Effects of Ultra-Weak Fractal Electromagnetic Signals on Malassezia furfur.

Malassezia spp. are dimorphic, lipophilic fungi that are part of the normal human cutaneous commensal microbiome. However, under adverse conditions, these fungi can be involved in various cutaneous diseases. In this study, we analysed the effect of ultra-weak fractal electromagnetic (uwf-EMF) field exposure (12.6 nT covering 0.5 to 20 kHz) on the growth dynamics and invasiveness of M. furfur. The ability to modulate inflammation and innate immunity in normal human keratinocytes was also investigated. Using a microbiological assay, it was possible to demonstrate that, under the influence of uwf-EMF, the invasiveness of M. furfur was drastically reduced (d = 2.456, p < 0.001), while at the same time, its growth dynamic after 72 h having been in contact with HaCaT cells both without (d = 0.211, p = 0.390) and with (d = 0.118, p = 0.438) uwf-EM exposure, were hardly affected. Real-time PCR analysis demonstrated that a uwf-EMF exposure is able to modulate human-ß-defensin-2 (hBD-2) in treated keratinocytes and at the same time reduce the expression of proinflammatory cytokines in human keratinocytes. The findings suggest that the underlying principle of action is hormetic in nature and that this method might be an adjunctive therapeutic tool to modulate the inflammatory properties of Malassezia in related cutaneous diseases. The underlying principle of action becomes understandable by means of quantum electrodynamics (QED). Given that living systems consist mainly of water and within the framework of QED, this water, as a biphasic system, provides the basis for electromagnetic coupling. The oscillatory properties of water dipoles modulated by weak electromagnetic stimuli not only affect biochemical processes, but also pave the way for a more general understanding of the observed nonthermal effects in biota.

Effects of ultra-weak fractal electromagnetic signals on the aqueous phase in living systems: a test-case analysis of molecular rejuvenation markers in fibroblasts.

Skin aging is primarily associated with the alterations in dermal extracellular matrix, in particular a decrease in collagen type-1 content. Recent studies have shown that collagen-degrading matrix metalloproteinase (MMP-1) is produced by fibroblasts in response to chronoaging, which in human dermal fibroblasts leads to the release of proinflammatory cytokines. Past studies showed that anti-inflammatory capabilities could be induced via non-chemical means. One of these methods makes use of ultra-weak fractal electromagnetic (uwf-EM) signals. Such ultra-/very-low frequency (U/VLF) signals (few nT in intensity and within 0.5-30 kHz) interact with aqueous solutions in living systems. The fractal nature of such EM-signals relates to the self-similar property by which a "cut-out" and magnified piece of this signal reveals again the original. Thus, the aim of this study is twofold, to i) investigate the extent of this modulating effect using Human Dermal Fibroblasts (HDF)-cells, and ii) analyse molecular rejuvenation markers therein. We could demonstrate that a 10 min uwf-EM exposure (prior to incubation) increases type-1 collagen and modulates elastin in human fibroblasts cultured up to 96 h, while at the same time reduces IL-6, TNF-α and MMP-1 (the later three being statistically significant). Such up- respectively down-regulation of corresponding genes are strong indicators of an EM-induced hormetic effect that influences the epigenomic landscape of HDFs. In the Appendix, we present, in the framework of Quantum Field Theory (QFT), water as a biphasic liquid and how its coherent fraction can be affected by uwf-EM signals while at the same time resolving the "kT paradox".

Transduction of DNA information through water and electromagnetic waves.

The experimental conditions by which electromagnetic signals (EMS) of low frequency can be emitted by diluted aqueous solutions of some bacterial and viral DNAs are described. That the recorded EMS and nanostructures induced in water carry the DNA information (sequence) is shown by retrieval of that same DNA by classical PCR amplification using the TAQ polymerase, including both primers and nucleotides. Moreover, such a transduction process has also been observed in living human cells exposed to EMS irradiation. These experiments suggest that coherent long-range molecular interaction must be present in water to observe the above-mentioned features. The quantum field theory analysis of the phenomenon is presented in this article.

Biologics for chronic spontaneous urticaria: toward a personalized treatment.

INTRODUCTION: Chronic spontaneous urticaria (CSU) is characterized by the recurrent occurrence of short-lived wheals with or without angioedema for more than 6 weeks. Although its pathogenesis is not completely defined, several mechanisms seem involved, including autoimmunity and autoallergy with complement and coagulation activation. Various biologics are currently available or under investigation to counteract different CSU pathomechanisms. AREAS COVERED: The recent literature dealing with biologics in the treatment of CSU was screened and analyzed; the different treatments were divided into anti-IgE and other than anti-IgE biologics. The latter were subdivided according to their target mechanisms. EXPERT OPINION: Biologic drugs exert their effects in a very precise and specific manner. A majority of patients (arguably those with type I disease) respond to anti-IgE treatment. Others, possibly with type IIa disease, show a slow response to anti-IgE drugs. Things are much more complicated in anti-IgE-refractory patients. Some respond well to nonspecific immune suppressors, such as corticosteroids and cyclosporin suggesting that an immune-mediated pathogenic mechanism, not involving the high-affinity IgE receptor, is probably active. Several ongoing studies are evaluating biologics and small molecules counteracting other pathomechanisms, including anti-receptor biologics, Bruton tyrosine kinase (BTK) inhibitors, mast cell targets, and specific cytokines.

JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy.

Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment; outcomes at 4, 7, 14, and 28 days; oxygen support requirements; clinical status; and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up; of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.

Heparin and tranexamic Acid therapy may be effective in treatment-resistant chronic urticaria with elevated d-dimer: a pilot study.

BACKGROUND: Chronic urticaria (CU) patients often present activation of the coagulation cascade and fibrinolysis whose markers correlate with disease severity. AIM: We evaluated whether CU patients with elevated plasma D-dimer have a poor response to antihistamines, and anticoagulation and inhibition of fibrinolysis may be beneficial in these patients. METHODS: Sixty-eight consecutive patients with CU were prescribed cetirizine 10 mg daily for 2 weeks; plasma D-dimer was measured. Non-responders were given cetirizine 30 mg daily for 1 week and subsequently, in case of failure, systemic steroids. Patients with persistent uncontrolled CU and elevated D-dimer plasma levels were offered subcutaneous nadroparin 11,400 IU once a day and oral tranexamic acid 1 g three times a day for 2 weeks. RESULTS: D-dimer levels were elevated in 14/68 (20.6%) patients (range 306-7,317 ng/ml; normal values <278 ng/ml) and were associated with a more severe disease. Twelve of 14 patients with elevated D-dimer levels did not respond to antihistamine treatment (p = 0.0001). On the whole, 14 patients reported a poor or absent response to cetirizine 10 mg daily and only 1 of these responded satisfactorily to cetirizine 30 mg daily. Eight patients with elevated D-dimer and whose disease was not satisfactorily controlled by prednisone received nadroparin and tranexamic acid. A marked improvement of symptoms was observed in 5/8 cases. CONCLUSION: Our findings indicate that CU patients with elevated D-dimer often present a more severe disease with reduced response to antihistamines. Based on this short pilot study, some of these patients may benefit from treatment with nadroparin and tranexamic acid.

Late Worsening of COVID-19 Pneumonia: Successful Treatment with Ruxolitinib and Steroid.

We describe the case of a patient hospitalized for the second time in a month due to delayed worsening of lung lesions in COVID-19 infection without bacterial superinfection. He was treated with hydroxychloroquine, IV dexamethasone and ruxolitinib with rapid improvement of respiratory failure; 1 month after the second discharge, maintaining low-dose oral prednisone, lung consolidations were significantly reduced on control CT. LEARNING POINTS: Modulation of immune over-response in late phases of COVID-19 can influence global outcome.Ruxolitinib and IV steroids can reverse the inflammatory process and lung lesions.

Expression of tissue factor by eosinophils in patients with chronic urticaria.

BACKGROUND: Although several cases of chronic urticaria (CU) are currently regarded as autoimmune in origin, associated with histamine-releasing autoantibodies, an activation of blood coagulation via tissue factor (TF) and a strong expression of TF in lesional skin have been described. Eosinophils, which are involved in CU skin lesions, have recently been demonstrated as the major source of TF in human blood. We assessed whether eosinophils are the cellular source of TF in CU skin lesions. METHODS: Twenty patients with severe CU were studied. Skin biopsy specimens were taken from wheals. The control group consisted of specimens of perilesional normal skin from different types of skin tumours (10) and various skin disorders with non-eosinophilic infiltrates, including leukocytoclastic vasculitis (7), lichen planus (8) and mastocytosis (3). TF expression was evaluated by immunohistochemical methods using an anti-TF monoclonal antibody. Co-localization of TF and eosinophil cationic protein, a classic cell marker of eosinophils, was investigated by double-staining studies using 2 specific monoclonal antibodies in the 4 specimens showing the highest TF reactivity scores. RESULTS: All specimens from patients with CU clearly showed TF expression that was absent in all normal control specimens (p = 0.0001) and in the skin disorders with non-eosinophilic infiltrates (p = 0.001-0.0001). The double-staining experiments for TF and eosinophil cationic protein clearly showed that the TF-positive cells were eosinophils. CONCLUSIONS: Eosinophils are the main source of TF in CU lesional skin. This finding highlights the role of these cells in the pathophysiology of CU and might pave the way for new therapeutic strategies.

Water and autocatalysis in living matter.

Water plays a fundamental role in living organisms. Liquid water includes coherence domains (CD) where all molecules oscillate in unison in tune with a self-trapped electromagnetic field at a well-defined frequency. The coherent oscillations produce an ensemble of quasi-free electrons, able to collect noise energy from the environment and transform it into high-grade coherent energy in the form of electron vortices. This high-grade energy may activate the biomolecules resonating with the water CD. In this way, water CDs become dissipative structures in the sense of Prigogine and Froehlich, such that they are able to oscillate and coherence among them can be established. Thus, autocatalysis in living matter is made possible.

Angioedema and emergency medicine: From pathophysiology to diagnosis and treatment.

Angioedema is a self-limiting edema of the subcutaneous or submucosal tissues due to localised increase of microvascular permeability whose mediator may be histamine or bradykinin. Patients present to emergency department when angioedema involves oral cavity and larynx (life-threatening conditions) or gut (mimicking an acute abdomen). After initial evaluation of consciousness and vital signs to manage breathing and to support circulation if necessary, a simple approach can be applied for a correct diagnosis and treatment. Forms of edema such as anasarca, myxedema, superior vena cava syndrome and acute dermatitis should be ruled out. Then, effort should be done to differentiate histaminergic from non-histaminergic angioedema. Concomitant urticaria and pruritus suggest a histaminergic origin. Exposure to allergens and drugs (mainly ACE inhibitors and non steroidal anti-inflammatory drugs) should be investigated as well as a family history of similar symptoms. Allergic histaminergic angioedema has a rapid course (minutes) whereas non histaminergic angioedema is slower (hours). Since frequently the intervention needs to be immediate, the initial diagnosis is only clinical. However, laboratory tests can be subsequently confirmatory. Allergic angioedema is sensitive to standard therapies such as epinephrine, glucocorticoids and antihistamines whereas non histaminergic angioedema is often resistant to these drugs. Therapeutic options for angioedema due C1-inhibitor deficiencies are C1-inhibitor concentrates, icatibant and ecallantide. If these drugs are not available, fresh frozen plasma can be considered. All these medications have been used also in ACE inhibitor-induced angioedema with variable results thus they are not currently recommended whereas experts agree on the discontinuation of the causative drug.

Chronic urticaria: a disease at a crossroad between autoimmunity and coagulation.

Chronic urticaria (CU), defined as recurrence of wheals with or without angioedema for more than 6 weeks, is a quite common disease that may severely worsen the quality of life. Studies carried out during the last 2 decades have demonstrated an autoimmune pathogenesis mediated by functionally active autoantibodies to the high affinity IgE receptor (FcepsilonRI) or to IgE which are able to induce histamine release from basophils and mast cells. However, such mechanism can be detected in less than 50% of patients only. The present article reviews recent findings showing an additional pathogenic mechanisms in CU patients: activation of the coagulation cascade resulting in thrombin production. Thrombin is a serine protease which may play a key role in urticaria, being able to induce edema through an increase in vascular permeability, mast cell activation and degranulation, and to induce the production of the anaphylotoxin C5a. Such mechanism seems to be active in the majority of CU patients, however their relationship with anti-FcepsilonRI or anti-IgE autoantibodies is still matter of research.

Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions.

BACKGROUND AND OBJECTIVES: This study explored variations in the clinical manifestations of intravascular lymphoma (IVL) on the bases of the association with hemophagocytosis and the country where the diagnosis was made. DESIGN AND METHODS: The clinical features of 50 Western patients with IVL were compared with those of 123 patients with IVL diagnosed in Eastern countries (87 diagnosed in Japan and 36 in other Asian countries), previously reported in English literature, and collected by an electronic bibliographic search. RESULTS: Hemophagocytosis was absent in Western patients, but reported in 38 (44%) Japanese patients (p=0.00001) and in seven (19%) patients from other Asian countries (p=0.002). No clinical differences were evident between patients with hemophagocytosis-negative IVL diagnosed in Western countries, Japan and other Asian Countries. Conversely, Japanese and non-Japanese patients with hemophagocytosis-related IVL more frequently had stage IV disease, fever, hepato-splenic involvement, marrow infiltration, dyspnea, anemia, and thrombocytopenia, and rarely exhibited cutaneous or central nervous system involvement. Lymph node and peripheral blood involvement was uncommon in all subgroups. In Western patients, anthracycline-based chemotherapy was associated with a 52% remission rate, and a 2-year overall survival of 46%. INTERPRETATION AND CONCLUSIONS: The clinical features of IVL vary according to the association with hemophagocytosis, regardless of the country in which the diagnosis is made. Western, Japanese and other Asian patients with hemophagocytosis-negative IVL display similar clinical characteristics and should be considered as having classical IVL. Patients with hemophagocytosis-related IVL show significantly different clinical features. Both forms have a poor prognosis. Extensive molecular studies are needed to explore whether these clinical differences might reflect discordant biological entities within IVL.

Chronic urticaria: a focus on pathogenesis.

Chronic urticaria is a spontaneous or inducible group of diseases characterized by the occurrence of wheals (and, in about half of cases, angioedema) for more than 6 weeks. These are rather frequent conditions that may severely affect patients' quality of life and sometimes represent a challenge for doctors as well. The causes of chronic urticaria are still poorly defined, although there is growing evidence that different biologic systems including immunity, inflammation, and coagulation may take part in the pathomechanism eventually leading to mast cell and basophil degranulation and hence to wheal formation. This review will discuss the main findings that are (slowly) shedding light on the pathogenesis of this disorder.

Emerging drugs for chronic urticaria.

Chronic urticaria (CU), with or without angioedema, is a frequent disorder defined as the occurrence of pruritic wheals for > 6 weeks. Studies carried out in the last two decades showed that the origin of the disease is autoimmune in up to 50% of cases. Currently available treatments include antihistamines, corticosteroids and ciclosporin; recently, leukotriene receptor antagonists proved effective in a subset of patients as well. For patients with an unremitting and extremely severe disease unresponsive to standard treatments, plasmapheresis and immunosuppressive drugs have been successfully attempted. Recent findings that the autologous plasma skin test scores positive in nearly all patients and that plasmas from patients with both autoimmune and 'idiopathic' chronic urticaria are frequently characterised by signs of thrombin activation (plasma levels of prothrombin fragment F(1.2) are significantly increased) suggest that clotting cascade might be somehow involved in the pathogenesis of CU. These findings put under a new light some rather sparse studies of the effect of drugs active on the coagulation system (heparin and oral anticoagulants) in patients with CU.

Diagnosis of latex hypersensitivity: comparison of different methods.

A standardized diagnostic protocol for latex allergy is still lacking, although latex-related manifestations are a common health problem especially among health-care workers and patients with spina bifida. The present study was aimed to compare different in vivo (skin prick test, patch test, use test) and in vitro (specific IgE determination by CAP-Rast, basophil histamine release assay, immunoblot) methods to diagnose latex sensitization in 47 health care workers reporting latex-related manifestations. According to the established criteria, 20 subjects (42.5%) were considered as truly sensitized to latex, 18 with type I and 2 with type IV hypersensitivity. Skin prick test displayed the highest diagnostic efficiency, having higher sensitivity and specificity than specific IgE determination and use test. Patch test with rubber chemicals had a low sensitivity, but a good specificity. Basophil histamine release and immunoblot showed low sensitivity and specificity. A combination of clinical history and skin prick test should be used in order to diagnose latex allergy, except in those subjects reporting life-threatening reactions, in which in vitro specific IgE determination must be preferred. Patch testing with rubber chemicals should be reserved to selected cases. Basophil histamine release and immunoblotting can be performed for research purpose, but cannot be recommended for routine diagnostic use.

Increased risk of venous thromboembolism in patients with bullous pemphigoid. The INVENTEP (INcidence of VENous ThromboEmbolism in bullous Pemphigoid) study.

Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59% females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95% confidence interval [CI]: 11.1-23.2), 56.7 (95%CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95%CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95%CI: 2.73-5.65), higher during the acute phase (14.86, 95%CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95%CI: 1.07-7.04) for ABSIS > 48 vs ABSIS < 28, and 2.56 (95%CI: 1.00-6.70) in patients with ≥ 2 concomitant risk factors. In conclusion, BP patients have a 15-fold increased VTE risk during acute phase, proportional to disease severity and heightened by concomitant risk factors.