Microcirculation disorders of the skin.

Changes in the microcirculation of the skin are a frequently observed accompanying phenomenon of many diseases, far beyond the spectrum of dermatological diseases. Not all of these changes are pathological, many are transient and have no serious consequences. This is true for many inflammatory diseases such as psoriasis vulgaris or atopic eczema. However, there are also diseases in which functionally and morphologically recognizable microangiopathies lead to severe disease consequences. One of the most important diseases in this context is systemic sclerosis, an autoimmune systemic disease with multiple organ manifestations. Investigations of the cutaneous microcirculation are of great importance for the initial diagnosis as well as for prognosis and assessment of disease progression. In peripheral hemodynamic disorders such as peripheral arterial disease (PAD) and chronic venous insufficiency (CVI), understanding microcirculatory disturbances also plays an important role in therapy and in monitoring the success of therapeutic interventions.

Effects of Extracorporeal Photopheresis on Quality of Life and the Course of Diseases in Patients With Mycosis Fungoides and Graft-Versus-Host Disease: A Single-Center Analysis.

INTRODUCTION: The aim of the study was to systematically analyze the influence of extracorporeal photopheresis (ECP) on the quality of life (LQ) and the course of the disease in patients with Mycosis Fungoides (MF), as well as with Graft-versus-Host Disease (GvHD). METHODS: LQ was monitored retrospectively by using the dermatology life quality index (DLQI) and Skindex-29 test before ECP onset and after the last ECP. Disease parameters were assessed by objective criteria i.e. number of associated medical drugs taken, intervals between therapeutic cycles, gradual change of the disease, and eventual side-effects and complications of ECP therapy. RESULTS: Fifty-one patients were treated with ECP during 2008-19; 19 out of 51 died, and follow-up was not completed in 13 patients. Finally, treatment protocols of 671 ECP procedures were evaluated in 19 patients (10 MF; 9 GvHD). MF and GvHD subpopulations did not differ in the individual scores of LQ questions, either before the outset or after the last ECP. DLQI and Skindex-29 scores were ameliorated by the ECP therapy (p= 0.001 and p< 0.001, respectively) due to improvement of individual scores of feelings, daily/social activities (p< 0.05), and functionality (p≤ 0.05). The median interval between ECP cycles was extended from two to eight weeks (p= 0.001). Needs of GvHD patients for drugs being received for the underlying disease were reduced (p= 0.035). Two of the 10 MF patients worsened from stage IIA to IIIA. Severe or minor side effects leading to a therapy interruption were not recorded. CONCLUSION: Patients with GvHD experienced a notable decrease in the administration of drugs for their underlying condition, and there were no instances of severe side effects that resulted in the discontinuation of treatment. ECP is safe and effective for the treatment of MF and GvHD.

Translational development of ABCB5+ dermal mesenchymal stem cells for therapeutic induction of angiogenesis in non-healing diabetic foot ulcers.

BACKGROUND: While rapid healing of diabetic foot ulcers (DFUs) is highly desirable to avoid infections, amputations and life-threatening complications, DFUs often respond poorly to standard treatment. GMP-manufactured skin-derived ABCB5+ mesenchymal stem cells (MSCs) might provide a new adjunctive DFU treatment, based on their remarkable skin wound homing and engraftment potential, their ability to adaptively respond to inflammatory signals, and their wound healing-promoting efficacy in mouse wound models and human chronic venous ulcers. METHODS: The angiogenic potential of ABCB5+ MSCs was characterized with respect to angiogenic factor expression at the mRNA and protein level, in vitro endothelial trans-differentiation and tube formation potential, and perfusion-restoring capacity in a mouse hindlimb ischemia model. Finally, the efficacy and safety of ABCB5+ MSCs for topical adjunctive treatment of chronic, standard therapy-refractory, neuropathic plantar DFUs were assessed in an open-label single-arm clinical trial. RESULTS: Hypoxic incubation of ABCB5+ MSCs led to posttranslational stabilization of the hypoxia-inducible transcription factor 1α (HIF-1α) and upregulation of HIF-1α mRNA levels. HIF-1α pathway activation was accompanied by upregulation of vascular endothelial growth factor (VEGF) transcription and increase in VEGF protein secretion. Upon culture in growth factor-supplemented medium, ABCB5+ MSCs expressed the endothelial-lineage marker CD31, and after seeding on gel matrix, ABCB5+ MSCs demonstrated formation of capillary-like structures comparable with human umbilical vein endothelial cells. Intramuscularly injected ABCB5+ MSCs to mice with surgically induced hindlimb ischemia accelerated perfusion recovery as measured by laser Doppler blood perfusion imaging and enhanced capillary proliferation and vascularization in the ischemic muscles. Adjunctive topical application of ABCB5+ MSCs onto therapy-refractory DFUs elicited median wound surface area reductions from baseline of 59% (full analysis set, n = 23), 64% (per-protocol set, n = 20) and 67% (subgroup of responders, n = 17) at week 12, while no treatment-related adverse events were observed. CONCLUSIONS: The present observations identify GMP-manufactured ABCB5+ dermal MSCs as a potential, safe candidate for adjunctive therapy of otherwise incurable DFUs and justify the conduct of a larger, randomized controlled trial to validate the clinical efficacy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03267784, Registered 30 August 2017, https://clinicaltrials.gov/ct2/show/NCT03267784.

Improvement of occupational leg edema and discomforts (RCT).

BACKGROUND: Edema and subjective leg complaints (e.g. pain, heaviness) after long standing or sitting, are defined as orthostatic leg complaints or occupational edema. Compression hosiery should help to prevent or decrease those symptoms. OBJECTIVE: Assess the effects on leg discomforts and leg volume and wearing comfort in two medical below-knee compression stocking types (A vs. B) with an interface pressure of 18 -20 mmHg and a below-knee-low-pressure support stocking (LPSS) with an interface pressure of 8-10mmHg (C). METHODS: Two different types of below-knee medical compression stockings and a LPSS were examined in this randomized, blinded, crossover trial in volunteers having leg discomforts and edema after being in an upright position during the day. Participants were divided into two cohorts, and each type of stocking was worn for three consecutive days in one week with a subsequent washout phase. The assessment of effects and wearing comfort was ascertained by questionnaires. Volume changes in the lower leg were measured with the Bodytronic 600® (Bauerfeind AG, Zeulenroda, Germany). RESULTS: A significant reduction of lower leg volume (mean stocking A: 204.7 ml; mean stocking B: 153.5 ml; mean stocking C: 48.2 ml) and a significant reduction of the life-quality dimension leg-complaints (p < 0.0001) was achieved by all three types of stockings. Compared to the LPSS both compression stockings decreased the lower leg volume significantly more (p < 0.001) and had a significant better fit (p < 0.001). CONCLUSION: Below-knee medical compression stockings with an interface pressure 18-21mmHg and LPSS with an interface pressure of 8-10 mmHg reduce significantly occupational orthostatic edema and leg discomforts which are due to long standing and sitting activities.

Validation of the psychometric properties of a "Modified Version of the Hornheider Screening Instrument" (HSI-MV) using a sample of outpatient and inpatient skin tumor patients.

BACKGROUND: The basis for adequate psycho-oncological care is the identification of patients with psychosocial support needs. The German Working Group for Psychooncology also recommends the Hornheider Screening Instrument (HSI) for this purpose. The question, "Is anyone in your family particularly burdened by the hospital stay?" is intended to capture disease-related family stress. But is this item equally suitable for outpatients and inpatients? The study objective was to examine how replacing the original item affects the test performance of this modified version of the HSI and the frequency of psychosocial stress. PATIENTS AND METHODS: 92 outpatients and 98 inpatients with skin tumors assessed their psychosocial situation using different questionnaires. RESULTS: Compared to inpatients, less than half as many outpatients answered the item in the affirmative. If the question was replaced by: "Is someone in your family particularly burdened by your disease or the course of the disease?" this setting-related difference did not arise. The "Alternative item" and the "Modified version of the HIS" (HSI-MV) proved to be superior to the original item and the original HSI with regard to all examined criteria. CONCLUSIONS: The HSI-MV can be used as a reliable and valid instrument for the systematic assessment of psychosocial care needs in outpatient and inpatient settings. Depending on care capacity, a threshold of ≥ 5 or ≥ 4 is appropriate. In addition to screening, the desire for support should be enquired.

Opportunities and challenges for commercializing microarray patches for vaccination from a MAP developer's perspective.

Continued advances in microarray patch (MAP) technology are starting to make needle-free delivery of a broad range of vaccines an achievable goal. The drivers and potential benefits of a MAP platform for pandemic response and routine vaccination are clear and include dose-sparing, cold-chain elimination, increased safety, and potential self-administration. MAP technology is regarded as a priority innovation to overcome vaccination barriers, ensure equitable access, and improve the effectiveness of vaccines. Vaxxas, a global leader in this technology, has built a strong evidence-base for the commercial application of their high-density (HD) MAP platform, and is rapidly advancing scale-up of the manufacturing process for HD-MAPs. A greater awareness and understanding of the implications of the technology amongst supply-chain participants, regulatory authorities, and global healthcare organizations and foundations is needed to accelerate adoption and, particularly, to prepare for MAP use in pandemics. Key challenges remain in the commercialization of MAP technology and its adoption, including market acceptance, scale-up of production, regulatory approval, and the availability of capital to build advanced manufacturing infrastructure ahead of late-stage clinical trials.

Walking instead of standing.

Background: Leg discomfort is common in the general population. Volume increase and discomfort in the lower legs especially occur in occupations with long standing or sitting periods and less movement. Are both related to each other? Patients and methods: A time-controlled standing period of 15 min was performed in this nonrandomized controlled study to investigate the change and temporal relationship of volume increase and the occurrence of lower leg discomfort. Sensations of discomfort and the urge to move were queried using a numerical rating scale from 0 to 10 (NRS). Correlation analysis was conducted between the lower leg volume and the data regarding the discomfort and urge to move in each subject. Further, linear mixed effect models were performed to detect a causal relationship between the lower leg volume and the sensations of discomfort/urge to move in the standing period. Results: Lower leg volume increased by an average of 63 ml (p<0.001) during the standing period. The sensations of discomfort increased by a mean of 3.46 points on the NRS (p<0.001) during orthostasis. Participants' urge to move increased by 3.47 points on the NRS (p<0.001) during the standing period. A significant correlation was shown between the increase of lower leg volume and the occurrence of discomfort sensation in 9 out of 15 subjects (p<0.05) and between the increase of lower leg volume and the urge to move in 11 out of 15 subjects (p<0.05). Association was shown between volume increase and symptoms in linear mixed effects models. Conclusions: Prolonged standing with lack of movement leads to an increase in the lower leg volume and a sensation of discomfort in venous healthy subjects. Causal relationships are indicated between these variables by linear mixed effects models.

Allogeneic ABCB5+ mesenchymal stem cells for treatment-refractory chronic venous ulcers: a phase I/IIa clinical trial.

A significant number of chronic venous ulcers (CVUs) fail to heal despite of guideline-conform standard of care. Skin-derived ABCB5+ mesenchymal stem cells (MSCs) can dampen the sustained IL-1ß-driven inflammation present in chronic wounds. Based on their wound healing-facilitating effects in a mouse CVU model and an autologous first-in-human study, ABCB5+ MSCs have emerged as a potential candidate for cell-based advanced therapy of non-healing CVUs. In the present interventional, multicenter, single-arm, phase I/IIa clinical trial, subjects whose CVU had emerged as standard therapy-resistant received one or two topical applications of 1×106 allogeneic ABCB5+ MSCs/cm2 wound area in addition to standard treatment. Out of 83 treatment-emergent adverse events, only three were judged related to the cell product; they were mild or moderate and recovered without sequelae. Wound size markedly decreased from baseline to week 12, resulting in a median wound size reduction of 76% (full analysis set, N=31), 78% (per-protocol set, N=27) and 87% (subset of responders; n=21). In conclusion, the study treatment was well tolerated and safe. The treatment elicited a profound wound size reduction within 12 weeks, identifying ABCB5+ MSCs as a potential candidate for adjunctive therapy of otherwise incurable CVUs. These results justify the conduct of a larger, randomized, controlled trial to confirm clinical efficacy.

Optimisation of intermittent pneumatic compression in patients with lymphoedema of the legs

Background: Intermittent pneumatic compression (IPC) has established itself as a cornerstone in the combined decongestive therapy (CDT) of leg oedema, however, there is little evidence on the degree of volume shifts. Objectives: We performed continuous volume measurements during CDT to quantify volume shifts in a controlled trial. In addition, "wrapping/underpadding" and medical compression stockings were evaluated regarding decongestion and leg oedema, respectively. Materials & Methods: The volume reduction of CDT in patients with lymphoedema of the legs was measured. The additive decongesting effect of a padding surrounding the leg under the lymph cuff (IPC +) was evaluated. The efficacy of compression stockings in the maintenance phase was analysed. Results: Volume reductions were observed on the thigh (2%) and lower leg (5%) utilising IPC. Further significant volume reduction of the thigh (6%, p < 0.001) and lower leg (8%, p = 0.002) was observed with IPC +. Considering the thigh volume, patients with thigh-length compression stockings in the maintenance phase showed a significantly less pronounced increase in volume than patients with below-knee compression stockings (98% vs. 101% after six weeks; p < 0.05). Conclusion: The additional padding of the leg during an IPC session induces significantly more pronounced volume reduction. Medical compression stockings help to prevent volume increase in the maintenance phase.

Improvement of dynamic venous function after thermal ablation with steam vein occlusion - 6-weeks and 1-year follow-up after 167 treatments.

BACKGROUND: In this paper, the method of steam vein occlusion for the treatment of the great/small saphenous vein (GSV/SSV) was analyzed in terms of a therapeutic influence on the dynamic parameters of global vein function, its effects on subjective symptoms based on chronic venous insufficiency (CVI) and the side effects of the steam vein sclerosis (SVS). It has been questioned whether the effects of this method lead to a recommendation for routine clinical practice. METHODS: The venous drainage and the venous refilling time (T0) of the leg treated were determined by photoplethysmography (Elcat, Wolfratshausen, Germany) before, six weeks and one year after the intervention to examine the effects on global venous function. Further changes of clinical symptoms and findings were assessed by the Venous Clinical Severity Score (VCSS), preoperatively and after one year, and the complication rate at 6-week follow-up was monitored. RESULTS: The SVS was performed on 167 veins (GSV: 124; SSV: 43) in a total of 156 patients. Eight patients (5.1%) did not attend the 6-week follow-up, while 29 patients (18.6%) were lost in the 1-year follow-up. Patients were suffering from symptoms such as leg pain and leg edema, which resulted in a VCSS of 9.4 (cumulated mean score of all patients) preoperatively. The T0 was reduced to mean values of 20.6 s (GSV cohort) and 21 s (SSV cohort). The VCSS improved to 6.0 after one year. This correlated with the hemodynamic parameters. The T0 increased in the GSV cohort after six weeks to 31.8 s, p < 0.001, and showed a nonsignificant improvement to 32.2 s, p = 0.509, in the 1-year check. The T0 also increased in the SSV cohort significantly after 6 weeks to 30.1 s, p < 0.001, and showed a nonsignificant reduction after one year, p = 0.289. A total of 71%of the GSV and 69.8%of the SSV of the patients involved no complications following the treatment. Light complications (grade 1) occurred (reddening, hematoma, hyperpigmentation) in the majority: 24.2%of the GSV and 18.6%of the SSV. We noticed one grade 3 complication with thrombosis in the SSV cohort, which led to a pulmonary embolism. Forty-seven complete questionnaires were analyzed (responder rate: 28.1%); 40.4%of the patients had light complaints after the treatment, such as pain, warmth or local pressure sensations (Fig. 7); 63%of those patients noticed only slight pain at a maximum of 3 out of 10. The majority (91%) would recommend this procedure. CONCLUSION: The SVS revealed endoluminal catheter-based intervention to abolish venous reflux of the G/SSV as safe. As one therapeutic target is to eliminate venous reflux, effectiveness of a method cannot be based on sonographic data alone; one must further assess patients' symptoms and dynamic venous function. This data shows an improvement of patients' symptoms which correlated well with the improvement of the venous function in digital photoplethysmography. The SVS can be recommended as a catheter-based treatment in the future.

Influence of compression stockings on the sensation of discomfort and the volume of the lower legs in healthy subjects during standing load.

BACKGROUND: Edema caused by orthostasis is a common clinical picture in the medical and occupational context. Medical compression therapy with compression stockings (CS) is considered a conservative therapeutic standard in edema therapy. The effect of CS on leg discomfort and the increase of the lower leg volume during a standing load still remains questionable. In addition, it is not entirely known whether there is a correlation between volume increase and discomfort in these individuals. METHOD: A timed, controlled standing load of 15 min was conducted by the participants in this non-randomized controlled study to analyze the change in and correlation between lower leg volume increase and the occurrence of lower leg discomfort under compression therapy. Below-knee CS with an interface pressure of 23-32 mmHg were used. The lower leg volume was measured following previous studies using an optical three-dimensional volume (ml) measurement system, and sensations of discomfort and the urge to move were asked about using a numerical rating scale (NRS) of 0-10. The subjects conducted a leg movement for 15 s immediately after the standing period; the data were collected again subsequently. A correlation was calculated between the lower leg volume and the data regarding the discomfort and urge to move for each participant. The experiments had already been performed as part of a previous study including the same subjects who did not wear CS. The results of the study conducted here were compared with those of the participants who did not wear CS to investigate the effect of the CS. RESULTS: Lower leg volume increased by an average of 27 ml (p < 0.001) (without CS: by 63 ml) during standing load in the right leg. During the leg movement after standing load, the lower leg volume increased by 5 ml (n.s.). The sensations of discomfort during the orthostasis increased by 2.6 points on the NRS (p < 0.001) (without CS: by 3.46 points) and decreased by 1.67 points (p < 0.001) during the leg movement shortly after the standing period. Participants' urge to move increased by 3.73 points on the NRS (p < 0.001) (without CS: by 3.47 points) while the participants performed the standing period and decreased by 2.73 points (p < 0.001) during the final movement exercise. A weakly significant correlation could be demonstrated between the increase in the lower leg volume and the occurrence of discomfort in 6 out of 13 subjects (p < 0.1), and between the increase in the lower leg volume and the urge to move in 8 out of 15 subjects (p < 0.1). CONCLUSION: Standing loads and lack of movement lead to an increase in the lower leg volume and sensation of discomfort in venous healthy subjects wearing CS, which are reduced by wearing them (p < 0.001). A weakly significant mathematical correlation (Pearson's correlation coefficient) could be shown between the increase in the lower leg volume and the occurrence of the urge to move in 8 out of 15 subjects (p < 0.1) and between the increase in lower leg volume and the occurrence of leg discomfort in 6 out of 13 subjects (p < 0.1).

[Comparison of HIV therapy applied in urban and rural areas - results of a retrospective study between Berlin and Greifswald/ Vorpommern]. / Vergleich der HIV-Therapie im städtischen und ländlichen Raum.

The steady development of the antiretroviral therapy (ART) has led to a significant change in the demands on the quality of care. There are different regional challenges.It is a non-interventional, bicentric correlation study in the form of a retrospective data analysis including data of 43 HIV-positive patients in Greifswald and 1669 in Berlin. All variables were evaluated with R. Statistical significance was assumed at a p-value of ≤ 0.05.The immunological parameters showed a significantly lower CD4+ T-lymphocyte cell count in patients from Greifswald compared to those from Berlin (B: 516/µl blood; G: 266/µl blood; p < 0.001). The supply of ART was > 80% (B: 153/184 [83.15%]; G: 36/41 [87.8%]; p = 0.64) in both cohorts and led to a permanent (> than 4 quarters) drop of the viral load below the detection limit in 115/184 [62.25%] patients in Berlin and 23/41 [56.09%] patients in Greifswald (p = 0.008).This study has shown that the quality of care for HIV-infected patients in both urban and rural areas is of a high standard and carried out in accordance with the guidelines.

Influence of Medical Compression Stockings on Skin Hydration in Mainly Health Care Givers with Occupational Leg Symptoms and Edema.

BACKGROUND AND OBJECTIVE: Although compression therapy is a very effective therapy in reducing stasis-induced complaints, the wearing comfort is not always as requested. Most frequent problems are dryness of the skin and itching. This randomized, cross-over trial investigated 33 healthy participants and compared 2 different medical compression stockings: conventional stockings (type A = MCS) versus compression stockings with integrated care emulsion (type B = MCS-SkC). METHODS: Participants were divided into 2 cohorts. Both compression types were worn one after the other, 1 week each. The cohorts were named according to the sequence of the wearing periods (cohort AB/BA). PRIMARY OUTCOME: skin hydration. SECONDARY OUTCOMES: transepidermal water loss (TEWL), skin roughness, leg volume, interface pressure, and questionnaires about stasis-induced complaints and wearing comfort. RESULTS: Skin hydration: significant reduction after wearing MCS in both cohorts (p < 0.001); preservation of skin moisture after wearing MCS-SkC (p = 0.546 and p = 0.1631). TEWL: significant increase after wearing MCS (p = 0.007 and p = 0.0031); significant reduction by wearing MCS-SkC (p = 0.006 and p = 0.0005). Skin roughness: significant increase after wearing MCS (p = 0.0015 and p = 0.010), and nonsignificant decrease of skin roughness after wearing MCS-SkC (p = 0.933 and p = 0.4570). Leg volume: significantly reduced with both stockings (p = 0.004 and p = 0.0047). Regarding stasis-induced complaints, both stockings achieved good results. CONCLUSIONS: Both compression stockings are appropriate to reduce leg edema and minimize leg symptoms. MCS-SkC helps to obtain the natural skin barrier function in preserving the epidermal water content and reducing the TEWL.

Psychosocial stress of dermatology inpatients and their relatives - Comparison of patients with and without cancer.

BACKGROUND: In the clinical treatment pathways of certified oncological centers, psychotherapeutic services are mandatory. Although patients with somatic, non-oncological illnesses show an equally high prevalence of psychosocial stress, these guidelines do not exist for the general hospital sector. Are these patients really less burdened and is psychological support only needed in individual cases? The example of dermatological patients will be used to show whether the need for psychosocial care and the desire for support vary between individuals with and without malignant disease. PATIENTS AND METHODS: Using the Hornheider screening instrument and distress thermometer, 216 dermatological inpatients assessed their psychosocial stress and that of a close relative. In addition, they were asked about their desire for support and preferred support provider. RESULTS: i) Patients without skin cancer were more frequently and more severely distressed than cancer patients. ii) Patients of both groups assessed their relatives to be approximately equally distressed. Compared with their own distress, cancer patients assessed their relatives as more frequently and on average more severely distressed. More than 50 % of all patients regarded their own disease as the cause of their relatives' distress. iii) The desire for support in both groups was about 18 %. iv) Doctors and psychologists were usually named as potential contact persons. CONCLUSIONS: The expansion of psychosocial support services for non-tumor patients and their relatives seems necessary. The establishment of appropriate screening methods should be considered. Further studies in other clinical areas are required.