The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of ⌬ 9 -tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB 1 receptors localized within the basolateral amygdala, a critical brain region for threat perception. However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

Although necrotizing enterocolitis (NEC) is the most lethal gastrointestinal disease in the neonatal population, its pathogenesis is poorly understood. Risk factors include prematurity, bacterial colonization, and formula feeding. This review examines how mucosal injury permits opportunistic pathogens to breach the gut barrier and incite an inflammatory response that leads to sustained overproduction of mediators such as nitric oxide and its potent adduct, peroxynitrite. These mediators not only exacerbate the initial mucosal injury, but they also suppress the intestinal repair mechanisms, which further compromises the gut barrier and culminates in bacterial translocation, sepsis, and full-blown NEC.

Aerobic exercise training is used for rehabilitation in patients with chronic obstructive pulmonary disease (COPD), although it has little effect on muscle weakness and atrophy. Resistance training may be a useful addition to aerobic programs for these patients. The purpose of the present study was to investigate the effects of resistance training in addition to aerobic training on functional outcomes in patients with COPD. Seventeen COPD patients enrolled in an aerobic-based program that met twice a week were assigned to a 12-week control/aerobic [CON: n=8; 63 (8) years; mean (SD)] or a resistance/aerobic group [RES: n=9; 61 (7) years]. RES trained an additional twice a week on 12 resistance machines, performing three sets of 8-12 repetitions at 32-64% of their one-repetition maximum (1-RM) lifts. RES (P<0.05) increased upper (36%) and lower (36%) body strength, as well as lean body mass (5%), while CON showed little to no change. The 12-min walk distance increased (P<0.05) in only the RES [676 (219) to 875 (172) m]. Measurements of three of the eight tasks of activities of daily living improved in RES (P<0.05) compared to CON. This study demonstrated that progressive resistance training was well tolerated and improved functional outcomes in COPD patients that were currently involved in an aerobic training program.

The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (UDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that UDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that UDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, UDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo UDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine injections, we found that UDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with either administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein UDCA had no effect on LPS-induced injury. Finally, we found increased COX-2 and phosphorylated ERK levels in LPS animals also treated with UDCA. Taken together, these data suggest that UDCA can stimulate intestinal epithelial cell migration and protect against acute intestinal injury via an EGFR- and COX-2-dependent mechanism. UDCA may be an effective treatment to prevent the early onset of gut-origin sepsis. NEW & NOTEWORTHY In this study, we show that the secondary bile acid ursodeoxycholic acid stimulates intestinal epithelial cell migration after cellular injury and also protects the intestinal barrier in an acute rodent injury model, neither of which has been previously reported. These effects are dependent on epidermal growth factor receptor activation and downstream cyclooxygenase 2 upregulation in the small intestine. This provides a potential treatment for acute, gut-origin sepsis as seen in diseases such as necrotizing enterocolitis.

The optimal management of pilonidal disease in the pediatric population is still debated. We conducted a retrospective review of patients 21 years old and younger who underwent surgical management for pilonidal disease between 2009 and 2013 at a single pediatric institution. Sixty patients (41.7% male) were included in the analysis, with a mean age of 15.0 years (range, 13–20). Twelve (20%) had a prior drainage procedure for pilonidal abscess before the definitive operative treatment. After excision to the presacral fascia, 36 (60%) had primary closure, 17 (28.3%) were left to heal by secondary intention, and 7 (11.7%) had flap closure. Overall recurrence rate was 41.7 per cent with 33.3 per cent in the primary, 58.8 per cent in the secondary, and 42.9 per cent in the flap group, respectively. Ten (16.7%) patients developed postoperative complications, which were similar among surgical groups, gender, and body mass index. The average length of stay was 0.67 (median 0, range, 0–5) days. Primary closure had the shortest length of stay (analysis of variance P = 0.04), and flap closure had no reoperations (analysis of variance P < 0.01). Pilonidal disease remains surgically challenging. Our data suggest that excision and primary closure is a better option in the pediatric population.

Abstract. Heterophil functio n was eva lua ted in 16 health y chickens and in 46 chickens with experime nta lly induced sta phylococcal tenosynovit is. In paired blood sa mples, heterophils from chicke ns with tenosynovit is had a significant increase in ad he rence, chemo tax is, pha gocyto sis, and bact erial killin g of S taphylococcus aureus compared to heterophils from healthy chickens. Th e percent adh erence of heterophils to nylon fiber columns increased significantly from a 78.4 % mean ± 6.6% standa rd deviati on to 87 .6% ± 3.2% aft er induct ion of sta phylococcal ten osynovitis. Heteroph il movem ent followi ng in vitro expos ure to saline or endo toxi n was increased in chickens with tenosy novitis; 3 ± I heterophil s/ 0.25 rnrn-to 10 ± 6 heteroph ils/ 0. 25 mrn ? and 136 ± 29 heterophils/0. 25 mrn -to 340 ± 74 het erophils/ 0. 25 mm -, respe ctively. Endotoxin-acti vated seru m was che moa tt rac tive for heterophil s from all chickens. Flow cyto me try was used to define th e heterophil population on light scatte r histogram s, eva luate ind ivid ua l cell phagocytosis of latex bead s, and qu antitat e the number of bead s ph agocytosed per heterophil. Wh en inc ubated with increase d num bers of beads , only heterophils from chickens with ten osynovitis phagocytosed higher numbers of beads . At heterophil to bead rat ios of I : 10, the percent age of heterophils that pha gocytosed bead s increased from baselin e values of 37.8% ± 9.0% to postin fecti on va lues of67.3% ± 7.5%. Us ing I : 20 heteroph il to bean rati os, heteroph il phago cytosis increased from 38 .7% ± 9.9% to pos t-infection va lues of79.8% ± 7.3%. Heterophils fro m all chickens were able to phagocytose and kill log phase sta phy lococca l bacteria . After phagocytosis, the heterophils from chicke ns with staphylococc al tenosyn oviti s rapidl y decrea sed the number o f viable bacterial colony forming-units per millil iter by approximately one log. Circulating heterophil s from chickens with ex perime ntally induced sta phylococcal ten osynoviti s th erefore appear to have increased function al ca pa bilities in thi s bacterial inflam matory disease.

The use of lactobacilli in prevention of necrotizing enterocolitis (NEC) is hampered by insufficient knowledge about optimal species/strains and effects on intestinal bacterial populations. We therefore sought to identify lactobacilli naturally occurring in postnatal rats and examine their ability to colonize the neonatal intestine and protect from NEC. L. murinus, L. acidophilus, and L. johnsonii were found in 42, 20, and 1 out of 51 4-day old rats, respectively. Higher proportion of L. murinus in microbiota correlated with lower NEC scores. Inoculation with each of the three species during first feeding significantly augmented intestinal populations of lactobacilli four days later, indicating successful colonization. L. murinus, but not L. acidophilus or L. johnsonii, significantly protected against NEC. Thus, lactobacilli protect rats from NEC in a species- or strain-specific manner. Our results may help rationalizing probiotic therapy in NEC.