In Vitro Safety Study on the Use of Cold Atmospheric Plasma in the Upper Respiratory Tract.

Cold atmospheric plasma (CAP) devices generate reactive oxygen and nitrogen species, have antimicrobial and antiviral properties, but also affect the molecular and cellular mechanisms of eukaryotic cells. The aim of this study is to investigate CAP treatment in the upper respiratory tract (URT) to reduce the incidence of ventilator-associated bacterial pneumonia (especially superinfections with multi-resistant pathogens) or viral infections (e.g., COVID-19). For this purpose, the surface-microdischarge-based plasma intensive care (PIC) device was developed by terraplasma medical GmbH. This study analyzes the safety aspects using in vitro assays and molecular characterization of human oral keratinocytes (hOK), human bronchial-tracheal epithelial cells (hBTE), and human lung fibroblasts (hLF). A 5 min CAP treatment with the PIC device at the "throat" and "subglottis" positions in the URT model did not show any significant differences from the untreated control (ctrl.) and the corresponding pressurized air (PA) treatment in terms of cell morphology, viability, apoptosis, DNA damage, and migration. However, pro-inflammatory cytokines (MCP-1, IL-6, and TNFα) were induced in hBTE and hOK cells and profibrotic molecules (collagen-I, FKBP10, and αSMA) in hLF at the mRNA level. The use of CAP in the oropharynx may make an important contribution to the recovery of intensive care patients. The results indicate that a 5 min CAP treatment in the URT with the PIC device does not cause any cell damage. The extent to which immune cell activation is induced and whether it has long-term effects on the organism need to be carefully examined in follow-up studies in vivo.

Expression of the plasma membrane citrate carrier (pmCiC) in human cancerous tissues-correlation with tumour aggressiveness.

We have recently shown that cancer cells of various origins take up extracellular citrate through the plasma membrane citrate carrier (pmCiC), a specific plasma membrane citrate transporter. Extracellular citrate is required to support cancer cell metabolism, in particular fatty acid synthesis, mitochondrial activity, protein synthesis and histone acetylation. In addition, cancer cells tend to acquire a metastatic phenotype in the presence of extracellular citrate. Our recent study also showed that cancer-associated stromal cells synthesise and release citrate and that this process is controlled by cancer cells. In the present study, we evaluated the expression of pmCiC, fibroblast activation protein-α (FAP) and the angiogenesis marker cluster of differentiation 31 (CD31) in human cancer tissues of different origins. In the cohort studied, we found no correlation between disease stage and the expression of FAP or CD31. However, we have identified a clear correlation between pmCiC expression in cancer cells and cancer-associated stroma with tumour stage. It can be concluded that pmCiC is increased in cancer cells and in cancer-supporting cells in the tumour microenvironment at the later stages of cancer development, particularly at the metastatic sites. Therefore, pmCiC expression has the potential to serve as a prognostic marker, although further studies are needed.

Retrospective Single-Center Case Study of Clinical Variables and the Degree of Actinic Elastosis Associated with Rare Skin Cancers.

(1) Background: Rare skin cancers include epithelial, neuroendocrine, and hematopoietic neoplasias as well as cutaneous sarcomas. Ultraviolet (UV) radiation and sunburns are important drivers for the incidence of certain cutaneous sarcomas; however, the pathogenetic role of UV light is less clear in rare skin cancers compared to keratinocyte cancer and melanoma. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure among selected rare skin cancers (atypical fibroxanthoma [AFX], pleomorphic dermal sarcoma [PDS], dermatofibrosarcoma protuberans [DFSP], Kaposi sarcoma [KS], Merkel cell carcinoma [MCC], and leiomyosarcoma [LMS]) while taking into account relevant clinical variables (age, sex, and body site). (2) Methods: We newly established a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 210 rare skin cancers from 210 patients with their clinical variables. (3) Results: TEG values were correlated with age and whether tumors arose on UV-exposed body sites. TEG values were significantly higher in AFX and PDS cases compared to all other analyzed rare skin cancer types. As expected, TEG values were low in DFSP and KS, while MCC cases exhibited intermediate TEG values. (4) Conclusions: High cumulative UV exposure is more strongly associated with AFX/PDS and MCC than with other rare skin cancers. These important results expand the available data associated with rare skin cancers while also offering insight into the value of differentiating among these tumor types based on their relationship with sun exposure, potentially informing preventative, diagnostic and/or therapeutic approaches.

Skin Cancer Induction by the Antimycotic Drug Voriconazole is Caused by Impaired DNA Damage Detection Due to Chromatin Compaction.

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair.

Association of Global Ultraviolet Radiation With the Incidence of Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND OBJECTIVES: Inflammation is a key pathomechanism for growth and rupture of intracranial aneurysms. Anti-inflammatory mechanisms may reduce rupture of intracranial aneurysms and the incidence of aneurysmal subarachnoid hemorrhage (SAH). Ultraviolet (UV) radiation from sunlight exposure induces systemic anti-inflammatory responses through immunosuppressive mechanisms. We studied whether SAH incidence is associated with UV radiation. METHODS: Global SAH incidence, time trends, and regional differences from 32 countries were linked to UV radiation data from the Tropospheric Emission Monitoring Internet Service. Odds between low vs high UV exposure and SAH incidence were calculated. Correlation analysis was performed using R (R 4.1.2). RESULTS: SAH incidences ranged from 1.3 to 27 per 100 000 patient-years (p-y) and UV index from 1.76 to 11.27. The correlation coefficient (rho) between SAH incidence and UV index was -0.48 (P = .012). SAH incidence was highest in Japan (13.7-27.9 p-y) with an UV index 6.28. UV index was highest in Chile 11.27 with a lower SAH incidence (3.8-4.8 p-y). The lowest UV index 1.76 was seen in Iceland with higher SAH incidence (9.8 p-y).Within Europe, regions with higher UV indices reported lower SAH incidences (Northwest Europe: SAH incidence p-y 8.61/UV index 2.85; Southeast Europe: SAH incidence p-y 7.37/UV index 4.65) with a significant inverse correlation (rho = -0.68, P = .004) and not a significant correlation between non-European countries (rho = -0.43, P = .19). Low exposure of UV radiation in global regions predicted higher than median incidences of SAH with an odds ratio 5.13 (95% CIs 1.02-31.5). CONCLUSION: The incidence of SAH is inversely associated with UV radiation. Further studies should assess the actual UV exposure in relation to SAH incidence and potential biological explanations for the relation we found.

[Ultraviolet radiation in the pathogenesis of lupus erythematosus]. / UV-induzierte Pathogenese des Lupus erythematodes.

Photosensitivity represents an increased inflammatory reaction to sunlight, which can be observed particularly in the autoimmune disease lupus erythematosus. Cutaneous lupus erythematosus (CLE) can be provoked by ultraviolet (UV) radiation and can cause both acute, nonscarring and chronic, scarring skin changes. In systemic lupus erythematosus, on the other hand, provocation by UV radiation can lead to flare or progression of systemic involvement. The etiology of lupus erythematosus is multifactorial and includes genetic, epigenetic and immunologic mechanisms. In this review, we address the effect of UV radiation on healthy skin and photosensitive skin using the example of lupus erythematosus. We describe possible mechanisms of UV-triggered immune responses that could offer therapeutic approaches. Currently, photosensitivity can only be prevented by avoiding UV exposure itself. Therefore, it is important to better understand the underlying mechanisms in order to develop strategies to counteract the deleterious effects of photosensitivity.

Hereditary epidermolytic palmoplantar keratosis due to a novel desmoglein-1 mutation: A case report.

Key Clinical Message: Keratosis palmoplantaris striata type I (SPPK-I) is a rare autosomal-dominant type of hereditary epidermolytic palmoplantar keratoderma, which can be caused by mutations in desmoglein-1 (DSG-1). Patients suffer from hyperkeratotic plaques and painful palmoplantar fissures. Unfortunately, treatment options including salicylic vaseline, topical corticosteroids, phototherapy, and retinoids are inefficient. Abstract: Hereditary palmoplantar keratodermas (PPKs) represent a heterogeneous group of rare skin disorders with epidermal palmoplantar hyperkeratosis. Mutations in the desmoglein 1 gene (DSG1), a transmembrane glycoprotein, have been reported primarily in striate PPKs. We report a patient with keratosis palmoplantaris striata type I (SPPK-I) with a specific pathogenic variant [c.349C>T, p.(Arg117*)] in DSG1. Despite increased understanding, effective treatment options for PPK, including SPPK-I, remain limited.

Complete lymph node dissection in cutaneous melanoma patients with positive sentinel lymph node: Outcome and predictors in a retrospective cohort study over 16 years.

BACKGROUND: In melanoma treatment, complete lymph node dissection (CLND) has been considered the therapeutic gold standard in patients with positive sentinel lymph node biopsy (SLNB). This long-held approach was revised in 2017, with recent evidence questioning the therapeutic benefit of CLND in malignant melanoma (MM) therapy. In this study, we aimed to fill this knowledge gap by retrospectively analyzing the impact of CLND on MM patients' survival. METHODS: We retrospectively analyzed the multi-center population-based Clinical Cancer Registry at the Tumor Center Regensburg (TUDOK) database (2004-2020) to identify patients who had been diagnosed with SLN-positive MM and underwent (non)invasive management thereof. Patient cohorts were subdivided according to the treatment received (CLND and waiving CLND). Primary outcomes included overall survival (OS), recurrence-free survival (RFS), and cumulative recurrence rate. RESULTS: We identified 1143 MM patients, of whom 126 (11.0%) had positive SLN status. CLND was waived in the majority of SLN-positive MM cases (n = 71; 56.3%), with 55 (43.7%) patients undergoing CLND. Univariable and multivariable Cox regression revealed no significant advantage for CLND patients compared to non-CLND patients in OS (HR=0.970, p = 0.915 and HR=1.295, p = 0.479, respectively), RFS (HR=1.050, p = 0.849 and HR=1.220, p = 0.544, respectively), and cumulative recurrence rate (HR=1.234, p = 0.441 and HR=1.220, p = 0.544), respectively). CONCLUSION: We found that CLND had no significant impact on patient survival and MM recurrence rate, thus corroborating the validity of current clinical guidelines.

Mitochondrial and Cellular Function in Fibroblasts, Induced Neurons, and Astrocytes Derived from Case Study Patients: Insights into Major Depression as a Mitochondria-Associated Disease.

The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria's involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD's pathogenesis. This study focused on cellular and mitochondrial (dys)function in two atypical cases: an antidepressant non-responding MDD patient ("Non-R") and another with an unexplained mitochondrial disorder ("Mito"). Skin biopsies from these patients and controls were used to generate various cell types, including astrocytes and neurons, and cellular and mitochondrial functions were analyzed. Similarities were observed between the Mito patient and a broader MDD cohort, including decreased respiration and mitochondrial function. Conversely, the Non-R patient exhibited increased respiratory rates, mitochondrial calcium, and resting membrane potential. In conclusion, the Non-R patient's data offered a new perspective on MDD, suggesting a detrimental imbalance in mitochondrial and cellular processes, rather than simply reduced functions. Meanwhile, the Mito patient's data revealed the extensive effects of mitochondrial dysfunctions on cellular functions, potentially highlighting new MDD-associated impairments. Together, these case studies enhance our comprehension of MDD.

Effect of the addition of a mental health specialist for evaluation of undiagnosed patients in centres for rare diseases (ZSE-DUO): a prospective, controlled trial with a two-phase cohort design.

Background: People with complex symptomatology but unclear diagnosis presenting to a centre for rare diseases (CRD) may present with mental (co-)morbidity. We hypothesised that combining an expert in somatic medicine with a mental health specialist working in tandem will improve the diagnostic outcome. Methods: Patients aged 12 years and older who presented to one of the 11 participating German CRDs with an unknown diagnosis were recruited into this prospective cohort trial with a two-phase cohort design. From October 1, 2018 to September 30, 2019, participants were allocated to standard care (SC, N = 684), and from October 1, 2019 to January 31, 2021 to innovative care (IC, N = 695). The cohorts consisted mainly of adult participants with only a minority of children included (N = 67). IC included the involvement of a mental health specialist in all aspects of care (e.g., assessing medical records, clinic visits, telehealth care, and case conferences). Clinicaltrials.gov identifier: NCT03563677. Findings: The proportion of patients with diagnoses established within 12 months after the first visit to the CRD explaining the entire symptomatology (primary outcome) was 19% (N = 131 of 672) in the SC and 42% (N = 286 of 686) in the IC cohort (OR adjusted for centre effects 3.45 [95% CrI: 1.99-5.65]). The difference was mainly due to a higher prevalence of mental disorders and non-rare somatic diseases in the IC cohort. The median time to explaining diagnoses was one month shorter with IC (95% CrI: 1-2), and significantly more patients could be referred to local regular care in the IC (27.5%; N = 181 of 659) compared to the SC (12.3%; N = 81 of 658) cohort (OR adjusted for centre effects 2.70 [95% CrI: 2.02-3.60]). At 12-month follow-up, patient satisfaction with care was significantly higher in the IC compared to the SC cohort, while quality of life was not different between cohorts. Interpretation: Our findings suggested that including a mental health specialist in the entire evaluation process of CRDs for undiagnosed adolescents and adults should become an integral part of the assessment of individuals with a suspected rare disease. Funding: The study was funded by the Global Innovation Fund from the Joint Federal Committee in Germany (Innovationsfonds des Gemeinsamen Bundesausschusses), grant number 01NVF17031.

[Progeroid syndromes : Aging, skin aging, and mechanisms of progeroid syndromes]. / Progeroide Syndrome : Alterung, Hautalterung und Mechanismen progeroider Erkrankungen.

Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. PSs display a wide range of heterogeneous pathological symptoms that also manifest during natural aging, including vision and hearing loss, atrophy, hair loss, progressive neurodegeneration, and cardiovascular defects. Recent advances in molecular pathology have led to a better understanding of the underlying mechanisms of these diseases. The genetic mutations underlying PSs are functionally linked to genome maintenance and repair, supporting the causative role of DNA damage accumulation in aging. While some of those genes encode proteins with a direct involvement in a DNA repair machinery, such as nucleotide excision repair (NER), others destabilize the genome by compromising the stability of the nuclear envelope, when lamin A is dysfunctional in Hutchinson-Gilford progeria syndrome (HGPS) or regulate the DNA damage response (DDR) such as the ataxia telangiectasia-mutated (ATM) gene. Understanding the molecular pathology of progeroid diseases is crucial in developing potential treatments to manage and prevent the onset of symptoms. This knowledge provides insight into the underlying mechanisms of premature aging and could lead to improved quality of life for individuals affected by progeroid diseases.

Phototherapy: Theory and practice.

Despite the development of highly effective biologics for skin diseases such as psoriasis or atopic dermatitis, UVA and UVB therapy, alone or in combination, are still essential components of various guidelines. Phototherapy is not only a first-line treatment and highly effective for a number of skin diseases, but is also economical and has few side effects. The targeted use of UVA and UVB, if necessary, in combination with the photosensitizer psoralen in the context of PUVA therapy, enables the dermatologist to effectively treat a wide variety of skin diseases. Indications for phototherapy include epidermal diseases such as atopic dermatitis, psoriasis and vitiligo, as well as photodermatoses, mycosis fungoides, graft-versus-host disease and deep dermal diseases such as scleroderma. This article reviews the physical principles, molecular mechanisms, current treatment regimens, and individual indications for phototherapy and photochemotherapy.

[Multilocular pyoderma gangrenosum : Association with primary manifestation of primary biliary cholangitis]. / Multilokuläres Pyoderma gangraenosum : Assoziation mit der Erstmanifestation einer primär biliären Cholangitis.

A 16-year-old female patient with previously diagnosed acne vulgaris was transferred to our clinic in reduced general condition with rapidly progressive and extremely painful ulcerations. In the laboratory exam, inflammatory parameters were highly elevated, but she was normothermic. Based on the findings, we diagnosed multilocular pyoderma gangrenosum. Further investigations established the diagnosis of primary biliary cholangitis as the underlying condition. Treatment with systemic corticosteroids was initiated and we started therapy with ursodeoxycholic acid. This led to improvement within a few days. PAPA-syndrome (pyogenic arthritis, pyoderma gangrenosum and acne vulgaris) could be ruled out by genetic analysis.

Investigation of Adverse Reactions in Tattooed Skin through Histological and Chemical Analysis.

BACKGROUND: Just as the number of tattooed people has increased in recent years, so has the number of adverse reactions in tattooed skin. Tattoo colourants contain numerous, partly unidentified substances, which have the potential to provoke adverse skin reactions like allergies or granulomatous reactions. Identification of the triggering substances is often difficult or even impossible. METHODS: Ten patients with typical adverse reactions in tattooed skin were enrolled in the study. Skin punch biopsies were taken and the paraffin-embedded specimens were analysed by standard haematoxylin and eosin and anti-CD3 stainings. Tattoo colourants provided by patients and punch biopsies of patients were analysed with different chromatography and mass spectrometry methods and X-ray fluorescence. Blood samples of 2 patients were screened for angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R). RESULTS: Histology showed variable skin reactions such as eosinophilic infiltrate, granulomatous reactions, or pseudolymphoma. CD3+ T lymphocytes dominated the dermal cellular infiltrate. Most patients had adverse skin reactions in red tattoos (n = 7), followed by white tattoos (n = 2). The red tattooed skin areas predominantly contained Pigment Red (P.R.) 170, but also P.R. 266, Pigment Orange (P.O.) 13, P.O. 16, and Pigment Blue (P.B.) 15. The white colourant of 1 patient contained rutile titanium dioxide but also other metals like nickel and chromium and methyl dehydroabietate - known as the main ingredient of colophonium. None of the 2 patients showed increased levels of ACE and sIL-2R related to sarcoidosis. Seven of the study participants showed partial or complete remission after treatment with topical steroids, intralesional steroids, or topical tacrolimus. CONCLUSIONS: The combination of the methods presented might be a rational approach to identify the substances that trigger adverse reactions in tattoos. Such an approach might help make tattoo colourants safer in the future if such trigger substances could be omitted.