Achalasia.

SummaryAchalasia is a rare motility disorder of the oesophagus characterised by loss of enteric neurons leading to absence of peristalsis and impaired relaxation of the lower oesophageal sphincter. Although its cause remains largely unknown, ganglionitis resulting from an aberrant immune response triggered by a viral infection has been proposed to underlie the loss of oesophageal neurons, particularly in genetically susceptible individuals. The subsequent stasis of ingested food not only leads to symptoms of dysphagia, regurgitation, chest pain, and weight loss, but also results in an increased risk of oesophageal carcinoma. At present, pneumatic dilatation and Heller myotomy combined with an anti-reflux procedure are the treatments of choice and have comparable success rates. Per-oral endoscopic myotomy has recently been introduced as a new minimally invasive treatment for achalasia, but there have not yet been any randomised clinical trials comparing this option with pneumatic dilatation and Heller myotomy

Anorectal function testing and anal endosonography in the diagnostic work-up of patients with primary pelvic organ prolapse

AIM: To study the pathophysiology of defecation disorders in patients with primary pelvic organ prolapse (POP) and the diagnostic potential of anorectal function testing (AFT) including endosonography in the work-up of these patients. METHODS: 59 Patients were evaluated with a validated questionnaire, clinical examination, AFT and endosonography. RESULTS: Women with POP showed lower squeezing pressure, postponed first sensation and desire, lower capacity and prolonged pudendal nerve terminal latency time compared to healthy controls (all p < 0.01). Manometric findings did not differ significantly between patients with and without constipation. Patients with fecal incontinence had significantly lower resting and squeezing pressures than patients without fecal incontinence and an increased risk of an external sphincter defect (odds ratio = 12.75, 95% confidence interval 2.40-66.67). Although digital rectal examination could quantify absent, decreased and normal squeezing pressure, the positive predictive value for external sphincter defects was low (0.32). CONCLUSION: AFT indicates the presence of neuromuscular damage of the anorectal region in patients with POP. AFT is not useful in the work-up of patients with POP and constipation, because it fails to discriminate between symptomatic and asymptomatic patients. In cases of fecal incontinence, AFT and endosonography are helpful to distinguish between functional and anatomical problems

A qualitative interpretation of challenges associated with helping patients with multiple chronic diseases identify their goals

Background Patients with multiple chronic diseases are usually treated according to disease-specific guidelines, with outcome measurements focusing mostly on biomedical indicators (e.g. blood sugar levels or lung function). However, for multimorbidity, a goal-oriented approach focusing on the goals defined by the individual patient, may be more suitable. Despite the clear theoretical and conceptual advantages of including patient-defined goals in clinical decision-making for multimorbidity, it is not clear how patients define their goals and which aspects play a role in the process of defining them. Objective To explore goal-setting in patients with multimorbidity. Design Qualitative analysis of interviews with 19 patients diagnosed with chronic obstructive pulmonary disease and comorbidities. Results Patients do not naturally present their goals. Their goals are difficult to elicit, even when different interviewing techniques are used. Four underlying hypotheses which may explain this finding were identified from the interviews: (1) patients cannot identify with the concept of goal-setting; (2) goal-setting is reduced due to acceptation; (3) actual stressors predominate over personal goal-setting; and (4) patients may consider personal goals as selfish. Conclusions Our findings advocate for specific attention to provider skills and strategies that help patients identify their personal goals. The hypotheses on why patients may struggle with defining goals may be useful to prompt patients in this process and support the development of a clinical method for goal-oriented care

Post infectious IBS: defining its clinical features and prognosis using an internet-based survey

Background: Gastrointestinal infection is an important risk factor for developing IBS. Our aim was to characterise postinfectious IBS (PI-IBS) compared to other IBS patients. Methods: An internet survey of IBS patients using Rome III diagnostic questionnaire, Hospital Anxiety & Depression Scale (HADS) and Patient Health Questionnaire-12 somatic symptom score (PHQ12-SS) documenting the mode of onset. Results: 7811 participants, 63.2% female of whom 1004 (13.3%) met criteria for PI-IBS. 70% of PI-IBS described sudden onset, 35% onset while travelling, 49.6% vomiting, 49.9 fever and 20.3% bloody diarrhoea. Compared to other IBS, PI-IBS was significantly associated with living in Northern Europe and North America, having a hysterectomy, not having an appendectomy, higher PHQ12-SS score and having more than one toilet in the family home. PI-IBS patients had more frequent stools. At 1 year recovery rate in PI-IBS and non-PI-IBS group was 19.7% and 22.2%, p=0.15. Recovery rates were lower for females (20.7%) versus males (38.8%), those with somatisation ( 23.0%) versus those without (33.2%) and living in North America or Northern Europe (21.1%) versus living elsewhere (33.9%) p=<0.001. Conclusion: PI-IBS accounts for around 13% of all IBS in this internet sample, with some distinctive features but a similar prognosis to the remainder

Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts

OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11\u2005326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 710(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus

Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility.status: publishe

The dopaminergic system in patients with functional dyspepsia analysed by single photon emission computed tomography (SPECT) and an alpha-methyl-para-tyrosine (AMPT) challenge test

Functional dyspepsia (FD) is a chronic condition characterized by upper abdominal symptoms without an identifiable cause. While the serotonergic system is thought to play a key role in the regulation of gut physiology, the role of the dopaminergic system, which is important in the regulation of visceral pain and stress, is under-studied. Therefore, this study investigated the dopaminergic system and its relationship with drinking capacity and symptoms in FD patients. In FD patients and healthy volunteers (HV) the dopaminergic system was investigated by in-vivo assessment of central dopamine D2 receptors (D2Rs) with [I-123]IBZM SPECT and by an acute, but reversible, dopamine depletion alpha-methyl-para-tyrosine (AMPT) challenge test. A nutrient drink test was performed to investigate the association between maximal ingested volume, evoked symptoms, and D2Rs. The HV subjects comprised 12 women and 8 men (mean age 31 +/- 3 years), and the FD patients comprised 5 women and 3 men (mean age 39 +/- 5 years). The FD patients had a lower left plus right average striatal binding potential (BPNP) for the caudate nucleus (p = 0.02), but not for putamen (p = 0.15), which in the FD patients was correlated with maximal ingested volume (r = 0.756, p = 0.03). The D2R BPNP in the putamen was correlated with nausea (r = 0.857, p = 0.01). The acute dopamine depletion test, however, failed to reveal differences in prolactin release between the FD patients and the HV subjects. These preliminary data suggest that chronic rather than acute alterations in the dopaminergic system may be involved in the pathogenesis of FD. Further studies are required to reproduce our novel findings and to evaluate to what extent the dopaminergic changes may be secondary to abnormalities in serotonergic pathway

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders.

Irritable bowel syndrome (IBS) results from disordered brain-gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain-gut interactions underlying IBS

No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome

Background The calcium-sensing receptor (CaSR) is a calcium (Ca2+) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca2+/Mg2+- homeostasis and senses interstitial Ca2+ levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity. Methods We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA. Results Genotype frequencies showed no association in the three genotyped case–control samples, neither with IBS nor with IBS subtypes. Conclusions Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca2+ levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies