Natalia Zarate

Physiology, Injury, and Recovery of Interstitial Cells of Cajal: Basic and Clinical Science

In the last 15 years, our understanding of the cellular basis of gastrointestinal function has been altered irreversibly by the discovery that normal gastrointestinal (GI) motility requires interstitial cells of Cajal (ICC). Research in this relatively short time period has modified our original concept that the core unit that controls motility is made up of nerves and smooth muscle, to one that now includes ICC. This concept has now expanded to beyond the GI tract, suggesting that it may be a fundamental property of the regulation of smooth muscle function that requires rhythmic contraction. ICC are distributed throughout the GI tract, have important functions in the control of GI motility, and are often abnormal in diseased states. Recently, significant steps forward have been made in our understanding of the physiology of ICC as well as mechanisms of injury and recovery. These advances are the focus of this review. The Physiology of ICC Unique motor patterns are intrinsic to every organ of the GI tract, which suit their functions related to mixing, absorption, and anally directed movement. The ICC are an integral part of the control of these motor activities. The distribution of ICC throughout the musculature is associated with nerve structures. Myenteric pacemaker ICC surround the myenteric or Auerbach’s plexus and intramuscular ICC are associated with nerve varicosities throughout the muscle layers (Figures 1 and 2). Other subpopulations of ICC are associated with nonganglionated plexuses of nerve varicosities at the inner borders of the circular muscle layers in the intestine and colon (Figures 1 and 2). The best understood function is that of pacemaker activity in the stomach and small intestine where the ICC generate a periodic depolarization at a characteristic frequency in each of these organs that is called the slow wave or pacemaker activity.

Clinical patterns over time in irritable bowel syndrome: symptom instability and severity variability.

OBJECTIVES:The clinical course of irritable bowel syndrome (IBS) remains poorly known. In 209 IBS patients meeting Rome II criteria (137 females and 72 males) we evaluated: (1) changes in frequency and intensity of abdominal pain/discomfort, abnormal number of bowel movements, loose or watery stools, defecatory urgency, hard or lumpy stools, straining during bowel movements, and feeling of incomplete evacuation); (2) use of resources, HRQoL, and psychological well being.METHODS:Observational, prospective, multicenter study. Symptoms were registered in a diary over two 28-day periods with an interval of 4 wk; direct resource use and indirect costs were noted weekly. Three HRQoL questionnaires were administered.RESULTS:High-intensity symptoms were present on more than 50% of the days. Sixty-one percent were classified in the same IBS subtype on both occasions (κ= 0.48), while 49% had the same symptom predominance and intensity (κ= 0.40). The greatest instability was observed among diarrhea (D-IBS) and constipation (C-IBS) subtypes: only 46% and 51% remained in the same pattern with a tendency to shift to alternating diarrhea/constipation subtype (A-IBS); however, practically no patient changed from D-IBS to C-IBS, or vice versa. The most reliable symptom characteristic was frequency, followed by intensity and number of episodes. Symptom frequency and intensity were directly related to resource use and HRQoL impairment.CONCLUSIONS:IBS symptoms are instable over time and variables in intensity. Many patients with D-IBS or C-IBS move to A-IBS; however, shift from D-IBS to C-IBS, or vice versa, is very infrequent.

Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link?

Background  Unexplained gastrointestinal (GI) symptoms and joint hypermobility (JHM) are common in the general population, the latter described as benign joint hypermobility syndrome (BJHS) when associated with musculo‐skeletal symptoms. Despite overlapping clinical features, the prevalence of JHM or BJHS in patients with functional gastrointestinal disorders has not been examined.

The origin of segmentation motor activity in the intestine

The segmentation motor activity of the gut that facilitates absorption of nutrients, was first described in the late 19th century but the fundamental mechanisms underlying it remain poorly understood. The dominant theory suggests alternate excitation and inhibition from the enteric nervous system. Here we demonstrate that typical segmentation can occur after total nerve blockade. The segmentation motor pattern emerges when the amplitude of the dominant pacemaker, the slow wave generated by ICC associated with the myenteric plexus (ICC-MP), is modulated by the phase of induced lower frequency rhythmic transient depolarizations, generated by ICC associated with the deep muscular plexus (ICC-DMP), resulting in a waxing and waning of the amplitude of the slow wave and a rhythmic checkered pattern of segmentation motor activity. Phase amplitude modulation of the slow waves points to an underlying system of coupled nonlinear oscillators originating in ICC.

Accurate localization of a fall in pH within the ileocecal region: validation using a dual-scintigraphic technique

Stereotypical changes in pH occur along the gastrointestinal (GI) tract. Classically, there is an abrupt increase in pH on exit from the stomach, followed later by a sharp fall in pH, attributed to passage through the ileocecal region. However, the precise location of this latter pH change has never been conclusively substantiated. We aimed to determine the site of fall in pH using a dual-scintigraphic technique. On day 1, 13 healthy subjects underwent nasal intubation with a 3-m-long catheter, which was allowed to progress to the distal ileum. On day 2, subjects ingested a pH-sensitive wireless motility capsule labeled with 4 MBq (51)Chromium [EDTA]. The course of this, as it travelled through the GI tract, was assessed with a single-headed γ-camera using static and dynamic scans. Capsule progression was plotted relative to a background of 4 MBq ¹¹¹Indium [diethylenetriamine penta-acetic acid] administered through the catheter. Intraluminal pH, as recorded by the capsule, was monitored continuously, and position of the capsule relative to pH was established. A sharp fall in pH was recorded in all subjects; position of the capsule relative to this was accurately determined anatomically in 9/13 subjects. In these nine subjects, a pH drop of 1.5 ± 0.2 U, from 7.6 ± 0.05 to 6.1 ± 0.1 occurred a median of 7.5 min (1-16) after passage through the ileocecal valve; location was either in the cecum (n = 5), ascending colon (n = 2), or coincident with a move from the cecum to ascending colon (n = 2). This study provides conclusive evidence that the fall in pH seen within the ileocolonic region actually occurs in the proximal colon. This phenomenon can be used as a biomarker of transition between the small and large bowel and validates assessment of regional GI motility using capsule technology that incorporates pH measurement.

Traditional measures of normal anal sphincter function using high-resolution anorectal manometry (HRAM) in 115 healthy volunteers

High‐resolution anorectal manometry (HRAM) is a relatively new method for collection and interpretation of data relevant to sphincteric function, and for the first time allows a global appreciation of the anorectum as a functional unit. Historically, traditional anal manometry has been plagued by lack of standardization and healthy volunteer data of variable quality. The aims of this study were: (i) to obtain normative data sets for traditional measures of anorectal function using HRAM in healthy subjects and; (ii) to qualitatively describe novel physiological phenomena, which may be of future relevance when this method is applied to patients.

Joint hypermobility and rectal evacuatory dysfunction: an etiological link in abnormal connective tissue?

Background  Previous studies report an association between joint hypermobility (JHM), as a clinical feature of underlying connective tissue (CT) disorder, and pelvic organ prolapse. However, its association with rectal evacuatory dysfunction (RED) has not been evaluated. To investigate the prevalence of JHM in the general population and in patients with symptoms of RED referred for anorectal physiological investigation.

Achalasia treatment in the elderly: is botulinum toxin injection the best option?

Background Achalasia treatment in elderly patients is a matter of controversy. Botulinum toxin injection has been proposed as the best option in this group of patients as it is a safe procedure. However, concern persists regarding its short-term effect. Aims To analyse the clinical and economic effectiveness of botulinum toxin injection in the treatment of achalasia patients who are elderly. Methods Seventeen consecutive achalasia patients older than 65 years were treated with 80 units of botulinum toxin. Clinical follow-up at 1, 6 and 12 months was performed. Control manometry when symptoms recurred was carried out. Results were compared with those of an historical control group of 16 achalasia patients also older than 65 years and who had been treated with endoscopic dilation. The costs of both procedures were compared. Results Twenty-nine botulinum toxin injections were performed in the 17 patients of the botulinum toxin group (follow-up, 12–36 months). In the dilation group only two patients had to be retreated (follow-up, 12–108 months). No major complications were observed in either group. The average duration of symptom alleviation was 48 ± 33 months for endoscopic dilation and 13.8 ± 9.5 months for botulinum toxin injection. Maintaining a patient free of symptoms cost &U20AC;348.31 per year for botulinum toxin injection, whilst if endoscopic dilation was chosen the cost was only &U20AC;117.47 per year. Conclusions The effect of botulinum toxin injections wanes with time in elderly patients, necessitating repeated injections to keep the patients symptom-free. Due to the required repeated injections this procedure is more expensive than endoscopic dilation.

Association between achalasia and nitric oxide synthase gene polymorphisms

BACKGROUND:Our group previously reported the absence of nitric oxide synthase (NOS) in the gastroesophageal junction of patients with achalasia. NOS exists in three distinct isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible isoform (iNOS). Some studies have shown that NO production is regulated by NOS polymorphisms.AIM:To assess whether some functional polymorphisms in the nNOS, iNOS, or eNOS genes are involved in susceptibility to suffer from achalasia.METHODS:Genomic DNA from 80 unrelated Spanish Caucasian patients with sporadic achalasia and 144 healthy subjects matched for age (±5 yr) and gender was typed by PCR and RFLP methods for the 27-bp variable number of tandem repeat (VNTR) polymorphism in intron 4 of the eNOS gene, a CA microsatellite repeat and a Nla III (C→T) restriction fragment length polymorphism (RFLP) in exon 29 of the nNOS gene, and two nucleotide substitutions located in exon 16 (C→T) and exon 22 (G→A) of the iNOS gene.RESULTS:No significant differences in carriage, genotype, and allele frequencies of the nNOS, iNOS, or eNOS gene polymorphisms were found between patients with achalasia and controls. Individuals homozygous for genotype iNOS22*A/A tended to be more frequent in achalasia (20% vs 11%, odds ratio [OR] 1.79, 95% confidence interval [CI] 0.89–3.59, p = 0.09) as were those homozygous for the rare eNOS*4a allele (6.2% vs 1.4%, OR 4.5, 95% CI 0.89–22.67, p = 0.1) although the difference did not reach statistical significance. No differences in genotype and allele distribution were found with respect to epidemiological and clinical characteristics of patients with achalasia.CONCLUSION:Our data suggest that NOS gene polymorphisms are not involved in the susceptibility to and nature of the clinical course of sporadic achalasia. However, studies in a greater number of patients are required to analyze the tendency toward a higher prevalence of genotypes iNOS22*A/A and eNOS*4a4a.

Bowel preparation affects the amplitude and spatiotemporal organization of colonic propagating sequences

Background  Colonic manometry is performed using either colonoscopically assisted catheter placement, after bowel preparation, or nasocolonic intubation of the unprepared bowel. There has been little systematic evaluation of the effects of bowel cleansing upon colonic propagating pressure wave sequences.