RadioLab is an Italian project, addressed to school-age people, and designed for the dissemination of scientific culture on the theme of environmental radioactivity, with particular regards to the ...importance of knowledge of radon gas exposure. The project is a nationwide initiative promoted by the National Institute of Nuclear Physics- INFN. First tool used by the project, and of immediate impact to assess the public awareness on radon, is the administration of the survey "do you know the radon gas?". In the survey, together with the knowledge of radon and of its sources, information on personal, cultural and territorial details regarding the interviewees are also taken. Reasonably, the survey invests not only young people, but also their relatives, school workers and, gradually, the public. The survey is administrated during exhibitions or outreach events devoted to schools, but also open to the public. The survey is in dual form: printed and online. The online mode clearly leads RadioLab project even outside the school environment. Based on the results of the survey, several statistical analyses have been performed and many conclusions are drawn about the knowledge of the population on the radon risk. The RadioLab benefit and the requirement to carry on the project goals, spreading awareness of environmental radioactivity from radon, emerge. The dataset involves all twenty Italian regions and consists of 28,612 entries covering the 5-year period 2018-2022.
Polycythemia vera (PV) is associated with increased risk of thrombosis and hemorrhage. Aspirin, recommended for primary thromboprophylaxis, is often combined with anticoagulants during management of ...acute thrombotic events. The safety of dual antiplatelet and anticoagulant therapy is not established in PV. In a prospective, observational study, 2,510 patients with PV were enrolled at 227 sites in the United States. Patients were monitored for the development of hemorrhage and thrombosis after enrollment. A total of 1,602 patients with PV received aspirin with median follow-up of 2.4 years (range, 0-3.6 years). The exposure-adjusted rate of all hemorrhages in patients receiving aspirin alone was 1.40 per 100 patient-years (95% confidence interval CI: 0.99-1.82). The combination of aspirin plus anticoagulant was associated with an incidence of hemorrhage of 6.75 per 100 patient-years (95% CI: 3.04-10.46). The risk of hemorrhage was significantly greater in patients receiving the combination of aspirin and anticoagulant compared with aspirin alone (total hemorrhages, hazard ratio HR: 5.83; 95% CI: 3.36-10.11; P<0.001; severe hemorrhage, HR: 7.49; 95% CI: 3.02-18.62; P<0.001). Periods of thrombocytosis (>600×109/L) were associated with an increased risk of hemorrhage (HR: 2.25; 95% CI: 1.16- 4.38; P=0.02). Rates of hemorrhage were similar for aspirin in combination with warfarin or direct-acting oral anticoagulants. We conclude that the combination of aspirin and anticoagulants is associated with significantly increased risk of hemorrhage in patients with PV (clinicaltrials gov. Identifier: NCT02252159).
Background: Anticoagulants are expected to promote fibrinolysis by counteracting the antifibrinolytic effects of thrombin, which include thrombin‐activatable fibrinolysis inhibitor (TAFI) activation ...and clot structure enhancement. However, the efficiency of anticoagulants may vary remarkably, and the ability of direct thrombin inhibitors to facilitate clot lysis remains controversial. Objective: To evaluate the profibrinolytic effect of dabigatran, a new, direct thrombin inhibitor, using different in vitro models. Methods and Results: The resistance of tissue factor‐induced plasma clots to fibrinolysis by exogenous tissue‐type plasminogen activator (t‐PA) (turbidimetric method) was reduced by dabigatran in a concentration‐dependent manner, with ≥ 50% shortening of lysis time at clinically relevant concentrations (1–2 μm). A similar effect was observed in the presence of low (0.1 and 1 nm) but not high (10 nm) concentrations of thrombomodulin. Acceleration of clot lysis by dabigatran was associated with a reduction in TAFI activation and thrombin generation, and was largely, although not completely, negated by an inhibitor of activated TAFI, potato tuber carboxypeptidase inhibitor. The assessment of the viscoelastic properties of clots showed that those generated in the presence of dabigatran were more permeable, were less rigid, and consisted of thicker fibers. The impact of these physical changes on fibrinolysis was investigated using a model under flow conditions, which demonstrated that dabigatran made the clots markedly more susceptible to flowing t‐PA, by a mechanism that was largely TAFI‐independent. Conclusions: Dabigatran, at clinically relevant concentrations, enhances the susceptibility of plasma clots to t‐PA‐induced lysis by reducing TAFI activation and by altering the clot structure. These mechanisms might contribute to the antithrombotic activity of the drug.
Essentials
Plasma of factor XI‐deficient patients (FXI‐dp) displays enhanced fibrinolysis.
We investigated the role of thrombin activatable fibrinolysis inhibitor (TAFI) in 18 FXI‐dp.
FXI‐dp ...generated less activated TAFI (TAFIa) on clotting challenge and were resistant to TAFIa.
TAFI activation and TAFIa resistance correlated with bleeding score and bleeding phenotype.
Summary
Background
Factor XI (FXI) deficiency, a rare disorder with unpredictable bleeding, has been associated with reduced fibrinolytic resistance as a result of abnormal fibrin density.
Objective
We investigated the involvement of thrombin‐activatable fibrinolysis inhibitor (TAFI) in the increased lysability of FXI‐deficient (FXI‐def) clots and the role of thrombin.
Patients/Methods
Eighteen patients with FXI deficiency (1–58%) and 17 matched controls were investigated for fibrinolytic resistance to t‐PA, thrombin generation, TAFI activation and response to TAFIa.
Results
When clotting was induced by 0.5 pm tissue factor (TF), FXI‐def plasmas displayed less thrombin and TAFIa generation and shorter lysis time than controls. A 100‐fold higher TF concentration (to bypass FXI) abolished the difference in thrombin generation but not in lysis time between patients and controls. Normalization of FXI levels by a FXI concentrate increased thrombin generation but had no effect on the lysis time of FXI‐def plasma. Moreover, when clots were induced by purified thrombin and high concentrations of FXa inhibitor, FXI‐def plasma still generated less TAFIa and displayed a shorter lysis time than controls. Finally, upon TAFIa addition, the lysis time of FXI‐def plasma was prolonged significantly less than that of control plasma, suggesting a TAFIa resistance. TAFIa generation and TAFIa resistance were correlated with the bleeding score, displaying a considerable capacity to discriminate between patients with and without bleeding.
Conclusions
TAFI pathway impairment, largely caused by a hitherto unknown TAFIa resistance, appears to be one main cause of decreased fibrinolytic resistance in FXI deficiency and might be clinically useful for assessing the bleeding risk of FXI‐def patients.
Published data estimate the prevalence of the vascular ring at approximately 7 per 10,000 live births. The association of a double aortic arch with a D-transposition of the great arteries has been ...rarely described in the literature. In this study, we report the prenatal diagnosis of a 28-year-old woman. A fetal echocardiography at a gestational age of 24 weeks + 6 days showed a D-transposition of the great arteries and a double aortic arch with a ventricular septal defect and pulmonary stenosis. On the first night after birth, the baby experienced an increase in lactate levels, with the rate of oxygen saturation consistently below 80%. A few hours after birth, the patient underwent a Rashkind procedure. An echocardiography, CT chest x-ray, and CT angiogram confirmed a diagnosis with a severe reduction of the tracheal lumen (>85%) and bronchomalacia. Then, the patient underwent posterior tracheopexy and aortopexy and later an arterial switch operation, ventricular septal defect closure, and resection of a part of the infundibular septum, accepting the risk of potential neoaortic obstruction. The literature has reported only two cases of patients with a fetal echocardiogram diagnosis. Therefore, our patient is only the third one with a fetal diagnosis and the second one with a complex intracardiac anatomy, characterized not only by a ventricular septal defect but also by two separate components of the obstruction (a bicuspid valve and a dysplastic valve with a posterior deviation of the infundibular septum). In conclusion, a D-transposition of the great arteries with a double aortic arch remains an extremely unusual association. The clinical outcome of these patients presents a high degree of variability and is entirely unpredictable in prenatal life. Our greatest aim as fetal and perinatal cardiologists is to improve the management and outcome of these patients through a fetal diagnosis, recognizing types of congenital heart disease in newborns who require early neonatal invasive procedures.
Background: The resistance of platelet‐rich thrombi to fibrinolysis is generally attributed to clot retraction and platelet PAI‐1 release. The role of TAFI in platelet‐mediated resistance to lysis is ...unclear. Objective: We investigated the contribution of TAFI to the antifibrinolytic effect of platelets in whole blood by thromboelastography. Methods: Platelet‐poor (PP‐WB, < 40 × 103 μL−1) and platelet‐rich (PR‐WB, > 400 × 103 μL−1) blood samples were obtained from normal human blood (N‐WB, 150–220 × 103 μL−1). Clot lysis time was measured by thromboelastography in recalcified blood supplemented with t‐PA (100 ng mL−1) and tissue factor (1:1000 Recombiplastin). Results: t‐PA‐induced lysis time increased in parallel with platelet concentration (up to 3‐fold). Neutralization of TAFI, but not of PAI‐1, shortened the lysis time by ∼ 50% in PR‐WB and by < 10% in PP‐WB. Accordingly, prothrombin F1+2 and TAFIa accumulation was greater in PR‐WB than in PP‐WB. A similar TAFI‐dependent inhibition of fibrinolysis was observed when clot retraction was prevented by cytochalasin D or abciximab, or when platelet membranes were tested. Moreover, in blood with an intact contact system, platelet‐mediated fibrinolysis resistance was attenuated by an anti‐FXI but not by an anti F‐XII antibody. Finally, platelets made the clots resistant to the profibrinolytic effect of heparin concentrations displaying a strong anticoagulant activity. Conclusions: Our data indicate that TAFI activation is one major mechanism whereby platelets make clots resistant to fibrinolysis and underscore the importance of TAFI inhibitors as new antithrombotic agents.
Patients with Parkinson's disease develop motor disturbances often accompanied by peripheral autonomic dysfunctions, including gastrointestinal disorders, such as dysphagia, gastric stasis and ...constipation. While the mechanisms subserving enteric autonomic dysfunctions are not clearly understood, they may involve the enteric dopaminergic and/or nitrergic systems. In the present study, we demonstrate that rats with unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons develop a marked inhibition of propulsive activity compared to sham-operated controls, as indicated by a 60% reduction of daily fecal output at the 4th week of observation. Immunohistochemical data revealed that 6-hydroxydopamine treatment did not affect the total number of HuC/D-positive myenteric neurons in both the proximal and distal segments of ileum and colon. Conversely, in the distal ileum and proximal colon the number of nitrergic neurons was significantly reduced. These results suggest that a disturbed distal gut transit, reminiscent of constipation in the clinical setting, may occur as a consequence of a reduced propulsive motility, likely due to an impairment of a nitric oxide-mediated descending inhibition during peristalsis.
The anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) monoclonal antibody ipilimumab was the first in-class immune- checkpoint inhibitor (ICI) approved for the treatment of melanoma patients. Initially ...approved for metastatic cutaneous melanoma, treatment with ipilimumab subsequently demonstrated to significantly improve recurrence free survival (RFS) in fully resected, highrisk, stage III melanoma patients. Therapeutic use of ipilimumab has also allowed the initial identification and characterization of unconventional clinical and radiological patterns of response (ie, tumor flare, pseudo-progression) that may occur during ICI therapy, unlike chemotherapy or targeted therapy. As a result, the standard Response Evaluation Criteria In Solid Tumors (RECIST) and the World Health Organization (WHO) criteria conventionally utilized to assess responses to chemo/targeted therapy have been initially replaced by the immune-related (ir) Response Criteria (irRC) and then by the irRECIST, that encompass all patterns of response typical of ICI therapy, being key for the optimal comprehensive management of treated patients. Here, we report a paradigmatic clinical case of a long-term survival in a stage III melanoma patient, experiencing tumor flares during adjuvant treatment with ipilimumab, and an untreated disease relapse several years after ending therapy. Keywords: melanoma, ipilimumab, adjuvant therapy, tumor flare, pseudo-progression, long-term survival
Acute renal failure is a rare occurrence in a patient with an unremarkable past medical history and should always lead to an in depth clinical study. The occurrence in the same healthy young subject, ...of consecutive episodes of heart failure and of acute renal failure is an even rarer event and should prompt diagnostic tests and restrict the diagnostic hypotheses.
We present the case of a 28 year-old man who, while waiting to undergo assessment for a mild chronic kidney disease, was diagnosed with decompensated dilated cardiomyopathy and placed on diuretics and β-blockers. After few weeks he developed a non oligoanuric acute renal failure with a slight elevation of serum calcium. Renal biopsy proved suggestive for renal sarcoidosis; thus the hypothesis of systemic sarcoidosis with cardiac and renal involvement was possible avoiding further delay in initiation of therapy.
Cardiac sarcoidosis is usually silent but the majority of cases are diagnosed when cardiac symptoms are present in a patient with systemic sarcoidosis. Renal involvement with granulomatous interstitial nephritis is also quite rare and can be an unexpected finding at kidney biopsy. This case highlights the need to evaluate thoroughly clinical problems that do not fit in a specific scenario and emphasizes the importance of performing a kidney biopsy in case of kidney failure of unknown etiology.
DMSO is one of the most common solvents used experimentally to dissolve hydrophobic substances for
in vivo and
in vitro purposes. A wide range of pharmacological effects exerted by DMSO has been ...documented in both animal and human experimental models. However, only a few and sometimes contrasting data about the effects of DMSO in animal models of nociception and inflammation are presently available. In this study, we evaluated the effects induced by DMSO and a DMSO-containing saline on thermal and chemical nociception, inflammation and locomotor activity in CD1 mice. We demonstrated that centrally or orally administered DMSO displayed anti-nociceptive effects to thermal (hot plate and tail-flick test) and chemical (formalin test) stimuli. Conversely, DMSO was able to increase both nociceptive phases in the formalin test when applied subcutaneously in the dorsal surface of the mouse hind paws 10
min before formalin administration. Oral administration of DMSO produced anti-inflammatory effects on zymosan-induced edema in the mouse paw, whereas local administration potentiated the inflammatory action exerted by zymosan. Oral and central, but not local, administration of DMSO improved the mouse locomotor activity. These results suggest that DMSO displayed opposite effects on nociception and inflammation, depending on the route of administration. New and helpful evidence about DMSO laboratory applications need to be considered in the
in vivo studies to assess correctly the pharmacological properties of investigated drugs.
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