Permanent sacral nerve stimulation for treatment of idiopathic constipation (Br J Surg 2002; 89: 882-8).
Explore the source record for details and available documents.
Constipation↗
Biomedical subjects
N S Williams
Publications and source records attributed to N S Williams.
Vanilloid receptor 1 immunoreactivity in inflamed human bowel.
Vanilloid receptor 1 (VR1) is expressed by sensory neurons. Once activated, these neurons evoke the sensation of burning pain and release neuropeptides that induce neurogenic inflammation. We used immunoblotting and immunostaining to estimate the density of VR1 in colonic tissues of patients with inflammatory bowel disease and of controls. Our study results indicate that VR1 immunoreactivity is greatly increased in colonic nerve fibres of patients with active inflammatory bowel disease. Thus, the discovery of new drugs that can bind the VR1 receptor, or antagonise endogenous inflammatory substances that activate this receptor, could lead to new therapies for pain and dysmotility.
Humans↗
Smooth muscle inclusion bodies in slow transit constipation.
Slow transit constipation (STC) is a disorder of intestinal motility of unknown aetiology. Myopathies, including those characterized by the finding of inclusion bodies, have been described in enteric disorders. Amphophilic inclusion bodies have been reported in the muscularis externa of the colon of STC patients. This study formally tested the hypothesis that these represent a primary muscle disorder, specific to STC. In a systematic, blinded, dual observer qualitative and quantitative analysis, colonic and ileal tissue from patients with STC (n=36) were compared with selected control populations: total colonic aganglionosis (n=10), Chagas' disease (n=6), isolated rectal evacuation disorders (n=6), and a control population of a range of ages (n=80). All sections were stained with haematoxylin and eosin and periodic acid Schiff. Further immunostains were used in an attempt to determine inclusion body composition. Round or ovoid (4-22 microm diameter) amphophilic inclusions increased in number in normal subjects with age. Inclusions were more frequent in idiopathic STC than in age-matched controls or rectal evacuation disorders [ileum (33% vs. 9%), ascending (50% vs. 19%, p<0.05), and sigmoid colon (43% vs. 20%)] and were very frequent in the sigmoid (71%) of patients with STC arising after pelvic surgery. The number of inclusions per unit area was significantly higher in patients with STC (p<0.001). Inclusions were found in all Chagas' patients, but not with aganglionosis. It was not possible to determine inclusion body composition, despite the use of a wide range of conventional and immunostains. This study demonstrates that inclusion body myopathy is identifiable in patients with STC and that it may arise secondary to denervation.
Adult↗
Rectal augmentation and stimulated gracilis anal neosphincter: a new approach in the management of fecal urgency and incontinence.
PURPOSE: The aim of this study was the development of a procedure which would successfully treat selected patients presenting with incapacitating urgency and fecal incontinence. Some patients presenting with urgency and fecal incontinence, with an intact anorectum but deficient sphincter mechanism, have low rectal compliance. Management is problematic, because correction of the sphincter defect does not abolish the incapacitating urgency caused by rectal hypersensitivity. METHODS: This was a prospective study of three female patients with urgency and fecal incontinence who underwent combined rectal augmentation using a segment of distal ileum and stimulated gracilis anal neosphincter. All patients had low rectal volumes and two exhibited a temporal relationship between high-amplitude (>60 mmHg) rectal pressure waves and urgency on prolonged ambulatory anorectal manometry. RESULTS: Urgency was abolished and continence restored in all individuals. When the level of stimulation was not optimal or had been discontinued, patients experienced only passive incontinence with no urgency. Postoperative physiology revealed elevated thresholds to rectal distention and a reduction in the number of high-amplitude rectal pressure waves in all cases. CONCLUSIONS: Combined rectal augmentation with stimulated gracilis anal neosphincter may be of benefit to some patients with distressing urgency and fecal incontinence not previously helped by current techniques.
Adult↗
Comparison of epineural or intramuscular nerve electrodes for stimulated graciloplasty.
OBJECTIVE: Two different techniques have been developed to stimulate the gracilis muscle when it is used in anal neosphincter reconstruction. These are direct neural stimulation and intramuscular electrode stimulation. The aim of this study was to compare these techniques. METHODS: Comparison was made of gracilis anal neosphincter reconstruction using neural stimulation (Royal London Hospital in the United Kingdom) with the intramuscular muscular method (University Hospital Maastricht in the Netherlands). The United Kingdom data were obtained from a retrospective database, whereas the Netherlands data were gathered prospectively. RESULTS: A successful outcome was achieved in 46 of 81 patients (57 percent) in London and 148 of 200 cases (74 percent) in the Maastricht study (chi-squared = 7.2; P < 0.01). There was no significant difference between the two techniques in voltage required for stimulation of the neosphincter muscle during a ten-year period. Reoperative surgery for electrode failure or dislocation was required in 21 (26 percent) patients in the London study, whereas only four (2.7 percent) of the Maastricht cases required such procedures (chi-squared = 37.8; P < 0.05). The high electrode plate failure rate in the London study was related to the source of manufacture. CONCLUSIONS: Both neural and intramuscular nerve techniques provide effective long-term stimulation of the gracilis anal neosphincter.
Adolescent↗
Scintigraphic assessment of colonic transit in women with slow-transit constipation arising de novo and following pelvic surgery or childbirth.
BACKGROUND: Colonic transit has not been compared between patients with slow-transit constipation (STC) arising de novo (idiopathic) and those whose symptoms followed pelvic surgery or childbirth (acquired). METHODS: In 48 women, with either idiopathic (n = 36) or acquired (n = 12) STC, 111In-radiolabelled diethylene-triamine penta-acetic acid colonic scintigraphy was performed to determine patterns of delay (generalized or left sided), the 'severity' of transit disturbance between subgroups, and the association with age or duration of symptoms. Results were compared with those in healthy women. Patterns of colonic transit disturbance were assessed using previously defined criteria. In those with a generalized delay, variables reflecting the overall rate of isotope progression throughout the colon were calculated: gradient of geometric centre of isotope progression and estimated evacuation time of the isotope. RESULTS: The pattern of transit delay was similar between the subgroups, but the 'severity' of the transit abnormality was significantly worse in those with chronic idiopathic symptoms. In the chronic idiopathic STC subgroup only, there was a significant correlation between both age and duration of symptoms and severity of transit disturbance. CONCLUSION: This study demonstrates that differences in colonic transit exist between subgroups of patients with STC. These might be explained by differences in duration of symptoms or differences in aetiology.
Adult↗
Decreased tyrosine kinase C expression may reflect developmental abnormalities in Hirschsprung's disease and idiopathic slow-transit constipation.
BACKGROUND: Some patients with Hirschsprung's disease have refractory constipation following excision of aganglionic bowel, as do patients with idiopathic slow-transit constipation (STC). Gut motility depends on enteric neuronal development in response to expression of trophic factors and their receptors. Recent studies indicate the importance of neurotrophin 3 (NT-3) and its high-affinity receptor tyrosine kinase C (trk C) in enteric neuronal development. METHODS: Blinded quantitative immunohistochemical analysis of colon from patients with Hirschsprung's disease (aganglionic, hypoganglionic and normoganglionic) (n = 5), STC (n = 6) and appropriate age-matched control tissues (n = 5) was performed for NT-3 and trk C. Sural nerve morphometry and immunostaining were undertaken in three patients with STC who had abnormalities on limb autonomic and sensory testing. RESULTS: A significantly higher proportion of submucous plexus neurones was trk C immunoreactive in control infant than adult colon (mean(s.e.m.) 73(9) versus 16(3) per cent of the total; P < 0.001), in accord with a role in development. The proportion of submucous plexus trk C-immunoreactive neurones was reduced in colon from patients with Hirschsprung's disease (28(7) per cent of total in normoganglionic Hirschsprung's disease; P < 0.007 versus infant controls) and STC (10(1) per cent of total; P = 0.053 versus adult controls). No abnormalities of STC sural nerves were detected by morphometry or immunostaining. CONCLUSION: Decreased trk C expression may reflect developmental abnormalities in Hirschsprung's disease and idiopathic STC. Trk C activation by NT-3 or drugs may provide novel treatments. Presented in abstract form to the Pacific Association of Pediatric Surgeons, Las Vegas, Nevada, USA, May 2000
Adult↗
ATP-gated ion channel P2X(3) is increased in human inflammatory bowel disease.
P2X(3) is a novel ATP-gated cation channel that is selectively expressed by small-diameter sensory neurones in rodents, and may play a role in nociception by binding ATP released from damaged or inflamed tissues. We have studied, for the first time, P2X(3) immunoreactivity in human inflammatory bowel disease, using Western blotting and immunohistochemistry. A major 66-kDa specific protein was found by Western blotting in all colon extracts. In the inflamed group there was a significant two-fold increase in the relative optical density of the 66-kDa band (21.2 +/- 3.1; n=8) compared to controls (11.4 +/- 3.7; n=8; P=0.009). In the control colon, P2X(3)-immunoreactive neurones were scattered throughout the myenteric and submucosal plexuses, with some neurones showing immunopositive axons/dendrites. The pattern of immunostaining was similar to the neuronal marker peripherin. In general, the intensity of the staining was greater in myenteric than submucosal neurones. The number of P2X(3)-immunoreactive neurones was significantly increased in the myenteric plexus of inflamed colon compared to controls (n=13; P=0.01). In humans, unlike rodents, P2X(3) is thus not restricted to sensory neurones. Increased P2X(3) in inflamed intestine suggests a potential role in dysmotility and pain, for which it represents a new therapeutic target.
Adenosine Triphosphate↗
Neuropathic pain with vesical and rectal hyperreflexia and cocontraction after pelvic surgery.
Explore the source record for details and available documents.
Adult↗
Clonal analysis of NK cell development from bone marrow progenitors in vitro: orderly acquisition of receptor gene expression.
In the mouse, two families of MHC class I-specific receptors, namely Ly49 and CD94/NKG2, have been identified on NK cells. Individual NK cells can express several Ly49 molecules as well as members of the CD94/NKG2 family. The expression of multiple receptors with different specificities for MHC class I is thus thought to generate NK cells with diverse recognition patterns. To delineate the mechanism by which NK cells begin to express different patterns of Ly49 and CD94/NKG2 molecules, we developed a clonal assay in which NK1.1(-), IL-2/ IL-15 receptor beta+ NK precursors generated by culture of multipotential Lin(-), c-kit+ progenitors in IL-7, stem cell factor and flt3 ligand are induced to differentiate into NK1.1+ , Ly49+ NK cells. Examination of the clonal populations thus generated revealed heterogeneity in the pattern of Ly49 and CD94/NKG2 gene expression. In addition, a distinct kinetic pattern of expression was observed. CD94, NKG2A, NKG2C and Ly49B were expressed first followed by Ly49G, then Ly49C and I and finally, Ly49A, D, E and F. The data suggest a stochastic but ordered acquisition of class I receptors on NK cells in which developing NK cells become capable of expressing distinct receptors at different times but show no absolute prerequisite to express the receptors that are acquired early in NK development for the expression of those that are acquired later.
Animals↗
Standards for anal sphincter replacement.
PURPOSE: Anal sphincter replacement offers a new treatment option for patients with severe refractory fecal incontinence or for those who require abdominoperineal resection for localized malignancy. The purpose of this study was to review the current status of anal sphincter replacement, formulate a consensus statement regarding its current use, and outline suggestions for future development. METHODS: Four areas of interests were selected: indications for sphincter replacement, continence scoring and quality of life, choice of therapy, and dissemination of new technology. A questionnaire regarding these issues was developed and circulated to working party members; its results served as the basis for this consensus document. RESULTS: Both electrically stimulated skeletal muscle neosphincter and artificial anal sphincter are options for patients with end-stage fecal incontinence. Electrically stimulated skeletal muscle neosphincter is also appropriate for reconstruction after surgical excision of the anorectum in selected cases. Avoidance of complications requires strict attention to sterile technique, prophylactic antibiotics, and deep venous thrombus prophylaxis. A standardized scoring system is proposed that evaluates both continence and evacuation. Quality of life is a critical endpoint for assessing sphincter replacement, and use of The American Society of Colon and Rectal Surgeons incontinence-specific quality-of-life instrument is recommended. As the efficacy of sphincter replacement becomes proven, dissemination of the technique should occur in a controlled manner to ensure adequate surgeon training, minimization of complications, and optimization of results. CONCLUSIONS: Sphincter replacement by electrically stimulated skeletal muscle neosphincter and artificial anal sphincter provide a continent option for patients with end-stage fecal incontinence and those requiring abdominoperineal resection. The guidelines offered in this document are intended to facilitate the controlled and safe development and acceptance of these new techniques.
Anal Canal↗
Idiopathic slow-transit constipation is not associated with mutations of the RET proto-oncogene or GDNF.
PURPOSE: Idiopathic slow-transit constipation is a severe disorder of unknown cause. The onset in early childhood and history of constipation or Hirschsprung's disease in close family relatives suggest that slow-transit constipation could have a genetic basis. Several germline mutations have been described in Hirschsprung's disease, including mutations of RET and the gene encoding its ligand glial cell-derived neurotrophic factor. The aim of this study was to screen a panel of 16 cases of familial idiopathic slow-transit constipation, including 4 families in which there were relatives with Hirschsprung's disease, for RET and glial cell-derived neurotrophic factor mutations previously identified in Hirschsprung's disease. METHODS: Genomic DNA from 16 patients with slow-transit constipation and four relatives with Hirschsprung's disease was analyzed using single strand and heteroduplex conformation polymorphism analysis at two conditions and by direct DNA sequencing using the fluorescent dideoxy terminator method. RESULTS: Although common sequence polymorphisms were demonstrated with a frequency comparable with published data, no published or new mutation was seen in any of the exons of RET or glial cell-derived neurotrophic factor. CONCLUSIONS: Mutation of RET or glial cell-derived neurotrophic factor is not a frequent cause of idiopathic slow-transit constipation.
Adult↗
Vertical reduction rectoplasty: a new treatment for idiopathic megarectum.
BACKGROUND: The aetiology of idiopathic megarectum is unknown and the results of surgery are often unsatisfactory. Rectal hyposensation is common and poor perception of rectal filling may contribute to the poor evacuatory function. By reducing the capacity of the rectum, it was hypothesized that sensory thresholds to rectal distension and perception of urge to defaecate would be improved. METHODS: Vertical reduction rectoplasty (VRR) and concomitant sigmoid colectomy was performed on six patients with idiopathic megarectum. Patients were evaluated before and after operation by detailed questionnaire and anorectal physiology. Postoperative rectal compliance was also studied by means of a programmable electronic barostat. Where appropriate, physiological data were compared with those obtained in eight healthy volunteers. RESULTS: Bowel frequency increased from a preoperative median of 2.5 to 16 per month after operation. Four patients reported improved rectal perception of the urge to defaecate. Thresholds for defaecatory urge and maximum tolerated volume were significantly reduced following VRR (P<0.05). Post-VRR rectal compliance was no different from that in healthy volunteers. Colonic transit time decreased significantly after VRR (P<0.05) and evacuation on proctography increased from a median of 30 per cent to 50 per cent. At a median of 57 weeks' follow-up five of the six patients expressed continued satisfaction with the results. CONCLUSION: VRR is a new approach to the treatment of idiopathic megarectum. Clinical and physiological studies confirm that it can improve sensory feedback and defaecation. The procedure needs further evaluation as the number of patients undergoing the procedure increases.
Adolescent↗
Hybrid resistance by mouse NK cells in vitro.
Explore the source record for details and available documents.
Animals↗
Differentiation of NK1.1+, Ly49+ NK cells from flt3+ multipotent marrow progenitor cells.
To delineate factors involved in NK cell development, we established an in vitro system in which lineage marker (Lin)-, c-kit+, Sca2+ bone marrow cells differentiate into lytic NK1.1+ but Ly49- cells upon culture in IL-7, stem cell factor (SCF), and flt3 ligand (flt3L), followed by IL-15 alone. A comparison of the ability of IL-7, SCF, and flt3L to generate IL-15-responsive precursors suggested that NK progenitors express the receptor for flt3L. In support of this, when Lin-, c-kit+, flt3+ or Lin-, c-kit+, flt3- progenitors were utilized, 3-fold more NK cells arose from the flt3+ than from the flt3- progenitors. Furthermore, NK cells that arose from flt3- progenitors showed an immature NK1.1dim, CD2-, c-kit+ phenotype as compared with the more mature NK1.1bright, CD2+/-, c-kit- phenotype displayed by NK cells derived from flt3+ progenitors. Both progenitors, however, gave rise to NK cells that were Ly49 negative. To test the hypothesis that additional marrow-derived signals are necessary for Ly49 expression on developing NK cells, flt3+ progenitors were grown in IL-7, SCF, and flt3L followed by culture with IL-15 and a marrow-derived stromal cell line. Expression of Ly49 molecules, including those of which the MHC class I ligands were expressed on the stromal or progenitor cells, as well as others of which the known ligands were absent, was induced within 6-13 days. Thus, we have established an in vitro system in which Ly49 expression on developing NK cells can be analyzed and possibly experimentally manipulated.
Animals↗
Surgery of anorectal incontinence.
Explore the source record for details and available documents.
Adult↗
Adrenoceptors and colocolonic inhibitory reflex.
The colocolonic inhibitory reflex is characterized by inhibition of proximal colonic motility induced by distal colonic distension. The aim of this study was to investigate the underlying neural mechanisms of this reflex, in vivo, using an isolated loop of canine colon. In five beagle dogs, motility was recorded from an exteriorized colonic loop via a serosal strain gauge connected to a digital data logger and chart recorder. Inflation of a balloon in the distal colon resulted in inhibition of motility in the isolated loop. Inhibition of motor activity persisted following injection of propranolol (100 microg/kg intravenously), a beta-adrenoceptor antagonist, but was abolished following administration of the alpha2-adrenoceptor antagonist yohimbine (200 microg/kg intravenously). This study confirms that the colocolonic inhibitory reflex is mediated via the extrinsic nerves to the colon. As the reflex was abolished by alpha2-, but not beta-adrenoceptor blockade, this indicates that the reflex pathway involves alpha2-adrenoceptors.
Adrenergic alpha-Antagonists↗
Detection of cytokeratins 19/20 and guanylyl cyclase C in peripheral blood of colorectal cancer patients.
The clinical significance of detecting supposed tumour cell-derived mRNA transcripts in blood using the polymerase chain reaction (PCR) remains unclear. We have used a fully quantitative 5'-nuclease RT-PCR assay to screen for the expression of cytokeratins (ck) 19 and 20 and guanylyl cyclase C (GCC) in the peripheral blood of 21 healthy controls and 27 colorectal cancer patients. Expression of cytokeratin 19 and 20 mRNA was detected in 30% and 100% of samples, respectively, taken from healthy volunteers. There was no apparent difference in ck19 and ck20 mRNA transcription levels between controls and patients, or between patients with different Dukes' stages. While GCC mRNA was detected in only 1/21 control samples, it was expressed in approximately 80% of patients, although again there was no correlation between GCC levels and disease stage. Transcription levels of all three markers varied considerably between samples, even between samples taken from the same person at different times. We conclude that neither ck19 nor ck20 are reliable markers for the detection of colon epithelial cells in peripheral blood and that an evaluation of the usefulness of GCC awaits further longitudinal studies.
Adult↗