Cyclic Adenosine 5′-Monophosphate and Calcium Induce CD152 (CTLA-4) Up-Regulation in Resting CD4+ T Lymphocytes

Abstract The CTLA-4 (CD152) molecule is up-regulated upon T cell activation and proliferation, and plays a critical role in the inhibition of immune responses. We show in this study that cAMP induces up-regulation of CD152 in human CD4+ T lymphocytes. This effect occurs in the absence of the up-regulation of CD69 and CD25 activation markers and T cell proliferation. In addition, we found that the Ca2+ ionophore ionomycin also up-regulates CD152, and that the combination of a cAMP analog or cAMP inducers with ionomycin further enhances the expression of CD152 in resting CD4+ T lymphocytes. However, cyclosporin A, which inhibits Ca2+/calcineurin signaling pathway, fully prevented the ionomycin- but not the cAMP-induced up-regulation of CD152. The effects of cAMP and ionomycin involve increase of both CD152 mRNA transcripts, coding for the membrane and the soluble forms of CD152. Furthermore, we show that CD152 molecules are translocated to the membrane and are functional, as their engagement by specific mAbs prevented NF-κB activation by anti-CD3/CD28 stimulation. These findings demonstrate that at least two novel signal pathways regulate CTLA-4 gene expression and CD152 molecule up-regulation in human CD4+ T lymphocytes, in the absence of full T cell activation

Integrated Care for Heart Failure in Primary Care

Chronic heart failure (CHF or simply HF) is a complex clinical syndrome that involves more than 2% of the general population and over 10% of the older people. For people with reduced ventricular function (the classical HFrEF phenotype), the guideline-directed medical therapy (GDMT) (e.g., Ace-inhibitors, beta-blockers, diuretics, rehabilitation or implantable ventricular devices) demonstrated to be efficacious in reducing hospitalisations and prolonging survival. Vice-versa, the HF with preserved ejection fraction (diastolic HF or HFpEF phenotype) is a much more complex syndrome, in which co-morbidities (such as COPD, depression, anemia, and diabetes, CAD) play a significant role in the decompensation episodes

The effects of primary care monitoring strategies on COVID-19 related hospitalisation and mortality: a retrospective electronic medical records review in a northern Italian province, the MAGMA study

Background: Most symptomatic SARS-CoV-2 infections produce mild to moderate symptoms. Although most patients are managed in the outpatient setting, little is known about the effect of general practitioners' (GP) management strategies on the outcomes of COVID-19 outpatients in Italy. Objectives: Describe the management of Italian GPs of SARS-CoV-2 infected adult patients and explore whether GP active care and monitoring are associated with reducing hospitalisation and death. Methods: Retrospective observational study of SARS-CoV-2 infected adult outpatients managed by GPs in Modena (Italy) from March 2020 to April 2021. Information on management and monitoring strategies, patients' socio-demographic characteristics, comorbidities, and outcomes (hospitalisation and death due to COVID-19) were retrieved through an electronic medical record review and analysed descriptively and through multiple logistic regression. Results: Out of the 5340 patients from 46 GPs included in the study, 3014 (56%) received remote monitoring, and 840 (16%) had at least one home visit. More than 85% of severe or critical patients were actively monitored (73% daily) and 52% were visited at home. Changes over time in patients' therapeutic management were observed in concordance with the guidelines' release. Active daily remote monitoring and home visits were strongly associated with reduced hospitalisation rate (OR 0.52, 95% CI 0.33-0.80 and OR 0.50, 95% CI 0.33-0.78 respectively). Conclusion: GPs effectively managed an increasing number of outpatients during the first waves of the pandemic. Active monitoring and home visits were associated with reduced hospitalisation in COVID-19 outpatients

Cholera Toxin Impairs the Differentiation of Monocytes into Dendritic Cells, Inducing Professional Antigen-Presenting Myeloid Cells ▿

Cholera toxin (CT) is a potent adjuvant for mucosal vaccination; however, its mechanism of action has not been clarified completely. It is well established that peripheral monocytes differentiate into dendritic cells (DCs) both in vitro and in vivo and that monocytes are the in vivo precursors of mucosal CD103− proinflammatory DCs. In this study, we asked whether CT had any effects on the differentiation of monocytes into DCs. We found that CT-treated monocytes, in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4), failed to differentiate into classical DCs (CD14low CD1ahigh) and acquired a macrophage-like phenotype (CD14high CD1alow). Cells differentiated in the presence of CT expressed high levels of major histocompatibility complex class I (MHC-I) and MHC-II and CD80 and CD86 costimulatory molecules and produced larger amounts of IL-1β, IL-6, and IL-10 but smaller amounts of tumor necrosis factor alpha (TNF-α) and IL-12 than did monocytes differentiated into DCs in the absence of CT. The enzymatic activity of CT was found to be important for the skewing of monocytes toward a macrophage-like phenotype (Ma-DCs) with enhanced antigen-presenting functions. Indeed, treatment of monocytes with scalar doses of forskolin (FSK), an activator of adenylate cyclase, induced them to differentiate in a dose-dependent manner into a population with phenotype and functions similar to those found after CT treatment. Monocytes differentiated in the presence of CT induced the differentiation of naïve T lymphocytes toward a Th2 phenotype. Interestingly, we found that CT interferes with the differentiation of monocytes into DCs in vivo and promotes the induction of activated antigen-presenting cells (APCs) following systemic immunization

Home management of Covid-19 pneumonia in the early phases of the pandemic: analysis of real-life data of General Practitioners in the Province of Modena from the MAGMA study.

Primary care management of Covid-19 pneumonia in the Province of Modena in the early phases of the pandemic: data integration from MAGMA study. Retrospective study on patients affected of Covid-19 and followed by General Practitioner from March 2020 to April 2021. 5340 patients were studied, 27% of them developed pneumoniae. Among these, most of them were managed entirely at home with an elevated intensity of care. Daily remote monitoring and home visits, together with a personalized pharmacological treatment, especially for the most severe forms, appeared to be the most effective interventions in reducing hospitalizations