Can polarization of macrophage metabolism enhance cardiac regeneration?

While largely appreciated for their antimicrobial and repair functions, macrophages have emerged as indispensable for the development, homeostasis, and regeneration of tissue, including regeneration of the neonatal heart. Upon activation, mammalian neonatal macrophages express and secrete factors that coordinate angiogenesis, resolution of inflammation, and ultimately cardiomyocyte proliferation. This is contrary to adult macrophages in the adult heart, which are incapable of inducing significant levels of cardiac regeneration. The underlying mechanisms by which pro-regenerative macrophages are activated and regulated remain vague. A timely hypothesis is that macrophage metabolism contributes to this proliferative and regenerative potential. This is because we now appreciate the significant contributions of metabolites to immune cell programming and function, beyond solely bioenergetics. After birth, the metabolic milieu of the neonate is subject to significant alterations in oxygenation and nutrient supply, which will affect how metabolic substrates are catabolized. In this context, we discuss potential roles for select macrophage metabolic pathways during cardiac regeneration.

Cardiopulmonary Bypass-Induced Inflammation and Myocardial Ischemia and Reperfusion Injury Stimulates Accumulation of Soluble MER.

OBJECTIVES: Soluble MER has emerged as a potential biomarker for delayed resolution of inflammation after myocardial injury and a therapeutic target to reduce cardiac-related morbidity and mortality in adults. The significance of soluble MER in pediatric populations, however, is unclear. We sought to investigate if soluble MER concentrations change in response to myocardial ischemia and reperfusion injury in pediatric patients. In parallel, we also sought to investigate for correlations between the change in soluble MER concentration and specific patient, bypass, and postoperative data. DESIGN: We quantified the change in plasma soluble MER concentration post- compared with precardiopulmonary bypass for each patient in a cohort of pediatric patients. Linear regression, correlation coefficients, and t tests were used to compare innate patient characteristics (i.e., sex, age, cyanotic vs acyanotic cardiac lesion), cardiac bypass data (i.e., total cardiac bypass time, total aortic cross-clamp time, perioperative steroid administration), and postcardiac bypass data (total postoperative ventilator days, total postoperative vasoactive medication days, and total postoperative ICU days) with change in soluble MER concentrations. SETTING: Whole blood samples were obtained intraoperatively at a single tertiary care children's hospital from April to October 2019. SUBJECTS: Our patient cohort included 24 pediatric patients ages ranging from birth to 19 years old with both cyanotic and acyanotic cardiac lesions. INTERVENTIONS: Retrospective analyses of pediatric blood specimens, as well as patient, bypass, and postoperative data, were performed. MEASUREMENTS AND MAIN RESULTS: We observed a statistically significant increase in soluble MER concentration post cardiac bypass in 17 of 24 patients (71%). CONCLUSIONS: Soluble MER concentrations increase with cardiopulmonary bypass-induced inflammation and myocardial ischemia and reperfusion injury in pediatric patients. The utility of soluble MER as a clinical biomarker to identify pediatric patients at risk for exacerbated postoperative outcomes after bypass-induced myocardial ischemia and reperfusion injury requires further investigation.

Novel Nutritional and Dietary Approaches to Weight Loss for the Prevention of Cardiovascular Disease: Ketogenic Diet, Intermittent Fasting, and Bariatric Surgery.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is highly associated with obesity and cardiometabolic dysfunction. This review will focus on three novel therapies that have been identified for potential treatment of obesity and its associated CVD risk factors. RECENT FINDINGS: Intermittent fasting (IF) studies in animal models have shown improvements in cardiometabolic factors, including improved glucose metabolism, reduced inflammation, and reduced blood pressure. However, there is still a lack of prospective human trials to support results from animal-based studies and observational data. Studies of ketogenic diets in humans have produced mixed effects in CVD risk factors. It has been shown that the ketogenic diet (KD) increases low-density lipoprotein cholesterol (LDL-C) but decreases triglycerides. Additionally, implementation of KD in rodent studies have demonstrated increased insulin resistance and glucose intolerance. Bariatric surgery is a useful tool to help patients with obesity lose significant amounts of weight while alleviating CVD risk factors such as hypertension, LDL-C levels, triglyceride levels, and diabetes. The type of procedure influences degree of improvement in weight and CVD risk factors, yet complications remain possible. IF and bariatric surgery offer potential for weight loss and treatment of CVD risk factors. Negative cardiovascular effects of KD have been noted and should be considered before recommending this diet to patients, particularly those with established cardiovascular disease.

Monocytes prime autoreactive T cells after myocardial infarction.

In humans, loss of central tolerance for the cardiac self-antigen α-myosin heavy chain (α-MHC) leads to circulation of cardiac autoreactive T cells and renders the heart susceptible to autoimmune attack after acute myocardial infarction (MI). MI triggers profound tissue damage, releasing danger signals and self-antigen by necrotic cardiomyocytes, which lead to recruitment of inflammatory monocytes. We hypothesized that excessive inflammation by monocytes contributes to the initiation of adaptive immune responses to cardiac self-antigen. Using an experimental model of MI in α-MHC-mCherry reporter mice, which specifically express mCherry in cardiomyocytes, we detected α-MHC antigen in myeloid cells in the heart-draining mediastinal lymph node (MLN) 7 days after MI. To test whether monocytes were required for cardiac self-antigen trafficking to the MLN, we blocked monocyte recruitment with a C-C motif chemokine receptor type 2 (CCR2) antagonist or immune modifying nanoparticles (IMP). Blockade of monocyte recruitment reduced α-MHC antigen detection in the MLN after MI. Intramyocardial injection of the model antigen ovalbumin into OT-II transgenic mice demonstrated the requirement for monocytes in antigen trafficking and T-cell activation in the MLN. Finally, in nonobese diabetic mice, which are prone to postinfarction autoimmunity, blockade of monocyte recruitment reduced α-MHC-specific responses leading to improved tissue repair and ventricular function 28 days after MI. Taken together, these data support a role for monocytes in the onset of pathological cardiac autoimmunity following MI and suggest that therapeutic targeting of monocytes may mitigate postinfarction autoimmunity in humans.NEW & NOTEWORTHY Our study newly identifies a role for inflammatory monocytes in priming an autoimmune T-cell response after myocardial infarction. Select inhibition of monocyte recruitment to the infarct prevents trafficking of cardiac self-antigen and activation of cardiac myosin reactive T cells in the heart-draining lymph node. Therapeutic targeting of inflammatory monocytes may limit autoimmune responses to improve cardiac remodeling and preserve left ventricular function after myocardial infarction.

HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults.

The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1α ( HIF-1α). In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1α dependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.

Antineoplastic Activity Evaluation of Brazilian Brown Propolis and Artepillin C in Colorectal Area of Wistar Rats.

OBJECTIVE: The study's aim was to evaluate Brazilian Brown Propolis (BBP) and Artepillin C (ARC) chemopreventive action in Wistar rats' colons. METHODS: Fifty male Wistar rats were divided into ten experimental groups, including control groups, groups with and without 1,2-dimethylhydrazine (DMH) induction, and BBP, ARC, and ARC enriched fraction (EFR) treatments, for sixteen weeks. Aberrant crypt foci (ACF) were classified as hyperplastic or dysplastic, and proliferating cell nuclear antigen (PCNA) expression was quantified. RESULT: ACF amounts in experimental groups (induced or not) decreased in both colon portions, while the isolated Aberrant Crypt (AC) number increased. Experimental groups of animals showed higher hyperplasia and dysplasia amounts compared with control groups. The ACF dysplastic amount present in groups induced and treated, in both colon portions, had similar values to IDMH (DMH induction group without treatment). In addition, DMH was effective in ACF inducing and there was positive staining for PCNA in basal and upper dysplastic foci portions in all experimental groups, in the mitotic index (MI) evaluation. To conclude, considering all the experimental groups, the one treated with EFR (fraction enriched with ARC) had the lowest rates of cell proliferation. CONCLUSION: BBP and its derivatives prevented crypt cell clonal expansion.

Marine subsidies produce cactus forests on desert islands.

In island systems, nitrogen-rich seabird guano is a marine subsidy that can shape terrestrial plant communities. In zones of nutrient upwelling such as the Gulf of California, copious seabird guano is commonplace on bird islands. Several bird islands host regionally unique cactus forests, especially of the large columnar cactus, cardón (Pachycereus pringlei). We show that a chain of interactions across the land-sea interface yields an allochthonous input of nitrogen in the form of seabird guano, fueling the production of some of the densest cactus populations in the world. Fish, seabird, guano, soil, and cactus samples were taken from the representative seabird island of San Pedro Mártir for nitrogen stable isotope ratio measurements, which were compared to soil and cactus samples from other seabird and non-seabird Gulf islands and terrestrial ecosystems throughout the range of the cardón. Isla San Pedro Mártir δ15N values are distinctively high, ranging from fish + 17.7, seabird + 19.7, guano + 14.8, soil + 34.3 and cactus + 30.3 compared to average values across non-bird sites of + 13.0 (N = 213, S.D. = 3.7) for soil and + 9.8 (N = 212, S.D. = 3.4) for cactus. These δ15N values are among the highest ever reported for plants. Seabird island soil and cactus δ15N values were consistently significantly enriched relative to mainland and non-bird islands, a relationship expected due to the progressive volatilization of 14N rich ammonia from decomposing guano deposits. Our findings demonstrate that seabird-mediated marine nutrient deposits provide the source for solubilized nitrogen on desert islands, which stimulate terrestrial plant production in the cardón cactus beyond that seen in either mainland ecosystems or non-seabird islands.

Continuous glucose monitoring reveals similar glycemic variability in individuals with obesity despite increased HOMA-IR.

Background/aims: Continuous glucose monitoring is a well-tolerated and versatile tool for management of diabetes and metabolic disease. While its use appears to be feasible to monitor glycemic profiles in diabetics, there is a paucity of data in individuals with obesity and normal glucose tolerance. The aim of this study is to investigate glucose fluctuations and insulin resistance patterns in normoglycemic participants with obesity vs. without obesity and contextualize these results against leading models for obesity. Materials and methods: We designed a prospective, observational pilot study of two cohorts including 14 normoglycemic participants with obesity and 14 normoglycemic participants without obesity. Participants were monitored with continuous glucose monitoring (CGM) for five consecutive days. Insulin resistance levels were measured and glucometric data were extracted from CGM for all participants. Results: Fasting serum insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly higher in the group with obesity (P < 0.05). While the group with obesity had a higher mean blood glucose (MBG), mean amplitude of glycemic excursions (MAGE), and continuous overall glycemic action-1 h (CONGA-1), these differences were not significant. On univariate linear regression, insulin resistance (HOMA-IR) was associated with body mass index (BMI), waist circumference (WC), cohort with obesity, cohort consuming a high glycemic diet, hemoglobin A1c (HbA1c), and fasting insulin levels. WC and fasting insulin levels remained predictors of HOMA-IR in our multivariable model. Conclusion: While there is much excitement surrounding the use of commercial CGM products in obesity management, our results suggest that fasting insulin and HOMA-IR values may be more clinically useful than CGM data alone.

The relationship of plasma Abeta levels to dementia in aging individuals with Down syndrome.

To study the relationship between plasma levels of amyloid beta (Abeta) peptides and dementia in aging individuals with Down syndrome, we investigated the relationship among plasma Abeta, apolipoprotein E genotype and cognitive and clinical factors using baseline specimens form participants in an ongoing clinical trial in individuals with Down syndrome 50 years of age and older. Because of substantial skew in the distribution of peptide levels, analyses used log transformations of the data. The ratio of Abeta42 to Abeta40 was associated with the presence of dementia (P=0.003, df=196, F=9.37); this association persisted after adjustment for age, sex level of mental retardation, and apolipoprotein E genotype. Consistent with recent reports regarding the effect of presenilin mutations on peptide generation, our finding supports the theory that the ratio of Abeta42 to Abeta40 rather than absolute levels of the peptides is important to the pathophysiology of Alzheimer's disease in genetically susceptible populations.

Immunometabolism of Phagocytes and Relationships to Cardiac Repair.

Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.

F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein.

A recent study showed that F-spondin, a protein associated with the extracellular matrix, interacted with amyloid precursor protein (APP) and inhibited beta-secretase cleavage. F-spondin contains a thrombospondin domain that we hypothesized could interact with the family of receptors for apolipoprotein E (apoE). Through coimmunoprecipitation experiments, we demonstrated that F-spondin interacts with an apoE receptor (apoE receptor 2 [ApoEr2]) through the thrombospondin domain of F-spondin and the ligand binding domain of ApoEr2. Full-length F-spondin increased coimmunoprecipitation of ApoEr2 and APP in transfected cells and primary neurons and increased surface expression of APP and ApoEr2. Full-length F-spondin, but none of the individual F-spondin domains, increased cleavage of APP and ApoEr2, resulting in more secreted forms of APP and ApoEr2 and more C-terminal fragments (CTF) of these proteins. In addition, full-length F-spondin, but not the individual domains, decreased production of the beta-CTF of APP and Abeta in transfected cells and primary neurons. The reduction in APP beta-CTF was blocked by receptor-associated protein (RAP), an inhibitor of lipoprotein receptors, implicating ApoEr2 in the altered proteolysis of APP. ApoEr2 coprecipitated with APP alpha- and beta-CTF, and F-spondin reduced the levels of APP intracellular domain signaling, suggesting that there are also intracellular interactions between APP and ApoEr2, perhaps involving adaptor proteins. These studies suggest that the extracellular matrix molecule F-spondin can cluster APP and ApoEr2 together on the cell surface and affect the processing of each, resulting in decreased production of Abeta.

Activity-Based Goals Generated by Older Adults With Mild Cognitive Impairment.

Client-centered care is one promising rehabilitation model that may support the unique needs of older adults with mild cognitive impairment (MCI). This secondary analysis examined (a) whether older adults with MCI generated activity-based goals using a client-centered model and (b) the types of goals generated. Thirteen older adults with MCI addressed 55 goals. Using client-centered care, the participants generated goals despite subtle limitations in activities and participation. Participants generated the greatest number of goals related to instrumental activities of daily living. This study demonstrated that older adults with MCI generated goals through a client-centered model. This is important because older adults with MCI are at risk for disability, and they may benefit from early rehabilitation care models that minimize activity limitations and participation restrictions despite underlying cognitive impairments.

Antibody against C-terminal Abeta selectively elevates plasma Abeta.

Accumulation of amyloid beta in the brain is a pathological hallmark of Alzheimer's disease, and the reduction of amyloid beta has been proposed as a primary therapeutic target. Mice immunized against amyloid beta and mice infused with anti-amyloid beta antibody (active and passive immunization, respectively) have reduced brain amyloid beta levels, and two mechanisms have been proposed: microglial phagocytosis in the brain and enhancement of amyloid beta efflux by antibodies present in the periphery (sequestration). The optimal antibody for microglial phagocytosis has been shown to be N-terminal-specific antibody; however, the potency of C-terminal-specific antibody in sequestration remains unclear. In this study, we found that anti-amyloid beta 40-specific antibody induces amyloid beta sequestration. These results indicate that C-terminal antibodies may be useful in amyloid beta sequestration therapy.

Activity and distribution of paxillin, focal adhesion kinase, and cadherin indicate cooperative roles during zebrafish morphogenesis.

We investigated the focal adhesion proteins paxillin and Fak, and the cell-cell adhesion protein cadherin in developing zebrafish (Danio rerio) embryos. Cadherins are expressed in presomitic mesoderm where they delineate cells. The initiation of somite formation coincides with an increase in the phosphorylation of Fak, and the accumulation of Fak, phosphorylated Fak, paxillin, and fibronectin at nascent somite boundaries. In the notochord, cadherins are expressed on cells during intercalation, and phosphorylated Fak accumulates in circumferential rings where the notochord cells contact laminin in the perichordal sheath. Subsequently, changes in the orientations of collagen fibers in the sheath suggest that Fak-mediated adhesion allows longitudinal expansion of the notochord, but not lateral expansion, resulting in notochord elongation. Novel observations showed that focal adhesion kinase and paxillin concentrate at sites of cell-cell adhesion in the epithelial enveloping layer and may associate with actin cytoskeleton at epithelial junctions containing cadherins. Fak is phosphorylated at these epithelial junctions but is not phosphorylated on Tyr397, implicating a noncanonical mechanism of regulation. These data suggest that Fak and paxillin may function in the integration of cadherin-based and integrin-based cell adhesion during the morphogenesis of the early zebrafish embryo.

Effects of nandrolone decanoate on time to consolidation of bone defects resulting from osteotomy for tibial tuberosity advancement.

STUDY DESIGN: Experimental study. OBJECTIVE: The aim of this study was to evaluate the effect of nandrolone decanoate (ND) on the time taken for bone consolidation in dogs undergoing tibial tuberosity advancement surgery (TTA). MATERIALS AND METHODS: Seventeen dogs that underwent TTA surgery were randomly divided into two groups: group C (TTA; 9 stifles), and group TTA+ND (TTA and systemic administration of ND; 8 stifles). Three observers (two radiologists and an orthopaedic surgeon), assessed bone consolidation by visual inspection of serial radiographs at intervals of 21 days following surgery. RESULTS: There were no differences in median weight and age between groups, nor between the medians of the variables right and left stifle. Only weight and age values were normally distributed. The other variables, right and left stifle and time to consolidation, showed non-normal distribution. Meniscal injury was present in all animals in group C and all animals in group TTA+ND. There was a significant difference between time to consolidation in groups C and TTA+ND (p <0.05). One animal in the group TTA+ND showed increased libido. Kappa agreement among observers on radiographs was 0.87. CONCLUSION: Administration of ND reduces time to bone consolidation in dogs undergoing TTA.

Creating Online Training for Procedures in Global Health with PEARLS (Procedural Education for Adaptation to Resource-Limited Settings).

The authors describe a multiinstitutional collaborative project to address a gap in global health training by creating a free online platform to share a curriculum for performing procedures in resource-limited settings. This curriculum called PEARLS (Procedural Education for Adaptation to Resource-Limited Settings) consists of peer-reviewed instructional and demonstration videos describing modifications for performing common pediatric procedures in resource-limited settings. Adaptations range from the creation of a low-cost spacer for inhaled medications to a suction chamber for continued evacuation of a chest tube. By describing the collaborative process, we provide a model for educators in other fields to collate and disseminate procedural modifications adapted for their own specialty and location, ideally expanding this crowd-sourced curriculum to reach a wide audience of trainees and providers in global health.

MACRA and the future of value-based care.

The passage of Medicare Access and Children's Health Insurance Program Reauthorization Act of 2015 (MACRA) heralded a fundamental shift from volume-based to value-based payment for health care services in the United States. Beginning in 2019, neurologists will participate in 1 of 2 Medicare pathways: the Merit-Based Incentive Payment System or Alternative Payment Models. Both options represent an important change from the current fee-for-service payment models, and neurologists will need to be prepared well in advance of the MACRA launch. This article reviews the background, structure, uncertainties, and implications of MACRA on the practice of neurology, with recommendations for preparation.

An Abeta sequestration approach using non-antibody Abeta binding agents.

Amyloid beta (Abeta) has been considered as a primary cause of Alzheimer's disease (AD), and Abeta lowering approaches have been tested. Active immunization against Abeta is one of several promising Abeta-lowering approaches. Two mechanisms have been proposed: enhancement of microglial phagocytosis and Abeta sequestration (also called "peripheral sink"). We hypothesized that Abeta sequestration without immune modulation is sufficient to reduce the brain Abeta load and have demonstrated effective sequestration with Abeta binding agents that do not stimulate an immune reaction. Recent reports from other groups showed two other non-immune related Abeta binding agents, which have no structural relation to compounds we previously tested, reduced brain Abeta after peripheral administration. Congo red is a chemically synthesized small molecule that has binding affinity to Abeta. In the present study, we tested three Congo red derivatives in Abeta plaque-forming mice at an early pathological stage. Unfortunately, peripheral administration for three weeks did not substantially alter brain Abeta load. Optimized Abeta binding agents with high affinity to soluble Abeta are necessary for the sequestration approach.

Medicare payments to the neurology workforce in 2012.

OBJECTIVE: Little is known about how neurology payments vary by service type (i.e., evaluation and management [E/M] vs tests/treatments) and compare to other specialties, yet this information is necessary to help neurology define its position on proposed payment reform. METHODS: Medicare Provider Utilization and Payment Data from 2012 were used. These data included all direct payments to providers who care for fee-for-service Medicare recipients. Total payment was determined by medical specialty and for various services (e.g., E/M, EEG, electromyography/nerve conduction studies, polysomnography) within neurology. Payment and proportion of services were then calculated across neurologists' payment categories. RESULTS: Neurologists comprised 1.5% (12,317) of individual providers who received Medicare payments and were paid $1.15 billion by Medicare in 2012. Sixty percent ($686 million) of the Medicare payment to neurologists was for E/M, which was a lower proportion than primary providers (approximately 85%) and higher than surgical subspecialties (range 9%-51%). The median neurologist received nearly 75% of their payments from E/M. Two-thirds of neurologists received 60% or more of their payment from E/M services and over 20% received all of their payment from E/M services. Neurologists in the highest payment category performed more services, of which a lower proportion were E/M, and performed at a facility, compared to neurologists in lower payment categories. CONCLUSION: E/M is the dominant source of payment to the majority of neurologists and should be prioritized by neurology in payment restructuring efforts.

How neurologists are paid: Part 3: Hospital support, Veterans Administration, and neurohospitalists.

Part 1 of this series focused on factors influencing payment for patient care services and Part 2 described compensation plans for neurologists in private practice and in academic medicine. In Part 3, we review how hospital salary support and appointments to Veterans Administration hospitals contribute to the salary structure of neurologists. We also discuss neurohospitalist care and ways neurologists can potentially increase compensation from on-call pay, telemedicine, and the use of new transitional care and complex chronic care codes. We conclude with an emphasis on the important role of neurologists as team players in a health care system that will rely on efficient coordination of care among many health care workers.