Small airway involvement in mixed connective tissue disease

We studied pulmonary functions in 17 female patients with mixed connective tissue disease (MCTD) to detect early pulmonary involvement in this disease; in 8 of the 17 patients follow-up studies were also performed at 1.2- to 5.9-year intervals. In the first pulmonary function tests, decreases in vital capacity (VC) and diffusing capacity (DLCO) were observed in 6 (35%) and 8 (47%) patients, respectively. The ratio of forced expiratory volume in one second to VC was normal in all the patients, but pulmonary resistance and static compliance were abnormal in 6 (35%) and 10 (59%) patients, respectively. However, frequency dependence of dynamic compliance was found in all 16 patients tested. Moreover, 4 (24%) of the 17 patients had normal DLCO and DLCO-to-alveolar volume ratio (DLCO/VA). Reductions in DLCO and DLCO/VA were significantly correlated with the disease duration. These results suggest that small airway obstruction is an early and frequent indication of functional pulmonary impairment, and that impairment of alveolar gas exchange is progressive in patients with MCTD.     

Autoimmune phenomena and hepatitis C virus in lymphoproliferative and connective tissue disorders

Since hepatitis C virus (HCV) infection is frequently detected in patients with lymphoproliferative or autoimmune disorders and since the virus may infect lymphocytes, the question is raised whether malignant transformation and autoimmune manifestations in the presence of HCV are HCV-related or merely fortuitous. A close association has been firmly established between HCV infection and essential type II mixed cryoglobulinemia (ECM), an indolent lymphoproliferative disorder characterized by cryoprecipitable immune-complexes (IC) that may evolve into classical non Hodgkin's lymphomas (NHL) retaining the ability to produce cryoprecipitable rheumatoid factor (RF). It is reasonable to consider HCV as one cofactor in lymphomagenesis, even if the precise pathogenetic relationship between HCV infection, the chronic presence of cryoprecipitable IC and the development of NHL have not been established yet. Several epidemiological studies have documented the ability of chronic HCV infection to favour the production of autoAb. It is not clear why only some patients with HCV infection develop autoAb, nor why the most frequent autoAb detected in HCV-infected subjects are cryoglobulins. Though a high prevalence of anti-HCV has been found in a variety of systemic and organ-specific autoimmune diseases, it is likely that several of these associations are fortuitous with the notable exception of membranoproliferative glomerulonephritis. As HCV can provoke or exacerbate inflammatory signs and cause the production of RF, it is reasonable to suspect that HCV infection may be able to trigger the development of some connective tissue diseases or to exacerbate their clinical course. Nonetheless, it is clinically prudent to conclude that the pathogenetic relationships of Sj?gren syndrome, rheumatoid arthritis and polyarthritis with HCV infection are more likely to be regarded as mediated via the intermediate development of ECM.     

Ultrastructure of sea urchin tube feet. Evidence for connective tissue involvement in motor control

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.     

Growth and aging of connective tissue

The organs and organ systems of neonates usually show a differently advanced development of connective tissue. This must be considered when determining the change caused by ageing in specific connective tissue structures, especially if it is desired to establish relations between structure, function and time. In those organs which assume important functions during or immediately after birth the connective tissue components are more highly developed than in those which, after birth, are not subject to full functional strains. This particular phenomenon has been demonstrated by specific examples.     

Morphometric analysis of the kidney lesions in mixed connective tissue disease (MCTD)

We examined histopathological changes of the kidney in patients with mixed connective tissue disease (MCTD) including those of glomeruli, arteries and interstitium by morphometric method. All specimens examined were collected from 25 autopsy cases diagnosed as MCTD according to the criteria for this disease proposed by the MCTD committee sponsored by the Japanese government. Clinical evidence of renal dysfunction such as proteinuria was present in 16 out of 25 cases (64%). Histopathologically, membranous type glomerular lesion was found most frequently (40%), followed by membrano-proliferative (6.7%) and mesangioproliferative types (6.7%). Nine cases had no glomerular lesion. Severe arterial lesion such as necrotizing angiitis was not found in our kidney specimens. However, morphometry revealed a high incidence of intimal thickening in the renal arteries of these patients as compared to control cases, showing this to be one of the most common features of MCTD with clinical importance. This type of arterial lesion, also seen in kidneys in other types of collagen diseases, may suggest an etiology common to them. The severity of the renal interstitial lesion in MCTD was intermediate between that of systemic lupus erythematosus (SLE) and progressive systemic sclerosis (PSS), poly-or dermatomyositis (PM/DM).     

Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms

A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs). This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases. The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects. Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.     

The demonstration of cartilaginous involvement in laryngeal carcinoma by computerized tomography

Thirty-six patients with laryngeal carcinoma were investigated by computerized tomography (CT). In 8 patients invasion of cartilage was shown at subsequent pathological examination of the excised larynges. In all there were 14 areas of cartilage involvement, 11 of which could be diagnosed on retrospective examination of the CT scans. Involvement of tumour was shown either as areas of decreased density (chondrolysis) or areas of local increased density (chondrosclerosis) due to cartilage ossification. False positive and false negative evidence of cartilage involvement was recorded in the series, but the accuracy of diagnosis in positive terms was approximately 79%. Histological evidence is put forward that the presence of carcinoma in relation to the cartilage produces perichondritis, which enhances ossification and the latter process may then in itself facilitate invasion by the tumour. Previous radiotherapy may also be a factor in the causation of the perichondritis and ossification.     

Blotting patterns of IgG anti-(U1)RNP antibodies in mixed connective tissue disease

Serum reactivities towards individual U1 snRNP proteins were determined by immunoblotting in 32 patients with mixed connective tissue disease (MCTD). Time persistence of immunoblot profiles and clinical significance of anti-(U1)RNP antibody specificities were also investigated. IgG anti-(U1)RNP antibodies were found in the sera of 29 out of 32 patients (90.6%): 21 (65.6%) reacted with the 70-kD protein, 25 (78.1%) with A, 23 (71.9%) with C and 20 (62.5%) with B/B' proteins. None were reactive with the Sm-D peptide. Seventy kilodalton antibody specificity was strongly associated with a higher antinuclear antibody titre (> 160) and slightly associated with disease activity; anti-B/B' specificity was associated with lymphadenopathy. Anti-A, -C and -B/B' antibodies were negatively associated with systemic lupus erythematosus (SLE) skin rashes. Two types of anti-(U1)RNP blotting patterns were selected: "full spectrum" (53.1% of cases) and a "partially/no reactive" one (46.9%). Such patterns were unchanged over time in 14 out of 16 cases prospectively examined (87.5%), while the pattern shifted from "full spectrum" to "partially/no reactive" in 2 cases (12.5%): in 1 after a prolonged clinical remission (> or = 4 years) and in the other following immunosuppressive therapy. The anti-(U1)RNP antibody immunoblot profile in MCTD patients consisted of various reactivities and remained unchanged over time in most cases. Antibody reactivity against the 70-kD protein represented the major U1 snRNP specificity. The various anti-(U1)RNP specific reactivities demonstrated poor clinical significance within MCTD. Thus, MCTD seems to be characterized by a longstanding serological heterogeneity whose reactivities do not apparently correspond to distinct features within the broad clinical spectrum of MCTD.     

Air oesophagogram: a frequent, but not a specific sign of oesophageal involvement in connective tissue diseases

OBJECTIVE: This study investigates the role of the air oesophagogram in conventional chest X-rays for the diagnosis of oesophageal dysmotility in patients with connective tissue diseases. METHODS: Fifty-one patients with connective tissue diseases were studied by oesophageal manometry and lateral and posterior-anterior chest X-rays. The presence or absence of oesophageal air on chest X-rays were evaluated separately in the upper, middle and distal segment of the oesophagus. Forty-seven chest X-rays of patients without connective tissue diseases, who had undergone manometry for the evaluation of oesophagus-related symptoms and who had normal oesophageal function, were analysed as a control. RESULTS: A total of 23/51 patients with connective tissue diseases showed oesophageal dysfunction in manometry; 16/51 patients (31%) had air in two or more oesophageal segments on the lateral chest X-ray. There was a significant association of manometrically proven oesophageal dysmotility and air in two or three oesophageal segments (P < 0.05; sensitivity 48%, specificity 82%). However, the prevalence of an air oesophagogram showed no significant difference between patients with connective tissue diseases and the control group (10/47; 21%). CONCLUSION: The radiological sign of an air oesophagogram is neither sensitive nor specific enough to omit oesophageal motility studies in patients with connective tissue diseases.     

Familial autoimmune hepatitis and C4 deficiency

A recently developed automated, nonradioactive system for the detection of mycobacteria (MB/BacT; Organon Teknika, Belgium) has provided good results, but the contamination rate was found to be higher than that obtained with the radiometric Bactec 460 system (Becton Dickinson, USA). In the present study, the effects of adding vancomycin (1 microg/ml) to the antibiotic mixture of the nonradioactive system were evaluated, and the performance of the system with versus without vancomycin was compared. Three hundred sputum samples were tested, using the radiometric system as the reference method. Mycobacteria were isolated from 47 (15.7%) samples. The nonradioactive system with and without vancomycin detected 42 and 43 strains, respectively; the time to detection was 1 day shorter with the medium without vancomycin (15.7 days vs. 14.3 days). The radiometric system detected 42 strains of mycobacteria in a mean detection time of 13.6 days. Contamination rates with the nonradioactive system were 6.7% in the medium without vancomycin and 2.7% in the medium with vancomycin. The latter figure was approximately the same as the contamination rate found with the radiometric system (2.3%). Our data suggest that the addition of vancomycin considerably reduces the number of contaminants in the MB/BacT medium without affecting the performance of the system.     

Etiology and pathogenesis of heritable connective tissue diseases

There are many heritable disorders of the connective tissues and many of them produce major musculoskeletal anomalies. The etiology of most of them is unknown, but collagen mutations have been characterized in osteogenesis imperfecta (OI), in some forms of the Ehlers-Danlos syndrome (EDS) and in some of the chondrodysplasias. These diseases, particularly OI, provide a model for investigation of other heritable connective tissue diseases in which the mutant genes have not yet been identified.     

Characterization of human orbital fat and connective tissue

This study was designed to evaluate the characteristics of human orbital fat and connective tissue. Two exenteration specimens were studied by light microscopy with special stains. Four distinct regions were identified on the basis of their connective tissue septa, which contained blood vessels and were composed of elastin and collagen types I, III, and IV. Transmission electron microscopy was performed on the opposite orbits. The fibroblasts and adipocytes appeared metabolically inactive and showed no regional differences. The fat was phase extracted from the connective tissue and subjected to biochemical analysis. No regional differences were found in the content of fatty acids and protein. The fatty acids included palmitic acid (22-24.6%), oleic acid (45-51.5%), and linoleic acid (15-18.6%). Despite demarcation of the orbital fat into distinct regions by the connective tissue septa, ultrastructural and biochemical analysis revealed no regional variations in the fat. The diagnostic and therapeutic implications of these findings are discussed.     

Suppression of murine experimental autoimmune hepatitis by T-cell vaccination or immunosuppression

Patients with autoimmune hepatitis (AIH) usually require immunosuppressive therapy for many years, if not for a lifetime. Experimental immunotherapy such as T-cell vaccination aims at manipulating the immune system in such a way that autoimmunity is specifically regulated to enable long-lasting correction of the disease process. We aimed to test the feasibility of T-cell vaccination as well as conventional immunosuppression in the murine model of experimental autoimmune hepatitis (EAH). EAH was induced in 5- to 7-week-old BALB/c mice by immunization with syngeneic liver homogenate in complete Freund's adjuvant. For T-cell vaccination, splenocytes were removed from animals 14 days after induction of EAH and from control animals, and activated in vitro by mitogen stimulation with Concanavalin A (Con A). Activated T cells were irradiated and injected at 5 x 10(7) cells per animal as T-cell vaccine. Immunosuppression in control animals was performed with prednisolone with or without azathioprine. T-cell vaccination with T cells from EAH animals, but not with irrelevant T cells, was able to protect animals from EAH, reducing the average disease severity from 2.2 (+/-0.3) to 0.5 (+/-0.3) (P < .01). T-cell vaccination was also able to treat EAH, because application of the vaccine 2 weeks after induction of the disease significantly reduced disease activity at week 4 from 2.4 (+/-0.4) to 1.1 (+/-0.2) (P < .05). Both passive transfer of disease and the capacity to protect by T-cell vaccination was mediated by CD4 T cells. Specific cellular recognition of activated disease-inducing T cells could be detected in vaccinated animals. Immunosuppressive drugs could also suppress EAH. Thus, T-cell vaccination in EAH is feasible and effective. Stimulation of a regulatory T-cell network is the likely mechanism of action by which T-cell vaccination can suppress EAH.     

Coexistence of ankylosing spondylitis and undifferentiated connective tissue disease

This paper describes a case report of an HIV-infected patient with mucocutaneous Kaposi's sarcoma (KS) with oral involvement, which presented complete clinical resolution of lesions on antiretroviral treatment with ritonavir, an HIV-1 protease inhibitor. Although it has still not been demonstrated that ritonavir has a specific antiviral action against HHV-8, a gamma herpesvirus probably involved in KS aetiopathogenesis, it has been proven that it reduces the HIV load significantly. This affects certain growth factors of KS, such as Tat protein and cytokines, and favours recovery of immune function, which correlates with protection against AIDS-defining conditions.     

Heart and autonomic nervous system in connective tissue disorders

Heart rate variability (HRV) is a suitable diagnostic tool in identifying patients with autonomic nervous system (ANS) disorders even in pre-clinical stage. We have enrolled in this study all patients with large variety of connective tissue disorders, given the possibility of an involvement of ANS in these diseases. The study population consisted in eighty-five patients (68 females and 17 males), 35 of whom affected by systemic lupus erythematosus, 16 by rheumatoid arthritis, 14 by Sj?gren syndrome, 12 by progressive systemic sclerosis, 3 by Beh?et syndrome and 5 by antiphospholipid antibodies syndrome. The mean age ranged between 33.7 of patients with lupus erythematosus and 51.8 of those with Sj?gren syndrome. As control, we enrolled healthy subjects of different age, divided into two groups, to rule out the aging as potential source of considered parameters alteration. The autonomic function has been evaluated by 24 hours ambulatory monitoring, using a Zymed 1210 Scanner with Zymed 3.74-PC 1990 software. We have considered: in the time domain, the standard deviation of the RR intervals average (SDNN) and the percentage of RR adjacent intervals differing each other more than 50 msec (pNN50); in the frequency domain, the low (LF) and high (HF) frequencies, the LF/HF ratio, and the total power (RT). The HRV parameters resulted abnormal in every type of the connective tissue diseases considered: particularly SDNN, pNN50, LF, HF and RT (p < or = 0.01). In conclusion: the results of our study suggest that autonomic neuropathy may be present in any kind of connective tissue disorders even in preclinical stage.