After decades of resistance there is now a genuine consensus that disease cannot be prevented or even successfully treated unless the role of stress is addressed alongside traditionally recognized factors such as genes and the environment. Measurement of allostatic load, which is quantified by the allostatic load score (ALS), is one of the most frequently used methods to assess the physiologic response to stress. Even though there is universal agreement that in the calculation of ALS, biomarkers from three categories should be included (cardiovascular, metabolic and immune), enormous variation exists in how ALS is calculated. Specifically, there is no consensus on which biomarkers to include or the method which should be used to determine whether the value of a biomarker represents high risk. In this Perspective, we outline the approach taken in 21 different NHANES studies.

Lipid-laden macrophages, or "foam cells," are observed in the lungs of patients with fibrotic lung disease, but their contribution to disease pathogenesis remains unexplored. Here, we demonstrate that fibrosis induced by bleomycin, silica dust, or thoracic radiation promotes early and sustained accumulation of foam cells in the lung. In the bleomycin model, we show that foam cells arise from neighboring alveolar epithelial type II cells, which respond to injury by dumping lipids into the distal airspaces of the lungs. We demonstrate that oxidized phospholipids accumulate within alveolar macrophages (AMs) after bleomycin injury and that murine and human AMs treated with oxidized phosphatidylcholine (oxPc) become polarized along an M2 phenotype and display enhanced production of transforming growth factor-b1. The direct instillation of oxPc into the mouse lung induces foam cell formation and triggers a severe fibrotic reaction. Further, we show that reducing pulmonary lipid clearance by targeted deletion of the lipid efflux transporter ATPbinding cassette subfamily G member 1 increases foam cell formation and worsens lung fibrosis after bleomycin. Conversely, we found that treatment with granulocyte-macrophage colony-stimulating factor attenuates fibrotic responses, at least in part through its ability to decrease AM lipid accumulation. In summary, this work describes a novel mechanism leading to foam cell formation in the mouse lung and suggests that strategies aimed at blocking foam cell formation might be effective for treating fibrotic lung disorders.

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ObjectivesObesity is on the rise in the US and is linked to the development of type 2 diabetes and cardiovascular disease. Emerging evidence over the last decade suggests that obesity may also adversely affect executive function and brain structure. Although a great deal of research focuses on how diet affects the brain and cognitive performance, no study focuses on how food choice may be associated with brain integrity. Here we investigated how lean and overweight/obese (o/o) adults differed in their food choices and how brain structure and cognition may be associated with those choices.DesignAs part of an ongoing study on diabetes and the brain, participants had routine blood work and a research MRI, received a battery of neurocognitive tests, and were instructed to keep a 3-day food diary.Results and conclusionsThe lean group ate more high quality foods and less low quality foods compared to the o/o group. In the o/o group, high quality food choices were associated with orbitofrontal cortex volume. The lean group performed better than the o/o group on neurocognitive measures of executive function, such as the Stroop Interference Test, the Wisconsin Card Sort Test and the Trail Making Test B-A, and on attention and concentration tasks such as the Digit Symbol Substitution Test. Taken together, these preliminary data suggest that in obesity poor food choices may be associated with frontal cognitive impairments that may be the result of, or contribute to, decreases in orbitofrontal cortex volume. Therefore, longitudinal studies are warranted to investigate a causal link between food choice and executive functioning.

Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5'-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI.

Obesity is a risk factor for the development of acute respiratory distress syndrome (ARDS) but mechanisms mediating this association are unknown. While obesity is known to impair systemic blood vessel function, and predisposes to systemic vascular diseases, its effects on the pulmonary circulation are largely unknown. We hypothesized that the chronic low grade inflammation of obesity impairs pulmonary vascular homeostasis and primes the lung for acute injury. The lung endothelium from obese mice expressed higher levels of leukocyte adhesion markers and lower levels of cell-cell junctional proteins when compared to lean mice. We tested whether systemic factors are responsible for these alterations in the pulmonary endothelium; treatment of primary lung endothelial cells with obese serum enhanced the expression of adhesion proteins and reduced the expression of endothelial junctional proteins when compared to lean serum. Alterations in pulmonary endothelial cells observed in obese mice were associated with enhanced susceptibility to LPS-induced lung injury. Restoring serum adiponectin levels reversed the effects of obesity on the lung endothelium and attenuated susceptibility to acute injury. Our work indicates that obesity impairs pulmonary vascular homeostasis and enhances susceptibility to acute injury and provides mechanistic insight into the increased prevalence of ARDS in obese humans.

OBJECTIVESlowing the diabetes epidemic in Africa requires improved detection of prediabetes. A1C, a form of glycated hemoglobin A, is recommended for diagnosing prediabetes. The glycated proteins, fructosamine and glycated albumin (GA), are hemoglobin-independent alternatives to A1C, but their efficacy in Africans is unknown. Our goals were to determine the ability of A1C, fructosamine, and GA to detect prediabetes in U.S.-based Africans and the value of combining A1C with either fructosamine or GA.RESEARCH DESIGN AND METHODSOral glucose tolerance tests (OGTT) were performed in 217 self-identified healthy African immigrants (69% male, age 39 ± 10 years [mean ± SD], BMI 27.6 ± 4.5 kg/m2). A1C, fructosamine, and GA were measured. Prediabetes was diagnosed by American Diabetes Association criteria for glucose obtained from a 2-h OGTT. The thresholds to diagnose prediabetes by A1C, fructosamine, and GA were the cutoff at the upper tertile for each variable: ≥5.7% (39 mmol/mol) (range 4.2–6.6% [22.4–48.6 mmol/mol]), ≥230 µmol/L (range 161–269 µmol/L), and ≥13.35% (range 10.20–16.07%), respectively.RESULTSPrediabetes occurred in 34% (74 of 217). The diagnostic sensitivities of A1C, fructosamine, and GA were 50%, 41%, and 42%, respectively. The P values for comparison with A1C were both >0.3. Combining A1C with either fructosamine or GA increased sensitivities. However, the sensitivity of A1C combined with fructosamine was not better than for A1C alone (72% vs. 50%, P = 0.172). In contrast, the sensitivity of A1C combined with GA was higher than for A1C alone (78% vs. 50%, P < 0.001).CONCLUSIONSAs individual tests, A1C, fructosamine, and GA detected ≤50% of Africans with prediabetes. However, combining A1C with GA made it possible to identify nearly 80% of Africans with prediabetes.

The early glomerular changes in diabetes include a podocyte phenotype with loss of slit diaphragm proteins, changes in the actin cytoskeleton and foot process architecture. This review focuses on the role of the protein kinase C (PKC) family in podocytes and points out the differential roles of classical, novel, and atypical PKCs in podocytes. Some PKC isoforms are indispensable for proper glomerular development and slit diaphragm maintenance, whereas others might be harmful when activated in the diabetic milieu. Therefore, some might be interesting treatment targets in the early phase of diabetes.