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A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4, 6-9, 12, 13), as well as the known antibiotic macrolide A26771B (5), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (5) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds 1 and 9 were determined by single-crystal X-ray crystallography. Berkeleylactone A (1) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1-2 μg/mL) against four MRSA strains, as well as Bacillus anthracis, Streptococcus pyogenes, Candida albicans, and Candida glabrata. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (1) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity.

Background Health is poorer in rural areas and a major challenge is care coordination for complex chronic conditions. The HITECH and 21st Century Cure Acts emphasize health information exchange which underpins activities required to improve care coordination. Objective and methods Using semi-structured interviews and surveys, we examined how providers experience electronic health information exchange during care coordination since these Acts were implemented, with a focus on rural settings where health disparities exist. We used a purposive sample that included primary care, acute care hospitals, and community health services in the United States. Findings We identified seven themes related to care coordination and information exchange: ‘insufficient trust of data’; ‘please respond’; ‘just fax it’; ‘care plans’; ‘needle in the haystack’; ‘re-documentation’; and ‘rural reality’. These gaps were magnified when information exchange was required between unaffiliated electronic health records (EHRs) about shared patients, which was more pronounced in rural settings. Conclusion Policy and incentive modifications are likely needed to overcome the observed health information technology (HIT) shortcomings. Rural settings in the United States accentuate problems that can be addressed through international medical informatics policy makers and the implementation and evaluation of interoperable HIT systems.

proNGF and p75NTR are induced following fatal myocardial infraction and are required for the development of microvascular injury., Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro–nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75NTR) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75NTR in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75NTR by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75NTR in proNGF-expressing mice rescues the phenotype, confirming the importance of p75NTR-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75NTR limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.

Pro–brain-derived neurotrophic factor (proBDNF) and mature BDNF utilize distinct receptors to mediate divergent neuronal actions. Using new tools to quantitate endogenous BDNF isoforms, we found that mouse neurons secrete both proBDNF and mature BDNF. The highest levels of proBDNF and p75 were observed perinatally and declined, but were still detectable, in adulthood. Thus, BDNF actions are developmentally regulated by secretion of proBDNF or mature BDNF and by local expression of p75 and TrkB.

e22126 Background: We have developed proprietary, innovative methods for the identification of actionable aberrations using NGS of malignant tissues. Prior to commencing prospective decisions based...

Ventilatory threshold (VT) is an important predictor of cardiorespiratory fitness, such as peak oxygen uptake (VO2peak) and is a valuable index of aerobic exercise intensity. However, little is known about the role of skeletal muscle (SM) mass in the age-associated decline of VT. Therefore, the present study was performed to investigate the effects of age on cardiopulmonary fitness normalised for regional SM mass in 1,463 Japanese men and women, and to determine the relevance of VT normalised to SM mass based on age and gender. Total, trunk and thigh SM mass were measured using an ultrasound method, while VO2peak and VT were determined during treadmill walking. VO2peak was estimated using the predicted maximum heart rate (HR) and the HR-VO2 relationship for sub-maximal treadmill walking. There were significant negative correlations between VT normalised for body mass and age in men and women (P < 0.001). Age-associated declines were also observed in VT normalised for body mass in both men and women; however, VT normalised for SM mass was not significantly different with age. Significant correlations were also observed between thigh SM mass and VT in both men and women. These results suggest that thigh SM mass is closely associated with VO2peak and/or VT in both men and women, and the decrease in VT with age is predominantly due to an age-related decline of SM mass. Moreover, this study provides normative cardiorespiratory fitness data regarding VT normalised SM mass in healthy men and women aged 20-80 years.