'Rapid transit' constipation in children: a possible genesis for irritable bowel syndrome.

Children with chronic idiopathic constipation (CIC) often end up at the surgeon when medical treatments have failed. This opinion piece discusses a recently described pattern of CIC called 'Rapid transit constipation (RTC)' first identified in 2011 as part of surgical workup. RTC was identified using a nuclear medicine gastrointestinal transit study (NMGIT or nuclear transit study) to determine the site of slowing within the bowel and to inform surgical treatment. Unexpectedly, we found that RTC occured in 29% of 1000 transit studies in a retrospective audit. Irritable bowel syndrome (IBS) occurs in 7-21% of the population, with a higher prevalence in young children and with constipation type dominating in the young. While 60% improve with time, 40% continue with symptoms. First-line therapy for IBS in adults is a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols which reduces symptoms in > 70% of patients. In children with functional gastrointestinal disorders, fructose intolerance occurs in 35-55%. Reducing fructose produced significant improvement in 77-82% of intolerant patients. In children with RTC and a positive breath test upon fructose challenge, we found that exclusion of fructose significantly improved constipation, abdominal pain, stool consistency and decreased laxative use. We hypothesise that positive breath tests and improvement of pain and bowel frequency with sugar exclusion diets in RTC suggest these children have IBS-C. These observations raise the possibility that many children with CIC could be treated by reducing fructose early in their diet and this might prevent the development of IBS in later life.

The effect of food withdrawal in children with rapid-transit constipation.

BACKGROUND: Rapid proximal colonic transit with anorectal holdup is a subtype of chronic constipation linked to food intolerance. We aimed to determine the effectiveness of dietary exclusion as a treatment for constipated children with rapid-transit constipation by scintigraphy. METHODS: Questionnaires on diet and symptoms were mailed out to 125 children with chronic constipation and rapid proximal colonic transit on nuclear transit study at our institute between 1998 and 2014 years. Patients were given instructions and encouraged to undertake a six-food elimination diet targeting common protein allergens (dairy, wheat, soy, eggs, nuts, seafood). Answers were completed by circling an option or on visual analogue scale. Results were evaluated statistically using GraphPad Prism 6 by a Wilcoxon matched-pairs rank test. P < 0.05 was considered significant. RESULTS: We received 44/125 responses, 26 patients [mean age 11 years (5-21)] had attempted elimination diet and 18 had not. Dairy and wheat were the most common foods eliminated and symptomatic improvement was greater for patients who had completely eliminated foods. Constipation, abdominal pain and pain on defecation were reduced (p < 0.01). Laxative usage decreased, although this was not statistically significant. Families encountered problems with dietary exclusion, particularly expense. Assistance from a dietician or nutritionist was sought by >50 % of families. CONCLUSION: Dietary exclusion is a promising strategy to treat constipation in children with rapid proximal colonic transit. However, it was hard for many families, demonstrating the need for identifying the cause more specifically and a better set of instructions for the family and/or dietitian to follow.

Substance P and vasoactive intestinal peptide are reduced in right transverse colon in pediatric slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is recognized in children but the etiology is unknown. Abnormalities in substance P (SP), vasoactive intestinal peptide (VIP) and nitric oxide (NO) have been implicated. The density of nerve fibers in circular muscle containing these transmitters was examined in colon from children with STC and compared to other pediatric and adult samples. METHODS: Fluorescence immunohistochemistry using antibodies to NO synthase (NOS), VIP and SP was performed on colonic biopsies (transverse and sigmoid colon) from 33 adults with colorectal cancer, 11 children with normal colonic transit and anorectal retention (NAR) and 51 with chronic constipation and slow motility in the proximal colon (STC). The percentage area of nerve fibers in circular muscle containing each transmitter was quantified in confocal images. KEY RESULTS: In colon circular muscle, the percentage area of nerve fibers containing NOS > VIP > SP (6 : 2 : 1). Pediatric groups had a higher density of nerve fibers than adults. In pediatric samples, there were no regional differences in NOS and VIP, while SP nerve fiber density was higher in sigmoid than proximal colon. STC children had lower SP and VIP nerve fiber density in the proximal colon than NAR children. Twenty-three percent of STC children had low SP nerve fiber density. CONCLUSIONS & INFERENCES: There are age-related reductions in nerve fiber density in human colon circular muscle. NOS and VIP do not show regional variations, while SP nerve fiber density is higher in distal colon. 1/3 of pediatric STC patients have low SP or VIP nerve fiber density in proximal colon.

Decrease in nerve fibre density in human sigmoid colon circular muscle occurs with growth but not aging.

BACKGROUND: Studies in animals suggest that enteric neurons decrease in density or number with increasing age. Neurons containing nitric oxide (NO), vasoactive intestinal peptide (VIP) and Substance P (SP) have been implicated. In human large intestine, NO-utilizing neurons decrease during childhood or early adulthood but it is not known if the innervation of the muscle changes. This study examined the density of nerve fibres containing these transmitters in sigmoid colon circular muscle from children and adults. METHODS: Fluorescence immunohistochemistry using antibodies to neuronal NO synthase (nNOS), VIP and SP was performed on sigmoid colon from 18 adults with colorectal cancer, two children with familial adenomatous polyposis, and normal colon from nine children with Hirschsprung's disease. The percentage area of immunoreactive (IR) nerve fibres containing each transmitter in circular muscle was quantified in confocal images. KEY RESULTS: In the adult sigmoid colon circular muscle, the percentage area of nerve fibres containing nNOS>VIP>SP (6 : 2 : 1). Paediatric groups had significantly higher percentage area of nerve fibres containing nNOS, VIP or SP-IR than adults, with the decrease in nerve fibre density occurring from birth to 30 years. Circular muscle thickness increased between 12 and 30 years. Total nerve fibre area remained constant, while the muscle increased in thickness. CONCLUSIONS & INFERENCES: In human sigmoid colon circular muscle, there are reductions in nNOS-, VIP- and SP-IR nerve fibre density with growth from newborn to late adolescence but little further change with aging. The reduction in nerve density is due to an increase in circular muscle thickness rather than a loss of nerve fibres.

Clitoroplasty: past, present and future.

This paper reviews the history of clitoral surgery throughout the twentieth century. The changing operations, from amputation through to attempts to produce a normal clitoris mirror the changing attitudes and available knowledge. It also examines the current issues that arise out of available data on long-term outcomes of clitoroplasty.

Lethal comorbidity with genital anomaly in the infant.

OBJECTIVE: Genital anomaly (GA) carries a risk of life-threatening comorbidity which is not well defined and is under reported. We aimed to determine the associated anomalies in children with GA who died. MATERIALS AND METHODS: We retrospectively reviewed the deaths among all GA patients presenting to our institution over 32 years (1970-2001). Seventy children with exstrophy/epispadias were excluded, leaving 200 patients, of whom 26 had died. Hospital and postmortem records were examined for biographical data, karyotype, morphological anomalies and causes of death. RESULTS: Sixty-eight out of 200 patients had congenital adrenal hyperplasia (CAH), with two deaths, from cardiomyopathy and encephalitis. Of the 132 non-CAH patients, 24 (17%) died. Sixteen deaths were in the non-CAH intersex group of patients with GA. There were eight deaths in the non-intersex genital anomaly group, which included five with a cloacal anomaly (+/- VATER association). Fifteen had major cardiac anomalies and 10 had facial dysmorphism suggesting a syndrome. Two infants died of renal failure with Denys-Drash syndrome. CONCLUSIONS: Infants with a non-CAH intersex GA have a high risk of mortality, particularly from an associated cardiac anomaly. This mortality may decrease in the future with cardiac surgical advances. There is a significant mortality in infants with non-intersex GA (anorectal malformations and cloacal anomalies) also due to complex cardiac and/or renal anomalies. Major chromosomal aberrations and facial dysmorphism were noted in some patients in both study groups. GA associated with testicular dysgenesis and/or imperforate anus requires screening for cardiac defects, chromosomal anomalies and dysmorphology syndromes.

Urethral polyps in prepubertal girls.

PURPOSE: Urethral polyps in girls are included in the differential diagnosis of interlabial masses. Only 6 cases have been described in the English literature to date and etiology is uncertain. We present 5 more cases and review the literature. We also propose an etiology for urethral polyps in young girls and compare polyps between girls and boys as well as older females. MATERIALS AND METHODS: The medical records of prepubertal girls with urethral polyps seen at our hospital between 1980 and 2003, including operative reports and followup, were reviewed. A senior pathologist re-inspected the specimens to confirm the diagnosis. A MEDLINE search of urethral polyps was performed. RESULTS: We identified 5 girls 2 to 10 years old with urethral polyps. All girls presented with "vaginal" bleeding, 1 had recurrent urinary tract infections and vulvitis, 1 had urinary frequency, and 1 had painful voiding. The polyps were not site specific and were located in the distal, mid and proximal urethra. All polyps were excised and were found benign. Four girls were cured after 1 procedure, while in one girl the polyp reappeared. The patients were followed for 1 to 17 years and eventually became asymptomatic. CONCLUSIONS: Urethral polyps in prepubertal girls are probably benign. We suggest that the etiology of most of polyps in girls is similar to those in older females, that is a prolapsing urothelium that has evolved into a polyp.

Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation.

Germ cell development is an active process in normal testes during the first 4 years after birth, with transformation of the neonatal gonocytes into adult dark spermatogonia and then primary spermatocytes. The hormonal regulation of these changes is not fully understood, with evidence both for and against a role for gonadotrophins and androgens. Early surgical intervention in infancy aims to prevent or reverse germ cell maldevelopment. Although hormonal treatment for maldescent has been shown to be ineffective, there is still controversy over whether it may be useful as an adjunct to surgery to stimulate germ cells. Current evidence suggests that hormonal therapy may not stimulate transformation of neonatal gonocytes but may trigger prepubertal mitosis of primary spermatocytes. Further studies are required to determine the role of hormone treatment on germ cell development.

Urinary diversion in children with pelvic tumors.

PURPOSE: The aim of this study was to investigate children presenting with malignant pelvic tumors obstructing the upper urinary tract. METHODS: Seventeen children with upper urinary tract obstruction by a malignant tumor were reviewed. A nephrostomy tube or Double J (DJ) stent was inserted into each obstructed urinary system and removed after tumor shrinkage and/or hydronephrosis regression. RESULTS: There were 9 boys and 8 girls in the study; the mean age and median follow-up were 5.7 years and 2.5 years, respectively. The most common obstructing tumor was rhabdomyosarcoma. Twelve children underwent diversion by nephrostomy tubes and 3 by DJ stents; 2 patients underwent resection of the tumors with ureteroureterostomy. Complications after the insertion of the stents included febrile urinary tract infections (UTI) or pyelonephritis in 4 of the children with DJ stents. In the nephrostomy group, febrile UTI developed in 3 and the tube fell out in 1, and was blocked in another. Of the 17 children, 9 have no evidence of disease, 2 are currently under treatment, and 6 died of cancer. CONCLUSIONS: The prognosis of children with malignant pelvic tumor obstructing the upper urinary system justifies urgent and optimal upper tract diversion, enabling chemotherapy to be started immediately.

Ranitidine-enhanced 99mtechnetium pertechnetate imaging in children improves the sensitivity of identifying heterotopic gastric mucosa in Meckel's diverticulum.

Meckel's diverticulum is the most common congenital gastrointestinal anomaly. (99m )Technetium pertechnetate imaging (Meckel's scan) is the best noninvasive method used to diagnose this condition when heterotopic gastric mucosa (HGM) is present. Although cimetidine enhancement has been shown to improve sensitivity of the Meckel's scan, ranitidine enhancement has also been advocated; however, this recommendation is based on unpublished data. Thirty-seven children with confirmed Meckel's diverticulum were reviewed retrospectively. Of eight children with HGM in the Meckel's diverticulum who presented with profuse rectal bleeding and underwent the conventional Meckel's scan, three of them (37.5%) had a false negative study. Ranitidine, when administered either intravenously or orally for 24 h prior to the Meckel's scan, enhanced the sensitivity of this test to 87.5% in our patient cohort.

Cholinergic transmission to colonic circular muscle of children with slow-transit constipation is unimpaired, but transmission via NK2 receptors is lacking.

Tachykinins (TKs) colocalize with acetylcholine in excitatory motor neurones supplying human colonic circular muscle (CCM). Some children with slow-transit constipation (STC) have reduced TK-immunoreactivity in nerve terminals in CCM suggesting a deficit in neuromuscular transmission. This study aimed to test this possibility. Seromuscular biopsies of transverse colon were obtained laparoscopically from STC children (37, 17 with low density of TK-immunoreactivity). Specimens of transverse (17) and sigmoid colon (20) were obtained from adults undergoing colonic resection for cancer. CCM contractions were measured isotonically and responses to carbachol, neurokinin A (NKA) and electrical field stimulation (EFS) recorded. Carbachol and NKA-evoked contractions in adult and STC colon. Hyoscine (2 micromol L-1) significantly depressed responses to EFS in all preparations. Blockade of NK2 receptors (SR 48968, 2 micromol L-1) significantly depressed EFS-evoked contractions of adult transverse CCM, but had no effect on STC preparations. Thus, neuromuscular transmission in both adults and STC children is predominantly cholinergic and this component is unimpaired in the latter, indicating that reduced TK-immunoreactivity is not a marker for depressed cholinergic responses. Although pharmacologically responsive TK receptors are present in STC colon, we did not detect neuromuscular transmission mediated by release of TKs in these preparations.

The absence of lateral fusion in cloacal partition.

BACKGROUND/PURPOSE: The mechanism by which the cloaca becomes partitioned into a dorsal rectal part and a ventral genitourinary sinus has been the subject of speculation for more than a century. Despite repeated suggestions that partitioning of the cloaca by fusion of lateral folds does not occur, the concept continues to hold sway in many student and surgical texts. The authors reviewed the histologic and 3-dimensional appearance of the urorectal septum in human and rat embryos to see if there was any evidence of lateral fusion in its formation. METHODS: Sprague-Dawley rat embryos (n = 143) were examined between 11 and 21 days' gestation and compared with human embryo sections (57 embryos) held in historical collections in Europe. Rat embryos were examined by microscopy, dissection, and serial histologic section. In addition, some specimens were sectioned in wax until the lumen of the cloaca was reached, after which they were dewaxed and the internal cavities imaged with scanning electronmicroscopy (n = 18 of 143). RESULTS: Cloacal "partitioning" resulted from a combination of growth of the mesenchyme of the hindgut and genitourinary sinus, an alteration in the position of the cloaca in relation to surrounding structures secondary to growth in the ventral, infraumbilical abdominal wall and changes in the curvature of the developing spine, and apoptosis in the dorsal wall of the cloaca with shortening of the dorsal cloacal wall. There was no septum, as it is usually defined, between the developing bladder and hindgut. There was no evidence on either histologic section or scanning electronmicroscopy of any process of fusion occurring between the 2 lateral folds within the lumen of the cloaca. CONCLUSIONS: Lateral fusion of the side walls of the cloaca does not play a role in cloacal "partition." Development of the bladder and hindgut occurs by a process that involves growth, differentiation, and remodeling.

In vitro analysis of esophageal atresia using a whole-embryo culture system.

BACKGROUND/PURPOSE: Administration of Adriamycin to pregnant rats leads to the development of esophageal atresia with tracheo-esophageal fistula. This defect arises from failure of the trachea to develop normally from the primitive foregut; instead,the upper foregut differentiates into trachea, then continues to the lower esophageal segment as a tracheo-esophageal fistula. Our aim was to explore the possibility of growing Adriamycin-exposed embryos using a whole-embryo culture technique and to determine whether or not esophageal atresia with tracheo-esophageal fistula could be prevented in an Adriamycin-treated rat model. METHODS: Rat embryos were exposed to Adriamycin in utero on days 6 - 9 of gestation, removed on day 10 and grown in vitro as described by New (11) for 48 hours using 100% serum from animals not exposed to Adriamycin. RESULTS: Thirty Adriamycin-exposed embryos were grown in vitro using normal serum. Histologic assessment of tracheo-esophageal development showed that 14 embryos had normal development, while 16 developed esophageal atresia. CONCLUSIONS: Growth of Adriamycin-exposed embryos was successful using "whole-embryo culture technique"; abnormal tracheo-esophageal development could in some cases be altered by removing the embryos at day 10 and exposing them to normal serum for 48 hours.

Chemical synthesis and biological activity of rat INSL3.

The recently identified protein, insulin 3 (INSL3), has structural features that make it a bona fide member of the insulin superfamily. Its predicted amino acid sequence contains the classic two-peptide chain (A- and B-) structure with conserved cysteine residues that results in a disulphide bond disposition identical to that of insulin. Recently, the generation of insl3 knockout mice has demonstrated that testicular descent is blocked due to the failure of a specific ligament, the gubernaculum, to develop. The mechanism by which INSL3 exerts its action on the gubernaculum is currently unknown. The purpose of this study was to, for the first time, synthesize rat INSL3 and test its action on organ cultures of foetal rat gubernaculum. INSL3 also contains a cassette of residues Arg-X-X-X-Arg within the B-chain, a motif that is essential for characteristic activity of another related member of the superfamily, relaxin. Hence, the relaxin activity of rat INSL3 was also tested in two different relaxin bioassays. The primary structure of rat INSL3 was determined by deduction from its cDNA sequence and successfully prepared by solid phase peptide synthesis of the two constituent chains followed by their combination in solution. Following confirmation of its chemical integrity by a variety of analytical techniques, circular dichroism spectroscopy confirmed the presence of high beta-turn and alpha-helical content, with a remarkable spectral similarity to the synthetic ovine INSL3 peptide and to synthetic rat relaxin. The synthetic rat INSL3 bound with very low affinity to rat relaxin receptors and had no activity in a relaxin bioassay. Furthermore, it did not augment or antagonize relaxin activity. The rat INSL3 did however induce growth of foetal rat gubernaculum in whole organ cultures demonstrating that INSL3 has a direct action on this structure.

Antegrade continence enemas in the treatment of slow-transit constipation.

BACKGROUND/PURPOSE: Children with anorectal dysfunction can now be treated by antegrade continence enema (ACE), as described Malone et al. Those with idiopathic constipation, however, are not thought to be suitable for this treatment. Over 150 children attend the authors' department with proven slow transit constipation (mostly proven on nuclear transit/X-ray study), and the authors reviewed the outcome in the 40 of these who have had the ACE procedure. Families completed a questionnaire and attended interview with an independent assessor. METHODS: Of the 40 patients, 32 patients were assessed. Follow-up ranged from 3 to 54 months (median, 18 months) and age ranged from 5 to 17 years (median age, 10 years). Three of 32 stomas were no longer in use. Frequency of soiling was reduced significantly in 20 patients, and a further 6 patients were clean (P <.01). Abdominal pains were relieved significantly (P <.05), and appetite and mood improved. RESULTS: Stomal complications were frequent, (stenosis in 16 of 29, mucus leak in 20 of 29, fecal leak 3 of 29, catheter-related pain in 20 of 29). Slow evacuation (12 of 29) and pain with enema (17 of 20) also were common. CONCLUSION: Malone appendicostomy does improve the well being of patients with slow transit constipation, but the advantages are less dramatic than in children with normal motility.

Early development of the gubernaculum and cremaster sac in estrogen receptor knockout mice.

AIM exogenous estrogen causes gubernacular atrophy and cryptorchidism in fetal rodents. Mice with an estrogen receptor-alpha (ERalpha) disrupted gene mutation (alphaERKO) were studied to determine whether ablation of endogenous estrogen action, through ERalpha, had an effect on gubernacular development. Serial sagittal sections were made of the pelvis in fetal and day 7 postnatal wild-type and alphaERKO mice with the estrogen receptor-alpha "knockout" gene mutation. Wild-type (n = 24), heterozygote (n = 13) and alphaERKO mice (n = 12) were sacrificed at 16, 17 and 18 days fetal life and at 7 days postnatally. The size of the gubernaculum, cremaster muscle, cremaster sac, and the width of the sac at both ends in day 7 mice were quantitated by computer analysis. Visually and statistically the ERKO mice could not be separated from the wild-type mice during fetal life. At day 7 postnatally, a thicker cremaster sac was noted morphologically, and also a statistically significant difference was seen in the width of the cremaster sac at the sac's tip. Sac area, cremaster muscle area and the width of the sac at the sac's end did not differ significantly. Overall there is minimal phenotypic change observed in the alphaERKO mouse compared to wild-type at the early developmental stages investigated. However, at postnatal day 7, there is a difference in the width of the cremasteric sac tip. This suggests that the effect of ERalpha, and thus signaling on the developing gubernaculum, occurs late in development. Alternatively, an action from the recently discovered ERbeta may be involved. Exploration of a betaERKO and the double knock-out alphaERKO/betaERKO mouse should be informative in evaluating the effect of endogenous estrogens in gubernacular development.

Enlargement of the processus vaginalis during testicular descent in rats.

The role of the processus vaginalis (PV) during inguinoscrotal testicular descent remains controversial. Some authors propose passive dragging of the PV by the migrating testis, while others suggest active elongation. In addition, the exact site of growth is unknown. Our aim was to determine whether the PV actively proliferates at its tip or stretches passively during the inguinoscrotal phase of descent in the rat. Gubernacula were removed from Sprague-Dawley (SD) rats and congenitally-cryptorchid TS mutants. Animals (at days 3, 7, 10, and 11) were treated with bromo-uridine deoxyribose (BUdR) 2 h before death. BUdR incorporation into newly-synthesised DNA served as a marker for cell division. The gubernacula were processed for haematoxylin and eosin and immunoperoxidase staining. Three sites were examined: (1) the tip of the PV on either side of the gubernacular bulb; (2) the proximal gubernacular cord; and (3) the proximal parietal PV. At each site, 50 adjacent cells were counted and the number of positive cells recorded. The highest BUdR labelling in SD rats was at the tip (site 1) on day 3 (17/50) compared with sites 2 (11/50) and 3 (9/50) (P < 0.05). Labelling decreased by 7 and 11 days to similar levels in all three sites. In TS rats, labelling rates were lower at day 3 and were highest at the tip at day 11. These results suggest active growth of the caudal tip of the PV during testicular descent. In normal rats, the growth rate slows as the testis approaches the scrotum. By contrast, in TS rats growth continued longer. We propose that the PV elongates actively from the tip to allow the intraperitoneal testis to leave the abdomen in a special peritoneal diverticulum.

Gastrointestinal transit and anorectal manometry in children with colonic substance P deficiency.

BACKGROUND AND AIMS: Severe intractable constipation in children may be associated with a reduction of substance P (SP)- containing fibers in colonic circular muscle. The aim of this study was to characterize gastrointestinal transit (GIT), anorectal manometry (ARM) and electromyographic (EMG) changes in these children. METHODS: Seromuscular laparoscopic biopsies of the colon were obtained from 35 children with severe constipation. Immunofluorescent staining for SP and vasoactive intestinal peptide (VIP) were then performed on these specimens. The cohort of patients studied included a SP-deficient group (SPD, n = 25) who had reduced numbers of SP-immunoreactive nerve fibers. The other group consisted of patients with normal staining for both SP and VIP (SPN, n = 10). Gastrointestinal transit studies (gastric emptying, orocecal and colonic transit) suitable for analysis were available for 17 patients (SPD, n = 9 and SPN, n = 8). The colon was divided into segments and radioactivity counts in each segment were expressed as a percentage of the total colonic count at each time point (6, 24, 32 and 48 h). The geometric center (GC), ARM, EMG, clinical and demographic data characteristics of both groups of patients were compared. RESULTS: There were no differences in demographic data, gastric emptying, orocecal transit or geometric center of transit in the colon between the two patient groups. The ARM and EMG studies suggested that the SPN group have a higher mean threshold volume of balloon distension required to initiate a rectoanal inhibitory reflex, and a higher incidence of anismus; however, this did not reach statistical significance. CONCLUSIONS: These data suggest a trend that the SPN patients have a greater problem with obstructive defecation and abnormal rectal sensation than those with SPD. We were unable to confirm any defect in colonic transit in the SPD patients compared with the SPN group.