Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation

Activation of inflammatory pathways represents a central mechanism in multiple disease states both acute and chronic. Triggered via either pathogen or tissue damage-associated molecular motifs, common biochemical pathways lead to conserved yet variable physiological and immunological alterations. Dissection and delineation of the determinants and mechanisms underlying phenotypic variance in response is expected to yield novel therapeutic advances. Intravenous (IV) administration of endotoxin (gram-negative bacterial lipopolysaccharide), a specific Toll-like receptor 4 agonist, represents an in vivo model of systemic inflammation in man. National Institutes for Health Clinical Center Reference Endotoxin (CCRE, Escherichia coli O:113:H10:K negative) is employed to reliably and reproducibly generate vascular, hematological, endocrine, immunological and organ-specific functional effects that parallel, to varying degrees, those seen in the early stages of pathological states. Alteration of dose (0.06 - 4 ng/kg) and time-scale of exposure (bolus vs. infusion) allows replication of either acute or chronic inflammation and a range of severity to be elicited, with higher doses (2 - 4 ng/kg) frequently being used to create a 'sepsis-like' state. Established and novel medicinal compounds may additionally be administered prior to or post endotoxin exposure to appreciate their effect on the inflammatory cascade. Despite limitations in scope and generalizability, human IV endotoxin challenge offers a unique platform to gain mechanistic insights into inducible physiological responses and inflammatory pathways. Rationally employed it may aid translation of this knowledge into therapeutic innovations

The experience of long-term opiate maintenance treatment and reported barriers to recovery: A qualitative systematic review

Background/Aim: To inform understanding of the experience of long-term opiate maintenance and identify barriers to recovery. Methods: A qualitative systematic review. Results: 14 studies in 17 papers, mainly from the USA (65%), met inclusion criteria, involving 1,088 participants. Studies focused on methadone prescribing. Participants reported stability; however, many disliked methadone. Barriers to full recovery were primarily ‘inward focused'. Conclusion: This is the first review of qualitative literature on long-term maintenance, finding that universal service improvements could be made to address reported barriers to recovery, including involving ex-users as positive role models, and increasing access to psychological support. Treatment policies combining harm minimisation and abstinence-orientated approaches may best support individualised recovery

REC-PATH (Recovery Pathways): overview of a four-country study of pathways to recovery from problematic drug use

Although there has been a growth in recent years in recovery research, much of this has been from the United States, and there is very little comparative research in this area. This article describes the rationale, conceptual foundations and methods for a prospective, multicountry, cohort study aimed to map pathways to recovery from problematic illicit drug use, with a specific focus on gender differences in recovery pathways. This study combines qualitative and quantitative components and examines the impact of recovery policy on the accessibility and viability of recovery pathways in England, Scotland, Belgium, and The Netherlands. Additionally, the article describes five processes through which mechanisms for behavior change for recovery may be triggered. This study will provide opportunities for linking recovery outcome research with analyses of national recovery policies, while also addressing the gap in literature around female pathways to recovery

Aerobic interval training and continuous training equally improve aerobic exercise capacity in patients with coronary artery disease:The SAINTEX-CAD study

AbstractBackgroundExercise-based cardiac rehabilitation increases peak oxygen uptake (peak VO2), which is an important predictor of mortality in cardiac patients. However, it remains unclear which exercise characteristics are most effective for improving peak VO2 in coronary artery disease (CAD) patients. Proof of concept papers comparing Aerobic Interval Training (AIT) and Moderate Continuous Training (MCT) were conducted in small sample sizes and findings were inconsistent and heterogeneous. Therefore, we aimed to compare the effects of AIT and Aerobic Continuous Training (ACT) on peak VO2, peripheral endothelial function, cardiovascular risk factors, quality of life and safety, in a large multicentre study.MethodsTwo-hundred CAD patients (LVEF >40%, 90% men, mean age 58.4±9.1years) were randomized to a supervised 12-week cardiac rehabilitation programme of three weekly sessions of either AIT (90–95% of peak heart rate (HR)) or ACT (70–75% of peak HR) on a bicycle. Primary outcome was peak VO2; secondary outcomes were peripheral endothelial function, cardiovascular risk factors, quality of life and safety.ResultsPeak VO2 (ml/kg/min) increased significantly in both groups (AIT 22.7±17.6% versus ACT 20.3±15.3%; p-time<0.001). In addition, flow-mediated dilation (AIT+34.1% (range –69.8 to 646%) versus ACT+7.14% (range –66.7 to 503%); p-time<0.001) quality of life and some other cardiovascular risk factors including resting diastolic blood pressure and HDL-C improved significantly after training. Improvements were equal for both training interventions.ConclusionsContrary to earlier smaller trials, we observed similar improvements in exercise capacity and peripheral endothelial function following AIT and ACT in a large population of CAD patients