The term ‘sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes ...according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first‐ and advanced‐line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.
Notch signaling is involved in several cell lineage determination processes during embryonic development. Recently, we have shown that Sox9 is most likely a primary target gene of Notch1 signaling in ...embryonic stem cells (ESCs). By using our in vitro differentiation protocol for chondrogenesis from ESCs through embryoid bodies (EBs) together with our tamoxifen-inducible system to activate Notch1, we analyzed the function of Notch signaling and its induction of Sox9 during EB differentiation towards the chondrogenic lineage. Temporary activation of Notch1 during early stages of EB, when lineage determination occurs, was accompanied by rapid and transient Sox9 upregulation and resulted in induction of chondrogenic differentiation during later stages of EB cultivation. Using siRNA targeting Sox9, we knocked down and adjusted this early Notch1-induced Sox9 expression peak to non-induced levels, which led to reversion of Notch1-induced chondrogenic differentiation. In contrast, continuous Notch1 activation during EB cultivation resulted in complete inhibition of chondrogenic differentiation. Furthermore, a reduction and delay of cardiac differentiation observed in EBs after early Notch1 activation was not reversed by siRNA-mediated Sox9 knockdown. Our data indicate that Notch1 signaling has an important role during early stages of chondrogenic lineage determination by regulation of Sox9 expression.
Chronic graft-versus-host disease (GVHD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT). In 2005 the National Institutes of Health (NIH) established new ...criteria for chronic GVHD based on retrospective data and expert recommendations. We prospectively evaluated the incidence of NIH-defined chronic GVHD and its prognostic impact in 178 consecutive patients. The cumulative incidence of chronic GVHD at 3 years was 64, 48 and 16% for chronic classic GVHD and overlap syndrome. Prior acute GVHD and myeloablative conditioning were significantly associated with increased risk of chronic GVHD. Three-year survival (overall survival (OS)) for late-acute GVHD, chronic classic and overlap chronic GVHD when assigned on day 100 were 69, 83 and 73%. OS was significantly worse for patients with platelet counts below 100 g/l at onset of chronic GVHD (35% versus 86%, P<0.0001) and progressive as compared with de novo and quiescent onset of chronic GVHD (54.5% versus 89.5% versus 84%, P = 0.022 and 0.001). Peak severity of chronic GVHD had no impact on non-relapse mortality (NRM) and OS. Recurrent acute GVHD, platelet counts below 100 g/l at diagnosis of chronic GVHD, progressive onset of chronic GVHD and advanced disease stage prior to HCT were significantly associated with increased NRM. This prospective analysis provides for the first-time data on the incidence rates of NIH-defined chronic GVHD categories and identified risk factors for the occurrence of chronic GVHD. A prognostic value of thrombocytopenia and progressive onset type of chronic GVHD for survival after HCT was observed in NIH-defined chronic GVHD.
A method is presented to correct positron emission tomography (PET) data for head motion during data acquisition. The method is based on simultaneous acquisition of PET data in list mode and ...monitoring of the patient's head movements with a motion tracking system. According to the measured head motion, the line of response (LOR) of each single detected PET event is spatially transformed, resulting in a spatially fully corrected data set. The basic algorithm for spatial transformation of LORs is based on a number of assumptions which can lead to spatial artifacts and quantitative inaccuracies in the resulting images. These deficiencies are discussed, demonstrated and methods for improvement are presented. Using different kinds of phantoms the validity and accuracy of the correction method is tested and its applicability to human studies is demonstrated as well.
Signaling mediated by activation of the transmembrane receptor Notch influences cell-fate decisions, differentiation, proliferation, and cell survival. Activated Notch reduces proliferation by ...altering cell-cycle kinetics and promotes differentiation in hematopoietic progenitor cells. Here, we investigated if the G(1) arrest and differentiation induced by activated mNotch1 are dependent on tumor suppressor p53, a critical mediator of cellular growth arrest. Multipotent wild-type p53-expressing (p53(wt)) and p53-deficient (p53(null)) hematopoietic progenitor cell lines (FDCP-mix) carrying an inducible mNotch1 system were used to investigate the effects of proliferation and differentiation upon mNotch1 signaling. While activated Notch reduced proliferation of p53(wt)-cells, no change was observed in p53(null)-cells. Activated Notch upregulated the p53 target p21(cip/waf) in p53(wt)-cells, but not in p53(null)-cells. Induction of the p21(cip/waf) gene by activated Notch was mediated by increased binding of p53 to p53-binding sites in the p21(cip/waf) promoter and was independent of the canonical RBP-J binding site. Re-expression of p53(wt) in p53(null) cells restored the inhibition of proliferation by activated Notch. Thus, activated Notch inhibits proliferation of multipotent hematopoietic progenitor cells via a p53-dependent pathway. In contrast, myeloid and erythroid differentiation was similarly induced in p53(wt) and p53(null) cells. These data suggest that Notch signaling triggers two distinct pathways, a p53-dependent one leading to a block in proliferation and a p53-independent one promoting differentiation.
To investigate autonomic regulation in juvenile migraine we studied 70 children and adolescents with migraine during the headache-free period and 81 healthy controls by cardiorespiratory function ...tests. Heart rate variability was analysed with time and frequency domain indices during spontaneous breathing at rest and during metronomic breathing. Changes of heart rate and blood pressure were studied during tilt-table test, active standing, Valsalva manoeuvre and sustained handgrip. We found significant differences in metronomic breathing, tilt-table test and Valsalva manoeuvre. We interpret our findings and results reported in the literature as pointing to a restricted ability of the system to rest, which supports therapies intending to further this ability. In autonomic tests, hyperreactivity in juvenile migraineurs changes to hyporeactivity and passive coping in adults. This might be explained by disturbances of raphe nuclei and the periaqueductal grey. It corresponds to psychological findings in juvenile migraineurs reporting hypersensitivity and repressed aggression and claiming learned helplessness.
Guidelines on the use of extracorporeal photopheresis Knobler, R.; Berlin, G.; Calzavara-Pinton, P. ...
Journal of the European Academy of Dermatology and Venereology,
January 2014, Letnik:
28, Številka:
s1
Journal Article
Recenzirano
Odprti dostop
Background
After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the ...FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.
Materials and methods
In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task.
Results and conclusion
These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.
Extracorporeal photopheresis (ECP) is a treatment approach that combines leukapheresis with photochemotherapy and is derived from PUVA; with this procedure, nucleated cells such as lymphocytes and ...monocytes are extracorporeally irradiated with UVA light after photosensitization. ECP is an effective treatment modality with few side effects that in recent years has been expanded to treat a range of indications. It has been proven effective in the treatment of cutaneous T cell lymphoma and is being increasing used in other lymphocyte-mediated, autoimmune and inflammatory diseases that are associated with proliferation of autoreactive T cells.
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