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PubMed2003

Altered conditioned fear behavior in glutamate decarboxylase 65 null mutant mice.

We investigated the involvement of the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and GAD65-mediated gamma-aminobutyric acid (GABA) synthesis in the formation and expression of Pavlovian fear memory. To this end, behavioral, endocrine and autonomic parameters were examined during conditioned fear retrieval of mice with targeted ablation of the GAD65 gene (GAD65-/- mice). These mutant mice were found to display specific fear behavior (freezing, escape), as well as autonomic (increased defecation) and endocrine activation (increased plasma corticosterone) during fear memory retrieval. However, freezing was reduced and flight and escape behavior were increased in GAD65-/- mice compared to their wild type and heterozygous littermates, while corticosterone levels and defecation rates did not differ between genotypes. Active defensive behavior of GAD65-/- mice was observed during both auditory cued and contextual retrieval of fear memory, as well as immediately after conditioning. These data indicate a selectively altered behavioral fear response in GAD65-/- mice, most likely due to deficits in threat estimation or the elicitation of appropriate conditioned fear behavior, and suggest that GAD65 is a genetic determinant of conditioned fear behavior. GAD65-/- mice provide a valuable tool to further dissect the GABAergic mechanisms involved in fear and anxiety and to model GABA-related neurological and psychiatric disorders.

Animals↗
PubMed1997

Converging evidence for one-trial context fear conditioning with an immediate shock: importance of shock potency.

In a sample of 208 Holtzman-descended albino rats, we found evidence with 4 measures of conditioning (freezing, defecation, side crossing, and nose crossing) that a single 2-s, 1.0-mA immediate shock could condition fear to a context (Experiments 1, 2, and 4). When we reduced the shock intensity to 0.5 mA, we obtained a complete immediate-shock conditioning deficit according to all measures in Experiment 3 and to all but the defecation measure in Experiment 4. Results suggest two conclusions: (a) Differences in shock potency between laboratories may help explain discrepant findings about whether immediate shock supports contextual conditioning; (b) theories of contextual conditioning need a mechanism that permits that conditioning to result from immediate shock.

Animals↗
PubMed1992

The benzodiazepine inverse agonist DMCM as an unconditional stimulus for fear-induced analgesia: implications for the role of GABAA receptors in fear-related behavior.

When the benzodiazepine inverse agonist DMCM (6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylic acid methyl ester) occupies the benzodiazepine recognition site on the GABAA receptor complex, the inhibitory action of gamma-aminobutyric acid (GABA) is attenuated. DMCM acted as an unconditional stimulus for one response associated with fear or anxiety, analgesia, as indicated by a dose-dependent (0.25-1.0 mg/kg) suppression of rats' responses to a formalin injection. This was accompanied by other fearlike responses (defecation and urination). The opioid antagonist naltrexone (1.75-14 mg/kg) did not affect these behaviors. Environmental cues associated with DMCM provoked analgesia and defecation in the absence of the drug. The conditional analgesia was reversed by naltrexone (7 mg/kg). DMCM functions as an unconditional fear stimulus by eliciting fear-related behaviors and conditioning those responses to neutral stimuli. The neural circuitry underlying fear conditioning appears to involve tonically inhibitory GABAergic synapses.

Animals↗
PubMed2001

Bowel dysfunction following spinal cord injury.

STUDY DESIGN: Review. OBJECTIVES: To outline the present knowledge of bowel dysfunction following spinal injury, and look at future directions of management and research. SETTING: Spinal Unit and Colorectal Unit, Christchurch, New Zealand. METHODOLOGY: Review. RESULTS: The underlying physiology of colorectal motility and defecation is reviewed, and consequences of spinal cord injury on defecation are reported. A discussion of present management techniques is undertaken and new directions in management and research are suggested. CONCLUSION: There is need for more intervention in regard to bowel function that could improve quality of life, but there is also a need for more research in this area.

Anal Canal↗
PubMed2005

Bowel management in patients with spinal cord injury -- a multicentre study of the German speaking society of paraplegia (DMGP).

STUDY DESIGN: A descriptive, cross-sectional, multicentre design was used. OBJECTIVE: To analyse bowel management in patients with spinal cord injury (SCI) especially the occurrence of unplanned bowel evacuations and duration of planned bowel evacuation. SETTING: In total, 29 rehabilitation facilities for SCI patients in Austria, Germany, the Netherlands and Switzerland, with a total of 837 hospitalized SCI patients. METHOD: Data were collected by nurses within 1 week in November 2001 using a quantitative questionnaire containing 14 questions. For data analysis, a chi (2)-test was used for differences in the outcome of bowel evacuation procedures associated with different interventions. Stepwise multiple logistic regression was used to analyse the relationship between the outcome of bowel management and the interventions as well as intervening factors. RESULTS: More unplanned bowel evacuations were associated with usage of oral laxatives (n=444, P<0.001) as well as bowel evacuation every day (n=270, P<0.05) or every second day (n=368, P<0.05). The outcome of less unplanned bowel evacuations was associated with manual removal of stool combined with digital stimulation (n=35, P<0.05) and spontaneous bowel evacuations (n=104, P<0.001). Short duration of bowel evacuation (<60 min) was associated with manual removal of stool (n=64, P<0.05), the sitting position at defecation (n=494, P<0.001) and low frequency of bowel evacuation (>or=3 days) (n=638, P<0.05). Duration >60 min was associated with the use of oral laxatives (n=444, P<0.001) and complete loss of sensory function (n=349, P<0.05). Stool of hard consistency was associated with the manual removal of stool (n=64, P<0.001), the manual removal of stool in combination with digital stimulation (n=53, P<0.001) and the sitting position at defecation (n=494, P<0.05). Stool of soft consistency (n=341) was associated with the complete motor lesion (n=443, P<0.05). CONCLUSION: Manual removal of stool was combined with low risk of unplanned bowel evacuations and short duration of evacuation time. These results are useful to improve the outcomes of bowel management in SCI patients.

Administration, Oral↗
PubMed2001

Bloodmeal digestion and Leishmania major infections in Phlebotomus duboscqi: effect of carbohydrates inhibiting midgut lectin activity.

The carbohydrates galactosamine and heparin, previously shown to inhibit phlebotomine lectin activity in vitro, were fed to the sandfly Phlebotomus duboscqi Neveu-Lemaire (Diptera: Psychodidae) with blood, and the effects on mortality, fecundity, protease activity and susceptibility to Leishmania major Yakimoff & Schokhor (Kinetoplastida: Trypanosomatidae) were studied. Previous study revealed that galactosamine considerably enhanced the establishment of L. major infection in P. duboscqi and significantly increased parasite loads in late infections. This work demonstrates a similar but less pronounced effect of heparin. Heparin increased infection rates and parasite loads 3 and 9 days post-feeding but did not affect the location of Leishmania promastigotes and their anterior migration. Galactosamine supplement caused pronounced changes in bloodmeal digestion. It abolished the activity of alkaline proteases and trypsin, caused premature defecation of bloodmeal, increased mortality of female sandflies in days 1-4 post-feeding and decreased their fecundity. Heparin had a less pronounced effect on sandfly physiology. It lowered trypsin activity 12 and 72 h post-bloodmeal but did not alter defecation, mortality and oviposition. The data suggest that the enhancing effect of these carbohydrates on Leishmania infections in sandfly midgut could be explained by their interference with midgut proteases. The study supports the hypothesis that proteolytic activities of midgut proteases strongly influence the vector competence of sandflies.

Animals↗
PubMed2004

Pathophysiology of pediatric fecal incontinence.

This article addresses the diagnosis and treatment of pediatric fecal incontinence in 4 main categories: (1) Functional fecal retention, the withholding of feces because of fear of painful defecation, results in constipation and overflow soiling. Treatment includes dietary changes, use of laxatives, and cognitive and behavioral interventions such as toilet training, which diminishes phobia and provides positive reinforcement through a rewards system. (2) For functional nonretentive fecal soiling (encopresis), antidiarrheal agents can increase the consistency of stools and facilitate continence. Anorectal biofeedback for children has been proposed, but its efficacy remains unproven. Parents should be educated to conduct nonaccusatory toilet training and help children alleviate guilt and enhance self-esteem. Appropriately constructed trials are necessary to gauge the effect of adding prolonged use of enemas to an intensive toilet training program. (3) Surgery can correct minor congenital anorectal anomalies by identifying the external sphincter, separating the rectum from the genitourinary tract, and reconstructing the anus. However, there is great variation in postsurgical functional outcomes for anorectal malformations. Double-blinded, randomized controlled trials could help define the role of appendicostomy, cecostomy, sphincter reconstruction, colostomy, and artificial sphincters. (4) Children with spina bifida and fecal incontinence may benefit from techniques that teach them how to defecate. A continent appendicostomy (Malone procedure) is a promising treatment that completely cleanses the colon, increases the child's autonomy, and decreases the chance of soiling. A cecostomy can be performed surgically, endoscopically, or radiologically to provide some of the same benefits.

Child↗
PubMed2006

Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia.

BACKGROUND & AIMS: Uncontrolled trials suggest biofeedback is an effective treatment for pelvic floor dyssynergia (PFD), a type of constipation defined by paradoxical contraction, or inability to relax, pelvic floor muscles during defecation. The aim was to compare biofeedback to laxatives plus education. METHODS: Patients with chronic, severe PFD were first treated with 20 g/day fiber plus enemas or suppositories up to twice weekly. Nonresponders were randomized to either 5 weekly biofeedback sessions (n = 54) or polyethylene glycol 14.6-29.2 g/day plus 5 weekly counseling sessions in preventing constipation (n = 55). Satisfaction with treatment, symptoms of constipation, and pelvic floor physiology were assessed 6 and 12 months later. The biofeedback group was also assessed at 24 months. Laxative-treated patients were instructed to increase the dose of polyethylene glycol from 14.6 to 29.2 g/day after 6 months. RESULTS: At 6 months, major improvement was reported by 43 of 54 (80%) biofeedback patients vs 12 of 55 (22%) laxative-treated patients (P < .001). Biofeedback's benefits were sustained at 12 and 24 months. Biofeedback also produced greater reductions in straining, sensations of incomplete evacuation and anorectal blockage, use of enemas and suppositories, and abdominal pain (all P < .01). Stool frequency increased in both groups. All biofeedback-treated patients reporting major improvement were able to relax the pelvic floor and defecate a 50-mL balloon at 6 and 12 months. CONCLUSIONS: Five biofeedback sessions are more effective than continuous polyethylene glycol for treating PFD, and benefits last at least 2 years. Biofeedback should become the treatment of choice for this common and easily diagnosed type of constipation.

Adult↗
PubMed2000

Dilation of benign strictures following low anterior resection using Savary-Gilliard bougies.

BACKGROUND AND STUDY AIMS: Benign anastomotic strictures occur in up to 22% of patients after colorectal resections. Initially, treatment for these strictures was surgical, but nowadays endoscopic dilation techniques are preferred. This study was conducted to assess the efficacy of dilation using SavaryGilliard bougies. PATIENTS AND METHODS: From 1987 to 1994, 256 consecutive patients underwent low anterior resection (LAR). Twenty-one patients (8.2%) developed a stricture of the colorectal anastomosis. Follow-up data were available for 18 of these patients. The patients were treated using endoscopic Savary dilation, with bougies of increasing diameters (10-19 mm). The mean follow-up period was 19 months (1-60 months). RESULTS: Stricture symptoms presented after a mean period of 7.7 months after LAR. In three of the 18 patients, the stenosis was caused by local recurrence, and these patients were excluded from further evaluation. Normal defecation was restored in 10 of the remaining 15 patients, and symptoms disappeared. In five patients, there was only partial improvement, but only three of them required another type of treatment. Of four patients who received radiotherapy and developed a strictured anastomosis, two had successful dilations. A normal defecation pattern was never regained if more than three dilations were necessary. No complications caused by Savary dilation were observed. CONCLUSIONS: In this study population, Savary dilation appeared to be a safe and effective treatment for benign anastomotic strictures after LAR. All successfully treated patients (ten of 15) required no more than three dilations. Two other patients had partial success. Only three patients required another form of treatment (two endoscopic, one surgical).

Adult↗
PubMed2002

Benign transient non-organic ileus of neonates.

There are a substantial number of neonates who present with Hirschsprung's disease-like symptoms, but respond very well to conservative therapy. However, once Hirschsprung's disease is ruled out, little attention is paid to these infants, because of the lack of necessity for surgical treatment and their excellent prognosis. The purpose of this study was to elucidate the clinical features of functional ileus of neonates, which we named benign transient non-organic ileus of neonates (BTNIN). Out of 61 neonates referred to our institution with suspected neonatal Hirschsprung's disease (NH), 10 were diagnosed as having NH and 51 as having BTNIN. All the cases of BTNIN showed marked abdominal distension, and 12 showed explosive defecation on digital examination at the first visit. Plain X-ray demonstrated marked whole intestinal dilatation in 12 cases including cases with niveau formation and segmental dilatation. These findings were indistinguishable from those of NH. However, all had a normal anorectal reflex, and rectal suction biopsy revealed normal acetylcholinesterase activity and submucosal ganglion cells. All the cases of BTNIN were treated with periodic glycerin enemas until daily spontaneous defecation was established, which took 2 to 14 months, with an average of 5.0 +/- 2.9 months. None of them showed residual symptoms during the follow-up period.

Age of Onset↗
PubMed2003

Transanal endorectal pull-through for Hirschsprung's disease: a comparison with the open technique.

AIM: To evaluate the indications, results, and complications of Transanal Endorectal Pull-Through (TEPT) in the management of rectosigmoid Hirschsprung's disease (HD) compared with the open technique. PATIENTS AND METHODS: Between November 1998 and March 2002, 68 Transanal Endorectal Pull-Through (TEPT) procedures were performed in infants and children. The patients' ages ranged from 6 days to 13 years. The primary diagnosis in all 68 patients was Hirschsprung's disease confined to the rectosigmoid region. All children were operated without construction of a pre-operative colostomy except for one patient. Follow-up period ranged from 6 - 46 months (mean 32 months). These patients were compared with fifty patients who had undergone open pull-through for HD during the period from November 1995 to October 1998. RESULTS AND COMPLICATIONS: For the TEPT group, the mean operating time was 90 min and the average length of resected bowel was 25 cm. Sixty-two patients had satisfactory results without complications. Blood transfusion was needed in eleven patients only. Recovery was very fast and patients were often hungry within 24 hours. Feeding was resumed within 48 hours. One patient required laparotomy during the procedure due to injury to the urethra. Two patients required colostomy 3 and 5 days after surgery because of delayed leakage. Three patients suffered from attacks of enterocolitis 6 - 9 months postoperatively. There was increased frequency of defecation (5 - 15 times daily) for 4 - 6 weeks after surgery in all patients. There was no constipation, no incontinence, no cuff abscess and no mortality in any of the patients. Average frequency of defecation was 1 - 3 times daily after 3 months postoperatively. For the open technique group, mean operating time was 150 min, the length of the average resected segment was 29 cm. Forty-one patients had satisfactory results without complications. The cost of the open technique was almost double that of the TEPT (6300 vs. 3200 pounds). CONCLUSIONS: Transanal Endorectal Pull-Through (TEPT) is characterized by a shorter operating time, less bleeding, shorter hospital stay, less morbidity and earlier recovery than similar open pull-through procedures. The hazards and morbidities associated with laparotomy and colostomy may be avoided with a one-stage technique in Hirschsprung's disease confined to the rectosigmoid area (70-80 %). Careful long-term follow-up is required to assess continence and sexual function.

Child↗
PubMed1997

Dynamic rectal examination: its significant clinical value.

The aim of the present study was to carry out a proper correlation between patients' clinical symptoms and the radiological findings obtained by dynamic rectal examination (DRE). At DRE, the small bowel and in females the vagina are routinely opacified in addition to defecography. A prospective study of 248 consecutive patients (193 women and 55 men, ratio 3.5:1) and 14 control subjects was conducted. The parameters assessed included the anorectal angle, the position of the anorectal junction, and the total movement of the pelvic floor during squeezing and defecation. Anatomical changes as rectoceles, enteroceles and intussusceptions were also observed. Based on the findings, the following conclusions can be drawn. There is no indication for measurement of the central or posterior anorectal angle. There is no indication for measurement of the perineal ascent, perineal descent, and anorectal junction level. Anterior rectoceles occur very frequently in females, and are only of clinical relevance if the patients need digital vaginal support to facilitate defecation. DRE is a sensitive method for diagnosing enteroceles and intussusceptions.

Anal Canal↗
PubMed1991

Fecal bile acid concentration in distance runners.

Fecal bile acid concentration, fecal characteristics, bowel habits and habitual food intake were measured in male distance runners (n = 14) and sedentary men (n = 14). Fecal bile acid concentration was significantly (p less than 0.05) lower and stool weight, frequency of defecation and daily intake of fibre, carbohydrate, and protein were significantly (p less than 0.01) higher in the runners. After adjustment for differences in dietary fibre intake, fecal bile acid concentration was no longer significantly different between the distance runners and the sedentary men, but frequency of defecation remained significantly (p less than 0.05) higher in the runners. This study has identified lower fecal bile acid concentration in distance runners, which was probably due mainly to dilution of colon contents by higher consumption of dietary fibre. These findings may be relevant to the reduced incidence of colon cancer in physically active subjects.

Adult↗
PubMed1995

Anal dynamic graciloplasty in the treatment of intractable fecal incontinence.

BACKGROUND: In patients with intractable fecal incontinence, conventional treatment is not always successful. Dynamic graciloplasty (transposition of the gracilis muscle to the anus with the implantation of stimulating electrodes) was developed to provide such patients with functional neosphincters. We evaluated the clinical results of this new surgical approach and the effects on quality of life. METHODS: We treated 52 patients with dynamic graciloplasty. The clinical results of treatment were evaluated in an interview, by anal manometry, and by enema testing. The degree of continence was scored. To assess quality of life, four questionnaires were administered (parts 1 and 2 of the Nottingham Health Profile, the State-Trait Anxiety Inventory, and the Self-rating Depression scale). RESULTS: Among the 52 patients, 38 (73 percent) were continent after a median follow-up of 2.1 years. At 52 weeks the patients' condition had improved with respect to the median frequency of defecation (from five to two times per 24 hours, P < 0.001), the median time defecation could be postponed (from 9 seconds to 19 minutes, P = 0.012), and the median time an enema could be retained (from 0 to 180 seconds, P = 0.005). Patients in whom the technique was successful became less anxious than those in whom it failed (P = 0.002) and improved with regard to effectiveness in their occupations, ability to perform tasks around the home, personal relationships, sexual function, and social life (P = 0.01). They also became less isolated socially (P = 0.05). CONCLUSIONS: Dynamic graciloplasty is a safe and reliable technique in patients with severe incontinence and may result in a better quality of life.

Adolescent↗
PubMed1998

Intolerance of cow's milk and chronic constipation in children.

BACKGROUND: Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cow's milk among children. On the basis of a prior open study, we hypothesized that intolerance of cow's milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. METHODS: We performed a double-blind, crossover study comparing cow's milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema. After 15 days of observation, the patients received cow's milk or soy milk for two weeks. After a one-week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. RESULTS: Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved. None of the children who received cow's milk had a response. In all 44 children with a response, the response was confirmed with a double-blind challenge with cow's milk. Children with a response had a higher frequency of coexistent rhinitis, dermatitis, or bronchospasm than those with no response (11 of 44 children vs. 1 of 21, P=0.05); they were also more likely to have anal fissures and erythema or edema at base line (40 of 44 vs. 9 of 21, P<0.001), evidence of inflammation of the rectal mucosa on biopsy (26 of 44 vs. 5 of 21, P=0.008), and signs of hypersensitivity, such as specific IgE antibodies to cow's-milk antigens (31 of 44 vs. 4 of 21, P<0.001). CONCLUSIONS: In young children, chronic constipation can be a manifestation of intolerance of cow's milk.

Animals↗
PubMed1999

HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor.

Two cannabinoid receptors have been identified: CB(1), present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB(2), present outside the CNS, in peripheral organs. There is evidence for the presence of CB(2)-like receptors in peripheral nerve terminals. We report now that we have synthesized a CB(2)-specific agonist, code-named HU-308. This cannabinoid does not bind to CB(1) (K(i) > 10 microM), but does so efficiently to CB(2) (K(i) = 22.7 +/- 3.9 nM); it inhibits forskolin-stimulated cyclic AMP production in CB(2)-transfected cells, but does so much less in CB(1)-transfected cells. HU-308 shows no activity in mice in a tetrad of behavioral tests, which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity in the CNS mediated by CB(1). However, HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. The hypotension, the inhibition of defecation, the anti-inflammatory and peripheral analgesic effects produced by HU-308 are blocked (or partially blocked) by the CB(2) antagonist SR-144528, but not by the CB(1) antagonist SR-141716A. These results demonstrate the feasibility of discovering novel nonpsychotropic cannabinoids that may lead to new therapies for hypertension, inflammation, and pain.

Analgesics↗
PubMed1999

Bowel problems in patients with systemic sclerosis.

BACKGROUND: The impact of systemic sclerosis on bowel function is still unknown. The aim of this study was therefore to assess the frequency and severity of colorectal problems among patients with systemic sclerosis and to determine whether these problems are associated with age, gender, type of systemic sclerosis, or time since diagnosis. METHODS: A detailed questionnaire describing diarrhoea, constipation, obstructed defecation, faecal incontinence, bowel habits, social activities, and quality of life was sent to 96 consecutive patients with systemic sclerosis. RESULTS: Among 83 respondents (86%) 16% did not have a normal desire to defecate, 18% regularly needed digital stimulation or evacuation of the rectum, and 38% had faecal incontinence. Most patients (79%) had episodes of diarrhoea, and 38% had this once or more each month. Overall, 20% reported that colorectal dysfunction caused some or a major restriction of social activities or the quality of life. CONCLUSIONS: Colorectal dysfunction is very common among patients with systemic sclerosis, often restricting social activities and the quality of life. Therefore, further studies of colorectal pathophysiology in patients with systemic sclerosis are needed.

Anal Canal↗
PubMed2006

Reliability of assessment of urgency and other symptoms indicating anal sphincter, large bowel or urinary dysfunction.

OBJECTIVE: The Radiumhemmets Scale of Disease-Specific Symptom Assessment-Prostate Cancer has been used in several studies. However, no test-retest reliability study of it has been conducted concerning the assessment of urinary, anal sphincter or large bowel function. The aim of this study was to evaluate the reliability of items assessing these functions. MATERIAL AND METHODS: We investigated 89 prostate cancer patients randomly selected from a group of patients diagnosed in Stockholm. The patients answered 24 questions assessing anal sphincter, large bowel and urinary function twice, with a 3-week interval in-between, to assess reliability. RESULTS: Most of the questions assessing bowel and urinary symptoms showed substantial or near-perfect agreement. The kappa value for bowel symptom items was > or = 0.60 for all items, except for defecation urgency (0.40-0.55). The kappa value for urinary symptom items varied between 0.43 and 1.0, except for urinary urgency (0.30-0.39). CONCLUSIONS: When comparing the impact of different symptoms of anal sphincter, large bowel or urinary tract dysfunction, it may be important to consider that defecation urgency and urinary urgency have the highest measuring error (low reliability). This error dilutes assessed associations with, for example, decreased quality of life. Nevertheless, the test-retest reliability for anal sphincter, large bowel and urinary symptoms indicates that surveys yield meaningful information.

Aged↗