Management of adults with diabetes on dialysis: Summary of recommendations of the Joint British Diabetes Societies guidelines 2022.

Diabetes is the commonest cause of end-stage kidney disease in many parts of the world, and many people on dialysis programmes live with diabetes. Such people are vulnerable to complications from their diabetes, and their care may be fragmented due to the many specialists involved. This updated guidance from the Joint British Diabetes Societies aims to review and update the 2016 guidance, with particular emphasis on glycaemic monitoring in the light of recent advances in this area. In addition, the guidance covers clinical issues related to the management of diabetes in people on peritoneal dialysis, along with acute complications such as hypoglycaemia and ketoacidosis, and chronic complications such as foot and eye disease.

Uterine Artery Embolisation of Fibroids and the Phenomenon of Post-Embolisation Syndrome: A Systematic Review.

Post-embolisation syndrome (PES) is a prevalent complication that occurs in patients following uterine artery embolisation (UAE) for the treatment of uterine fibroids. The aetiology of PES remains incompletely understood, although postulated to result secondary to tissue infarction resulting in release of inflammatory mediators. We followed PRISMA guidelines and performed a systematic review of studies of PES following UAE from inception to October 2022. Our published protocol was prospectively registered. Our search yielded 54 results. We reviewed 22 full texts, and nine articles were included. Observational studies comprised 6/9 relevant studies, with 5/9 retrospective design. The rate of PES was documented in 5/8 studies (excluding case report) with a reported incidence ranging from 4-34.6%. Five of the nine studies studies postulated that the aetiological basis of PES is inflammatory related. Further research is necessary to advance our understanding of PES to define the biological basis of the syndrome with more certainty and gain a consensus on peri-procedure management to reduce incidence and improve patient outcomes.

The role of structured exercise interventions on cognitive function in older individuals with stable Chronic Obstructive Pulmonary Disease: A scoping review.

A decline in cognitive performance has been associated with disease severity, exacerbations rate, presence of comorbidities, and low activity level in people with chronic obstructive pulmonary disease (COPD). Participation in exercise programs appears to have neuroprotective effects and to improve cognitive performance in older people. The present work undertook a scoping review of the effects of exercise-based interventions on cognitive function in older individuals with stable COPD. Methods: The methodological framework for scoping review was used and electronic searches of five databases performed. Original research and observational studies published between January 2010 and December 2021, administering exercise-based interventions and cognitive function evaluation, were included. Results: Of 13 full-text manuscripts assessed for eligibility, five were allocated to analysis. Three studies administered exercise training within pulmonary outpatient rehabilitation program (PR), and one inpatient PR. The fifth study conducted a structured training intervention in which either aerobic or a combination with resistance exercises were included. Twelve cognitive function screening tools were used in the five studies included in the analysis. Results extracted were based on 245 COPD (33% female) with moderate to very-severe airflow limitation. Interventions ranged from 12 to 36 sessions. Studies reported statistically significant improvements after intervention in different cognitive function domains, such as global cognition, immediate and delayed recall ability, cognitive flexibility, verbal fluency, attention, abstract reasoning, praxis ability. Conclusions: Exercise-based interventions improve several areas of cognitive function in patients with stable COPD. However, the magnitude of gain varies among studies, and this is possibly due to the heterogeneity of tests used. Future research is needed to validate the optimal battery of screening tests, and to support the definition of guidelines for cognitive function evaluation in COPD.

Divergent effects of exendin-4 and interleukin-6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling.

BACKGROUND: The pro-inflammatory cytokine, interleukin (IL)-6 is elevated in individuals with the functional bowel disorder, irritable bowel syndrome (IBS). IL-6 can independently modify intestinal secreto-motor function, thereby contributing to IBS pathophysiology. Additionally, hormonal changes may underlie symptom flares. Post-prandial exacerbation of IBS symptoms has been linked to secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), which can also influence colonic secreto-motor activity. This study aimed to ascertain if the effects of GLP-1 on colonic secretory and contractile activity was impacted by elevated IL-6 levels and if sensory signals regarding such changes were reflected in altered vagal afferent activity. METHODS: Colonic secretory currents and circular muscle contractile activity was investigated in Sprague Dawley rats using Ussing chamber and organ bath electrophysiology. Regional afferent signaling was assessed using extracellular electrophysiological recordings from colonic vagal afferents. KEY RESULTS: Application of the GLP-1 receptor agonist, exendin-4 (Ex-4) in the presence of IL-6 potentiated colonic secretory currents and transepithelial resistance. Vagal afferent fibers originating in the submucosal layer exhibited larger responses to Ex-4 when IL-6 was also present. In contrast, co-application of Ex-4 and IL-6 to gut-bath chambers suppressed circular muscle contractile activity. The activity in extrinsic afferents originating in the colonic myenteric layer was similarly suppressed. CONCLUSIONS & INFERENCES: Application of Ex-4 in the presence of IL-6 had divergent modulatory effects on colonic secretion and contractile activity. Similar patterns were observed in vagal afferent signaling originating in the submucosal and myenteric neuronal layers, indicating regional afferent activity reflected immune- and endocrine-mediated changes in colonic function.

Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System.

An intact gut epithelium preserves the immunological exclusion of "non-self" entities in the external environment of the gut lumen. Nonetheless, information flows continuously across this interface, with the host immune, endocrine, and neural systems all involved in monitoring the luminal environment of the gut. Both pathogenic and commensal gastrointestinal (GI) bacteria can modulate centrally-regulated behaviors and brain neurochemistry and, although the vagus nerve has been implicated in the microbiota-gut-brain signaling axis, the cellular and molecular machinery that facilitates this communication is unclear. Studies were carried out in healthy Sprague-Dawley rats to understand cross-barrier communication in the absence of disease. A novel colonic-nerve electrophysiological technique was used to examine gut-to-brain vagal signaling by bacterial products. Calcium imaging and immunofluorescent labeling were used to explore the activation of colonic submucosal neurons by bacterial products. The findings demonstrate that the neuromodulatory molecule, glucagon-like peptide-1 (GLP-1), secreted by colonic enteroendocrine L-cells in response to the bacterial metabolite, indole, stimulated colonic vagal afferent activity. At a local level indole modified the sensitivity of submucosal neurons to GLP-1. These findings elucidate a cellular mechanism by which sensory L-cells act as cross-barrier signal transducers between microbial products in the gut lumen and the host peripheral nervous system.

Informal caregiving for dementia patients: the contribution of patient characteristics and behaviours to caregiver burden.

OBJECTIVES: The burden often associated with informal caregiving for patients with dementia is associated with negative effects on health, both physiologically and in terms of caregiver cognition. There is wide variation in the level of burden experienced by dementia caregivers. To better understand caregiver burden, it is thus important to understand the factors associated with level of burden. METHODS: In the current study, we collected carer burden and putative associated factors at baseline, 6 and 12 months. Hierarchical regression was used to assess the impact of these factors on caregiver burden. We assessed self-reported carer burden, patient behavioural and safety issues, and level of difficulty associated with providing assistance with activities of daily living (ADL). Patients' age was also recorded, and trained nurses assessed patient cognitive performance using the quick mild cognitive impairment screen. RESULTS: At baseline, patients' age, cognition and ADLs were associated with burden, and safety and challenging behaviour were both significantly associated with burden independent of the other factors. Change in burden was associated with change in carer-reported safety at 6-month follow-up, and with change in safety and change in carer-reported challenging behaviours at 12-month follow-up. CONCLUSIONS: Safety issues and challenging behaviours are associated with carer burden, even after accounting for cognitive and functional impairment in the person with dementia. As dementia progresses, monitoring these factors may help to inform stress-management strategies for caregivers.

GHSR-1 agonist sensitizes rat colonic intrinsic and extrinsic neurons to exendin-4: A role in the manifestation of postprandial gastrointestinal symptoms in irritable bowel syndrome?

BACKGROUND: Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon-like peptide 1 (GLP-1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP-1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP-1 receptor agonist, and if this differs in a rat model of IBS. METHODS: Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains. KEY RESULTS: Circulating GLP-1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin-4, a GLP-1 receptor agonist, are potentiated by a ghrelin receptor (GHSR-1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin-4 to alter smooth muscle function was modified by a GHSR-1 agonist in both strains. Gut-brain signaling via GLP-1-mediated activation of vagal afferents was also potentiated by the GHSR-1 agonist. CONCLUSIONS & INFERENCES: These findings support a temporal interaction between ghrelin and GLP-1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP-1. While the sensitizing effects of the GHSR-1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.

PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons.

BACKGROUND: Glucagon-like peptide (GLP-1) can modify colonic function, with beneficial effects reported in the functional bowel disorder, irritable bowel syndrome (IBS). IBS pathophysiology is characterized by hyper-activation of the hypothalamic-pituitary-adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP-1 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction. METHODS: Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP-1 receptor agonist, exendin-4 (Ex-4). Colonic contractile activity was assessed using organ bath physiological recordings. KEY RESULTS: Ex-4 induced an elevation of intracellular calcium arising from store release and influx via voltage-gated calcium channels. Ex-4 activated both ERK-MAPK and PI 3-kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin-releasing factor (CRF) potentiated the neuronal response to Ex-4, and the functional effects of Ex-4 on colonic circular muscle activity were not altered. CONCLUSIONS AND INFERENCES: Ex-4 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex-4 were dependent upon activation of PI 3-kinase and ERK-MAPK signaling cascades. No further change in circular muscle function was noted in the presence of CRF suggesting that stress does not impact on colonic function in health. Further studies in a model of IBS are needed to determine whether mechanisms are modified in the context of bowel dysfunction.

Improvements in Depressive Symptoms and Affect During Cardiac Rehabilitation: PREDICTORS AND POTENTIAL MECHANISMS.

PURPOSE: Depression is indicative of poor prognosis in cardiac patients. Reductions in depression have been observed following cardiac rehabilitation (CR). Whether similar improvements in positive and negative affect occur is unknown. Greater understanding of depressive symptom and affect change is needed to enhance facilitators of emotional improvement after a cardiac event. METHODS: Cardiac rehabilitation attendees (n = 637) completed measures of depressive symptoms, affect, health status, and social support at CR intake and discharge. Body mass index, metabolic equivalents, and blood pressure were also measured. Relationships between changes in psychosocial and physical health indicators and depressive symptoms, positive affect, and negative affect were examined. RESULTS: From intake to discharge, depressive symptoms (d = 0.40, P < .001) and negative affect (d = 0.26, P < .001) decreased. Positive affect increased (d = 0.34, P < .001). In multivariate regression, predictors of depressive symptom reduction were increased vitality (ß = -.26) and decreased bodily pain (ß = -.08). Predictors of positive affect increase were increased vitality (ß = .25), social support (ß = .16), and physical role functioning (ß = .09). Predictors of negative affect reduction were increased vitality (ß = -.23) and social support (ß = -.10). Changes in indicators of physical health were not related to depressive symptom or affect change. CONCLUSIONS: Depressive symptom and affect improvements following CR were observed and most strongly associated with improvements in vitality and social support. Future research should explore how enhancement of these mechanisms may further improve depressive symptom and affect during CR.

Prioritization, Development, and Validation of American Association of Cardiovascular and Pulmonary Rehabilitation Performance Measures.

BACKGROUND: In 2014, the American Association of Cardiovascular and Pulmonary Rehabilitation Quality of Care Committee was asked to develop performance measures (PMs) to assess program quality and aid in program improvement and certification. METHODS: A 3-step process was used to prioritize, develop, and then validate new PMs for both cardiac and pulmonary rehabilitation programs. First, we surveyed national leadership, medical directors, and program directors to identify and rank various American Association of Cardiovascular and Pulmonary Rehabilitation potential PM topics. Then, the face validity of the drafted PMs was assessed in a second national survey. Finally, we assessed the inter- and intrarater reliability and feasibility of each PM by abstracting patient charts at programs throughout the United States. At each step, modifications were made to refine and improve the measures for clarity, reliability, and consistency. RESULTS: Through survey answers received from 302 people (19% response rate), we identified 5 categories for PM development: optimal blood pressure control, tobacco use cessation, and improvement in functional capacity, depression, and sensation of dyspnea. After drafting the PMs, a second survey with 82 respondents (57% response rate), found that the proposed PMs had good face validity. Finally, we found excellent inter- and intrarater reliability for the blood pressure, functional capacity, depression, and dyspnea measures (κ generally >0.80.) However, validity concerns were raised about the tobacco intervention PM as written, and it continues to undergo further refinement and testing. CONCLUSIONS: We developed and validated 5 new PMs for use in cardiac and pulmonary rehabilitation program quality assessment, improvement, and certification.

Chronic Obstructive Pulmonary Disease Education in Pulmonary Rehabilitation. An Official American Thoracic Society/Thoracic Society of Australia and New Zealand/Canadian Thoracic Society/British Thoracic Society Workshop Report.

According to the 2013 American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation (PR), education to promote effective self-management is a cornerstone of this intervention. Despite education's stature within PR, there is currently limited evidence supporting its overall efficacy, and minimal evidence guiding its optimal design and delivery. This workshop was convened to focus on the current state of education in PR for patients with chronic obstructive pulmonary disease, who are the most common people referred to PR. The workshop explored the learning needs and limitations of patients participating in PR, promising design features (from work done outside of PR) that may inform our approach to education, and professional development of PR healthcare educators. Areas identified as needing development include: 1) outcome assessment for the educational component; 2) screening patients for conditions that will impede the learning process (anxiety, depression, cognitive deficits and health literacy issues); 3) tailoring content and optimizing delivery of the educational component; and 4) training PR professionals in their roles as educators. By necessity, the workshop conclusions are painted in broad strokes. However, with ongoing interest in improving quality through individualized patient assessment, educational design innovations, and scientific scrutiny comparable to that given to exercise training, the educational component of PR may achieve effective self-management, leading to successful behavior change and enhancement in health.

Development of an ex Vivo Method for Multi-unit Recording of Microbiota-Colonic-Neural Signaling in Real Time.

Background and Objectives: Bidirectional signaling between the gastrointestinal tract and the brain is vital for maintaining whole-body homeostasis. Moreover, emerging evidence implicates vagal afferent signaling in the modulation of host physiology by microbes, which are most abundant in the colon. This study aims to optimize and advance dissection and recording techniques to facilitate real-time recordings of afferent neural signals originating in the distal colon. New Protocol: This paper describes a dissection technique, which facilitates extracellular electrophysiological recordings from visceral pelvic, spinal and vagal afferent neurons in response to stimulation of the distal colon. Examples of Application: Focal application of 75 mM KCl to a section of distal colon with exposed submucosal or myenteric nerve cell bodies and sensory nerve endings evoked activity in the superior mesenteric plexus and the vagal nerve. Noradrenaline stimulated nerve activity in the superior mesenteric plexus, whereas application of carbachol stimulated vagal nerve activity. Exposure of an ex vivo section of distal colon with an intact colonic mucosa to peptidoglycan, but not lipopolysaccharide, evoked vagal nerve firing. Discussion: Previous studies have recorded vagal signaling evoked by bacteria in the small intestine. The technical advances of this dissection and recording technique facilitates recording of afferent nerve signals evoked in extrinsic sensory pathways by neuromodulatory reagents applied to the distal colon. Moreover, we have demonstrated vagal afferent activation evoked by bacterial products applied to the distal colonic mucosa. This protocol may contribute to our understanding of functional bowel disorders where gut-brain communication is dysfunctional, and facilitate real-time interrogation of microbiota-gut-brain signaling.

Combined XIL-6R and urocortin-2 treatment restores MDX diaphragm muscle force.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration leading to immobility, respiratory failure, and premature death. As chronic inflammation and stress are implicated in DMD pathology, the efficacy of an anti-inflammatory and anti-stress intervention strategy in ameliorating diaphragm dysfunction was investigated. METHODS: Diaphragm muscle contractile function was compared in wild-type and dystrophin-deficient mdx mice treated with saline, anti-interleukin-6 receptor antibodies (xIL-6R), the corticotrophin-releasing factor receptor 2 (CRFR2) agonist, urocortin 2, or both xIL-6R and urocortin 2. RESULTS: Combined treatment with xIL-6R and urocortin 2 rescued impaired force in mdx diaphragms. Mechanical work production and muscle shortening was also improved by combined drug treatment. DISCUSSION: Treatment which neutralizes peripheral IL-6 signaling and stimulates CRFR2 recovers force-generating capacity and the ability to perform mechanical work in mdx diaphragm muscle. These findings may be important in the search for therapeutic targets in DMD. Muscle Nerve 56: E134-E140, 2017.

Leptin modifies the prosecretory and prokinetic effects of the inflammatory cytokine interleukin-6 on colonic function in Sprague-Dawley rats.

NEW FINDINGS: What is the central question of this study? Does crosstalk exist between leptin and interleukin-6 in colonic enteric neurons, and is this a contributory factor in gastrointestinal dysfunction associated with irritable bowel syndrome? What is the main finding and its importance? Leptin ameliorates the prosecretory and prokinetic effects of the pro-inflammatory cytokine interleukin-6 on rat colon. Leptin also suppresses the neurostimulatory effects of irritable bowel syndrome plasma, which has elevated concentrations of interleukin-6, on enteric neurons. This may indicate a regulatory role for leptin in immune-mediated bowel dysfunction. In addition to its role in regulating energy homeostasis, the adipokine leptin modifies gastrointestinal (GI) function. Indeed, leptin-resistant obese humans and leptin-deficient obese mice exhibit altered GI motility. In the functional GI disorder irritable bowel syndrome (IBS), circulating leptin concentrations are reported to differ from those of healthy control subjects. Additionally, IBS patients display altered cytokine profiles, including elevated circulating concentrations of the pro-inflammatory cytokine interleukin-6 (IL-6), which bears structural homology and similarities in intracellular signalling to leptin. This study aimed to investigate interactions between leptin and IL-6 in colonic neurons and their possible contribution to IBS pathophysiology. The functional effects of leptin and IL-6 on colonic contractility and absorptosecretory function were assessed in organ baths and Ussing chambers in Sprague-Dawley rat colon. Calcium imaging and immunohistochemical techniques were used to investigate the neural regulation of GI function by these signalling molecules. Our findings provide a neuromodulatory role for leptin in submucosal neurons, where it inhibited the stimulatory effects of IL-6. Functionally, this translated to suppression of IL-6-evoked potentiation of veratridine-induced secretory currents. Leptin also attenuated IL-6-induced colonic contractions, although it had little direct effect on myenteric neurons. Calcium responses evoked by IBS plasma in both myenteric and submucosal neurons were also suppressed by leptin, possibly through interactions with IL-6, which is elevated in IBS plasma. As leptin has the capacity to ameliorate the neurostimulatory effects of soluble mediators in IBS plasma and modulated IL-6-evoked changes in bowel function, leptin may have a role in immune-mediated bowel dysfunction in IBS patients.

Prevalence, Reasons for Use, and Risk Perception of Electronic Cigarettes Among Post-Acute Coronary Syndrome Smokers.

PURPOSE: The use of electronic cigarettes (e-cigarettes) has risen dramatically in recent years. However, there are currently no published data on the use of e-cigarettes among cardiac patients. The current study reports on the prevalence, reasons for use, and perceived risks of e-cigarettes among patients with post-acute coronary syndrome (ACS). The relationship between e-cigarette use and post-ACS tobacco smoking cessation is also explored. METHODS: Participants were drawn from a randomized trial of smoking cessation treatments following hospitalization for ACS. The current study focused on 49 participants who completed e-cigarette questions at 24 weeks post-ACS. RESULTS: Of the 49 of participants, 51.0% reported ever use of an e-cigarette and 26.5% reported using an e-cigarette at some time during the 24 weeks post-ACS. Ever use and post-ACS use were both significantly associated with lower rates of abstinence from tobacco cigarettes. Participants perceived e-cigarettes as less harmful to cardiac health than tobacco use and Chantix (varenicline), and similarly harmful as nicotine replacement therapy. Participant perceived likelihood of experiencing a heart attack in the next year was 34.6% if they were to regularly use only e-cigarettes, significantly lower than the perceived risk of recurrence if they were to regularly smoke only tobacco cigarettes (56.2%) and significantly higher than the perceived risk of recurrence if they were to use no nicotine (15.2%). CONCLUSIONS: A significant minority of patients are using e-cigarettes post-ACS. Providers should be prepared to discuss potential discrepancies between patient beliefs about the safety of e-cigarettes and the current state of the science.

Soluble mediators in plasma from irritable bowel syndrome patients excite rat submucosal neurons.

BACKGROUND: Episodic bouts of abdominal pain and altered bowel habit are characteristic of irritable bowel syndrome (IBS). Although a comprehensive understanding of IBS pathophysiology remains elusive, support is growing for a primary role for immune activation in disease severity as evidenced by altered cytokine profiles in IBS plasma. Additionally, aberrant stimulation of the stress axis is likely to result in altered plasma constituents. METHODS: Whole-mount preparations of submucosal plexus from adult male Sprague Dawley rats were exposed to plasma from IBS patients and healthy controls. Ratiometric calcium imaging recordings were used to measure changes in intracellular calcium ([Ca(2+)]i) as a marker of neuronal excitability. KEY RESULTS: IBS plasma stimulated a robust increase in [Ca(2+)]i (0.09 ± 0.02) whereas plasma from healthy volunteers had little effect (-0.02 ± 0.02, n=24, p<0.001). The neuromodulatory actions of IBS plasma were reduced by pre-neutralisation with anti-interleukin (IL)-6 (p<0.01) but not IL-8, immunoglobulin G or C-reactive protein. Moreover, IBS plasma-evoked responses (0.22 ± 0.06) were inhibited by the corticotrophin releasing factor receptor (CRFR) 1 antagonist, antalarmin (1µM, 0.015 ± 0.02, n=14, p<0.05), but not the CRFR2 antagonist, astressin 2B. Neuronal activation was mediated by ERK/MAPK signalling. CONCLUSIONS: These data provide evidence that factors present in IBS plasma modulate neuronal activity in the submucosal plexus and that this is likely to involve CRFR1 activation and IL-6 signalling. These neuromodulatory actions of stress and immune factors indicate a potential mechanism by which immune activation during periods of stress may lead to symptom flares in IBS.

Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome.

The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg(-1) i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg(-1) i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.

Convergence of neuro-endocrine-immune pathways in the pathophysiology of irritable bowel syndrome.

Disordered signalling between the brain and the gut are generally accepted to underlie the functional bowel disorder, irritable bowel syndrome (IBS). However, partly due to the lack of disease-defining biomarkers, understanding the aetiology of this complex and multifactorial disease remains elusive. This common gastrointestinal disorder is characterised by alterations in bowel habit such as diarrhoea and/or constipation, bloating and abdominal pain, and symptom exacerbation has been linked with periods of stress, both psychosocial and infection-related. Indeed, a high level of comorbidity exists between IBS and stress-related mood disorders such as anxiety and depression. Moreover, studies have observed alterations in autonomic output and neuro-endocrine signalling in IBS patients. Accumulating evidence indicates that a maladaptive stress response, probably mediated by the stress hormone, corticotropin-releasing factor contributes to the initiation, persistence and severity of symptom flares. Other risk factors for developing IBS include a positive family history, childhood trauma, dietary factors and prior gastrointestinal infection. An emerging role has been attributed to the importance of immune factors in the pathophysiology of IBS with evidence of altered cytokine profiles and increased levels of mucosal immune cells. These factors have also been shown to have direct effects on neural signalling. This review discusses how pathological changes in neural, immune and endocrine pathways, and communication between these systems, contribute to symptom flares in IBS.

Depressed mood predicts pulmonary rehabilitation completion among women, but not men.

BACKGROUND: As many as 30% of patients who start pulmonary rehabilitation (PR) fail to complete it, and depressed mood has been associated with PR non-completion. Depression is more common in women than men with COPD and historically women with COPD have been under studied. However, no studies to date have investigated gender-specific predictors of PR completion. METHODS: The study included 111 patients with COPD who enrolled in a community based outpatient PR program in Providence, RI. Patients who attended 20 or more sessions were designated "completers". Depression was measured using the CES-D. Logistic regression models were evaluated to test depressed mood as a predictor of PR completion. Analyses controlled for demographic and health variables found to differ between completers and non-completers. RESULTS: Patients were 95% white and 49.5% women, and 74% had a GOLD stage ≥3. Sixty-eight percent of patients were PR completers. A logistic regression model, showed that lower depressed mood independently predicted PR completion across all patients (adjusted OR = 0.92, p = .002). In gender-stratified analyses, lower depressed mood was an independent predictor of PR completion for women (adjusted OR = .91, p = .024) but not men (adjusted OR = .97, p = .45). Greater 6-min walk test distance was also an independent predictor of PR completion among women. CONCLUSION: Depressed mood is an important predictor of completion of community based PR among women. Screening and brief treatment of depression should be considered in practice.