SKIN, INFLAMMATION AND SULFUROUS WATERS: WHAT IS KNOWN, WHAT IS BELIEVED

One could argue that balneotherapy and mud therapy would have not lasted 2,000 years or so If they were not effective. No doubt a long history cannot be taken per se as scientific proof of efficacy. Some empiricism is still present in the field: the concept of spa itself is quite confounding, whereas spring waters are used for leisure purposes but also for non-acute patient therapy and late phases of clinical recovery. These confounding elements ultimately feed the opinion of those who aprioristically reject any potential beneficial effect of balneotherapy: instead, it should at least generate questions that deserve scientific answers. Clinical practices sequentially integrating pharmacological therapy with those natural principles for which a sufficient scientific demonstration is available, would probably cut the costs of public health, generating widespread advantages for the community. Recently, it has become evident that mineral waters may have intrinsic pharmacological properties. Of the numerous salts dissolved in thermal waters that might show pharmacological properties, for certain hydrogen sulfide (H2S) contained in sulfurous waters is the one that has obtained greater scientific attention, to which should be added the extensive scientific effort recently dedicated to H2S as a cellular gasotransmitter, independently from its natural sources. Dermatology and cosmetics are among the most studied applications of sulfurous waters, around which, however, some empiricism still confounds opinions: we therefore considered that a state-of-the-art focus on this topic might be timely and useful for future studies

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs

Tracking fibrosis in myeloproliferative neoplasms by CCR2 expression on CD34+ cells

In myeloproliferative neoplasm (MPNs), bone marrow fibrosis - mainly driven by the neoplastic megakaryocytic clone - dictates a more severe disease stage with dismal prognosis and higher risk of leukemic evolution. Therefore, accurate patient allocation into different disease categories and timely identification of fibrotic transformation are mandatory for adequate treatment planning. Diagnostic strategy still mainly relies on clinical/laboratory assessment and bone marrow histopathology, which, however, requires an invasive procedure and frequently poses challenges also to expert hemopathologists. Here we tested the diagnostic accuracy of the detection, by flow cytometry, of CCR2+CD34+ cells to discriminate among MPN subtypes with different degrees of bone marrow fibrosis. We found that the detection of CCR2 on MPN CD34+ cells has a very good diagnostic accuracy for the differential diagnosis between “true” ET and prePMF (AUC 0.892, P<0.0001), and a good diagnostic accuracy for the differential diagnosis between prePMF and overtPMF (AUC 0.817, P=0.0089). Remarkably, in MPN population, the percentage of CCR2-expressing cells parallels the degree of bone marrow fibrosis. In ET/PV patients with a clinical picture suggestive for transition into spent phase, we demonstrated that only patients with confirmed secondary MF showed significantly higher levels of CCR2+CD34+ cells. Overall, flow cytometric CCR2+CD34+ cell detection can be envisioned in support of conventional bone marrow histopathology in compelling clinical scenarios, with the great advantage of being extremely rapid. For patients in follow-up, its role can be conceived as an initial patient screening for subsequent bone marrow biopsy when disease evolution is suspected

Buffering Adaptive Immunity by Hydrogen Sulfide

Abstract: T cell-mediated adaptive immunity is designed to respond to non-self antigens and pathogens through the activation and proliferation of various T cell populations. T helper 1 (Th1), Th2, Th17 and Treg cells finely orchestrate cellular responses through a plethora of paracrine and autocrine stimuli that include cytokines, autacoids, and hormones. Hydrogen sulfide (H2S) is one of these mediators able to induce/inhibit immunological responses, playing a role in inflammatory and autoimmune diseases, neurological disorders, asthma, acute pancreatitis, and sepsis. Both endogenous and exogenous H2S modulate numerous important cell signaling pathways. In monocytes, polymorphonuclear, and T cells H2S impacts on activation, survival, proliferation, polarization, adhesion pathways, and modulates cytokine production and sensitivity to chemokines. Here, we offer a comprehensive review on the role of H2S as a natural buffer able to maintain over time a functional balance between Th1, Th2, Th17 and Treg immunological responses

ROS in platelet biology: Functional aspects and methodological insights

© 2020 by the authors. Reactive oxygen species (ROS) and mitochondria play a pivotal role in regulating platelet functions. Platelet activation determines a drastic change in redox balance and in platelet metabolism. Indeed, several signaling pathways have been demonstrated to induce ROS production by NAPDH oxidase (NOX) and mitochondria, upon platelet activation. Platelet-derived ROS, in turn, boost further ROS production and consequent platelet activation, adhesion and recruitment in an auto-amplifying loop. This vicious circle results in a platelet procoagulant phenotype and apoptosis, both accounting for the high thrombotic risk in oxidative stress-related diseases. This review sought to elucidate molecular mechanisms underlying ROS production upon platelet activation and the effects of an altered redox balance on platelet function, focusing on the main advances that have been made in platelet redox biology. Furthermore, given the increasing interest in this field, we also describe the up-to-date methods for detecting platelets, ROS and the platelet bioenergetic profile, which have been proposed as potential disease biomarkers

A rare case of symptomatic creatine kinase elevation in a patient with rheumatoid arthritis treated with baricitinib

The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance

Current Practice of Imaging-Guided Interventional Procedures in Rheumatic and Musculoskeletal Diseases: Results of a Multinational Multidisciplinary Survey

Objectives: To investigate opinion and routine practice of specialists from different disciplines on imaging techniques for interventional procedures related to rheumatic and musculoskeletal diseases (RMDs). Methods: An English-language questionnaire was developed by an international working group and distributed to health care providers of various disciplines involved in the care of people with RMDs via an online survey tool (SoSci Survey®) from December 2019 to May 2020. Results: A total of 1,105 respondents from 56 countries completed the survey, over 60% of participants were rheumatologists. The majority of respondents (88%) performed interventional procedures in RMDs patients and 90% of them used imaging guidance. Ultrasonography was the most frequently used technique, particularly among rheumatologists. X-ray and computed tomography were mainly used by radiologists. A discrepancy emerged between the importance assigned to certain items such as the availability of a second operator and their actual implementation in clinical practice. Local barriers, lack of resources and facilities were mentioned as the most relevant obstacles in this regard. Lack of training on imaging and/or imaging guided procedures did not emerge as a barrier to perform such interventions; in fact, 19% of respondents performing the procedures indicated not to have received adequate training in this field. Conclusions: This is the first multinational multidisciplinary survey exploring in detail the opinions and practice on imaging guidance for interventional procedures in RMDs. A harmonization of protocols based on international guidelines, along with adequate training programmes and interventions on barriers at national/local levels are the main unmet needs requiring attention

Different waters for different performances: Can we imagine sport-related natural mineral spring waters?

Preserving the hydration status means to balance daily fluids and salt losses with gains, where the losses depend on several physiological and environmental factors. Especially for athletes, these losses could be relevant and negatively influence the performance: therefore, their hydro-saline status must be preserved with personalized pre-and rehydration plans all along the performance period. Scientific literature in this field is mainly dedicated to artificial sport drinks. Different territories in most world areas are rich in drinking natural mineral spring waters with saline compositions that reflect their geological origin and that are used for human health (often under medical prescription). However, scarce scientific attention has been dedicated to the use of these waters for athletes. We therefore reviewed the existing literature from the innovative viewpoint of matching spring water mineral compositions with different athletic performances and their hydro-saline requirements

Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: Potential relevance to prevention of cardiovascular events

Background: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. Method: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 μM] to assess their effects on SA (100 μM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. Results: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 μM) significantly reduced SA-induced inflammation (IL1β, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 μM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. Conclusions: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection

Physical activity and redox balance in the elderly: Signal transduction mechanisms

Reactive Oxygen Species (ROS) are molecules naturally produced by cells. If their levels are too high, the cellular antioxidant machinery intervenes to bring back their quantity to physiological conditions. Since aging often induces malfunctioning in this machinery, ROS are considered an effective cause of age-associated diseases. Exercise stimulates ROS production on one side, and the antioxidant systems on the other side. The effects of exercise on oxidative stress markers have been shown in blood, vascular tissue, brain, cardiac and skeletal muscle, both in young and aged people. However, the intensity and volume of exercise and the individual subject characteristics are important to envisage future strategies to adequately personalize the balance of the oxidant/antioxidant environment. Here, we reviewed the literature that deals with the effects of physical activity on redox balance in young and aged people, with insights into the molecular mechanisms involved. Although many molecular pathways are involved, we are still far from a comprehensive view of the mechanisms that stand behind the effects of physical activity during aging. Although we believe that future precision medicine will be able to transform exercise administration from wellness to targeted prevention, as yet we admit that the topic is still in its infancy