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Biomedical subjects

S Generini

Publications and source records attributed to S Generini.

At least 37 records · Page 2Linked to original sources
PubMed1998

Synoviocytes from osteoarthritis and rheumatoid arthritis produce plasminogen activators and plasminogen activator inhibitor-1 and display u-PA receptors on their surface.

The production of plasminogen activators and their inhibitors was studied in vitro in osteoarthritic (OA) and rheumatoid arthritic (RA) synovial fibroblasts (SF), obtained from RA and OA patients undergoing joint surgery. Subcultured SF were cultivated for 2, 4, 6, 8, 10 and 13 days and the medium assayed for the presence of both plasminogen activators (PAs) and plasminogen activator inhibitor-1 (PAI-1). The presence of urokinase-Plasminogen Activator (u-PA) receptors (u-PAR) on the surface of synovial cells was investigated by radio-ligand binding assay and cross-linking and by transmission electron microscopy (TEM) of a gold-u-PA complex. Our results showed a low production of tissue-type-Plasminogen Activator (t-PA) in both OA and RA SF, but relatively high levels of u-PA, until confluence, both in OA and in RA. SF were also able to produce plasminogen activator inhibitor in large amounts, in particular in RA since the very beginning of the culture. Receptors for u-PA were evident on both RA and OA SF. Our data show that SF in vitro produce mainly u-PA, the most important plasminogen activator involved in tissue modifications. The demonstration of u-PA receptors on the surface of OA and RA SF represents a step forward in the understanding of the possible role of fibrinolytic and tissue destructive proteinase cascade in joint inflammation.

Arthritis, Rheumatoid↗
PubMed1998

Neuropeptides and steroid hormones in arthritis.

Primary afferent nociceptive and peptidergic efferent nerves are sensitized in arthritis and thus easily stimulated by mechanical and chemical stimuli. This leads to increased or disturbed release of neuropeptides from nerve terminals. This local (at the site of stimulation), expanded (expanded and additional receptive fields), and remote (cross-spinal reflexes) neuropeptide release leads to disturbed tissue homeostasis and neurogenic inflammation. In arthritis, raised levels of neuropeptides were detected in the synovial fluid, whereas nerve fibers were lacking in the synovial tissue. It has been hypothesized that cycles of nerve fiber destruction and degeneration follow the cycles of joint inflammation. This evidence suggests that the peripheral nervous system, through its neuropeptides, may contribute to the generation of inflammation, i.e., "neurogenic inflammation." Altered hypothalamic-pituitary-adrenocortical axis function and sex hormone status have been suggested to contribute to the development and persistence of arthritis. In particular, current evidence indicates that glucocorticoid secretion is closely and reciprocally interrelated with inflammation, and that an adrenal insufficiency is present in many forms of immune-mediated arthritis. Conversely, gonadal steroids seem to play a central role as predisposing factors in many forms of arthritis, with estrogens involved as immuno-enhancing hormones and androgens as natural immunosuppressors. Functional receptors for sex hormones have been described in cells involved in the immune response and, after activation, the hormone-receptor complex might modulate the expression of selected cytokines. The possibility of targeting the efferent nerves with specific peptides and replacement therapies with selected steroid hormones may represent a new and potentially efficient and natural system of modulation of the arthritis.

Animals↗
PubMed1997

New approaches to Raynaud's phenomenon [corrected].

Dysfunction of vascular tone control is mainly caused by the derangement of endothelium and of the peripheral nervous system. Studies have suggested changes in the nervous system at either the peripheral level (loss of sensory motor nerves, increased alpha 2-receptor activity, and so on) or the central level (impaired thermoregulation), always linked to the profound abnormality of endothelial function. This dual involvement consistently affects the blood flow, which can be measured with several tools (laser Doppler velocimetry, digital blood pressure response, and so on). Studies have analyzed serologic and instrumental predictors of a possible development of a connective tissue disease in Raynaud's phenomenon. A new wave of studies addressed the role of reperfusion injury and oxygen radicals in provoking chromosomal breakage and generating an immune response through fragmentation of autoantigens in the presence of metals. Antioxidants have been proposed as efficacious treatment of Raynaud's phenomenon. The continued study of regeneration of vessels (therapeutic angiogenesis) may open a new avenue for the treatment of Raynaud's phenomenon and the loss of angiogenesis as in diffuse scleroderma.

Connective Tissue Diseases↗
PubMed1996

The nervous system in systemic sclerosis (scleroderma). Clinical features and pathogenetic mechanisms.

The involvement of the nervous system in SSc is well recognized today. Different pathogenetic mechanisms are suggested that may alternatively explain the multiform appearance of the clinical spectrum (mononeuritis, mononeuritis multiplex, carpal tunnel syndrome, and so forth). It is now clear that the ANS is the earliest structure targeted by the disease in the gastrointestinal tract. The importance of this observation has not yet been adequately interpreted but may, together with the increasing evidence of the nervous system involvement in SSc, become a leading factor in understanding of the importance of the nervous system in the onset, development, and maintenance of the disease.

Autonomic Nervous System Diseases↗
PubMed1996

Increased circulating nerve growth factor is directly correlated with disease activity in juvenile chronic arthritis.

OBJECTIVE: To determine the circulating serum concentrations of nerve growth factor (NGF) and compare them with indices of disease activity in juvenile chronic arthritis. METHODS: NGF concentrations were evaluated with a two site immunoenzymatic assay (ELISA), in 17 children with systemic, 39 with polyarticular, and 24 with pauciarticular onset juvenile chronic arthritis. Each subset was divided according to different variables, appropriate to each subset, reflecting active and inactive disease. RESULTS: NGF concentrations were significantly higher in children with systemic [254 (SD 256.1) pg ml-1; P < 0.001], polyarticular [165.2 (300.8) pg ml-1; P < 0.05], and pauciarticular [106.8 (111.8) pg ml-1; P < 0.005] onset juvenile chronic arthritis than in controls. In all subsets, NGF concentrations were higher in the active than in the inactive phase of the disease. A significant direct correlation between NGF concentrations and erythrocyte sedimentation rate was found both in the systemic and in the polyarticular onset juvenile chronic arthritis. CONCLUSIONS: The increase in NGF concentrations in all juvenile chronic arthritis subsets and the correlation with disease activity suggest that NGF may take an active part in joint inflammation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Nerve growth factor circulating levels are increased in Kawasaki disease: correlation with disease activity and reduced angiotensin converting enzyme levels.

OBJECTIVE: To investigate the serum levels of nerve growth factor (NGF) and their possible relationship with disease activity in Kawasaki disease. METHODS: Twelve children with Kawasaki disease, 12 healthy children (afebrile controls), and 12 children with high fever related to upper respiratory tract viral infections (URTVI) were enrolled in the study. Serum NGF levels were measured by an ELISA method before and after therapy. In addition, angiotensin converting enzyme (ACE), and erythrocyte sedimentation rate (ESR), complete hemochrome, and C-reactive protein were tested as indicators of endothelial injury and disease activity, respectively. RESULTS: NGF levels were strikingly increased in the acute phase of Kawasaki disease (1219.54 +/- 1660.29 pg/ml) and decreased in the inactive phase of the disease (277.08 +/- 245.64 pg/ml), while remaining significantly higher than controls (6.5 +/- 2.03 pg/ml). In febrile patients with URTVI, NGF levels (30.18 +/- 44.70 pg/ml) were moderately but significantly increased compared to afebrile controls, but remarkably lower in respect to active and inactive Kawasaki disease. In active Kawasaki disease, ACE values were significantly lower than in healthy children (2.8 +/- 1.7 vs 10.1 +/- 4.2 pmol/ml/min; p < 0.001) and increased during the inactive phase, but remaining lower than in controls (4.8 +/- 2.7 pmol/ml/min); ESR, hemoglobin level, and platelet count showed significant correlation with NGF, while ACE levels showed a significant inverse correlation with ESR and NGF. CONCLUSION: In Kawasaki disease, NGF increased together with decreased ACE may be linked to a diffuse vascular inflammatory process. NGF and ACE levels remained abnormal even when there was no clinical sign of disease activity. This may indicate that the disease process is not in complete remission and suggests careful and prolonged cardiac followup until their normalization.

Child, Preschool↗
PubMed1995

Somatostatin-induced modulation of inflammation in experimental arthritis.

OBJECTIVE: To study the antiinflammatory effect of different doses of intraarticular somatostatin in experimental arthritis in rabbits. METHODS: Chronic arthritis was induced by a single injection of fibrin into the knee joint of rabbits previously sensitized to this antigen. The effects of sequential intraarticular injections of somatostatin into the rabbit knee, at doses of 500, 750, and 1,000 micrograms, were monitored by measuring knee joint circumferences and hematologic parameters. The measurements were compared with those obtained following use of triamcinolone acetonide and placebo. At the end of the experiments, the knee joints were examined histologically. RESULTS: Somatostatin treatment induced a statistically significant and dose-related reduction of knee joint swelling. This effect was shorter than that produced by triamcinolone acetonide; however, the antiinflammatory activity elicited by successive doses of triamcinolone acetonide declined both in extent and duration, while the effects of somatostatin remained unchanged at each successive treatment. Histopathologic observations showed that both somatostatin and triamcinolone acetonide reduced the inflammatory signs in the joint structures, although triamcinolone acetonide appeared to be more effective. CONCLUSION: These findings suggest that somatostatin exerts an antiinflammatory effect in this model of experimental arthritis and may represent a valid and safer alternative to corticosteroids for intraarticular therapy of arthritis.

Animals↗
PubMed1994

[Expression of p53 in the skin in systemic sclerosis. Immunohistochemical study of 8 cases].

P53 gene belongs to the family of "Tumor suppressor gene". It encodes a nuclear phosphoprotein involved in cell proliferation control; mutations of p53 gene are the most common genetic alterations found in human tumors. These mutations may cause the production of an altered protein that usually loses its physiological function. The mutant p53 protein is more stable than the wild type form and it is immunohistochemically detectable. Systemic Sclerosis is characterized by activation of fibroblasts, endotheliocytes and lymphocytes; furthermore, in this disease, a proto-oncogenic activation has already been shown in fibroblasts and lymphocytes. The aim of this study was to verify p53 expression in the skin of SSc patients. Eight patients, all classified in the limited cutaneous subset of SSc, after informed consent, underwent skin biopsies of the affected and apparently unaffected skin. P53 was investigated by immunohistochemistry, using a monoclonal anti-p53 antibody (DO-7), on formalin fixed, paraffin embedded tissue. P53 immunoreactive cells were found in 4 out of 8 biopsies; in all cases the positivity was confined to cells of the basal layer of the epidermis, histologically identified as keratinocytes. A large case series and a molecular biology approach are needed to support these preliminary observations.

Adult↗
PubMedDate not supplied

[Peripheral nervous system in limited systemic sclerosis].

OBJECTIVES: PNS is involved in Systemic Sclerosis (SSc) since the earliest phases. Our aim is to perform an ultrastructural study on skin PNS fibers in SSc. METHODS: Skin biopsies were taken from forearms of 8 patients affected by limited SSc (lSSc) and 3 controls and processed for transmission electron microscopy (TEM). The semithin sections (2 mm) were observed at light microscope and optical fields were chosen for ultrathin sections (1 mm) preparation and TEM examination. RESULTS: In lSSc skin, in the semithin sections, damaged areas are close to apparently spared areas. At TEM, in early lSSc patients, signs of inflammation and damaged microvessels are visible in derma. PNS fibers are no damaged. In advanced lSSc, fibrosis prevails on inflammation, and slight ultrastructural alterations of PNS fibers are evident in papillar derma. CONCLUSIONS: PNS lesions are different in severity in lSSc according to the disease duration, resulting more severe in advanced than in early phase.

Biopsy↗
PubMedDate not supplied

Bcl-2, p53 and c-myc expression in juvenile dermatomyositis.

OBJECTIVE: To investigate p53, bcl-2 and c-myc expression in muscle biopsies from children affected with juvenile dermatomyositis (JDM) and to verify a possible dysregulation of programmed cell death in this autoimmune disease. METHODS: Ten muscle biopsies of children affected with JDM were formalin fixed and paraffin embedded. After haematoxylin and eosin staining, immunohistochemistry was performed employing monoclonal antibodies, anti-p53, anti-bcl-2 and anti-myc. Two normal muscle biopsies were studied as controls. RESULTS: In the biopsies of JDM, two different patterns of myofibers damage were observed: the first, with zones characterised by necrosis; and the second, with zones where an apoptotic process was dominant. Immunoreactivity for bcl-2 was positive in 8 out of 10 biopsies. P53 and c-myc expression were not present in any case. No relationship between the degree of bcl-2 immunostaining and the disease course or outcome was observed. CONCLUSIONS: The over-expression of bcl-2 protein in JDM may suggest a dysregulation of apoptosis in myofibers. Further studies are required in order to better understand the role of our data in the pathogenetic pathways of the disease.

Apoptosis↗
PubMedDate not supplied

Evidence for hyaluronan production in the air pouch model in rats.

OBJECTIVE: The aim of our work was to investigate the presence of hyaluronan (HA) in the rat air pouch and its behaviour in response to inflammatory stimuli. METHODS: HA levels (by a microplate assay) and the leucocyte count were determined in the fluid obtained from air pouches in which acute or subacute inflammation had been induced by the injection of monosodium urate crystals (MSU) or high density polyethylene (HDPE) debris respectively and in relative controls. RESULTS: In control pouches of both groups, remarkable levels of HA were found; these levels were higher in the very first hours (2475 and 1850 micrograms/l at 6 hrs) and then gradually decreased. In pouches injected with MSU, HA moderately increased (p < 0.001) after 6 hrs, reached a peak after 12 hrs (p < 0.001) and began to taper at 24 hrs (p < 0.001). The leucocyte count was also increased at 6 hrs (p < 0.001), became higher at 12 hrs (p < 0.001) and tapered at 24 hrs (p < 0.001). In the HDPE pouches, HA levels were significantly reduced with respect to controls after 6 hours (p < 0.001), increasing later (p < 0.001) to reach a peak at 24 hrs (p < 0.001), and returning to the original levels, or even below, in the following 72 hours. CONCLUSIONS: These data confirm that the pouch lining produces fair amounts of HA and provide evidence that, in this system, HA levels seem to be influenced by the degree of inflammation even if with variable behaviour in relation to the different characteristics and phases of phlogosis. The present data suggest that the air pouch is a useful experimental model for studies on HA metabolism in either acute or chronic inflammation.

Air↗
PubMedDate not supplied

Therapy of spondylarthropathy in inflammatory bowel disease.

Musculoskeletal manifestations represent the most common extra-intestinal complication of inflammatory bowel diseases (IBD) and are usually included in the clinical spectrum of the spondyloarthropathies (SpA). Although control of intestinal inflammation often ameliorates articular symptoms, sometimes arthropathy is independent of the gut disease course and may require the same therapeutic options which apply to primary SpA diseases, but with caution so as not aggravate the IBD. At the moment, salicylates (sulphasalazine and mesalazine) and selective COX-2 inhibitors (which are preferable to traditional NSAIDs although they cannot be assumed to be safe for the gastrointestinal tract) are the first choice treatment. Several immunosuppressive and biological agents including methotrexate, thalidomide and TNFalpha antagonists have efficacy for both articular and intestinal inflammation and are currently in use for the induction of remission and for maintenance in more severe cases. New combination therapies and novel biologically-driven treatments, targeted to specific pathophysiological processes, might offer less toxicity and the potential for better treatment outcomes.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

The fibrinolytic system components are increased in systemic sclerosis and modulated by Alprostadil (alpha1 ciclodestryn).

OBJECTIVES: To evaluate urokinase plasminogen activator (u-PA), urokinase plasminogen activator soluble receptor (su-PAR), plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) plasma levels in SSc patients (pts) versus healthy controls and their modulation by intravenous alphacyclodestrine (Alprostadil). METHODS: Plasma levels of u-PA, su-PAR, PAI-1 and t-PA were measured in 40 SSc (34 lSSc and 6 dSSc) pts and in 30 healthy controls. In SSc, blood was drawn before and after 3 consecutive daily of Alprostadil infusion (60 mg in 250 cc NaCl 0.9%). RESULTS: In SSc su-PAR basal levels were higher than controls (7.48 +/- 2.5 vs 4.69 +/- 0.4 ng/ml; p = 0.001) and were significantly reduced by Alprostadil (5.93 +/- 1.7; p = 0.002), but remain higher than controls (p = 0.03). u-PA basal levels were higher than controls (3.78 +/- 1.5 vs 1.29 +/- 0.3 ng/ml; p < 0.001) and were reduced by Alprostadil (2.39 +/- 1.7; p < 0.001) to control levels. SSc PAI-1 basal levels were lower than controls (31.60 +/- 7.7 vs 48.30 +/- 6.8 ng/ml; p < 0.001) and increased by Alprostadil (34.66 +/- 5.4; p = 0.04), but lower than controls (p < 0.001). SSc t-PA basal levels were higher in respect to controls (1645.81 +/- 792.7 vs 571.95 +/- 75.5 pg/ml; p < 0.0001) and reduced by Alprostadil (1318.06 +/- 603.5; p = 0.04), but still higher than controls (p = 0.001). CONCLUSION: Fibrinolysis were increased in SSc. Infusions of Alprostadil modulate u-PA, su-PAR, PAI-1 and t-PA, restoring near normal levels. In SSc, fibrinolysis system may become a potential target for new therapies.

Aged↗
PubMedDate not supplied

Iliopsoas bursitis in rheumatoid arthritis.

A 58-year-old woman with rheumatoid arthritis (RA) presented with persistent hip pain and an inguinal mass. Considerable liquid had collected inside the iliopsoas bursa, apparently not in communication with the hip joint, as shown by ultrasonography and computed tomography (CT). After one month of systemic steroidal therapy (25 mg/day prednisone), the palpable inguinal mass and pain had disappeared. Iliopsoas bursitis should be suspected in RA patients with a long history of disease presenting with an inguinal mass, persistent groin pain or unilateral leg swelling. The lack of communication between the hip joint cavity and bursa may be considered as a favourable prognostic index. Steroid treatment should be always attempted in order to avoid surgery.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Raynaud's phenomenon and systemic sclerosis.

In systemic sclerosis, the exaggerated generalized vasospastic tendency is clinically represented by Raynaud's phenomenon as shown by an early digital arterial closure after cold stimulation, and by an inadequate vasodilatory response to heat. The phenomenon is not restricted to the extremities, and can also occur in internal organs. Repeated attacks of Raynaud's phenomenon may contribute to vascular disease in systemic sclerosis by a mechanism of reperfusion injury of the endothelium, and may contribute to tissue fibrosis. Although the aetiology and pathogenesis of Raynaud's phenomenon remain unknown, recent advances in the understanding of mechanisms of vascular tone control provide us with an opportunity to reconsider the pathogenetic process of Raynaud's phenomenon. It is now clear that neuropeptides, the vascular endothelium, and platelets are the three major contributors to the control of vascular tone. Our hypothesis suggests the presence of a sensory nervous system failure, leading to an unopposed endothelial and platelet control of vascular tone. Endothelial injury and platelet activation in systemic sclerosis lead to a shift in vascular function to a pro-vasospastic function not balanced by a vasodilatory sensory input; thus, enhanced vasospasm is generated. The investigation of the role of local vascular mediators in vasospasm may lead to a better understanding of vascular tone control and of Raynaud's phenomenon pathophysiology in systemic sclerosis.

Humans↗