Ferumoxytol-enhanced magnetic resonance imaging assessing inflammation after myocardial infarction.

OBJECTIVES: Macrophages play a central role in the cellular inflammatory response to myocardial infarction (MI) and predict subsequent clinical outcomes. We aimed to assess temporal changes in cellular inflammation and tissue oedema in patients with acute MI using ultrasmallsuperparamagnetic particles of iron oxide (USPIO)-enhanced MRI. METHODS: Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2*-mapping MRI. Regions of interest were categorised into infarct, peri-infarct and remote myocardial zones, and compared with control tissues. RESULTS: Following a single dose, USPIO enhancement was detected in the myocardium until 24 hours (p<0.0001). Histology confirmed colocalisation of iron and macrophages within the infarcted, but not the non-infarcted, myocardium. Following repeated doses, USPIO uptake in the infarct zone peaked at days 2-3, and greater USPIO uptake was detected in the infarct zone compared with remote myocardium until days 10-16 (p<0.05). In contrast, T2-defined myocardial oedema peaked at days 3-9 and remained increased in the infarct zone throughout the 3-month follow-up period (p<0.01). CONCLUSION: Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to the more prolonged myocardial oedema detectable using T2 mapping. This imaging technique holds promise as a non-invasive method of assessing and monitoring myocardial cellular inflammation with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions. TRIAL REGISTRATION NUMBER: Trial registration number: 14663. Registered on UK Clinical Research Network (http://public.ukcrn.org.uk) and also ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02319278?term=DECIFER&rank=2).

Monitoring signaling by the p75(NTR) receptor utilizing a caspase-3 activation assay amenable to small-molecule screening.

p75(NTR) is a neurotrophin receptor that can mediate either survival or death of neurons depending on the cell context. Modulation of p75(NTR) is a promising strategy to promote neuronal survival for treatment of cognitive disorders such as Alzheimer's disease. Despite years of investigation into the signaling mechanisms of p75(NTR), no p75(NTR) signaling assay has yet been developed that is compatible with efficient screening of small-molecule modulators. In this work, we developed a homogeneous cell-based assay for screening p75(NTR) modulators and studying p75(NTR) function. Stimulation of p75(NTR)-transfected cells using either nerve growth factor (NGF) or Pro-NGF resulted in an enhanced caspase-3 activity as assessed by cleavage of a fluorescent caspase-3 substrate. Optimization of the assay with respect to time, cell density, NGF and Pro-NGF concentration, and other factors provided a twofold increase in the caspase-3 activity compared to background. Withdrawal of serum during the NGF or Pro-NGF treatment period was found to be essential for p75(NTR)-dependent caspase-3 activation. We validated the method by demonstrating that a signaling-incompetent p75(NTR) mutant could not substitute for wild-type p75(NTR) in mediating caspase-3 activation. A focused library screen identified new inhibitors of p75(NTR) signaling. This method will be useful for identifying small-molecule modulators of p75(NTR) as well as further characterizing downstream signaling events.

Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate ß-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by γ-secretase, are highlighted.

Post Christian pastoral care: the wisdom of not knowing.

Emergent religious pluralism leads many of us to reflect on pastoral care practices that have evolved mostly within the Judeo Christian tradition. This article makes public my reflections and offers ideas for a ministry of curiosity that is more conversant with an increasingly Post Christian society.

The effect of 3D hydrogel scaffold modulus on osteoblast differentiation and mineralization revealed by combinatorial screening.

Cells are known to sense and respond to the physical properties of their environment and those of tissue scaffolds. Optimizing these cell-material interactions is critical in tissue engineering. In this work, a simple and inexpensive combinatorial platform was developed to rapidly screen three-dimensional (3D) tissue scaffolds and was applied to screen the effect of scaffold properties for tissue engineering of bone. Differentiation of osteoblasts was examined in poly(ethylene glycol) hydrogel gradients spanning a 30-fold range in compressive modulus ( approximately 10 kPa to approximately 300 kPa). Results demonstrate that material properties (gel stiffness) of scaffolds can be leveraged to induce cell differentiation in 3D culture as an alternative to biochemical cues such as soluble supplements, immobilized biomolecules and vectors, which are often expensive, labile and potentially carcinogenic. Gel moduli of approximately 225 kPa and higher enhanced osteogenesis. Furthermore, it is proposed that material-induced cell differentiation can be modulated to engineer seamless tissue interfaces between mineralized bone tissue and softer tissues such as ligaments and tendons. This work presents a combinatorial method to screen biological response to 3D hydrogel scaffolds that more closely mimics the 3D environment experienced by cells in vivo.

Relating disparity in competitive foraging behavior between two populations of fiddler crabs to the subcellular partitioning of metals.

Behavioral changes in aquatic organisms such as reduced prey capture and decreased mobility have been linked to exposure to contaminants in the field. The purpose of this study was to compare competitive foraging and dominance behaviors of two populations of the fiddler crab, Uca pugnax, and to examine the relationship between tissue metal residues and observed differences in behavior. Foraging behavior (number of total scoops and scoops on a protein-rich patch) and dominance behavior (percentage of successful attacks) of fiddler crabs from an impacted site (Meredith Creek, New York) and a reference site (Tuckerton, New Jersey) were compared in the laboratory. Tuckerton (Tk) crabs were found to have twice the number of total scoops (70 vs. 38 scoops, p < 0.05) and three times the number of scoops on patch (34 vs. 10 scoops, p < 0.05) than Meredith (Me) crabs. No difference was observed between crab populations in the number of successful attacks (i.e., fights over the protein-rich patch). Analyses of total metal body burdens and metals associated with various subcellular fractions showed that, when compared with Tk crabs, Me crabs had higher levels of Ag, Cd, Cu, Ni, and Se in the heat-denatured proteins (HdeP) (i.e., enzymes). Metal bioaccumulation can have inhibitory effects on enzymes, which play an essential role in the regulation of various biochemical, metabolic, and physiological activities in crustaceans. This study suggests that there is a relationship between the accumulation of metals in HdeP (i.e., enzymes) and impairment of competitive foraging behavior in fiddler crabs. Additionally, this study shows that when compared with dominance behavior, foraging behavior is a more sensitive indicator of metal exposure and might be used as an end point in ecotoxicology studies.

False recognition following study of semantically related lists presented in jumbled word form.

Three experiments explored a jumbled word effect in false recognition. Lists of theme-related items were presented in word or nonword form. Results indicated that critical lures semantically related to studied items were falsely recognised regardless of whether they were presented as words or nonwords. High false recognition rates to either SLEEP or SELEP following study of an appropriate theme list of items in nonword form should only occur if nonwords are recoded at study. With study conditions conducive to recoding, jumbled words induced false recognitions based on semantic associations among their respective base words. Disrupting a recoding process by creating "difficult" letter rearrangements for jumbled words (Experiment 2) appeared to eliminate the false recognition effect. In Experiment 3, presentation durations ranged from 110 ms to 880 ms. Although there was little evidence of a semantic false recognition effect at the fastest presentation rate, the brief durations appeared to be effective in eliminating the effect when items were studied in nonword form. These results appear to be consistent with an encoding activation/retrieval monitoring model.

Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen.

Hypoxia, caused by disrupted vasculature and peripheral vasculopathies, is a key factor that limits dermal wound healing. Factors that can increase oxygen delivery to the regional tissue, such as supplemental oxygen, warmth, and sympathetic blockade, can accelerate healing. Clinical experience with adjunctive hyperbaric oxygen therapy (HBOT) in the treatment of chronic wounds have shown that wound hyperoxia may increase granulation tissue formation and accelerate wound contraction and secondary closure. However, HBOT is not applicable to all wound patients and may pose the risk of oxygen toxicity. Thus, the efficacy of topical oxygen treatment in an experimental setting using the pre-clinical model involving excisional dermal wound in pigs was assessed. Exposure of open dermal wounds to topical oxygen treatment increased tissue pO2 of superficial wound tissue. Repeated treatment accelerated wound closure. Histological studies revealed that the wounds benefited from the treatment. The oxygen treated wounds showed signs of improved angiogenesis and tissue oxygenation. Topically applied pure oxygen has the potential of benefiting some wound types. Further studies testing the potential of topical oxygen in pre-clinical and clinical settings are warranted.

A parathyroid hormone-related protein-secreting metastatic epithelioid leiomyosarcoma. A case report and review of the literature.

A diagnosis of parathyroid hormone-related protein (PTH-rP)-secreting metastatic uterine epithelioid leiomyosarcoma was made in a 61-year-old woman with humoral hypercalcemia of malignancy. A primary uterine tumor had been removed 10 years previously, which had been associated with a short history of hypercalcemia. The original uterine tumor was diagnosed as a smooth muscle tumor of uncertain malignant potential. To the best of our knowledge, this is the first reported case of a PTH-rP-secreting uterine leiomyosarcoma. We demonstrate the dramatic changes in serum calcium, phosphorus, PTH, and PTH-rP levels after tumor resection. Extensive biochemical analysis and detailed immunohistochemical and ultrastructural characterization demonstrate several features of this tumor.