Functional MRI correlates of cognitive performance in patients with a clinically isolated syndrome suggestive of MS at presentation: an activation and connectivity study

Background/Objective: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis. Methods: Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered ‘cognitive impairment’ (CI); eight patients were defined as ‘cognitively preserved’ (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed. Results: During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC. Conclusions: During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment.This research has been supported by the following grants: Alicia Koplowitz Foundation; CSD2007-00012 (Consolider-Ingenio 2010 Programme), SEJ2007-65929/PSIC and PSI2010-20168 from the Spanish Ministry of Science and Education; the Dávalos Foundation Grant and P1·1A2010-07 from Bancaixa

Cold Tumors: A Therapeutic Challenge for Immunotherapy

Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called “cold tumors.” In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ‘‘supra-physiological’’ therapies, such as T cell recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism involved, especially in MHC class I negative tumors. The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors

Antagonism/Agonism modulation to build novel antihypertensives selectively triggering i1-imidazoline receptor activation

Pharmacological studies have suggested that I1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I1-agonists, devoid of the side effects associated with the common hypotensive α2-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I1 proteins

Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study

Introduction In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). Methods BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and &gt;= 3 (late add-on) prior antiseizure medications. Results A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p &lt; 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p &lt; 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p &lt; 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. Conclusion Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32–56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12&nbsp;months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy

Changement de l’homéostasie du Zinc et du Cadmium par l’inflammation chronique et nouvelles options thérapeutiques pour le traitement de l’arthrite

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Synoviocytes, cells forming the inner layer the synovium, become refractory to apoptosis and participate in the chronicity of inflammation through the production of IL-6. The perpetuation of inflammation causes an important induction of bone loss in joints.Zinc (Zn) and Cadmium (Cd) share many physico-chemical properties and cell transport mechanism. Zn is known as a regulator of the normal function of the immune system, while Cd properties on the immune system are not well defined.Our aim was to provide information on the metal homeostasis mechanisms in synoviocytes during chronic inflammation and on the consequences of metal homeostasis changes. After studying the differential effect of Zn and Cd at the cellular level, we could provide an innovative tool to control synoviocyte contribution to rheumatoid arthritis, which was tested on an in vivo model of arthritis.Results show that IL-17/TNF-a combination drives the accumulation of metals inside synoviocytes through the enhancing of ZIP-8 importer expression and regardless of the concentration of metals in the culture medium. In contrast, the expression of the metal exporter ZnT1 and of the homeostasis regulators metallothioneins (MTs) was primarily dependent on metal levels.Addition of Zn stimulated the inflammatory response, while addition of Cd can reduce both viability and inflammation.The anti-proliferative and anti-inflammatory properties of Cd were used in the rat model of arthritis as intra-articular treatment to reduce local inflammation and joint destruction and it may represent a new local therapeutic approach for RA treatmentLa polyarthrite rhumatoïde (PR) est une maladie inflammatoire chronique caractérisée par des atteintes articulaires. Les synoviocytes, cellules qui tapissent la membrane synoviale, deviennent réfractaires à l‘apoptose et, en produisant la cytokine inflammatoire Interleukin 6 (IL-6), participent à la chronicité de l‘inflammation qui est à l‘origine de la perte osseuse dans la PR.Le zinc (Zn) et le cadmium (Cd) partagent leurs propriétés physico-chimiques et leurs mécanismes de transport cellulaire. Le Zn régule des fonctions du système immunitaire, contrairement au Cd avec des propriétés sur le système immunitaire peu décrites dans la littérature.Notre travail vise à identifier les mécanismes impliqués dans la modification de l‘homéostasie des métaux dans les synoviocytes par l‘inflammation et les conséquences de cette altération.L‘inflammation induit l‘accumulation des métaux dans les synoviocytes en augmentant l‘expression de l‘importeur ZIP-8. En revanche, l‘expression de l‘exporteur ZnT1 et des metallothionéines (MTs, régulateurs de l‘homéostasie des métaux) est dépendante de la présence des métaux. L‘affinité Cd-MTs permet une accumulation irréversible du Cd dans les cellules qui réduit leur prolifération et la production d‘IL-6.Les effets antiprolifératif et anti-inflammatoire du Cd ont été testés dans le modèle d‘arthrite chez le rat où une seule injection intra-articulaire de Cd à faible dose prévient la perte osseuse et réduit les scores cliniques d‘arthrite. Cela pourrait représenter une nouvelle approche thérapeutique pour le traitement de la PR et d'autres pathologies caractérisées par une hyperplasie et une inflammation localisée

Zinc an Cadmium homeostasis changes in chronic inflammation and new treatment options in arthritis

La polyarthrite rhumatoïde (PR) est une maladie inflammatoire chronique caractérisée par des atteintes articulaires. Les synoviocytes, cellules qui tapissent la membrane synoviale, deviennent réfractaires à l‘apoptose et, en produisant la cytokine inflammatoire Interleukin 6 (IL-6), participent à la chronicité de l‘inflammation qui est à l‘origine de la perte osseuse dans la PR.Le zinc (Zn) et le cadmium (Cd) partagent leurs propriétés physico-chimiques et leurs mécanismes de transport cellulaire. Le Zn régule des fonctions du système immunitaire, contrairement au Cd avec des propriétés sur le système immunitaire peu décrites dans la littérature.Notre travail vise à identifier les mécanismes impliqués dans la modification de l‘homéostasie des métaux dans les synoviocytes par l‘inflammation et les conséquences de cette altération.L‘inflammation induit l‘accumulation des métaux dans les synoviocytes en augmentant l‘expression de l‘importeur ZIP-8. En revanche, l‘expression de l‘exporteur ZnT1 et des metallothionéines (MTs, régulateurs de l‘homéostasie des métaux) est dépendante de la présence des métaux. L‘affinité Cd-MTs permet une accumulation irréversible du Cd dans les cellules qui réduit leur prolifération et la production d‘IL-6.Les effets antiprolifératif et anti-inflammatoire du Cd ont été testés dans le modèle d‘arthrite chez le rat où une seule injection intra-articulaire de Cd à faible dose prévient la perte osseuse et réduit les scores cliniques d‘arthrite. Cela pourrait représenter une nouvelle approche thérapeutique pour le traitement de la PR et d'autres pathologies caractérisées par une hyperplasie et une inflammation localiséesRheumatoid arthritis (RA) is a chronic inflammatory disease. Synoviocytes, cells forming the inner layer the synovium, become refractory to apoptosis and participate in the chronicity of inflammation through the production of IL-6. The perpetuation of inflammation causes an important induction of bone loss in joints.Zinc (Zn) and Cadmium (Cd) share many physico-chemical properties and cell transport mechanism. Zn is known as a regulator of the normal function of the immune system, while Cd properties on the immune system are not well defined.Our aim was to provide information on the metal homeostasis mechanisms in synoviocytes during chronic inflammation and on the consequences of metal homeostasis changes. After studying the differential effect of Zn and Cd at the cellular level, we could provide an innovative tool to control synoviocyte contribution to rheumatoid arthritis, which was tested on an in vivo model of arthritis.Results show that IL-17/TNF-a combination drives the accumulation of metals inside synoviocytes through the enhancing of ZIP-8 importer expression and regardless of the concentration of metals in the culture medium. In contrast, the expression of the metal exporter ZnT1 and of the homeostasis regulators metallothioneins (MTs) was primarily dependent on metal levels.Addition of Zn stimulated the inflammatory response, while addition of Cd can reduce both viability and inflammation.The anti-proliferative and anti-inflammatory properties of Cd were used in the rat model of arthritis as intra-articular treatment to reduce local inflammation and joint destruction and it may represent a new local therapeutic approach for RA treatmen

Cancer vaccines: what’s next?

International audienc