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Connective tissue diseases.

The classic connective tissue diseases (lupus erythematosus, dermatomyositis, and scleroderma) have been described with respect to their pathogenesis, clinical picture, laboratory diagnosis, and management. Because the aim of this volume is to provide an interface between plastic surgery and dermatology, the cutaneous manifestations, both shared and pathognomonic for each of these diseases, have been emphasized. An attempt has been made to point out opportunities for surgical management of some of the problems associated with these diseases.

Dermatomyositis↗

Three-dimensional architecture of the subepithelial connective tissue in the omasal laminae of sheep and cattle.

The three-dimensional architecture of the subepithelial connective tissue in the omasal laminae of sheep and cattle was studied by scanning electron microscopy after treatment with 2 N NaOH solution. The omasal laminae were equipped with highly undulated subepithelial connective tissue showing various projections or ridges. In the sheep, the subepithelial connective tissue in the omasal papillae formed flat papillary projections in the oral and middle regions of the laminae. Ridges were arranged in cellular or rosette-like form in the aboral region. In the interpapillary space, the subepithelial connective tissue formed papillary projections in the oral region, parallel ridges with dentate projections in the middle region and smooth low ridges in the aboral region. In the cattle, the projections of the subepithelial connective tissue were more developed than in the sheep. The reticular or cellular ridges were uniformly arranged. The omasal papillae with horny tips located near the reticulo-omasal orifice showed various shapes of papillary projections. In the interpapillary space, round-edged and complex folded ridges with high undulations and deep grooves were observed. These findings may indicate regional and interspecies diversities in the function of the omasal mucosa.

Animals↗

Studies on the nature and significance of connective tissue antibodies in adult coeliac disease and Crohn's disease.

Sera from 92 patients with adult coeliac disease, 20 patients with Crohn's disease, and 89 control patients were tested for the presence and immunoglobulin class of anticonnective tissue antibodies. In adult coeliac disease patients taking a normal diet there was a high frequency of sera positive for connective tissue antibodies and the majority were IgA in class. Following gluten withdrawal, IgA class connective tissue antibody activity was strikingly reduced. No such antibody activity was detected in concentrated jejunal fluid collected from 15 patients with adult coeliac disease, seven of whose sera were positive for connective tissue antibody. Connective tissue antibody activity was not absorbed by fractions of gluten. Similarly, preparations of human reticulin and glomerular basement membrane together with elastin and collagen failed to absorb connective tissue antibody.

Absorption↗

A prospective study of Raynaud phenomenon and early connective tissue disease. A five-year report.

To define features of patients with Raynaud phenomenon that predict the evolution of connective tissue disorders, a prospective study was initiated. Patients with history or physical evidence of Raynaud phenomenon without causal or associated disorders underwent initial multisystem evaluation. Scleroderma (systemic sclerosis) of less than five years' duration was included for comparison. Patients were classified as having Raynaud phenomenon "only," undifferentiated connective tissue syndrome or scleroderma. Nailfold capillary microscopy was performed, and patterns were scored blindly from coded photographs. Of 91 patients with Raynaud phenomenon entered (Raynaud phenomenon only, n = 49; undifferentiated connective tissue syndrome, n = 22; scleroderma, n = 20), abnormal "scleroderma pattern" capillaries were noted in seven of 49, 19 of 22 and 19 of 20, respectively (p less than 0.005). Of 39 patients with Raynaud phenomenon only followed (mean duration, 23.7 months) undifferentiated connective tissue syndrome developed in three. Of 17 patients with undifferentiated connective tissue syndrome followed (mean duration, 27.6 months), six patients had transitions (four scleroderma; one scleroderma-systemic lupus erythematosus overlap; one SLE). Nailfold capillary abnormalities best identified transitional patients in both groups (eight of nine) and were more sensitive than ANA (six of nine), presence of digital ulcers (four of nine) or decreased esophageal motility (two of nine). This prospective study documents a useful role for capillary examinations in evaluating Raynaud phenomenon. Abnormal capillaries indicate an increased risk for connective tissue disease; normal capillaries favor idiopathic Raynaud phenomenon.

Capillaries↗

Undifferentiated connective tissue disease and its cutaneous manifestations.

Undifferentiated connective tissue disease (UCTD, also named UCT syndrome, latent lupus or incomplete lupus) is regarded as an autoimmune disorder in which signs and symptoms are widely variable and evocative for connectivitis but not sufficiently evolved to fulfil any of the accepted classification criteria for the defined connective tissue diseases. In this paper we describe the case of a 47-year-old woman affected by UCTD according to the preliminary classification criteria supplied by Mosca et al. in 1999.

Adrenal Cortex Hormones↗

Influence of ionic environment of the stress relaxation behavior of an invertebrate connective tissue.

The rheological properties of an invertebrate connective tissue were measured in three different ionic environments. Short-term stress relaxation tests were conducted on sections of holothurian (Echinodermata) body wall immersed in isotonic monovalent and divalent salt solutions and deionized water. Using a reduced modulus format, the viscoelastic behavior over the experimental time scale was described by a two term Maxwell equation with empirically determined spring constants and relaxation times. In addition, equilibrium relaxation moduli (Ge) were estimated from the empirical relationship of Chasset and Thirion (1965, in Physics of Non Crystalline Solids, ed. Prins, North Holland). The experiments indicated that both relaxation times and equilibrium moduli decreased in the presence of monovalent and divalent inorganic ions whereby the effect of the Na+ was greater than that of the Ca++. The present findings are compared with those reported for vertebrate connective tissue.

Animals↗

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

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.

Adolescent↗

Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle.

Transforming growth factor (TGF)-beta and connective tissue growth factor may be implicated in extracellular matrix protein deposition in asthma. We have recently reported that TGF-beta increased connective tissue growth factor expression in airway smooth muscle cells isolated from patients with asthma. In this study, we examined fibronectin and collagen production and signal transduction pathways after stimulation with TGF-beta and connective tissue growth factor. In both asthmatic and nonasthmatic airway smooth muscle cells, TGF-beta and connective tissue growth factor led to the production of fibronectin and collagen I. Fibronectin and collagen expression was extracellular regulated kinase-dependent in both cell types but phosphoinositide-3 kinase-dependent only in asthmatic airway smooth muscle cells. p38 was implicated in fibronectin but not collagen expression in both cell types. TGF-beta induction of fibronectin and collagen was in part mediated by an autocrine action of connective tissue growth factor. Phosphorylation of SMAD-2 may represent an additional pathway because this was increased in asthmatic cells. Our results suggest that these two cytokines may be important in the deposition of extracellular matrix proteins and that the signal transduction pathways may be different in asthmatic and nonasthmatic cells.

Adolescent↗

The primary structure of a basic leucine-rich repeat protein, PRELP, found in connective tissues.

We have determined the primary structure of a connective tissue matrix protein from the nucleotide sequence of a clone isolated from a human articular chondrocyte cDNA library. The major part of the amino acid sequence has also been determined by direct protein sequencing. The translated primary sequence corresponds to 382 amino acid residues, including a 20-residue signal peptide. The molecular mass of the mature protein is 41,646 Da. The main part of the protein consists of 10 leucine-rich repeats ranging in length from 20 to 26 residues, with asparagine at position 10 (B-type). The N-terminal part is unusual in that it is basic and rich in arginine and proline. There are four potential N-linked glycosylation sites present. In three of these sites, post-translational modifications are likely to be present since Asn was not found by direct protein sequencing. The amino- and carboxyl-terminal parts contain four and two cysteine residues, respectively, probably forming disulfide bonds by analogy with the other members of this family. The protein shows highest identity (36%) to fibromodulin and 33% to bovine lumican, two other leucine-rich repeat connective tissue proteins. Northern blot analysis showed the presence of an approximately 3.8-kilobase mRNA in different types of bovine cartilage and cultured osteoblasts, whereas RNAs isolated from bovine kidney, skin, spleen, thymus, and trabecular bone and rat calvaria were negative. Human articular chondrocyte and rat chondrosarcoma cell RNAs contained an additional mRNA of approximately 1.6 and 1.8 kilobases, respectively.

Amino Acid Sequence↗

Isolated trigeminal sensory neuropathy: early manifestation of mixed connective tissue disease.

A young woman with mixed connective tissue disease (MCTD) had an isolated trigeminal sensory neuropathy as an early manifestation of the disease. Raynaud phenomenon occurred almost synchronously with the onset of trigeminal neuropathy and was followed by myositis, diffuse hand swelling, synovitis, and increased ribonucleoprotein antibody. Mixed connective tissue disease has overlapping features of systemic lupus erythematosus, scleroderma, and polymyositis, and is differentiated from them by high-titer antibody to ribonucleoprotein.

Adult↗

Interactions between mast cells, fibroblasts and connective tissue components.

It has long been recognized that mast cells occur throughout connective tissues. Histologic studies have revealed that such cells release their granules into the surrounding environment upon exposure to both immunologic and nonimmunologic stimuli. By microscopy these extracellular granules appeared to be phagocytosed by fibroblasts and by blood-borne phagocytic cells as they entered the site of mast cell degranulation. Such in vivo observations led to the suggestion that mast cells both altered connective tissue components and influenced fibroblast function through these discharged granules. Recent in vitro studies using cultured fibroblasts and isolated mast cells and mast cell granules have confirmed both these hypotheses. In addition, such studies have also documented that fibroblasts degrade ingested mast cell granules. Such studies document that a number of critical interactions may occur between mast cells and connective tissue components.

Animals↗

The effect of immobilization on the types of collagen synthesized in periarticular connective tissue.

The distribution of collagen types was studied in control and immobilized periarticular connective tissue to test the hypothesis that inflammatory tissue is the basis of the contracture process. The hypothesis derives from the fact that Type III collagen is prominent in inflammatory processes. The content of Type I and Type III collagen was determined by standard differential salt precipitation of the pepsin solubilized collagen, followed by resolution of the subunits on CM-cellulose. Analysis of the peptide fragments produced by cyanogen bromide was performed and their distribution determined by SDS gel electrophoresis. The collagen of control and immobilized periarticular connective tissue proved to be entirely Type I. Type III was not present. The periarticular connective tissue contracture process, therefore, is different from the intraarticular process in which fibrofatty connective tissue proliferation is prominent.

Amino Acids↗

Immunological methods for the detection and determination of connective tissue proteoglycans.

In this paper we report the use of immunological methods for specifically detecting and determining proteoglycan in cartilage and other connective tissues. Antibodies (polyclonal and monoclonal) have been raised against specific components of cartilage proteoglycan aggregates (i.e., proteoglycan monomer and link protein). Radioimmunoassay procedures and immunohistochemical procedures have been developed and used to demonstrate the occurrence of cartilage-like proteoglycan and link protein in bovine aorta. Similarly, immunofluorescent studies have been used to analyze proteoglycan distribution in skin. Using antibodies specific for chondroitin-4-sulfated proteoglycan, their presence was demonstrated in dermal connective tissue and connective tissue surrounding nerve and muscle sheaths. However, chondroitin-4-sulfated proteoglycan was completely absent in the epidermis of skin and areas surrounding invaginating hair follicles. These immunological procedures are currently being used to complement conventional biochemical analyses of proteoglycans found in different connective tissue matrices.

Animals↗

Controlled clinical evaluation of the subpedicle connective tissue graft for the coverage of gingival recession.

The purpose of this study was to clinically evaluate the 1-year coverage of gingival recessions by a subpedicle connective tissue graft according to the original technique compared to untreated recessions by measuring probing sulcus depth (PSD), height of keratinized tissue (HKT), and mucogingival junction location changes. Paired gingival recessions were selected in 15 patients. In each patient, one recession was randomly assigned for treatment (test group) and the other recession was left untreated (control group) for 1 year. Surgery consisted of a connective tissue graft covered by a double papilla full thickness flap. Height of recession (HR), PSD, HKT, and cemento-enamel junction to mucogingival junction distance (CEJ-MGJ) were recorded with a calibrated probe before surgery and 1 year postoperatively. The control group showed no statistically significant differences in any of the parameters. In the test group, HR mean decreased significantly (P < 0.0006) from 3.66 mm to 1.09 mm, representing a mean root coverage of 70.5%. HKT mean increased significantly (P < 0.0006) from 1.60 mm to 4.30 mm, and PSD mean showed no statistical difference. CEJ-MGJ remained statistically unchanged. The subpedicle connective tissue graft may provide a good amount of root coverage and a substantial increase of keratinized tissue. Connective tissue grafted beneath the alveolar mucosa does not induce its transformation into keratinized gingival tissue.

Adult↗

Inflammatory myopathy associated with mixed connective tissue disease and scleroderma renal crisis.

Mixed connective tissue disease is a rheumatological syndrome with neuromuscular manifestations that may include inflammatory myopathy and carpal tunnel syndrome. We report a patient who presented with an inflammatory myopathy and bilateral carpal tunnel syndrome prior to the diagnosis of a connective tissue disorder. Early in the course of treatment, a syndrome of acute renal failure developed. Knowledge of this syndrome, scleroderma renal crisis, and its possible relation to corticosteroid treatment is important to clinicians involved in the management of patients with inflammatory myopathies.

Acute Kidney Injury↗

A modification of the connective tissue graft procedure for the treatment of type II and type III ridge deformities.

Various grafting procedures have been developed for reconstruction of partially edentulous ridge deformities prior to prosthetic rehabilitation. The majority of these procedures have been applicable to reconstruction of Type I (buccolingual) ridge deformities. Type II and Type III defects present a more difficult challenge because of the need for apicocoronal augmentation and replacement of greater volumes of lost tissue. The onlay and subepithelial connective tissue grafts have been predominately used for the treatment of these type of defects, however, each procedure presents certain limitations. This report describes a simple modification of the connective tissue graft that enhances its ability to augment tissue for Type II and Type III deformities. The technique is an effective and predictable procedure for advanced ridge deformities.

Adult↗

Actin-dependent regulation of connective tissue growth factor.

Expression of connective tissue growth factor (CTGF) in endothelial cells is modulated by shear stress affecting the organization of the cytoskeleton. The molecular connection between alterations of actin and CTGF expression was investigated in human umbilical vein endothelial cells (HUVEC) and a microvascular endothelial cell line. Overexpression of nonpolymerizable monomeric actin R62D interfered with stress fiber formation in HUVEC and concomitantly reduced immunoreactive CTGF. In microvascular endothelial cells, flow-dependent upregulation of CTGF was prevented by this actin mutant. In contrast, overexpression of actin S14C strengthened filamentous actin and increased CTGF expression. These data indicated an inverse relationship between CTGF expression and monomeric actin. Coexpression of the mutant actins and different CTGF promoter constructs revealed an actin-sensitive site between 3 and 4.5 kb of the CTGF promoter. A CArG-like box at -3791 bp was responsible for actin-dependent CTGF induction as shown by mutagenesis. Overexpression of actin S14C activated the nonmutated promoter significantly more strongly than the mutated promoter. Actin polymerization is regulated by the small GTPase RhoA and activation of serum response factor (SRF). Overexpression of constitutively active RhoA or SRF significantly increased CTGF protein synthesis. The 4.5-kb promoter construct, but not the construct with a mutation in the CArG box, was activated by SRF or RhoA, providing evidence for a functional role of this site in CTGF induction. These findings provide novel evidence that monomeric actin is the connecting link between alterations in the cytoskeleton and CTGF gene expression and demonstrate the importance of SRF in regulating CTGF transcription.

Actins↗