Clinical features and potential markers of disease in idiopathic non-histaminergic angioedema, a real-life study.

Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease, with unknown etiology and pathogenesis, characterized by recurrent clinical manifestations and resistance to antihistamines and corticosteroids. We aim to evaluate clinical features and potential markers of disease in an Italian cohort of patients with InH-AAE. We enrolled 26 patients diagnosed with InH-AAE. Information about clinical features, treatments, routine laboratory investigations, immunological and genetic tests were collected. We assessed plasma levels of complement components, angiogenic and lymphangiogenic mediators, proinflammatory cytokines and chemokines, and activity of phospholipases A2. Finally, patients underwent nailfold videocapillaroscopy (NVC); both quantitative and qualitative capillaroscopic parameters were analyzed. Plasma levels of VEGFs were similar in healthy controls and in InH-AAE patients. ANGPT1 was decreased in InH-AAE patients compared to controls while ANGPT2 was similar to controls. Interestingly, the ANGPT2/ANGPT1 ratio (an index of vascular permeability) was increased in InH-AAE patients compared to controls. sPLA2 activity, elevated in patients with C1-INH-HAE, showed differences also when measured in InH-AAE patients. TNF-α concentration was higher in InH-AAE patients than in healthy controls, conversely, the levels of CXCL8, and IL-6 were similar in both groups. At the NVC, the capillary loops mainly appeared short and tortuous in InH-AAE patients. InH-AAE represents a diagnostic challenge. Due to the potential life-threatening character of this condition, a prompt identification of the potentially bradykinin-mediated forms is crucial. A better comprehension of the mechanism involved in InH-AAE would also lead to the development of new therapeutic approaches to improve life quality of patients affected by this disabling disease.

Worldwide Heterogeneity of Food Allergy: Focus on Peach Allergy in Southern Italy.

Food allergy (FA) has shown an increasing prevalence in the last decades, becoming a major public health problem. However, data on the prevalence of FA across the world are heterogeneous because they are influenced by several factors. Among IgE-mediated FA, an important role is played by FA related to plant-derived food which can result from the sensitization to a single protein (specific FA) or to homologous proteins present in different foods (cross-reactive FA) including non-specific lipid transfer proteins (nsLTPs), profilins, and pathogenesis-related class 10 (PR-10). In addition, the clinical presentation of FA is widely heterogeneous ranging from mild symptoms to severe reactions up to anaphylaxis, most frequently associated with nsLTP-related FA (LTP syndrome). Considering the potential life-threatening nature of nsLTP-related FA, the patient's geographical setting should always be taken into account; thereby, it is highly recommended to build a personalized approach for managing FA across the world in the precision medicine era. For this reason, in this review, we aim to provide an overview of the prevalence of nsLTP-mediated allergies in the Mediterranean area and to point out the potential reasons for the different geographical significance of LTP-driven allergies with a particular focus on the allergenic properties of food allergens and their cross reactivity.

Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Orbital/ocular inflammatory involvement in VEXAS syndrome: Data from the international AIDA network VEXAS registry.

VEXAS syndrome is a recently described monogenic autoinflammatory disease capable of manifesting itself with a wide array of organs and tissues involvement. Orbital/ocular inflammatory manifestations are frequently described in VEXAS patients. The objective of this study is to further describe orbital/ocular conditions in VEXAS syndrome while investigating potential associations with other disease manifestations. In the present study, twenty-seven out of 59 (45.8 %) VEXAS patients showed an inflammatory orbital/ocular involvement during their clinical history. The most frequent orbital/ocular affections were represented by periorbital edema in 8 (13.6 %) cases, episcleritis in 5 (8.5 %) patients, scleritis in 5 (8.5 %) cases, uveitis in 4 (6.8 %) cases, conjunctivitis in 4 (6.8 %) cases, blepharitis in 3 (5.1 %) cases, orbital myositis in 2 (3.4 %) cases. A diagnosis of systemic immune-mediated disease was observed in 15 (55.6 %) cases, with relapsing polychondritis diagnosed in 12 patients. A significant association was observed between relapsing polychondritis and orbital/ocular involvement in VEXAS syndrome (Relative Risk: 2.37, 95 % C.I. 1.03-5.46, p = 0.048). Six deaths were observed in the whole cohort of patients after a median disease duration of 1.2 (IQR=5.35) years, 5 (83.3 %) of which showed orbital/ocular inflammatory involvement. In conclusion, this study confirms that orbital/ocular inflammatory involvement is a common finding in VEXAS patients, especially when relapsing polychondritis is diagnosed. This makes ophthalmologists a key figure in the diagnostic process of VEXAS syndrome. The high frequency of deaths observed in this study seems to suggest that patients with orbital/ocular involvement may require increased attention and more careful follow-up.

The Crosstalk between N-Formyl Peptide Receptors and uPAR in Systemic Sclerosis: Molecular Mechanisms, Pathogenetic Role and Therapeutic Opportunities.

Systemic Sclerosis (SSc) is a heterogeneous autoimmune disease characterized by widespread vasculopathy, the presence of autoantibodies and the progressive fibrosis of skin and visceral organs. There are still many questions about its pathogenesis, particularly related to the complex regulation of the fibrotic process, and to the factors that trigger its onset. Our recent studies supported a key role of N-formyl peptide receptors (FPRs) and their crosstalk with uPAR in the fibrotic phase of the disease. Here, we found that dermal fibroblasts acquire a proliferative phenotype after the activation of FPRs and their interaction with uPAR, leading to both Rac1 and ERK activation, c-Myc phosphorylation and Cyclin D1 upregulation which drive cell cycle progression. The comparison between normal and SSc fibroblasts reveals that SSc fibroblasts exhibit a higher proliferative rate than healthy control, suggesting that an altered fibroblast proliferation could contribute to the initiation and progression of the fibrotic process. Finally, a synthetic compound targeting the FPRs/uPAR interaction significantly inhibits SSc fibroblast proliferation, paving the way for the development of new targeted therapies in fibrotic diseases.

Eosinophilic Patterns in Patients with Seasonal Allergy Affected by Bronchial Asthma and Rhinitis/Rhinosinusitis: Efficacy of Benralizumab in Patients with the Persistent Pattern.

BACKGROUND: Eosinophilia can be influenced by multiple factors. This study aims to set a protocol for monitoring blood absolute eosinophil count (AEC) in patients with seasonal allergy affected by bronchial asthma (BA), allergic rhinitis (AR), or chronic rhinosinusitis with or without nasal polyposis (CRSw/sNP). METHODS: We planned a total of four annual blood samples to measure AEC in- and out-seasonal pollen exposure (i.e., one measurement every three months for one year). RESULTS: We identified two distinct groups of patients (non-eosinophilic and eosinophilic). Patients in the eosinophilic group presented with four different patterns (episodic, transient, floating, and persistent). Most patients with episodic, transient, and floating patterns were affected by mild allergy and the increase in eosinophils was related to allergen exposure. In contrast, patients with the persistent pattern mostly presented with more severe allergy (i.e., severe BA and relapsing CRSwNP) and the eosinophilia was unrelated to allergen exposure. The subgroup of patients with severe BA, relapsing CRSwNP, and persistent eosinophilc pattern were treated with benralizumab, which induced a noteworthy improvement in both severe BA and CRSwNP. CONCLUSIONS: Multiple AEC measurements in patients with seasonal allergy can better reflect patient's eosinophilic status and help define the relationship of AEC enhancement with allergen exposure.

Early Ear, Nose and Throat Manifestations in Eosinophilic Granulomatosis with Poliangioitis: Results from Our Cohort Group and Literature Review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, systemic necrotizing vasculitis affecting small-to-medium-sized vessels. EGPA's clinical manifestations are heterogeneous, affecting different organs and systems, and the upper respiratory tract can be affected by ear, nose and throat (ENT) involvement. The aim of our study was to assess type manifestations at the time of diagnosis in a cohort of EGPA patients and correlate findings with baseline variables (sex, age, antineutrophil cytoplasmic antibodies-ANCA-status) and literature reports. The main ENT manifestations in our patients at the time of diagnosis were: chronic rhinosinusitis with nasal polyposis (CRSwNP) (52%), turbinate hypertrophy (48%), nasal swelling (40%), rhinorrhea (40%), chronic rhinosinusitis without nasal polyposis (CRSsNP) (32%), nasal bone deformities (32%), nasal crusts (20%), nasal mucosal ulcers (12%), corditis (12%), hoarseness/dysphonia (12%), hearing loss (12%), mucoceles (4%) and eosinophilic rhinitis (4%). No correlations were found between sex, age, ANCA status and ENT clinical manifestations. A polymorphic ENT involvement is often observed in the early stages of EGPA. The presence of nasal, sinus, ear and/or laryngeal manifestations in patients with asthma and hypereosinophilia, independently of sex, age or ANCA status, should raise an alert for further investigation and differential diagnosis for EGPA. ENT specialists should be aware of their leading position in this diagnostic race.

Unfolding dermatologic spectrum of Behçet's disease in Italy: real-life data from the International AIDA Network Behçet's disease Registry.

Behçet's disease (BD) is a heterogeneous multifactorial autoinflammatory disease characterized by a plethora of clinical manifestations. Cutaneous lesions are considered hallmarks of the disease. However, their evolution over time and a thorough description are scarcely reported in non-endemic regions. The aim of this study was to detail BD skin manifestations and their evolution over time in Italy, as well as the dermatological prognostic impact of specific cutaneous features in long-standing disease. Data were collected in a double fashion, both retrospectively and prospectively, from the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to BD, between January 2022 and December 2022. A total of 458 Italian patients were included. When assessing skin manifestations course, the constant or sporadic presence or absence of cutaneous involvement between onset and follow-up was considered. Oral ulcers (OU) (88.4%) and genital ulcers (GU) (52.6%), followed by skin involvement (53.7%) represented the most common presenting mucocutaneous manifestations at disease onset. Up to the time of enrolment into the AIDA registry, 411 (93.8%) patients had suffered from OU and 252 (57.9%) from GU; pseudofolliculitis (PF) accounted for the most common skin manifestation (170 patients, 37.1%), followed by erythema nodosum (EN) (102 patients, 22.3%), skin ulcers (9 patients, 2%) and pyoderma gangrenosum (4 patients, 0.9%). A prospective follow-up visit was reported in 261/458 patients; 24/148 (16.2%) subjects with skin involvement as early as BD onset maintained cutaneous lesions for the entire period of observation, while 120 (44.1%) patients suffered from sporadic skin involvement. Conversely, 94/113 (83.2%) with no skin involvement at disease onset did not develop skin lesions thereafter. At follow-up visits, cutaneous involvement was observed in 52 (20%) patients, with a statistically significant association between PF and constant skin involvement (p = 0.031). BD in Italy is characterized by a wide spectrum of clinical presentations and skin manifestations in line with what is described in endemic countries. Patients with skin disease at the onset are likely to present persistent cutaneous involvement thereafter; mucocutaneous lesions observed at the onset, especially PF, could represent a warning sign for future persistent skin involvement requiring closer dermatological care.

The Benefits of Water from Nitrodi's Spring: The In Vitro Studies Leading the Potential Clinical Applications.

Natural products (water, plants, and minerals) have been studied for diverse applications in health and disease. Since there has been a growing interest in the introduction of thermal water as a clinical complementary approach in the treatment of low-grade inflammation and stress-related conditions, this review focuses on the oldest spa in the world: Nitrodi's spring. Substantial studies in the 1960s showed that both the internal and external use of Nitrodi's water yielded several benefits in physiological processes and in treating certain disorders, mainly allergic and autoimmune inflammatory conditions. More recently, a novel interest in Nitrodi's water has prompted researchers to further explore the effects of this water and shed light on the molecular mechanisms sustaining its therapeutic efficacy. In different epithelial cell models, Nitrodi's water had strong promotional effects on proliferation, cell migration, cell viability, and fibroblast to myofibroblast transition, all of which essential for wound healing and tissue remodeling. Moreover, Nitrodi's water exhibited anti-oxidant and anti-inflammatory properties through the inhibition of ROS production and protein S-nitrosylation. Here, we have collected the clinical and basic data on Nitrodi's water and reviewed articles that have discussed its use as a potential treatment for several inflammatory and autoimmune diseases and age-related skin deterioration.

Neurologic and Psychiatric Manifestations of Bradykinin-Mediated Angioedema: Old and New Challenges.

Neurologic manifestations have been occasionally described in patients with bradykinin-mediated angioedema. The existing literature is currently limited to case series and case reports mainly described in the hereditary forms (HAE) concerning central nervous system (CNS) involvement. On the contrary, very little is known about peripheral and autonomic nervous system manifestations. CNS involvement in HAE may present with symptoms including severe headaches, visual disturbance, seizures, and various focal and generalized deficits. In addition, a stroke-like clinical picture may present in HAE patients. In turn, some drugs used in patients with cardiovascular and neurologic disorders, such as recombinant tissue plasminogen activator (r-tPA) and angiotensin-converting enzyme inhibitors (ACEI), may produce medication-induced angioedema, resulting in a diagnostic challenge. Finally, most patients with HAE have higher levels of psychological distress, anxiety, and depression. With this review, we aimed to provide an organized and detailed analysis of the existing literature on neurologic and psychiatric manifestations of HAE to shed light on these potentially invalidating symptoms and lay the foundation for further personalized diagnostic pathways for patients affected by this protean disease.

A patient-driven registry on Behçet's disease: the AIDA for patients pilot project.

Introduction: This paper describes the creation and preliminary results of a patient-driven registry for the collection of patient-reported outcomes (PROs) and patient-reported experiences (PREs) in Behçet's disease (BD). Methods: The project was coordinated by the University of Siena and the Italian patient advocacy organization SIMBA (Associazione Italiana Sindrome e Malattia di Behçet), in the context of the AIDA (AutoInflammatory Diseases Alliance) Network programme. Quality of life, fatigue, socioeconomic impact of the disease and therapeutic adherence were selected as core domains to include in the registry. Results: Respondents were reached via SIMBA communication channels in 167 cases (83.5%) and the AIDA Network affiliated clinical centers in 33 cases (16.5%). The median value of the Behçet's Disease Quality of Life (BDQoL) score was 14 (IQR 11, range 0-30), indicating a medium quality of life, and the median Global Fatigue Index (GFI) was 38.7 (IQR 10.9, range 1-50), expressing a significant level of fatigue. The mean Beliefs about Medicines Questionnaire (BMQ) necessity-concern differential was 0.9 ± 1.1 (range - 1.8-4), showing that the registry participants prioritized necessity belief over concerns to a limited extent. As for the socioeconomic impact of BD, in 104 out of 187 cases (55.6%), patients had to pay from their own pocket for medical exams required to reach the diagnosis. The low family socioeconomic status (p < 0.001), the presence of any major organ involvement (p < 0.031), the presence of gastro-intestinal (p < 0.001), neurological (p = 0.012) and musculoskeletal (p = 0.022) symptoms, recurrent fever (p = 0.002), and headache (p < 0.001) were associated to a higher number of accesses to the healthcare system. Multiple linear regression showed that the BDQoL score could significantly predict the global socioeconomic impact of BD (F = 14.519, OR 1.162 [CI 0.557-1.766], p < 0.001). Discussion: Preliminary results from the AIDA for Patients BD registry were consistent with data available in the literature, confirming that PROs and PREs could be easily provided by the patient remotely to integrate physician-driven registries with complementary and reliable information.

Melanoma-derived soluble mediators modulate neutrophil biological properties and the release of neutrophil extracellular traps.

Polymorphonuclear neutrophils (PMNs) are the main effector cells in the inflammatory response. The significance of PMN infiltration in the tumor microenvironment remains unclear. Metastatic melanoma is the most lethal skin cancer with an increasing incidence over the last few decades. This study aimed to investigate the role of PMNs and their related mediators in human melanoma. Highly purified human PMNs from healthy donors were stimulated in vitro with conditioned media (CM) derived from the melanoma cell lines SKMEL28 and A375 (melanoma CM), and primary melanocytes as controls. PMN biological properties (chemotaxis, survival, activation, cell tracking, morphology and NET release) were evaluated. We found that the A375 cell line produced soluble factors that promoted PMN chemotaxis, survival, activation and modification of morphological changes and kinetic properties. Furthermore, in both melanoma cell lines CM induced chemotaxis, activation and release of neutrophil extracellular traps (NETs) from PMNs. In contrast, the primary melanocyte CM did not modify the biological behavior of PMNs. In addition, serum levels of myeloperoxidase, matrix metalloprotease-9, CXCL8/IL-8, granulocyte and monocyte colony-stimulating factor and NETs were significantly increased in patients with advanced melanoma compared to healthy controls. Melanoma cell lines produce soluble factors able to "educate" PMNs toward an activated functional state. Patients with metastatic melanoma display increased circulating levels of neutrophil-related mediators and NETs. Further investigations are needed to better understand the role of these "tumor-educated neutrophils" in modifying melanoma cell behavior.

A Multidisciplinary Approach for Type 2 Allergic Diseases: What Do Biologics Teach Us?

Patients with atopic/allergic disorders, including atopic dermatitis (AD), allergic rhino-conjunctivitis (AR), chronic rhinosinusitis with/without nasal polyps (CRSwNP/CRSsNP), bronchial asthma, food allergy, and eosinophilic esophagitis (EoE), often share a common genetic background, a type Th2 polarized immune response, and several environmental factors [...].

Calcinosis Cutis and Calciphylaxis in Autoimmune Connective Tissue Diseases.

Calcinosis represents a severe complication of several autoimmune disorders. Soft-tissue calcifications have been classified into five major types: dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Autoimmune diseases are usually associated with dystrophic calcifications, including calcinosis cutis, occurring in damaged or devitalized tissues in the presence of normal serum levels of calcium and phosphate. In particular, calcinosis cutis has been described in dermatomyositis, polymyositis, juvenile dermatomyositis, systemic sclerosis, systemic lupus erythematosus, primary Sjögren's syndrome, overlap syndrome, mixed connective tissue disease, and rheumatoid arthritis. Calciphylaxis, a severe and life-threatening syndrome presenting with vascular calcifications and thrombosis, has also been associated with some autoimmune conditions. Due to the potentially disabling character of calcinosis cutis and calciphylaxis, physicians' awareness about the clinical presentation and management of these diseases should be increased to select the most appropriate treatment option and avoid long-term complications. In this review, we aim to analyze the clinical features of calcinosis cutis and calciphylaxis associated with autoimmune diseases, and the main treatment strategies evaluated up to now for treating this potentially disabling disease.

Basophils beyond allergic and parasitic diseases.

Basophils bind IgE via FcεRI-αßγ2, which they uniquely share only with mast cells. In doing so, they can rapidly release mediators that are hallmark of allergic disease. This fundamental similarity, along with some morphological features shared by the two cell types, has long brought into question the biological significance that basophils mediate beyond that of mast cells. Unlike mast cells, which mature and reside in tissues, basophils are released into circulation from the bone marrow (constituting 1% of leukocytes), only to infiltrate tissues under specific inflammatory conditions. Evidence is emerging that basophils mediate non-redundant roles in allergic disease and, unsuspectingly, are implicated in a variety of other pathologies [e.g., myocardial infarction, autoimmunity, chronic obstructive pulmonary disease, fibrosis, cancer, etc.]. Recent findings strengthen the notion that these cells mediate protection from parasitic infections, whereas related studies implicate basophils promoting wound healing. Central to these functions is the substantial evidence that human and mouse basophils are increasingly implicated as important sources of IL-4 and IL-13. Nonetheless, much remains unclear regarding the role of basophils in pathology vs. homeostasis. In this review, we discuss the dichotomous (protective and/or harmful) roles of basophils in a wide spectrum of non-allergic disorders.

Eosinophilic Airway Diseases: From Pathophysiological Mechanisms to Clinical Practice.

Eosinophils play a key role in airway inflammation in many diseases, such as allergic and non-allergic asthma, chronic rhinosinusitis with nasal polyps, and chronic obstructive pulmonary disease. In these chronic disabling conditions, eosinophils contribute to tissue damage, repair, remodeling, and disease persistence through the production a variety of mediators. With the introduction of biological drugs for the treatment of these respiratory diseases, the classification of patients based on clinical characteristics (phenotype) and pathobiological mechanisms (endotype) has become mandatory. This need is particularly evident in severe asthma, where, despite the great scientific efforts to understand the immunological pathways underlying clinical phenotypes, the identification of specific biomarkers defining endotypes or predicting pharmacological response remains unsatisfied. In addition, a significant heterogeneity also exists among patients with other airway diseases. In this review, we describe some of the immunological differences in eosinophilic airway inflammation associated with severe asthma and other airway diseases and how these factors might influence the clinical presentation, with the aim of clarifying when eosinophils play a key pathogenic role and, therefore, represent the preferred therapeutic target.

Early and Late Response and Glucocorticoid-Sparing Effect of Belimumab in Patients with Systemic Lupus Erythematosus with Joint and Skin Manifestations: Results from the Belimumab in Real Life Setting Study-Joint and Skin (BeRLiSS-JS).

AIM: To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. METHODS: All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (<2.6) and LDA (≥2.6, ≤3.2), CLASI = 0, 1, and improvement in DAS28 and CLASI indices ≥20%, ≥50%, and ≥70% were evaluated at 6, 12, 24, and 36 months. RESULTS: DAS28 < 2.6 was achieved by 46%, 57%, and 71% of patients at 6, 12, and 24 months, respectively. CLASI = 0 was achieved by 36%, 48%, and 62% of patients at 6, 12, and 24 months, respectively. Belimumab showed a glucocorticoid-sparing effect, being glucocorticoid-free at 8.5%, 15.4%, 25.6%, and 31.6% of patients at 6, 12, 24, and 36 months, respectively. Patients achieving DAS-LDA and CLASI-50 at 6 months had a higher probability of remission at 12 months compared with those who did not (p = 0.034 and p = 0.028, respectively). CONCLUSIONS: Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.

Water from Nitrodi's Spring Induces Dermal Fibroblast and Keratinocyte Activation, Thus Promoting Wound Repair in the Skin: An In Vitro Study.

The Romans knew of Nitrodi's spring on the island of Ischia more than 2000 years ago. Although the health benefits attributed to Nitrodi's water are numerous, the underlying mechanisms are still not understood. In this study, we aim to analyze the physicochemical properties and biological effects of Nitrodi's water on human dermal fibroblasts to determine whether the water exerts in vitro effects that could be relevant to skin wound healing. The results obtained from the study indicate that Nitrodi's water exerts strong promotional effects on dermal fibroblast viability and a significant stimulatory activity on cell migration. Nitrodi's water induces alpha-SMA expression in dermal fibroblasts, thus promoting their transition to myofibroblast-protein ECM deposition. Furthermore, Nitrodi's water reduces intracellular reactive oxygen species (ROS), which play an important role in human skin aging and dermal damage. Unsurprisingly, Nitrodi's water has significant stimulatory effects on the cell proliferation of epidermal keratinocytes and inhibits the basal ROS production but enhances their response to the oxidative stress caused by external stimuli. Our results will contribute to the development of human clinical trials and further in vitro studies to identify inorganic and/or organic compounds responsible for pharmacological effects.

Immunogenicity and Safety of Anti-SARS-CoV-2 mRNA Vaccines in a Cohort of Patients with Hereditary Angioedema.

Many factors may trigger hereditary angioedema (HAE) attacks. This study aims to gain insights into the benefits and potential risks of COVID-19 vaccination in HAE patients, focusing particularly on the possibility of triggering attacks. We enrolled 31 patients with HAE undergoing two doses of the SARS-CoV-2 mRNA Comirnaty-BioNTech/Pfizer vaccine. To evaluate the possible influence of the vaccine on disease control and attack frequency, we administered the angioedema control test (AECT) 4-week version before (T0), 21 days after the first dose (T1), and between 21 and 28 days after the second dose (T2). Despite 5 patients (16.1%) experiencing attacks within 72 h of the first dose administration, no significant variation in attack frequency was observed before and after vaccination [F(2,60) = 0.123; p = 0.799]. In addition, patients reported higher AECT scores at T1 and T2 compared to T0 [F(2,44) = 6.541; p < 0.05; post hoc p < 0.05)], indicating that the disease was rather more controlled after vaccinations than in the previous period. All patients showed a positive serological response to the vaccine without significant differences from healthy controls (U = 162; p = 0.062). These observations suggest that the vaccine administration is safe and effective in HAE patients.