RESUMEN
Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs.
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Citocinas/sangre , Trasplante de Células Madre Hematopoyéticas/normas , Esclerodermia Sistémica/terapia , Adulto , Estudios de Casos y Controles , Citocinas/metabolismo , Femenino , Fibrosis/sangre , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inflamación/sangre , Masculino , Persona de Mediana Edad , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
INTRODUCTION: The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement exist on dissection of pelvic LN. This study aimed at investigating predictors of pelvic LN metastasis and prognostic significance of having metastasis in the pelvic LNs. METHODS: Clinicopathologic data of 740 patients with positive groin sentinel LN who underwent ilioinguinal completion LN dissection at four Italian centre were analysed. Multivariable logistic and Cox regression analysis was used to identify independent predictors of pelvic LN metastasis and to adjust prognostic significance of pelvic LN metastasis. RESULTS: More than a quarter (26%) of patients had positive non-SLNs after inguinal and pelvic lymphadenectomy, which were located in their pelvis in the 12% of cases. Older patients [(OR) 1.69; 95% confidence interval (CI) 1.02-2.78] having thick primary (OR 1.6; 95% CI, 1.01-2.53) and ≥ 2 positive SLNs (OR 2.5; 95% CI, 1.4-4.47) were more likely to harbour pelvic LN metastasis. Interestingly, 4% of all patients (34% of patients with positive pelvic LNs) had pelvic LN metastasis with negative inguinal LNs. Pelvic LN metastasis was independently associated with higher risk of recurrence and lower survival. 5-year disease free and overall survival was 30% and 50%, respectively, for patients with pelvic LN metastasis. CONCLUSIONS: Pelvic LNs are frequently positive after ilioinguinal lymphadenectomy and it should be considered for all patients, especially those who are older, have thick primary and ≥ 2 positive SLN. Patients with pelvic LN metastasis have worse prognosis.
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Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Melanoma/secundario , Melanoma/cirugía , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Conducto Inguinal , Italia , Estimación de Kaplan-Meier , Ganglios Linfáticos/cirugía , Metástasis Linfática/diagnóstico , Masculino , Melanoma/mortalidad , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Oportunidad Relativa , Pelvis , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Resultado del TratamientoRESUMEN
At the end of March 2015 the onboard software configuration of the Astrorivelatore Gamma a Immagini Leggero (AGILE) satellite was modified in order to disable the veto signal of the anticoincidence shield for the minicalorimeter instrument. The motivation for such a change was the understanding that the dead time induced by the anticoincidence prevented the detection of a large fraction of Terrestrial Gamma-Ray Flashes (TGFs). The configuration change was highly successful resulting in an increase of one order of magnitude in TGF detection rate. As expected, the largest fraction of the new events has short duration (<100 µs), and part of them has simultaneous association with lightning sferics detected by the World Wide Lightning Location Network. The new configuration provides the largest TGF detection rate surface density (TGFs/km2/yr) to date, opening prospects for improved correlation studies with lightning and atmospheric parameters on short spatial and temporal scales along the equatorial region.
RESUMEN
The present pilot study aims to evaluate the frequency and the function of regulatory T (Treg) cells in patients with diffuse cutaneous SSc (dcSSc) before and after autologous hematopoietic SCT (aHSCT). Peripheral blood lymphocytes from seven dcSSc patients were analyzed before and 24 months after aHSCT and were compared with those from seven healthy donors (controls). Immunophenotyping of CD4(+)CD25(high)FoxP3(+) natural Treg (nTreg), CD4(+)CD25(+)TGF-ß(+) and CD4(+)CD25(+)IL-10(+) adaptive Treg (aTreg) cell subsets was performed using four-color flow cytometry. Treg-suppressive capability was measured after coculture with autologous T effector cells by evaluation of T-cell proliferation using (3)H-thymidine incorporation. Peripheral CD4(+)CD25(high)FoxP3(+) (2±0.5 vs 4.2±1.1, P<0.01), CD4(+)CD25(+)TGF-ß(+) (6.9±1.8 vs 14.6±5.0, P<0.05) and CD4(+)CD25(+)IL-10(+) (10.7±0.5 vs 16.1±3.2, P<0.01) Tregs as well as CD4(+)CD25(high)CD127(low) Tregs suppressive capacity (P<0.05) were decreased in dcSSc patients vs controls. After aHSCT (n=7), the percentages of CD4(+)CD25(high)FoxP3(+) (4.1±1.8) and CD4(+)CD25(+)IL-10(+) (15.7±2.2) Treg cells and the suppressive activity of CD4(+)CD25(high)CD127(low) were restored to the levels in controls. The decreased frequency and the functional defect of peripheral Treg cells from patients with dcSSc are reversed following aHSCT to reach those observed in controls. This pilot study brings evidence of an effective restoration of nTreg and aTreg subsets, and recovery of nTreg suppressive function following aHSCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Esclerodermia Difusa/sangre , Linfocitos T Reguladores/citología , Adulto , Linfocitos T CD4-Positivos/citología , Proliferación Celular , Técnicas de Cocultivo , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunofenotipificación , Interleucina-10/metabolismo , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Linfocitos/citología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Esclerodermia Difusa/terapia , Factor de Crecimiento Transformador beta/metabolismo , Trasplante AutólogoAsunto(s)
Biología/tendencias , Patología Clínica/tendencias , Edición/tendencias , Biología/métodos , Trasplante de Células/métodos , Trasplante de Células/tendencias , Condrocitos/trasplante , Tejido Conectivo/fisiología , Humanos , Patología Clínica/métodos , Medicina Regenerativa/métodos , Medicina Regenerativa/tendencias , Publicaciones Seriadas/tendenciasRESUMEN
OBJECTIVES: Interleukin (IL) 34 is a new cytokine implicated in macrophage differentiation and osteoclastogenesis. This study assessed IL-34 expression in the tissue of patients with rheumatoid arthritis (RA). METHODS: Immunohistochemistry was performed in synovial biopsies from patients with RA (n=20), osteoarthritis (n=3) or other inflammatory arthritis (n=4). IL-34 was detected in the synovial fluid by ELISA and its messenger RNA expression was studied by quantitative PCR in rheumatoid synovial fibroblasts after stimulation by tumour necrosis factor α (TNFα) and IL-1ß. Wild-type, jnk1(-/-)-jnk2(-/-) and nemo(-/-) murine fibroblasts and pharmacological inhibition were used to determine the involvement of nuclear factor kappa B (NF-κB) and JNK in that effect. RESULTS: IL-34 was expressed in 24/27 biopsies, with three samples from RA patients being negative. A significant association was found between IL-34 expression and synovitis severity. Levels of IL-34 and the total leucocyte count in synovial fluid were correlated. TNFα and IL-1ß stimulated IL-34 expression by synovial fibroblasts in a dose/time-dependent manner through the NF-κB and JNK pathway. CONCLUSION: This work for the first time identifies IL-34 expression in the synovial tissue of patients with arthritis. This cytokine, as a downstream effector of TNFα and IL-1ß, may contribute to inflammation and bone erosions in RA.
Asunto(s)
Artritis Reumatoide/metabolismo , Interleucinas/metabolismo , Sinovitis/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/complicaciones , Artritis Reumatoide/genética , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta/farmacología , Interleucinas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Persona de Mediana Edad , FN-kappa B/fisiología , Osteoartritis/genética , Osteoartritis/metabolismo , ARN Mensajero/genética , Líquido Sinovial/metabolismo , Sinovitis/etiología , Sinovitis/genética , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The balance in the production and release of cytokines "Th1/Th2" or "Th17" or "regulatory T" is one of the key events in the pathogenesis of systemic sclerosis (SSc). Specifically, the Th2 cytokine response, characterized by the production of IL-4, IL-10 and TGF-ß, leads to tissue fibrosis in patients with SSc. Many studies have shown the importance of analyzing the levels of cytokines as diagnostic or prognostic markers in the blood or in situ in patients with SSc. The restoration of the Th1/Th2/Th17/Treg balance will contribute to the effectiveness of treatment and the use of cytokine modulators may therefore be considered in developing new therapeutic approaches.
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Citocinas/metabolismo , Esclerodermia Sistémica/metabolismo , Comunicación Celular/fisiología , Citocinas/sangre , Citocinas/clasificación , Citocinas/fisiología , Humanos , Modelos Biológicos , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/inmunología , Células TH1/metabolismo , Células TH1/fisiología , Balance Th1 - Th2 , Células Th2/metabolismo , Células Th2/fisiologíaRESUMEN
The well-known Crab Nebula is at the center of the SN1054 supernova remnant. It consists of a rotationally powered pulsar interacting with a surrounding nebula through a relativistic particle wind. The emissions originating from the pulsar and nebula have been considered to be essentially stable. Here, we report the detection of strong gamma-ray (100 mega-electron volts to 10 giga-electron volts) flares observed by the AGILE satellite in September 2010 and October 2007. In both cases, the total gamma-ray flux increased by a factor of three compared with the non-flaring flux. The flare luminosity and short time scale favor an origin near the pulsar, and we discuss Chandra Observatory x-ray and Hubble Space Telescope optical follow-up observations of the nebula. Our observations challenge standard models of nebular emission and require power-law acceleration by shock-driven plasma wave turbulence within an approximately 1-day time scale.
RESUMEN
Strong electric discharges associated with thunderstorms can produce terrestrial gamma-ray flashes (TGFs), i.e., intense bursts of x rays and γ rays lasting a few milliseconds or less. We present in this Letter new TGF timing and spectral data based on the observations of the Italian Space Agency AGILE satellite. We determine that the TGF emission above 10 MeV has a significant power-law spectral component reaching energies up to 100 MeV. These results challenge TGF theoretical models based on runaway electron acceleration. The TGF discharge electric field accelerates particles over the large distances for which maximal voltages of hundreds of megavolts can be established. The combination of huge potentials and large electric fields in TGFs can efficiently accelerate particles in large numbers, and we reconsider here the photon spectrum and the neutron production by photonuclear reactions in the atmosphere.
RESUMEN
Bone tumours can be dissociated in two main categories: i) primary bone tumours (benign or malignant) including mainly osteosarcoma and other sarcomas.ii)and giant cell tumour and bone metastases originate from others cancer (Breast, prostate, kidney cancer, etc). These tumours are able to destroy or/and induce a new calcified matrix. However, the first step of bone tumour development is associated with an induction of bone resorption and the establishment of a vicious cycle between the osteoclasts and the tumour growth. Indeed, bone resorption contributes to the pathogenesis of bone tumour by the release of cytokines (IL6, TNFα) which govern the bone tumour's development and which are trapped into the bone matrix. Bisphosphonates (BPs) are chemical compounds of P-C-P structure with a high affinity for bone hydroxyapatite crystals. Thus, they have been used as a carrier for radio nucleotides to develop novel approaches of bone imaging. BPs exert also indirect anti-tumour activities in vivo. Indeed, BPs directly interfere with the bone microenvironment and target osteoclasts, endothelial cells and immune cells (tumour-associated macrophages, γ9δ2 T cells). BPs induce tumour cell death in vitro and same activity is suspected in vivo. The present review summarizes the mechanisms of actions of BPs as well as their clinical interests in bone primary tumours.
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Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Difosfonatos/farmacología , Difosfonatos/uso terapéutico , Diseño de Fármacos , Animales , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/diagnóstico por imagen , Condrosarcoma/tratamiento farmacológico , Tumor Óseo de Células Gigantes/tratamiento farmacológico , Humanos , Osteosarcoma/tratamiento farmacológico , RadiografíaRESUMEN
Better understanding of the pathogenesis of tissue fibrosis, and especially the pivotal role of the extracellular matrix components, shed new light on the use of several immunosuppressive drugs to treat systemic sclerosis. We review the recent experimental data demonstrating the specific antifibrotic effect of several immunosuppressive drugs, independent of their immunosuppressive action, in light of the clinical results obtained when treating severe systemic sclerosis patients. Refined analysis of the molecular mechanisms underlying the direct antifibrotic effects of these immunosuppressive drugs (rapamycin and mycophenolate mofetil) will contribute to improve the therapeutic strategy in systemic sclerosis patients.
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Inmunosupresores/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Animales , Ciclofosfamida/uso terapéutico , Fibrosis/tratamiento farmacológico , Fibrosis/etiología , Humanos , Pronóstico , Esclerodermia Sistémica/etiologíaRESUMEN
Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis. Membrane RAGE expression was confirmed by FACS analysis. Microarray methods, RT-PCR, and Northern blot analysis were used to detect and confirm specific gene induction. Zymographic analysis and ELISA were used to measure the induction of tPA and PAI-1. We show herein that cultured human mesangial cells express AGE receptor type 1, type 2 and type 3 and RAGE. AGEs (200 microg/ml) induced at least a 2-fold increase in mRNA for 10 genes involved in ECM remodelling, including tPA, PAI-1 and TIMP-3. The increase in tPA synthesis was confirmed by fibrin zymography. The stimulation of PAI-1 synthesis was confirmed by ELISA. AGEs increased PAI-1 mRNA through a signalling pathway involving reactive oxygen species, the MAP kinases ERK-1/ERK-2 and the nuclear transcription factor NF-kappaB, but not AP-1. Carboxymethyl lysine (CML, 5 microM), which is a RAGE ligand, also stimulated PAI-1 synthesis by mesangial cells. In addition, a blocking anti-RAGE antibody partially inhibited the AGE-stimulated gene expression and decreased the PAI-1 accumulation induced by AGEs and by CML. Inhibition of AGE receptors or neutralization of the protease inhibitors TIMP-3 and PAI-1 could represent an important new therapeutic strategy for diabetic nephropathy.
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Proteínas de la Matriz Extracelular/genética , Productos Finales de Glicación Avanzada/farmacología , Metaloproteinasa 2 de la Matriz/genética , Células Mesangiales/efectos de los fármacos , Anticuerpos/farmacología , Northern Blotting , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Proteínas de la Matriz Extracelular/metabolismo , Flavonoides/farmacología , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Humanos , Lisina/análogos & derivados , Lisina/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Células Mesangiales/citología , Células Mesangiales/metabolismo , Norleucina/farmacología , Análisis de Secuencia por Matrices de Oligonucleótidos , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidor Tisular de Metaloproteinasa-3/genética , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Activador de Tejido Plasminógeno/genética , Activador de Tejido Plasminógeno/metabolismo , alfa-Macroglobulinas/genética , alfa-Macroglobulinas/metabolismoRESUMEN
Mesenchymal stem cells (MSCs) are multipotent non-haematopoietic progenitor cells that are being explored as a promising new treatment for tissue regeneration. Although their immunomodulatory properties are not yet completely understood, their low immunogenic potential together with their effects on immune response make them a promising therapeutic tool for severe refractory autoimmune diseases. Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. While insulin replacement represents the current therapy for type 1 diabetes, its metabolic control remains difficult, as exogenous insulin cannot exactly mimic the physiology of insulin secretion. Pancreatic or islet transplantation can provide exogenous insulin independence, but is limited by its intrinsic complications and the scarcity of organ donors. In this context, stem cell therapy, based on the generation of insulin-producing cells (IPCs) derived from MSCs, represents an attractive possibility. In this review, we provide a brief characterization of MSC immunomodulatory effects, and present the current experimental evidence for the potential therapeutic efficacy of MSC transplantation in diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1/terapia , Células Secretoras de Insulina/citología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/fisiología , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Humanos , Terapia de Inmunosupresión , Células Secretoras de Insulina/fisiología , Células Madre Mesenquimatosas/inmunologíaRESUMEN
Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration. Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions. Although MSC immunomodulating properties are not yet completely understood, their low immunogenic potential can be used as a therapeutic tool not only for regenerative medicine, but also for the treatment of graft-versus-host disease (GVHD) after bone marrow transplantation as well as for specific cases of severe refractory autoimmune diseases. Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction. Phase I-II studies are in progress in various countries to investigate the potential benefit from MSC due to their immunosuppressive properties, as an adjunctive therapy for severe refractory autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes/terapia , Terapia de Inmunosupresión , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Adulto , Animales , Artritis Reumatoide/terapia , Trasplante de Médula Ósea/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos , Células Cultivadas , Niño , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/terapia , Humanos , Lupus Eritematoso Sistémico/terapia , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Endogámicos NOD , Esclerosis Múltiple/terapia , Infarto del Miocardio/terapia , Osteogénesis Imperfecta/terapia , Papio , Estudios Prospectivos , Esclerodermia Sistémica/terapiaRESUMEN
BACKGROUND: Mesenchymal stem cells (MSCs) have a potential immunomodulatory role in autoimmune disease; however, the qualitative properties and haematopoietic support capacity of MSCs derived from patients with autoimmune disease is unclear. OBJECTIVES: To further characterise phenotypically and functionally bone marrow (BM)-derived MSCs from patients with systemic sclerosis (SSc). METHODS: Key parameters of BM-derived MSC function and phenotype were assessed in 12 patients with SSc and compared with 13 healthy normal controls. The parameters included the ability to: form colony-forming unit fibroblasts (CFU-F), differentiate along the adipogenic and osteogenic lineages, express cell surface antigens defining the MSCs population, support normal haematopoiesis and suppress in vitro lymphocyte proliferation induced by either anti-CD3epsilon plus anti-CD28 monoclonal antibodies or the mixed lymphocyte reaction. RESULTS: SSc MSCs were shown to have a similar characteristic phenotype, capacities to form CFU-F and to differentiate along adipogenic and osteogenic lineages as those of healthy donor MSCs. The ability of SSc MSCs to support long-term haematopoiesis was also identical to that of controls. Both healthy donor and SSc BM MSCs reduced the proliferation of autologous and allogeneic peripheral blood mononuclear cells in a cell number dependent fashion. CONCLUSIONS: These results show that BM-derived MSCs from patients with SSc under the described culture conditions exhibit the same phenotypic, proliferative, differentiation potential and immunosuppressive properties as their healthy counterparts and could therefore be considered in an autologous setting. Further studies are needed to ensure the quality and safety of large-scale expansion of patient MSCs prior to their potential use in clinical trials.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Células de la Médula Ósea/inmunología , Células Madre Mesenquimatosas/inmunología , Esclerodermia Sistémica/inmunología , Adulto , Enfermedades Autoinmunes/terapia , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Femenino , Fibroblastos/patología , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Prueba de Cultivo Mixto de Linfocitos , Masculino , Persona de Mediana Edad , Esclerodermia Sistémica/terapiaRESUMEN
OBJECTIVES: A clinico-pathological study in diffuse systemic sclerosis (SSc) patients was performed to analyse whether the skin histological organization and the pro-fibrotic signals elicited by TGF-beta in fibroblasts vary according to the modified Rodnan skin score (mRSS). METHODS: Twenty-seven SSc patients underwent 45 skin biopsies with simultaneous measure of mRSS before or after treatment by immunosuppressive drugs, with or without autologous peripheral haematopoietic stem cell transplantation (HSCT). RESULTS: Double-blind optic microscopy analysis of the biopsies standard extracellular matrix stains allowed to define three histological subgroups: 6 with grade 1 weak fibrosis, 30 with grade 2 moderate fibrosis and 9 with grade 3 severe fibrosis. A significant (P < 0.0001) was identified between the grades of fibrosis and the mRSS. In skin fibroblast cultures, Smad3 phosphorylation levels, as well as mRNA steady-state levels of two transforming growth factor (TGF)-beta/Smad3 targets, COL1A2 and PAI-1, increased in parallel with the mRSS. When compared with pre-transplant values the degree of fibrosis observed after HSCT in the papillary and in the reticular dermis decreased in parallel with the fall in mRSS (n = 5 consecutive patients with repeated biopsies). CONCLUSIONS: The histological extent of skin fibrosis correlates closely with the mRSS. Both parameters appeared to regress after HSCT. The extent of TGF-beta signalling activation in SSc skin fibroblasts appears to parallel the severity of disease.