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Biomedical subjects

M K Younoszai

Publications and source records attributed to M K Younoszai.

At least 19 recordsLinked to original sources

Relation of ornithine decarboxylase and tyrosine kinase activity in the jejunal mucosa in vivo.

Our aim was to study the relationship between jejunal mucosal activity of ornithine decarboxylase and tyrosine kinase during proliferation in adolescent rats in vivo. Their relationship in the proliferating intestinal mucosa under in vivo conditions has not been reported before. From the results of in vitro studies, it was speculated that tyrosine kinase activity modulated ornithine decarboxylase activity during colonic mucosal proliferation (Majumdar AP. Am J Physiol 259:G626-G630, 1990). Jejunal mucosal hyperplasia was induced by Type 1 diabetes and suppressed in both control and diabetic rats by administration of difluoromethylornithine. Jejunal mucosal weight and enzyme activity were determined after 3, 6, and 10 days, and tyrosine-specific phosphorylated proteins after 10 days of induction of diabetes. Difluoromethylornithine suppressed jejunal mucosal proliferation and tyrosine kinase activity after the 6- and 10- day study periods. After the 3-day study period although jejunal mucosal growth was suppressed, tyrosine kinase activity was not. Activity of tyrosine kinase and ornithine decarboxylase were highly significantly correlated at all time periods in both control and diabetic rats. Tyrosine-specific phosphorylated proteins of 34, 54, 80, and 200 kDa proteins were observed in jejunal mucosa of both control and diabetic rats. In the difluoromethylornithine-treated rats, phosphorylation of the above proteins was negligible while the phosphorylation of a 14-kDa protein was prominent. We speculate that in vivo ornithine decarboxylase activity may be modulating tyrosine kinase activity and that phosphorylation of a 14-kDa protein was associated with suppressed mucosal growth in difluoromethylornithine-treated rats.

Animals

Diagnosis of gastroesophageal reflux in pediatrics.

Gastroesophageal reflux (GER) may be normal, functional, or pathogenic. Normal GER is of short duration and seen in all individuals. Functional GER, or effortless regurgitation, is common during infancy, causing no ill effects. Pathogenic GER causes diseases such as failure-to-thrive, coughing, choking, aspiration, apnea and/or bradycardia, esophagitis with irritability and excessive crying. Clinically it becomes imperative to distinguish normal and functional from pathogenic GER. The tests presently employed to detect GER are roentgenogram of the upper gastrointestinal tract (showing barium GER), scintigraphy of the esophagus after ingestion of a 99mTc labeled meal (indicating meal GER) and prolonged pH probe monitoring the lower esophagus (depicting acid GER). There seems to be a controversy regarding the usefulness of these tests for the diagnosis of pathogenic GER. In the present study of 89 infants and children presenting with signs and symptoms of pathogenic GER, 70% had significant acid GER, while 36% and 17% had barium and meal GER respectively. No statistically significant correlations were detected between acid GER, barium GER, and meal GER. We conclude that these three tests probably represent different phenomena, and that prolonged esophageal pH monitoring should be considered the most reliable and gold standard for detection of pathogenic GER.

Adolescent

Polyamines and intestinal epithelial hyperplasia in streptozotocin-diabetic rats.

We measured specific activity of ornithine decarboxylase (ODC) and contents of putrescine and of the polyamines (spermidine and spermine) in isolated villus and crypt enterocytes from the jejunum of adolescent streptozotocin-diabetic and weight-matched control rats and diabetic and control rats treated with difluoromethyl ornithine (DFMO) 10 days after induction of diabetes. Consistent with previous observations by others of elevated ODC activity and contents of putrescine and of the polyamines in the intestinal epithelium undergoing hyperplasia, our studies showed elevated ODC activity and contents of putrescine and spermidine, but not of spermine, in the hyperplastic intestinal epithelium of diabetic rats. As in previous studies, suppression of ODC activity by DFMO prevented not only the jejunal epithelial hyperplasia in the diabetic rats, but also retarded jejunal epithelial growth in the control rats. DFMO administration lowered ODC activity by over 80% in both diabetic and control rat enterocytes and prevented the rise in enterocyte contents of putrescine and spermidine in the diabetic rat. The observation that, in both diabetic and control rats, treatment with DFMO lowered spermidine content in the crypt enterocytes but had no similar consistent effect on contents of putrescine or spermine suggested that spermidine could have been responsible for the intestinal epithelial hyperplasia in the diabetic rats and for the normal growth of the intestinal epithelium in control rats.

Animals

Intestinal mucosal ornithine decarboxylase and brush border membrane vesicle Na(+)-H+ exchange activities in diabetic rats.

To determine the possibility that intestinal mucosal ornithine decarboxylase activity can modulate mucosal brush border membrane Na(+)-H+ exchange activity, we studied the relationship between jejunal mucosal ornithine decarboxylase activity and mucosal brush border membrane Na(+)-H+ exchange activity in adolescent streptozotocin-diabetic and normal control rats. Diabetes was associated with enhanced intestinal mucosal ornithine decarboxylase and Na(+)-H+ exchange activities. Groups of diabetic and control rats were given difluoromethylornithine in drinking water to suppress intestinal mucosal ornithine decarboxylase activity. As expected, 10 days after induction of diabetes, intestinal mucosal weight (67.7 mg/cm vs 56.1 mg/cm), DNA (47.3 micrograms/mg protein vs 32.7 micrograms/mg protein), ornithine decarboxylase activity (1107 units/hr vs 654 units/hr), and brush border membrane vesicle Na(+)-H+ exchange activity, assessed as Vmax of 22Na+ uptake (32.5 nmol/mg protein/15 min vs 15.2 nmol/mg protein/15 min), were significantly greater in diabetic than in control rats. Treating diabetic and control rats with difluoromethylornithine suppressed jejunal mucosal growth by over 30%, ornithine decarboxylase activity by over 80%, and brush border membrane vesicle 22Na+ uptake by over 60%. Highly significant direct correlations (r > 0.900) were observed between jejunal DNA content, mucosal ornithine decarboxylase activity, and brush border membrane vesicle Na(+)-H+ exchange activity. The above findings suggest that jejunal mucosal ornithine decarboxylase activity can modulate mucosal epithelial proliferation and mucosal brush border membrane Na(+)-H+ exchange activity.

Animals

Stooling problems in patients with myelomeningocele.

In children with myelomeningocele fecal and urinary incontinence lowers self-esteem and decreases social interaction. The defects in the lumbosacral spine disturb the sensory and motor nerves supplying the skin and muscles of the perianal region, including the puborectalis muscle, and the external anal sphincter. The sensations in the region, as well as the motor functions of the striated muscles suffer, compromising the dynamics of continence and the normal process of stooling and leading to incontinence and constipation. Constipation has been treated by disimpaction of stools from the colon and rectum, administration of stool softeners, and a healthy diet containing adequate bulk-forming items. Incontinence has usually been managed by behavior modification of self-initiating stooling after meals and positive reinforcement of this process. This method has helped up to 75% of patients to become socially continent. Biofeedback training has been helpful in patients who have preservation of some sensorimotor functions in the perianal region and who understand and cooperate in the process of biofeedback training. The enema continence catheter has been used to empty the rectosigmoid every 48 hours; most children treated in this manner have achieved social continence. Electric stimulation of the pudendal nerves using a neuroprosthetic device has been used in some patients. The pudendal nerve is stimulated continuously to achieve continence; stimulation is discontinued only for stooling and/or urination.

Biofeedback, Psychology

Intestinal absorption of aspartame decomposition products in adult rats.

The dipeptide sweetener aspartame (N-L-alpha-aspartyl-L-phenylalanine, 1-methyl ester; alpha-APM) is relatively stable in dry powder form. However, when exposed to elevated temperature, extremes of pH and/or moisture, alpha-APM is converted into a variety of products. In aqueous solution alpha-APM decomposes to yield methanol, two isomeric forms of L-aspartyl-L-phenylalanine (Asp-Phe) [alpha-Asp-Phe and beta-Asp-Phe], and APM's diketopiperazine cyclo-Asp-Phe. Depending on beverage storage conditions, individuals drinking alpha-APM-sweetened beverages may consume small quantities of these three compounds. Relatively little has been published about the metabolism of beta-Asp-Phe and cyclo-Asp-Phe. We compared the absorption and metabolism of alpha-Asp-Phe, beta-Asp-Phe, and cyclo-Asp-Phe with that of L-phenylalanine (Phe) in adult rats. Steady-state perfusion studies of rat jejunum indicated rapid carrier-assisted uptake of Phe and alpha-Asp-Phe, but only slow passive diffusion of beta-Asp-Phe and cyclo-Asp-Phe from the lumen. Homogenates of rat intestinal mucosa, liver, and cecal contents, as well as homogenates of pure cultures of Escherichia coli B, catalyzed the hydrolysis of alpha-Asp-Phe, but not cyclo-Asp-Phe. Homogenates of E coli and rat cecal contents, but not homogenates of rat liver or intestinal mucosa catalyzed the hydrolysis of beta-Asp-Phe.

Absorption

Solitary ulcer syndrome of the rectum in children.

We present two children with solitary ulcer syndrome of the rectum (SUSR): a 7-year-old and an 11-year-old. Although well recognized in the adult literature, the pediatric experience with this condition is limited. We review the clinicopathologic features of SUSR with emphasis on the pediatric experience. Greater awareness of this syndrome by both the pediatrician and pathologist may lead to more diagnosed cases in children.

Biopsy

Pseudo-Zollinger--Ellison syndrome in a child presenting with anemia.

Pseudo-Zollinger--Ellison syndrome appears to very rarely afflict young children. Hypergastrinemia, regardless of the etiology, presents with signs and symptoms of nonhealing or multiple gastric or duodenal ulcers, or both. We present a 7-yr-old boy with fasting hypergastrinemia (serum gastrin 200-500 pg/ml) who had mild to moderate iron deficiency anemia, but was asymptomatic. Stool guaiac was positive and gastric acid secretion was almost 40-fold above normal. Endoscopy showed multiple small gastric fundal ulcerations and severe gastritis. Workup for Zollinger--Ellison syndrome was negative. Changes in serum gastrin levels after secretin injection and after ingestion of a protein meal were compatible with those noted in adults with pseudo-Zollinger--Ellison syndrome. This child may be the first case of pseudo-Zollinger--Ellison syndrome under the age of 17 yr.

Anemia, Hypochromic

Chronic intestinal pseudoobstruction in young children.

We studied 8 young children (4 boys and 4 girls) with chronic intestinal pseudoobstruction. Intestinal pseudoobstruction, recurrent urinary tract infections, and dysuria occurred between the ages of a few weeks to 5 yr old. All had marked dilatation of the entire gastrointestinal tract distal to the esophagus, and megacystis. Conventional pathologic examinations of the full-thickness specimens of the gastrointestinal tract were normal in 5 and abnormal in 2 patients. The abnormalities included increased fibrosis and lipofuscin pigment in the smooth muscle cells. Myenteric plexus examination, using the Smith's method in 2 patients, was normal. Biopsy specimens from urinary bladders examined in 3 patients revealed separation of individual smooth muscle cells by collagen fibers. Intestinal manometric studies performed in 3 patients showed only weak and infrequent contractions during fasting and after feeding. Severe and extensive dysfunction of the gastrointestinal and urinary tracts with relatively normal histologic appearance are typical for these children.

Abdomen

Effect of acidosis and hypoxia on intestinal blood flow of sheep fetus.

In sheep fetuses 110-130 days of age acidosis (blood pH 6.95; produced by infusion with 1.1 M lactic acid) significantly lowered blood flow (ml/min/100g) to the full thickness wall of the jejunum from 135 +/- 11 to 93 +/- 14 and in the full thickness wall of the ileum from 122 +/- 13 to 95 +/- 11. The decrease was mainly due to the decline in blood flow to mucosa of the segment, where flow decreased from 182 +/- 20 to 83 +/- 14 in the jejunum and from 130 +/- 10 to 107 +/- 9 in the ileum. Fetal hypoxemia (PaO2 of 14.9 mm Hg; induced by allowing ewes to breath 11.1% O2 and 88.9% nitrogen) reduced blood flow only to the jejunal mucosa from 142 +/- 14 to 99 +/- 16. The reduction in blood flow to the full thickness wall of the jejunum and the ileum did not change significantly from the control period, when PaO2 was 25 mm Hg.

Acidosis

Intestinal calcium absorption is enhanced by D-glucose in diabetic and control rats.

The effect of glucose on intestinal absorption of calcium was studied in the jejunum and ileum of control, diabetic (streptozotocin-induced), and insulin-treated diabetic rats. Intestinal absorption was determined in vivo using an in situ one-pass perfusion technique. In the jejunum of control and diabetic rats, net absorption and unidirectional lumen to mucosa flux of calcium and net absorption of water were significantly greater during perfusion of an isotonic NaCl solution, containing 15 mmol/L of glucose, than during perfusion of the same solution containing 15 mmol/L of mannitol instead of glucose. To determine if net absorption of calcium and water were related, the jejunum was perfused with a hypotonic solution (260 mosmol/kg) in separate groups of rats. Although net absorption of water was equivalent during perfusion of the hypotonic solution to that noted during perfusion of the isotonic glucose-containing solution, rate of absorption of calcium was not enhanced. Thus, it appeared that, if the enhancement in absorption of calcium by glucose was an effect on the passive absorption of calcium, it was through a mechanism not related to passive absorption of water. As expected, jejunal absorption of calcium was lower in diabetic than in control rats. Because in diabetic rats the metabolism of vitamin D to its active metabolite, 1,25-dihydroxy vitamin D, is defective, the enhancement in absorption of calcium by glucose did not appear to be due to a mechanism influenced by vitamin D metabolism. In the ileum, rate of absorption of calcium was lower than in the corresponding jejunum and was not significantly altered by the presence of glucose in the perfusion solution, by perfusion of a hypotonic solution, or by the diabetic state. The mechanism of action of glucose on calcium absorption in the jejunum needs to be studied further.

Animals

Effect of nutritional method on adaptation of the intestinal remnant after massive bowel resection.

Adaptation of the intestinal remnant with hypertrophy/hyperplasia and increased absorption occurs, ultimately, after massive bowel resection. During the early postresection period, the rate of the adaptational process may be influenced by the method of nutritional support. Nutrients given by mouth may support a strong stimulus for hypertrophy but may be incompletely absorbed from the short intestinal remnant. Intravenous nutrition, while eliminating the need for intestinal absorption, may not support the hypertrophic process of that remnant. We tested the effect of different nutritional methods on the hypertrophic and functional adaptation of the intestinal remnant after 90% resection in the rat. The methods included oral feeding with regular rat chow, oral feeding with elemental diet, intravenous nutrition, and a combination of intravenous nutrition and oral feedings. Full thickness intestinal wall wet weight and mucosal wet weight, as well as in vivo L-valine absorption, were measured 9 days after operation. Resected subgroups were compared to sham-operated controls receiving similar diets. Increase in the weight of the intestinal remnant and its mucosa was noted in all resected subgroups receiving oral diets. Valine absorption per unit length and/or unit weight was significantly decreased in rats receiving oral diets alone and rats receiving a combination of intravenous and oral elemental diet. Significant increase in intestinal and mucosal weight without decrease in valine absorption was demonstrated in the animals receiving a combination of intravenous nutrition and regular chow diet. The results suggest that a combination of intravenous nutrition and ad libitum oral feedings with regular diet may represent the best method of nutritional support in the early postresectional period.

Adaptation, Physiological

Comparison of in vitro jejunal uptake of L-valine and L-lysine in the rat during maturation.

The maturational characteristics and patterns of absorption of the neutral amino acid L-valine were compared with those of the basic amino acid L-lysine using in vitro preparations of everted sacs obtained from the jejunum of suckling (2 weeks old), weanling (3 weeks old), and adolescent (6 weeks old) rats. Absorption rates determined as net transport into sac fluid and mucosal uptake (mumol/h/g protein or weight of mucosal scrapings) for both valine and lysine were greater in the suckling than in the weanling or adolescent rats. This appeared to be true for both the carrier-mediated and the diffusive processes for absorption, determined from the relationship between the observed absorption rates and the corresponding mucosal incubation medium amino acid concentrations. The major decline in rate of absorption occurred before the period of weaning. Between the period of suckling and adolescence the carrier-mediated absorption decreased by 55% for valine and by 90% for lysine, suggesting that during maturation of the jejunum the number of the carrier macromolecules responsible for absorption of valine and lysine per unit protein or weight of mucosa decreases with increasing age.

Age Factors

Intestinal maturation: effect of growth retardation on L-valine absorption.

The absorption of L-valine was studied in segments of the jejunum and ileum using a one pass in situ perfusion technique in 1-, 2-, 3-, and 4-wk-old healthy control and in growth-retarded rats (suckled with mothers fed a protein-deficient diet and fed the same diet after weaning). In the jejunum of control rats, rate of absorption of L-valine declined from about 270 to 80 mumol/h per g mucosal weight, between 2 and 4 wk of life. At each age period, in both segments, rates of absorption of L-valine based on weight of the segments were significantly greater in the growth-retarded than in the control rats. However, based on length of the intestinal segments rates of absorption were similar in corresponding segments of the control and growth-retarded rats. These findings indicated that although the intestine in the growth-retarded rats was atrophic compared to that in control rats, the capability to absorb L-valine had been preserved, by increasing the rate of absorption per unit weight of intestine.

Animals

Effect of treatment on rectal and sigmoid motility in chronically constipated children.

Using three pressure transducers, motility of the lower and upper rectum and sigmoid was recorded in 18 healthy and 18 chronically constipated children. The 36 children had a wide range of values for frequency of contractions, duration, amplitude, percent of activity, and surface area under the contraction curves. The mean values for percent of activity and surface area were significantly lower in the constipated than in the control children in all three recording areas (P less than .05). Motility in the constipated children, after 2 months of treatment that included milk of magnesia, showed significant increase when compared with corresponding pretreatment values (P less than .05), and were not different from corresponding values of the control children (P greater than .1). Seven to 12 months and 3 years later, rectal and sigmoid motility remained normal. Three-year follow-up revealed that most of the constipated children were not completely free of constipation and fecal soiling in spite of normal motility. Therefore, it appears that the hypomotility in the untreated patients was the result of the chronic fecal impaction and rectal distension and while it was not the cause of the constipation, it may have contributed to its severity.

Bisacodyl

Abnormal and sphincter response in chronically constipated children.

Using a strain gauge, we measured anal sphincter function in 116 chronically constipated and 18 healthy children. Eighteen constipated children were re-evaluated two months later (receiving laxative), and 15 were again studied seven to 12 months later. The anal resting tone varied along the length of the anal canal and was highest at 1 to 1.5 cm from the anal verge. This region was used to study the resting motor activity of the internal anal sphincter, the amplitude of the rectosphincteric reflex after 30 and 60 ml rectal distension, and the rectosphincteric reflex threshold. The mean and resting tone was significantly lower in constipated than in control children (P less than 0.001), but normalized in patients who recovered. Resting motor activity of the internal anal sphincter and the amplitude of RSR were significantly lower in constipated patients than were the corresponding values in control children (P less than 0.001), and remained lower during and after treatment, even in patients who recovered. The length of the anal canal and the RSR threshold were comparable in control and constipated children. Thus, the basic problem in chronically constipated children appears to be an abnormal internal anal sphincter, which is weaker and less responsive to rectal distension than in nonconstipated children.

Adolescent

Secretory diarrhea in ulcerative colitis.

Severe secretory diarrhea developed in a 15-year-old girl with ulcerative colitis restricted to the distal 30 cm of the colon. No known hormonal or pathologic cause for the secretory diarrhea was discovered. Since the diarrhea subsided after colectomy, it appeared to be secondary to a factor(s) in the inflamed bowel. We believe this is the first report of secretory diarrhea secondary to ulcerative colitis restricted to the distal portion of the large bowel.

Adolescent