[Rapid resolution of severe psoriasis vulgaris in an HIV-positive patient treated with antiretroviral therapy]. / Schnelle Abheilung einer schweren Psoriasis vulgaris bei einem HIV-positiven Patienten unter antiretroviraler Therapie.

Psoriasis exacerbation may occur in patients with human immunodeficiency virus (HIV). We present the case of a patient with severe psoriasis vulgaris (PASI 34.2) and an initial HIV diagnosis who showed rapid resolution of psoriasis upon initiation of antiretroviral therapy. Antiretroviral therapy is an effective treatment option for HIV-associated psoriasis. Especially in patients with a sudden psoriasis flare-up or resistance to therapy, HIV testing should be considered as knowledge of an underlying infection is elementary to treatment decision-making.

Value of cemiplimab in progressive metastatic cutaneous squamous cell carcinoma after kidney transplantation: a case report.

Cutaneous squamous cell carcinoma (CSCC) is the most frequent post-transplant tumour entity resulting from immunosuppression treatment that is needed to prevent organ rejection. Solid organ transplant (SOT) recipients are at higher risk for CSCC and vulnerable for aggressive disease or a fatal course. Here, we report on a case of post-kidney transplant metastatic CSCC, demonstrating efficacy of cemiplimab in achieving complete remission after previous disease progression under cetuximab treatment. Unfortunately, the patient developed severe pneumonia, which was only later diagnosed as cemiplimab-associated pneumonitis. Due to a rapidly evolving septic condition, intensive care treatment was required and resulted in a fatal outcome. The patient's transplant remained intact, yet first-line treatment of advanced CSCC, such as with cemiplimab, should be weighed critically in SOT recipients, as transplant rejection may occur. However, the present case underlines the feasibility of cemiplimab as a second-line treatment option in this patient collective.

Incidence of pemphigoid diseases in Northern Germany in 2016 - first data from the Schleswig-Holstein Registry of Autoimmune Bullous Diseases.

BACKGROUND: Autoimmune bullous diseases (AIBD) are rare disorders characterized by autoantibody formation against components of adhesion molecules; in pemphigoid diseases (PD), these are proteins of hemidesmosomes and basement membrane, important for cell-matrix adhesion in skin and/or mucous membranes. Incidences of these diseases vary considerably between different populations. OBJECTIVES: To establish a registry prospectively recruiting all AIBD patients in a geographically well-defined region in Northern Germany (Schleswig-Holstein). METHODS: Only patients with verified disease (by clinical presentation, histology, direct and/or indirect immunofluorescence and /or ELISA) living in Schleswig-Holstein were included. Incidences of PD were estimated based on the total number of inhabitants in Schleswig-Holstein, stratified by birth year and sex. RESULTS: Of 67 patients with PD [35 male, 32 female, mean age 75 (standard deviation 14.3 years)], 83% were patients with bullous pemphigoid [n = 56, 28 male, 28 female, mean age 78 (SD 9.9)]. The resulting crude incidences were 23.4 patients/million/year for all pemphigoid patients, 19.6 patients/million/year for bullous pemphigoid (age-standardized 16.9 patients/million/year) with a strong increase in bullous pemphigoid patients in the age group of 85-90 years with 262 patients/million/year. Incidences for bullous pemphigoid were higher in urban compared to rural areas. Other PD (mucous membrane pemphigoid, linear IgA disease, anti-p200 pemphigoid) were less frequent with crude incidences of 2.1, 1.0 and 0.7 patients/million/year, respectively. CONCLUSIONS: This study prospectively analyses the incidence of PD in a carefully defined geographical area. The highest incidence among PD patients was found for bullous pemphigoid. The incidence of bullous pemphigoid is considerably increased compared to previous reports and reveals regional differences. Further studies are needed in order to clarify these findings.

Bladder cancer-derived interleukin-1 converts the vascular endothelium into a pro-inflammatory and pro-coagulatory surface.

BACKGROUND: Bladder cancer cells orchestrate tumour progression by pro-inflammatory cytokines. Cytokines modulate the local tumour microenvironment and increase the susceptibility of tumour distant tissues for metastasis. Here, we investigated the impact of human bladder cancer cell derived factors on the ability to modulate and activate human vascular endothelial cells. METHODS: The pro-inflammatory and pro-coagulatory potential of four different bladder cancer cell lines was accessed by qRT-PCR arrays and ELISA. Modulation and activation of endothelial cells was studied in microfluidic devices. Clinical relevance of our findings was confirmed by immune histology in tissue samples of bladder cancer patients and public transcriptome data. RESULTS: The unbalanced ratio between interleukin (IL)-1 and IL-1 receptor antagonist (IL-1ra) in the secretome of bladder cancer cells converted the quiescent vascular endothelium into a pro-adhesive, pro-inflammatory, and pro-coagulatory surface. Microfluidic experiments showed that tumour cell induced endothelial cell activation promoted leukocyte recruitment and platelet adhesion. Human bladder cancer tissue analysis confirmed that loss of IL-1ra and elevated IL-1 expression was associated with enhanced cancer progression. CONCLUSIONS: Our data indicate that IL-1 and IL-1ra were dysregulated in bladder cancer and could facilitate tumour dissemination through endothelial cell activation. Targeting the IL-1/IL-1ra axis might attenuate tumour-mediated inflammation and metastasis formation.

Characteristics, risk factors and treatment reality in livedoid vasculopathy - a multicentre analysis.

BACKGROUND: Livedoid vasculopathy (LV) is a rare cutaneous thrombotic disease. It is characterized by occlusion of dermal vessels resulting in livedo racemosa, ulceration and atrophie blanche. Clear guidelines for diagnosis and treatment are missing. OBJECTIVE: The purpose of this study was to better characterize epidemiology, clinical appearance and treatment reality of LV in a well-defined patient cohort. METHODS: The cohort was allocated within a prospective, multicentre, phase IIa trial that investigated the effect of rivaroxaban in LV. RESULTS: Analysis of 27 patients revealed that LV patients had an increased Body Mass Index (BMI; 11/27), hypertension (19/27) and increased levels of lipoprotein (a) (5/12) and homocysteine (10/12) in the blood. The female-to-male ratio was 2.1 : 1, and the median age was 53.0 years [interquartile range (IQR) 40.5-68]. Investigation of the clinical appearance found that 82% of patients had livedo racemosa, and the ankle region was most likely to be affected by ulceration (56-70%). The analysis of patient treatment history showed that heparin was most effective (12/17), while anti-inflammatory regimens were, although often used (17/24), not effective (0/17). CONCLUSION: We add clinical clues for a data supported diagnosis of LV, and we provide evidence that anticoagulants should be administered in monotherapy first line (EudraCT number 2012-000108-13-DE).

Treating onychomycosis with the short-pulsed 1064-nm-Nd:YAG laser: results of a prospective randomized controlled trial.

BACKGROUND: The role of the short-pulsed 1064-nm-Nd:YAG laser in treating onychomycosis has been the subject of controversial discussion ever since it received FDA approval in 2010. Research to date provides no valid conclusions supporting its use from an evidence-based perspective. OBJECTIVE: In this prospective randomized controlled pilot study, we analysed the effect of the short-pulsed 1064-nm-Nd:YAG laser on the rate of mycological remission and clinical improvement after excluding relevant confounders with regard to our previous studies. PATIENTS AND METHODS: Twenty patients with a total of 82 mycotic toenails were randomized to the treatment group (short-pulsed 1064-nm-Nd:YAG laser) or control group (no laser treatment). We conducted four laser treatments at 4- to 6-week intervals. In both groups, a local antimycotic agent was applied to the sole of the foot, the area between the toes and the skin directly surrounding the nails. The primary endpoint was complete remission of the onychomycosis after 12 months (fungal culture and histology); secondary endpoints included clinical improvement (Onychomycosis Severity Index, OSI) and the occurrence of pain or other adverse events. RESULTS: Mycological remission was not achieved in either study group. A comparison of both groups yielded no difference in the OSI score, both at the beginning of the trial (P = 0.9873) and after 12 months (P = 0.4317). In the treatment group, the OSI score worsened by a mean 2.0 points, and in the control group, by a mean 3.5 points. On a visual analogue scale (0 = 'no pain' to 10 = 'most intense pain'), pain in the treatment group was indicated at a mean score of five. Other adverse events were not reported. CONCLUSIONS: The short-pulsed 1064-nm-Nd:YAG laser shows no long-term efficacy as a monotherapy. Its role as an adjuvant therapy should be investigated in upcoming trials.

Surgical procedures in patients with haemophilic arthropathy of the ankle.

BACKGROUND: In haemophilia, the ankle joint is one of the most common and earliest joints affected by recurrent bleeding, commonly resulting in end-stage ankle osteoarthritis during early adulthood. The surgical treatment of haemophilic ankle arthropathy is challenging. PURPOSE: This review aims to highlight the literature addressing clinical outcomes following the most common approaches for different stages of haemophilia-induced ankle osteoarthritis: arthroscopic debridement, joint distraction arthroplasty, supramalleolar osteotomies, total ankle replacement, and ankle arthrodesis. METHODS: A systematic literature review was performed using established medical literature databases. The following information was retrieved from the literature: patients' demographics, surgical technique, duration of follow-up, clinical outcome including pain relief and complication rate. RESULTS: A total of 42 clinical studies published between 1978 and 2015 were included in the systematic literature review. Eight and 34 studies had prospective and retrospective design, respectively. The most common studies were level IV studies (64.3%). DISCUSSION: The orthopaedic treatment of patients with haemophilic ankle osteoarthritis is often challenging and requires complete and careful preoperative assessment. In general, both joint-preserving and joint non-preserving procedure types can be performed. All specific relative and absolute contraindications should be considered to achieve appropriate postoperative outcomes. CONCLUSION: The current literature demonstrated that orthopaedic surgeries, with appropriate indication, in patients with haemophilic ankle arthropathy result in good postoperative results comparable to those observed in non-haemophiliacs. The surgical treatment should be performed in a setting with the ability to have multidisciplinary management, including expertise in haematology.

[Total ankle replacement in patients with bleeding disorders]. / Endoprothetischer Ersatz des oberen Sprunggelenks bei Patienten mit Gerinnungsstörungen.

BACKGROUND: Total ankle replacement (TAR) is a well-accepted treatment option in patients with end-stage ankle osteoarthritis. However, published literature on patients with bleeding disorders treated with TAR is limited. Therefore, we carried out this prospective study to analyze mid-term postoperative results in patients with bleeding disorders treated by TAR. METHODS: A total of 34 patients with end-stage ankle osteoarthritis--14 patients with hemophilia type A and 20 patients with von Willebrand disease (VWD)--treated by TAR were included in this prospective study. The mean age of patients was 46.0 ± 9.0 years. Intraoperative and postoperative complications were recorded. The postoperative pain relief and functional results including range of motion (ROM) and American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score were assessed after a mean follow-up of 6.3 ± 3.4 years. Additionally, the quality of life was analyzed using the SF-36 questionnaire. The alignment of prosthesis components was assessed using weight-bearing conventional radiographs. The results were compared with those obtained in the control group, including 72 and 33 patients with post-traumatic and rheumatoid ankle osteoarthritis respectively. RESULTS: One patient sustained an intraoperative medial malleolar fracture. In total, three revision surgeries were necessary in our patient cohort. There was significant pain relief from 8.2 ± 0.8 to 0.9 ± 1.0, as assessed using a visual analog scale. All categories of the SF-36 score showed significant improvement. The average ROM increased from 20.1° ± 6.9° to 27.5° ± 7.4°. The AOFAS hindfoot score increased from 34.5 ± 10.0 to 82.4 ± 10.2 of a maximum of 100 points. Radiographic assessment showed the neutral alignment of prosthesis components in all patients. The postoperative clinical and radiographic outcomes were comparable in both patients with hemophilia and those with VWD. Patients with bleeding disorders had significantly higher pain relief and significantly lower ROM than the patients in the control group with ankle osteoarthritis of post-traumatic or rheumatoid etiology. CONCLUSION: Our prospective study revealed encouraging mid-term outcomes after TAR in patients with bleeding disorders. However, this surgery should be limited to highly experienced foot and ankle surgeons. Furthermore, this patient cohort requires a multidisciplinary approach to ensure a good outcome.

A new subtype of pachydermodactyly: unilateral pachydermodactyly transgrediens.

Pachydermodactyly describes a rare condition of localized fibromatosis, usually symmetrically affecting the interphalangeal joints of both hands. We describe a case of a new subtype of pachydermodactyly in a 14-year-old boy, which we term 'unilateral pachydermodactyly transgrediens'. This atypical pattern is caused by specific localized mechanical manipulation of the hands. This condition contributes to the completely indolent spectrum of pachydermodactyly, and usually does not need therapy. Therefore it is essential not to misinterpret it as an inflammatory state such as juvenile idiopathic arthritis. The correct diagnosis of pachydermodactyly and its rare subtypes, as we describe in this case, often spares the affected patients unnecessary invasive diagnostic procedures and immunosuppressive therapy.

Nuclear heparanase-1 activity suppresses melanoma progression via its DNA-binding affinity.

Heparanase-1 (HPSE) plays a pivotal role in structural remodeling of the ECM and the glycocalyx, thus conferring protumorigenic, proangiogenic and prometastatic properties to many cancer entities. In addition to its extracellular function, recent studies suggest an intracellular activity of HPSE with a largely unknown significance during tumor progression. Therefore, we investigated the relevance of the dual functions of HPSE to malignant melanoma in vitro, as well as in different mouse melanoma models based on the intradermal or intravenous injection of melanoma cells. Consistent with its extracellular action, an HPSE deficiency led to a reduced shedding of the glycocalyx accompanied by a reduced availability of vascular endothelial growth factor, affecting tumor growth and vascularization. In contrast, we measured an elevated expression of the protumorigenic factors pentraxin-3, tissue factor, TNF-α and most prominently, MMP-9, upon HPSE knockdown. In vivo, an HPSE deficiency was related to increased lymph node metastasis. Since the inhibition of its extracellular function with heparin was unable to block the gene regulatory impact of HPSE, we proposed an intracellular mechanism. Immunostaining revealed a counter-staining of HPSE and NF-κB in the nucleus, suggesting a close relationship between both proteins. This finding was further supported by the discovery of a direct charge-driven molecular interaction between HPSE and DNA by using atomic force microscopy and a co-precipitation approach. Our findings are novel and point towards a dual function for HPSE in malignant melanoma with a protumorigenic extracellular activity and a tumor-suppressive nuclear action. The identification of molecular strategies to shuttle extracellular HPSE into the nuclei of cancer cells could provide new therapeutic options.

Total ankle replacement in patients with von Willebrand disease: mid-term results of 18 procedures.

von Willebrand disease (VWD) is a recognized cause of secondary ankle osteoarthritis (OA). Few studies have examined orthopaedic complications and outcomes in VWD patients treated for end-stage ankle OA with total ankle replacement (TAR). To determine the clinical presentation, intraoperative and postoperative complications and evaluate the mid-term outcome in VWD patients treated with TAR. Eighteen patients with VWD with mean age 47.3 years (range = 34.0-68.7) were treated for end-stage ankle OA with TAR. The mean duration of follow-up was 7.5 years (range = 2.9-13.2). Intraoperative and perioperative complications were recorded. Component stability was assessed with weight-bearing radiographs. Clinical evaluation included range of motion (ROM) tests using a goniometer and under fluoroscopy using a lateral view. Clinical outcomes were analysed by a visual analogue scale, the American Orthopaedic Foot and Ankle Society hindfoot score and Short Form (36) Health Survey (SF-36) health survey. One patient sustained an intraoperative medial malleolar fracture. In two patients delayed wound healing was observed. Two secondary major surgeries were performed. Pain level decreased from 8.2 ± 0.9 (range = 7-10) preoperatively to 1.1 ± 1.2 (range = 0-4) postoperatively. Significant functional improvement including ROM was observed. All categories of SF-36 score showed significant improvement in quality of life. Mid-term results of TAR in patients with VWD are encouraging. The total rate of intraoperative and postoperative complications was 33.3%. However, longer term outcomes are necessary to fully understand the clinical benefit of TAR in patients with VWD.

von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor.

The bleeding disorder von Willebrand disease (VWD) is caused by mutations of von Willebrand factor (VWF), a multimeric glycoprotein essential for platelet-dependent primary haemostasis. VWD type 2A-associated mutations each disrupt VWF biosynthesis and function at different stages, depending on the VWF domain altered by the mutation. These effects cause considerable heterogeneity in phenotypes and symptoms. To characterise the molecular mechanisms underlying the specific VWF deficiencies in VWD 2A/IIC, IID and IIE, we investigated VWF variants with patient-derived mutations either in the VWF pro-peptide or in domains D3 or CK. Additionally to static assays and molecular dynamics (MD) simulations we used microfluidic approaches to perform a detailed investigation of the shear-dependent function of VWD 2A mutants. For each group, we found distinct characteristics in their intracellular localisation visualising specific defects in biosynthesis which are correlated to respective multimer patterns. Using microfluidic assays we further determined shear flow-dependent characteristics in polymer-platelet-aggregate formation, platelet binding and string formation for all mutants. The phenotypes observed under flow conditions were not related to the mutated VWF domain. By MD simulations we further investigated how VWD 2A/IID mutations might alter the ability of VWF to form carboxy-terminal dimers. In conclusion, our study offers a comprehensive picture of shear-dependent and shear-independent dysfunction of VWD type 2A mutants. Furthermore, our microfluidic assay might open new possibilities for diagnosis of new VWD phenotypes and treatment choice for VWD patients with shear-dependent VWF dysfunctions that are currently not detectable by static tests.

[Thromboembolic complications following ankle prosthesis implantation]. / Thrombembolische Komplikationen nach Sprunggelenkprothesenimplantation.

BACKGROUND: Total ankle replacement is becoming an increasingly used treatment for patients with degenerative arthritis of the ankle; however, there is limited literature available addressing the incidence of thromboembolic complications after total ankle replacement. Therefore, we performed a systematic literature review addressing thrombosis prophylaxis and incidence of thromboembolic complications after total ankle replacement. Furthermore, we evaluated the incidence of thromboembolic complications in our clinic. METHODS: A systemic literature review was performed using established medical literature data bases. The following information was retrieved from the literature: thrombosis prophylaxis and duration and deep vein thrombosis/pulmonary embolism as postoperative complication. The incidence of thromboembolic complications was evaluated in our patient cohort including 964 total ankle replacement procedures. RESULTS: A total of 21 clinical studies were included in the systematic literature review. The range of incidence of thromboembolic complications was between 0.0 % and 4.8 %. In our patient cohort the incidence of symptomatic deep vein thrombosis was 3.4 %. There were no cases of pulmonary embolism. All patients received low molecular weight heparin prophylaxis. CONCLUSION: The incidence of thromboembolic complications in our patient cohort was comparable to that of symptomatic deep vein thrombosis in patients undergoing total knee or hip replacement or ankle fusion. We suggest the prophylactic use of low molecular weight heparin for patients after total ankle replacement.

Circulating but not immobilized N-deglycosylated von Willebrand factor increases platelet adhesion under flow conditions.

The role of von Willebrand factor (VWF) as a shear stress activated platelet adhesive has been related to a coiled-elongated shape conformation. The forces dominating this transition have been suggested to be controlled by the proteins polymeric architecture. However, the fact that 20% of VWF molecular weight originates from glycan moieties has so far been neglected in these calculations. In this study, we present a systematic experimental investigation on the role of N-glycosylation for VWF mediated platelet adhesion under flow. A microfluidic flow chamber with a stenotic compartment that allows one to mimic various physiological flow conditions was designed for the efficient analysis of the adhesion spectrum. Surprisingly, we found an increase in platelet adhesion with elevated shear rate, both qualitatively and quantitatively fully conserved when N-deglycosylated VWF (N-deg-VWF) instead of VWF was immobilized in the microfluidic channel. This has been demonstrated consistently over four orders of magnitude in shear rate. In contrast, when N-deg-VWF was added to the supernatant, an increase in adhesion rate by a factor of two was detected compared to the addition of wild-type VWF. It appears that once immobilized, the role of glycans is at least modified if not-as found here for the case of adhesion-negated. These findings strengthen the physical impact of the circulating polymer on shear dependent platelet adhesion events. At present, there is no theoretical explanation for an increase in platelet adhesion to VWF in the absence of its N-glycans. However, our data indicate that the effective solubility of the protein and hence its shape or conformation may be altered by the degree of glycosylation and is therefore a good candidate for modifying the forces required to uncoil this biopolymer.

[Foam sclerotherapy. Uses and indications in dermatology and phlebology]. / Schaumsklerosierung. Anwendung und Indikation in der Dermatologie und Phlebologie.

Foam sclerotherapy is a minimally invasive, effective technique for the treatment of varicoses up though venous malformations. This efficient therapy can be easily integrated in daily clinical practice and shows only minor side effects. It provides an alternative to invasive therapies like vein stripping, endovenous laser therapy or endovenous radiofrequency ablation, but without the need for anesthesia. The treatment can be performed in an outpatient setting and the patient is able to return quickly to everyday life.