Alveolar hypoxia, alveolar macrophages, and systemic inflammation

Diseases featuring abnormally low alveolar PO2 are frequently accompanied by systemic effects. The common presence of an underlying inflammatory component suggests that inflammation may contribute to the pathogenesis of the systemic effects of alveolar hypoxia. While the role of alveolar macrophages in the immune and defense functions of the lung has been long known, recent evidence indicates that activation of alveolar macrophages causes inflammatory disturbances in the systemic microcirculation. The purpose of this review is to describe observations in experimental animals showing that alveolar macrophages initiate a systemic inflammatory response to alveolar hypoxia. Evidence obtained in intact animals and in primary cell cultures indicate that alveolar macrophages activated by hypoxia release a mediator(s) into the circulation. This mediator activates perivascular mast cells and initiates a widespread systemic inflammation. The inflammatory cascade includes activation of the local renin-angiotensin system and results in increased leukocyte-endothelial interactions in post-capillary venules, increased microvascular levels of reactive O2 species; and extravasation of albumin. Given the known extrapulmonary responses elicited by activation of alveolar macrophages, this novel phenomenon could contribute to some of the systemic effects of conditions featuring low alveolar PO2

Immunodesign of experimental sepsis by cecal ligation and puncture

Sepsis remains a prevalent clinical challenge and the underlying pathophysiology is still poorly understood. To investigate the complex molecular mechanisms of sepsis, various animal models have been developed, the most frequently used being the cecal ligation and puncture (CLP) model in rodents. In this model, sepsis originates from a polymicrobial infectious focus within the abdominal cavity, followed by bacterial translocation into the blood compartment, which then triggers a systemic inflammatory response. A requirement of this model is that it is performed with high consistency to obtain reproducible results. Evidence is now emerging that the accompanying inflammatory response varies with the severity grade of sepsis, which is highly dependent on the extent of cecal ligation. In this protocol, we define standardized procedures for inducing sepsis in mice and rats by applying defined severity grades of sepsis through modulation of the position of cecal ligation. The CLP procedure can be performed in as little as 10 min for each animal by an experienced user, with additional time required for subsequent postoperative care and data collection

Evidence-Based Treatment and Supervision Practices for Co-Occurring Mental and Substance Use Disorders in the Criminal Justice System

Over seven million persons in the United States are supervised by the criminal justice system, including many who have co-occurring mental and substance use disorders (CODs). This population is at high risk for recidivism and presents numerous challenges to those working in the justice system. Objectives: To provide a contemporary review of the existing research and examine key issues and evidence-based treatment and supervision practices related to CODs in the justice system. Methods: We reviewed COD research involving offenders that has been conducted over the past 20 years and provide an analysis of key findings. Results: Several empirically supported frameworks are available to guide services for offenders who have CODs, including Integrated Dual Disorders Treatment (IDDT), the Risk-Need-Responsivity (RNR) model, and Cognitive-Behavioral Therapy (CBT). Evidence-based services include integrated assessment that addresses both sets of disorders and the risk for criminal recidivism. Although several evidence-based COD interventions have been implemented at different points in the justice system, there remains a significant gap in services for offenders who have CODs. Existing program models include Crisis Intervention Teams (CIT), day reporting centers, specialized community supervision teams, pre- and post-booking diversion programs, and treatment-based courts (e.g., drug courts, mental health courts, COD dockets). Jail-based COD treatment programs provide stabilization of acute symptoms, medication consultation, and triage to community services, while longer-term prison COD programs feature Modified Therapeutic Communities (MTCs). Conclusion: Despite the availability of multiple evidence-based interventions that have been implemented across diverse justice system settings, these services are not sufficiently used to address the scope of treatment and supervision needs among offenders with CODs

From sewer to saviour-targeting the lymphatic system to promote drug exposure and activity

The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy