Early Social Stress Promotes Inflammation and Disease Risk in Rhesus Monkeys.

Early social stress has potent lifelong health effects. We examined the association of early stress in the attachment relationship (low maternal sensitivity, low MS), lower maternal social hierarchy rank, and greater frequency of group-level social conflict, with biomarkers of inflammatory stress response in plasma (IL-8, MCP-1 and CRP collected two hours after temporary separation from mothers and social groups) and risk for developing a common macaques disease outcome (infectious colitis) in 170 socially-housed rhesus monkeys. We controlled for gene-environment correlations by comparing cross-fostered subjects with infants reared by their biological mothers. Low MS predicted higher levels of pro-inflammatory cytokines and proteins at 3-4 months of age (F(3, 162) = 3.508, p = 0.002, partial eta2 = 0.061) and higher lifetime risk for developing colitis for up to twelve years of age (chi square = 5.919, p = 0.026). Lower maternal social rank (F (3, 162) = 3.789, p = 0.012, partial eta2 = 0.06) and higher rates of social conflict (F (3, 162) = 4.264, p = 0.006, partial eta2 = 0.074) each also predicted greater inflammation in infancy, but not lifetime colitis risk (both p > 0.05). The effects of low MS, lower social rank, and higher social conflict were significant in infants reared by biological mothers and cross-fostered infants, suggesting that our results did not arise from gene-environment correlations, but environmental stressors alone. We conclude that several types of early social stress confer risk for inflammation in infancy, but that stress in the mother-infant relationship may confer the longest-term risk for adverse health outcomes

Urinary excretion of RAS, BMP, and WNT pathway components in diabetic kidney disease.

Abstract The renin-angiotensin system (RAS), bone morphogenetic protein (BMP), and WNT pathways are involved in pathogenesis of diabetic kidney disease (DKD). This study characterized assays for urinary angiotensinogen (AGT), gremlin-1, and matrix metalloproteinase 7 (MMP-7), components of the RAS, BMP, and WNT pathways and examined their excretion in DKD. We measured urine AGT, gremlin-1, and MMP-7 in individuals with type 1 diabetes and prevalent DKD (n = 20) or longstanding (n = 61) or new-onset (n = 10) type 1 diabetes without DKD. These urine proteins were also quantified in type 2 DKD (n = 11) before and after treatment with candesartan. The utilized immunoassays had comparable inter- and intra-assay and intraindividual variation to assays used for urine albumin. Median (IQR) urine AGT concentrations were 226.0 (82.1, 550.3) and 13.0 (7.8, 20.0) μg/g creatinine in type 1 diabetes with and without DKD, respectively (P < 0.001). Median (IQR) urine gremlin-1 concentrations were 48.6 (14.2, 254.1) and 3.6 (1.7, 5.5) μg/g, respectively (P < 0.001). Median (IQR) urine MMP-7 concentrations were 6.0 (3.8, 10.5) and 1.0 (0.4, 2.9) μg/g creatinine, respectively (P < 0.001). Treatment with candesartan was associated with a reduction in median (IQR) urine AGT/creatinine from 23.5 (1.6, 105.1) to 2.0 (1.4, 13.7) μg/g, which did not reach statistical significance. Urine gremlin-1 and MMP-7 excretion did not decrease with candesartan. In conclusion, DKD is characterized by markedly elevated urine AGT, MMP-7, and gremlin-1. AGT decreased in response to RAS inhibition, suggesting that this marker reflects therapeutic response. Urinary components of the RAS, BMP, and WNT pathways may identify risk of DKD and aid development of novel therapeutics

Using stratified medicine to understand, diagnose, and treat neuropathic pain

Neuropathic pain (NeuP) is defined as pain arising from a lesion or disease of the somatosensory nervous system. NeuP is common, affecting approximately 6-8% of the general population and currently treatment is inadequate due to both poor drug efficacy and tolerability. Many different types of injury can cause neuropathic pain including genetic (e.g. SCN9A gain of function variants), metabolic (e.g. diabetic polyneuropathy), infective (e.g. HIV associated neuropathy, hepatitis), traumatic and toxic (e.g. chemotherapy induced neuropathy) causes. Such injurious events can impact on anatomically distinct regions of the somatosensory nervous system ranging from the terminals of nociceptive afferents (in small fiber neuropathy) to the thalamus (in post-stroke pain). Classification of neuropathic pain using etiology and location remains an important aspect of routine clinical practice; however, pain medicine is coming to the realization that we need more precision in this classification. The hope is that improved classification will lead to better understanding of risk, prognosis and optimal treatment of NeuP

Management of Mechanical Ventilation in Decompensated Heart Failure.

Mechanical ventilation (MV) is a life-saving intervention for respiratory failure, including decompensated congestive heart failure. MV can reduce ventricular preload and afterload, decrease extra-vascular lung water, and decrease the work of breathing in heart failure. The advantages of positive pressure ventilation must be balanced with potential harm from MV: volutrauma, hyperoxia-induced injury, and difficulty assessing readiness for liberation. In this review, we will focus on cardiac, pulmonary, and broader effects of MV on patients with decompensated HF, focusing on practical considerations for management and supporting evidence

Differences in reactivation of tuberculosis induced from anti-tnf treatments are based on bioavailability in granulomatous tissue

The immune response to Mycobacterium tuberculosis (Mtb) infection is complex. Experimental evidence has revealed that tumor necrosis factor (TNF) plays a major role in host defense against Mtb in both active and latent phases of infection. TNF-neutralizing drugs used to treat inflammatory disorders have been reported to increase the risk of tuberculosis (TB), in accordance with animal studies. The present study takes a computational approach toward characterizing the role of TNF in protection against the tubercle bacillus in both active and latent infection. We extend our previous mathematical models to investigate the roles and production of soluble (sTNF) and transmembrane TNF (tmTNF). We analyze effects of anti-TNF therapy in virtual clinical trials (VCTs) by simulating two of the most commonly used therapies, anti-TNF antibody and TNF receptor fusion, predicting mechanisms that explain observed differences in TB reactivation rates. The major findings from this study are that bioavailability of TNF following anti-TNF therapy is the primary factor for causing reactivation of latent infection and that sTNF-even at very low levels-is essential for control of infection. Using a mathematical model, it is possible to distinguish mechanisms of action of the anti-TNF treatments and gain insights into the role of TNF in TB control and pathology. Our study suggests that a TNF-modulating agent could be developed that could balance the requirement for reduction of inflammation with the necessity to maintain resistance to infection and microbial diseases. Alternatively, the dose and timing of anti-TNF therapy could be modified. Anti-TNF therapy will likely lead to numerous incidents of primary TB if used in areas where exposure is likely. © 2007 Marino et al

Repeated stressors in adulthood increase the rate of biological ageing

Background Individuals of the same age can differ substantially in the degree to which they have accumulated tissue damage, akin to bodily wear and tear, from past experiences. This accumulated tissue damage reflects the individual’s biological age and may better predict physiological and behavioural performance than the individual‘s chronological age. However, at present it remains unclear how to reliably assess biological age in individual wild vertebrates. Methods We exposed hand-raised adult Eurasian blackbirds (Turdus merula) to a combination of repeated immune and disturbance stressors for over one year to determine the effects of chronic stress on potential biomarkers of biological ageing including telomere shortening, oxidative stress load, and glucocorticoid hormones. We also assessed general measures of individual condition including body mass and locomotor activity. Results By the end of the experiment, stress-exposed birds showed greater decreases in telomere lengths. Stress-exposed birds also maintained higher circulating levels of oxidative damage compared with control birds. Other potential biomarkers such as concentrations of antioxidants and glucocorticoid hormone traits showed greater resilience and did not differ significantly between treatment groups. Conclusions The current data demonstrate that repeated exposure to experimental stressors affects the rate of biological ageing in adult Eurasian blackbirds. Both telomeres and oxidative damage were affected by repeated stress exposure and thus can serve as blood-derived biomarkers of biological ageing.</p

Adversarial Unsupervised Representation Learning for Activity Time-Series

Sufficient physical activity and restful sleep play a major role in the prevention and cure of many chronic conditions. Being able to proactively screen and monitor such chronic conditions would be a big step forward for overall health. The rapid increase in the popularity of wearable devices provides a significant new source, making it possible to track the user's lifestyle real-time. In this paper, we propose a novel unsupervised representation learning technique called activity2vec that learns and "summarizes" the discrete-valued activity time-series. It learns the representations with three components: (i) the co-occurrence and magnitude of the activity levels in a time-segment, (ii) neighboring context of the time-segment, and (iii) promoting subject-invariance with adversarial training. We evaluate our method on four disorder prediction tasks using linear classifiers. Empirical evaluation demonstrates that our proposed method scales and performs better than many strong baselines. The adversarial regime helps improve the generalizability of our representations by promoting subject invariant features. We also show that using the representations at the level of a day works the best since human activity is structured in terms of daily routinesComment: Accepted at AAAI'19. arXiv admin note: text overlap with arXiv:1712.0952

Impact of Vitamin D Supplementation on Arterial Vasomotion, Stiffness and Endothelial Biomarkers in Chronic Kidney Disease Patients

Background: Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated. Methods: We assessed non-diabetic patients with CKD stage 3/4, age 17–80 years and serum 25(OH)D ,75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks. Results: Clinical characteristics of 26 patients were: age 50614 (mean61SD) years, eGFR 41611 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%. At 16-week serum 25(OH)D and calcium increased (43616 to 84629 nmol/L, p,0.001 and 2.3760.09 to 2.4260.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.868.6 to 7.464.4; p = 0.001). FMD improved from 3.163.3% to 6.163.7%, p = 0.001. Endothelial biomarker concentrations decreased: E-Selectin from 566662123 to 525662058 pg/mL; p = 0.032, ICAM-1, 3.4560.01 to 3.1061.04 ng/mL; p = 0.038 and VCAM-1, 54633 to 42633 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged. Conclusion: This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23. Trial Registration: ClinicalTrials.gov NCT0200571