The perianal complications of Crohn's disease (CD) seen in children and adolescents include skin tags, anal fissures, fistulae, and abscesses. While these lesions are often chronic and variably responsive to medical therapy, only rarely are they severely destructive. In this report, we characterize the frequency, severity, and clinical course of a highly destructive form of perianal disease (HDPD) that we have noted in a number of children and adolescents with Crohn's disease. A database containing records from 350 children with inflammatory bowel disease was reviewed to identify all children with CD treated between 1970 and 1993. For each, the occurrence or absence of significant perianal pathology, including fistula, abscess, and HDPD, was determined. Pertinent clinical details were recorded for all patients. In addition, the clinical characteristics of those children with HDPD were compiled, and the courses of those with HDPD characterized. A search of the database identified 230 children and adolescents with CD followed for a total of 1,518 patient years. Sixty-seven of these patients (29% of the CD population) had significant perianal pathology. This included 6 with HDPD, 8 with complicated fistulae [rectourethroperineal (1), rectovaginal (1), rectolabial (2), and multiple communicating perineal (4)], and 53 with simple perianal fistulae or abscesses. All six with HDPD had deeply destructive perineal ulcerations, marked undermining of the perineal and perirectal tissues, and copious exudate, and often there was a deeply cleaved or fileted perineum on separating the buttocks. Two children with HDPD had fecal incontinence.

Markowitz, J; McKinley, M; Kahn, F.; Steil, L; Grancher, K; Rosa, J; Simpser, E; Daum, F Author Information

Bile salt uptake by hepatocytes is modulated in part by changes in intracellular cyclic AMP. We studied the effect of activation of protein kinase C on cyclic AMP-mediated taurocholate uptake in isolated rat hepatocytes. Both dibutyryl cyclic AMP (2 x 10(-6) mol/L) and glucagon (10(-6) mol/L), which increase intracellular cyclic AMP, enhanced the initial uptake rate of taurocholate into hepatocytes, with maximal increases of 45% to 50% over the basal uptake rate. Vasopressin (10(-9) mol/L), a hormone known to activate protein kinase C, and phorbol-12,13-dibutyrate (10(-5) moI/L) significantly inhibited the glucagon-stimulated increase in taurocholate uptake rate (72% +/- 10% and 105% +/- 13% inhibition, respectively). Basal (unstimulated) taurocholate uptake rate was not affected by vasopressin or phorbol-12,13 dibutyrate. Down-regulation of the glucagon-stimulated transport was rapid and persisted during the 20-min experimental period. Angiotensin II had a similar but more transient inhibitory effect. Vasopressin and phorbol-12,13-dibutyrate suppression of glucagon-stimulated taurocholate uptake rate was not accompanied by diminished cyclic AMP levels. Moreover, vasopressin and phorbol-12,13-dibutyrate inhibited dibutyryl cyclic AMP-stimulated taurocholate uptake rate can be dissociated from alterations in the cyclic AMP levels.

Glucagon (G) enhances bile flow and stimulates bile acid uptake by hepatocytes, although the mechanism of action is unclear. G may stimulate bile acid uptake by increasing intracellular cAMP concentration. Cyclic cAMP dependent cell functions may be modulated by protein kinase C. The authors evaluated the interaction of G-induced cAMP formation and PKC activation on bile acid uptake by rat hepatocytes. The effect of PKC activation by Phorbol-12,13-dibutyrate (PDBu) on intracellular cAMP or taurocholate (TC) uptake in unstimulated or G-stimulated isolated rat hepatocytes was investigated. {sup 3}H-TC uptake was measured 5, 10, 20 and 30 min after the addition of G. The effect of db-cAMP {plus minus} PDBu was also evaluated. Intracellular cAMP was measured by RIA. G stimulation increased TC uptake at all time points, with maximum stimulation from 10-20 min. PDBu virtually abolished the G effect. Uptake kinetics showed only a change in Vmax. PDBu had no effect on unstimulated TC uptake. PDBu did not alter the G-stimulated intracellular cAMP rise. PDBu decreased TC uptake even when hepatocytes were treated with db-cAMP. G-stimulation of hepatic TC uptake coincided with a rise in intracellular cAMP, although only low levels of cAMP were necessary to achieve maximum TC uptake. Calciummore » depletion caused 20% decrease in basal TC uptake, but did not alter the pattern of G-stimulation of TC uptake, but did not alter the pattern of G-stimulation of TC uptake nor the inhibitory effects of PDBu. PKC down-regulates G-stimulated TC uptake via mechanisms which appear to be independent of changes in either intracellular cAMP or calcium.« less

Neuronal intestinal dysplasia (NID) clinically resembles Hirschsprung's disease but is characterized by hyperplasia rather than aganglionosis of the intramural plexus. Surgical intervention is common. We report the 5-year follow-up of an infant with the mixed form of NID managed medically and a method by which NID can be quantified histologically. Hyperganglionosis was determined by counting the number of ganglia per high-power field and the number of ganglion cells per ganglia from at least two biopsy specimens. The patient's biopsies and biopsies from "normal" and "inflamed" patients were compared. Normals contained 0.68 +/- 0.28 (mean +/- SD) ganglia per high-power field and 2.16 +/- 0.31 ganglion cells per ganglion. The inflamed biopsies were similar, 0.69 +/- 0.38 ganglia per high-power field and 2.63 +/- 0.40 ganglion cells per ganglion. The patient's initial rectal biopsy revealed 7.6 ganglia per high-power field and 3.8 ganglion cells per ganglion. Management of the patient included saline colonic irrigations and hyperalimentation with gradual reinstitution of breast-feeding. Clinical improvement was associated with normalization of manometry and biopsy findings, a phenomenon not documented previously in the literature. Irrigations were stopped at age 9 months, and the child is now asymptomatic.

Summary Reactive systemic or secondary amyloidosis occurs in 1–29% of adults with Crohn's disease, but only sporadic cases of amyloidosis have been recognized in children with inflammatory bowel disease. We therefore have studied operative specimens (ileal, ileocolonic, and colonic) from 46 children (30 with Crohn's disease and 16 with ulcerative colitis) to determine the frequency of amyloid deposits. Sections of bowel, skin, and lymph nodes (n = 940) were stained by Congo red and examined by light microscopy and by polarized light. Amyloid deposits were found in only one of 46 subjects, an 18‐year‐old girl who had had Crohn's disease for 6 years. Intestinal amyloid deposits, present 16 months before the clinical diagnosis of amyloidosis, were patchy and seen predominantly in the intestinal mucosa. We conclude that amyloidosis is rare in children requiring surgery for Crohn's disease and ulcerative colitis. Examination of Congo red‐stained sections can detect even subclinical amyloidosis. The amyloid deposits in our patient, which were both patchy and consistently mucosal, suggest that multiple endoscopic biopsy samples, not necessarily containing submucosa, are sufficient for diagnosis.

This study was undertaken to determine if asymptomatic children and adolescents with inflammatory bowel disease and moderate to severe anorectosigmoid inflammation might remain symptom-free for at least 12 months without specific intrarectal therapy. We prospectively studied 13 asymptomatic patients 6-21 years of age (four with Crohn's disease and nine with nonspecific colitis) with previously documented anorectosigmoid inflammation. Of these 13, four had moderate to severe anorectosigmoid inflammation both endoscopically and histologically. These four patients (two with Crohn's disease and two with nonspecific colitis) were entered into the second phase of the study. Three were receiving sulfasalazine, and one received methylprednisolone, 4 mg/day, and 6-mercaptopurine, 50 mg/day. None received intrarectal therapy. Clinical evaluation revealed that all four remained asymptomatic for 12 months despite the continued presence of moderate to severe anorectosigmoid inflammation. These results indicate that in children and adolescents with inflammatory bowel disease, the presence of inflammation of the anorectosigmoid does not necessarily correlate with or presage the onset of symptoms of proctosigmoiditis. Therefore, active inflammation of the anorectosigmoid is not the sole prerequisite for intrarectal therapy. The clinician should be guided by the symptoms of the patient, not by the presence or absence of active anorectosigmoid inflammation.

We observed an unexpectedly high incidence of late sepsis in infants with bowel resection. To define the epidemiology of sepsis, we reviewed the records of all infants with bowel resection from 1978-83. 50 infants had resection for: NEC-38, Gastroschisis-3, Hirschsprung-3, atresia-4, other-2. 19(38%) had 27 episodes of late sepsis, as defined by clinical deterioration plus positive blood cultures. Onset of sepsis was 17 wks. (range 1-71) after surgery. In 3 episodes, cultures(S.epidermidis, enterococcus, and streptococcus) from a central venous line(CVL) were positive, with negative peripheral blood cultures. In the remaining 24 episodes Enterobacteriacea-12, Candida-4, S.epidermidus-2, S.aureus-2, enterococcus-2, S.pneumonia-1, and alpha-streptococcus-1 were recovered. Sex, race, birth wt. (1.9v2.1kg),primary diagnosis, age at resection, cms. resected (26.8v18.4), presence of ileocecal valve (37v47%), or enterostomy (89v75%) were similar in septic and nonseptic infants. However, septic infants had a CVL more frequently than those without sepsis (89v63%). (p 0.05). 21 of 27 episodes(77%) occurred with a CVL in place. 4 (21%) in the septic group died: 2 with gram negative sepsis, 2 from complications of long-term ventilator therapy. We conclude that infants with bowel resection are at increased risk for sepsis, particularly gram negative sepsis. A CVL may increase this risk. In these patients, a high index of suspicion of sepsis, meticulous catheter care, and early catheter removal is prudent.

Mice infected with Schistosoma mansoni represent a model for study of hepatic fibrosis in humans. Production of trypsin-activatable inactive collagenase and EDTA-sensitive neutral protease was measured in the culture medium in which granuloma explants or primary cultures were maintained. Collagenase production was maximal in granulomas obtained from liver of mice 8 weeks postinfection and was inhibited by Actinomycin D or cycloheximide, and enhanced by lymphocyte factor(s) or heparin. Isolated schistosome eggs did not release these enzymatic activities but did release EDTA-insensitive protease activity. Both enzymes were separated by ion-exchange chromatography and purified to homogeneity. Isolated collagenase had an isoelectric point of 6.2 and molecular weight of 60,000 and had the functional characteristics of a tissue collagenase. The specific activity of collagenase was 33 units per mg protein at an optimum pH 7.5 and lacked proteolytic activity against noncollagenous protein substrates. Isolated EDTA-sensitive neutral protease had specific caseinolytic activity of 150 units per mg protein and gelatinolytic activity of 300 units per mg protein at an optimum pH 7.5; the enzyme lacked activity against undenatured collagen. Isoelectric point was pH 6.0. Protease activity was inhibited by known inhibitors of collagenases. Production and activation of EDTA-sensitive neutral protease and collagenase accompany increased collagen synthesis and content in the liver of mice 8 weeks postinfection with S. mansoni cercariae. Continued accumulation of liver collagen under these conditions suggests an insufficiency in collagenase activity relative to the increase in collagen synthesis.