A giant mystery in giant cell myocarditis: navigating diagnosis, immunosuppression, and mechanical circulatory support.

Giant cell myocarditis is a rare but often devastating diagnosis. Advances in cardiac imaging and mechanical circulatory support have led to earlier and more frequent diagnoses and successful management. This disease state has wide variation in acuity of presentation, and consequently, optimal treatment ranging from intensity and type of immunosuppression to mechanical circulatory support is not well defined. The following case describes the management of a patient with an unusual presentation of giant cell myocarditis over a 10 year course of advanced heart failure therapies and immunomodulatory support. This case highlights emerging concepts in the management of giant cell myocarditis including sub-acute presentations, challenges in diagnosis, and treatment modalities in the modern era

A single dose of trichloroethylene given during development does not substantially alter markers of neuroinflammation in brains of adult mice

Trichloroethylene (TCE) is a widespread environmental contaminant associated with developmental immu- notoxicity and neurotoxicity. Previous studies have shown that MRLþ/þ mice exposed to TCE from gesta- tion through early-life demonstrate robust increases in inflammatory markers in peripheral CD4þ T-cells, as well as glutathione depletion and increased oxidative stress in cerebellum-associated with alterations in behavior. Since increased oxidative stress is associated with neuroinflammation, we hypothesized that neuroinflammatory markers could be altered relative to unexposed mice. MRLþ/þ mice were given 0.5mg/ml of TCE in vehicle or vehicle (water with 1% Alkamuls EL-620) from conception through early adulthood via drinking water to dams and then directly to post-weaning offspring. Animals were euthan- ized at 49days of age and levels of pro- and anti-inflammatory cytokines, density of T-cell staining, and micro-glial morphology were evaluated in brains to begin to ascertain a neuroinflammatory profile. Levels of IL-6 were decreased in female animals and while not statistically significant, and levels of IL-10 were higher in brains of exposed male and female animals. Supportive of this observation, although not statis- tically significant, the number of ameboid microglia was higher in exposed relative to unexposed animals. This overall profile suggests the emergence of an anti-inflammatory/neuroprotective phenotype in exposed animals, possibly as a compensatory response to neuroinflammation that is known to be induced by developmental exposure to TCE

Physical separation from the mate diminishes male’s attentiveness towards other females: a study in monogamous prairie voles Microtus ochrogaster

We tested whether continuous cohabitation in monogamous voles affects the mated male’s attentiveness to his breeding partner versus another female. Each male was housed in a 3-chamber apparatus with a Focal female (FF) and a Control female (CF) for 13 days then placed in a T-maze to assess his attentiveness to and memory of those females. The Distal male remained physically separated from both females, but received their distal cues. The Separate male cohabited with the FF for 3 days then remained physically separated from both females. The Disrupt male’s continuous cohabitation with the FF was disrupted by having him physically separated from her after 10 days and placed with the CF for the last 3 days. The Continuous male cohabited continuously with the FF for 13 days. With females in the T-maze, the Separate and Disrupt males spent more time near the FF’s box and the Disrupt males spent more time manipulating the FF’s box than the CF’s box. The Separate males groomed themselves more when near the FF’s box than the CF’s box. The Distal and Continuous males’ attentiveness to the two females did not differ. Results suggest that physical distance from the partner may reduce male’s attentiveness toward other potential mates. Prairie voles might be similar to socially monogamous primates in using tactile cues as a signal for maintaining their social bonds

Stakeholder views on the acceptability of human infection studies in Malawi.

BACKGROUND: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMICs) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMICs. METHODS: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members, and district health government officials. RESULTS: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to the safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example, balancing equity, safety, and relevance in inclusion criteria. CONCLUSIONS: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out

Plasma anandamide concentrations are lower in children with autism spectrum disorder

Background: Autism spectrum disorder (ASD) is a neurodevelopmentaldisorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children withand without ASD (N= 112). Findings: Anandamide concentrations significantly differentiated ASD cases (N= 59) from controls (N= 53), such that children with lower anandamide concentrations were more likely to have ASD (p= 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p= 0.034). Conclusions: These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD

FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone

Carbon on the Northwest European Shelf: Contemporary Budget and Future Influences

A carbon budget for the northwest European continental shelf seas (NWES) was synthesized using available estimates for coastal, pelagic and benthic carbon stocks and flows. Key uncertainties were identified and the effect of future impacts on the carbon budget were assessed. The water of the shelf seas contains between 210 and 230 Tmol of carbon and absorbs between 1.3 and 3.3 Tmol from the atmosphere annually. Off-shelf transport and burial in the sediments account for 60–100 and 0–40% of carbon outputs from the NWES, respectively. Both of these fluxes remain poorly constrained by observations and resolving their magnitudes and relative importance is a key research priority. Pelagic and benthic carbon stocks are dominated by inorganic carbon. Shelf sediments contain the largest stock of carbon, with between 520 and 1600 Tmol stored in the top 0.1 m of the sea bed. Coastal habitats such as salt marshes and mud flats contain large amounts of carbon per unit area but their total carbon stocks are small compared to pelagic and benthic stocks due to their smaller spatial extent. The large pelagic stock of carbon will continue to increase due to the rising concentration of atmospheric CO2, with associated pH decrease. Pelagic carbon stocks and flows are also likely to be significantly affected by increasing acidity and temperature, and circulation changes but the net impact is uncertain. Benthic carbon stocks will be affected by increasing temperature and acidity, and decreasing oxygen concentrations, although the net impact of these interrelated changes on carbon stocks is uncertain and a major knowledge gap. The impact of bottom trawling on benthic carbon stocks is unique amongst the impacts we consider in that it is widespread and also directly manageable, although its net effect on the carbon budget is uncertain. Coastal habitats are vulnerable to sea level rise and are strongly impacted by management decisions. Local, national and regional actions have the potential to protect or enhance carbon storage, but ultimately global governance, via controls on emissions, has the greatest potential to influence the long-term fate of carbon stocks in the northwestern European continental shelf

Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells

During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling