[Social media-Chances and risks for rheumatology]. / Social Media ­ Chancen und Risiken für die Rheumatologie.

The use of social media and social networks has increased significantly in recent years. They are becoming progressively more important as information channels in private and professional contexts. Also, in medicine, social media are already being used in a variety of ways. For example, professional societies and patient interest groups are being increasingly represented in social networks. The broad use and wide audience of these networks offer new opportunities for the field of rheumatology. This review article provides an overview of the characteristics of some major social media platforms and systematically analyses the existing publications in the context of rheumatology. Furthermore, advantages, but also potential risks that may arise due to social media use are being addressed.

[Pregnancy with lupus erythematosus-an update]. / Schwangerschaft bei Lupus erythematodes ­ ein Update.

Current research in the field of systemic lupus erythematosus (SLE) and pregnancy focuses on predictors of adverse pregnancy outcomes, the safety and efficacy of hydroxychloroquine (HCQ) in pregnancy and the importance of preconception counselling. In particular, the prospective predictors of pregnancy outcome: biomarkers in antiphospholipid antibody syndrome and SLE (PROMISSE) study adds to the understanding of risk factors for adverse outcomes. There is increasing evidence of the numerous benefits associated with continuing HCQ treatment in pregnancy and for the use of low-dose acetylsalicylic acid in the prevention of preeclampsia. The European League Against Rheumatism (EULAR) has published evidence-based recommendations for the treatment of women with SLE and/or antiphospholipid syndrome before, during and after pregnancy. Rheumatologists caring for women with SLE should be familiar with the current state of knowledge in order to help optimize the management and thus the outcome of pregnancy in their patients.

[Sexuality in adolescents with rheumatic diseases : Contraception, HPV vaccination and pregnancy]. / Sexualität bei Jugendlichen mit rheumatischen Erkrankungen : Verhütung, HPV-Impfung und Schwangerschaft.

Young patients and adolescents with chronic rheumatic diseases have the same desires, fears and needs in terms of sexuality and pregnancy as their healthy peers. In most cases adolescents are already sexually active before transition from pediatric to adult rheumatological care takes place. Pregnancies in women with rheumatic diseases are associated with increased maternal and fetal risks, especially when they occur unplanned in the course of active disease or under teratogenic drugs. Safe contraception is therefore crucial in preventing unwanted pregnancies. The choice of contraception should anticipate the safety of the method of contraception as well as age-dependent practicability. A strategy of "double protection" through the use of condoms for contraception and prevention of sexually transmitted diseases combined with another safe contraception method should be recommended. Women with rheumatic diseases are more susceptible to acquire persisting human papilloma virus (HPV) infections and the subsequent progression to cervical cancer. In women with rheumatic diseases HPV vaccination induces high seroconversion rates, is safe and does not seem to induce disease activity. The care of adolescent women with rheumatic diseases before, during and after medical transition needs to encompass an open, early and continuous counselling regarding these topics in order to retain the individual health-related quality of life and to adapt this care to age-specific needs.

Patient-reported outcomes in large vessel vasculitis: insights from a retrospective analysis of disease activity and associated factors.

BACKGROUND: Patient-reported outcomes (PROs) play a crucial role in assessing rheumatic diseases, offering insights into disease evaluation and treatment efficacy. This study focuses on PRO assessment in large vessel vasculitides, including Takayasu Arteritis and Giant Cell Arteritis (GCA). METHODS: We retrospectively analyzed routine data from patients treated at our rheumatology clinic over a 10-year span. Patient and physician-rated global disease activity scale (G-DAS) scores, measured on a numeric rating scale (0-10 points), were collected at each visit. Clinical variables like age, sex, body mass index (BMI), disease duration, lab values, pain perception, and questionnaire responses were recorded. Linear regression and generalized additive linear regression (GAM analysis) examined associations between PROs and these factors. RESULTS: The study included 138 patients, primarily diagnosed with GCA (94.4%). Mean follow-up was 2.5 years (0-7.7). Patient and physician G-DAS exhibited a moderate correlation (Pearson R 0.19, CI 0.14-0.24, p < 0.001). Higher patient G-DAS correlated with younger age (CI -3.4 - -1.5, p < 0.001), increased pain (CI 3.5-4, p < 0.001), functional limitations (HAQ, CI 0.5-0.6, p < 0.001), reduced physical (CI 2.3-2.7, p ≤ 0.001) and psychological well-being (CI 2.1-2.5, p < 0.001), and higher BMI (CI 1.3-2.4, p < 0.001). Physician G-DAS correlated with Birmingham Vasculitis Activity Score (V3.0; R 0.42, p 0.046) and were significantly linked to serum CRP elevations (ß = 0.04, CI 0.0-0.08, p 0.028). CONCLUSIONS: These findings underscore the need to integrate PRO measures into vasculitis disease management strategies, enhancing the understanding of disease activity from the patient's perspective.

[Whole body hyperthermia in pain therapy. A controlled trial on patients with fibromyalgia]. / Ganzkörperhyperthermie in der Schmerztherapie. Eine kontrollierte Studie an Patienten mit Fibromyalgiesyndrom.

BACKGROUND: The aim of this study was to evaluate whether mild water-filtered near infrared whole body hyperthermia in patients with fibromyalgia produces a benefit when applied as an addition to a standard multimodal rehabilitation. PATIENTS AND METHODS: In this study 67 patients at a German rehabilitation clinic were included and allocated to 3 study groups: the 2 intervention groups received additional mild water-filtered near infrared whole body hyperthermia once or twice a week over 3 weeks and the control group received only standard multimodal rehabilitation. Main outcome measure was pain intensity measured at baseline, discharge from the rehabilitation clinic and 6 months after discharge. RESULTS: Additional mild water-filtered near infrared whole body hyperthermia once a week proved to be significantly better than the second hyperthermia group and the control group with respect to pain reduction and affective sense of pain. Furthermore, hyperthermia once a week tended to result in better outcome regarding fibromyalgia-related quality of life and depression. CONCLUSION: There is evidence that mild water-filtered near infrared whole body hyperthermia is a reasonable complement to multimodal rehabilitation in the treatment of fibromyalgia.

[Importance of education level for effectiveness of multimodal pain therapy]. / Bedeutung des Bildungsniveaus für die Wirksamkeit der multimodalen Schmerztherapie.

BACKGROUND: The recommended treatment for chronic pain is multidisciplinary with a cognitive approach. The aim of this study was to investigate whether the education level of patients was predictive of main outcome dimensions (pain intensity, disability, depression, physical functioning and return to work). PATIENTS AND METHODS: This was a secondary analysis of 413 patients who participated in an in-patient multidisciplinary pain treatment program. All patients were studied at baseline and after 6 months. The aim was to find predictors for the changes in scores of outcome measures (from admission to follow-up). Possible predictors were educational level and other available variables that are considered prognostic of treatment outcome, including age, gender, body mass index, endurance of pain, pain intensity, depressive symptoms and work status. Classification trees were used to predict outcome variables. RESULTS: The outcome was markedly improved in the sampling collective at follow-up compared with baseline. Education was the best predictor of treatment outcome and affected 4 out of the 5 outcome dimensions analyzed. CONCLUSION: If education level proves to be an intervening variable in further research, education adjusted treatment programs should be developed and evaluated.

Resolving lesions in human cutaneous leishmaniasis predominantly harbour chemokine receptor CXCR3-positive T helper 1/T cytotoxic type 1 cells.

BACKGROUND: Cutaneous leishmaniasis (CL) is an epidemic disease affecting millions of individuals worldwide. Treatment options have several side-effects and a vaccine does not exist at present. OBJECTIVES: To translate information about protection against CL from mice to man, we studied the local immune response in CL skin biopsies and correlated these findings with clinical information. METHODS: The frequency of inflammatory cells was determined in skin biopsies of 20 patients diagnosed with CL using immunohistochemistry. In addition, the nature of the resulting adaptive immune response was assessed by (double) immunostaining against CD4 and chemokine receptors CXCR3 (T helper 1, Th1)/CCR4 (Th2). RESULTS: All lesions contained CD4+ and CD8+ T cells, B cells and CD68+ macrophages. CD1a+ epidermal Langerhans cells were absent above the centre of the lesions, but normally distributed in the surrounding tissue. Mast cell and CD56+ natural killer cell numbers were not affected. Interestingly, CCR4+ Th2 cells were not detected in any of the 20 samples. In contrast, the number of infiltrating CXCR3+ cells was high and the majority of these were CD4+ or CD8+ indicating that they represent interferon-gamma-producing Th1/T cytotoxic type 1 (Tc1) cells. Finally, these findings did not correlate with clinical information about the country where the infection was acquired, or age or sex of the patients. However, lesions that had already persisted for more than 6 months contained fewer CXCR3+ CD4 and CD8 T cells than those that had persisted for less than 6 months. CONCLUSIONS: Our data on the inflammatory infiltrate of human CL lesions underline the relevance of findings obtained in experimental models. Both Th1 and Tc1 cells appear to be critical for healing in CL in mouse and man.

A role for mitogen-activated protein kinase activation by integrins in the pathogenesis of psoriasis.

In normal epidermis, beta1 integrin expression is confined to the basal layer, whereas in hyperproliferative epidermis, integrins are also expressed in the suprabasal layers. Transgenic mice in which integrins are expressed suprabasally via the involucrin promoter have a sporadic psoriatic phenotype; however, the mechanism by which integrins contribute to the pathogenesis of psoriasis is unknown. We observed activation of mitogen-activated protein kinase (MAPK) in basal and suprabasal keratinocytes of human and transgenic mouse psoriatic lesions and healing mouse skin wounds, correlating in each case with suprabasal integrin expression. Phenotypically normal human and transgenic mouse epidermis did not contain activated MAPK. Transgene-positive keratinocytes produced more IL-1alpha than controls did, and keratinocyte MAPK could be activated by ligation of suprabasal integrins or treatment with IL-1alpha. Constitutive activation of MAPK increased the growth rate of human keratinocytes and delayed the onset of terminal differentiation, recreating many of the histological features of psoriatic epidermis. We propose that activation of MAPK by integrins, either directly or through increased IL-1alpha production, is responsible for epidermal hyperproliferation in psoriasis and wound healing, and that the sporadic phenotype of the transgenic mice may reflect the complex mechanisms by which IL-1 release and responsiveness are controlled in skin.

Use of geographic and genotyping tools to characterise tuberculosis transmission in Montreal.

SETTING: In Canada, tuberculosis (TB) is increasingly an urban health problem. Montreal is Canada's second-largest city and the second most frequent destination for new immigrants and refugees. OBJECTIVES: To detect spatial aggregation of cases, areas of excess incidence and local 'hot spots' of transmission in Montreal. DESIGN: We used residential addresses to geocode active TB cases reported on the Island of Montreal in 1996-2000. After a hot spot analysis suggested two areas of overconcentration, we conducted a spatial scan, with census tracts (population 2500-8000) as the primary unit of analysis and stratification by birthplace. We linked these analyses with genotyping of all available Mycobacterium tuberculosis isolates, using IS6110-RFLP and spoligotyping. RESULTS: We identified four areas of excess incidence among the foreign-born (incidence rate ratios 1.3-4.1, relative to the entire Island) and one such area among the Canadian-born (incidence rate ratio 2.3). There was partial overlap with the two hot spots. Genotyping indicated ongoing transmission among the foreign-born within the largest high-incidence zone. While this zone overlapped the area of high incidence among Canadian-born, genotyping largely excluded transmission between the two groups. CONCLUSIONS: In a city with low overall incidence, spatial and molecular analyses highlighted ongoing local transmission.

[High-dose rate brachytherapy for high-risk prostate cancer]. / High-dose-rate-Brachytherapie beim Risikoprostatakarzinom.

To estimate disease-free survival it is necessary to allocate patients into tumor risk groups: locally advanced prostate carcinoma with extracapsular spread or localized prostate carcinoma of tumor stage T2c or one of the risk factors PSA >20 or Gleason > or =8 apply for the high-risk group. Intermediate-risk carcinomas are those belonging to tumor stage T2b or with PSA >10-20 or Gleason 7. Particularly for patients with intermediate and high-risk disease early PSA relapse is of major interest. This phenomenon could be a consequence of current inadequate imaging of lymph node or bone metastasis or as a consequence subclinical metastatic spread remains undetectable during radical treatment. However, tumor biology itself could lead to the progression of the disease in the high-risk group. As a consequence, risk-adapted therapy is very important in these cases. The applied radiation dose plays an important role in radiotherapy. Several publications have shown that the biochemical relapse correlates with the generally accepted risk factors and the radiation dose. Regarding this, high-quality treatment planning and HDR brachytherapy combined with EBRT (external beam radiation therapy) leads to good treatment results in selected groups. So far in our own experience, HDR brachytherapy in combination with EBRT is a successful form of treatment with few acute and late side effects in the first 42 patients examined. First results concerning to PSA relapse-free time, quality of life, miction, and erectile function are promising.

[Computed tomographic examination of muscle volume, cross-section and density in patients with dysgnathia]. / Computertomographische Untersuchung von Muskelvolumen, -querschnitt und -dichte bei Dysgnathiepatienten.

PURPOSE: The individual jaw position is determined by the masticatory muscle among other factors. Before surgical treatment of malocclusions, thorough evaluation of the muscles is required to estimate the relapse risk. MATERIALS AND METHODS: By means of computer tomography, lateral radiographs of the skull and denture models, the relationships between morphological parameters of the masticatory muscles and the jaw bone were analyzed. Furthermore, possible causes for the extent of the malocclusion are described. RESULTS: A patient group with deep overbite was found to have significantly higher muscle densities (measured in Hounsfield units [HU]) in the medial pterygoideus muscle (59.89 +/- 3.91 HU to 48.94 +/- 4.14 HU, p < 0.01), masseter muscle, and genioglossus muscle (p < 0.05) in comparison to open bite patients. Significant differences of the muscle cross-section were measured in the masseter muscle between patients with retroclined maxillary incisors and with an open bite (5.4 +/- 0.7 cm (2) to 3.8 +/- 0.4 cm (2), p < 0.05). CONCLUSION: The results show a correlation between different jaw positions and masticatory muscles. They also suggest that the function of each muscle may be different. Additional examinations of the muscle structures are required for verification of the influence of the masticatory muscles on facial morphology.

A role for Rac1 activity in malignant progression of sebaceous skin tumors.

The small GTPase Rac1 is crucial for maintaining stem cells (SCs) in mammalian epidermis, and Rac1 activation leads to SC expansion. Loss or inhibition of Rac1 correlates with decreased frequency of skin cancer formation in a chemical carcinogenesis model. Here, we have addressed whether Rac1 activation would enhance carcinogenesis and result in tumor progression. We used K14ΔNLef1 mice, a model for differentiated sebaceous adenomas (SAs), and activated Rac1 in an epidermis-specific manner (K14L61Rac1). Surprisingly, Rac1 activation did not change the incidence and frequency of sebaceous tumors. However, tumors, which occurred exclusively in K14ΔNLef1/K14L61Rac1 double-transgenic mice, were poorly differentiated resembling malignant sebaceous tumors and were termed sebaceous carcinoma-like tumors (SCLTs). Compared with SAs, SCLTs showed an aberrant pattern of cell proliferation, invasive growth and less abundant expression of sebocyte differentiation markers, including stearoyl-CoA desaturase-1 and adipophilin. Interestingly, the adnexal SC marker Lrig1 was upregulated in SCLTs, showing that active Rac1 leads to the accumulation of sebocyte precursors in the context of K14ΔNLef1-induced skin tumors. In a search for targets of Rac1, we found cancer progression-related proteins, Dhcr24/Seladin1 and Nuclear protein 1/P8, to be strongly regulated in SCLTs. At last, Rac1 and Dhcr24/Seladin1 were detected in human sebaceous tumors demonstrating a potential high impact of our findings for human skin disease. This is the first study showing that Rac1 activity can lead to malignant progression of skin tumors.

Phospholipase C-mediated signaling is altered during HaCaT cell proliferation and differentiation.

To elucidate the signaling mechanisms associated with keratinocyte differentiation, we studied in vitro phospholipase C-mediated signal transduction, which results in the generation of inositol phosphates, comparing proliferating versus differentiated HaCaT cells, a human keratinocyte line. Bradykinin- or A23187-induced formation of inositol 1,4,5-trisphosphate, inositol 1,4-bisphosphate, and inositol monophosphates, as determined by anion exchange high performance liquid chromatography, were found to be highest in the early logarithmic growth phase of the cells. In more highly differentiated HaCaT cells, which expressed maximal amounts of the differentiation marker involucrin, inositol phosphate formation was reduced to about one third of that in proliferating cells. Thin layer chromatography of membrane phosphatidylinositol phosphates revealed that this reduction was associated with a steady decrease in phospholipase C substrates. Immunoblot analysis of phospholipase C isozymes, however, and of expression of Gq alpha, the G protein subunit that activates phospholipase C beta, revealed no decrease during the differentiation phase. The results suggest that the inositol-phospholipid signal transduction pathway is involved in keratinocyte proliferation and in the induction of differentiation, with attenuated signal transduction activity via phospholipase C-coupled receptors in more differentiated keratinocytes.

Role of p53 in UVB-induced apoptosis in human HaCaT keratinocytes.

Apoptosis represents an active form of cell death that is involved in the control of tissue homeostasis and in the deletion of DNA-damaged cells. Because the product of the tumor suppressor gene p53 has been demonstrated to be crucial for the induction of apoptosis in certain cell types, the present study was aimed at elucidating its role in ultraviolet-induced apoptosis in HaCaT keratinocytes. After in vitro ultraviolet B irradiation, p53 protein levels were noted to increase prior to the induction of apoptosis in a time- and concentration-dependent fashion. This increase could not be inhibited by the protein synthesis inhibitor cycloheximide. Because HaCaT keratinocytes are known to bear two p53 point mutations and because it is unclear whether p53 in HaCaT cells is still functional regarding induction of apoptosis, HaCaT cells were stably transfected with wild-type p53 cDNA inserted into the expression vector pCMV-Neo-Bam in sense (pC53-SN3) and anti-sense (pC53-ASN) direction. After selection with geniticin, growing colonies were screened for the presence of the transfected cDNA constructs by polymerase chain reaction. Cell clones bearing the anti-sense product were further analyzed for p53 expression by western blotting. Clones showing reduced p53 protein levels were irradiated with ultraviolet B light, and there was a clear reduction of apoptosis in the pC53-ASN bearing cell clones compared with the parental HaCaT cells. These studies demonstrate that blocking mutated p53 can partially block apoptosis in HaCaT keratinocytes and furthermore can confirm the key role for p53 in ultraviolet-induced apoptosis in human keratinocytes. Moreover, HaCaT keratinocytes and their p53-transfectants provide a convenient model that allows for further detailed analyses of apoptosis-associated biochemical and molecular events in human keratinocytes.

Design of biofunctional assemblies on solids through recombinant spherical bacterial protein lumazine synthase.

The stepwise design of large protein assemblies such as actin-myosin complexes on solid supports is presented. The functional entities are anchored to the solid surface or solid-supported membranes through lumazine synthase, a 15 nm icosahedral capsid which can be functionalized by recombinant coupling of different linkers to the protomer, as shown in the cartoon. Separating the protein assemblies from the solid by 15 nm spaces avoids protein denaturing by nonspecific adsorption.

Retinoic acid attenuates phospholipase C-mediated signaling in HaCaT keratinocytes.

Release of inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) generated by phospholipase C (PLC) upon receptor stimulation plays an important role in the regulation of cell growth and differentiation. A second, completely different, signal transduction system involves retinoic acid (RA) and related derivatives. Binding to intracellular receptor sites can modulate keratinocyte growth and inhibits differentiation. The present study was aimed at characterizing possible interactions between the two signalling pathways in HaCaT keratinocytes. As determined by anion exchange chromatography and HPLC analysis, HaCaT keratinocytes treated with 1 microM RA for up to 72 h showed a marked decrease in Ins(1,4,5)P3 release upon stimulation with 10 microM bradykinin or 10 microM ionomycin. Thin-layer chromatography of phosphatidylinositol phosphates, the substrates of PLC, revealed no differences between RA-treated and untreated cells. Western blot analysis of the PLC isozymes present in HaCaT cells, PLC beta 3 and PLC gamma 1, showed no alterations in the expression of these proteins in RA-treated cells as compared to vehicle-treated controls. In addition, expression of the PLC-activating G protein G alpha q was not affected by RA treatment. Our results show that RA downregulates the PLC-mediated signaling system. The point of interference of this signal transduction crosstalk has yet to be elucidated. Our results suggest, furthermore, that RA-induced attenuation of keratinocyte differentiation might be mediated at least in part by the downregulation of Ins(1,4,5)P3 release.

Enhanced contact allergen- and UVB-induced keratinocyte apoptosis in the absence of CD95/Fas/Apo-1.

FAS/CD95/Apo-1 is a ubiquitously expressed cell-surface receptor involved in the initiation of programmed cell death. Its function in epidermal keratinocytes has been incompletely defined. Available evidence from in vitro studies points to important roles of Fas in the pathogenesis of contact dermatitis and in keratinocyte apoptosis induced by ultraviolet light. To define functions of Fas in the epidermis in vivo, we have generated mice with epidermis-specific deletion of the fas gene and tested its requirement for 2,4-dinitrofluorobenzene-induced contact dermatitis and for ultraviolet light B (UVB)-induced keratinocyte apoptosis. We report here our unexpected finding that keratinocyte apoptosis induced by both a contact allergen and UVB irradiation was significantly enhanced in Fas-negative epidermis. Expression of Fas by epidermal keratinocytes was neither necessary for the normal development of contact hypersensitivity of the skin, nor required for keratinocyte apoptosis following UVB irradiation. Our study results thus show that in the epidermis in vivo Fas exerts antiapoptotic effects that outweigh its proapoptotic role in contact hypersensitivity responses of the skin and in the tissue response of the epidermis to UVB irradiation.