Heartburn as a Marker of the Success of Acid Suppression Therapy in Chronic Cough.

PURPOSE: Gastro-oesophageal reflux disease (GORD) is commonly thought to play an important role in chronic cough and patients are often empirically treated with acid suppression therapy. We sought to investigate the response rate to acid suppression treatment in patients with and without heartburn attending two specialist cough clinics. METHODS: A retrospective review of 558 consecutive patients referred to two specialist cough clinics was performed (UK and USA). Patients who were treated with acid suppression were included and their documented response to treatment was collected. Binary logistic regression was used to ascertain the value of reported heartburn in predicting the response of chronic cough to acid suppression therapy. RESULTS: Of 558 consecutive referrals, 238 patients were excluded due to missing data or cough duration of < 8 weeks. The remaining 320 patients were predominantly female (76%), with mean age 61 yrs (± 13) and 96.8% non-smokers, with chronic cough for 36 (18-117) months. Of 72 patients with heartburn, 20 (28%) noted improvement in their cough with acid suppression, whereas of 248 without heartburn, only 35 (14%) responded. Patients reporting heartburn were 2.7 (95% C.I. 1.3-5.6) times more likely to respond to acid suppression therapy (p = 0.007). CONCLUSION: In specialist cough clinics, few patients report a response of their chronic cough to acid suppression therapy. Nonetheless, heartburn is a useful predictor substantially increasing the likelihood of benefit.

Circulating maternal and umbilical cord steroid hormone and insulin-like growth factor concentrations in twin and singleton pregnancies.

In addition to being associated with a higher risk of complications during pregnancy, twinning may also be a proxy for altered hormonal exposure for mothers and twin offspring, with implications for their health later in life. We compared maternal and fetal steroid hormone and insulin-like growth factor concentrations between singleton (n=62) and twin (n=41) pregnancies. Maternal concentrations of androgens, estrogens, insulin-like growth factor (IGF)-1, IGF-binding protein (BP)-3 and prolactin were quantified during the third trimester and at delivery, as well as in the fetal circulation at birth. Geometric means accounting for gestational age were calculated for hormone concentrations and compared between matched twin and singleton pregnancies. Most maternal hormone concentrations were modestly higher in twin than in singleton pregnancies in the third trimester (ranging from 8.3% for IGF-1 to 17.1% for estradiol) and at delivery (ranging from 11.1% for IGFBP-3 to 15.2% for estriol). Cord serum hormones were generally similar in twin and singleton pregnancies, except for IGFBP-3, which was 200% lower in twins. The modest differences in maternal hormones in late gestation seem unlikely to explain alterations in hormonally related disease risk in mothers of twins compared with singletons. The large deficit of IGFBP-3 in the fetal circulation of twins at birth may allow for sufficient concentrations of IGF-2 for growth and development in an environment of shared nutritional resources.

Esophageal dysmotility according to Chicago classification v3.0 vs v2.0: Implications for association with reflux, bolus clearance, and allograft failure post-lung transplantation.

BACKGROUND: Proximal reflux and incomplete transit of boluses swallowed are risk factors for obstructive chronic lung allograft dysfunction (o-CLAD) post-lung transplantation (LTx). Likewise, so is esophagogastric junction outflow obstruction (EGJOO), but not hypo-contractility, when diagnosed using Chicago Classification (CC) v3.0. Given, peristaltic breaks as defined using CCv2.0 can prolong esophageal clearance, both swallowed and refluxed, but which are deemed within normality using CCv3.0, our aim was to determine whether hypo-contractility as diagnosed using CCv2.0, influences the association with reflux, along with its clearance, and that of boluses swallowed, and thus its association to allograft failure. METHODS: Esophageal motility abnormalities were classified using CC v3.0 and v2.0 in 50 patients post-LTx (26 female, 55 years (20-73 years)). RESULTS: Reclassification from CCv3.0 to v2.0 resulted in 7 patients with normal motility being reclassified to hypo-contractility (n = 6) or hyper-contractility (n = 1); 2 patients with hypo-contractility to normal motility; and 3 patients with EGJOO without hyper-contractility to EGJOO with hyper-contractility. The main consequence of reclassification was that the sub-group exhibiting hypo-contractility became more likely to have abnormal numbers of reflux events (P = .025) and incomplete bolus transit (P = .002) than those with normal motility using CCv2.0; associations not seen using CCv3.0. Irrespective of CC used only patients with EGJOO appeared more likely to develop o-CLAD than those with normal motility (P < .05). CONCLUSIONS: Irrespective of CC used, o-CLAD appears linked to EGJOO. CCv2.0 however, accentuates the increased reflux and incomplete bolus transit associated with hypo-contractility post-LTx, suggesting that these motor abnormalities, though considered minor, may be of importance after lung transplant.

The effect of inflammation on serum zinc concentrations and the prevalence estimates of population-level zinc status among Congolese children aged 6-59 months.

BACKGROUND/OBJECTIVES: Zinc is a negative acute-phase reactant; hence, its concentration decreases in the presence of inflammation. There is no current consensus on how to control for the effect of inflammation on serum zinc, which has implications for accurate estimates of population-level zinc status. We aimed to measure the association between inflammation and serum zinc concentrations and to compare the means and the prevalence of zinc deficiency using unadjusted and inflammation-adjusted serum zinc concentrations among Congolese children. SUBJECTS/METHODS: Non-fasting blood was collected in the afternoon in trace element-free vacutainers from 744 apparently healthy children aged 6-59 months in the Democratic Republic of the Congo. Serum was analyzed for zinc, C-reactive protein (CRP) and α-1 acid glycoprotein (AGP) for 665 children with complete data for all three biomarkers. Linear regression was used to generate correction factors (CFs) based on three stages of inflammation: incubation (CRP >5 mg/l and normal AGP), early convalescence (CRP >5 mg/l and AGP >1 g/l) and late convalescence (AGP >1 g/l and normal CRP), relative to no inflammation. RESULTS: Overall unadjusted mean±s.d. serum zinc concentration was 9.4±2.1 µmol/l. Study-generated CFs (95% confidence interval) for incubation, early and late convalescence were 1.01 (0.88, 1.14), 1.15 (1.11, 1.21) and 1.07 (1.03, 1.11), respectively. After applying the CFs, overall adjusted mean±s.d. serum zinc concentration was 10.1±2.2 µmol/l, and prevalence of zinc deficiency (<8.7 µmol/l) decreased from 35% (n=234/665) to 24% (n=160/665). CONCLUSIONS: Adjustment of zinc concentrations for inflammation is warranted when assessing population-level zinc status.European Journal of Clinical Nutrition advance online publication, 23 August 2017; doi:10.1038/ejcn.2017.127.

Predictors of vitamin D status in New Zealand preschool children.

Vitamin D deficiency has adverse health effects in young children. Our aims were to determine predictors of vitamin D status and then to use these factors to develop a practical tool to predict low 25(OH)D concentrations in preschool New Zealand children. A cross-sectional sample of 1329 children aged 2 to <5 years were enrolled from throughout New Zealand in late-winter to spring 2012. 25-Hydroxyvitamin D (25(OH)D) was measured on dried blood spot (DBS) samples collected using finger-prick sampling. Caregivers completed a questionnaire. Mean (SD) DBS 25(OH)D concentration was 52(19)nmol/L. 25(OH)D < 25 nmol/L was present in 86(7%), 25(OH)D < 50 nmol/L in 642(48%), 25(OH)D 50- < 75 nmol/L in 541(41%) and 25(OH)D > 75 nmol/L in 146(11%) of children. Factors independently associated with the risk of 25(OH)D < 25 nmol/L were female gender (OR 1.92,95%CI 1.17-3.14), other non-European ethnicities (not including Maori or Pacific) (3.51,1.89-6.50), had olive-dark skin colour (4.52,2.22-9.16), did not take vitamin D supplements (2.56,1.06-6.18), had mothers with less than secondary-school qualifications (5.00,2.44-10.21) and lived in more deprived households (1.27,1.06-1.53). Children who drank toddler milk (vitamin D fortified cow's milk formula marketed to young children) had a zero risk of 25(OH)D < 25 nmol/L. The predictive tool identified children at risk of 25(OH)D < 25 nmol/L with sensitivity 42%, specificity 97% and ROC area-under-curve 0.76(95%CI 0.67-0.86, p < 0.001). Predictors of low vitamin D status were consistent with those identified in previous studies of New Zealand children. The tool had insufficient predictive ability for use in clinical situations, and suggests a need to promote safe, inexpensive testing to determine vitamin D status in preschool children.

Phenotyping of subjects for large scale studies on patients with IBS.

BACKGROUND: Irritable bowel syndrome (IBS) is a complex condition with multiple factors contributing to its aetiology and pathophysiology. Aetiologically these include genetics, life-time events and environment, and physiologically, changes in motility, central processing, visceral sensitivity, immunity, epithelial permeability and gastrointestinal microflora. Such complexity means there is currently no specific reliable biomarker for IBS, and thus IBS continues to be diagnosed and classified according to symptom based criteria, the Rome Criteria. Carefully phenotyping and characterisation of a 'large' pool of IBS patients across Europe and even the world however, might help identify sub-populations with accuracy and consistency. This will not only aid future research but improve tailoring of treatment and health care of IBS patients. PURPOSE: The aim of this position paper is to discuss the requirements necessary to standardize the process of selecting and phenotyping IBS patients and how to organise the collection and storage of patient information/samples in such a large multi-centre pan European/global study. We include information on general demographics, gastrointestinal symptom assessment, psychological factors, quality of life, physiological evaluation, genetic/epigenetic and microbiota analysis, biopsy/blood sampling, together with discussion on the organisational, ethical and language issues associated with implementing such a study. The proposed approach and documents selected to be used in such a study was the result of a thoughtful and thorough four-year dialogue amongst experts associated with the European COST action BM1106 GENIEUR (www.GENIEUR.eu).

Maternal weight gain in excess of pregnancy guidelines is related to daughters being overweight 40 years later.

BACKGROUND: Exceeding the Institute of Medicine guidelines for pregnancy weight gain increases childhood and adolescent obesity. However, it is unknown if these effects extend to midlife. OBJECTIVE: We sought to determine if exceeding the Institute of Medicine guidelines for pregnancy weight gain increases risk of overweight/obesity in daughters 40 years later. STUDY DESIGN: This cohort study is based on adult offspring in the Child Health and Development Studies and the Collaborative Perinatal Project pregnancy cohorts originally enrolled in the 1960s. In 2005 through 2008, 1035 daughters in their 40s were recruited to the Early Determinants of Mammographic Density study. We classified maternal pregnancy weight gain as greater than vs less than or equal to the 2009 clinical guidelines. We used logistic regression to compare the odds ratios of daughters being overweight/obese (body mass index [BMI] ≥25) at a mean age of 44 years between mothers who did not gain or gained more than pregnancy weight gain guidelines, accounting for maternal prepregnant BMI, and daughter body size at birth and childhood. We also examined potential family related confounding through a comparison of sisters using generalized estimating equations, clustered on sibling units and adjusted for maternal age and race. RESULTS: Mothers who exceeded guidelines for weight gain in pregnancy were more likely to have daughters who were overweight/obese in their 40s (odds ratio [OR], 3.4; 95% confidence interval {CI}, 2.0-5.7). This magnitude of association translates to a relative risk (RR) increase of 50% (RR = 1.5; 95% CI, 1.3-1.6). The association was of the same magnitude when examining only the siblings whose mother exceeded guidelines in 1 pregnancy and did not exceed the guidelines in the other pregnancy. The association was stronger with increasing maternal prepregnancy BMI (P trend < .001). Compared to mothers with BMI <25 who did not exceed guidelines, the relative risks (RR) for having an overweight/obese adult daughter were 1.3 (95% CI, 1.1-1.7), 1.7 (95% CI, 1.4-2.1) and 1.8 (95% CI, 1.5-2.1), respectively, if mothers exceeded guidelines and their prepregnancy BMI was <25, overweight (BMI 25-<30), or obese (BMI >30). This pattern held irrespective of daughters' weight status at birth, at age 4 years, or at age 20 years. CONCLUSION: Our findings support that obesity prevention before pregnancy and strategies to maintain weight gain during pregnancy within the IOM guidelines might reduce the risk of being overweight in midlife for the offspring.

A meta-analysis of immunogenetic Case-Control Association Studies in irritable bowel syndrome.

BACKGROUND: To date, genetic-association studies of single nucleotide polymorphisms (SNP) in selected candidate genes with the symptom phenotype of irritable bowel syndrome (IBS) have typically involved hundreds to 2000 patients. SNPs in immune-related genes, such as cytokine and cytokine receptor encoding genes, have been reported to associate with IBS risk. METHODS: We conducted two independent case-control studies on 16 SNPs in IL1R1, IL4, IL6, IL8, IL10, IL23R, TNFA, and TNFSF15, one from the UK (194 patients and 92 healthy volunteers) and one from the USA (137 patients and 96 healthy volunteers). The main aim was to examine the relationship between inherited immunological diversity and IBS risk in a meta-analysis which included 12 additional, earlier studies. The meta-analysis comprised a total of 2894 patients (839 IBS-C, 1073 IBS-D, 502 IBS-M), and 3138 healthy volunteers with self-reported Caucasian ancestry. KEY RESULTS: The association of SNP rs4263839 (TNFSF15) was investigated in four studies and confirmed in the meta-analysis: IBS (OR 1.19, 95% CI 1.08-1.31), and IBS-C (OR 1.24, 95% CI 1.08-1.42). No additional SNPs residing in immunogenes associated with IBS symptom phenotypes. CONCLUSIONS & INFERENCES: Our meta-analysis could not confirm a major role of most investigated SNPs, but a moderate association between rs4263839 TNFSF15 and IBS, in particular IBS-C. The analysis emphasizes the importance of definition and phenotype homogeneity, adequate study size and representativeness of the patient and control collective.

Data management challenges in analysis and synthesis in the ecosystem sciences.

Open-data has created an unprecedented opportunity with new challenges for ecosystem scientists. Skills in data management are essential to acquire, manage, publish, access and re-use data. These skills span many disciplines and require trans-disciplinary collaboration. Science synthesis centres support analysis and synthesis through collaborative 'Working Groups' where domain specialists work together to synthesise existing information to provide insight into critical problems. The Australian Centre for Ecological Analysis and Synthesis (ACEAS) served a wide range of stakeholders, from scientists to policy-makers to managers. This paper investigates the level of sophistication in data management in the ecosystem science community through the lens of the ACEAS experience, and identifies the important factors required to enable us to benefit from this new data-world and produce innovative science. ACEAS promoted the analysis and synthesis of data to solve transdisciplinary questions, and promoted the publication of the synthesised data. To do so, it provided support in many of the key skillsets required. Analysis and synthesis in multi-disciplinary and multi-organisational teams, and publishing data were new for most. Data were difficult to discover and access, and to make ready for analysis, largely due to lack of metadata. Data use and publication were hampered by concerns about data ownership and a desire for data citation. A web portal was created to visualise geospatial datasets to maximise data interpretation. By the end of the experience there was a significant increase in appreciation of the importance of a Data Management Plan. It is extremely doubtful that the work would have occurred or data delivered without the support of the Synthesis centre, as few of the participants had the necessary networks or skills. It is argued that participation in the Centre provided an important learning opportunity, and has resulted in improved knowledge and understanding of good data management practices.

Weak peristalsis with large breaks in chronic cough: association with poor esophageal clearance.

BACKGROUND: Gastroesophageal reflux plays an important role in chronic cough (CC). Whether disturbed esophageal motility contributes to increased esophageal reflux exposure or interferes with swallowed bolus clearance is unclear. This study used high resolution esophageal manometry and impedance (HRIM) together with Chicago Classification, and 24-h impedance pH (MII/pH) to address these questions in patients with CC compared with heartburn (HB). METHODS: A retrospective review of 32 patients with CC (mean age 57 [95% CI: 52-62] years) and 32 patients with symptoms of HB (55 [52-62] years) referred for HRIM and MII/pH between September 2012 and September 2013 was undertaken. KEY RESULTS: Weak peristalsis with large breaks (WPLBs) was observed in 34% of CC patients compared with only 12% of HB patients (p = 0.027). Pathological acid exposure time (AET) was identified in 81% of CC patients with WPLBs compared with 29% without (p = 0.011). Increased AET was associated with prolonged clearance time of refluxed events (p = 0.006) rather than increased number of events. AET correlated with the percentage of peristaltic events with large breaks in CC (ρ = 0.467, p = 0.007). Similar data were obtained for total bolus (acid and non-acid) exposure time. Only one of the CC patients with WPLBs exhibited complete bolus transit (CBT) on swallowing compared with 81% without WPLBs (p < 0.001). Moreover, the percentage of peristaltic events associated with CBT negatively correlated with the percentage of peristaltic events with large breaks (r = -0.653, p < 0.001) in CC. CONCLUSIONS & INFERENCES: One-third of CC patients exhibit WPLBs, which directly impacts on clearance of refluxed events and bolus's swallowed. These observations may have important implications for esophageal-bronchial interaction in CC.

Tissue iron deficiency and adiposity-related inflammation in disadvantaged preschoolers from NE Brazil.

BACKGROUND/OBJECTIVES: Earlier we reported an association between iron deficiency and overweight in Brazilian preschoolers. Here, we investigate whether this is the result of adipose-related inflammation. SUBJECTS/METHODS: Fasting serum C-reactive protein, α-1-acid glycoprotein (AGP), hepcidin, interleukin-6 (IL-6) and leptin, together with two iron biomarkers (serum ferritin and transferrin receptor (sTfR)), were measured in 364 disadvantaged preschoolers with a mean BMIZ (standardised Z-score for BMI) of 0.015, aged 3-6 years and attending day care in Salvador, Brazil. The role of genetic haemoglobin (Hb) disorders, intestinal parasites and dietary iron supply (calculated from serving sizes of 20 weekday menus) were also examined. RESULTS: Forty-eight children (13%) were overweight (BMIZ >1). Prevalence of tissue iron deficiency (sTfR >113.3 nmol/l; 30.6 vs 12.5%; P=0.002) and chronic inflammation (AGP >25 µmol/l; 19 vs 10%; P=0.025) were higher in overweight than in normal-weight children. From multiple regression, BMIZ was a positive predictor of log serum sTfR, ferritin and leptin, but not of log hepcidin or IL-6. Instead, major positive predictors of log hepcidin were log IL-6, followed by an elevated AGP and sex (male), whereas for log IL-6 elevated AGP was the only significant predictor. Besides BMIZ, sex (female) was also a major positive predictor of leptin. Heterozygous variant of sickle cell Hb (n=20), but not helminths, was also a positive predictor of log sTfR. Median dietary iron supply (mg/day) was above the WHO Recommended Nutrient Intake assuming moderate bioavailability and appeared adequate. CONCLUSIONS: The role of adiposity-related inflammation in tissue iron deficiency should be considered even when the prevalence of overweight is relatively low.

Outcomes following pharyngolaryngectomy reconstruction with the anterolateral thigh (ALT) free flap.

We retrospectively reviewed 15 cases of pharyngolaryngectomy for advanced laryngeal carcinoma reconstructed with the anterolateral thigh (ALT) free flap. Thirteen patients had primary surgery and adjuvant treatment (radiotherapy or chemoradiotherapy), and two had salvage surgery. Thirteen had stage III or IV disease, and eight had cervical nodal extracapsular spread. In this series all the flaps survived, and at median follow-up of 14.5 months (range 3.7-31.2), 12 of the 15 patients were alive. One patient developed a chronic pharyngocutaneous fistula, and five required repeat balloon dilatations for late pharyngeal strictures. Six patients enjoyed restoration of full oral intake, seven were able to take a soft diet, and two were dependent on feeding by percutaneous endoscopic gastrostomy. Four patients developed adequate tracheo-oesophageal speech, and one successfully developed oesophageal speech. In this series many of the surgical problems associated with pharyngolaryngectomy reconstruction were addressed successfully by the ALT, but late dysphagia remained troublesome in an appreciable minority. While adjuvant radiotherapy could have contributed to this, future innovations will focus on the reduction of late strictures.

5-hydroxytryptamine signalling in irritable bowel syndrome with diarrhoea: effects of gender and menstrual status.

BACKGROUND: Symptomatology and physiology differ between men and women and across the menstrual cycle in irritable bowel syndrome (IBS). Ovarian hormones influence 5-hydroxytryptamine (5-HT), an amine known to play a role in gut motor-sensory function. AIM: To assess the effects of gender and menstrual status on platelet-depleted plasma (PDP) 5-HT concentration in IBS patients with diarrhoea (IBS-D) patients compared with healthy volunteers (HV). METHODS: Platelet-depleted plasma 5-HT concentrations were assessed under fasting and fed conditions in 73 IBS-D patients (aged 18-58 years; 18 men) and 64 HV (aged 18-50 years; 24 men). Women were divided into those with low or high progesterone/oestrogen (P/O) levels. RESULTS: Irritable bowel syndrome patients with diarrhoea had higher PDP 5-HT concentrations than HV under fasting (P = 0.002) and fed (P = 0.049) conditions. This was particularly related to IBS-D men having higher PDP 5-HT concentrations than healthy controls (P = 0.002). Moreover, PDP 5-HT concentrations in IBS-D women with low P/O levels were similar to healthy controls. CONCLUSIONS: Similar to IBS-D women with high P/O levels, IBS-D men also have raised PDP 5-HT concentrations. 5-HT concentration normalizes at menses in IBS-D women, suggesting a shift in the mechanisms responsible for abnormal 5-HT signalling in these patients.

Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173 010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation.

BACKGROUND: A sensation of abdominal swelling (bloating) and actual increase in girth (distension) are troublesome features of irritable bowel syndrome (IBS), which is more common in patients with constipation, especially those with delayed transit. AIM: To establish whether a fermented dairy product containing Bifidobacterium lactis DN-173 010 reduces distension in association with acceleration of gastrointestinal transit and improvement of symptoms in IBS with constipation. METHODS: A single centre, randomized, double-blind, controlled, parallel group study in which patients consumed the test product or control product for 4 weeks. Distension, orocaecal and colonic transit and IBS symptoms were assessed on an intention-to-treat population of 34 patients. RESULTS: Compared with control product, the test product resulted in a significant reduction in the percentage change in maximal distension [median difference - 39%, 95% CI (-78, -5); P = 0.02] and a trend towards reduced mean distension during the day [-1.52 cm (-3.33, 0.39); P = 0.096]. An acceleration of orocaecal [-1.2 h (-2.3,0); P = 0.049] as well as colonic [-12.2 h (-22.8, -1.6); P = 0.026] transit was observed and overall symptom severity [-0.5 (-1.0, -0.05); P = 0.032] also improved. CONCLUSIONS: This probiotic resulted in improvements in objectively measured abdominal girth and gastrointestinal transit, as well as reduced symptomatology. These data support the concept that accelerating transit is a useful strategy for treating distension.

Effect of the NK(3) receptor antagonist, talnetant, on rectal sensory function and compliance in healthy humans.

Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK(3) receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK(3) receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14- to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants.

Sigmoid-colonic motility in health and irritable bowel syndrome: a role for 5-hydroxytryptamine.

Abstract Evidence suggests that sigmoid-colonic motility is increased in patients with irritable bowel syndrome (IBS). 5-Hydroxytryptamine (5-HT) plays a role in the control of motility, but its involvement in the dysmotility seen in IBS remains unclear. To investigate the relationship between platelet depleted plasma 5-HT (PDP 5-HT) concentration and sigmoid-colonic motility in patients with IBS and healthy volunteers. Pre- and postprandial PDP 5-HT concentrations were assessed while recording sigmoid-colonic motility in 35 IBS patients (aged 19-53 years, eight male) and 16 healthy volunteers (aged 18-39 years, six male). Motility was recorded using a five-channel solid-state catheter introduced to a depth of 35 cm into an unprepared bowel. 5-Hydroxytryptamine concentration was measured by reverse-phase HPLC with fluorimetric detection. Irritable bowel syndrome patients had elevated concentrations of PDP 5-HT under fasting (P < 0.004) and fed (P = 0.079) conditions compared with controls. Likewise, they exhibited increased sigmoid-colonic motility under fasting (activity index: P < 0.02) and fed (P < 0.05) conditions compared with controls. Platelet depleted plasma 5-HT concentration positively correlated with colonic activity index under both fasting (r = 0.402; P = 0.003) and fed (r = 0.439; P = 0.001) conditions. These data show a possible relationship between endogenous concentrations of 5-HT and sigmoid-colonic motility recorded in both IBS and healthy subjects.

Guidelines on the irritable bowel syndrome: mechanisms and practical management.

BACKGROUND: IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. AIM: To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. METHODS: Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. RESULTS: Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. CONCLUSIONS: Better ways of identifying which patients will respond to specific treatments are urgently needed.

Effect of a second-generation alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome.

BACKGROUND: Visceral hypersensitivity is an important pathophysiological factor in irritable bowel syndrome (IBS). Pre-clinical studies suggest that the alpha(2)delta ligand pregabalin reduces both visceral allodynia and hyperalgesia, but is inactive on basal sensitivity. AIM: To assess the effect of pregabalin on the perception of rectal distension in hypersensitive IBS patients. METHODS: Twenty-six patients with Rome-II-defined IBS (aged 18-46 years, 7 male) were included in a randomized, double-blind, placebo-controlled, parallel-group study in which they received either 3 weeks oral pregabalin (titrated: 50 mg tid days 1-3, 100 mg tid days 4-7, 150 mg tid days 8-11; fixed 200 mg tid days 12-21 +/-4) or placebo control. Rectal sensitivity was assessed using a barostat technique, in which sensory thresholds were determined using the ascending method of limits, followed by tracking both before and after treatment. Only patients with a pain threshold of

Systematic review: the efficacy of treatments for irritable bowel syndrome--a European perspective.

BACKGROUND: Irritable bowel syndrome (IBS) is a common, chronic disorder, characterized by abdominal pain/discomfort, bloating and altered bowel habit. AIM: To conduct a systematic evidence-based review of pharmacological therapies currently used, or in clinical development, for the treatment of IBS in Europe. The safety and tolerability of these therapies are the subject of an accompanying review. METHODS: A literature search was completed for randomized controlled studies which included adult patients with IBS and an active or placebo control, assessed IBS symptoms, and were published in English between January 1980 and June 2005. The level of evidence for efficacy was graded according to the quality of the trial design and the study outcome. RESULTS: There is some evidence for improvement of individual IBS symptoms with antidiarrhoeals (diarrhoea), antispasmodics (abdominal pain/discomfort), bulking agents (constipation), tricyclic antidepressants (abdominal pain/discomfort) and behavioural therapy. In contrast, there is strong evidence for the improvement of global IBS symptoms with two new serotonergic agents: the 5-HT4 selective agonist tegaserod (IBS with constipation) and the 5-HT3 antagonist alosetron (IBS with diarrhoea). Further data are required for the 5-HT3 antagonist, cilansetron, and the mixed 5-HT3 antagonist/5-HT4 agonist renzapride before their utility in IBS can be appraised. CONCLUSIONS: There is limited evidence for the efficacy, safety and tolerability of therapies currently available in Europe for the treatment of IBS. Overall, there is an absence of pharmacological agents licensed specifically for the treatment of IBS subtypes, and new agents are awaited in Europe that will allow changes in clinical practice to focus on and improve global IBS symptoms.