[Lichen sclerosus in clinically relevant phimosis: incidence, risk factors, and association with squamous cell carcinoma of the penis]. / Lichen sclerosus bei klinisch relevanter Phimose: Häufigkeit, Risikofaktoren und Assoziation mit Plattenepithelkarzinomen des Penis.

BACKGROUND: Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory skin disease. It is frequently diagnosed following circumcision. Diabetes mellitus (DM) is a known risk factor in men. Malignant pathology is more common in patients with LSA. Data on LSA in men are very limited. OBJECTIVE: This study investigated the incidence of LSA in men who had undergone circumcision. Risk factors and likelihood of malignancy were captured. MATERIALS AND METHODS: Data of 215 patients were retrospectively analyzed. As potential risk factors, age, body mass index (BMI), DM, coronary heart disease (CHD) and arterial hypertension were identified. Data were analyzed and displayed graphically as spike histograms. Logistic regression was applied. Age and BMI were transformed using cubic spline function. RESULTS: Mean age of patients was 37 years (±â€¯22 years). Mean BMI was 26.4. In all, 24% of the patients had a BMI > 30. Of the patients, 11% had DM, 5.1% had CHD, and 19% had arterial hypertension. Pathology revealed LSA in 47% of patients. Malignant disease was apparent in 3.3% of patients (2.7% without concomitant LSA, 4% with concomitant LSA). Age (55 vs 20 years, odds ratio [OR]: 3.210 [1.421, 7.251]) was a significant risk factor for LSA. BMI (30 vs 22 kg/m2, OR 1.059 [0.614, 1.828]) and DM (OR: 0.42 [0.148, 1.192]) elevated the risk for LSA. CONCLUSION: We saw high rates of LSA in patients had undergone circumcision. Higher age represents a significant risk factor. In 3.3%, final pathology revealed squamous cell carcinoma of the penis. Therefore, pathologic work-up of circumcision specimen is mandatory.

Autoimmune pre-disease.

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease.

Dapsone Suppresses Disease in Preclinical Murine Models of Pemphigoid Diseases.

Epidermolysis bullosa acquisita and mucous membrane pemphigoid are autoimmune blistering diseases characterized by mucocutaneous blisters elicited by an autoantibody-mediated immune response against specific proteins of the epidermal basement membrane. The antibiotic dapsone is frequently used to treat both diseases, but its therapeutic effectiveness is uncertain, and its mode of action in these diseases is largely unknown. We evaluated the effect of dapsone in antibody transfer mouse models of epidermolysis bullosa acquisita and mucous membrane pemphigoid, which do not allow the drawing of conclusions on clinical treatment regimens but can be instrumental to partially uncover the mode(s) of action of dapsone in these diseases. Dapsone significantly mitigated inflammation in both models, reducing the recruitment of neutrophils into the skin and disrupting their release of leukotriene B4 (LTB4) and ROS in response to immune complexes. LTB4 has been implicated in numerous diseases, but effective LTB4 inhibitors for clinical use are not available. Our findings indicate that the mode of action of dapsone in these models may be based on the inhibition of LTB4 and ROS release from neutrophils. Moreover, they encourage testing the use of dapsone as an effective, albeit nonspecific, inhibitor of LTB4 biosynthesis in other LTB4-driven diseases.

Adjuvant auricular electroacupuncture and autogenic training in rheumatoid arthritis: a randomized controlled trial. Auricular acupuncture and autogenic training in rheumatoid arthritis.

BACKGROUND: In contrast to psychological interventions the usefulness of acupuncture as an adjuvant therapy in rheumatoid arthritis (RA) has not yet been demonstrated. OBJECTIVE: The efficacy of auricular electroacupuncture (EA) was directly compared with autogenic training (AT). METHODS: Patients with RA (n = 44) were randomized into EA or AT groups. EA and lessons in AT were performed once weekly for 6 weeks. Primary outcome measures were the mean weekly pain intensity and the disease activity score 28 (DAS 28); secondary outcome measures were the use of pain medication, the pain disability index (PDI), the clinical global impression (CGI) and pro-inflammatory cytokine levels, which were assessed during the study period and 3 months after the end of treatment. RESULTS: At the end of the treatment and at 3-month follow-up a clinically meaningful and statistically significant improvement (p < 0.05) could be observed in all outcome parameters and both groups. In contrast to the AT group, the onset of these effects in the EA group could already be observed after the 2nd treatment week. In the 4th treatment week the EA group reported significantly less pain than the AT group (p = 0.040). After the end of treatment (7th week) the EA group assessed their outcome as significantly more improved than the AT group (p = 0.035). The erythrocyte sedimentation rate in the EA group was significantly reduced (p = 0.010), and the serum concentration of tumor necrosis factor-alpha was significantly increased compared to the AT group (p = 0.020). CONCLUSIONS: The adjuvant use of both EA and AT in the treatment of RA resulted in significant short- and long-term treatment effects. The treatment effects of auricular EA were more pronounced.

Caspase-cleaved HPK1 induces CD95L-independent activation-induced cell death in T and B lymphocytes.

Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-kappaB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-kappaB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappaB-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim. Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes.

How T lymphocytes switch between life and death.

While insufficient cell death of activated T cells can result in autoimmune disorders, elimination of too many T cells can lead to immunodeficiency. Therefore, T lymphocyte fate is highly regulated and requires that cells can switch from an apoptosis-resistant towards an apoptosis-sensitive state. This switch is tightly controlled by various effector molecules. Basically, two separate pathways control the fate of antigen-activated T cells: activation-induced cell death (AICD) and activated T cell autonomous death (ACAD). Autoreactive T lymphocytes are eliminated by restimulation via their T cell receptor (TCR) and undergo AICD involving death receptors (extrinsic pathway). In contrast, ACAD can lead to T cell deletion without TCR restimulation, and is determined by the ratio between anti- and pro-apoptotic Bcl-2 family members at the mitochondria (intrinsic pathway). While the extrinsic and the intrinsic pathway lead to caspase activation, non-caspase proteases (e.g., cathepsins) can be released by the lysosomes and might contribute to AICD as well as to ACAD. Activated T cells poses cell death escape mechanisms which are needed for survival of (memory) T cells, but are deleterious for autoimmune disorders or progression of T cell lymphomas.