of gene expression signatures between healthy and diseased gingival tissues would provide novel insights in the pathobiology of periodontitis, and would inform the design of future studies. Methods Ninety systemically healthy non-smokers with moderate to advanced periodontitis (63 with chronic and 27 with aggressive periodontitis) each contributed with ≥2 “diseased” interproximal papillae [with bleeding on probing (BoP), pocket depth (PD) ≥4mm, and attachment loss (AL) ≥3mm)] and a “healthy” papilla, if available (no BoP, PD ≤4mm and AL ≤2mm). RNA was extracted, amplified, reverse-transcribed, labeled, and hybridized with AffymetrixU133Plus2.0 arrays. Differential expression was assayed in 247 individual tissue samples (183 from diseased and 64 from healthy sites) using a standard mixed-effects linear model approach, with patient effects considered random with a normal distribution, and gingival tissue status considered a two-level fixed effect. Gene ontology analysis summarized the expression patterns into biologically relevant categories. Results Transcriptome analysis revealed that a total of 12,744 probe sets were differentially expressed after adjusting for multiple comparisons (p<9.15×10-7). Of those, 5,295 were up-regulated and 7,449 down-regulated in disease when compared to health. Gene ontology analysis identified 61 differentially expressed groups (adjusted p<0.05) including apoptosis, antimicrobial humoral response, antigen presentation, regulation of metabolic processes, signal transduction, and angiogenesis. Conclusions Gingival tissue transcriptomes provide a valuable scientific tool for further hypothesis-driven studies of the pathobiology of periodontitis. PMID:18980520

  10. Intrinsic connective tissue abnormalities in the heart muscle of cardiomyopathic Syrian hamsters.

    PubMed Central

    Cohen-Gould, L.; Robinson, T. F.; Factor, S. M.

    1987-01-01

    Significant connective tissue abnormalities occurring in hearts of cardiomyopathic Syrian hamsters are reported. These abnormalities include a pronounced loss of the intrinsic connective tissue skeletal framework around foci of myocytolytic necrosis within the non-necrotic myocardium. These changes were demonstrated by a silver impregnation technique, and they were confirmed by scanning electron microscopy. Quantitation demonstrated more than a twofold increase in the area of ventricular wall affected by pathologic changes, when the connective tissue alterations were included with the myocardial necrosis. In addition, the authors also observed focal, thick "tethering" connective tissue fibers at the termini of necrotic lesions, seemingly connecting them to normal muscle. These connective tissue abnormalities may contribute to the progressive loss of ventricular function that occurs in this model of cardiomyopathy. They may permit greater wall thinning than would occur with focal necrosis alone, and they may increase focal mural stiffness in the tethered regions. Further investigation of the pathogenesis of these changes and their mechanical significance is indicated. Images Figure 5 Figure 6 Figure 1 Figure 2 Figure 3 Figure 4 PMID:3578490

  11. A survey of clearing techniques for 3D imaging of tissues with special reference to connective tissue.

    PubMed

    Azaripour, Adriano; Lagerweij, Tonny; Scharfbillig, Christina; Jadczak, Anna Elisabeth; Willershausen, Brita; Van Noorden, Cornelis J F

    2016-08-01

    For 3-dimensional (3D) imaging of a tissue, 3 methodological steps are essential and their successful application depends on specific characteristics of the type of tissue. The steps are 1° clearing of the opaque tissue to render it transparent for microscopy, 2° fluorescence labeling of the tissues and 3° 3D imaging. In the past decades, new methodologies were introduced for the clearing steps with their specific advantages and disadvantages. Most clearing techniques have been applied to the central nervous system and other organs that contain relatively low amounts of connective tissue including extracellular matrix. However, tissues that contain large amounts of extracellular matrix such as dermis in skin or gingiva are difficult to clear. The present survey lists methodologies that are available for clearing of tissues for 3D imaging. We report here that the BABB method using a mixture of benzyl alcohol and benzyl benzoate and iDISCO using dibenzylether (DBE) are the most successful methods for clearing connective tissue-rich gingiva and dermis of skin for 3D histochemistry and imaging of fluorescence using light-sheet microscopy. Copyright © 2016 The Authors. Published by Elsevier GmbH.. All rights reserved.

  12. 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

  13. 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

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

    PubMed

    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.

  15. Water transport and IIF parameters for a connective tissue equivalent.

    PubMed

    Balasubramanian, Saravana Kumar; Bischof, John C; Hubel, Allison

    2006-02-01

    Understanding the biophysical processes that govern freezing injury of a tissue equivalent (TE) is an important step in characterizing and improving the cryopreservation of these systems. TEs were formed by entrapping human dermal fibroblasts (HDFs) in collagen or in fibrin gels. Freezing studies were conducted using a Linkam cryostage fitted to an optical microscope allowing observation of the TEs cooled under controlled rates between 5 and 130 degrees C/min. Typically, freezing of cellular systems results in two biophysical processes that are both dependent on the cooling rate: dehydration and/or intracellular ice formation (IIF). Both these processes can potentially be destructive to cells. In this study, the biophysics of freezing cells in collagen and fibrin TEs have been quantified and compared to freezing cells in suspension. Experimental data were fitted in numerical models to extract parameters that governed water permeability, E(Lp) and L(pg), and intracellular ice nucleation, omega(o) and kappa(o). Results indicate that major differences exist between freezing HDFs in suspension and in a tissue equivalent. During freezing, 55% of the HDFs in suspension formed IIF as compared to 100% of HDFs forming IIF in collagen and fibrin TE at a cooling rate of 130 degrees C/min. Also, both the water permeability and the IIF parameters were determined to be higher for HDFs in TEs as compared to cell suspensions. Between the TEs, HDFs in fibrin TE exhibited higher values for the biophysical parameters as compared to HDFs in collagen TE. The observed biophysics seems to indicate that cell-cell and cell-matrix interactions play a major role in ice propagation in TEs.

  16. High expression of connective tissue growth factor accelerates dissemination of leukaemia.

    PubMed

    Wells, J E; Howlett, M; Halse, H M; Heng, J; Ford, J; Cheung, L C; Samuels, A L; Crook, M; Charles, A K; Cole, C H; Kees, U R

    2016-09-01

    To improve treatment of acute lymphoblastic leukaemia (ALL), a better understanding of disease development is needed to tailor new therapies. Connective tissue growth factor (CTGF/CCN2) is highly expressed in leukaemia cells from the majority of paediatric patients with B-lineage ALL (pre-B ALL). CTGF is a matricellular protein and plays a role in aggressive cancers. Here we have genetically engineered leukaemia cells to modulate CTGF expression levels. Elevated CTGF levels accelerated disease dissemination and reduced survival in NOD/SCID mice. In vitro studies showed that CTGF protein induces stromal cell proliferation, promotes adhesion of leukaemia cells to stromal cells and leads to overexpression of genes associated with cell cycle and synthesis of extracellular matrix (ECM). Corresponding data from our leukaemia xenograft models demonstrated that CTGF leads to increased proliferation of non-leukaemia cells and deposition of ECM in the bone marrow. We document for the first time a functional role of CTGF in altering disease progression in a lymphoid malignancy. The findings provide support for targeting the bone marrow microenvironment in aggressive forms of leukaemia.

  17. Molecular Connections Between Arousal and Metabolic Disease: Orexin and Modafinil

    DTIC Science & Technology

    2007-04-01

    and Metabolic Disease: Orexin and Modafinil PRINCIPAL INVESTIGATOR: Stephen C. Benoit, Ph.D. CONTRACTING ORGANIZATION: University of...NUMBER Molecular Connections Between Arousal and Metabolic Disease: Orexin and Modafinil 5b. GRANT NUMBER W81XWH-06-2-0019 5c. PROGRAM...the central orexin system may modulate energy balance. Ongoing studies are assessing the effects of treatment on insulin sensitivity and also the

  18. Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis

    PubMed Central

    Jiang, Jie; Leong, Natalie L.; Khalique, Umara.; Phan, Tien M.; Lyons, Karen M.; Luck, James V.

    2016-01-01

    Introduction Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. Aim We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. Methods Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. Results All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin-and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. Conclusion Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products. PMID:27704689

  19. Connective tissue growth factor (CTGF/CCN2) in haemophilic arthropathy and arthrofibrosis: a histological analysis.

    PubMed

    Jiang, J; Leong, N L; Khalique, U; Phan, T M; Lyons, K M; Luck, J V

    2016-11-01

    Joint haemorrhage is the principal clinical manifestation of haemophilia frequently leading to advanced arthropathy and arthrofibrosis, resulting in severe disability. The degree and prevalence of arthrofibrosis in hemophilic arthropathy is more severe than in other forms of arthropathy. Expression of connective tissue growth factor (CTGF) has been linked to many fibrotic diseases, but has not been studied in the context of haemophilic arthropathy. We aim to compare synovial tissues histologically from haemophilia and osteoarthritis patients with advanced arthropathy in order to compare expression of proteins that are possibly aetiologic in the development of arthrofibrosis. Human synovial tissues were obtained from 10 haemophilia and 10 osteoarthritis patients undergoing joint surgery and processed for histology and immunohistochemistry. All samples from haemophilia patients had synovitis with hypertrophy and hyperplasia of synovial villi. Histologically, synovial tissues contained hyperplastic villi with increased cellularity and abundant haemosiderin- and ferritin-pigmented macrophage-like cells (HMCs), with a perivascular localization in the sub-surface layer. CTGF staining was observed in the surface layer and sub-surface layer in all haemophilia patients, exclusively co-localizing with HMCs. Quantification showed that the extent of CTGF-positive areas was correlated with the degree of detection of HMCs. CTGF was not observed in any of the samples from osteoarthritis patients. Using histological analysis, we showed that CTGF expression is elevated in haemophilia patients with arthrofibrosis and absent in patients with osteoarthritis. Additionally, we found that CTGF is always associated with haemosiderin-pigmented macrophage-like cells, which suggests that CTGF is produced by synovial A cells following the uptake of blood breakdown products. © 2016 John Wiley & Sons Ltd.

  20. 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

  1. Perimuscular connective tissue contains more and larger lymphatic vessels than the shallower layers in human gallbladders.

    PubMed

    Nagahashi, Masayuki; Shirai, Yoshio; Wakai, Toshifumi; Sakata, Jun; Ajioka, Yoichi; Hatakeyama, Katsuyoshi

    2007-09-07

    To clarify whether perimuscular connective tissue contains more lymphatic vessels than the shallower layers in human gallbladders. Lymphatic vessels were stained immunohistochemically with monoclonal antibody D2-40, which is a specific marker of lymphatic endothelium, in representative sections of 12 normal human gallbladders obtained at the time of resection for colorectal carcinoma liver metastases. In individual gallbladder specimens, nine high-power (x 200) fields with the highest lymphatic vessel density (LVD), termed "hot spots", were identified for each layer (mucosa, muscle layer, and perimuscular connective tissue). In individual hot spots, the LVD and relative lymphatic vessel area (LVA) were measured microscopically using a computer-aided image analysis system. The mean LVD and LVA values for the nine hot spots in each layer were used for statistical analyses. In the mucosa, muscle layer, and perimuscular connective tissue, the LVD was 16.1 +/- 9.2, 35.4 +/- 15.7, and 65.5 +/- 12.2, respectively, and the LVA was 0.4 +/- 0.4, 2.1 +/- 1.1, and 9.4 +/- 2.6, respectively. Thus, both the LVD and LVA differed significantly (P < 0.001 and P < 0.001, respectively; Kruskal-Wallis test) among the individual layers of the wall of the gallbladder, with the highest LVD and LVA values in the perimuscular connective tissue. Most (98 of 108) of the hot spots within the perimuscular connective tissue were located within 500 mum of the lower border of the muscle layer. The perimuscular connective tissue contains more and larger lymphatic vessels than the shallower layers in the human gallbladder. This observation partly explains why the incidence of lymph node metastasis is high in T2 (tumor invading the perimuscular connective tissue) or more advanced gallbladder carcinoma.

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

    PubMed

    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.

  3. 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. Copyright © 2013 Wiley Periodicals, Inc.

  4. [Problems connected with sexual activity in patients with heart disease].

    PubMed

    Rembek, Magdalena; Tylkowski, Michał; Piestrzeniewicz, Katarzyna; Goch, Jan Henryk

    2007-08-01

    The paper presents some basic data on sexual activity in patients with heart disease. The most typical problems of people with stable angina or after myocardial infarction connected with sexual intercourse have been presented. Modulation of risk of heart attack during sexual activity and main problems of sexual dysfunction after acute coronary syndromes have been described.

  5. Behavioral connectivity among bighorn sheep suggests potential for disease spread

    USGS Publications Warehouse

    Borg, Nathan J.; Mitchell, Michael S.; Lukacs, Paul M.; Mack, Curt M.; Waits, Lisette P.; Krausman, Paul R.

    2017-01-01

    Connectivity is important for population persistence and can reduce the potential for inbreeding depression. Connectivity between populations can also facilitate disease transmission; respiratory diseases are one of the most important factors affecting populations of bighorn sheep (Ovis canadensis). The mechanisms of connectivity in populations of bighorn sheep likely have implications for spread of disease, but the behaviors leading to connectivity between bighorn sheep groups are not well understood. From 2007–2012, we radio-collared and monitored 56 bighorn sheep in the Salmon River canyon in central Idaho. We used cluster analysis to define social groups of bighorn sheep and then estimated connectivity between these groups using a multi-state mark-recapture model. Social groups of bighorn sheep were spatially segregated and linearly distributed along the Salmon River canyon. Monthly probabilities of movement between adjacent male and female groups ranged from 0.08 (±0.004 SE) to 0.76 (±0.068) for males and 0.05 (±0.132) to 0.24 (±0.034) for females. Movements of males were extensive and probabilities of movement were considerably higher during the rut. Probabilities of movement for females were typically smaller than those of males and did not change seasonally. Whereas adjacent groups of bighorn sheep along the Salmon River canyon were well connected, connectivity between groups north and south of the Salmon River was limited. The novel application of a multi-state model to a population of bighorn sheep allowed us to estimate the probability of movement between adjacent social groups and approximate the level of connectivity across the population. Our results suggest high movement rates of males during the rut are the most likely to result in transmission of pathogens among both male and female groups. Potential for disease spread among female groups was smaller but non-trivial. Land managers can plan grazing of domestic sheep for spring and summer

  6. Regulatory mechanisms of anthrax toxin receptor 1-dependent vascular and connective tissue homeostasis

    PubMed Central

    Besschetnova, Tatiana Y.; Ichimura, Takaharu; Katebi, Negin; St. Croix, Brad; Bonventre, Joseph V.; Olsen, Bjorn R.

    2015-01-01

    It is well known that angiogenesis is linked to fibrotic processes in fibroproliferative diseases, but insights into pathophysiological processes are limited, due to lack of understanding of molecular mechanisms controlling endothelial and fibroblastic homeostasis. We demonstrate here that the matrix receptor anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8 (TEM8), is an essential component of these mechanisms. Loss of TEM8 function in mice causes reduced synthesis of endothelial basement membrane components and hyperproliferative and leaky blood vessels in skin. In addition, endothelial cell alterations in mutants are almost identical to those of endothelial cells in infantile hemangioma lesions, including activated VEGF receptor signaling in endothelial cells, increased expression of the downstream targets VEGF and CXCL12, and increased numbers of macrophages and mast cells. In contrast, loss of TEM8 in fibroblasts leads to increased rates of synthesis of fiber-forming collagens, resulting in progressive fibrosis in skin and other organs. Compromised interactions between TEM8-deficient endothelial and fibroblastic cells cause dramatic reduction in the activity of the matrix-degrading enzyme MMP2. In addition to insights into mechanisms of connective tissue homeostasis, our data provide molecular explanations for vascular and connective tissue abnormalities in GAPO syndrome, caused by loss-of-function mutations in ANTXR1. Furthermore, the loss of MMP2 activity suggests that fibrotic skin abnormalities in GAPO syndrome are, in part, the consequence of pathophysiological mechanisms underlying syndromes (NAO, Torg and Winchester) with multicentric skin nodulosis and osteolysis caused by homozygous loss-of-function mutations in MMP2. PMID:25572963

  7. Effect of connective tissue grafting on peri-implant tissue in single immediate implant sites: a RCT.

    PubMed

    Zuiderveld, Elise G; Meijer, Henny J A; den Hartog, Laurens; Vissink, Arjan; Raghoebar, Gerry M

    2017-09-23

    To assess the effect of connective tissue grafting on the mid-buccal mucosal level (MBML) of immediately placed and provisionalized single implants in the maxillofacial esthetic zone. Sixty patients with a failing tooth were provided with an immediately placed and provisionalized implant. During implant placement, patients randomly received either a connective tissue graft from the maxillary tuberosity (n=30, test group) or no graft (n=30, control group). Follow-up visits were at one (T1 ) and twelve months (T12 ) after final crown placement. The primary outcome measure was any change in MBML compared to the pre-operative situation. In addition, gingival biotype, esthetics (using the Pink Esthetic Score-White Esthetic Score), marginal bone level, soft tissue peri-implant parameters and patient satisfaction were assessed. The mean MBML change at T12 was -0.5±1.1mm in the control group and 0.1±0.8mm in the test group (p=0.03). No significant differences regarding other outcome variables were observed, neither was gingival biotype associated with a gain or loss in MBML. This one-year study shows that connective tissue grafting in single, immediately placed and provisionalized implants leads to less recession of the peri-implant soft tissue at the mid-buccal aspect, irrespective of the gingival biotype (www.trialregister.nl: TC3815). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  8. 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

  9. Spatial remapping of cortico-striatal connectivity in Parkinson's disease.

    PubMed

    Helmich, Rick C; Derikx, Loes C; Bakker, Maaike; Scheeringa, René; Bloem, Bastiaan R; Toni, Ivan

    2010-05-01

    Parkinson's disease (PD) is characterized by striatal dopamine depletion, especially in the posterior putamen. The dense connectivity profile of the striatum suggests that these local impairments may propagate throughout the whole cortico-striatal network. Here we test the effect of striatal dopamine depletion on cortico-striatal network properties by comparing the functional connectivity profile of the posterior putamen, the anterior putamen, and the caudate nucleus between 41 PD patients and 36 matched controls. We used multiple regression analyses of resting-state functional magnetic resonance imaging data to quantify functional connectivity across different networks. Each region had a distinct connectivity profile that was similarly expressed in patients and controls: the posterior putamen was uniquely coupled to cortical motor areas, the anterior putamen to the pre-supplementary motor area and anterior cingulate cortex, and the caudate nucleus to the dorsal prefrontal cortex. Differences between groups were specific to the putamen: although PD patients showed decreased coupling between the posterior putamen and the inferior parietal cortex, this region showed increased functional connectivity with the anterior putamen. We conclude that dopamine depletion in PD leads to a remapping of cerebral connectivity that reduces the spatial segregation between different cortico-striatal loops. These alterations of network properties may underlie abnormal sensorimotor integration in PD.

  10. 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.

  11. Connective tissue regeneration in skeletal muscle after eccentric contraction-induced injury.

    PubMed

    Mackey, Abigail L; Kjaer, Michael

    2017-03-01

    Human skeletal muscle has the potential to regenerate completely after injury induced under controlled experimental conditions. The events inside the myofibers as they undergo necrosis, followed closely by satellite cell-mediated myogenesis, have been mapped in detail. Much less is known about the adaptation throughout this process of both the connective tissue structures surrounding the myofibers and the fibroblasts, the cells responsible for synthesizing this connective tissue. However, the few studies investigating muscle connective tissue remodeling demonstrate a strong response that appears to be sustained for a long time after the major myofiber responses have subsided. While the use of electrical stimulation to induce eccentric contractions vs. voluntary eccentric contractions appears to lead to a greater extent of myofiber necrosis and regenerative response, this difference is not apparent when the muscle connective tissue responses are compared, although further work is required to confirm this. Pharmacological agents (growth hormone and angiotensin II type I receptor blockers) are considered in the context of accelerating the muscle connective tissue adaptation to loading. Cautioning against this, however, is the association between muscle matrix protein remodeling and protection against reinjury, which suggests that a (so far undefined) period of vulnerability to reinjury may exist during the remodeling phases. The role of individual muscle matrix components and their spatial interaction during adaptation to eccentric contractions is an unexplored field in human skeletal muscle and may provide insight into the optimal timing of rest vs. return to activity after muscle injury.

  12. 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

  13. Shear Strain and Motion of the Subsynovial Connective Tissue and Median Nerve During Single Digit Motion

    PubMed Central

    Yoshii, Yuichi; Zhao, Chunfeng; Henderson, Jacqueline; Zhao, Kristin D.; An, Kai-Nan; Amadio, Peter C.

    2010-01-01

    Purpose The objective of this study was to measure the relative motion of the middle finger flexor digitorum superficialis tendon, its adjacent subsynovial connective tissue, and the median nerve during single digit motion within the carpal tunnel in human cadaver specimens, and estimate the relative motions of these structures in different wrist positions. Methods Using fluoroscopy during simulated single digit flexion, we measured the relative motion of the middle finger flexor digitorum superficialis (FDS) tendon, subsynovial connective tissue and median nerve within the carpal tunnel in twelve human cadavers. Measurements were obtained for three wrist positions: neutral; 60 degrees flexion; and 60 degrees extension. After testing with an intact carpal tunnel was completed, the flexor retinaculum was cut with a scalpel and the same testing procedure was repeated for each wrist position. The relative motions of the tendon, subsynovial connective tissue and median nerve were compared using a shear index, defined as the ratio of the difference in motion along the direction of tendon excursion between two tissues divided by tendon excursion, expressed as a percentage. Results Both tendon-subsynovial connective tissue and tendon-nerve shear index were significantly higher in the 60 degrees of wrist flexion and extension positions, compared to the neutral position. After division of the flexor retinaculum, the shear index in the 60 degrees of wrist extension position remained significantly different, compared to the neutral position. Conclusions In summary, we have found that the relative motion between a tendon and subsynovial connective tissue in the carpal tunnel is maximal at extremes of wrist motion. These positions may predispose the subsynovial connective tissue to shear injury. PMID:19121732

  14. CONTRIBUTIONS TO THE STUDY OF THE MECHANISM OF THE GROWTH OF CONNECTIVE TISSUE

    PubMed Central

    Carrel, Alexis

    1913-01-01

    When connective tissue cells have been cultivated for a certain length of time in a medium which has been repeatedly changed, a definite relation arises between the rate of growth of the cells and the composition of the medium. It is possible, by adding to the culture medium a given quantity of certain substances, such as embryonic juices, to foresee the extent to which a fragment of tissue composed of a given strain of cells will increase in a given time. The rate of growth of a strain of cells can be accelerated or retarded by the addition to the medium of activating or retarding substances. The dynamic condition of a strain of connective tissue cells, which have been living in a given medium for some time, is not a definitely acquired characteristic, but a temporary state, and is the product or function of the medium in which the cells are living, and is readily modified merely by altering the composition of the medium. A knowledge of the characteristics of the growth of connective tissue described has led to a new result,—the indefinite proliferation of a strain of connective tissue cells outside of the organism. The strain of connective tissue originally obtained from a fragment of chick embryo heart, which had been pulsating in vitro for 104 days, was still actively alive after sixteen months of independent life and more than 190 passages. The rate of proliferation of the connective tissue sixteen months old equalled and even exceeded that of fresh connective tissue taken from an eight day old embryo. It appears, therefore, that time has no effect on the tissues isolated from the organism and preserved by means of the technique described above. During the sixteenth month of life in vitro the cells increased rapidly in number and were able in a short time to produce a large quantity of new tissue. This fact, therefore, definitely demonstrates that the tissues were not in a state of survival, as was the case in certain earlier experiments, but in a condition

  15. Effect of MELT method on thoracolumbar connective tissue: The full study.

    PubMed

    Sanjana, Faria; Chaudhry, Hans; Findley, Thomas

    2017-01-01

    Altered connective tissue structure has been identified in adults with chronic low back pain (LBP). A self-care treatment for managing LBP is the MELT method. The MELT method is a hands-off, self-treatment that is said to alleviate chronic pain, release tension and restore mobility, utilizing specialized soft treatments balls, soft body roller and techniques mimicking manual therapy. The objective of this study was to determine whether thickness of thoracolumbar connective tissue and biomechanical and viscoelastic properties of myofascial tissue in the low back region change in subjects with chronic LBP as a result of MELT. This study was designed using a quasi experimental pre-post- design that analyzed data from subjects who performed MELT. Using ultrasound imaging and an algorithm developed in MATLAB, thickness of thoracolumbar connective tissue was analyzed in 22 subjects. A hand-held digital palpation device, called the MyotonPRO, was used to assess biomechanical properties such as stiffness, elasticity, tone and mechanical stress relaxation time of the thoracolumbar myofascial tissue. A forward bending test assessing flexibility and pain scale was added to see if MELT affected subjects with chronic LBP. A significant decrease in connective tissue thickness and pain was observed in participants. Significant increase in flexibility was also recorded.

  16. Parieto-motor functional connectivity is impaired in Parkinson's disease.

    PubMed

    Palomar, Francisco J; Conde, Virginia; Carrillo, Fátima; Fernández-del-Olmo, Miguel; Koch, Giacomo; Mir, Pablo

    2013-03-01

    Bradykinesia in Parkinson's disease is associated with a difficulty in selecting and executing motor actions, likely due to alterations in the functional connectivity of cortico-cortical circuits. Our aims were to analyse the functional interplay between the posterior parietal cortex and the ipsilateral primary motor area in Parkinson's disease using bifocal transcranial magnetic stimulation, to evaluate its modulation by dopaminergic treatment and its relationship to a simple choice reaction task. We studied 12 Parkinson's disease patients with and without dopaminergic treatment and 12 healthy controls. A paired-pulse transcranial magnetic stimulation protocol was applied over the right posterior parietal cortex and the right primary motor area using different conditioning stimulus intensities and interstimulus intervals. Reaction and movement times were studied by a simple choice reaction task. In controls, we observed a significant facilitation of motor evoked potential amplitudes at 4 ms interstimulus interval when conditioning stimulus intensity was set to 90% of resting motor threshold. This functional interaction was not observed in Parkinson's disease patients without dopaminergic treatment and was not restored with treatment. Moreover, correlation analyses revealed that Parkinson's disease patients with less impaired parieto-motor interaction were faster in executing reaching movements in a choice reaction time task, suggesting that the functional parieto-motor impairment described here could be related to bradykinesia observed in Parkinson's disease patients. Parieto-motor functional connectivity is impaired in Parkinson's disease. The reduced efficacy of this connection could be related to presence of bradykinesia previously observed in Parkinson's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Molecular mechanisms for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

    PubMed

    Watanabe, Hiroshi

    2013-01-01

    Chronic kidney disease (CKD), marked by a progressive loss in renal function, is a leading cause of hemodialysis initiation and cardiovascular disease (CVD). There are currently 13.3 million patients with CKD and 300 thousand patients are currently undergoing hemodialysis in Japan. Therefore, preventing the initiation of dialysis and reducing the risk of cardiovascular death are high-priority issues from the viewpoint of public health and economic implications. Understanding the molecular mechanism responsible for the progression of CKD and cardiovascular damage regarding crosstalk between the kidney and cardiovascular system is an important issue in controlling the pathogenesis of CKD-CVD. However, the mechanisms involved in CKD-CVD are not well understood. This hinders the development of new treatment strategies. We have been investigating the role of protein bound uremic toxins, that are difficult to remove by hemodialysis, on the onset and progression of CKD and CVD. The relationship between their redox properties and the pathogenesis of CKD-CVD was examined. In this review, we focus on two sulfate conjugated uremic toxins, namely, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), and summarize recent studies that provide new insights on the molecular mechanisms responsible for uremic toxin-induced oxidative tissue damage via a cardiovascular-renal connection.

  18. Epithelial and connective tissue healing following electrosurgical incisions in human gingiva.

    PubMed

    Kalkwarf, K L; Krejci, R F; Wentz, F M; Edison, A R

    1983-02-01

    Electrosurgery is used for intraoral incisions by many clinicians. Much controversy surrounds the effect of lateral heat produced during the electrosurgical incision upon the healing of adjacent connective tissue. Ten electrosurgical incisions were made in the gingiva in each of five adult male volunteers. The duration of incision and actual energy production for each incision were calculated. Excisional biopsies of the incisions were obtained at 0-504 hours. At the light microscopic level, epithelium, totally degenerated immediately following the electrosurgery incision, showed extensive activity at 24-48 hours and had covered all wounds by 72 hours. Early hour specimens showed a homogenous connective tissue region, adjacent to the wound site, devoid of cells and fibers. This zone of denatured connective tissue gradually diminished until it was no longer present at 396 hours.

  19. 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

  20. Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis

    PubMed Central

    2009-01-01

    Introduction A protein analysis using a mass spectrometry indicated that there are serum proteins showing significant quantitative changes after the administration of infliximab. Among them, connective tissue growth factor (CTGF) seems to be related to the pathogenesis of rheumatoid arthritis (RA). Therefore, this study was conducted to investigate how CTGF is associated with the disease progression of RA. Methods Serum samples were collected from RA patients in active or inactive disease stages, and before or after treatments with infliximab. CTGF production was evaluated by ELISA, RT-PCR, indirect immunofluorescence microscopy, and immunoblotting. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase (TRAP) staining, a bone resorption assay and osteoclasts specific catalytic enzymes productions. Results The serum concentrations of CTGF in RA were greater than in normal healthy controls and disease controls. Interestingly, those were significantly higher in active RA patients compared to inactive RA patients. Furthermore, the CTGF levels significantly were decreased by infliximab concomitant with the disease amelioration. In addition, tumour necrosis factor (TNF)α can induce the CTGF production from synovial fibroblasts even though TNFα can oppositely inhibit the production of CTGF from chondrocytes. CTGF promoted the induction of the quantitative and qualitative activities of osteoclasts in combination with M-CSF and receptor activator of NF-κB ligand (RANKL). In addition, we newly found integrin αVβ3 on the osteoclasts as a CTGF receptor. Conclusions These results indicate that aberrant CTGF production induced by TNFα plays a central role for the abnormal osteoclastic activation in RA patients. Restoration of aberrant CTGF production may contribute to the inhibition of articular destruction in infliximab treatment. PMID:19922639

  1. 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.

  2. [Advances in the study on the role of connective tissue in the mechanical signal transduction of acupuncture].

    PubMed

    Jiang, Xue-Mei; Zhang, Xue-Quan; Yuan, Lin

    2009-04-01

    Non-specific connective tissue (fascia connective tissue) plays an important role in the mechanical signal transduction of acupuncture. Acupuncture needle manipulation-induced mechanical stress has a certain effect on the fibroblasts and cytoskeleton in the nonspecific connective tissue (including loose connective tissue and fat tissue) in morphology, histochemistry and biochemistry. For example, acupuncture-needle manipulation can make the fibroblast deformed, the cytoskeleton remodeled and result in the release of biochemical materials from the connective tissue. The present review summarizes new results of studies on the effect of acupuncture needle manipulation from cytobiology, imageology and physiology; and holds that making clear the transduction pathways of acupuncture mechanical stress signals in the connective tissue and its impact on the organism possesses an important significance in revealing the mechanism of acupuncture underlying clinical therapeutic effects.

  3. Mechanical tension as a driver of connective tissue growth in vitro.

    PubMed

    Wilson, Cameron J; Pearcy, Mark J; Epari, Devakara R

    2014-07-01

    We propose the progressive mechanical expansion of cell-derived tissue analogues as a novel, growth-based approach to in vitro tissue engineering. The prevailing approach to producing tissue in vitro is to culture cells in an exogenous "scaffold" that provides a basic structure and mechanical support. This necessarily pre-defines the final size of the implantable material, and specific signals must be provided to stimulate appropriate cell growth, differentiation and matrix formation. In contrast, surgical skin expansion, driven by increments of stretch, produces increasing quantities of tissue without trauma or inflammation. This suggests that connective tissue cells have the innate ability to produce growth in response to elevated tension. We posit that this capacity is maintained in vitro, and that order-of-magnitude growth may be similarly attained in self-assembling cultures of cells and their own extracellular matrix. The hypothesis that growth of connective tissue analogues can be induced by mechanical expansion in vitro may be divided into three components: (1) tension stimulates cell proliferation and extracellular matrix synthesis; (2) the corresponding volume increase will relax the tension imparted by a fixed displacement; (3) the repeated application of static stretch will produce sustained growth and a tissue structure adapted to the tensile loading. Connective tissues exist in a state of residual tension, which is actively maintained by resident cells such as fibroblasts. Studies in vitro and in vivo have demonstrated that cellular survival, reproduction, and matrix synthesis and degradation are regulated by the mechanical environment. Order-of-magnitude increases in both bone and skin volume have been achieved clinically through staged expansion protocols, demonstrating that tension-driven growth can be sustained over prolonged periods. Furthermore, cell-derived tissue analogues have demonstrated mechanically advantageous structural adaptation in

  4. 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.

  5. The connective tissue of the adductor canal – a morphological study in fetal and adult specimens

    PubMed Central

    de Oliveira, Flavia; de Vasconcellos Fontes, Ricardo Bragança; da Silva Baptista, Josemberg; Mayer, William Paganini; de Campos Boldrini, Silvia; Liberti, Edson Aparecido

    2009-01-01

    The adductor canal is a conical or pyramid-shaped pathway that contains the femoral vessels, saphenous nerve and a varying amount of fibrous tissue. It is involved in adductor canal syndrome, a claudication syndrome involving young individuals. Our objective was to study modifications induced by aging on the connective tissue and to correlate them to the proposed pathophysiological mechanism. The bilateral adductor canals and femoral vessels of four adult and five fetal specimens were removed en bloc and analyzed. Sections 12 µm thick were obtained and the connective tissue studied with Sirius Red, Verhoeff, Weigert and Azo stains. Scanning electron microscopy (SEM) photomicrographs of the surfaces of each adductor canal were also analyzed. Findings were homogeneous inside each group. The connective tissue of the canal was continuous with the outer layer of the vessels in both groups. The pattern of concentric, thick collagen type I bundles in fetal specimens was replaced by a diffuse network of compact collagen bundles with several transversal fibers and an impressive content of collagen III fibers. Elastic fibers in adults were not concentrated in the thick bundles but dispersed in line with the transversal fiber system. A dynamic compression mechanism with or without an evident constricting fibrous band has been proposed previously for adductor canal syndrome, possibly involving the connective tissue inside the canal. The vessels may not slide freely during movement. These age-related modifications in normal individuals may represent necessary conditions for this syndrome to develop. PMID:19245505

  6. Permeability of the subsynovial connective tissue in the human carpal tunnel: a cadaver study.

    PubMed

    Osamura, Naoki; Zhao, Chunfeng; Zobitz, Mark E; An, Kai-Nan; Amadio, Peter C

    2007-06-01

    The purpose of this study was to determine the permeability of the normal carpal tunnel subsynovial connective tissue. Subsynovial connective tissue samples (10mm(2)) were obtained from 10 fresh frozen human cadavers without a history of carpal tunnel syndrome. The thickness of the sample was measured using a charge-coupled device laser displacement system. Each specimen was tested for permeability in a closed pressure chamber at 13.8, 41.3, 68.9 and 96.5 kPa. Since permeated flow was very low in all specimens, the permeability could be calculated only for eight specimens at 96.5 kPa pressure and for three specimens at 68.9 kPa. The mean permeability at 96.5 kPa was mean 0.89 (SD 0.93)x10(-14)m(4)/Ns and at 68.9 kPa was mean 1.04 (SD 1.54)x10(-14)m(4)/Ns. The subsynovial connective tissue is the most characteristic tissue in the carpal tunnel; it is found in no other location in such abundance. It is well known that carpal tunnel syndrome is the result of increased pressure within the carpal tunnel. This lack of permeability in the subsynovial connective tissue may explain the predisposition of this region for pressure buildup and subsequent neuropathy.

  7. The connective tissue of the adductor canal--a morphological study in fetal and adult specimens.

    PubMed

    de Oliveira, Flavia; de Vasconcellos Fontes, Ricardo Bragança; da Silva Baptista, Josemberg; Mayer, William Paganini; de Campos Boldrini, Silvia; Liberti, Edson Aparecido

    2009-03-01

    The adductor canal is a conical or pyramid-shaped pathway that contains the femoral vessels, saphenous nerve and a varying amount of fibrous tissue. It is involved in adductor canal syndrome, a claudication syndrome involving young individuals. Our objective was to study modifications induced by aging on the connective tissue and to correlate them to the proposed pathophysiological mechanism. The bilateral adductor canals and femoral vessels of four adult and five fetal specimens were removed en bloc and analyzed. Sections 12 microm thick were obtained and the connective tissue studied with Sirius Red, Verhoeff, Weigert and Azo stains. Scanning electron microscopy (SEM) photomicrographs of the surfaces of each adductor canal were also analyzed. Findings were homogeneous inside each group. The connective tissue of the canal was continuous with the outer layer of the vessels in both groups. The pattern of concentric, thick collagen type I bundles in fetal specimens was replaced by a diffuse network of compact collagen bundles with several transversal fibers and an impressive content of collagen III fibers. Elastic fibers in adults were not concentrated in the thick bundles but dispersed in line with the transversal fiber system. A dynamic compression mechanism with or without an evident constricting fibrous band has been proposed previously for adductor canal syndrome, possibly involving the connective tissue inside the canal. The vessels may not slide freely during movement. These age-related modifications in normal individuals may represent necessary conditions for this syndrome to develop.

  8. Urinary tissue factor activity in colorectal disease.

    PubMed

    Carty, N; Taylor, I; Roath, O S; el-Baruni, K; Francis, J L

    1990-10-01

    Procoagulant activity (PCA) in normal urine has been recognized for over 50 years. Although tissue factor (TF) is produced by certain tumours, and is increased in both tumour-associated macrophages and blood monocytes, the possibility that it might also be increased in urine has not been studied in patients with cancer. We have measured urinary PCA in hospital controls without inflammatory or neoplastic disease (n = 79), in patients with rheumatoid arthritis (n = 8), inflammatory bowel disease (n = 19), colorectal cancer (n = 70) and in patients undergoing colonoscopy (n = 50). Urinary PCA was higher (P less than 0.001) in patients with colorectal cancer and inflammatory bowel disease than controls or patients with rheumatoid arthritis. Fourteen (88 per cent) out of 16 colonoscopy patients subsequently found to have carcinoma or inflammatory bowel disease had levels above the control upper quartile, compared with 8 (24 per cent) out of 34 with normal colonoscopy (P less than 0.001). TF inhibitors confirmed the nature of the PCA and Western blotting studies indicated a urinary TF molecular weight of approximately 38,000. These studies provide further evidence of abnormal haemostasis in malignancy and suggest that determination of urinary TF may provide a useful screening test in patients undergoing colonoscopy.

  9. Live Imaging of Axolotl Digit Regeneration Reveals Spatiotemporal Choreography of Diverse Connective Tissue Progenitor Pools.

    PubMed

    Currie, Joshua D; Kawaguchi, Akane; Traspas, Ricardo Moreno; Schuez, Maritta; Chara, Osvaldo; Tanaka, Elly M

    2016-11-21

    Connective tissues-skeleton, dermis, pericytes, fascia-are a key cell source for regenerating the patterned skeleton during axolotl appendage regeneration. This complexity has made it difficult to identify the cells that regenerate skeletal tissue. Inability to identify these cells has impeded a mechanistic understanding of blastema formation. By tracing cells during digit tip regeneration using brainbow transgenic axolotls, we show that cells from each connective tissue compartment have distinct spatial and temporal profiles of proliferation, migration, and differentiation. Chondrocytes proliferate but do not migrate into the regenerate. In contrast, pericytes proliferate, then migrate into the blastema and give rise solely to pericytes. Periskeletal cells and fibroblasts contribute the bulk of digit blastema cells and acquire diverse fates according to successive waves of migration that choreograph their proximal-distal and tissue contributions. We further show that platelet-derived growth factor signaling is a potent inducer of fibroblast migration, which is required to form the blastema.

  10. [Biological Role of Oligomerny Matriksny of Protein of the Cartilage in Exchange Processes Connecting Tissue].

    PubMed

    Belova, Yu S

    2015-01-01

    In the review the literary data on studying of biological role of a oligomerny matriksny of protein of the cartilage in exchange processes connecting tissue at people and animals are provided, and also results of own researches on definition of a oligomerny matriksny of protein of the cartilage as a modern marker of a metabolism of an articulate cartilage at children from undifferentiated displaziy conjunctive tissue are briefly described.

  11. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease.

    PubMed

    Pandey, Manoj K; Burrow, Thomas A; Rani, Reena; Martin, Lisa J; Witte, David; Setchell, Kenneth D; Mckay, Mary A; Magnusen, Albert F; Zhang, Wujuan; Liou, Benjamin; Köhl, Jörg; Grabowski, Gregory A

    2017-03-02

    Gaucher disease is caused by mutations in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA1 mutations drive extensive accumulation of glucosylceramide (GC) in multiple innate and adaptive immune cells in the spleen, liver, lung and bone marrow, often leading to chronic inflammation. The mechanisms that connect excess GC to tissue inflammation remain unknown. Here we show that activation of complement C5a and C5a receptor 1 (C5aR1) controls GC accumulation and the inflammatory response in experimental and clinical Gaucher disease. Marked local and systemic complement activation occurred in GCase-deficient mice or after pharmacological inhibition of GCase and was associated with GC storage, tissue inflammation and proinflammatory cytokine production. Whereas all GCase-inhibited mice died within 4-5 weeks, mice deficient in both GCase and C5aR1, and wild-type mice in which GCase and C5aR were pharmacologically inhibited, were protected from these adverse effects and consequently survived. In mice and humans, GCase deficiency was associated with strong formation of complement-activating GC-specific IgG autoantibodies, leading to complement activation and C5a generation. Subsequent C5aR1 activation controlled UDP-glucose ceramide glucosyltransferase production, thereby tipping the balance between GC formation and degradation. Thus, extensive GC storage induces complement-activating IgG autoantibodies that drive a pathway of C5a generation and C5aR1 activation that fuels a cycle of cellular GC accumulation, innate and adaptive immune cell recruitment and activation in Gaucher disease. As enzyme replacement and substrate reduction therapies are expensive and still associated with inflammation, increased risk of cancer and Parkinson disease, targeting C5aR1 may serve as a treatment option for patients with Gaucher disease and, possibly, other lysosomal storage diseases.

  12. Presence of simple renal cysts is associated with increased risk of aortic dissection: a common manifestation of connective tissue degeneration?

    PubMed

    Kim, Eun Kyoung; Choi, E Ryoung; Song, Bong Gun; Jang, Shin Yi; Ko, Sung Min; Choi, Seung-Hyuk; Sung, Jidong; Sung, Kiick; Choe, Yeon Hyeon; Oh, Jae K; Kim, Duk-Kyung

    2011-01-01

    Aortic dissection is a multifactorial disease whose primary pathology is connective tissue degeneration of the aorta's medial layer. It was hypothesised that the presence of renal cysts, another possible manifestation of connective tissue weakness, would be associated with increased risk of aortic dissection. The incidence of simple renal cysts on CT angiography in 518 patients with aortic dissection (AD group) and 1366 healthy subjects (control group) who underwent CT for routine health screening was compared. To reduce the effects of selection bias and confounding variables, data were adjusted by propensity score matching. The prevalence of simple renal cysts was 37.8% in the AD group and 22.0% in the control group, a statistically significant difference (p<0.0001). The prevalence of renal cysts was even greater in patients with the following characteristics: intramural haematoma, type B dissection, normal blood pressure or advanced age. In the 311 matched cohorts after propensity score matching, the prevalence of simple renal cysts was still significantly higher in the AD group than in the control group (33.8% vs 25.7%, p = 0.023). Multivariate analysis confirmed that the presence of renal cysts (OR 1.49, p = 0.0245) could be a marker of having a common underlying mechanism with aortic dissection. Patients with aortic dissection have an increased burden of renal cysts compared with healthy controls. This finding suggests that the connective tissue weakness that predisposes patients to renal cysts may be associated with aortic dissection.

  13. 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.

  14. 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.

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

    USDA-ARS?s Scientific Manuscript database

    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...

  16. Elastin Cables Define the Axial Connective Tissue System in the Murine Lung.

    PubMed

    Wagner, Willi; Bennett, Robert D; Ackermann, Maximilian; Ysasi, Alexandra B; Belle, Janeil; Valenzuela, Cristian D; Pabst, Andreas; Tsuda, Akira; Konerding, Moritz A; Mentzer, Steven J

    2015-11-01

    The axial connective tissue system is a fiber continuum of the lung that maintains alveolar surface area during changes in lung volume. Although the molecular anatomy of the axial system remains undefined, the fiber continuum of the lung is central to contemporary models of lung micromechanics and alveolar regeneration. To provide a detailed molecular structure of the axial connective tissue system, we examined the extracellular matrix of murine lungs. The lungs were decellularized using a 24 hr detergent treatment protocol. Systematic evaluation of the decellularized lungs demonstrated no residual cellular debris; morphometry demonstrated a mean 39 ± 7% reduction in lung dimensions. Scanning electron microscopy (SEM) demonstrated an intact structural hierarchy within the decellularized lung. Light, fluorescence, and SEM of precision-cut lung slices demonstrated that alveolar duct structure was defined by a cable line element encased in basement membrane. The cable line element arose in the distal airways, passed through septal tips and inserted into neighboring blood vessels and visceral pleura. The ropelike appearance, collagenase resistance and anti-elastin immunostaining indicated that the cable was an elastin macromolecule. Our results indicate that the helical line element of the axial connective tissue system is composed of an elastin cable that not only defines the structure of the alveolar duct, but also integrates the axial connective tissue system into visceral pleura and peripheral blood vessels.

  17. 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.

  18. Ultrastructure of sea urchin tube feet. Evidence for connective tissue involvement in motor control.

    PubMed

    Florey, E; Cahill, M A

    1977-02-09

    An analysis of the ultrastructure of the tube feet of three species of sea urchins (Strongylocentrotus franciscanus, Arbacia lixula and Echinus esculentus) revealed that the smooth muscle, although known to be cholinoceptive, receives no motor innervation. The muscle fibers are attached to a double layer of circular and longitudinal connective tissue which surrounds the muscle layer and contains numerous bundles of collagen fibers. On its outside, the connective tissue cylinder is invested by a basal lamina of the outer epithelium to which numerous nerve terminals are attached. These are part of a nerve plexus which surrounds the connective tissue cylinder. The plexus itself is an extension of a longitudinal nerve that extends the whole length of the tube foot. It is composed of axons, but nerve cell bodies and synapses are conspicuously lacking, suggesting that the axons and terminals derive from cells of the radial nerve. Processes of the epithelial cells penetrate the nerve plexus and attach to the basal lamina. There is no evidence that the epithelial cells function as sensory cells. On the basis of supporting evidence it is suggested that the transmitter released by the nerve terminals diffuses to the muscle cells over a distance of several microns and in doing so affects the mechanical properties of the connective tissue.

  19. Connective tissue growth factor production by activated pancreatic stellate cells in mouse alcoholic chronic pancreatitis

    PubMed Central

    Charrier, Alyssa; Brigstock, David R.

    2010-01-01

    Alcoholic chronic pancreatitis (ACP) is characterized by pancreatic necrosis, inflammation, and scarring, the latter of which is due to excessive collagen deposition by activated pancreatic stellate cells (PSC). The aim of this study was to establish a model of ACP in mice, a species that is usually resistant to the toxic effects of alcohol, and to identify the cell type(s) responsible for production of connective tissue growth factor (CTGF), a pro-fibrotic molecule. C57Bl/6 male mice received intraperitoneal ethanol injections for three weeks against a background of cerulein-induced acute pancreatitis. Peak blood alcohol levels remained consistently high in ethanol-treated mice as compared to control mice. In mice receiving ethanol plus cerulein, there was increased collagen deposition as compared to other treatment groups as well as increased frequency of α-smooth muscle actin and desmin-positive PSC which also demonstrated significantly enhanced CTGF protein production. Expression of mRNA for collagen α1(I), α-smooth muscle actin or CTGF were all increased and co-localized exclusively to activated PSC in ACP. Pancreatic expression of mRNA for key profibrotic markers were all increased in ACP. In conclusion, a mouse model of ACP has been developed that mimics key pathophysiological features of the disease in humans and which shows that activated PSC are the principal producers of collagen and CTGF. PSC-derived CTGF is thus a candidate therapeutic target in anti-fibrotic strategies for ACP. PMID:20368699

  20. Development of a novel gene silencer pyrrole-imidazole polyamide targeting human connective tissue growth factor.

    PubMed

    Wan, Jian-Xin; Fukuda, Noboru; Ueno, Takahiro; Watanabe, Takayoshi; Matsuda, Hiroyuki; Saito, Kosuke; Nagase, Hiroki; Matsumoto, Yoshiaki; Matsumoto, Koichi

    2011-01-01

    Pyrrole-imidazole (PI) polyamide can bind to specific sequences in the minor groove of double-helical DNA and inhibit transcription of the genes. We designed and synthesized a PI polyamide to target the human connective tissue growth factor (hCTGF) promoter region adjacent to the Smads binding site. Among coupling activators that yield PI polyamides, 1-[bis(dimethylamino)methylene]-5-chloro-1H-benzotriazolium 3-oxide hexafluorophosphate (HCTU) was most effective in total yields of PI polyamides. A gel shift assay showed that a PI polyamide designed specifically for hCTGF (PI polyamide to hCTGF) bound the appropriate double-stranded oligonucleotide. A fluorescein isothiocyanate (FITC)-conjugated PI polyamide to CTGF permeated cell membranes and accumulated in the nuclei of cultured human mesangial cells (HMCs) and remained there for 48 h. The PI polyamide to hCTGF significantly decreased phorbol 12-myristate acetate (PMA)- or transforming growth factor-β1 (TGF-β1)-stimulated luciferase activity of the hCTGF promoter in cultured HMCs. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated expression of hCTGF mRNA in a dose-dependent manner. The PI polyamide to hCTGF significantly decreased PMA- or TGF-β1-stimulated levels of hCTGF protein in HMCs. These results indicate that the developed synthetic PI polyamide to hCTGF could be a novel gene silencer for fibrotic diseases.

  1. 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.

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

    PubMed

    Tsai, Chieh-Chih; Wu, Shi-Bei; 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.

  3. Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro.

    PubMed

    Sonnylal, Sonali; Xu, Shiwen; Jones, Helen; Tam, Angela; Sreeram, Vivek R; Ponticos, Markella; Norman, Jill; Agrawal, Pankaj; Abraham, David; de Crombrugghe, Benoit

    2013-05-15

    Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathways. In addition to an expansion of the dermal compartment in Col1a2-CTGF transgenic mice, the epidermis was characterized by focal hyperplasia, and basal cells stained positive for αSMA, Snail, S100A4 and Sox9, indicating that these cells had undergone a change in their genetic program. Activation of phosphorylated p38 and phosphorylated Erk1/2 was observed in the granular and cornified layers of the skin. Lung fibrosis was associated with a marked increase in cells co-expressing epithelial and mesenchymal markers in the lesional and unaffected lung tissue of Col1a2-CTGF mice. In epithelial cells treated with TGFβ, CTGF-specific siRNA-mediated knockdown suppressed Snail, Sox9, S100A4 protein levels and restored E-cadherin levels. Both adenoviral expression of CTGF in epithelial cells and treatment with recombinant CTGF induced EMT-like morphological changes and expression of α-SMA. Our in vivo and in vitro data supports the notion that CTGF expression in mesenchymal cells in the skin and lungs can cause changes in the differentiation program of adjacent epithelial cells. We speculate that these changes might contribute to fibrogenesis.

  4. Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro

    PubMed Central

    Sonnylal, Sonali; Xu, Shiwen; Jones, Helen; Tam, Angela; Sreeram, Vivek R.; Ponticos, Markella; Norman, Jill; Agrawal, Pankaj; Abraham, David; de Crombrugghe, Benoit

    2013-01-01

    Summary Connective tissue growth factor (CTGF) plays an important role in the pathogenesis of chronic fibrotic diseases. However, the mechanism by which paracrine effects of CTGF control the cell fate of neighboring epithelial cells is not known. In this study, we investigated the paracrine effects of CTGF overexpressed in fibroblasts of Col1a2-CTGF transgenic mice on epithelial cells of skin and lung. The skin and lungs of Col1a2-CTGF transgenic mice were examined for phenotypic markers of epithelial activation and differentiation and stimulation of signal transduction pathwa