Platelets and multi-organ failure in sepsis

Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models

Clima scolastico e variabili soggettive dei docenti di scuola secondaria

The theme of our research is understanding why many aspects of school climate are interrelated and how such relations influence subsequent scholastic functioning. The research is oriented towards the determination of personal and environmental factors that provide to explain several aspects of the construct. We administered a test battery to analyze: Scholastic Climate; Personal and Collective Efficacy; Organizational Commitment, Involvement, and Job Satisfaction. Findings confirm the constant influence of personal efficacy on determining of the level of job involvement and satisfaction. If teachers’ personal efficacy convictions play a significant role on stamp their scholastic perceptions and evaluations, they reflectthe experience of each teacher, the history of successes and failures of individuals in their own experience of teaching.Il tema della nostra ricerca è capire il motivo per cui molti aspetti del clima scolastico sono interconnessi e come tali relazioni influenzano il successivo funzionamento scolastico. La ricerca è orientata verso la determinazione di fattori personali e ambientali che tendono a spiegare alcuni aspetti del costrutto. Abbiamo somministrato una batteria di test per analizzare: il clima scolastico; l’efficacia personale e collettiva; l’impegno organizzativo, il coinvolgimento e la soddisfazione sul lavoro. I risultati confermano l’influenza costante dell’efficacia personale sulla determinazione del livello di coinvolgimento e di soddisfazione. Le convinzioni di efficacia personale degli insegnanti svolgono un ruolo significativo sulla determinazione delle proprie percezioni e valutazioni scolastiche. Esse riflettono l’esperienza di ogni insegnante, la storia di successi e fallimenti degliindividui nella loro propria esperienza di insegnamento

Testosterone and Biological Characteristics of Breast Cancers in Postmenopausal Women

Abstract Androgens are involved in the development of breast cancer, although the mechanisms remain unclear. To further investigate androgens in breast cancer, we examined the relations between serum testosterone and age, body mass index (BMI), tumor size, histologic type, grade, axillary node involvement, estrogen receptor status, progesterone receptor status, and HER2 overexpression in a cross-sectional study of 592 postmenopausal breast cancer patients. Mean testosterone differences according to categories of patient and tumor characteristics were assayed by Fisher's or Kruskall-Wallis test as appropriate; adjusted odds ratios (OR) of having a tumor characteristic by testosterone tertiles were estimated by logistic regression. Testosterone concentrations were significantly higher in women with BMI ≥30 versus BMI <25. ORs of having a tumor ≥2 cm increased significantly with increasing testosterone tertiles, and the association was stronger in women ≥65 years. The OR of having infiltrating ductal carcinoma was significantly higher in the highest compared with the lowest testosterone tertile. ORs of having estrogen receptor– and progesterone receptor–negative versus estrogen receptor– and progesterone receptor–positive tumors decreased significantly with increasing testosterone tertiles. In women ≥70 years, those with high testosterone had a significantly greater OR of HER2-negative cancer than those with low testosterone. These results support previous findings that high-circulating testosterone is a marker of hormone-dependent breast cancer. The age-related differences in the association of testosterone with other disease and patient characteristics suggest that breast cancers in older postmenopausal women differ markedly from those in younger postmenopausal women. The relationship between testosterone and HER2 status in the oldest patients merits further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2942–8

What's new and what's next for biological and targeted synthetic treatments in psoriatic arthritis?

introductionpsoriatic arthritis (PsA) is a chronic arthritis typically associated with cutaneous psoriasis (PsO). Its pathogenesis is connected to an innate and acquired immune response, as well as genetic risk alleles. the extent of immunopathogenic mechanisms and the heterogenicity of clinical manifestation make the identification of patient-targeted therapies a critical issue, and the treatment decision challenging in patients' management.areas coveredThis review includes a brief overview of biological and small-molecule therapies, focusing on evidence from clinical trials and real-world data that support their use in PsA. We summarize novel and future possible therapeutic strategies, the importance that comorbidities have on selection of therapy and discuss the adverse event of each drug. relevant papers for up to 1 august 2022 (trials, real-life studies, and reviews) regarding biologics and/or small molecules were summarized.Expert opinionIn recent years, the treatment of PsA has been revolutionized by new targeted therapies, which offer the opportunity to perform a tailored-tail management, considering risk factors, comorbidities, and the different PsA phenotypes. growing experience with these new agents allows novel treatment approaches that may improve clinical outcomes for PsA patients, in terms of remission/low disease activity and quality of life

Allosterism vs. Orthosterism: Recent Findings and Future Perspectives on A2B AR Physio-Pathological Implications

The development of GPCR (G-coupled protein receptor) allosteric modulators has attracted increasing interest in the last decades. The use of allosteric modulators in therapy offers several advantages with respect to orthosteric ones, as they can fine-tune the tissue responses to the endogenous agonist. Since the discovery of the first A1 adenosine receptor (AR) allosteric modulator in 1990, several efforts have been made to develop more potent molecules as well as allosteric modulators for all adenosine receptor subtypes. There are four subtypes of AR: A1, A2A, A2B, and A3. Positive allosteric modulators of the A1 AR have been proposed for the cure of pain. A3 positive allosteric modulators are thought to be beneficial during inflammatory processes. More recently, A2A and A2B AR allosteric modulators have also been disclosed. The A2B AR displays the lowest affinity for its endogenous ligand adenosine and is mainly activated as a consequence of tissue damage. The A2B AR activation has been found to play a crucial role in chronic obstructive pulmonary disease, in the protection of the heart from ischemic injury, and in the process of bone formation. In this context, allosteric modulators of the A2B AR may represent pharmacological tools useful to develop new therapeutic agents. Herein, we provide an up-to-date highlight of the recent findings and future perspectives in the field of orthosteric and allosteric A2B AR ligands. Furthermore, we compare the use of orthosteric ligands with positive and negative allosteric modulators for the management of different pathological conditions

Blockade of thrombopoietin reduces organ damage in experimental endotoxemia and polymicrobial sepsis

BACKGROUND AND PURPOSE:Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions. METHODS:We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model. RESULTS:In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01), and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01) and from 1.43±0.37 to 0.40±0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01) and from 1.25±0.31 to 0.13±0.13 (P<0.001), respectively, in the CLP model. Similarly, the number of hepatic microabscesses was decreased from 14.14±1.41 to 3.64±0.56 in the LPS model at 3 hours (P<0.001), and from 1.71±0.29 to 0.13±0.13 in the CLP model (P<0.001). Finally, the diameter of intestinal villi decreased from 90.69±3.95 μm to 70.74±3.60 μm in the LPS model at 3 hours (P<0.01), and from 74.29±4.29 μm to 57.50±1.89 μm in the CLP model (P<0.01). This protective effect was associated with the blunting of the increase in platelet-monocyte adhesion, and, on the contrary, with increased platelet-neutrophil aggregates in the circulation, which may be related to decreased neutrophil sequestration into the inflamed tissues. Conversely, circulating cytokine levels were not significantly changed, in both models, by mTPOR-MBP administration. CONCLUSION:Our results demonstrate that TPO participates in the development of organ damage induced by experimental endotoxemia or polymicrobial sepsis via a mechanism involving increased platelet-leukocyte adhesion, but not cytokine release, and suggest that blocking TPO may be useful in preventing organ damage in patients affected by systemic inflammatory response or sepsis

Novel positive allosteric modulators of A2B adenosine receptor acting as bone mineralisation promoters

Small-molecules acting as positive allosteric modulators (PAMs) of the A2B adenosine receptor (A2B AR) could potentially represent a novel therapeutic strategy for pathological conditions characterised by altered bone homeostasis, including osteoporosis. We investigated a library of compounds (4-13) exhibiting different degrees of chemical similarity with three indole derivatives (1-3), which have been recently identified by us as PAMs of the A2B AR able to promote mesenchymal stem cell differentiation and bone formation. Evaluation of mineralisation activity of 4-13 in the presence and in the absence of the agonist BAY60-6583 allowed the identification of lead compounds with therapeutic potential as anti-osteoporosis agents. Further biological characterisation of one of the most performing compounds, the benzofurane derivative 9, confirmed that such a molecule behaves as PAM of the A2B AR

In-hospital and web-based intervention to counteract vaccine hesitancy in very preterm infants’ families: a NICU experience

Background Vaccine hesitancy is a global problem, carrying significant health risks for extremely vulnerable population as that of preterm infants. Social media are emerging as significant tools for public health promotion. Our aim was to evaluate both the coverage and the timeliness of routine immunizations in a cohort of preterm infants (&lt; 33 weeks of gestational age) at 24 months of age whose families have been subjected to in-hospital and web-based interventions to counteract vaccine hesitancy. Methods For a period of 2 years parents of preterm infants were instructed during their follow up visits by a member of the NICU team to get correct informations about vaccines from a social network page. Vaccination rates of preterm infants were assessed at 24 months of chronological age with an electronic database and compared to both general population and historical cohort. Results Coverage and timeliness of vaccinations at 24 months of age of 170 preterm infants were analyzed in December 2019. Gestational age and birth weight median (IQR) were, respectively, 31.0 (5.0) weeks and 1475.0 (843.8) g. Coverage rates were similar to those of the regional population (p &gt; 0.05), while timeliness of administration was significantly delayed compared to the recommended schedule (p &lt; 0.001). Age of administration was not correlated with either body weight and gestational age at birth (Spearman rank, p &gt; 0.05). DTaP-IPV-HBV-Hib 2nd and 3rd doses, MMR and Varicella vaccines coverage data were higher compared to historical cohort (p &lt; 0.05). Conclusion Increasing vaccine confidence through web-based interventions could have a positive impact on vaccination acceptance of parents of preterm infants, although timeliness results still delayed. There is a strong need to develop different and effective vaccination strategies to protect this very vulnerable population