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.

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.

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.

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".

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 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.

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.

Current challenges and controversies in the management of chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is characterized by the recurrence of itchy wheals for at least 6 weeks, affects up to 1% of the general population and may severely impair quality of life. H1-antihistamines are the cornerstones of treatment, but in about 10% of cases they fail to control the disease even at higher than licensed doses. In these patients, short courses of oral steroids may induce a remission in about 50% of cases. Omalizumab, a monoclonal anti-IgE, is effective in antihistamine-unresponsive patients although optimal treatment duration needs to be defined. Immunosuppressive treatment with cyclosporine is also effective in the majority of antihistamine-resistant chronic spontaneous urticaria (CSU) patients, but its use is limited by potential side effects. In refractory patients, other approaches include intravenous immunoglobulin, rituximab, dapsone and anticoagulants. The present review looks with particular interest at the prevalence of treatment failures with the main third-level treatments (corticosteroids, omalizumab and cyclosporine) and discusses them in light of the possible different pathogenic mechanisms underlying chronic spontaneous urticaria.

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.

Activation of Blood Coagulation in Two Prototypic Autoimmune Skin Diseases: A Possible Link with Thrombotic Risk.

Coagulation activation has been demonstrated in two prototypic autoimmune skin diseases, chronic autoimmune urticaria and bullous pemphigoid, but only the latter is associated with increased thrombotic risk. Two markers of coagulation activation (prothrombin fragment F1+2 and fibrin fragment D-dimer) were measured by immunoenzymatic methods in plasma samples from 30 patients with active chronic autoimmune urticaria, positive for autologous serum skin test, 30 patients with active bullous pemphigoid and 30 healthy subjects. In skin biopsies, tissue factor expression was evaluated by both immunohistochemistry and in situ hybridization. F1+2 and D-dimer levels were higher in active chronic autoimmune urticaria (276.5±89.8 pmol/L and 5.56±4.40 nmol/L, respectively) than in controls (145.2±38.0 pmol/L and 1.06±0.25 nmol/L; P=0.029 and P=0.011) and were much higher in active bullous pemphigoid (691.7±318.7 pmol/L and 15.24±9.09 nmol/L, respectively) (P<0.0001). Tissue factor positivity was evident in skin biopsies of both disorders with higher intensity in bullous pemphigoid. F1+2 and D-dimer, during remission, were markedly reduced in both disorders. These findings support the involvement of coagulation activation in the pathophysiology of both diseases. The strong systemic activation of coagulation in bullous pemphigoid may contribute to increase the thrombotic risk and provides the rationale for clinical trials on anticoagulant treatments in this disease.

Evaluation of a method based on coherence in aqueous systems and resonance-based isotherapeutic remedy in the treatment of chronic psoriasis vulgaris.

Psoriasis is a chronic skin disorder that exhibits three main features: lymphocytic infiltration into the dermis and epidermis, uncontrolled proliferation and abnormal differentiation of keratinocytes. In this study we have evaluated the effect of treatment with WHITE Holographic Bioresonance Method and a resonance-based isotherapeutic remedy on patients affected by chronic psoriasis vulgaris. The WHITE Holographic Bioresonance Method is based on the principles of electrodynamic coherence. By exploiting the phenomenon of bio-resonance, it uses a transfer plate to produce resonance- and light-based isotherapeutic coherent acqueous remedies and gels that emit coherent oscillations which "imprint" the area of psoriasis-affected skin. Levels of proinflammatory cytokines have been evaluated in the plasma of psoriatic patients treated with isotherapeutic remedies. The obtained results demonstrate a positive effect on the natural course of the disease and matched the results obtained by psoriatic patients treated with narrow band UVB. A significant reduction in plasma levels of cytokines involved in pathogenesis of psoriasis has been observed. Our findings may suggest that WHITE Holographic Bioresonance method used in combination with resonance-based isotherapeutic remedy could well be a new useful treatment option for patients with limited psoriatic plaques.

Enhanced tissue factor expression by blood eosinophils from patients with hypereosinophilia: a possible link with thrombosis.

Thrombotic risk is increased in eosinophil-mediated disorders, and several hypotheses have been proposed to link eosinophilia and thrombosis. In particular, eosinophils have been described as source of tissue factor (TF), the main initiator of blood coagulation; however, this aspect is still controversial. This study was aimed to evaluate whether TF expression varies in eosinophils isolated from normal subjects and patients with different hypereosinophilic conditions. Eosinophils were immunologically purified from peripheral blood samples of 9 patients with different hypereosinophilic conditions and 9 normal subjects. Western blot analysis and real-time polymerase chain reaction (RT-PCR) were performed to test eosinophil TF expression. For comparison, TF expression was evaluated in monocytes from blood donors and in human endothelial (ECV304) and fibroblast (IMR90) cell lines. Western blot analysis revealed a major band of 47,000 corresponding to native TF in homogenates of purified eosinophils with a higher intensity in the 9 patients than in the 9 controls (p<0.0001). According to RT-PCR cycle threshold (Ct), TF gene expression was higher in eosinophils from patients than in those from controls, median (range) 35.10 (19.45-36.50) vs 37.17 (35.33-37.87) (p = 0.002), and was particularly abundant in one patient with idiopathic hypereosinophilic syndrome and ischemic heart attacks (Ct: 19.45). TF gene expression was moderate in monocytes, Ct: 31.32 (29.82-33.49) and abundant in endothelial cells, Ct: 28.70 (27.79-29.57) and fibroblasts, Ct: 22.77 (19.22-25.05). Our results indicate that human blood eosinophils contain variable amounts of TF. The higher TF expression in patients with hypereosinophilic disorders may contribute to increase the thrombotic risk.

Salvage therapy with high dose Intravenous Immunoglobulins in acquired Von Willebrand Syndrome and unresponsive severe intestinal bleeding.

A 91-year-old woman affected with acquired Von Willebrand (VW) syndrome and intestinal angiodysplasias presented with severe gastrointestinal bleeding (hemoglobin 5 g/dl). Despite replacement therapy with VW factor/factor VIII concentrate qid, bleeding did not stop (eleven packed red blood cell units were transfused over three days). High circulating levels of anti-VW factor immunoglobulin M were documented immunoenzimatically. Heart ultrasound showed abnormalities of the mitral and aortic valves with severe flow alterations. When intravenous immunoglobulins were added to therapy, prompt clinical and laboratory responses occurred: complete cessation of bleeding, raise in hemoglobin, VW factor antigen, VW ristocetin cofactor and factor VIII levels as well as progressive reduction of the anti-VWF autoantibody levels.

Treatment of chronic urticaria.

Second-generation antihistamines are unquestionably the first-line treatment for chronic urticaria and can be used at higher than licensed doses if normal doses fail to control the disease. A short course of oral corticosteroids should be considered for patients not responding to antihistamines before trying other immunosuppressive drugs. Ciclosporin is effective in most antihistamine-resistant patients who require long-term corticosteroid treatments to control their disease. Omalizumab is effective in most subsets of chronic urticaria sufferers who do not respond to other treatments but its high cost represents a limitation to its widespread use.

Autoantibodies to coagulation factors: from pathophysiology to diagnosis and therapy.

Autoantibodies may develop against coagulation factors altering their function or promoting their rapid clearance. In non-congenitally deficient patients, they are usually in association with autoimmune diseases, malignancies, pregnancy or advanced age. The possible development of coagulation factor autoantibodies should be considered when a patient presents with bleeding symptoms without any prior bleeding diathesis. The most common disorder associated with coagulation factor autoantibodies is acquired factor VIII deficiency, which is characterized by hemorrhages involving soft tissues, muscles and skin; hemarthroses are less frequent than in the inherited form. Acquired deficiencies of von Willebrand factor and factor XIII due to autoantibodies are emerging conditions. Autoantibodies to the other coagulation factors may be associated with a wide spectrum of clinical manifestations ranging from minimal or no bleeding to life-threatening conditions. The diagnostic approach begins with global coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). In case of prolonged times, mixing studies (typically using normal plasma in a 1:1 proportion) should be performed. Specific factor and inhibitor assays, assessment of lupus anticoagulant and eventually enzyme immunoassays for specific anti-factor antibodies complete the evaluation. A prompt diagnosis of specific coagulation factor inhibitors is mandatory for starting an appropriate treatment aimed at overcoming the deficient factor, in case of bleeding, and, if possible, at the suppression of the autoantibody's production.

Treatment of refractory chronic urticaria: current and future therapeutic options.

Chronic urticaria is a distressing disease that affects up to 1 % of the general population at a time point in life and may severely worsen the quality of life. First-line treatment has been based on antihistamines, and presently relies on the use of non-sedating, second-generation antihistamines; following the recommendations of the recent international guidelines, in patients who do not respond to antihistamines at licensed doses, the daily dosage of these drugs can be increased up to fourfold. Nonetheless, a significant proportion of patients with chronic urticaria remain poorly controlled; in these cases, alternative therapeutic approaches have to be considered. This article critically reviews all of the third- and fourth-line treatment options suggested for patients whose disease is refractory to antihistamines, including systemic corticosteroids, leukotriene receptor antagonists, several different anti-inflammatory drugs (dapsone, sulfasalazine, hydroxychloroquine), various immunosuppressive drugs (calcineurin inhibitors, methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil), intravenous immunoglobulin, and newer treatment options, such as omalizumab and other biologic drugs. In addition, the article examines possible future treatment options based on recent findings about pathogenic mechanisms, and considers the treatment of antihistamine-unresponsive urticaria in special conditions such as children and pregnancy/lactation. The evidence supporting the use of several of the discussed drugs is presently limited and thus insufficient to recommend their routine use; as a consequence, such compounds should be considered only in specific cases and in adequate settings.