Serotonin exerts a direct modulatory role on bladder afferent firing in mice.

KEY POINTS: Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non-5-HT3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5-HT. Whilst 5-HT3 receptors were not detected in mouse urothelium, 5-HT3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5-HT3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders. ABSTRACT: Serotonin (5-HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut-brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross-sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5-HT in bladder afferent signalling and its role in colon-bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5-HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid-induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5-HT receptor subtypes, the serotonin transporter (SERT) and 5-HT-producing enzymes was determined in the urothelium using RT-PCR. Retrograde labelling of bladder-projecting dorsal root ganglion neurons was used to investigate expression of 5-HT3 receptors using single cell RT-PCR, while sensory neuronal and urothelial responses to 5-HT were determined by live cell calcium imaging. 5-HT elicited bladder afferent firing predominantly via 5-HT3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5-HT bioavailability. Granisetron, a 5-HT3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5-HT exerts a direct effect on bladder afferents to enhance signalling. 5-HT3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.

Using the Medical Research Council framework to develop a complex intervention to improve delivery of care for young people with type 1 diabetes.

AIMS: We describe how we have used the development phase of the Medical Research Council (MRC) Guidelines to construct a complex intervention to improve physical and psychological health among young people (16-21 years) with Type 1 diabetes. METHODS: We consulted previous reviews where available and conducted systematic searches of electronic databases to determine physical and mental health among the population, audited medical records, surveyed self-reported psychological health among our clinic population; and interviewed staff (n = 13), young people (n = 27) and parents (n = 18) about their views of current care. RESULTS: Our audit (n = 96) confirmed a high HbA1c [86 mmol/mol (10.0%)] and one third (36.1%) reported significant eating problems. Young people did not attend 12% of their clinic appointments. Staff described difficulties communicating with young people who wanted staff to take account of their individual lifestyle when giving information. CONCLUSION: Based on the findings of the systematic reviews and our audit, we concluded that there was sufficient evidence to justify development of a model of care specific to this age group. The components of the complex intervention include changes to standard care, an optional 5-day self-management course directed at young people and a separate family communication programme. The MRC Guidelines provided a valuable structure to guide development and evaluation of this intervention.

Eating problems in adolescents with Type 1 diabetes: a systematic review with meta-analysis.

AIMS: We report a systematic review to determine (1) prevalence of eating problems compared with peers and (2) the association between eating problems and glycaemic control in young adults with Type 1 diabetes. METHOD: We conducted a systematic literature search via electronic databases and meta-analysis. Cohen's d (the mean difference score between Type 1 diabetes and comparison groups) was calculated for 13 studies that met inclusion criteria. RESULTS: Eating problems [both disordered eating behaviour (39.3 and 32.5%; d = 0.52, 95% CI 0.10-0.94) and eating disorders (7.0 and 2.8%; d = 0.46, 95% CI 0.10-0.81)] were more common in adolescents with Type 1 diabetes compared with peers and both were associated with poorer glycaemic control (d = 0.40, 95% CI 0.17-0.64). In restricted analyses involving measures adapted for diabetes, associations between eating problems and poorer glycaemic control remained (d = 0.54, 95% CI 0.32-0.76). Disordered eating behaviour (51.8 and 48.1%; d = 0.06, 95% CI -0.05 to 0.21) and eating disorders (6.4 and 3.0%; d = 0.43, 95% CI -0.06 to 0.91) were more common in adolescents with Type 1 diabetes compared with peers, but differences were non-significant. CONCLUSIONS: Eating problems are common among this age group. Future work in populations with Type 1 diabetes should develop sensitive measures of eating problems and interventions, and establish predictors of eating problems. Screening in clinics is recommended.