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Protein A from Staphylococcus aureus (Staph A) induces histamine secretion from human basophil leucocytes in the concentration range 10-4-10 μg/ml. This reaction has great similarities to that of antigen or anti-IgE-induced release. It is characterized by a two stage reaction, requires extracellular calcium and is optimal at 37°C. The rate of release is similar to that of IgE-mediated reactions. Histamine release induced by Staph A is inhibited by metabolic inhibitors, drugs which increase intracellular cyclic AMP levels, inhibitors of lipoxygenase pathways and a phospholipase A2 inhibitor. D2O and cytochalasin B which affect microtubules and microfilaments respectively, enhance histamine release induced by Staph A. These results suggest that Staph A-induced release is modulated by intracellular cyclic AMP, arachidonic acid metabolites, requires energy and is enhanced by the disruption of microfilaments and stabilization of microtubules. [ABSTRACT FROM AUTHOR]

COVID-19 infection evokes various systemic alterations that push patients not only towards severe acute respiratory syndrome but causes an important metabolic dysregulation with following multi-organ alteration and potentially poor outcome. To discover novel potential biomarkers able to predict disease's severity and patient's outcome, in this study we applied untargeted lipidomics, by a reversed phase ultra-high performance liquid chromatography-trapped ion mobility mass spectrometry platform (RP-UHPLC-TIMS-MS), on blood samples collected at hospital admission in an Italian cohort of COVID-19 patients (45 mild, 54 severe, 21 controls). In a subset of patients, we also collected a second blood sample in correspondence of clinical phenotype modification (longitudinal population). Plasma lipid profiles revealed several lipids significantly modified in COVID-19 patients with respect to controls and able to discern between mild and severe clinical phenotype. Severe patients were characterized by a progressive decrease in the levels of LPCs, LPC-Os, PC-Os, and, on the contrary, an increase in overall TGs, PEs, and Ceramides. A machine learning model was built by using both the entire dataset and with a restricted lipid panel dataset, delivering comparable results in predicting severity (AUC= 0.777, CI: 0.639-0.904) and outcome (AUC= 0.789, CI: 0.658-0.910). Finally, re-building the model with 25 longitudinal (t1) samples, this resulted in 21 patients correctly classified. In conclusion, this study highlights specific lipid profiles that could be used monitor the possible trajectory of COVID-19 patients at hospital admission, which could be used in targeted approaches., (Copyright © 2022 Elsevier B.V. All rights reserved.)

To date, there are no specific therapeutic strategies for treatment of COVID-19. Based on the hypothesis that complement and coagulation cascades are activated by viral infection, and might trigger an acute respiratory distress syndrome (ARDS), we report clinical outcomes of 17 consecutive cases of SARS-CoV-2-related ARDS treated (N = 7) with the novel combination of ruxolitinib, a JAK1/2 inhibitor, 10 mg/twice daily for 14 days and eculizumab, an anti-C5a complement monoclonal antibody, 900 mg IV/weekly for a maximum of three weeks, or with the best available therapy (N = 10). Patients treated with the combination showed significant improvements in respiratory symptoms and radiographic pulmonary lesions and decrease in circulating D-dimer levels compared to the best available therapy group. Our results support the use of combined ruxolitinib and eculizumab for treatment of severe SARS-CoV-2-related ARDS by simultaneously turning off abnormal innate and adaptive immune responses., (Copyright © 2020 Giudice, Pagliano, Vatrella, Masullo, Poto, Polverino, Gammaldi, Maglio, Sellitto, Vitale, Serio, Cuffa, Borrelli, Vecchione, Filippelli and Selleri.)

Hydrogels are widespread materials, used in several frontier fields, due to their peculiar behavior: they couple solvent mass transport to system mechanics, exhibiting viscoelastic and poroelastic characteristics. The full understanding of this behavior is crucial to correctly design such complex systems. In this study agarose gels has been investigated through experimental stress-relaxation tests and with the aid of a 3D poroviscoelastic model. At the investigated experimental conditions, the agarose gels samples show a prevalent viscoelastic behavior, revealing limited water transport and an increase of the stiffness as well as of the relaxation time along with the polymer concentration. The model parameters, derived from the fitting of some experimental data, have been generalized and used to purely predict the behavior of another set of gels. The stress-relaxation tests coupled with mathematical modeling demonstrated to be a powerful tool to study hydrogels' behavior., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia, occurring in 1-2% of overall population, involving more than 6 millions of European people. It is associated to a reduced quality of life and an increased morbidity and mortality. The Framingham study showed the link between angina and AF. The same risk factors, such as hypertension, diabetes and obesity promote both AF and coronary artery disease (CAD). About 1/4 of AF patients develop a CAD and, in this setting, about 1/5 undergoes a percutaneous coronary intervention (PCI). In patients with both AF and CAD, the optimal medical strategy is challenging and it is still debated in cardiological community, since patients treated by dual (two antiplatelets drugs ore one antiplatelets drug and an oral anticoagulant drug) or triple therapy (two antiplatelets drugs and an oral anticoagulant drug) are exposed to divergent risk of bleeding or thromboembolic and ischemic complications. Aim of this paper is to focus the attention on the different problems arising from the presence of AF in patients undergoing PCI, such as the risk of stroke, bleeding and stent thrombosis.

Clinical presentation of pheochromocytoma can vary, and it can sometimes mimic other diseases. Some patients with pheochromocytoma may have atypical presentations, such as clinical features consistent with an acute coronary syndrome, that only later suggest a classical picture of stress-related cardiomyopathy. To our best knowledge, pheochromocytoma has been incidentally revealed in a few cases of catecholamine-induced cardiomyopathy and in only 1 case of peripheral arterial thrombosis. This is the first case of pheochromocytoma revealed after left ventricular dysfunction caused by stress-related cardiomyopathy associated with inferior limb artery thrombosis in a patient with a complex cardiovascular history.

In this study, we used the affected sibling-pairs approach to investigate the linkage of HLA (human leukocyte antigen)-DRB* with phenotypes related to allergy to Parietaria, the most common pollinosis in Mediterranean countries. The study population consisted of 51 nuclear families (235 subjects). Linkage was detected with Parietaria skin test positivity (p < (0.01), presence of IgG and IgE antibodies specific for the major allergen Par o 1 (p < 0.020 and p < 0.025, respectively), and absence of Par o 1-specific IgE (p < 0.020). High levels of Par o 1-specific IgG were associated with DRB1*1101 and/or DRB1*1104 (p < 0.0001 and p < 0.0119, respectively) in parents and probands. High levels of Par o 1-specific IgE were associated with DRB*1104 in parents (p < 0.017) and with DRB1*1101 in probands (p < 0.0146). When siblings were categorized according to high/low total IgE levels (> or =125 IU/ml and <125 IU/ml, respectively), high IgE antibody response was associated with DRB1*1104 in siblings with low total IgE (p < 0.034) and with DRB1*1101 in siblings with high total IgE (p < 0.05). These results demonstrate that HLA-DRB1*, or genes in linkage disequilibrium, contributes to susceptibility to Parietaria allergy and that total IgE levels can discriminate population subsets where different alleles (at the HLA region or at loci in linkage disequilibrium) contribute to control allergen-specific IgE synthesis.

We investigated the possible role of calmodulin (CaM) in the control of histamine release from human basophil leukocytes using several CaM antagonists. Trifluoperazine (TFP) (10(-6)-2 X 10(-5) M), pimozide (10(-6)-1.5 X 10(-5) M), chlorpromazine (CPZ) (10(-5)-10(-4) M) and promethazine (PMZ) (2 X 10(-5)-10(-4) M) inhibited in vitro histamine secretion from human basophils induced by several immunological (antigen, anti-IgE, and formyl-L-methionyl-L-leucyl-L-phenylalanine: f-met peptide) and nonimmunological (Ca2+ ionophore A23187 and the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate: TPA) stimuli. Trifluoperazine sulfoxide (TFP-S) and chlorpromazine sulfoxide (CPZ-S), which have very low affinity to CaM, had practically no inhibitory effect on histamine release from human basophils. The inhibitory effect of TFP could be made irreversible by irradiating the cells with UV light. A sulfonamide derivative, the compound N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) (2.5 X 10(-5)-2 X 10(-4) M), which selectively binds to CaM, inhibited the release of histamine from basophils. In contrast, the chloride deficient analogue, W-5, which interacts only weakly with CaM, had practically no inhibiting effect. The IC50 for enzyme release by a series of eight CaM antagonists was closely correlated (r = 0.91; p less than 0.001) with the CaM specific binding, supporting the concept that these agents act by binding to CaM and thereby inhibiting histamine release. TFP and W-7 inhibited histamine release in the absence and in the presence of increasing concentrations of extracellular Ca2+. These results emphasize the possible role of CaM in the control of histamine secretion from human basophils.

Platelets, basophils and neutrophils from a patient with the Wiskott-Aldrich syndrome (WAS) were exposed to stimuli that activate specific membrane receptor or directly initiate biochemical events (e.g. the Ca2+ ionophore A23187 and ionomycin or arachidonic acid). Platelets from this patient did not aggregate in response to ADP, collagen, thrombin or adrenaline, which activate specific membrane receptors. Platelet aggregation, however, was normal in response to compound A23187, ionomycin or exogenous arachidonic acid. Histamine release from basophils of the WAS patient was normal in response to anti-IgE, a formylated peptide (f-met peptide), and to A23187. Similarly, the release of the lysosomal enzymes, beta-glucuronidase and lysozyme, from neutrophils of the WAS patient in response to serum treated zymosan (Zx), f-met peptide, and A23187 was not significantly different from that of his parents and 13 normal donors. These results suggest that the primary defect in WAS is selectively present in platelets and is located in a biochemical step between receptor activation and Ca2+ influx and/or initiation of arachidonate metabolism.

Releasability of human basophils (i.e., the response to a standard stimulus) is an important parameter in several pathophysiologic conditions. We studied the IgE (anti-IgE)- and non-IgE-mediated (f-met peptide and Ca2+ ionophore A23187) releasability of human basophils obtained from 63 normal donors whose ages ranged from 1 to 86 years. The maximum percent of histamine release induced by anti-IgE was significantly correlated (rs = 0.57; p less than 0.001) with the age of donors. The sensitivity to a standard concentration of anti-IgE (3 X 10(-2) mcg/ml) was also correlated with the age of cell donors (rs = 0.68; p less than 0.001). In the population of 63 donors tested, the maximum percent of histamine release and the cell sensitivity to anti-IgE appeared to be independent of the serum concentration of IgE. However, we found a positive correlation (rs = 0.55; p less than 0.05) between serum IgE level and anti-IgE-induced histamine release in the group less than 20 years of age. In contrast, a negative correlation (rs = -0.32; p less than 0.05) between serum IgE level and anti-IgE-induced histamine secretion was found in the group greater than 21 years of age. The maximum percent of histamine release induced by f-met peptide and Ca2+ ionophore A23187 appeared to be independent to both the age of the donors and the serum IgE level.(ABSTRACT TRUNCATED AT 250 WORDS)

We reviewed the clinical, hemodynamic and angiographic data of 105 patients with right coronary artery occlusion and 82 patients with left anterior descending coronary artery occlusion, subdivided into 3 groups by the presence and quality of collaterals to the occluded coronary (absent, poor or good collaterals). We found that patients with right coronary artery occlusion and good collaterals had a lower frequency of diaphragmatic myocardial infarction (60%) than patients with absent collaterals (100%) (P less than 0.01). In addition, in patients with old diaphragmatic myocardial infarction, both poor and good collaterals were associated with a lower frequency of severe asynergy of the diaphragmatic left ventricular segments at left ventriculography (54% and 14%, respectively), compared to patients with no collaterals to the right coronary artery (92%, P less than 0.02 vs. poor collaterals, P less than 0.001 vs. good collaterals). In contrast, in patients with left anterior descending coronary artery occlusion, the presence of either poor or good collaterals to the left anterior descending coronary artery was not associated with a lower frequency of old anterior myocardial infarction, or, in patients with old anterior myocardial infarction, with a less severe asynergy of the anterior left ventricular segments. Our results suggest that collaterals are effective in protecting the diaphragmatic left ventricular wall in patients with right coronary artery occlusion, but not the anterior left ventricular wall in patients with left anterior descending coronary artery occlusion.

We studied the clinical, hemodynamic and angiographic findings of 34 women (W) and of 184 men (M) with significant (greater than or equal 50%) CAD. W, compared to M, presented a higher incidence of systemic hypertension (p less than .025), while less frequent were among W smoking habits (p less than .001), history of old myocardial infarction (MI) (p less than .005), and patients in III-IV NYHA class (p less than .025). Left ventricular (LV) dP/dt was higher in W than in M (p less than .005). At coronary arteriography, single vessel disease (SVD) was more frequently found in W than in M (70% vs 23%, respectively, p less than .001); this findings was more evident in patients under 50 years of age (100% vs 30%, respectively, p less than .055). Prevalence of left anterior descending (LAD) over right (RCA) and circumflex (Cx) coronary artery stenoses was more marked in W than in M, especially in patients under 50 years of age (SVD of the LAD in 67% and of RCA in 33% of young W). Poor angiographic run-off of LAD was found in 21% of W, and only in 10% of M. In 2 of the 3 W with poor run-off of LAD operated on, a coronary bypass on the distal LAD was no technically feasible. At left ventriculography, a lower frequency of LV segmental wall motion abnormalities was found in W than in M, especially in patients with no history of MI (p less than .001). In summary, W with significant CAD, compared to age matched M, presented in our experience with a higher frequency of SVD and of LAD stenoses, and with a better LV contractile performance at left ventriculography. Furthermore, in W LAD more frequently showed a poor angiographic run-off. Such findings may bear important implications on the indication and results of coronary surgery in W with CAD.

We have studied the role of arachidonic acid (AA) metabolism in the release of lysosomal enzymes (beta-glucuronidase and lysozyme) from human polymorphonuclear leukocytes (PMNs). 5,8,11,14-Eicosatetraenoic acid (ETYA), which inhibits both the cyclo-oxygenase and the lipoxygenase pathways of AA metabolism, was found to cause a dose-dependent inhibition of lysosomal enzyme release from human PMNs induced by immunological (i.e., serum-treated zymosan: Zx) and nonimmunological stimuli (i.e., formyl methionine-containing peptide and the Ca2+ ionophore A23187). In contrast, the non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid and aspirin), which only block the cyclo-oxygenase pathway of AA metabolism, had little effect on enzyme release from PMNs induced by the same stimuli. 5,8,11-Eicosatriynoic acid (ETI), a selective inhibitor of the lipoxygenase pathway of AA metabolism, caused a dose-dependent inhibition of lysosomal enzyme release elicited by Zx, f-met peptide, and A23187. p-Bromophenacyl bromide (BPB), which inhibits the phospholipase A2 (PLA2) activity in several tissues, was found to cause a dose-dependent inhibition of lysosomal enzyme release induced by the same immunological and non-immunological stimuli. The inhibitory effect of BPB on enzyme release was irreversible and extremely rapid. It appears that activation of PLA2 and the products of the AA metabolism, generated via a lipoxygenase pathway, play an essential role in the biochemical control of human PMNs activation and secretion.

Calmodulin is a ubiquitous and versatile Ca2+-binding protein that plays a pivoting role in cellular metabolism. We have investigated the possibility that calmodulin plays a role in immediate hypersensitivity reactions by evaluating the effects of two agents, trifluoperazine dihydrochloride (TFP) and the sulfonamide derivative N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) which selectively bind to calmodulin. TFP and W-7 cause a dose-dependent inhibition of histamine secretion from human basophils in vitro induced by several immunological (i.e., antigen and anti-IgE) and nonimmunological (i.e., formyl-methionine-containing peptide and the Ca2+ ionophore A23187) stimuli. These results indicating that two specific calmodulin antagonists are potent inhibitors of the secretory response of human basophils support the hypothesis that calmodulin may play a role in the control of the release of preformed mediators from human inflammatory cells.

Histamine (H) is stored in man in the cardiovascular as well as in other systems, from where it can be released under exposure to immunologic and nonimmunologic stimuli. To understand better the hemodynamic changes produced in man by endogenous H release, we infused H for 3.5-7 min at the rate of 0.4 microgram/kg/min i.v. in four patients with normal left ventricular (LV) function undergoing diagnostic cardiac catheterization. We observed a significant fall in systolic, diastolic, and mean aortic pressure, systemic vascular resistance, LV end-diastolic pressure, and stroke index, and a significant rise in heart rate, cardiac output, and LV dP/dtmax, with small changes in mean pulmonary arterial pressure and pulmonary vascular resistance. During infusion there was also a significant rise in plasma H, epinephrine, and norepinephrine. All hemodynamic changes started 1-2 min after the beginning of H infusion and reverted to normal within 5 min from the end of the infusion. Subjective complaints were mild and transient in all patients. One patient progressed from first- to third-degree atrioventricular block, with prompt recovery of 1:1 atrioventricular conduction at the end of infusion. Thus, exogenous H administration in man at the rate of 0.4 microgram/kg/min produces significant and transient hemodynamic changes, mainly represented by systemic hypotension, tachycardia, and increased LV performance. These latter can be attributed to the associated increase in sympathoadrenergic activity, although a direct cardiac effect of H cannot be excluded.