A New Subspecies of Heliconius hermathena (Nymphalidae: Heliconiinae) from Southern Amazonia.

The present paper describes Heliconius hermathena curua Freitas & Ramos ssp. nov. This subspecies exhibits a non-mimetic phenotype typical of H. hermathena, but is characterized by the merging of the yellow streak over the forewing cubitus with the red postmedian band in the dorsal forewing. The subspecies is known from two localities in the south of Altamira, Pará State, Brazil, where it inhabits an isolated patch of "campina" vegetation more than 600 km from the nearest known H. hermathena populations. Geographic isolation of the population is supported by molecular data; based on the mitochondrial gene COI, all individuals of H. hermathena curuassp. nov. form a monophyletic group and all haplotypes found in it are unique, suggesting that gene flow is not currently on-going. Given the fragile situation of Amazonian white sand forests and the proximity of the population to areas of intensive agriculture, this new subspecies and its habitat deserve attention.

Monitoring changes in back fat thickness and its effect on the restoration of ovarian activity and fertility in Bos indicus cows.

With the objective of testing the hypothesis if animals with a stable layer of body fat (FAT) during the peripartum have a better chance of becoming pregnant after calving, fifty-nine multiparous Brahman cows in their last trimester of pregnancy were used. Animals averaged four parturitions and were stocked at a rate of 1.25 animal units per hectare and divided into two groups depending on the time postpartum (dpp) that the intravaginal releasing device CIDR was inserted; Group 1 (<30 dpp; n = 30) received the implant at 25.2 ± 4.21 and withdrawn 9 days later. Group 2 (≥30 dpp; n = 29) received the CIDR at 38.41 ± 5.8. Animals were AI at detected oestrus until 170 dpp and calculated as pregnant at first service or requiring more than one service (1s and >1s), not pregnant but cycling (not pregnant) and those not cycling at all (anestrus). The FAT measurements were taken twice each month from the last trimester of gestation until 96 dpp. The onset of ovarian activity was monitored through blood levels of progesterone (P4) at days 14 and 9 prior to CIDR insertion and days 10, 13, 30 and 33 after CIDR withdrawal. Animals pregnant did not have any major changes in their fat thickness. In contrast, cows pregnant in the group ≥30 dpp had changes in their FAT homoeostasis, and pregnant animals in the 1s and >1s groups did not show differences in dorsal back fat in the last trimester of pregnancy and early postpartum. In contrast, animals not pregnant and in anestrus FAT values decreased considerably after parturition. Overall, fertility was 49%, but 18% of all the animals remained anestrus losing FAT. Thus, animals with adequate metabolic conditions will have a better chance of pregnancy regardless of the time postpartum when the reproductive programme starts.

New blends of ethylene-butyl acrylate copolymers with thermoplastic starch. Characterization and bacterial biodegradation.

Ethylene-butyl acrylate copolymer (EBA) with 13% of butyl acrylate content was used to produce blends with 10, 30 and 60% of thermoplastic starch (TPS) plasticized with glycerol. Ethylene-acrylic acid copolymer (EAA) was used as compatibilizer at 20% content with respect to EBA. The blends were characterized by X-ray diffraction, ATR-Fourier Transform Infrared Spectroscopy (ATR-FTIR), Scanning Electron Microscopy (SEM), water-Contact Angle measurements (CA), Differential Scanning Calorimetry (DSC) and Stress-strain mechanical tests. Initiated autoxidation of the polymer blends was studied by chemiluminescence (CL) confirming that the presence of the polyolefin-TPS interphase did not substantially affect the oxidative thermostability of the materials. Three bacterial species have been isolated from the blend films buried in soil and identified as Bacillus subtilis, Bacillus borstelensis and Bacillus licheniformis. Biodegradation of the blends (28days at 45°C) was evaluated by carbon dioxide measurement using the indirect impedance technique.

Transforming growth factor (TGF)-ß signalling is increased in rheumatoid synovium but TGF-ß blockade does not modify experimental arthritis.

The aim of this study was to analyse the distribution of regulatory and inhibitory mothers against decapentaplegic homologue (Smad) proteins as markers of active transforming growth factor (TGF)-ß signalling in rheumatoid arthritis (RA) synovial tissue and to investigate the effect of TGF-ß blockade in the development and progression of collagen-induced arthritis. The expression of Smad proteins in synovial tissues from RA, osteoarthritic and healthy controls was analysed by immunohistochemistry. Arthritis was induced in DBA/1 mice by immunization with chicken type-II collagen (CII). TGF-ß was blocked in vivo with the specific peptide p17 starting at the time of immunization or on the day of arthritis onset. T cell population frequencies and specific responses to CII were analysed. The expression of cytokines and transcription factors was quantified in spleen and joint samples. Statistical differences between groups were compared using the Mann-Whitney U-test or one-way analysis of variance (anova) using the Kruskal-Wallis test. p-Smad-2/3 and inhibitory Smad-7 expression were detected in RA and control tissues. In RA, most lymphoid infiltrating cells showed nuclear p-Smad-2/3 without Smad-7 expression. Treatment with TGF-ß antagonist did not affect clinical severity, joint inflammation and cartilage damage in collagen-induced arthritis. Frequency of T cell subsets, mRNA levels of cytokines and transcription factors, specific proliferation to CII, serum interleukin (IL)-6 and anti-CII antibodies were comparable in p17 and phosphate-buffered saline (PBS)-treated groups. The pattern of Smad proteins expression demonstrates active TGF-ß signalling in RA synovium. However, specific TGF-ß blockade does not have a significant effect in the mice model of collagen-induced arthritis.

A protection system for the JET ITER-like wall based on imaging diagnostics.

The new JET ITER-like wall (made of beryllium and tungsten) is more fragile than the former carbon fiber composite wall and requires active protection to prevent excessive heat loads on the plasma facing components (PFC). Analog CCD cameras operating in the near infrared wavelength are used to measure surface temperature of the PFCs. Region of interest (ROI) analysis is performed in real time and the maximum temperature measured in each ROI is sent to the vessel thermal map. The protection of the ITER-like wall system started in October 2011 and has already successfully led to a safe landing of the plasma when hot spots were observed on the Be main chamber PFCs. Divertor protection is more of a challenge due to dust deposits that often generate false hot spots. In this contribution we describe the camera, data capture and real time processing systems. We discuss the calibration strategy for the temperature measurements with cross validation with thermal IR cameras and bi-color pyrometers. Most importantly, we demonstrate that a protection system based on CCD cameras can work and show examples of hot spot detections that stop the plasma pulse. The limits of such a design and the associated constraints on the operations are also presented.

Control de las cifras de presión arterial en diabéticos tipo 2 tratados con insulina / Blood pressure control in diabetics type 2 treated with insulin

Objetivo: Valorar el control de las cifras de presión arterial (PA) tras 2 añosde seguimiento, en pacientes diabéticos tipo 2 (DM2) tratados con insulina.Métodos: Estudio prospectivo, longitudinal y multicéntrico, realizado en atenciónprimaria, con la participación de 121 pacientes con DM2 que precisaroninicio o modificación del tratamiento con insulina y con seguimiento de 2 años.Se efectuaron 5 visitas (inclusión y 6, 12, 18 y 24 meses). Se midió la PA endos ocasiones. Se calcularon las medias de PA y el grado de control. Se considerócontrol cuando la PA fue <140 y 90 mmHg para la PAS y la PAD, respectivamente.Resultados: Concluyeron 103 pacientes (85,1%) (edad 66,4años; DE 11,6), de los que 45 (43,69%) eran varones. Las PAS y PAD fueron,respectivamente, de 140,2 (DE 14,2) y 86,1 (DE 9,2) mmHg en la visitainicial, de 140,3 (DE 14) y 86,8 (DE 8,6) mmHg al año, y de 141,3 (DE14,5) y 86,9 (DE 8,3) mmHg a los 2 años (p= NS entre la visita inicial y lafinal). Estaban controlados el 37,8% (IC 95%: 28,4-47,2), el 53,4% (IC95%: 43,8-63) y el 38,8% (IC 95%: 29,43-48,17) por visitas (inicial y 12 y24 meses, respectivamente) (p= NS inicial-final). Conclusiones: El controlde la PA en la DM2 tratada con insulina es muy bajo, no modificándose a los2 años de seguimiento(AU)

Objective: To know the blood pressure (BP) control in patients with type 2 diabetestreated with insulin after two years of follow-up. Setting: 9 health centersof Primary Care. Design: Prospective, longitudinal, multicentric study performedin Primary Care settings. 121 patients with type 2 diabetes who needed initiationor modifi cation of insulin therapy were included. During the 2 years of follow-up,5 visits (inclusion, and 6,12,18, and 24 months) were performed. The compliancewas studied by means of count of insulin. BP was measured in two occasionsand mean BP and degree of BP control was evaluated. Good control wasdefi ned when SBP was <140 mmHg, and DBP was <90 mmHg, respectively.Results: 103 patients (85.1%) (mean age 66.4 years, SD 11.6) concluded thestudy, of which 45 were men (43.69%). SBP and DBP were respectively 140.2(SD 14.2) and 86.1 (SD 9.2) mmHg at the initial visit, 140.3 (SD 14) and 86.8(SD 8.6) mmHg at 1 year and 141.3 (SD 14.5) and 86.9 (SD 8.3) at 2 years(p= NS between initial-fi nal visit). 37.8% (CI 95%: 28.4-47.2), 53.4% (CI 95%:43.8-63) and 38.8% (CI 95%: 29.43-48.17) for visits (initial, 12 and 24months, respectively) (p= NS initial-fi nal) had BP controlled. Conclusions:Blood pressure control in patients with type 2 diabetes treated with insulin is verylow, without changes after 2 years of follow-up(AU)

c/EBPbeta is a major regulatory element driving transcriptional activation of the CXCL12 promoter.

CXCL12 is considered a constitutively expressed chemokine with homeostatic functions. However, induction of CXCL12 expression and its potential role in several pathologic conditions have been reported, suggesting that CXCL12 gene expression can be induced by different stimuli. To elucidate the molecular mechanisms involved in the regulation of CXCL12 gene expression, we aim to define the molecular factors that operate at the transcriptional level. Basal, constitutive expression of CXCL12 was dependent on basic helix-loop-helix factors. Transcriptional up-regulation of the CXCL12 gene was induced by cellular confluence or inflammatory stimuli such as interleukin-1 and interleukin-6, in a CCAAT/enhancer binding protein beta (c/EBPbeta)-dependent manner. Chromatin immunoprecipitation assays confirmed c/EBPbeta binding to a specific response element located at -1171 of the promoter region of CXCL12. Our data show that c/EBPbeta is a major regulatory element driving transcription of the CXCL12 gene in response to cytokines and cell confluence.

Clinical significance of synovial lymphoid neogenesis and its reversal after anti-tumour necrosis factor alpha therapy in rheumatoid arthritis.

OBJECTIVE: To investigate the clinical significance of lymphoid neogenesis (LN) in rheumatoid arthritis (RA), the clinicopathological correlates of this process and its evolution after anti-tumour necrosis factor (TNF)alpha therapy in a large series of synovial tissues were analysed. METHODS: Arthroscopic synovial biopsies from 86 patients with RA were analysed by immunohistochemistry. LN was defined as the presence of large aggregates of lymphocytes with T/B cell compartmentalisation and peripheral node addressin (PNAd) positive high endothelial venules. Clinical variables at baseline and after prospective follow-up were compared in LN positive and negative RA subsets. The evolution of LN and its correlation with the clinical course in a subgroup of 24 patients that underwent a second arthroscopic biopsy after anti-TNFalpha therapy was also analysed. RESULTS: LN was present in 49% of RA synovial tissues. Patients with LN had a significantly higher disease duration and a higher previous use of anti-TNFalpha agents. During prospective follow-up, the proportion of patients achieving good or moderate European League Against Rheumatism (EULAR) 28-joint Disease Activity Score (DAS28) responses was significantly lower in patients who were LN positive despite a significantly higher use of anti-TNFalpha agents. By multivariate logistic regression analysis, LN remained as an independent negative predictor of response to therapy. In the subgroup of patients rebiopsied after anti-TNFalpha therapy, reversal of LN features occurred in 56% of the patients and correlated with good clinical responses. CONCLUSIONS: Synovial LN in RA predicts a lower response to therapy. LN features can be reversed after a short period of anti-TNFalpha therapy in parallel to good clinical responses.

Progress of the ITER equatorial vis/IR wide angle viewing system optical design.

The equatorial vis/IR wide angle viewing system is present in four ITER diagnostic equatorial ports. This instrument will cover a large field of view with high spatial and temporal resolutions, to provide real time temperature measurements of plasma facing components, spectral data in the visible range, information on runaway electrons, and pellet tracking. This diagnostic needs to be reliable, precise, and long lasting. Its design is driven by both the tokamak severe environment and the high performances required for machine protection. The preliminary design phase is ongoing. Paramount issues are being tackled, relative to wide spectral band optical design, material choice, and optomechanical difficulties due to the limited space available for this instrument in the ports, since many other diagnostics and services are also present. Recent progress of the diagnostic optical design and status of associated R&D are presented.

Poly(ADP-ribose) polymerase inhibition reduces tumor necrosis factor-induced inflammatory response in rheumatoid synovial fibroblasts.

OBJECTIVES: To investigate the effect of poly(ADP-ribose) polymerase (PARP) inhibition on the production of inflammatory mediators and proliferation in tumour necrosis factor (TNF)-stimulated fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: Cultured FLS from patients with RA were treated with two PARP inhibitors, 3,4-dihydro-5-[4-1(1-piperidinyl)buthoxy]-1(2H)-isoquinolinona (DPQ) or 4-amino-1,8-naphthalimida (ANI) before TNF stimulation. PARP-1 expression was also suppressed in RA FLS by small interfering RNA (siRNA) transfection. Expression and secretion of inflammatory mediators were analysed by quantitative polymerase chain reaction and by enzyme-linked immunosorbent assay, respectively. Proliferation of RA FLS was also determined. Mitogen-activated protein kinase (MAPK) activity was analysed by western blot assay and activator protein (AP)-1 and nuclear factor (NF)kappaB binding by electrophoretic mobility shift assay. RESULTS: We show, for the first time, that PARP inhibition either with specific inhibitors or by siRNA transfection significantly reduced TNF-induced cytokine and chemokine expression in FLS from patients with RA. PARP inhibitors also decreased TNF-induced RA FLS proliferation. PARP inhibition reduced TNF-induced JNK phosphorylation and AP-1 and NF kappaB binding activities were partially impaired by treatment with PARP inhibitors or by PARP-1 knockdown. CONCLUSION: PARP inhibition reduces the production of inflammatory mediators and the proliferation of RA FLS (in response to TNF), suggesting that PARP inhibitors could have therapeutic benefits in RA.

VIP decreases TLR4 expression induced by LPS and TNF-alpha treatment in human synovial fibroblasts.

It has been demonstrated that VIP produces beneficial effects both in a murine model of rheumatoid arthritis and in human rheumatoid synovial fibroblasts through the modulation of proinflammatory mediators. Toll-like receptors (TLRs) play a key role in the immediate recognition of microbial surface components by immune cells prior to the development of adaptative microbe-specific immune responses. In this study, we demonstrate that VIP decreases lipopolysaccharide (LPS) and TNF-alpha-induced expression of TLR4 and its correlation with the production of CCL2 and CXCL8 chemokines in human synovial fibroblasts from patients with rheumatoid arthritis and osteoarthritis. Our results add a new step for the use of VIP, as a promising candidate, for the treatment of rheumatoid arthritis.

VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumatoid synovial fibroblasts.

OBJECTIVES: Vasoactive intestinal peptide (VIP) has demonstrated therapeutic effects in arthritis by inhibiting both innate and acquired immune responses. We investigated the potential effects of VIP in the regulation of Toll-like receptor (TLR) expression and function in synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA and OA. The effects of VIP on basal or TNF-alpha or lipopolysaccharide (LPS)-induced TLR2, TLR4 and MyD88 expression and its effects on TLR4-mediated CCL2 and CXCL8 chemokine production were studied by reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: TLR2, TLR4 and MyD88 mRNA expression was increased in RA FLS compared with OA FLS. The largest increase was observed for TLR4 and there was also overexpression at the protein level in RA FLS. TLR4 and MyD88 mRNA and proteins were induced by LPS and TNF-alpha in RA FLS. VIP down-regulated the induced but not the constitutive expression of TLR4 and MyD88 in RA FLS. VIP treatment decreased CCL2 and CXCL8 chemokine production in response to TLR4 activation with LPS in RA FLS. CONCLUSIONS: We demonstrate that VIP down-regulates LPS and TNF-alpha activation of TLR4 expression and the TLR4 functional response in terms of proinflammatory chemokine production. These studies suggest that the pleiotropic anti-inflammatory actions of VIP involve inhibitory effects on TLR4 expression and signalling.

The tight skin mouse: an animal model of systemic sclerosis.

The search for an animal model of systemic sclerosis (SSc) was tenaciously pursued by E.C. LeRoy. We studied several aspects of the tight skin mouse (Tsk) genetics and pathogenesis under his stimulating influence that contributed to a better understanding of the fibrotic scleroderma-like phenotype of this mouse. The identification of the fibrillin-1 mutation in the Tsk mouse and the characterization of the cellular and molecular pathways leading to Tsk fibrosis by numerous research groups has opened new avenues in the investigation of human SSc. The enigmatic connections between autoimmunity and ECM homeostasis in fibrotic diseases have received extensive attention in this mouse in which a prirmary alteration of a connective tissue microfibrilar protein leads to the reproduction of cellular and autoimmune abnormalities strikingly similar to human SSc. The use of this mouse as a tool to explore anti-fibrotic therapeutic interventions has demonstrated its value in providing useful information on the search for a therapy for this untreatable facet of human disease.

Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells.

OBJECTIVE: Vasoactive intestinal peptide (VIP) has demonstrated beneficial effects in several murine models of immune-mediated inflammation by inhibiting both the inflammatory and the autoimmune components of the disease. We investigate its potential to modulate the release of proinflammatory cytokines and chemokines by human synovial cells from patients with rheumatoid arthritis (RA). METHODS: Fresh suspensions of synovial tissue cells (STC) or cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA or osteoarthritis (OA). The effects of VIP on basal or tumour necrosis factor alpha (TNF-alpha)-stimulated production of CCL2 (MCP-1, monocyte chemotactic protein 1), CXCL8 [interleukin (IL)-8], IL-6 and TNF-alpha were studied by specific ELISAs (enzyme-linked immunosorbent assays). The mRNAs for CCL2, CXCL8 and IL-6 in FLS were analysed by real-time reverse transcription-polymerase chain reaction. RESULTS: VIP at 10 nm down-regulated chemokine production by STC and FLS from RA and OA patients. VIP also down-regulated the expression of mRNAs for CCL2, CXCL8 and IL-6. The effects of VIP were more clearly detected in RA samples and after stimulation with TNF-alpha. CONCLUSION: Our observations confirm that the proposed anti-inflammatory actions of VIP in murine models also apply to human synovial cells ex vivo. Further studies are encouraged to evaluate the use of VIP as a potential therapy for chronic inflammatory joint diseases.

CARD15/NOD2 analysis in rheumatoid arthritis susceptibility.

OBJECTIVE: To determine if the mutations in the CARD15/NOD2 gene predisposing to Crohn's disease (CD) contribute also to the genetic susceptibility to rheumatoid arthritis (RA). METHODS: The frequencies of the three commonest mutations of CARD15/NOD2 predisposing to CD (2104C > T, 2722G>C and 3020insC) were determined in 210 RA patients and 227 controls. RESULTS: Allelic frequencies of the CARD15/NOD2 mutations in RA patients (2104C>T, 2.8%; 2722G>C, 0.9%; and 3020insC, 2.4%) did not differ significantly from the controls (2104C>T, 5.3%; 2722G>C, 0.7%; and 3020insC, 1.1%). CONCLUSION: There was no evidence of association between the commonest CD CARD15/NOD2 mutations and RA susceptibility.

Importante hipertrofia de ventrículo izquierdo,ecocardiográficamente, en paciente hipertensode reciente comienzo / Echocardiograph manifestation of significant left-ventricular hypertrophy in early-stage hypertensive patients

No disponible

The chemoattraction of lymphocytes by rheumatoid arthritis - synovial fluid is not dependent on the chemokine receptor CCR5.

OBJECTIVE: The objective was to study the potential role of the chemokine receptor CCR5 in the chemoattraction of lymphocytes by rheumatoid arthritis synovial fluid (RA-SF). METHODS: The expression of the CCR5 receptor was studied by flow cytometry. Chemotaxis of peripheral blood lymphocytes in response to RA-SF was analyzed on transmigration chambers. Chemotaxis of immortalized lymphocytes from individuals homozygous for the Delta32 deletion of the CCR5 gene (CCR5-/-) was analyzed. The effect of a neutralizing anti-CCR5 antibody on the migration of CCR5+/+ cells was also studied. RESULTS: We confirmed an increase in the proportion of CCR5-expressing lymphocytes in RA-SF and a preferential migration of CCR5+ lymphocytes toward RA-SF in vitro. CCR5-/- lymphocytes showed decreased chemotactic responses to the chemokine MIP-1beta but not to RA-SF. The chemotactic responses of CCR5+/+ lymphocytes to RA-SF were not modified by anti-CCR5 neutralizing antibody. CONCLUSIONS: We confirm a preferential accumulation of CCR5-expressing lymphocytes into RA-SF. However, the chemotactic responses of lymphocytes to RA-SF were not dependent on a functional CCR5 receptor, suggesting that CCR5 is a marker of a lymphocyte subset rather than a specific mediator of chemotactic responses to chemokines in RA-SF.

Cyclooxygenase-2 inhibition lacks immunomodulatory effects on T cells.

OBJECTIVE: In T cells, cyclooxygenase-1 is constitutively expressed, and cyclooxygenase-2 is induced during activation but their functions are not well known. Although exogenous prostaglandins are potent inhibitors of T cell activation, both immunoactivation and immunosuppression have been attributed to cyclooxygenases inhibitors (NSAIDs). Understanding the functions of the cyclooxygenases on T cells is relevant to the therapeutic use of NSAIDs on T cell mediated rheumatic diseases such as rheumatoid arthritis. In this study, we analyze whether cyclooxygenases play a significant role in T cell functions. METHODS: Activation, proliferation, and Fas induced apoptosis were analyzed in T cells treated with non-selective (indomethacin) or cyclooxygenase-2 selective (dimethyl-furanone) inhibitors. Intracellular peroxidation was studied in activated T cells by dihydrorhodamine 123 fluorescence analysis of cells treated with COX-2 antisense or control oligonucleotides. COX-2 expression was analyzed by RT-PCR analysis. RESULTS: Our data show that neither non-selective or selective cyclooxygenase-2 inhibition modify T cell activation, proliferation or apoptosis susceptibility. Furthermore, inhibition of cyclooxygenase-2 expression by antisense oligonucleotides lacks significant effects on T lymphocytes and does not modify their peroxydative capacity. CONCLUSIONS: According to these data, cyclooxygenases do not seem to play a relevant role in T cells functions in vitro. Therefore, the use of either cyclooxygenase-2 selective or non-selective NSAIDs in patients with autoimmune inflammatory diseases is not expected to induce direct immunomodulatory effects through direct effects on T cells.

Decreased susceptibility to Fas-induced apoptosis of systemic sclerosis dermal fibroblasts.

OBJECTIVE: To determine whether dysregulated apoptosis of systemic sclerosis (SSc) fibroblasts contributes to progressive fibrosis by promoting fibroblast longevity. METHODS: We examined the pattern of fibroblast proliferation and apoptosis in SSc skin lesions and the susceptibility of cultured SSc dermal fibroblasts to apoptosis. Skin biopsy samples from SSc patients and control subjects were used to establish fibroblast cultures and were examined histologically. In skin sections, apoptosis was examined by TUNEL, and proliferation by immunostaining for proliferating cell nuclear antigen. Susceptibility of fibroblasts to apoptosis induced in vitro by different stimuli was studied by TUNEL. Expression of Bcl-2, Bcl-x, and Bax proteins in cultured fibroblasts was studied by Western blotting. RESULTS: Proliferation of dermal fibroblasts was not observed in normal skin but was present in skin from patients with SSc and other inflammatory skin diseases. Apoptosis of fibroblasts in SSc fibrotic skin lesions was not observed. In vitro, SSc fibroblasts were specifically resistant to apoptosis induced by Fas receptor stimulation but had normal susceptibility to apoptosis induced by nonspecific stimuli (protein kinase inhibition or serum withdrawal). Decreased susceptibility to Fas stimulation was not caused by decreased levels of surface Fas receptor. In SSc fibroblasts, quiescence induced by confluence and serum starvation was followed by an abnormal down-regulation of proapoptotic Bax protein. Up-regulation of the Bax:Bcl-2 ratio in SSc fibroblasts by Bcl-2 antisense oligonucleotides restored their susceptibility to Fas-mediated apoptosis. CONCLUSION: Our findings suggest that abnormal apoptotic regulation in fibroblasts can contribute to the pathogenesis of progressive fibrosis in SSc. Modulation of Bcl-2-related proteins appears to be a potential target for the development of apoptosis-based antifibrotic strategies.