The role of skin tests with polyethylene glycol and polysorbate 80 in the vaccination campaign for COVID-19: results from an Italian multicenter survey.

Summary: Background. International guidelines suggested skin tests with Polyethylene-glycol (PEG) and polysorbate 80 (PS-80), to investigate a possible hypersensitivity to these excipients either to identify subjects at risk of developing allergic reactions to Covid-19 vaccines, or in patients with suspected IgE mediated hypersensitivity reactions (HR) to the Covid-19 vaccine. The main purpose of this study was to investigate the prevalence of PEG and PS sensitization in patients with a clinical history of HR to drugs containing PEG/PS and in patients with a suspected Covid-19 vaccine immediate HR. Methods. This was a multicenter retrospective study conducted by allergists belonging to 20 Italian medical centers. Skin testing was performed in 531 patients with either a clinical history of suspected hypersensitivity reaction (HR) to drugs containing PEG and/or PS-80 (group 1:362 patient) or a suspected HR to Covid-19 vaccines (group 2: 169 patient), as suggested by the AAIITO/SIAAIC guidelines for the "management of patients at risk of allergic reactions to Covid-19 vaccines" [1]. Results. 10/362 (0.02%) had positive skin test to one or both excipients in group 1, 12/169 (7.1%) in group 2 (p less than 0.01). In group 2 HRs to Covid-19 vaccines were immediate in 10/12 of cases and anaphylaxis occurred in 4/12 of patients. Conclusions. The positivity of skin test with PEG and or PS before vaccination is extremely rare and mostly replaceable by an accurate clinical history. Sensitization to PEG and PS has to be investigated in patients with a previous immediate HR to a Covid-19 vaccine, in particular in patients with anaphylaxis.

Tumor Necrosis Factor Related Apoptosis Inducing Ligand (Trail) in endothelial response to biomechanical and biochemical stresses in arteries.

Shear stress is determined by three physical components described in a famous triad: blood flow, blood viscosity and vessel geometry. Through the direct action on endothelium, shear stress is able to radically interfere with endothelial properties and the physiology of the vascular wall. Endothelial cells (ECs) have also to sustain biochemical stresses represented by chemokines, growth factors, cytokines, complement, hormones, nitric oxide (NO), oxygen and reactive oxygen species (ROS). Many growth factors, cytokines, chemokines, hormones, and chemical substances, like NO, act and regulate endothelium functions and homeostasis. Among these cytokines Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) has been assigned a regulatory role in ECs physiology and physiopathology. Thus, the aim of this review is to provide a general overview of the endothelial response pathways after different types of biomechanical and biochemical stress in in vitro models and to analyze the crucial role of TRAIL under pathological conditions of the cardiocirculatory system like atherosclerosis, coronary artery disease, and diabetes.

Regulatory T-cell modulation by green tea in chronic lymphocytic leukemia.

Regulatory T cells (Tregs) are considered to be key immunomodulatory cells of the immune system and are increased in chronic lymphocytic leukemia (CLL). Rai stage 0 identifies patients with early stage CLL for which there is no effective intervention at the present time and a "wait and see" policy is usually adopted. Some biological and clinical studies have reported that green tea constituents, such as epigallocatechin-gallate (EGCG), have antitumor effects on hematologic malignancies including CLL. We report data on a clinical trial in which green tea extracts were given orally to 12 patients with stage 0 CLL and 12 healthy subjects. Ten patients and 10 controls completed the 6-month scheduled therapy. Two patients and 2 controls stopped therapy within 1 month because of tachycardia and epigastralgia. Eight out 10 evaluable patients (80 percent) showed a reduction of lymphocytosis and absolute number of circulating Tregs, as well. One patient (10 percent) had a stabilization of lymphocytosis and a reduction of Tregs, and 1 patient (10 percent) showed an increase of both lymphocytosis and Tregs. Only the non-responding patient progressed after 5 months from the end of green tea administration and chemotherapy was given. Interestingly, both IL-10 and TGF-beta serum levels declined throughout the green tea intake period, in both patients and controls. These data seem to indicate that green tea is able to modulate circulating Tregs in CLL patients with early stage of the disease. This can result in the control of lymphocytosis as well as in the prevention of disease progression.

Circulating regulatory T cells in "clinical" monoclonal B-cell lymphocytosis.

Regulatory T-cells (Tregs) constitute a small subset of cells involved in antitumour immunity and are generally increased in patients with chronic lymphocytic leukemia (CLL). No data is available on Tregs in monoclonal B-cell lymphocytosis (MBL), a disease entity characterized by less than 5000/microL circulating clonal B-cells in absence of other features of lymphoproliferative disorders. We used multicolour flow cytometry to evaluate the number of circulating Tregs in 56 patients with "clinical" MBL, 74 patients with previously untreated CLL and 40 healthy subjects. MBL patients showed a lower absolute number of Tregs, compared to CLL patients, but slightly higher than controls. Moreover, the absolute cell number of Tregs directly correlated both with more advanced Rai/Binet clinical stages and peripheral blood B-cell lymphocytosis. Of note, the absolute number of Tregs was found lower in MBL patients than in CLL patients staged as 0/A Rai/Binet. The study showed that Treg increase gradually from normal subjects to "clinical" MBL patients and are significantly higher in CLL patients as compared to MBL patients. Moreover, a significant direct relationship was found between higher Treg values and a higher tumor burden expressed by B-lymphocytosis or more advanced clinical stages. In light of this data, MBL seems to be a preliminary phase preceding CLL. The progressive increase of Treg numbers might contribute both to the clinical evolution of MBL to overt CLL and to CLL progression.

High-density neutrophils in MGUS and multiple myeloma are dysfunctional and immune-suppressive due to increased STAT3 downstream signaling.

To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.

Multifactorial aspects of antimicrobial activity of propolis.

We investigated the antibacterial activity of sub-inhibitory concentrations of ethanolic extract of propolis (EEP), and its effect on the antibacterial activity of some antibiotics. Some clinically isolated Gram-positive strains were used. Moreover, sub-inhibitory concentrations of EEP were used to value its action on some important virulence factors like lipase and coagulase enzymes, and on biofilm formation in Staphylococcus aureus. Our results indicated that EEP had a significant antimicrobial activity towards all tested clinical strains. Adding EEP to antibacterial tested drugs, it drastically increased the antimicrobial effect of ampicillin, gentamycin and streptomycin, moderately the one of chloramphenicol, ceftriaxon and vancomycin, while there was no effect with erithromycin. Moreover, our results pointed out an inhibitory action of EEP on lipase activity of 18 Staphylococcus spp. strains and an inhibitory effect on coagulase of 11 S. aureus tested strains. The same EEP concentrations showed a negative interaction with adhesion and consequent biofilm formation in S. aureus ATCC 6538P.

Heart Failure in a Dedicated Outpatient Clinic: Results after 58 Month Follow-Up. Can it be Enough?

Incidence of chronic heart failure (HF) is rapidly increasing, approaching a 10 per 1000 rate after 65 years of age. In the last decades, despite pharmacological, interventional and supportive innovations, HF prognosis remained poor, with about 30% of death within one year from the diagnosis. Current guidelines recommend for these patients management programs providing follow-up through dedicated outpatient clinic. Limits of these programs are represented by great difficulties in getting patients adherence, being still too elevated the rate of abandonments. In this paper, we analyzed the impact of 58 months of activity in our dedicated to heart failure outpatient clinic on mortality, hospitalization and abandonment rate. 477 HF patients (346 M, 72.5%, mean age 69.6 years) were enrolled. Mean follow-up and visit were 18.2 and 2.6 months respectively. Total mortality rate was 11.5%, 4% of patients per year. Total hospitalizations for acute HF were 212 and, among all patients left in follow-up, the number of hospitalizations for acute de-compensation significantly decreased from 0.49/patient/year before enrollment to 0.29/patient/year during follow-up (p=0.015). Patients who abandoned outpatient clinic were 94 (19%, 1 abandonment every 23 days), mostly observed over the first months of activity. In conclusion, our patients experienced a major decrease in rates of acute de-compensation and need of in-hospital admissions.

Investigations of the activity by contact of miconazole sulfosalicylate.

The in-vitro antimicrobial activity of miconazole sulfosalicylate (M.SSA) has been investigated on mycetes (Candida albicans, Cryptococcus neoformans, Aspergillus niger, Trichophyton mentagrophytes), Gram-positive bacteria (Staphylococcus aureus, Streptococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens and Proteus vulgaris) in comparison with miconazole nitrate (M.NIT). The results showed M.SSA has a greater activity than M.NIT, particularly on mycetes and Gram-negative bacteria. The study of activity by contact with M.SSA showed some characteristics of this sulfosalicylate imidazole, such as the lack of a latency time, an antimicrobic action related directly to the concentration, the limited influence of pH and ionic strength of medium used. The greater activity by contact of M.SSA than M.NIT could be related to its higher lipophilia (due also to the lipophilic characteristics of SSA) and, therefore, to increased interaction with the cell membrane.

Antimicrobial contact activity of econazole sulfosalicylate.

The aim of this investigation was to compare the contact action of econazole sulfosalicylate (E-SSA) on mycetes (Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, T. cutaneum, Pityrosporum sp.), Gram-positive bacteria (Staphylococcus aureus, Streptococcus faecalis) and Gram-negative bacteria (Escherichia coli, Citrobacter freundii) with that exerted by econazole nitrate (E-NIT). The results show E-SSA activity greater than E-NIT (in particular against mycetes and Gram-negative bacteria). The E-SSA contact activity trials illustrated certain properties of this imidazole sulfosolicylate such as: absence of latency time, antimicrobial activity proportional to its concentration, when a high concentration is used, given the limiting influence of pH and ionic strength of the medium. The higher E-SSA contact activity, in relation to E-NIT, can be correlated to its greater lipophylia considering also the lipophylic properties of SSA and the scarce dissociation of E-SSA.

In vitro activity of tea tree oil against Candida albicans mycelial conversion and other pathogenic fungi.

The antifungal activity of Melaleuca alternifolia Maiden (Myrtaceae) essential oil against yeasts (Candida spp., Schizosaccharomyces pombe, Debaryomyces hansenii) and dermatophytes (Microsporum spp. and Tricophyton spp.) is reported. We focused on the ability of tea tree oil to inhibit Candida albicans conversion from the yeast to the pathogenic mycelial form. Moreover we carried out broth microdilution test and contact tests to evaluate the killing time. M. alternifolia essential oil inhibited the conversion of C. albicans from yeast to the mycelial form at a concentration of 0.16% (v/v). The minimum inhibitory concentrations (MICs) ranged from 0.12% to 0.50% (v/v) for yeasts and 0.12% to 1% (v/v) for dermatophytes; the cytocidal activity was generally expressed at the same concentration. These results, if considered along with the lipophilic nature of the oil which enables it to penetrate the skin, suggest it may be suitable for topical therapeutic use in the treatment of fungal mucosal and cutaneous infections.

Effect of propolis on virulence factors of Candida albicans.

Propolis is a resinous substance collected by honeybees from plant sources. Its antimicrobial activity has been well documented but little is specifically known about its activity on virulence factors of Candida albicans. The aim of this work was therefore to evaluate in vitro the propolis effect on yeast-mycelial conversion (Y-M), extracellular phospholipase activity and fungal adhesion to epithelial cells. The two propolis samples used significantly inhibited the C. albicans strains tested, showing a rapid (between 30 seconds and 15 minutes), dose-dependent cytocidal activity and an inhibitory effect on Y-M conversion at a concentration of 0.22 mg/ml. Moreover, the hyphal length was reduced even at lower propolis concentration. Propolis also caused a dose- and time-dependent inhibition of phospholipase activity. No clear effect was shown on adherence to buccal epithelial cells and surface structure hydrophobicity, but damage to the plasma membrane structure was demonstrated with the Propidium Iodide test.

Glycogen medium, antitrichomonal drug activity in vaginal liquids.

The amount of glycogen in vaginal liquids decreases with Trichomonas vaginalis and this is connected with T. vaginalis activity in specimens. A glycogen-hydrolysed casein medium ("glycogen medium") added to vaginal liquid is a valid maintenance medium for T. vaginalis and therefore enables a direct test for antitrichomonas drugs to be performed.

In vitro antimicrobial activity of econazole and miconazole sulfosalicylate.

The in vitro activities of new sulfosalicylic salts of econazole (E.SSA) and miconazole (M.SSA) have been investigated in comparison with the respective nitrate (NIT) salts and sulfosalicylic acid (SSA) alone. The results reveal good antimicrobial activity of M.SSA and E.SSA against different strains of Candida, dermatophytes, moulds, Gram-positive bacteria and Trichomonas vaginalis. The MIC values demonstrate that M.SSA is more active than M.NIT on Candida and T. vaginalis. E.SSA was also more active than E.NIT on T.vaginalis. Both SSA and sodium sulfosalicylate (NaSSA) were practically without activity by themselves. Finally, the pH variations did not significantly modify the activity of the SSA salts, suggesting that their greater activity could be due to better lipophilic activity of these compounds with respect to the nitrate salts.

Itraconazole: increased activity by chlorhexidine.

Chlorhexidine increases the activity of itraconazole against Candida isolates; itraconazole-chlorhexidine combinations show synergistic activity in culture media. The activity of itraconazole is discussed.

[Substances with antibacterial and antifungal activity. VII. Synthesis and microbiologic activity of new derivatives of 1,5-diarylpyrrole]. / Ricerche su sostanze ad attività antibatterica ed antifungina. Nota VII--Sintesi ed attività microbiologica di nuovi derivati dell'1,5-diarilpirrolo.

The synthesis and antifungal activities of new 1,5-diarylpyrrole derivatives are reported. Antimicrobial data in comparison with pyrrolnitrin show that N-methylpiperazinylamides exhibit very poor activity against Candida albicans and Candida sp. while acid and ester derivatives are inactive. Vice-versa many acid or amide derivatives show interesting antibacterial activity. The results obtained are discussed on the basis of structure-activity relationships.

[Suprasystolic dP/dt max an additional parameter of contractile cardiac function obtained by cuff oscillometric tracings]. / Un paramètre additionnel de fonction ventriculaire gauche dérivé du profil oscillométrique artériel.

Technological evolution allowed to record high fidelity traces that--when analysed by complex mathematical systems--may provide extremely detailed and new information about all the factors involved in the determinism of pulse wave. Suprasystolic waves, i.e. those recorded immediately before systolic pressure, may be regarded as similar to aortic pressure waves evaluated during cardiac catheterization. Suprasystolic dP/dt max was calculated from the profile of pulse wave recorded by the DynaPulse, an automatic portable non-invasive oscillometric method to simultaneously measure BP and analyse arterial waveforms, in 10 normal healthy subjects (age 37 +/- 5) and 5 subjects with ischaemic dilatative cardiomyopathy (age 41 +/- 7) whose ejection fraction--invasively assessed--was < 40%. The 24 h dP/dt max curves were analysed by parametric and non parametric tests. We found a significant difference (p < 0.001) in the average 24-h dP/dt max between healthy subjects (471 +/- 36.7 mmHg/sec) and patients with impaired cardiac function (271 +/- 54.2 mmHg/sec). The average daytime and nighttime dP/dt max values showed significantly higher values in normal subject in comparison to patients with heart failure (daytime 7.23 h: 529 +/- 74 mmHg/s versus 227 +/- 64 mmHg/s, p < 0.001; nighttime: 572 +/- 82 mmHg/s versus 202 +/- 67 mmHg/s, p < 0.001). We also found a difference in the occurrence of acrophases, at similar blood pressure value, i.e. the highest dP/dt values occurred during the night in normal subject, the opposite in ischaemic patients. Furthermore, the dP/dt max correlates only with systolic blood pressure.

[Effects of antihypertensive treatment on carotid vascular changes]. / Effetti del trattamento antipertensivo sulle alterazioni vascolari del distretto carotideo.

The carotid artery is one of the most important sites in the progression of atherosclerotic lesions. Atherosclerosis is known to be determined by a variety of factors, among which arterial hypertension is one of the most important. Blood pressure control by antihypertensive treatment is thus of great benefit in management of atherosclerosis, particularly in view of the direct action of some classes of antihypertensive agents on atheromatous lesions. Today, modern diagnostic technique allow a non-invasive examination of the artery wall (B-mode ultrasound and pulsed-Doppler), so that early detection of structural and functional alterations is possible. In order to evaluate the efficacy of the long term blood pressure reduction in the progression and/or in the regression of cardiovascular structural abnormalities, we studied intima-media thickness and arterial compliance during one-year antihypertensive treatment with a new calcium-antagonist, lacidipine, or a diuretic hydrochlorothiazide. In both groups we observed a comparable blood pressure reduction (lacidipine: from 166 +/- 5/100 +/- 1 to 142 +/- 4/88 +/- 2 mmHg; hydrochlorothiazide: from 154 +/- 5/102 +/- 2 to 140 +/- 4/88 +/- mmHg; both p < 0.01). On the contrary, only in patients treated with lacidipine did we obtain a significant improvement in carotid blood flow (383 +/- 16 vs 411 +/- 16 ml/min p <) and in arterial compliance (0.8 +/- 0.1 vs 1.2 +/- 0.2 cm/dyne p < 0.01). Indeed, we observed a different behaviour of the intima-media thickness in the two groups (lacidipine: 1.11 +/- 1.4 vs 1.13 +/- 1.5 mm n.s.; hydrochlorothiazide: 1.15 +/- 0.15 vs 1.21 +/- 0.17 mm p < 0.06). Our results demonstrate that an effective antihypertensive treatment with calcium antagonists may influence the progression of carotid vascular abnormalities.

[Carotid vascular structural changes and left ventricular hypertrophy]. / Alterazioni strutturali vascolari carotidee ed ipertrofia ventricolare sinistra.

In the literature there are few studies evaluating carotid vascular atherosclerotic involvement in patients with essential arterial hypertension. Nowadays with new non-invasive methodological methods, such as Doppler-echotomography, it is possible to evaluate accurately structural vascular and cardiac changes. In this study we evaluated the relationship between carotid vascular structural changes and cardiac left ventricular mass index in 15 normotensive subjects and in 15 patients with essential hypertension. We performed a B-mode echotomography (7.5 MHz) of a common carotid in order to measure the diameter of the vessel and intima-media wall thickness. In the same subjects we determined echocardiographic left ventricular mass index and we measured arterial pressure by sphygmomanometric method. There was no statistical significant difference in the two groups except that in systolic, diastolic and mean arterial pressure (96 +/- 2 vs 123 +/- 2 mmHg, p < 0.01), left ventricular mass index (102 +/- 3 vs 118 +/- 3 g/m2, p < 0.01) and in the common carotid intima media wall thickness (0.91 +/- 0.01 vs 2.23 +/- 0.02 mm). In the normotensive subject mean arterial pressure correlated significantly with age (r = 0.699) and with common carotid arterial diameter (r = 0.523) (both p < 0.05). In hypertensive patients, on the contrary, mean arterial pressure correlated with left ventricular mass index (r = 0.523), carotid arterial diameter (r = 0.627) and common carotid intima media wall thickness (r = 0.847). These results demonstrate that in hypertensive patients cardiac abnormalities accompanied vascular structural changes.

[Holter monitoring of the arterial pressure in the follow up of a group of aged patients with chronic uremia]. / Follow-up della pressione arteriosa in un gruppo di uremici anziani cronici mediante monitoraggio Holter.

The cardiovascular complication represents the principal effect of death in patients uraemics cronics. The hypertension is one of most cause; for this, the control of hypertension is one important objective in this patients. The introduction of dynamic monitoring permit to estimate the adeguatesse of hypertension control or the appearance of extradialitic hypotension. The dynamic monitoring permit to value the difference in two groups, young and elderly and to conform the hypertension therapy.

[Efficacy of recombinant erythropoietin on the quality of life in patients over 60 years of age undergoing hemodialysis]. / Efficacia dell'eritropoietina ricombinante sulla qualità di vita in pazienti emodializzati ultrasessantenni.

We followed for a period of six months, 54 patients of over 60 years old, submitted to hemodialitic treatment. We gave human recombinant erythropoietin, average dosage 50 UI/Kg subcutaneously on alternative days, folic acid and iron supplements together with a proteic supply of 1.2 g/Kg/die (35 Kcal/Kg). The medullary response has been monitored with hematochemical tests; blood pressure and nutritional conditions have been evaluated. Furthermore, the patients were given a questionnaire to evaluate their quality of life. At the end of the follow up, 50 patients responded positively to therapy. These patients showed an increase of RBC (from 2,789,780 +/- 259,310 to 3,313,110 +/- 472,780 p < 0.001) of HCT (from 21.86% +/- 2.16% to 27.18 +/- 2.74% p < 0.0001) and of Hb (from 7.72 +/- 1.12 g/dl to 9.28 +/- 0.98 g/dl p < 0.006). Total protein and albumin increased too. Furthermore they showed a progressive increase of "performance status". Our results confirm efficacy of erythropoietin in the treatment of anemia in elderly hemodialized patients.