Type 2 cannabinoid receptor expression on microglial cells regulates neuroinflammation during graft-versus-host disease.

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.

Endocannabinoid signaling in the central nervous system.

It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.

A Retrospective Review of Primary Percutaneous Endoscopic Gastrostomy and Laparoscopic Gastrostomy Tube Placement.

OBJECTIVES: The laparoscopic-assisted gastrostomy tube placement (LAP) has increasingly become the preferred method for placing gastrostomy tubes in infants and children. The goal of this retrospective review was to examine our institutional experiences with our transition from the percutaneous endoscopic gastrostomy (PEG) procedure to LAP technique. METHODS: All patients undergoing primary PEG or LAP gastrostomy at Boston Children's Hospital between January 2010 and June 2015 were identified. The primary aim was to compare complication rates within the first 6 months after tube placement; differences in total hospital procedural costs, hospital resource utilization, and postoperative gastroesophageal reflux disease were examined. RESULTS: Nine hundred and eighty-seven patients (442 PEG and 545 LAP gastrostomy tubes) were included. No differences in total complications within 6 months were seen. Patients undergoing PEG placement had more gastrostomy-related complications (PEG 30 [6.7%] vs LAP 13 [2.4%], P = 0.0007) and cellulitis (PEG 23 [5.1%] vs LAP 2 [0.4%], P = 0.03) within the first week of placement. Patients undergoing LAP procedures had more granulation tissue episodes (PEG 19 [4.4%] vs LAP 107 [19.8%], P = 0.005). No differences in emergency room visits, hospital readmissions, or postoperative gastroesophageal reflux disease were seen, although transition to a gastrojejunal tube was higher in patients undergoing LAP procedure (PEG 20 patients [4.6%] vs LAP 51 patients [9.5%], P = 0.0008). CONCLUSIONS: Total complications were similar between patients undergoing PEG versus LAP gastrostomy tube placement. Patients with the PEG procedure had more complications within the first week of placement versus patients with the LAP procedure had more granulation skin complications.

Urinary levels of melatonin and risk of postmenopausal breast cancer: women's health initiative observational cohort.

BACKGROUND: Results from prospective studies on the association between urinary levels of melatonin and risk of postmenopausal breast cancer have been mixed. Several although not all studies have found lower urinary levels of melatonin in women who developed breast cancer compared with cancer-free women. METHODS: We examined the association between urinary levels of melatonin and breast cancer risk in postmenopausal women in a case-control study nested in the Women's Health Initiative Observational Cohort. Levels of 6-sulfatoxymelatonin were measured in first morning voids from 258 women who later developed breast cancer and from 515 matched controls. Multivariable conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI). RESULTS: Fully adjusted risk estimates of breast cancer, relative to the lowest quartile level of creatinine-adjusted melatonin, were 1.07 (95% CI, 0.67-1.71), 1.26 (95% CI, 0.79-2.01), and 1.25 (95% CI, 0.78-2.02) for women in the second, third, and highest quartile (Ptrend = 0.27). Comparable results for cases diagnosed less than four years after urinary collection and matched controls were 1.0, 1.25 (95% CI, 0.51-3.06), 1.85 (95% CI, 0.75-4.57), and 1.94 (95% CI, 0.75-5.03; Ptrend = 0.11). Melatonin levels and breast cancer were not associated in cases diagnosed four or more years after urinary collection and matched controls (Ptrend = 0.89). CONCLUSIONS: We found no evidence that higher urinary levels of melatonin are inversely associated with breast cancer risk in postmenopausal women. IMPACT: Accumulating discrepancies in results across studies warrant further exploration.

Adiponectin is a candidate biomarker of lower extremity bone density in men with chronic spinal cord injury.

Adipose tissue is a major regulator of bone metabolism and in the general population obesity is associated with greater bone mineral density (BMD). However, bone-fat interactions are multifactorial, and may involve pathways that influence both bone formation and resorption with competing effects on the skeleton. One such pathway involves adipocyte production of adipokines that regulate bone metabolism. In this study we determined the association between BMD, walking status, and circulating adipokines (adiponectin and leptin) in 149 men with chronic spinal cord injury (SCI). Although adipokine levels did not vary significantly based on walking status, there was a significant inverse association between adiponectin and BMD in wheelchair users independent of body composition. We found no association between adiponectin and BMD in the walkers and no association between leptin and BMD in either group. These findings suggest that for subjects with chronic SCI, walking may mitigate the effect of adiponectin mediated bone loss. For wheelchair users, adipose-derived adiponectin may contribute to SCI-induced osteoporosis because the osteoprotective benefits of obesity appear to require mechanical loading during ambulation.

Participation in organized sports is positively associated with employment in adults with spinal cord injury.

OBJECTIVE: The aim of this study was to determine the association between participation in organized sports programs and employment in adults with chronic spinal cord injury. DESIGN: This is a cross-sectional study of 149 adults with chronic spinal cord injury. Motor level and completeness of injury were confirmed by physical examination. Information related to demographics, employment, level of education, body mass index, duration of injury, participation in individually planned exercise, and participation in organized sports was obtained using a standardized questionnaire. Multivariable logistic regression analyses were used to assess factors associated with employment. RESULTS: In univariate analyses, employment was associated with younger age (P = 0.001) and a higher level of education (P = 0.01), whereas obesity decreased the likelihood of employment (P = 0.04). Participation in organized sports approached significance (P = 0.06). In the multivariable analysis and after adjusting for age, education, and body mass index, participation in organized sports was significantly associated with employment (odds ratio, 2.4; P = 0.04). Sex, duration of injury, wheelchair use, and participation in individually planned exercise were not significantly associated with employment (P = 0.16-0.94). CONCLUSIONS: In the adults with chronic spinal cord injury, participation in organized sports was positively associated with employment. Further studies are necessary to determine the causative nature of this association and how various factors related to sports participation may contribute.