Diagnóstico de esclerose sistêmica em pacientes com hipertensão pulmonar inicialmente considerada idiopática / Diagnosis of systemic sclerosis in patients with pulmonary hypertension initially considered idiopathic

Introdução: A Hipertensão Arterial Pulmonar está associada a uma ampla gama de doenças, sendo comum nas doenças do tecido conjuntivo. Porém, um dos maiores desafios diagnósticos em relação à Hipertensão Arterial Pulmonar inclui doenças do tecido conjuntivo clinicamente não identificadas ou tardiamente evidenciadas, principalmente Esclerose Sistêmica. Objetivos: Relatar casos de Hipertensão Arterial Pulmonar secundária à Esclerose Sistêmica que inicialmente foi classificada como Idiopática. Materiais e métodos: Estudo observacional analítico transversal no qual sete pacientes com diagnóstico de Hipertensão Arterial Pulmonar Idiopática foram avaliados quanto ao quadro clínico, exame físico, pesquisa de autoanticorpos e capilaroscopia periungueal na busca de critérios que os classificassem como Esclerose Sistêmica. Resultados: Todos os pacientes preencheram os Critérios Classificatórios para Esclerose Sistêmica ACR/EULAR 2013, sendo que Fenômeno de Raynaud, telangiectasias e positividade de autoanticorpos estiveram presentes em 100% dos casos. A maioria dos pacientes apresentava Esclerose Sistêmica forma cutânea limitada. Conclusões: A determinação do diagnóstico de Hipertensão Arterial Pulmonar secundária à Esclerose Sistêmica é fundamental, pois tais pacientes têm menor sobrevida quando comparados aos casos Idiopáticos. A presença de Fenômeno de Raynaud tem grande relevância no diagnóstico dos pacientes com Hipertensão Arterial Pulmonar associada à Esclerose Sistêmica.

Introduction: Pulmonary Arterial Hypertension is associated with a wide range of diseases. It is common in connective tissue diseases. However, one of the major diagnostic challenges in relation to Pulmonary Arterial Hypertension includes clinically unidentified or late-onset diseases of the connective tissue, mainly Systemic Sclerosis. Objectives: To report cases of Pulmonary Arterial Hypertension secondary to Systemic Sclerosis, which was initially classified as Idiopathic. Patients and methods: We carried out a cross-sectional observational study in which seven patients with a diagnosis of Idiopathic Pulmonary Arterial Hypertension was evaluated for clinical examination, physical examination, autoantibody and nailfold capillaroscopy examination in search of criteria that reclassified them as Systemic Sclerosis. Results: All patients met the Classification Criteria for Systemic Sclerosis ACR/EULAR 2013, with Raynaud's Phenomenon, telangiectasia and autoantibody positivity being present in 100% of the cases. The majority of patients presented limited cutaneous Systemic Sclerosis. Conclusions: The diagnosis of Pulmonary Arterial Hypertension secondary to Systemic Sclerosis is essential, considering the association with lower survival when compared to the idiopathic cases. The presence of Raynaud's Phenomenon has an important relevance in the diagnosis of patients with Pulmonary Arterial Hypertension associated with Systemic Sclerosis.

Biallelic COL3A1 mutations result in a clinical spectrum of specific structural brain anomalies and connective tissue abnormalities.

Vascular Ehlers-Danlos syndrome (type IV) is an autosomal dominant disorder caused by heterozygous variants of COL3A1. We identified biallelic COL3A1 variants in two unrelated families. In a 3-year-old female with developmental delay the nonsense variant c.1282C>T, p.(Arg428*) was detected in combination the c.2057delC, p.(Pro686Leufs*105) frame shift variant. Both compound heterozygous variants were novel. This patient was born with bilateral clubfoot, joint laxity, and dysmorphic facial features. At the age of 2 years she developed an aneurysmal brain hemorrhage. Cerebral MRI showed a peculiar pattern of profound cerebral abnormalities including bilateral frontoparietal polymicrogyria of the cobblestone variant. In the second family, the two affected siblings were homozygous for the missense variant c.145C

Altered mechanical interaction between rat plantar flexors due to changes in intermuscular connectivity.

Connective tissue formation following muscle injury and remedial surgery may involve changes in the stiffness and configuration of the connective tissues linking adjacent muscles. We investigated changes in mechanical interaction of muscles by implanting either a tissue-integrating mesh (n = 8) or an adhesion barrier (n = 8) to respectively increase or decrease the intermuscular connectivity between soleus muscle (SO) and the lateral gastrocnemius and plantaris complex (LG+PL) of the rat. As a measure of mechanical interaction, changes in SO tendon forces and proximal-distal LG+PL force differences in response to lengthening LG+PL proximally were assessed 1 and 2 weeks post-surgery. The extent of mechanical interaction was doubled 1 week post-implantation of the tissue-integrating mesh compared to an unaffected compartment (n = 8), and was more than four times higher 2 weeks post-surgery. This was found only for maximally activated muscles, but not when passive. Implanting the adhesion barrier did not result in a reduction of the mechanical interaction between these muscles. Our findings indicate that the ratio of force transmitted via myofascial, rather than myotendinous pathways, can increase substantially when the connectivity between muscles is enhanced. This improves our understanding of the consequences of connective tissue formation at the muscle boundary on skeletal muscle function.

Alternatively activated macrophages determine repair of the infarcted adult murine heart.

Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction (MI) remains to be fully characterized. Here, we identified CD206+F4/80+CD11b+ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (Trib1-/-), which exhibit a selective depletion of M2 macrophages after MI. Compared with control animals, Trib1-/- mice had a catastrophic prognosis, with frequent cardiac rupture, as the result of markedly reduced collagen fibril formation in the infarct area due to impaired fibroblast activation. The decreased tissue repair observed in Trib1-/- mice was entirely rescued by an external supply of M2-like macrophages. Furthermore, IL-1α and osteopontin were suggested to be mediators of M2-like macrophage-induced fibroblast activation. In addition, IL-4 administration achieved a targeted increase in the number of M2-like macrophages and enhanced the post-MI prognosis of WT mice, corresponding with amplified fibroblast activation and formation of more supportive fibrous tissues in the infarcts. Together, these data demonstrate that M2-like macrophages critically determine the repair of infarcted adult murine heart by regulating fibroblast activation and suggest that IL-4 is a potential biological drug for treating MI.

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

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

Role of Age-Associated Alterations of the Dermal Extracellular Matrix Microenvironment in Human Skin Aging: A Mini-Review.

Human skin is largely composed of a collagen-rich connective tissue, which provides structural and functional support. The collagen-rich connective tissue is produced, organized, and maintained by dermal fibroblasts. During aging, dermal collagen fibrils undergo progressive loss and fragmentation, leading to thin and structurally weakened skin. Age-related alterations of collagen fibrils impairs skin structure and function and creates a tissue microenvironment that promotes age-related skin diseases, such as delayed wound healing and skin cancer development. This mini-review describes cellular mechanisms that give rise to self-perpetuating, collagen fibril fragmentation that creates an age-associated dermal microenvironment, which contributes to decline of human skin function.

Effect of a tunnel-structured ß-tricalcium phosphate graft material on periodontal regeneration: a pilot study in a canine one-wall intrabony defect model.

BACKGROUND AND OBJECTIVE: Tissue regeneration is affected by the porosity, chemical properties and geometric structure of graft materials. Regeneration of severe periodontal defects, such as one-wall intrabony defects, is difficult because of reduced tissue support, and bone grafts are commonly used in such cases. In the present study, a tunnel-structured ß-tricalcium phosphate (tunnel ß-TCP) graft material designed to stimulate bone formation was fabricated. The objective of this pilot study was to evaluate the effect of this graft material on periodontal regeneration in one-wall intrabony defects in dogs. MATERIAL AND METHODS: Six male beagle dogs were used in this study. First, the mandibular second and third incisors were extracted. Experimental surgery was performed 12 wk after tooth extraction. Bilateral 4 × 8 mm (width × depth) one-wall intrabony defects were created in the mesial side of the mandibular canines. At the experimental sites, the defects were filled with tunnel ß-TCP, whereas the control defects were left empty. Twelve weeks after surgery, qualitative and quantitative histological analyses were performed. RESULTS: There were no signs of clinical inflammation 12 wk after surgery. Coronal extension indicative of new bone formation was higher at the experimental sites than at the control sites, although the differences between both the sites in the newly formed cementum and connective tissue attachment were not significant. Newly formed periodontal ligament and cementum-like tissue were evident along the root surface at the experimental sites. The inner surface of the tunnels was partially resorbed and replaced with new bone. New blood vessels were observed inside the lumens of tunnel ß-TCP. CONCLUSION: Tunnel ß-TCP serves as a scaffold for new bone formation in one-wall intrabony defects.

[Gastroesophageal reflux disease and connective tissue dysplasia in aspect of premorbid and comorbid disorders].

AIM: To investigate the phenotypic and visceral signs of connective tissue dysplasia (CTD) and comorbid diseases of the digestive system in gastroesophageal reflux disease (GERD) patients with different types of esophageal reflux as the predictors of its variants. MATERIAL AND METHODS: In 124 patients with GERD the clinical features, phenotypic and visceral signs of undifferentiated CTD were studied in details. RESULTS: In 82.0% of patients with GERD associated with gastroesophageal type of reflux (GER) phenotypic and especially visceral signs of STD were detected, mainly in the form of cardiochalasia and hiatal hernia. In patients with duodenogastroesophageal reflux symptoms (DGER) the signs of STD were marked in 42.0% of cases, mostly in the form of biliary tract structure abnormalities. The risk of GERD associated with prevalence of GER, was 11.9 times higher in the presence of diagnostically meaningful combination of 6 or more signs of STD than in patients with DGER. Realization of predictor options in GER occurs in the preference of sharp, acidic foods, spices, taking medications that reduce lower esophageal sphincter tone. GERD, associated with DGER, is formed in patients with family history of diseases of the biliary tract and in the preference of food rich of calories. CONCLUSION: Study of STD symptoms as predictors of structural development of GERD and its variants is prospective to predict disease, choice of profession and eating behavior, primarily in young adults.

The influence of unilateral disc displacement on stress in the contralateral joint with a normally positioned disc in a human temporomandibular joint: an analytic approach using the finite element method.

OBJECTIVES: To investigate the influence of unilateral disc displacement (DD) in the temporomandibular joint (TMJ) on the stress in the contralateral joint, with a normally-positioned disc, during clenching. STUDY DESIGN: A finite element model of the TMJ was constructed based on MRI and 3D-CT of a single patient with a unilateral DD. A second model with bilateral normally-positioned discs served as a reference. The differences in stress distribution in various TMJ components during clenching were predicted with these models. RESULTS: In the unaffected joint of the unilateral DD model, the largest von Mises stress at the start of clenching was predicted in the inferior surface of the disc and increased by 30% during clenching. In the connective tissue the largest stress (1.16 MPa) did not reduce during clenching, in contrast to the (unaffected) joints of the reference model. In the affected joint, the largest stress was predicted in the temporal cartilage throughout clenching. In the surrounding connective tissue, the largest stress (1.42 MPa) hardly changed during clenching indicating no, or negligible, stress relaxation. CONCLUSIONS: This suggested that a unilateral DD could affect the stresses in the unaffected (contralateral) joint during clenching, where it may lead to weakening of the tissues that keep the disc on the top of the condyle. The results may be helpful in counseling worried patients, since they give insight into possible future developments of the disorder.

[Evaluation of systemic involving of the connective tissue in children with different localisation of isolated abnormal chords of the left ventricle (ACLV)].

Evaluation of the systemic involving of the connective tissue (SICT) under the new Ghent nosology (2010) showed that in children with isolated ACLV born to parents exposed to the Chernobyl disaster, its expression is associated with their location and quantity. The degree of systemic involvement of connective tissue is confirmed by the results of the analysis of features echostructure of isolated ACLV (the presence of thickening and calcification), echomorphometry, assessment of systolic (hypokinetic organization of the central hemodynamics), and the relaxation functions of the heart (initiation of diastolic dysfunction). High level of SICT (score greater than 5) indicates systemic damage to the body and particularly the heart, which requires dynamic monitoring and preventive measures. Found that the diagnostic and monitoring of children with isolated ACLV may be based on registration of systemic involvement of connective tissue with the calculation of points under the new Ghent nosology of 2010.

The Apt Lecture. Connective tissues reflect different mechanisms of strabismus over the life span.

BACKGROUND: Connective tissue pulleys determine extraocular muscle force directions and pulley heterotopy can induce strabismus. The etiology and type of pulley abnormalities vary with patient age, resulting in different but predictable types presentations of strabismus. METHODS: Magnetic resonance imaging (MRI) was obtained in 95 patients with pulley heterotopy, of whom 56 had childhood-onset pattern strabismus, and was compared with published data on 28 patients aged 69 ± 12 years who had sagging eye syndrome. Control data were from age-matched normal controls with no strabismus. RESULTS: Patients with childhood-onset strabismus had intact lateral rectus-superior rectus band ligaments and straight extraocular muscle paths but exhibited pulley array A pattern-associated incyclorotation or V pattern-associated excyclorotation. Rectus transposition surgery collapsed patterns. Patients with sagging eye syndrome exhibited blepharoptosis, superior sulcus defect, and inferolateral displacement of rectus pulleys with elongation of extraocular muscles that followed curved paths. Symmetrical lateral rectus pulley sag was associated with divergence paralysis esotropia; asymmetrical sag > 1 mm, with cyclovertical strabismus. Both lateral rectus resection and medial rectus recession treated divergence paralysis esotropia. Partial vertical rectus tenotomy treated cyclovertical strabismus. CONCLUSIONS: Childhood onset pulley abnormalities are associated with A or V pattern strabismus and external anatomical features suggest that these pulley defects are probably congenital. Adult onset pulley defects commonly result from age-related tissue involution and external features such as adnexal laxity are also helpful in recognizing involution as a possible etiology of strabismus.

Painful connections: densification versus fibrosis of fascia.

Deep fascia has long been considered a source of pain, secondary to nerve pain receptors becoming enmeshed within the pathological changes to which fascia are subject. Densification and fibrosis are among such changes. They can modify the mechanical properties of deep fasciae and damage the function of underlying muscles or organs. Distinguishing between these two different changes in fascia, and understanding the connective tissue matrix within fascia, together with the mechanical forces involved, will make it possible to assign more specific treatment modalities to relieve chronic pain syndromes. This review provides an overall description of deep fasciae and the mechanical properties in order to identify the various alterations that can lead to pain. Diet, exercise, and overuse syndromes are able to modify the viscosity of loose connective tissue within fascia, causing densification, an alteration that is easily reversible. Trauma, surgery, diabetes, and aging alter the fibrous layers of fasciae, leading to fascial fibrosis.

Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement.

Aseptic loosening and osteolysis are the most frequent late complications of total hip arthroplasty (THA) leading to revision of the prosthesis. This review aims to demonstrate how histopathological studies contribute to our understanding of the mechanisms of aseptic loosening/osteolysis development. Only studies analysing periprosthetic tissues retrieved from failed implants in humans were included. Data from 101 studies (5532 patients with failure of THA implants) published in English or German between 1974 and 2013 were included. "Control" samples were reported in 45 of the 101 studies. The most frequently examined tissues were the bone-implant interface membrane and pseudosynovial tissues. Histopathological studies contribute importantly to determination of key cell populations underlying the biological mechanisms of aseptic loosening and osteolysis. The studies demonstrated the key molecules of the host response at the protein level (chemokines, cytokines, nitric oxide metabolites, metalloproteinases). However, these studies also have important limitations. Tissues harvested at revision surgery reflect specifically end-stage failure and may not adequately reveal the evolution of pathophysiological events that lead to prosthetic loosening and osteolysis. One possible solution is to examine tissues harvested from stable total hip arthroplasties that have been revised at various time periods due to dislocation or periprosthetic fracture in multicenter studies.

Hamartoma fibroso de la infancia. Presentación de un caso / Fibrous hamartoma of the childhood. Presentation of a case

Presentación de un caso de hamartoma fi broso de la infancia, en un niño de 8 meses de edad. El tumor es benigno, muy poco frecuente y en el diagnóstico diferencial están los fi brosarcomas.

A rare case of fi brous hamartoma of childhood, in an eight month old child is presented. These are benign and very infrequent tumors. Fibrosarcoma have to be considered in diff erential diagnosis.

[Accommodation examination in myopia associated with nondifferentiated connective tissue dysplasia].

Features of accommodative response in children with myopia associated with nondifferentiated connective tissue dysplasia (NCTD) were studied using computered accommodography. A variety of accommodative response patterns were found in myopia associated with NCTD, that is indicative of a great functional potential of ciliary muscle. Theoretic side is discussed for normal accommodative response and for muscle fibers hyperfunction as well.

Low yield of genetic testing for known vascular connective tissue disorders in patients with fibromuscular dysplasia.

Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-ß receptor 1 and 2 (TGFßR1 and TGFßR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFßR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFßR1 gene, a finding which merits further investigation.

The role of adipokines in connective tissue diseases.

OBJECTIVE: To discuss the relationship between adipokines and connective tissue diseases, by putting special emphasis on the potential role of leptin, adiponectin, resistin, and other adipose tissue products in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus and on possible application of adipokine-targeted therapy in the treatment of these disorders with emphasis on the recent findings. METHODS: PubMed literature search complemented by review of bibliographies listed in identified articles. RESULTS: Most of the data presented by different research groups showed changed levels of leptin, adiponectin, and resistin and occasionally also other adipokines in rheumatoid arthritis and systemic lupus erythematosus. The relationship between the remaining connective tissue diseases and adipokines is less documented. CONCLUSIONS: Plasma levels of adipokines might tell us too little about their role in connective tissue disorders, whereas adipokine effects on synovial tissues might differ from their known metabolic or cardiovascular effects, which implies that some re-appraisal of adipokines role may need to take place. It still remains obscure whether the observed disturbances in various adipokine systems in subjects with connective tissue diseases contribute to their development or only reflect the presence or activity of inflammatory process, which itself is induced by other pro-inflammatory factors.

Fibroproliferative disorders and their mechanobiology.

Benign and malignant fibroproliferative disorders (FPDs) include idiopathic pulmonary fibrosis, hepatic cirrhosis, myelofibrosis, systemic sclerosis, Dupuytren's contracture, hypertrophic scars, and keloids. They are characterized by excessive connective tissue accumulation and slow but continuous tissue contraction that lead to progressive deterioration in the normal structure and function of affected organs. In recent years, research in diverse fields has increasingly highlighted the potential role of mechanobiology in the molecular mechanisms of fibroproliferation. Mechanobiology, the heart of which is mechanotransduction, is the process whereby cells sense mechanical forces and transduce them, thereby changing the intracellular biochemistry and gene expression. Understanding mechanosignaling may provide new insights into the convergent roles played by interrelated molecules and overlapping signaling pathways during the inflammatory, proliferative, and fibrotic cellular activities that are the hallmarks of fibroproliferation. The main cellular players in FPDs are fibroblasts and myofibroblasts. Consequently, this article discusses integrins and the roles they play in cellular-extracellular matrix interactions. Also described are the signaling pathways that are known to participate in mechanosignaling: these include the transforming growth factor-ß/Smad, mitogen-activated protein kinase, RhoA/ROCK, Wnt/ß-catenin, and tumor necrosis factor-α/nuclear factor kappa-light-chain-enhancer of activated B cells pathways. Also outlined is the progress in our understanding of the cellular-extracellular matrix interactions that are associated with fibroproliferative mechanosignaling through matricellular proteins. The tensegrity and tensional homeostasis models are also discussed. A better understanding of the mechanosignaling pathways in the FPD microenvironment will almost certainly lead to the development of novel interventions that can prevent, reduce, or even reverse FPD formation and/or progression.