We present qualitative research findings on care-seeking and treatment uptake for pneumonia, diarrhoea and malaria among children under 5 in Kenya, Nigeria and Niger. The study aimed to determine the ...barriers caregivers face in accessing treatment for these conditions; to identify local solutions that facilitate more timely access to treatment; and to present these findings as a platform from which to develop context-specific strategies to improve care-seeking for childhood illness. Kenya, Nigeria and Niger are three high burden countries with low rates of related treatment coverage, particularly in underserved areas. Data were collected in Homa Bay County in Nyanza Province, Kenya; in Kebbi and Cross River States, Nigeria; and in the Maradi and Tillabéri regions of Niger. Primary caregivers of children under 5 who did not regularly engage with health services or present their child at a health facility during illness episodes were purposively selected for interview. Data underwent rigorous thematic analysis. We organise the identified barriers and related solutions by theme: financial barriers; distance/location of health facilities; socio-cultural barriers and gender dynamics; knowledge and information barriers; and health facility deterrents. The relative importance of each differed by locality. Participant suggested solutions ranged from community-level actions to facility-level and more policy-oriented actions, plus actions to change underlying problems such as social perceptions and practices and gender dynamics. We discuss the feasibility and implications of these suggested solutions. Given the high burden of childhood morbidity and mortality due to pneumonia, diarrhoea and malaria in Kenya, Nigeria and Niger, this study provides important insights relating to demand-side barriers and locally proposed solutions. Significant advancements are possible when communities participate in both problem identification and resolution, and are engaged as important partners in improving child health and survival.
BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid ...antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.
EXPERIMENTAL APPROACH Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated.
KEY RESULTS AM6545 binds to CB1 receptors with a Ki of 1.7 nM and CB2 receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 receptor antagonist. AM6545 reversed the effects of WIN55212‐2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose‐dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 receptor gene‐deficient mice, but not in CB1/CB2 receptor double knockout mice.
CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.
Background
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder of unknown etiology; although infection and inflammation have recently been considered as important etiologic ...agents. A recent meta‐analysis showed correlations between cytokine interleukin‐10 (IL‐10) and tumor necrosis factor (TNF) gene polymorphisms and IBS; however, it is still unknown whether patients with IBS have different cytokine profiles compared to healthy population.
Methods
To determine the relationships between serum/plasma levels or mucosal expression of IL‐10/TNF‐α and IBS, we conducted a systematic review and meta‐analysis based on case–control studies retrieved from PubMed and EMBASE search through August 2013. Standardized mean difference (SMD) was generated by using the inverse variance method. Heterogeneity was assessed based on I2 values.
Key Results
Serum/plasma levels of TNF‐α tended to be higher in IBS vs controls (p = 0.09); this reached significance in IBS subtypes vs controls and in female patients with IBS. However, serum/plasma levels of IL‐10 were not significantly different in IBS patients vs controls. Further analysis of serum/plasma IL‐10 levels in IBS subtypes did not show any difference; however, analysis based on gender showed a significantly lower serum/plasma IL‐10 levels in male patients with IBS vs male controls (p = 0.02). Colonic IL‐10 mRNA had a significantly lower expression in IBS vs control (p = 0.001).
Conclusions & Inferences
There is an imbalance of proinflammatory TNF‐α, and anti‐inflammatory IL‐10, cytokines in IBS. Stratifying IBS patients based on cytokine profile may represent an opportunity for personalized treatment of this condition.
There is an imbalance of proinflammatory TNF‐α, and anti‐inflammatory IL‐10, cytokines in IBS. This figure shows circulating TNF‐α levels based on IBS subtypes in patients vs healthy controls. Stratifying IBS patients based on cytokine profile may represent an opportunity for personalized treatment of this condition.
The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for ...gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB
1
receptor activation. However, the presence and function of the CB
2
receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB
2
receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB
2
receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB
2
receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction.
British Journal of Pharmacology
(2008)
153
, 263–270; doi:
10.1038/sj.bjp.0707486
; published online 1 October 2007
Background & Aims
Increases in mucosal immune cells have frequently been observed in irritable bowel syndrome (IBS) patients. However, this finding is not completely consistent between studies, ...possibly due to a combination of methodological variability, population differences and small sample sizes. We performed a meta‐analysis of case–control studies that compared immune cell counts in colonic biopsies of IBS patients and controls.
Methods
PubMed and Embase were searched in February 2017. Results were pooled using standardized mean difference (SMD) and were considered significant when zero was not within the 95% confidence interval (CI). Heterogeneity was assessed based on I2 statistics where I2 ≤ 50% and I2 > 50% indicated fixed and random effect models, respectively.
Key Results
Twenty‐two studies on 706 IBS patients and 401 controls were included. Mast cells were increased in the rectosigmoid (SMD: 0.38 95% CI: 0.06‐0.71; P = .02) and descending colon (SMD: 1.69 95% CI: 0.65‐2.73; P = .001) of IBS patients. Increased mast cells were observed in both constipation (IBS‐C) and diarrhea predominant IBS (IBS‐D). CD3+ T cells were increased in the rectosigmoid (SMD: 0.53 95% CI: 0.21‐0.85; P = .001) and the descending colon of the IBS patients (SMD: 0.79, 95% CI 0.28‐1.30; P = .002). This was possibly in relation to higher CD4+ T cells in IBS (SMD: 0.33 95% CI: 0.01‐0.65; P = .04) as there were no differences in CD8+ T cells.
Conclusions & Inferences
Mast cells and CD3+ T cells are increased in colonic biopsies of patients with IBS vs non‐inflamed controls. These changes are segmental and sometimes IBS‐subtype dependent. The diagnostic value of the quantification of colonic mucosal cells in IBS requires further investigation.
Studies have indicated changes in the intestinal immune cell counts of IBS patients; however, these findings are not consistent. The current study shows that the number of colonic mast cells, CD3+ T cells and CD4+ T cells are increased in IBS. These changes are colonic segmental and sometimes IBS‐subtype dependent. Figure shows density/number of mast cells in colorectal biopsies of patients with IBS vs healthy controls. (A) Ascending colon, (B) Descending colon, (C) Rectosigmoid.
Summary
The therapeutic actions of cannabinoids have been known for centuries. In the last 25 years this area of research has grown exponentially with the discovery of specific cannabinoid receptors ...and endogenous ligands.
In the enteric nervous system of gastrointestinal tract, cannabinoid receptors are located on enteric nerve terminals where they exert inhibitory actions on neurotransmission to reduce motility and secretion. Endogenous cannabinoids are present in the enteric nervous system, as are the degradative enzymes necessary to inhibit their action. The cellular mechanism of action of endocannabinoids has not been established in the enteric nervous system. Endocannabinoids not only act at cannabinoid receptors, but potentially also at vanilloid and 5‐HT3 receptors, both of which are expressed in the gastrointestinal tract. The interactions between endocannabinoids and these other important receptor systems have not been extensively investigated.
A greater understanding of the endocannabinoid system in the enteric nervous system could lead to advances with important therapeutic potential in the treatment of gastrointestinal disorders such as irritable bowel syndrome, inflammatory bowel disease, secretory diarrhoea and gastro‐oesophageal reflux disease.
The emerging potential for the cannabinoid (CB) system in modulating gastrointestinal inflammation has gained momentum over the last few years. Traditional and anecdotal use of marijuana for ...gastrointestinal disorders, such as diarrhoea and abdominal cramps is recognized, but the therapeutic benefit of cannabinoids in the 21st century is overshadowed by the psychoactive problems associated with CB1 receptor activation. However, the presence and function of the CB2 receptor in the GI tract, whilst not yet well characterized, holds great promise due to its immunomodulatory roles in inflammatory systems and its lack of psychotropic effects. This review of our current knowledge of CB2 receptors in the gastrointestinal tract highlights its role in regulating abnormal motility, modulating intestinal inflammation and limiting visceral sensitivity and pain. CB2 receptors represent a braking system and a pathophysiological mechanism for the resolution of inflammation and many of its symptoms. CB2 receptor activation therefore represents a very promising therapeutic target in gastrointestinal inflammatory states where there is immune activation and motility dysfunction.
British Journal of Pharmacology (2008) 153, 263–270; doi:10.1038/sj.bjp.0707486; published online 1 October 2007
Knowledge of neural circuits, neurotransmitters and receptors involved in the sympathetic regulation of gastrointestinal (GI) function is well established. However, it is only recently that the ...interaction of sympathetic neurons, and of sympathetic transmitters, with the GI immune system and with gut flora has begun to be explored. Changes in the behaviour of sympathetic nerves when gut function is compromised, for example in ileus and in inflammation, have been observed, but the roles of the sympathetic innervation in these and other pathologies are not adequately understood. In this article, we first review the principal roles of the sympathetic innervation of the GI tract in controlling motility, fluid exchange and gut blood flow in healthy individuals. We then discuss the evidence that there are important interactions of sympathetic transmitters with the gut immune system and enteric glia, and evidence that inflammation has substantial effects on sympathetic neurons. These reciprocal interactions contribute to pathological changes in ways that are not yet clarified. Finally, we focus on inflammation, diabetes and postoperative ileus as conditions in which there is sympathetic involvement in compromised gut function.
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Osteoporosis and bone fractures occur at higher frequency in patients with inflammatory bowel disease (IBD), and decreased bone mass is observed in animal models of colitis. Another ...consistent feature of colitis is increased serotonin (5-HT) availability in the intestinal mucosa. Since gut-derived 5-HT can decrease bone mass, via activation of 5-HT1B receptors on pre-osteoblasts, we tested the hypothesis that 5-HT contributes to bone loss in colitis. Colitis was chronically induced in mice by adding dextran sodium sulfate (DSS) to their drinking water for 21 days. At day 21, circulating 5-HT levels were elevated in DSS-inflamed mice. Micro-computed tomography of femurs showed a decrease in trabecular bone volume fraction, formation, and surface area, due largely to decreased trabecular numbers in DSS-treated mice. The colitis-induced loss of trabecular bone was significantly suppressed in mice treated with the 5-HT synthesis inhibitor, p-chloro-DL-phenylalanine (PCPA; 300 mg/kg/day IP daily), and in mice treated with the 5-HT1B receptor antagonist GR55562 (1 mg/Kg/day SC daily). The 5-HT reuptake transporter (SERT) is critical for moving 5-HT from the interstitial space into enterocytes and from serum into platelets. Mice lacking SERT exhibited significant deficits in trabecular bone mass that are similar to those observed in DSS-inflamed mice, and these deficits were not extensively worsened by DSS-induced colitis in the SERT−/− mice. Taken together, findings from both the DSS and SERT−/− mouse models support a contributing role for 5-HT as a significant factor in bone loss induced by colitis.
Highlights ► Lipopolysaccharide (LPS) activates microglial cells in a region, time and dose-dependent manner. ► LPS induced an increase of CB1 mRNA in the hippocampus and brainstem. ► LPS treatment ...reduced CB1 immunoreactivity in the CA3 pyramidal layer of the hippocampus. ► Reduced CB1 expression was largely restricted to glutamatergic terminals. ► Peripheral LPS treatment leads to limited changes in CB1 expression in the brain.
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