Neuroimaging is a critical component of triage and treatment for patients who present with neuropathology. Magnetic resonance imaging and non-contrast computed tomography are the gold standard for ...diagnosis and prognostication of patients with acute brain injuries. However, these modalities require intra-hospital transport to strict, access-controlled environments, which puts critically ill patients at risk for complications and secondary injuries. A novel, portable MRI (pMRI) device that can be deployed at the patient's bedside provides a needed solution. In a dual-center investigation, Yale New Haven Hospital has obtained regular neuroimaging on patients using the pMRI as part of routine clinical care in the Emergency Department and Intensive Care Unit (ICU) since August of 2020. Massachusetts General Hospital has begun using pMRI in the Neuroscience Intensive Care Unit since January 2021. This technology has expanded the population of patients who can receive MRI imaging by increasing accessibility and timeliness for scan completion by eliminating the need for transport and increasing the potential for serial monitoring. Here we describe our methods for screening, coordinating, and executing pMRI exams and provide further detail on how to scan specific patient populations.
Patients admitted to the Neuroscience Intensive Care Unit (Neuro-ICU) with acute neurological illnesses (ANI; e.g., stroke, tumor, TBI) and their informal caregivers experience high rates of anxiety, ...depression, and posttraumatic stress. To address this need, we previously developed the Recovering Together (RT) dyadic intervention to help prevent chronic emotional distress in both patients and caregivers. Currently, we are conducting a fully-powered, single-blind randomized clinical trial (RCT) to evaluate the efficacy of RT versus an attention matched health education control. Here, we describe the protocol and current status of this RCT.
We aim to recruit 194 at risk patient-caregiver dyads from the Neuro-ICU at MGH. Eligible dyads include patients diagnosed with ANI, cognitively intact, at least one partner endorses emotional distress (on Hospital Anxiety and Depression Scale), English speaking, age 18 or older. Dyads are randomized to the intervention (RT-1) or control condition (RT-2) (both six sessions). RT-1 teaches resiliency (e.g., coping, mindfulness) and interpersonal skills. RT-2 provides education on health-related topics (e.g., stress, self-care, adhering to medical recommendations). Blinded research assistants collect measures at baseline, post-intervention, and three months follow-up. We will conduct mixed linear, mediation, and actor-partner interdependence models to examine changes in dyads' outcomes across time.
We have recruited 41 dyads and aim to recruit 194 total.
If successful, we plan to test RT in a large-scale, multisite hybrid effectiveness-implementation study in Neuro-ICUs across the country. Enhancing psychosocial supports for patients and families could improve health outcomes, healthcare efficiency, and the culture of these units.
•20–40% of patients and caregivers in the Neuro-ICU report emotional distress.•Psychosocial services are needed for patient-caregiver dyads in the Neuro-ICU.•We developed a feasible and acceptable intervention called Recovering Together.•Here, we present the current protocol to test the efficacy of Recovering Together.
Microbicidal NO production is reliant on inducible NO synthase-mediated L-arginine metabolism in macrophages (MΦs). However, L-arginine supply can be restricted by arginase activity, resulting in ...inefficient NO output and inhibition of antimicrobial MΦ function. MΦs circumvent this by converting L-citrulline to L-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine MΦs supplied L-arginine, L-citrulline, or both amino acids. Using liquid chromatography-tandem mass spectrometry, we determined that L-arginine synthesized from L-citrulline was less effective as a substrate for arginase-mediated L-ornithine production compared with L-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette-Guérin infection and costimulation with IFN-γ, we observed that MΦ arginase activity did not inhibit production of NO derived from L-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in L-arginine. Furthermore, we found that arginase-expressing MΦs preferred L-citrulline over L-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of L-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.
Macrophages are indispensable immune cells tasked at eliminating intracellular pathogens.
Mycobacterium tuberculosis
(
Mtb
), one of the most virulent intracellular bacterial pathogens known to man, ...infects and resides within macrophages. While macrophages can be provoked by extracellular stimuli to inhibit and kill
Mtb
bacilli, these host defense mechanisms can be blocked by limiting nutritional metabolites, such as amino acids. The amino acid L-arginine has been well described to enhance immune function, especially in the context of driving macrophage nitric oxide (NO) production in mice. In this study, we aimed to establish the necessity of L-arginine on anti-
Mtb
macrophage function
independent
of NO. Utilizing an
in vitro
system, we identified that macrophages relied on NO for only half of their L-arginine-mediated host defenses and this L-arginine-mediated defense in the absence of NO was associated with enhanced macrophage numbers and viability. Additionally, we observed macrophage glycolysis to be driven by both L-arginine and mechanistic target of rapamycin (mTOR), and inhibition of glycolysis or mTOR reduced macrophage control of
Mtb
as well as macrophage number and viability in the presence of L-arginine. Our data underscore L-arginine as an essential nutrient for macrophage function, not only by fueling anti-mycobacterial NO production, but also as a central regulator of macrophage metabolism and additional host defense mechanisms.
Metabolomics analyses suggest changes in amino acid abundance, particularly l-arginine (L-ARG), occur in patients with tuberculosis. Immune cells require L-ARG to fuel effector functions following ...infection. We have previously described an L-ARG synthesis pathway in immune cells; however, its role in APCs has yet to be uncovered. Using a coculture system with mycobacterial-specific CD4
T cells, we show APC L-ARG synthesis supported T cell viability and proliferation, and activated T cells contained APC-derived L-ARG. We hypothesize that APCs supply L-ARG to support T cell activation under nutrient-limiting conditions. This work expands the current model of APC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.
Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting l-arginine metabolism is intriguing, considering this amino acid is the substrate for ...antimicrobial NO production by macrophages. The importance of l-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor l-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in l-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the l-citrulline-generating (i.e., iNOS) and l-citrulline-using (i.e., Ass1) enzymes in key myeloid populations. Eliminating l-arginine synthesis from l-citrulline in myeloid cells via conditional deletion of either
or
resulted in increased
bacillus Calmette-Guérin and
H
R
burden in the lungs compared with controls. Our data illustrate the necessity of l-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.
Dendritic Cells Supply CD4+ T Cells With L-arginine Crowther, Rebecca R; Schmidt, Stephanie M; Zhao, Junfang ...
The Journal of immunology (1950),
05/2021, Volume:
206, Issue:
1_Supplement
Journal Article
Peer reviewed
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is responsible for over 1 million deaths each year. Mycobacteria-infected dendritic cells (DCs) migrate to the lymph node to initiate ...adaptive immune priming, which is vital to antimycobacterial immunity. This response is intimately tied to nutrient availability – especially the amino acid L-arginine (L-ARG), metabolism of which is altered in TB patients. We have characterized a pathway utilized by immune cells to synthesize L-ARG. Loss of L-ARG synthesis in CD11c+ cells, which includes DCs, results in increased mycobacterial burden following infection in mice. To characterize the role of this pathway in DCs, we developed a co-culture system with mycobacterial-specific CD4+ T cells and bone marrow derived DCs. Using CD4+ T cells and DCs with differing capabilities of L-ARG synthesis, we found 1) DC L-ARG synthesis supports CD4+ T cell proliferation and 2) activated T cells contain DC-derived L-ARG. We hypothesize DCs “share” synthesized L-ARG to support CD4+ T cell activation when L-ARG is limiting. Our data suggest nutrient availability as a 4th signal – following antigen presentation, co-stimulation, and cytokine receptor ligation – required for T cell activation. This work expands the current model of DC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.
Metabolomics analyses suggest changes in amino acid abundance, particularly L-arginine (L-ARG), occur in tuberculosis patients. Immune cells require L-ARG to fuel effector functions following ...infection. We have previously described an L-ARG synthesis pathway in immune cells, however its role in antigen presenting cells (APCs) has yet to be uncovered. Using a co-culture system with mycobacterial-specific CD4
+
T cells, we show APC L-ARG synthesis supported T cell viability and proliferation, and activated T cells contained APC-derived L-ARG. We hypothesize APCs supply L-ARG to support T cell activation under nutrient limiting conditions. This work expands the current model of APC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.
Objective: Group delivery of posttraumatic stress disorder (PTSD) treatment has several advantages, however group research is not comparable to individual trials. This study extends the group ...literature by improving methodology in examining the efficacy of a 3-module (cognitive, exposure, skills) group treatment for PTSD, establishes a format for the delivery of group exposure therapy, and compares 3 treatment modules within the group. Method: Eighty-six Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) women veterans were randomized to a 16-week, 3-member group treatment (Tx) or a waitlist (WL) condition. The primary (Clinician Administered PTSD Scale CAPS) and secondary (Medical Outcomes Study Short Form-36 SF-36, Quality of Life Inventory QOLI, and PTSD Checklist PCL) outcome measures were administered at baseline, post Tx/WL, and at 3- and 6-months post Tx (PCL additionally at pre/post for each treatment module). Results: PTSD symptoms significantly improved in Tx arm participants (p < .001, ES = 1.72; unit of analysis group: n = 14), as did mental and physical life functioning (SF-36; p < .001), and quality of life (QOLI; p < .001). The WL significantly improved on the SF-36 (mental; p = .04) and QOLI (p = .02). Clinical improvement (CAPS) in the Tx arm reflected a treatment response (≥10-point decrease) in 77% and loss of PTSD diagnosis (<45) in 52% of participants, comparable to individual prolonged exposure (PE) treatment. Finally, PCL scores significantly lowered in exposure and cognitive modules. Conclusions: This study supports the use of group format for PTSD with 3 modules using improved methodology, with a novel, 3-member group which allows repeated in-session weekly imaginal exposures. The results suggest future examination of group delivered PE.
Full text
Available for:
CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ
Microbicidal nitric oxide (NO) production is reliant on inducible NO synthase (iNOS)- mediated L-arginine metabolism in macrophages (MΦs). L-arginine supply, however, can be restricted by arginase ...activity, resulting in inefficient NO and inhibition of anti-microbial MΦ function. MΦs circumvent this by converting L-citrulline to L-arginine, thereby resupplying substrate for NO production. Here we define the metabolic signature of mycobacteria-infected murine MΦs supplied L-arginine, L-citrulline, or both amino acids (AAs). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we determined L-arginine synthesized from L-citrulline was less effective as a substrate for arginase-mediated L-ornithine production as compared to L-arginine directly imported from the extracellular milieu. Following
Mycobacterium bovis
BCG infection and co-stimulation with interferon-γ (IFN-γ), we observed MΦ arginase activity did not inhibit production of NO derived from L-citrulline, contrary to NO inhibition witnessed when MΦs were cultured in L-arginine. Furthermore, we found arginase-expressing MΦs preferred L-citrulline, as compared to L-arginine, to promote anti-mycobacterial activity. We expect defining the consequences of L-citrulline metabolism in MΦs will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.
PDF
