Platelets activate a pathogenic response to blood-stage Plasmodium infection but not a protective immune response

© 2017 by The American Society of Hematology. Clinical studies indicate that thrombocytopenia correlates with the development of severe falciparum malaria, suggesting that platelets either contribute to control of parasite replication, possibly as innate parasite killer cells or function in eliciting pathogenesis. Removal of platelets by anti-CD41 mAb treatment, platelet inhibition by aspirin, and adoptive transfer of wild-type (WT) platelets to CD40-KO mice, which do not control parasite replication, resulted in similar parasitemia compared with control mice. Human platelets at a physiologic ratio of 1 platelet to 9 red blood cells (RBCs) did not inhibit the in vitro development or replication of blood-stage Plasmodium falciparum. The percentage of Plasmodium-infected (iRBCs) with bound platelets during the ascending parasitemia in Plasmodium chabaudi- and Plasmodium berghei-infected mice and the 48-hour in vitro cycle of P falciparum was <10%. P chabaudi and P berghei iRBCs with apoptotic parasites (TdT1) exhibited minimal platelet binding (<5%), which was similar to nonapoptotic iRBCs. These findings collectively indicate platelets do not kill bloodstage Plasmodium at physiologically relevant effector-to-target ratios.Pchabaudi primary andsecondary parasitemiawassimilar in mice depleted of platelets by mAb-injection just before infection, indicating that activation of the protective immune response does not require platelets. In contrast to the lack of an effect on parasite replication, adoptive transfer ofWTplatelets to CD40-KOmice, which are resistant to experimental cerebral malaria, partially restored experimental cerebral malaria mortality and symptoms in CD40-KO recipients, indicating platelets elicit pathogenesis and platelet CD40 is a key molecule

Anxiety and Expressed Emotion in a Sample of Obese Patients

INTRODUCTION Expressed Emotion (EE) is a measure of the intensity of the affective family climate and plays a role in disease course and outcome. Especially in urban settings, obesity is a severe problem with serious implications as far as health risks are concerned. Having a high EE caregiver has been suggested to correlate with a worse treatment compliance in obese patients. OBJECTIVES To measure level of EE, stressful events and anxiety in obese patients and their caregivers; to investigate the possible correlations between compliance with treatment and emotional temperature of families. METHODS We have already recruited more than 150 obese patients and their caregivers. Assessment included: Level of Expressed Emotion Scale (LEE), one version for patients and one for relatives in order to evaluate 4 dimensions: intrusiveness, emotional response, attitude toward disease, tolerance and expectation; the Paykel\u2019s Interview for Recent Life Events; STAI Y1 concerning state anxiety and STAI Y2 concerning trait anxiety. Furthermore we collected demographic characteristics and BMI (Body Mass Index). RESULTS Data collection and analyses are still ongoing. Preliminary results suggest a correlation between obesity and level of anxiety. We expect to find a correlation between level of EE and variation of BMI. CONCLUSIONS Levels of EE and anxiety should be considered when planning treatment interventions to enhance compliance in obese patients and to support change in their life-style

Early Rehabilitation in a Psychiatric Ward for Acute Patients: the Experience of the S.C. Psichiatria, Aou Maggiore Della Carit\ue0, Novara, Italy

Introduction Our Psychiatry Ward (SC Psichiatria, Maggiore della Carit\ue0 Hospital, Novara) has a longstanding tradition in the training of clinicians (psychiatrists, but also non-psychiatrists) about the importance of the approach in helping relationships. This tradition reflects itself in the organization of the assistance to the acute psychiatric inpatients admitted to the Ward. In addition to treatment as usual, patients have the opportunity of being involved in several group activities. The activities are proposed to them, with an approach that varies according to the patient's lifetime diagnosis, current conditions, relational difficulties, etc. In other words, different activities may be proposed to different patients, in different ways. Aims To describe the integrated treatment approach we use in our Psychiatry Ward. Methods Group activities are guided by a group leader who is supported by one or two assistants whose role is to facilitate discussion. Activities include: Newspaper Reading (everyday in the morning, 1 hour); Music Listening Group (once a week; 1 hour); Cinema Group (once a week; 2 hours and a half); Fairytale Group (on alternating days in the evening, 1 hour). Results More details will be supplied regarding the theoretical background for the group, the group features/implementation, and its specific objectives. Conclusions All the group activities integrate themselves in an early rehabilitation project tailored to each patients' characteristics and needs. Briefly, their main objectives include: 1) to help patients endorse their cognitive, emotional and relational skills; 2) to offer support to the crisis they are experiencing, which led them to admission to the Ward

Clinical characteristics of 80 subjects with KCNQ2-related encephalopathy: Results from a family-driven survey

Variants of KCNQ2 are associated with a wide spectrum of disorders, ranging from Self-limiting Neonatal Epilepsy (SelNE) to Early Onset Developmental and Epileptic Encephalopathy (KCNQ2-DEE). Comorbidities associated with this end of the spectrum have been seldomly described and their impact on the life of patients and their families is yet to be investigated. Collaborating with caregivers from different European family associations, we have developed a questionnaire aimed at investigating the onset and frequency of epileptic seizures, anti-seizure medications (ASM), hospitalizations, stages of development, and comorbidities. Responses from 80 patients, 40 males, from 14 countries have been collected. Median age 7.6&nbsp;years (4&nbsp;months - 43.6&nbsp;years). Of 76 epileptic patients (93.6%), 55.3% were seizure-free with a mean age at last seizure of 26.7&nbsp;months. Among patients with active epilepsy, those older have a lower frequency of seizures (p&nbsp;&gt;&nbsp;0.05). We were able to identify three different clusters of varying severity (Mild, Severe, Profound), based on neurodevelopmental features and symptoms, excluding epilepsy. Patients in a higher severity cluster had a higher mean number of comorbidities, which had a higher impact on families. Notably, patients in different clusters presented different epilepsy onset and courses. This study constitutes the most extensive data collection of patients with KCNQ2-DEE, with a focus on comorbidities in a wide age group. The participation of caregivers helps to define the impact of the disease on the lives of patients and families and can help identify new primary and secondary outcomes beyond seizures in future studies

Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression

The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy

Gadd45α activity is the principal effector of Shigella mitochondria-dependent epithelial cell death in vitro and ex vivo

Modulation of death is a pathogen strategy to establish residence and promote survival in host cells and tissues. Shigella spp. are human pathogens that invade colonic mucosa, where they provoke lesions caused by their ability to manipulate the host cell responses. Shigella spp. induce various types of cell death in different cell populations. However, they are equally able to protect host cells from death. Here, we have investigated on the molecular mechanisms and cell effectors governing the balance between survival and death in epithelial cells infected with Shigella. To explore these aspects, we have exploited both, the HeLa cell invasion assay and a novel ex vivo human colon organ culture model of infection that mimics natural conditions of shigellosis. Our results definitely show that Shigella induces a rapid intrinsic apoptosis of infected cells, via mitochondrial depolarization and the ensuing caspase-9 activation. Moreover, for the first time we identify the eukaryotic stress-response factor growth arrest and DNA damage 45α as a key player in the induction of the apoptotic process elicited by Shigella in epithelial cells, revealing an unexplored role of this molecule in the course of infections sustained by invasive pathogens

In Vivo Depletion of Lymphotoxin-Alpha Expressing Lymphocytes Inhibits Xenogeneic Graft-versus-Host-Disease

Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic cell transplantation and is largely mediated by activated donor lymphocytes. Lymphotoxin (LT)-α is expressed by subsets of activated T and B cells, and studies in preclinical models demonstrated that targeted depletion of these cells with a mouse anti-LT-α monoclonal antibody (mAb) was efficacious in inhibiting inflammation and autoimmune disease. Here we demonstrate that LT-α is also upregulated on activated human donor lymphocytes in a xenogeneic model of GVHD and targeted depletion of these donor cells ameliorated GVHD. A depleting humanized anti-LT-α mAb, designated MLTA3698A, was generated that specifically binds to LT-α in both the soluble and membrane-bound forms, and elicits antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Using a human peripheral blood mononuclear cell transplanted SCID (Hu-SCID) mouse model of GVHD, the anti-human LT-α mAb specifically depleted activated LT-expressing human donor T and B cells, resulting in prolonged survival of the mice. A mutation in the Fc region, rendering the mAb incapable of mediating ADCC, abolished all in vitro and in vivo effects. These data support a role for using a depleting anti-LT-α antibody in treating immune diseases such as GVHD and autoimmune diseases

Social cognition in people with schizophrenia: A cluster-analytic approach

Background The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. Method A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. Results We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI &lt;10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. Conclusions If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person