Can Medication Free, Treatment-Resistant, Depressed Patients Who Initially Respond to TMS Be Maintained Off Medications? A Prospective, 12-Month Multisite Randomized Pilot Study

AbstractBackgroundRepetitive transcranial magnetic stimulation (TMS) is efficacious for acute treatment of resistant major depressive disorder (MDD), but there is little information on maintenance TMS after acute response.Objective/hypothesisThis pilot feasibility study investigated 12-month outcomes comparing two maintenance TMS approaches – a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS).MethodsAntidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial.ResultsSixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥2 antidepressants (p = .035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI .38–3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study.ConclusionsMaintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. Those who initially respond to TMS have a strong chance of re-responding if relapse occurs

Cytolytic DNA vaccine encoding lytic perforin augments the maturation of- and antigen presentation by- dendritic cells in a time-dependent manner

The use of cost-effective vaccines capable of inducing robust CD8+ T cell immunity will contribute significantly towards the elimination of persistent viral infections and cancers worldwide. We have previously reported that a cytolytic DNA vaccine encoding an immunogen and a truncated mouse perforin (PRF) protein significantly augments anti-viral T cell (including CD8+ T cell) immunity. Thus, the current study investigated whether this vaccine enhances activation of dendritic cells (DCs) resulting in greater priming of CD8+ T cell immunity. In vitro data showed that transfection of HEK293T cells with the cytolytic DNA resulted in the release of lactate dehydrogenase, indicative of necrotic/lytic cell death. In vitro exposure of this lytic cell debris to purified DCs from naïve C57BL/6 mice resulted in maturation of DCs as determined by up-regulation of CD80/CD86. Using activation/proliferation of adoptively transferred OT-I CD8+ T cells to measure antigen presentation by DCs in vivo, it was determined that cytolytic DNA immunisation resulted in a time-dependent increase in the proliferation of OT-I CD8+ T cells compared to canonical DNA immunisation. Overall, the data suggest that the cytolytic DNA vaccine increases the activity of DCs which has important implications for the design of DNA vaccines to improve their translational prospects.Danushka K. Wijesundara, Wenbo Yu, Ben J. C. Quah, Preethi Eldi, John D. Hayball, Kerrilyn R. Diener, Ilia Voskoboinik, Eric J. Gowans, and Branka Grubor-Bau

Tongue immune compartment analysis reveals spatial macrophage heterogeneity

The tongue is a unique muscular organ situated in the oral cavity where it is involved in taste sensation, mastication, and articulation. As a barrier organ, which is constantly exposed to environmental pathogens, the tongue is expected to host an immune cell network ensuring local immune defence. However, the composition and the transcriptional landscape of the tongue immune system are currently not completely defined. Here, we characterised the tissue-resident immune compartment of the murine tongue during development, health and disease, combining single-cell RNA-sequencing with in situ immunophenotyping. We identified distinct local immune cell populations and described two specific subsets of tongue-resident macrophages occupying discrete anatomical niches. Cx3cr1(+) macrophages were located specifically in the highly innervated lamina propria beneath the tongue epidermis and at times in close proximity to fungiform papillae. Folr2(+) macrophages were detected in deeper muscular tissue. In silico analysis indicated that the two macrophage subsets originate from a common proliferative precursor during early postnatal development and responded differently to systemic LPS in vivo. Our description of the under-investigated tongue immune system sets a starting point to facilitate research on tongue immune-physiology and pathology including cancer and taste disorders

Critical analysis of information security culture definitions

This article aims to advance the understanding of information security culture through a critical reflection on the wide-ranging definitions of information security culture in the literature. It uses the hermeneutic approach for conducting literature reviews. The review identifies 16 definitions of information security culture in the literature. Based on the analysis of these definitions, four different views of culture are distinguished. The shared values view highlights the set of cultural value patterns that are shared across the organization. An action-based view highlights the behaviors of individuals in the organization. A mental model view relates to the abstract view of the individual’s thinking on how information security culture must work. Finally, a problem-solving view emphasizes a combination of understanding from shared value-based and action-based views. The paper analyzes and presents the limitations of these four views of information security culture definitions

Potentiating Effects of MPL on DSPC Bearing Cationic Liposomes Promote Recombinant GP63 Vaccine Efficacy: High Immunogenicity and Protection

Visceral leishmaniasis (VL), a vector-transmitted disease caused by Leishmania donovani, is potentially fatal if left untreated. Vaccination against VL has received limited attention compared with cutaneous leishmaniasis, although the need for an effective vaccine is pressing for the control of the disease. Earlier, we observed protective efficacy using leishmanial antigen (Ag) in the presence of either cationic liposomes or monophosphoryl lipid A-trehalose dicorynomycolate (MPL-TDM) against experimental VL through the intraperitoneal (i.p.) route of administration in the mouse model. However, this route of immunization is not adequate for human use. For this work, we developed vaccine formulations combining cationic liposomes with MPL-TDM using recombinant GP63 (rGP63) as protein Ag through the clinically relevant subcutaneous (s.c.) route. Two s.c. injections with rGP63 in association with cationic liposomes and MPL-TDM showed enhanced immune responses that further resulted in high protective levels against VL in the mouse model. This validates the combined use of MPL-TDM as an immunopotentiator and liposomes as a suitable vaccine delivery system

Altering an Artificial Gagpolnef Polyprotein and Mode of ENV Co-Administration Affects the Immunogenicity of a Clade C HIV DNA Vaccine

HIV-1 candidate vaccines expressing an artificial polyprotein comprising Gag, Pol and Nef (GPN) and a secreted envelope protein (Env) were shown in recent Phase I/II clinical trials to induce high levels of polyfunctional T cell responses; however, Env-specific responses clearly exceeded those against Gag. Here, we assess the impact of the GPN immunogen design and variations in the formulation and vaccination regimen of a combined GPN/Env DNA vaccine on the T cell responses against the various HIV proteins. Subtle modifications were introduced into the GPN gene to increase Gag expression, modify the expression ratio of Gag to PolNef and support budding of virus-like particles. I.m. administration of the various DNA constructs into BALB/c mice resulted in an up to 10-fold increase in Gag- and Pol-specific IFNγ+ CD8+ T cells compared to GPN. Co-administering Env with Gag or GPN derivatives largely abrogated Gag-specific responses. Alterations in the molar ratio of the DNA vaccines and spatially or temporally separated administration induced more balanced T cell responses. Whereas forced co-expression of Gag and Env from one plasmid induced predominantly Env-specific T cells responses, deletion of the only H-2d T cell epitope in Env allowed increased levels of Gag-specific T cells, suggesting competition at an epitope level. Our data demonstrate that the biochemical properties of an artificial polyprotein clearly influence the levels of antigen-specific T cells, and variations in formulation and schedule can overcome competition for the induction of these responses. These results are guiding the design of ongoing pre-clinical and clinical trials

Vascular Endothelial Dysfunction in β-Thalassemia Occurs Despite Increased eNOS Expression and Preserved Vascular Smooth Muscle Cell Reactivity to NO

The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments.Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall.A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression

Deterrence in Cyberspace: An Interdisciplinary Review of the Empirical Literature

The popularity of the deterrence perspective across multiple scientific disciplines has sparked a lively debate regarding its relevance in influencing both offenders and targets in cyberspace. Unfortunately, due to the invisible borders between academic disciplines, most of the published literature on deterrence in cyberspace is confined within unique scientific disciplines. This chapter therefore provides an interdisciplinary review of the issue of deterrence in cyberspace. It begins with a short overview of the deterrence perspective, presenting the ongoing debates concerning the relevance of deterrence pillars in influencing cybercriminals’ and cyberattackers’ operations in cyberspace. It then reviews the existing scientific evidence assessing various aspects of deterrence in the context of several disciplines: criminology, law, information systems, and political science. This chapter ends with a few policy implications and proposed directions for future interdisciplinary academic research

Generation, Annotation and Analysis of First Large-Scale Expressed Sequence Tags from Developing Fiber of Gossypium barbadense L

BACKGROUND: Cotton fiber is the world's leading natural fiber used in the manufacture of textiles. Gossypium is also the model plant in the study of polyploidization, evolution, cell elongation, cell wall development, and cellulose biosynthesis. G. barbadense L. is an ideal candidate for providing new genetic variations useful to improve fiber quality for its superior properties. However, little is known about fiber development mechanisms of G. barbadense and only a few molecular resources are available in GenBank. METHODOLOGY AND PRINCIPAL FINDINGS: In total, 10,979 high-quality expressed sequence tags (ESTs) were generated from a normalized fiber cDNA library of G. barbadense. The ESTs were clustered and assembled into 5852 unigenes, consisting of 1492 contigs and 4360 singletons. The blastx result showed 2165 unigenes with significant similarity to known genes and 2687 unigenes with significant similarity to genes of predicted proteins. Functional classification revealed that unigenes were abundant in the functions of binding, catalytic activity, and metabolic pathways of carbohydrate, amino acid, energy, and lipids. The function motif/domain-related cytoskeleton and redox homeostasis were enriched. Among the 5852 unigenes, 282 and 736 unigenes were identified as potential cell wall biosynthesis and transcription factors, respectively. Furthermore, the relationships among cotton species or between cotton and other model plant systems were analyzed. Some putative species-specific unigenes of G. barbadense were highlighted. CONCLUSIONS/SIGNIFICANCE: The ESTs generated in this study are from the first large-scale EST project for G. barbadense and significantly enhance the number of G. barbadense ESTs in public databases. This knowledge will contribute to cotton improvements by studying fiber development mechanisms of G. barbadense, establishing a breeding program using marker-assisted selection, and discovering candidate genes related to important agronomic traits of cotton through oligonucleotide array. Our work will also provide important resources for comparative genomics, polyploidization, and genome evolution among Gossypium species