Retroperitoneal approach for robot-assisted partial nephrectomy: technique and early outcomes.

OBJECTIVES: The aim of our study is to present early outcomes of our series of retroperitoneal-RAPN (Robot Assisted Partial Nephrectomy). MATERIALS AND METHODS: From September 2010 until December 2015, we performed 81 RAPN procedures (44 at left kidney and 37 at right). Average size was 3cm (1-9). Average PADUA score 7.1 (5-10). Average surgical time (overall and only robot time), ischemia time, blood loss, pathological stage, complications and hospital stay have been recorded. RESULTS: All of the cases were completed successfully without any operative complication or surgical conversion. Average surgical time was 177 minutes (75-340). Operative time was 145 minutes (80-300), overall blood loss was 142cc (60-310cc). In 30 cases the pedicle was late clamped with an average ischemia time of 4 minutes (2-7). None of the patient had positive surgical margins at definitive histology (49pT1a, 12pT1b, 3pT2a, 2pT3a). Hospital stay was 3 days (2-7). CONCLUSIONS: The retroperitoneal robotic partial nephrectomy approach is safe and allows treatment of even quite complex tumors. It also combines the already well known advantages guaranteed by the da Vinci® robotic surgical system, with the advantages of the retroperitoneoscopic approach.

Rheumatologic rehabilitation: towards recommendations.

Rheumatic patients are highly complex and often affected by chronic diseases. Rehabilitation is generally needed for proper management of the underlying disease. This article describes the characteristics of an effective rheumatologic rehabilitation, takes into account data published in international literature, suggests recommendations based on scientific evidence to develop a correct rehabilitation plan for rheumatic patients and proposes the basis to draw up guidelines in the field of rheumatologic rehabilitation.

Impact of hand and face disabilities on global disability and quality of life in systemic sclerosis patients.

OBJECTIVES: In systemic sclerosis (SSc), the frequent involvement of hand and face leads to their disability. We aimed to assess influence of hand and face disability on global disability and Health related Quality of life (HRQoL). METHODS: 119 SSc patients were assessed for global disability by HAQ, HRQoL, by SF36; hand disability by HAMIS, CHFDS, fist closure and hand opening measures; face disability by MHISS and mouth opening measure. RESULTS: Diffuse SSc (dSSc) patients present higher HAQ, lower Summary Physical Index (SPI) of SF36, major hand disability at hand (higher HAMIS, CHFDS, fist closure, lower hand opening) and face (lower mouth opening, higher MHISS) than lSSc patients (p<0.05). SPI of SF36 is negatively correlated with MHISS, CHFDS, HAMIS and positively correlated to mouth and hand opening (p<0.05). Summary Mental Index (SMI) of SF36 is negatively correlated with MHISS (p<0.05). HAQ is negatively correlated with mouth opening and positively correlated to MHISS, HAMIS, CHFDS (p<0.05). By hierarchical multiple linear regression, SPI of SF36 is significantly associated with total MHISS (B=-0.34; t=-3.78; p<0.001) and CHFDS (B=-0.27; t=-3.01; p=0.003), together, explaining 22% of SPI variance. SMI of SF36 is significantly associated only with MHISS total score (B=-0.22; t=-2.41; p=0.017), explaining 4% of its variance. HAQ is significantly associated with CHFDS score (B=0.61; t=7.90; p<0.001), explaining 36% of HAQ variance. CONCLUSIONS: dSSc patients present higher global and local disability, and lower HRQoL in SPI than lSSc patients. Local disabilities, assessed by CHDFS and MHISS, are independently related to global disability and HRQoL.

Poor diagnostic performance of tilt testing in hypertensive patients with unexplained syncope.

Syncope is a common condition. Tilt testing with sublingual nitroglycerin (TT-TNT) provides a test with good specificity and positivity rate in young and old patients. Its use in hypertensive patients with unexplained syncope has not been validated. The aims of this study were to evaluate the positivity rate, specificity and tolerability of TT-TNT in hypertensive patients with unexplained syncope. Five hundred and ten subjects (mean age 55 years) were enrolled, 388 patients with unexplained syncope (73 hypertensive and 315 normotensive) and 122 controls (59 hypertensive and 63 normotensive). All subjects underwent TT-TNT. The responses were classified as positive, negative or exaggerated (aspecific). In hypertensive patients, the usual hypotensive therapy was taken on the day of the test. In hypertensive controls, the positive responses were higher than in normotensives (19% vs 6%, P<0.001). The overall specificity was 81% in hypertensives and 94% in normotensives. The positivity rate was significantly lower in hypertensives (55% vs 72%, P<0.03). There was no significant difference between young patients and patients >65 years. TT was well tolerated, and no serious side effects occurred. TT potentiated with TNT has a lower positivity rate and specificity in hypertensive than in normotensive patients with syncope.

[Sildenafil assumption and acute effects on the uroflowmetric parameters]. / Assunzione di sildenafil e repida variazione dei parametri uroflussometrici.

AIM: In the recent literature, great attention has been given to the evaluation of the real effectiveness of the phosphodiesterase type 5 inhibitors (PDE-5i), usually prescribed for the erectile dysfunction (ED), in the treatment of the lower urinary tracts symptoms (LUTS). The aim of this study was the evaluation of the acute effects of sildenafil on the uroflowmetric parameters. METHODS: Within September 2011 and February 2012, twenty-seven patients, affected by ED with a IIEF-5 score ≤21 and a contextual IPSS within 8 e 19, have been selected and enrolled in this study. Two uroflowmetric measurements with suprapubic ultrasound valuation of the post voiding residual (PVR) were performed on each patient, 2 hours before and after the administration of sildenafil (50 mg). RESULTS: The average age of the patients came out within di 47.3±9.4 years. On the baseline, the average of the Qmax registered has been 15.6±3.3 mL/s, the average Qave has been 8.2±3.2 mL/s and the average resulted 32.5±11.4 mL. After the mono-administration of sildenafil 50 mg, the average Qmax value, the Qave one and the RPM one turned out into 17.7±5.1 mL/s, 10.1±3.5 mL/s and 22.6±9.6 mL. The differences within the standard values, were considered statistically relevant (P<0.05). CONCLUSIONS: Actually, the study shows that, in the acute phase, the administration of sildenafil 50 mg leads to effects on the uroflowmetric standards on men affected by LUTS and DE.

The Italian version of the Mouth Handicap in Systemic Sclerosis scale (MHISS) is valid, reliable and useful in assessing oral health-related quality of life (OHRQoL) in systemic sclerosis (SSc) patients.

In systemic sclerosis (SSc), mouth and face involvement leads to problems in oral health-related quality of life (OHRQoL). Mouth Handicap in Systemic Sclerosis scale (MHISS) is a 12-item questionnaire specifically quantifying mouth disability in SSc, organized in 3 subscales. Our aim was to validate Italian version of MHISS, by assessing its test-retest reliability and internal and external consistency in Italian SSc patients. Forty SSc patients (7 dSSc, 33 lSSc; age and disease duration: 57.27 ± 11.41, 9.4 ± 4.4 years; 22 with sicca syndrome) were evaluated with MHISS. MHISS was translated following a forward-backward translation procedure, with independent translations and counter-translation. Test-retest reliability was evaluated, comparing the results of two administrations, with intraclass correlation coefficient (ICC). Internal consistency was assessed by Cronbach's α and external consistency by comparison with mouth opening. MHISS has a good test-retest reliability (ICC: 0.93) and internal consistency (Cronbach's α:0.99). A good external consistency was confirmed by correlation with mouth opening (rho: -0,3869, p: 0.0137). Total MHISS score was 17.65 ± 5.20, with scores of subscale 1 (reduced mouth opening) of 6.60 ± 2.85 and scores of subscales 2 (sicca syndrome) and 3 (aesthetic concerns) of 7.82 ± 2.59 and 3.22 ± 1.14. Total and subscale 2 scores are higher in dSSc than in lSSc. This result may be due to the higher presence of sicca syndrome in dSSc than in lSSc (p = 0.0109). Our results support validity and reliability in Italian SSc patients of MHISS, specifically measuring SSc OHRQoL.

Efficacy of the "body movement and perception" method in the treatment of fibromyalgia syndrome: an open pilot study.

OBJECTIVES: Group exercises may be useful in fibromyalgia syndrome (FMS). The 'Body movement and perception' (BMP) method is based on low impact exercises, awareness of body perception and relaxation, aimed at treating small groups of patients following the Resseguier method (RM) and integrating RM with exercises derived from soft gymnastics. We assessed the effects of BMP method on FMS. METHODS: 40 women with FMS (age and disease duration: 51.7±7.2 and 4.9±3.8 years) participated in an open pilot study. BMP sessions were performer twice a week (50 minutes each) for 8 weeks. Patients were assessed at enrolment (T0) and at the end of the study (T1) by a self-administered questionnaire (temporal characteristics of pain, pain interference in working and recreational activities and in night-time rest, awareness of pain, fatigue, irritability, well-being, quality of movement, ability to focus on perception and to perceive whole body, postural selfcontrol, ability to relax) and a clinical evaluation (tender points, assumption of analgesics/NSAIDs, distribution of pain, pain in sitting and standing position, pain during postural passages and gait, postural body alignment, muscular contractures). RESULTS: At T1, FMS patients significantly improved with respect to T0 in pain, fatigue, irritability, well-being, quality of movement, postural self-control, ability to relax mind and body, movement perception, tender point scores, assumption of analgesic/NSAIDs, body alignment and muscle contractures (p<0.05 for all the comparisons T1 versus T0). CONCLUSIONS: In FMS patients, rehabilitation with BMP improves pain and well being, reduces the number of tender points and muscle contractures, thus it is useful in FMS management.

The rehabilitation of facial involvement in systemic sclerosis: efficacy of the combination of connective tissue massage, Kabat's technique and kinesitherapy: a randomized controlled trial.

In Systemic Sclerosis (SSc), face involvement causes functional loss as well as aesthetic changes and loss of the self-image. The aim of the work is to evaluate the efficacy of a rehabilitation program based on the combination of Kabat's technique, connective massage and kinesitherapy specifically conceived for the face of SSc patients. Forty SSc patients were enrolled: 20 patients (interventional group) were treated for 9 weeks (twice a week, 1 h per session) with a combined connective tissue massage, Kabat's technique, kinesitherapy and home exercise program, and 20 patients (control group) were assigned only home exercise program. All patients were assessed at baseline (T0), at the end of the treatment (T1) and after 9 weeks of follow-up (T2). They were evaluated with SF-36, HAQ, modified Rodnan skin score, mouth opening in centimeters and Mouth Handicap in Systemic Sclerosis (MHISS) scale. At T1, both groups improved in mouth opening (P < 0.05), but the improvement was maintained at T2 only in interventional group. In interventional group, facial skin score ameliorated at T1 and maintained at T2 (P < 0.05 vs. T0), while no change was observed in controls. In both groups, SF-36 and HAQ were not affected by the treatment. MHISS scale improved significantly in interventional group at T1 (P < 0.001), while no change was found in controls. The combination of connective tissue massage, Kabat's technique, kinesitherapy and home-based exercises is more effective than a home exercise program alone in the rehabilitative treatment of SSc facial involvement.

The efficacy of the Rességuier method in the treatment of fibromyalgia syndrome: a randomized controlled trial.

OBJECTIVES: In fibromyalgia syndrome (FMS) defined rehabilitation guidelines are yet to be validated. Our aim is to evaluate the efficacy of the Rességuier method (RM) in FMS. METHODS: Forty-one patients were randomly assigned to Interventional (22 pts) and Observational (19 pts) Group (IG and OG). The study lasted 8 months. Patients were assessed at baseline (T0) after a 2-month rehabilitation (T1) and at a 6-month follow-up (T2) (only IG) with SF-36 Physical (PSI) and Mental Synthetic Index (MSI), Regional Pain Scale (RPS), Fibromyalgia Impact Questionnaire (FIQ), Number Rating Scales 0-10 to measure pain, movement quality, sleep, relax ability, analgesics number/per week. OG patients maintained their lifestyle for the duration of the study. RM aims to obtain patient awareness and control of bodily perceptions, thus reaching a modulation of responses to pain. Therapist controls patient attention and perception by verbal and manual contacts and leads them to perform bodily and respiratory active and conscious movements. RESULTS: In IG, at T1 all items were improved: PSI and MSI (p<0.001 and =0.001), FIQ (p<0.0001), RPS (p<0.001), pain (p<0.0001), movement quality (p=0.001), relax ability (p<0.0001), sleep (p<0.001); analgesics number/per week was reduced (p<0.001). All results obtained at T1, except FIQ, were maintained at T2. In OG at T1 versus T0, no difference in any of the assessed parameters was observed. CONCLUSION: In FMS patients, the rehabilitation with RM improves HRQoL, FMS-related disability and perceived pain, thus reducing the assumption of analgesics.

The Italian version of the Hand Mobility in Scleroderma (HAMIS) test: evidence for its validity and reliability.

OBJECTIVES: In systemic sclerosis (SSc), hand involvement is frequent and leads to prominent disability. The Hand Mobility in Scleroderma (HAMIS) test is a hand function test for SSc patients assessing the movements included in an ordinary range of motion examination. Our aim is to validate the Italian version of HAMIS, by assessing its test-retest reliability, internal consistency and external consistency in Italian SSc patients. METHODS: The Italian version of HAMIS was administered to 40 SSc patients. HAMIS was translated according to international procedures. Test-retest reliability was assessed by intra-class correlation coefficient (ICC), internal consistency by Cronbach's alpha and external consistency by comparison with Cochin Hand Function Scale (CHFS), fist closure, hand opening, HAQ. RESULTS: HAMIS showed a good testretest reliability (ICCs=0.99 for right and left hand) and internal consistency (Cronbach's α=0.94 for right and 0.93 for left hand) for both hands. A good external consistency was confirmed by the correlation of right and left hand HAMIS with CHFS (p<0.0001, in both cases); fist closure of homolateral hand (p<0.0001 in both cases), opening of homolateral hand (p<0.05 and <0.005, respectively), HAQ (p<0.001 in both cases). HAMIS scores for right and left hands were 7.95±6 .68 and 7.5±6.60 (p=NS), respectively. HAMIS scores for both hands were higher in dSSc and in patients with hand arthritis and flexion contractures. CONCLUSIONS: HAMIS is a hand function test measuring hand disability in SSc. Our results support its validity and reliability in Italian SSc patients.

[How to prescribe physical exercise in rheumatology]. / Come si prescrive l'esercizio fisico in reumatologia.

Physical exercise, aiming to improve range of movement, muscle strength and physical well being, lately substituted the immobilization previously prescribed in rheumatic diseases. International guidelines, recommendations of Scientific Societies, and structured reviews regard physical exercise as of pivotal importance in treating rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, fibromyalgia syndrome, osteoporosis, and to be considered in connective tissue diseases. Therapeutic exercise should: aim to improve firstly local symptoms and then general health; respect the pain threshold; be a part of a treatment including pharmacological therapies and other rehabilitation techniques, be administered by skilled physiotherapist under the guide of a rheumatologist, be different according to different diseases, disease phases and patient expectations.

Efficacy of a tailored rehabilitation program for systemic sclerosis.

INTRODUCTION: Rehabilitation may contribute to the management of Systemic Sclerosis (SSc) dealing with disabilities due to skin and joint involvement. AIM: to evaluate the efficacy of a district specific and global rehabilitation program tailored for SSc patients. MATERIALS AND METHODS: 20 SSc patients were enrolled and randomly assigned to 2 groups. Interventional group (10 pts) was treated that included hand and face specific rehabilitation and at least a global rehabilitation technique such as hydrokinesytherapy or land-based program, also comprising respiratory exercises. Hand lymphatic drainage was added when necessary. Observational group (10 patients) was only provided with educational advices and medical information about SSc. Patients were evaluated at baseline (T0) and after the 9 weeks treatment period (T1). Interventional group was also assessed after a 9 weeks follow-up (T2). Patients were evaluated by SF-36, HAQ and a purpose-built-questionnaire for global health condition and with Hamis test, Duruöz scale, range of motion, water volumetric test, mouth opening and a purpose-built-questionnaire for hand and face involvement. RESULTS: At the end of the treatment, patients of interventional group improved in all the parameters evaluated. At follow-up, mouth mobility and functionality such as global health status was partially lost, only hand mobility and functionality parameters were maintained. No changes were observed in controls. CONCLUSION: The association and of district-specific and global rehabilitative techniques conceived and tailored for SSc patients improves disability, HRQoL, hand and face disability and functionality, with its effects partially maintained at the follow-up.

Vitamin E gel reduces time of healing of digital ulcers in systemic sclerosis.

BACKGROUND: In systemic sclerosis (SSc), digital ulcers (DU) are painful, difficult to heal and frequently infected, thus greatly affecting quality of life and increasing SSc-related disability. Vitamin E has been previously used in cutaneous lesions for its antioxidant and anti-inflammatory effects. OBJECTIVES: To study the healing effect of D-alpha-tocopheryl acetate (acetic ester of alpha-tocopherol) (VE) gel on DU of SSc patients. METHODS: 27 SSc patients with a total of 86 DU were enrolled in an open pilot study. The patients were randomly assigned to two groups: 15 patients were treated until DU healing with the local standard ulcer care protocol with the application of vitamin E gel (experimental group), while 12 patients were treated with standard ulcer care protocol only (control group). In both groups, DU were treated twice a week and pain was scored by a NRS (numeric rating scale). In both groups the cost of medications was analysed. RESULTS: VE induced a faster healing of DU in respect to controls (13.22+/-2.72 weeks, versus 20.94+/-3.65; p<0.0001) with a lower number of medications (26.18+/-5.63 vs. 41.88+/-7.31; p<0.0001). Resolution of pain was faster in experimental (17.82+/-4,59 medications) than in controls (26.26+/-19.16 medications) (p=0.0022). In the experimental group, the cost of medications was significantly lower (6,919.15 euros/patient) than in the control group (11,056.32 euros/patient). CONCLUSION: The application of VE reduces time of healing and has a faster resolution of pain, with a significant reduction of costs. Topical VE may improve the management of DU in SSc.

The management of syncope in older adults.

Syncope is a frequent symptom in older patients. The diagnostic and therapeutic management may be complex, particularly in older adults with syncope and comorbidities or cognitive impairment. Morbidity related to syncope is more common in older persons and ranges from loss of confidence, depressive illness and fear of falling, to fractures and consequent institutionalization. Moreover, advan-ced age is associated with short and long-term morbidity and mortality after syncope. A standardized approach may obtain a definite diagnosis in more than 90% of the older patients with syncope and may reduce diagnostic tools and hospitalizations. The initial evaluation, including anamnesis, medical examination, orthostatic hypotension test and electrocardiogram (ECG), may be more difficult in the elderly, specially for the limited value of medical history, particularly for the certain diagnosis of neuro-mediated syncope. For this reason neuroautonomic assessment is an essential step to confirm a suspect of neuromediated syncope. Orthostatic blood pressure measurement, head up tilt test, carotid sinus massage and insertable cardiac monitor are safe and useful investigations, particularly in older patients. The most common causes of syncope in the older adults are orthostatic hypotension, carotid sinus hypersensitivity, neuromediated syncope and cardiac arrhythmias. The diagnostic evaluation and the treatment of cardiac syncope are similar in older and young patients and for this reason will not be discussed. In older patients unexplained falls could be related to syncope, particularly in patients with retrograde amnesia. There are no consistent differences in the treatment of syncope between older and younger population, but a specific approach is necessary for orthostatic hypotension, drug therapy and pacemaker implantation.

Clinical predictors of cardiac syncope at initial evaluation in patients referred urgently to a general hospital: the EGSYS score.

OBJECTIVE: To develop, in patients referred for syncope to an emergency department (ED), a diagnostic score to identify those patients likely to have a cardiac cause. DESIGN: Prospective cohort study. SETTING: ED of 14 general hospitals. PATIENTS: 516 consecutive patients with unexplained syncope. INTERVENTIONS: Subjects underwent a diagnostic evaluation on adherence to Guidelines of the European Society of Cardiology. The clinical features of syncope were analysed using a standard 52-item form. In a validation cohort of 260 patients the predictive value of symptoms/signs was evaluated, a point score was developed and then validated in a cohort of 256 other patients. MAIN OUTCOME MEASUREMENTS: Diagnosis of cardiac syncope, mortality. RESULTS: Abnormal ECG and/or heart disease, palpitations before syncope, syncope during effort or in supine position, absence of autonomic prodromes and absence of predisposing and/or precipitating factors were found to be predictors of cardiac syncope. To each variable a score from +4 to -1 was assigned to the magnitude of regression coefficient. A score >or=3 identified cardiac syncope with a sensitivity of 95%/92% and a specificity of 61%/69% in the derivation and validation cohorts, respectively. During follow-up (mean (SD) 614 (73) days) patients with score >or=3 had a higher total mortality than patients with a score <3 both in the derivation (17% vs 3%; p<0.001) and in the validation cohort (21% vs 2%; p<0.001). CONCLUSIONS: A simple score derived from clinical history can be usefully employed for the triage and management of patients with syncope in an ED.

Circulating levels of Nepsilon-(carboxymethyl)lysine are increased in systemic sclerosis.

OBJECTIVE: Advanced glycation endproducts (AGEs), including Nepsilon-(carboxymethyl)lysine-protein adducts (CML) are involved in micro/macrovascular changes and are co-localized with adhesion molecules in inflamed tissues. Serum levels of CML were investigated in systemic sclerosis (SSc) characterized by microvascular modifications and correlated with indices of micro/macrovascular damage. METHODS: In 66 SSc patients (limited SSc, n = 55; diffuse SSc, n = 11) and 20 controls, CML serum levels were measured by enzyme-linked immunosorbent assay. Nailfold capillaroscopy, intima-media thickness (IMT) and the ankle-brachial index (ABI) were also recorded, to characterize micro/macrovascular involvement. RESULTS: CML levels were significantly higher in SSc (79.2 +/- 39 mg/ml vs 49.6 +/- 26.1 mg/ml, mean +/- s.d.; P<0.01), without significant differences between SSc subsets. CML levels were significantly higher in all capillaroscopic patterns: the 'early' pattern showed higher levels than 'active' and 'late' patterns. IMT was significantly higher in SSc (P<0.01) than in controls, whilst ABI was no different from controls. CONCLUSIONS: These data indicate that although both CML formation and macrovascular involvement are increased in SSc, there is no correlation between these two parameters. However, the characteristic early nailfold capillaroscopy changes of SSc are associated with proportionally greater CML formation, suggesting that AGEs are involved in SSc microangiopathy.

Piascledine modulates the production of VEGF and TIMP-1 and reduces the invasiveness of rheumatoid arthritis synoviocytes.

BACKGROUND: In rheumatoid arthritis (RA), hypertrophy of the synovial membrane generates a tumour-like pannus that invades the joint cavity and erodes cartilage and bone. Invasion of the extracellular matrix (ECM) is accompanied by angiogenesis, in which vascular endothelial growth factor (VEGF) and tissue inhibitors of metalloproteinases (TIMPs), produced by synoviocytes lining the pannus, have a primary role. Piascledine (PSD) is used in the treatment of osteoarthritis and has anti-inflammatory effects in vitro. OBJECTIVE: To study the effects of PSD on levels of VEGF and TIMP-1 and chemoinvasion in RA synoviocytes and healthy controls. METHODS: The effects of PSD 5, 10, and 20 microg/mL were evaluated, with/without interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha) 20 ng/mL, on synoviocytes. The levels of VEGF and TIMP-1 were assayed in the culture medium by enzyme-linked immunosorbent assay (ELISA). Chemoinvasion was measured by the Boyden chamber invasion assay. RESULTS: RA synoviocytes treated with PSD showed, compared to basal, lower levels of VEGF (41080+/-830 vs. 79210+/-920 pg/106 cells, p<0.001) and increased levels of TIMP-1 (23540+/-93.2 vs. 12860+/-42.9 ng/106 cells, p<0.001). PSD decreased dose-dependently IL-1beta and TNFalpha induced migration. CONCLUSIONS: In RA synoviocytes, and also to a lesser extent in control cells, PSD modulates VEGF and TIMP-1 and decreases chemoinvasion. PSD might have a role in the treatment of RA synovitis controlling invasiveness.

Systemic sclerosis fibroblasts inhibit in vitro angiogenesis by MMP-12-dependent cleavage of the endothelial cell urokinase receptor.

Failure of endothelial cells to develop new vessels in response to hypoxia is a distinctive feature of systemic sclerosis (SSc) in the avascular phase. We have previously shown that SSc endothelial cells over-express matrix metalloproteinase-12 (MMP-12), which blocks angiogenesis by cleavage of the endothelial urokinase-type plasminogen activator receptor (uPAR). In the present study, we have investigated whether over-expression of MMP-12 and of angiostatic factors, or hypo-expression of angiogenic factors by SSc fibroblasts, contributes to impaired angiogenesis in SSc. Dermal fibroblasts were isolated from healthy subjects (N-Fb) and patients with diffuse SSc (SSc-Fb). Angiogenesis of target normal human microvascular endothelial cells (H-MVECs) was assayed by Matrigel invasion, cell proliferation, and capillary morphogenesis. uPAR cleavage and MMP-12 activity were evaluated by western blotting. We show that the over-expression of MMP-12 by SSc-Fb determines uPAR cleavage in H-MVECs. Conditioned medium from SSc-Fb impaired H-MVEC proliferation, invasion, and capillary morphogenesis. Anti-MMP-12 antibodies restored such impairment. Altered expression of angiostatic/angiogenic factors, including transforming growth factor beta1, did not account for SSc-Fb-dependent impairment of angiogenesis. The over-expression of MMP-12 by both SSc-Fb and SSc endothelial cells indicates that MMP-12 over-production may have a critical pathogenic role in SSc-associated vascular alterations.

Raloxifene reduces urokinase-type plasminogen activator-dependent proliferation of synoviocytes from patients with rheumatoid arthritis.

Extracellular fibrinolysis, controlled by the membrane-bound fibrinolytic system, is involved in cartilage damage and rheumatoid arthritis (RA) synovitis. Estrogen status and metabolism seem to be impaired in RA, and synoviocytes show receptors for estrogens. Our aims in this study were to evaluate in healthy and RA synoviocytes the effects of Raloxifene (RAL), a selective estrogen receptor modulator (SERM), on: proliferation; the components of the fibrinolytic system; and chemoinvasion. The effects of RAL were studied in vitro on synoviocytes from four RA patients and four controls. Proliferation was evaluated as cell number increase, and synoviocytes were treated with 0.5 microM and 1 microM RAL with and without urokinase-plasminogen activator (u-PA) and anti-u-PA/anti-u-PA receptor (u-PAR) antibodies. Fibrinolytic system components (u-PA, u-PAR and plasminogen activator inhibitor (PAI)-1) were assayed by ELISA with cells treated with 0.5 microM and 1 microM RAL for 48 h. u-PA activity was evaluated by zymography and a direct fibrinolytic assay. U-PAR/cell and its saturation were studied by radioiodination of u-PA and a u-PA binding assay. Chemoinvasion was measured using the Boyden chamber invasion assay. u-PA induced proliferation of RA synoviocytes was blocked by RAL (p < 0.05) and antagonized by antibodies alone. The inhibitory effect of RAL was not additive with u-PA/u-PAR antagonism. RA synoviocytes treated with RAL showed, compared to basal, higher levels of PAI-1 (10.75 +/- 0.26 versus 5.5 +/- 0.1 microg/10(6) cells, respectively; p < 0.01), lower levels of u-PA (1.04 +/- 0.05 versus 3.1 +/- 0.4 ng/10(6) cells, respectively; p < 0.001), and lower levels of u-PAR (11.28 +/- 0.22 versus 23.6 +/- 0.1 ng/10(6) cells, respectively; p < 0.001). RAL also significantly inhibited u-PA-induced migration. Similar effects were also shown, at least partially, in controls. RAL exerts anti-proliferative and anti-invasive effects on synoviocytes, mainly modulating u-PAR and, to a lesser extent, u-PA and PAI-1 levels, and inhibiting cell migration and proliferation.