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Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment.

Increasing evidence points to an important role for neutrophils in participating in the pathogenesis of the human demyelinating disease MS and the animal model EAE. Therefore, a better understanding of the signals controlling migration of neutrophils as well as evaluating the role of these cells in demyelination is important to define cellular components that contribute to disease in MS patients. In this study, we examined the functional role of the chemokine CXCL1 in contributing to neuroinflammation and demyelination in EAE. Using transgenic mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells, we have shown that sustained CXCL1 expression within the CNS increased the severity of clinical and histologic disease that was independent of an increase in the frequency of encephalitogenic Th1 and Th17 cells. Rather, disease was associated with enhanced recruitment of CD11b+ Ly6G+ neutrophils into the spinal cord. Targeting neutrophils resulted in a reduction in demyelination arguing for a role for these cells in myelin damage. Collectively, these findings emphasize that CXCL1-mediated attraction of neutrophils into the CNS augments demyelination suggesting that this signaling pathway may offer new targets for therapeutic intervention

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis.

CXCR2 is a chemokine receptor expressed on oligodendroglia that has been implicated in the pathogenesis of neuroinflammatory demyelinating diseases as well as enhancement of the migration, proliferation, and myelin production by oligodendroglia. Using an inducible proteolipid protein (Plp) promoter-driven Cre-loxP recombination system, we were able to assess how timed ablation of Cxcr2 in oligodendroglia affected disease following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Generation of Plp-Cre-ER(T)::Cxcr2flox/flox transgenic mice (termed Cxcr2-CKO mice) allows for Cxcr2 to be silenced in oligodendrocytes in adult mice following treatment with tamoxifen. Ablation of oligodendroglia Cxcr2 did not influence clinical severity in response to intracranial infection with JHMV. Infiltration of activated T cells or myeloid cells into the central nervous system (CNS) was not affected, nor was the ability to control viral infection. In addition, the severity of demyelination was similar between tamoxifen-treated mice and vehicle-treated controls. Notably, deletion of Cxcr2 resulted in increased remyelination, as assessed by g-ratio (the ratio of the inner axonal diameter to the total outer fiber diameter) calculation, compared to that in vehicle-treated control mice. Collectively, our findings argue that CXCR2 signaling in oligodendroglia is dispensable with regard to contributing to neuroinflammation, but its deletion enhances remyelination in a preclinical model of the human demyelinating disease multiple sclerosis (MS).IMPORTANCE Signaling through the chemokine receptor CXCR2 in oligodendroglia is important for developmental myelination in rodents, while chemical inhibition or nonspecific genetic deletion of CXCR2 appears to augment myelin repair in animal models of the human demyelinating disease multiple sclerosis (MS). To better understand the biology of CXCR2 signaling on oligodendroglia, we generated transgenic mice in which Cxcr2 is selectively ablated in oligodendroglia upon treatment with tamoxifen. Using a viral model of neuroinflammation and demyelination, we demonstrate that genetic silencing of CXCR2 on oligodendroglia did not affect clinical disease, neuroinflammation, or demyelination, yet there was increased remyelination. These findings support and extend previous findings suggesting that targeting CXCR2 may offer a therapeutic avenue for enhancing remyelination in patients with demyelinating diseases

Harm Reduction Approach to Increasing Self-reported Safe Medication Storage Among Pregnant and Parenting People Receiving Opioid Use Disorder Treatment

ObjectivesThe expansion of access to buprenorphine-naloxone (BUP-NAL) for the treatment of opioid use disorder (OUD) is critical to combat the overdose crisis. Evidence is lacking to guide providers on how to best promote BUP-NAL medication safety for their patients. This study assessed (1) the current medication storage practices among a sample of pregnant and parenting people receiving BUP-NAL for OUD; (2) the feasibility and acceptability of providing a lockbox for safe medication storage.MethodsPregnant and/or parenting patients receiving sublingual BUP-NAL in an outpatient OUD clinic were recruited between June and November 2021. Participants completed a baseline survey, received a lockbox, and a follow-up survey 3 to 8 weeks later. The primary outcome of current self-reported safe medication storage practice was defined by storing BUP-NAL in a locked/latched place "almost always" or "always" on the baseline survey. Outcomes were analyzed using simple proportions.ResultsSixty-three participants completed the baseline survey, and 50 completed the follow-up survey. Baseline survey results indicated that only a quarter of patients (26.6%) were practicing safe BUP-NAL medication storage practices. At follow up, 93.6% of patients were using the lockbox provided by the study, 93.4% reported being satisfied with the lockbox, and most participants (89.3%) reported safe BUP-NAL medication storage practices.ConclusionsMany pregnant and parenting patients with OUD receiving BUP-NAL do not store their medications safely. The provision of a lockbox as part of OUD treatment is a feasible, acceptable, and potentially effective harm reduction intervention

Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination following Toxin-Induced Spinal Cord Demyelination.

Remyelination is the regenerative response to demyelination. Although the oligodendrocyte progenitor is established as the major source of remyelinating cells, there is no conclusive evidence on whether mature, differentiated oligodendrocytes can also contribute to remyelination. Using two different inducible myelin-CreER mouse strains in which mature oligodendrocytes were prelabeled by the expression of membrane-bound Green fluorescent protein, we found that after focal spinal cord demyelination, the surrounding surviving labeled oligodendrocytes did not proliferate but remained at a consistent density. Furthermore, existing (prelabeled) oligodendrocytes showed no evidence of incorporation or migration into the lesioned area, or of process extension from the peripheral margins into the lesion. Thus, mature oligodendrocytes do not normally contribute to remyelination and are therefore not a promising target for regenerative therapy.Supported by European Research Council grant agreement 293544 (W.D.R.), Wellcome Trust grant WT100269AIA, Medical Research Council grant G0800575, a Royal Society-USA/Canada Exchange Fellowship (I.M.), the UK Multiple Sclerosis Society, and a Wellcome Trust Integrated Veterinary Training Fellowship (A.H.C.)

Tracing oceanic sources of heat content available for Atlantic hurricanes

In the Main Development Region (MDR) for Atlantic hurricanes, the volume of water warmer than 26.5°C quantifies the potential source of energy for major storms. Taking a Lagrangian perspective, this warm water is backtracked on seasonal timescales in an eddy-resolving ocean model hindcast spanning 1988–2010. Being confined near the surface and assuming a mixed layer depth of 50 m, net heat fluxes into or out of water parcels advected toward the MDR are inferred from along-trajectory temperature tendencies. To first order, these heat fluxes match surface net heat fluxes during the months over which water advects into the region. Contributions to this warm water in the preceding 6 months include water resident in the MDR (20%–40%), arriving via the North Brazil Current (NBC, 5%–15%), or via Ekman drift across 10°S. In relative terms, decreased contributions from the NBC and Ekman drift and more in situ warming within the MDR lead to warmer, more active hurricane seasons

Innovations in Practice: Avatar‐based virtual reality in CAMHS talking therapy: two exploratory case studies

BackgroundAvatar‐based virtual reality therapy is an emerging digital technology that can be used to assist the treatment of common mental health problems. This may be particularly appealing to young people who are highly familiar with digital technologies and may provide a medium to facilitate communication within face‐to‐face therapy.MethodWe present two case summaries of young people who used ProReal, who had difficulties engaging in talking therapies. ProReal is a software package providing avatar‐based virtual reality therapy, used as part of talking psychological therapies provided within a CAMHS outpatient clinic. Young people completed pre and postuse routine outcome measures and took part in qualitative interviews assessing their experience of ProReal.ResultsOutcome measures showed a reduction over time. The two young people felt ProReal was highly accessible, with both young people positively describing how ProReal helped them externalize their inner worlds to help them to reappraise their thoughts, feelings and experiences. They also reported ProReal being a helpful tool to facilitate communication with the clinician.ConclusionThese case summaries demonstrate how ProReal can be readily integrated into clinical practice and how it can facilitate communication and therapy with young people who find it difficult to express themselves

Extreme air–sea interaction over the North Atlantic subpolar gyre during the winter of 2013–2014 and its sub-surface legacy

Exceptionally low North American temperatures and record-breaking precipitation over the British Isles during winter 2013–2014 were interconnected by anomalous ocean evaporation over the North Atlantic subpolar gyre region (SPG). This evaporation (or oceanic latent heat release) was accompanied by strong sensible heat loss to the atmosphere. The enhanced heat loss over the SPG was caused by a combination of surface westerly winds from the North American continent and northerly winds from the Nordic Seas region that were colder, drier and stronger than normal. A distinctive feature of the air–sea exchange was that the enhanced heat loss spanned the entire width of the SPG, with evaporation anomalies intensifying in the east while sensible heat flux anomalies were slightly stronger upstream in the west. The immediate impact of the strong air–sea fluxes on the ocean–atmosphere system included a reduction in ocean heat content of the SPG and a shift in basin-scale pathways of ocean heat and atmospheric freshwater transport. Atmospheric reanalysis data and the EN4 ocean data set indicate that a longer-term legacy of the winter has been the enhanced formation of a particularly dense mode of Subpolar Mode Water (SPMW)—one of the precursors of North Atlantic Deep Water and thus an important component of the Atlantic Meridional Overturning Circulation. Using particle trajectory analysis, the likely dispersal of newly-formed SPMW is evaluated, providing evidence for the re-emergence of anomalously cold SPMW in early winter 2014/2015

Hyperpolarized13c mri of tumor metabolism demonstrates early metabolic response to neoadjuvant chemotherapy in breast cancer

Purpose: To compare hyperpolarized carbon 13 (13C) MRI with dynamic contrast material–enhanced (DCE) MRI in the detection of early treatment response in breast cancer. Materials and Methods: In this institutional review board–approved prospective study, a woman with triple-negative breast cancer (age, 49 years) underwent13C MRI after injection of hyperpolarized [1–carbon 13 {13C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The13C-labeled lactate-to-pyruvate ratio derived from hyperpolarized13C MRI and the pharmacokinetic parameters transfer constant (Ktrans) and washout parameter (kep ) derived from DCE MRI were compared before and after treatment. Results: Exchange of the13C label between injected hyperpolarized [1-13C]-pyruvate and the endogenous lactate pool was observed, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the13C-labeled lactate-to-pyruvate ratio resulted in correct identification of the patient as a responder to therapy, which was subsequently confirmed via a complete pathologic response. However, DCE MRI showed an increase in mean Ktrans (132%) and mean kep (31%), which could be incorrectly interpreted as a poor response to treatment. Conclusion: Hyperpolarized13C MRI enabled successful identification of breast cancer response after one cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI