The VZV/IE63-specific T cell response prevents herpes zoster in fingolimod-treated patients.

OBJECTIVE: To assess longitudinally the antiviral immune response of T cells from patients with multiple sclerosis (MS) treated with fingolimod (FTY) vs other disease-modifying treatments (DMTs). METHODS: We assessed cellular immune responses specific to influenza virus (FLU), JC virus (JCV), and varicella-zoster virus (VZV) using quantification of interferon-γ secretion by enzyme-linked immunospot in patients with MS on FTY (n = 31), including 2 with herpes zoster (HZ), natalizumab (n = 11), and other DMTs (n = 11). We used viral lysates for FLU and VZV and a pool of peptides for FLU, JCV (VP-1), and VZV (IE63). RESULTS: Besides an expected drop of T cells, we found that, proportionally to the number of CD3(+) T cells, only FTY-treated patients with MS exhibited an increased VZV/IE63-specific T cell response peaking 6 months into treatment, a response that returned to baseline after 12 and 24 months. Two FTY-treated patients developed an HZ 6 months into treatment, coinciding with an absent VZV/IE63-specific T cell response. However, cellular immune responses specific to VZV lysate, JCV, and FLU (lysate and pool of peptide epitopes) were similar between all 3 categories (FTY, natalizumab, and other DMTs) of study patients. CONCLUSIONS: FTY-treated patients with MS exhibit an increased VZV/IE63-specific cellular immune response after 6 months of treatment. FTY-treated patients who develop an HZ are not able to mount such a response, suggesting that a T cell response directed against this viral protein may be key in preventing the occurrence of HZ

Cold affects the transcription of fatty acid desaturases and oil quality in the fruit of Olea europaea L. genotypes with different cold hardiness

The olive tree lacks dormancy and is low temperature sensitive, with differences in cold tolerance and oil quality among genotypes. The oil is produced in the drupe, and the unsaturated fatty acids contribute to its quality. The aim of the present research was to investigate the relationship among development, cold response, expression of fatty acid desaturase (FAD) genes, and unsaturated fatty acid composition in drupes belonging to genotypes differing in leaf cold tolerance, but producing good oil (i.e. the non-hardy Moraiolo, the semi-hardy Frantoio, and the hardy Canino). In all genotypes, cold sensitivity, evaluated by cold-induced transient increases in cytosolic calcium, was high in the epi-mesocarp cells before oil body formation, and decreased during oil biogenesis. However, genotype-dependent differences in cold sensitivity appeared at the end of oil production. Genotype-dependent differences in FAD2.1, FAD2.2, FAD6, and FAD7 expression levels occurred in the epi-mesocarp cells during the oleogenic period. However, FAD2.1 and FAD7 were always the highest in the first part of this period. FAD2.2 and FAD7 increased after cold applications during oleogenesis, independently of the genotype. Unsaturated fatty acids increased in the drupes of the non-hardy genotype, but not in those of the hardy one, after cold exposure at the time of the highest FAD transcription. The results show a direct relationship between FAD expression and lipid desaturation in the drupes of the cold-sensitive genotype, and an inverse relationship in those of the cold-resistant genotype, suggesting that drupe cold acclimation requires a fine FAD post-transcriptional regulation. Hypotheses relating FAD desaturation to storage and membrane lipids, and genotype cold hardiness are discussed

Prognostic factors and biomarkers of responses to immune checkpoint inhibitors in lung cancer

Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses

COVID-19 and the elderly: insights into pathogenesis and clinical decision-making

The elderly may represent a specific cluster of high-risk patients for developing COVID-19 with rapidly progressive clinical deterioration. Indeed, in older individuals, immunosenescence and comorbid disorders are more likely to promote viral-induced cytokine storm resulting in life-threatening respiratory failure and multisystemic involvement. Early diagnosis and individualized therapeutic management should be developed for elderly subjects based on personal medical history and polypharmacotherapy. Our review examines the pathogenesis and clinical implications of ageing in COVID-19 patients; finally, we discuss the evidence and controversies in the management in the long-stay residential care homes and aspects of end-of-life care for elderly patients with COVID-19

Sensitisation of spinal cord pain processing in medication overuse headache involves supraspinal pain control.

Medication overuse could interfere with the activity of critical brain regions involved in the supraspinal control of pain signals at the trigeminal and spinal level, leading to a sensitisation phenomenon responsible for chronic pain. We hypothesised that medication-overuse headache ( MOH) patients might display abnormal processing of pain stimuli at the spinal level and defective functioning of the diffuse noxious inhibitory controls. We tested 31 MOH patients before (bWT) and after (aWT) standard inpatient withdrawal treatment, 28 episodic migraine ( EM) patients and 23 healthy control subjects. We measured the threshold, the area and the temporal summation threshold (TST) of the nociceptive withdrawal reflex before, during and after activation of the diffuse noxious inhibitory controls by means of the cold pressor test. A significantly lower TST was found in both the MOH (bWT and aWT) and the EM patients compared with the controls, and in the MOH patients bWT compared with both the MOH patients aWT and the EM patients. In the MOH bWT patients the cold pressor test induced a TST increase significantly lower than that found in the MOH aWT, EM and control groups. Abnormal spinal cord pain processing and a decrease of the antinociceptive activity of the supraspinal structures in MOH patients can be hypothesised. These abnormalities could, in part, be related to the medication overuse, given that the withdrawal treatment was related to an improvement in the neurophysiological findings

The Fluid-dynamics of endo vascular aneurysm sealing (EVAS) system failure

Purpose The main objective of this work is to investigate hemodynamics phenomena occurring in EVAS (Endo Vascular Aneurysm Sealing), to understand if and how they could lead to type 1a endoleaks and following re-intervention. To this aim, methods based on computational fluid mechanics are implemented as a tool for checking the behavior of a specific EVAS configuration, starting from the post-operative conditions. Pressure and velocity fields are detailed and compared, for two configurations of the Nellix, one as attained after correct implantation and the other in pathological conditions, as a consequence of migration or dislocation of endobags. Methods The computational fluid dynamics (CFD) approach is used to simulate the behavior of blood within a segment of the aorta, before and after the abdominal bifurcation. The adopted procedure allows reconstructing the detailed vascular geometry from high-resolution computerized tomography (CT scan) and generating the mesh on which the equations of fluid mechanics are discretized and solved, in order to derive pressure and velocity field during heartbeats. Results The main results are obtained in terms of local velocity fields and wall pressures. Within the endobags, velocities are usually quite regular during the whole cardiac cycle for the post-implanted condition, whereas they are more irregular for the migrated case. The largest differences among the two cases are observed in the shape and location of the recirculation region in the rear part of the aorta and the region between the endobags, with the formation of a gap due to the migration of one or both of the two. In this gap, the pressure fields are highly different among the two conditions, showing pressure peaks and pressure gradients at least four times larger for the migrated case in comparison to the post-implanted condition. Conclusions In this paper, the migration of one or both endobags is supposed to be related to the existing differential pressures acting in the gap formed between the two, which could go on pushing the two branches one away from the other, thus causing aneurysm re-activation and endoleaks. Regions of flow recirculation and low-pressure drops are revealed only in case of endobag migration and in presence of an aneurysm. These regions are supposed to lead to possible plaque formation and atherosclerosis

S100B is not a reliable prognostic index in paediatric TBI.

Pediatr Neurosurg. 2007;43(4):258-64

Non-chaotic dynamics in general-relativistic and scalar-tensor cosmology

In the context of scalar-tensor models of dark energy and inflation, the dynamics of vacuum scalar-tensor cosmology are analysed without specifying the coupling function or the scalar field potential. A conformal transformation to the Einstein frame is used and the dynamics of general relativity with a minimally coupled scalar field are derived for a generic potential. It is shown that the dynamics are non-chaotic, thus settling an existing debate.Comment: 20 pages, LaTeX, to appear in Class. Quantum Gra