A preliminary study of phosphodiesterases and adenylyl cyclase signaling pathway on red blood cell deformability of sickle cell patients

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic anemia, intravascular hemolysis, and the occurrence of vaso-occlusive crises due to the mechanical obstruction of the microcirculation by poorly deformable red blood cells (RBCs). RBC deformability is a key factor in the pathogenesis of SCD, and is affected by various factors. In this study, we investigated the effects of adenylyl cyclase (AC) signaling pathway modulation and different phosphodiesterase (PDE) modulatory molecules on the deformability and mechanical stress responses of RBC from SCD patients (HbSS genotype) by applying 5 Pa shear stress with an ektacytometer (LORRCA). We evaluated RBC deformability before and after the application of shear stress. AC stimulation with Forskolin had distinct effects on RBC deformability depending on the application of 5 Pa shear stress. RBC deformability was increased by Forskolin before shear stress application but decreased after 5 Pa shear stress. AC inhibition with SQ22536 and protein kinase A (PKA) inhibition with H89 increased RBC deformability before and after the shear stress application. Non-selective PDE inhibition with Pentoxifylline increased RBC deformability. However, modulation of the different PDE types had distinct effects on RBC deformability, with PDE1 inhibition by Vinpocetine increasing deformability while PDE4 inhibition by Rolipram decreased RBC deformability after the shear stress application. The effects of the drugs varied greatly between patients suggesting some could benefit from one drug while others not. Developing drugs targeting the AC signaling pathway could have clinical applications for SCD, but more researches with larger patient cohorts are needed to identify the differences in the responses of sickle RBCs

Heterogeneity of pollen food allergy syndrome in seven Southern European countries: The @IT.2020 multicenter study

Background Pollen food allergy syndrome (PFAS) is a frequently underdiagnosed disease due to diverse triggers, clinical presentations, and test results. This is especially relevant in geographic areas with a broad spectrum of pollen sensitization, such as Southern Europe. Objectives To elucidate similarities and differences of PFAS in nine Southern European centers and identify associated characteristics and unique markers of PFAS. Methods As part of the @IT.2020 Multicenter Study, 815 patients with seasonal allergic rhinitis (SAR), aged 10-60 years, were recruited in seven countries. They completed questionnaires regarding SAR, comorbidities, family history, and PFAS, and underwent skin prick testing (SPT) and serum IgE testing. Results Of the 815 patients, 167 (20.5%) reported PFAS reactions. Most commonly, eliciting foods were kiwi (58, 34.7%), peach (43, 25.7%), and melon (26, 15.6%). Reported reactions were mostly local (216/319, 67.7%), occurring within 5 min of contact with elicitors (209/319, 65.5%). Associated characteristics included positive IgE to at least one panallergen (profilin, PR-10, or nsLTP) (p = 0.007), maternal PFAS (OR: 3.716, p = 0.026), and asthma (OR: 1.752, p = 0.073). Between centers, heterogeneity in prevalence (Marseille: 7.5% vs. Rome: 41.4%, p < 0.001) and of clinical characteristics was apparent. Cypress played a limited role, with only 1/22 SPT mono-sensitized patients reporting a food reaction (p < 0.073). Conclusions PFAS is a frequent comorbidity in Southern European SAR patients. Significant heterogeneity of clinical characteristics in PFAS patients among the centers was observed and may be related to the different pollen sensitization patterns in each geographic area. IgE to panallergen(s), maternal PFAS, and asthma could be PFAS-associated characteristics

“Whole” vs. “fragmented” approach to EAACI pollen season definitions: A multicenter study in six Southern European cities

Background: The adequate definition of pollen seasons is essential to facilitate a correct diagnosis, treatment choice, and outcome assessment in patients with seasonal allergic rhinitis. A position paper by the European Academy of Allergy and Clinical Immunology (EAACI) proposed season definitions for Northern and Middle Europe. Objective: To test the pollen season definitions proposed by EAACI in six Mediterranean cities for seven pollen taxa. Methods: As part of the @IT.2020 multi-center study, pollen counts for Poaceae, Oleaceae, Fagales, Cupressaceae, Urticaceae (Parietaria spp.), and Compositae (Ambrosia spp., Artemisia spp.) were collected from January 1 to December 31, 2018. Based on these data, pollen seasons were identified according to EAACI criteria. A unified monitoring period for patients in AIT trials was created and assessed for feasibility. Results: The analysis revealed a great heterogeneity between the different locations in terms of pattern and length of the examined pollen seasons. Further, we found a fragmentation of pollen seasons in several segments (max. 8) separated by periods of low pollen counts (intercurrent periods). Potential monitoring periods included often many recording days with low pollen exposure (max. 341 days). Conclusion: The Mediterranean climate leads to challenging pollen exposure times. Monitoring periods for AIT trials based on existing definitions may include many intermittent days with low pollen concentrations. Therefore, it is necessary to find an adapted pollen season definition as individual solution for each pollen and geographical area

Exhaled Breath Analysis in Diagnosis of Malignant Pleural Mesothelioma: Systematic Review

Malignant pleural mesothelioma (MPM) is mainly related to previous asbestos exposure. There is still dearth of information on non-invasive biomarkers to detect MPM at early stages. Human studies on exhaled breath biomarkers of cancer and asbestos-related diseases show encouraging results. The aim of this systematic review was to provide an overview on the current knowledge about exhaled breath analysis in MPM diagnosis. A systematic review was conducted on MEDLINE (PubMed), EMBASE and Web of Science databases to identify relevant studies. Quality assessment was done by the Newcastle-Ottawa Scale. Six studies were identified, all of which showed fair quality and explored volatile organic compounds (VOC) based breath profile using Gas Chromatography Coupled to Mass Spectrometry (GC-MS), Ion Mobility Spectrometry Coupled to Multi-capillary Columns (IMS-MCC) or pattern-recognition technologies. Sample sizes varied between 39 and 330. Some compounds (i.e, cyclohexane, P3, P5, P50, P71, diethyl ether, limonene, nonanal, VOC IK 1287) that can be indicative of MPM development in asbestos exposed population were identified with high diagnostic accuracy rates. E-nose studies reported breathprints being able to distinguish MPM from asbestos exposed individuals with high sensitivity and a negative predictive value. Small sample sizes and methodological diversities among studies limit the translation of results into clinical practice. More prospective studies with standardized methodologies should be conducted on larger populations.status: publishe

Coexistence of Nickel Allergy and Palmoplantar Pustulosis

Nickel is a very common metal and is a common cause of allergic contact dermatitis. Although nickel allergy often causes allergic contact dermatitis at contact areas, oral exposure to nickel may cause various skin reactions and systemic disorders. Herein, we aimed to draw attention to the different presentations of nickel allergy by presenting our case with palmoplantar pustulosis with accompanying nickel allergy

Proteomic Analysis of the Role of the Adenylyl Cyclase&ndash;cAMP Pathway in Red Blood Cell Mechanical Responses

Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p &lt; 0.05). Capillary SS slightly increased the phosphorylation of RBC cytoskeletal proteins. Tyrosine phosphorylation was significantly elevated by the modulation of the cAMP/PKA pathway (p &lt; 0.05), while serine phosphorylation significantly decreased as a result of the inhibition of PDE (p &lt; 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs

Proteomic Analysis of the Role of the Adenylyl Cyclase–cAMP Pathway in Red Blood Cell Mechanical Responses

Red blood cell (RBC) deformability is modulated by the phosphorylation status of the cytoskeletal proteins that regulate the interactions of integral transmembrane complexes. Proteomic studies have revealed that receptor-related signaling molecules and regulatory proteins involved in signaling cascades are present in RBCs. In this study, we investigated the roles of the cAMP signaling mechanism in modulating shear-induced RBC deformability and examined changes in the phosphorylation of the RBC proteome. We implemented the inhibitors of adenylyl cyclase (SQ22536), protein kinase A (H89), and phosphodiesterase (PDE) (pentoxifylline) to whole blood samples, applied 5 Pa shear stress (SS) for 300 s with a capillary tubing system, and evaluated RBC deformability using a LORRCA MaxSis. The inhibition of signaling molecules significantly deteriorated shear-induced RBC deformability (p p p < 0.05). AC is the core element of this signaling pathway, and PDE works as a negative feedback mechanism that could have potential roles in SS-induced RBC deformability. The cAMP/PKA pathway could regulate RBC deformability during capillary transit by triggering significant alterations in the phosphorylation state of RBCs