Role of Adhesion Molecules in the Mechanism of Non-MHC (Major Histocompatibility Complex) Restricted Cell-Mediated Cytotoxicity

Adhesion molecules involved in the interaction between immune system effector cells and tumor targets are surface molecules which contribute to the formation of cell-to-cell contacts and belong to the integrin family. In this paper, the role played by the adhesion molecules in the process of cell-mediated cytotoxicity is reviewed. Furthermore, the contact area between effector and target cells has been analyzed by scanning electron microscopy. This region, termed closed chamber , seems to contribute to killing efficiency by creating an intimate contact region in which cytotoxic factors can easily induce lethal hit in target cell. Thus, the extension of the closed chamber seems to be positively related to effector cell killing potential as well as to target cell sensitivity and, in this context, the adhesion molecules prove to play a pivotal role. In fact, a receptor-ligand interaction occurs between CD11a/CD18 (LFA-1) and CD2 molecules, expressed on the effector cells, and the respective counterparts on target cells, i.e., ICAM-1, ICAM-2, or LFA-3. Treatment with antibodies against such molecules strongly modifies closed chamber formation without inhibiting cell-to-cell binding. Nevertheless, in these conditions, the killing ability of different effector cells toward tumor targets appears to be strongly impaired. Hence, the adhesion molecules seem to be strongly involved in the formation of the closed chamber as well as in the activation of effector cell killing machinery

Integration of HVSR measures and stratigraphic constraints for seismic microzonation studies: the case of Oliveri (ME)

Because of its high seismic hazard the urban area of Oliveri has been subject of first level seismic microzonation. The town develops on a large coastal plain made of mixed fluvial/marine sediments, overlapping a complexly deformed substrate. In order to identify points on the area probably suffering relevant site effects and define a preliminary Vs subsurface model for the first level of microzonation, we performed 23 HVSR measurements. A clustering technique of continuous signals has been used to optimize the calculation of the HVSR curves. 42 reliable peaks of the H/V spectra in the frequency range 0.6–10 Hz have been identified. A second clustering technique has been applied to the set of 42 vectors, containing Cartesian coordinates, central frequency and amplitude of each peak to identify subsets which can be attributed to continuous spatial phenomena. The algorithm has identified three main clusters that cover significant parts of the territory of Oliveri. The HVSR data inversion has been constrained by stratigraphic data of a borehole. To map the trend of the roof of the seismic bedrock, from the complete set of model parameters only the depth of the seismic interface that generates peaks fitting those belonging to two clusters characterized by lower frequency has been extracted

A Scanning Electron Microscopy Analysis of Human Cytotoxic Cell Subsets and of Their Mode of Conjugation with Tumor Cell Targets

In this study we describe the surface features of non-MHC (Major Histocompatibility Complex)-restricted cytotoxic cells isolated from human peripheral blood. Purified populations of CD3-, natural killer (NK) cells were allowed to interact with NK-sensitive (K562) and NK-resistant (THP-1-0) tumor cell targets. The type of effector to target cell binding was investigated by scanning electron microscope (SEM) analysis. A different interaction with the effectors is described for NK-resistant targets in comparison with NK-susceptible tumor cells. SEM was also used to investigate the relationship between interleukin 2 (IL2)-activated cytotoxic cells (lymphokine-activated killer, LAK, cells) and the tumor targets. We also describe the unique growth features of certain clones of cytotoxic T cells expressing γδ antigen receptors which support the contention that these cells may have a special ability of homing into tissues. We conclude that non-specific cytotoxic cells constitute a diverse population of effectors which differ not only for the expression of surface antigens, but also for their ability to interact with tumor cell targets and to home into the peripheral tissues where they may exert their lytic functions

Ambiente e clima della Sicilia durante gli ultimi 20 mila anni

Environment and Climate in Sicily over the last 20, 000 years. (IT ISSN 0394-3356, 2010). A series of recent studies shed light on the central Mediterranean, and Sicily, climate and environment, starting from the last glacial maximum (about 20 ka cal BP). In the present paper, we examine most of these works, in order to unravel environmental changes of the past, mainly in terms of temperature, atmospheric pattern, precipitation, vegetation and faunal associations. The climate of the last glacial maximum was characterised by very low temperature and by repeated northerlies penetration, even during summer. Low precipitation values led to a steppe- or semisteppe-like vegetation pattern, dominated by herbs and shrubs. Episodes of climatic anomaly, characterised by lower temperature and strengthened wind activity, could have occurred during the Holocene, as testified by micropaleontological and geochemical investigations carried out on the southern Tyrrhenian Sea and in the northern Sicily Channel. In the terrestrial record, there is evidence of drought at 8.2 ka cal BP, from the isotopic composition of a stalagmite recovered near Palermo, and of prolonged drought intervals during the Little Ice Age in the Erice village (Trapani). The vegetation pattern shows the development of Mediterranean Maquis in coastal sites and deciduous forests in sub-montane and montane regions, approximately from the Holocene base. The human impact is the main factor that forced the present vegetation pattern, as a consequence of intensive land-use, which started about 2.7 ka cal BP, when Greek colonies were first established. Human activity is however superimposed on a natural trend towards aridity, with climatic forces still not fully understood

Effects of Sacubitril/Valsartan on Exercise Capacity in Patients with Heart Failure with Reduced Ejection Fraction and the Role of Percentage of Delayed Enhancement Measured by Cardiac Magnetic Resonance in Predicting Therapeutic Response: A Multicentre Study

Background: This study aims to evaluate the cardiopulmonary effects of sacubitril/valsartan therapy in patients with heart failure with reduced ejection fraction (HFrEF), investigating a possible correlation with the degree of myocardial fibrosis, as assessed by cardiac magnetic resonance. Methods: A total of 134 outpatients with HFrEF were enrolled. Results: After a mean follow-up of 13.3 ± 6.6 months, an improvement in ejection fraction and a reduction in E/A ratio, inferior vena cava size and N-terminal pro-B-type natriuretic peptide levels were observed. At follow-up, we observed an increase in VO2 peak of 16% (p34 (OR 3.98; 95% CI [1.59–10.54]; p=0.0028); ventilatory oscillatory pattern (OR 4.65; 95% CI [1.55–16.13]; p=0.0052); and haemoglobin level (OR 0.35; 95% CI [0.21–0.55]; p4.6% was detected, a lower response after sacubitril/valsartan therapy was observed as expressed by improvement in ΔVO2 peak, O2 pulse, LVEF and N-terminal pro-B-type natriuretic peptide. No significant differences were observed in ΔVO2/Δ work and VE/VCO2 slope. Conclusion: Sacubitril/valsartan improves cardiopulmonary functional capacity in HFrEF patients. The presence of myocardial fibrosis on cardiac magnetic resonance is a predictor of response to therapy

COVID-19-associated Guillain-Barré syndrome in the early pandemic experience in Lombardia (Italy)

Objective To estimate the incidence and describe clinical characteristics and outcome of GBS in COVID-19 patients (COVID19-GBS) in one of the most hit regions during the frst pandemic wave, Lombardia. Methods Adult patients admitted to 20 Neurological Units between 1/3–30/4/2020 with COVID19-GBS were included as part of a multi-center study organized by the Italian society of Hospital Neuroscience (SNO). Results Thirty-eight COVID19-GBS patients had a mean age of 60.7 years and male frequency of 86.8%. CSF albuminocytological dissociation was detected in 71.4%, and PCR for SARS-CoV-2 was negative in 19 tested patients. Based on neurophysiology, 81.8% of patients had a diagnosis of AIDP, 12.1% of AMSAN, and 6.1% of AMAN. The course was favorable in 76.3% of patients, stable in 10.5%, while 13.2% worsened, of which 3 died. The estimated occurrence rate in Lombardia ranges from 0.5 to 0.05 GBS cases per 1000 COVID-19 infections depending on whether you consider positive cases or estimated seropositive cases. When we compared GBS cases with the pre-pandemic period, we found a reduction of cases from 165 to 135 cases in the 2-month study period in Lombardia. Conclusions We detected an increased incidence of GBS in COVID-19 patients which can refect a higher risk of GBS in COVID-19 patients and a reduction of GBS events during the pandemic period possibly due to a lower spread of more common respiratory infectious diseases determined by an increased use of preventive measures

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.The Lombardia GENS project has received funding from the Regione Lombardia Government as a Research Independent Project (DGR n°VIII/006128-12/12/2007). Lombardia GENS is an investigator-driven, academic, non-profit consortium and is publicly funded. Hugh Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals NIHR Biomedical Research Centr

La Piattaforma Carbonatica Panormide : un caso anomalo nell’evoluzione dei bacini della Tetide giurassica

Negli ultimi anni sono state proposte diverse ricostruzioni paleogeografiche dell’area Centro Mediterranea durante il Mesozoico. La Piattaforma Carbonatica Panormide (PCPA) viene collocata tra la Tetide Alpina e la Tetide Ionica, in un’area geodinamicamente molto complessa. Recenti studi hanno documentato la presenza di superfici di discontinuità che caratterizzano l’evoluzione stratigrafica della PCPA rispetto alle adiacenti Piattaforme Carbonatiche Siciliane. La presenza di superfici di discontinuità negli intervalli Retico-Hettangiano e Giurassico Medio-Oxfordiano vengono messe in relazione, attraverso il confronto della storia della subsidenza tra le Piattaforme Carbonatiche, con gli stadi evolutivi della Tetide Alpin