Stanley E. Fisher

Peripheral neuropathy in Crohn's disease patients treated with metronidazole.

Thirteen pediatric patients with Crohns disease, aged 12-22 yr, were studied to assess the prevalence of peripheral neuropathy due to oral metronidazole. After 4-11 mo of therapy, 11 of 13 patients (85%) had a sensory peripheral neuropathy, determined by abnormal neurologic examinations or reduced nerve conduction velocities, or both. Only 6 of the 11 patients were symptomatic. Nine of 11 patients with peripheral neuropathy had their metronidazole discontinued and 2 had the dose reduced to less than 10 mg/kg X day. Follow-up evaluations of the 9 patients whose metronidazole had been discontinued 5.5-13 mo earlier demonstrated complete resolution of the peripheral neuropathy in 5, improvement in 3, and no change in 1. In the 2 patients whose metronidazole dose was reduced, 1 showed worsening and 1 showed complete resolution of the neuropathy after 10-12 mo of continued therapy.

Characteristics of Histidine Uptake by Human Placental Microvillous Membrane Vesicles

ABSTRACT: L-histidine is an essential amino acid. Its fetal-to-maternal blood concentration ratio is high, suggesting active placental transport. In this study, human placental microvillous membrane vesicles were used to characterize L-histidine transport, heretofore not evaluated in human tissue. L-Histidine uptake by microvillous membrane vesicles was stimulated by an inward sodium gradient, leading to an “overshoot,” followed by apparent equilibration. Linear uptake at 22° C was limited to the 1st min. The initial sodium-dependent uptake rate was proportional to the sodium concentration in the medium. The sodium-dependent uptake was markedly diminished or lost when potassium, cesium, or choline was substituted for sodium but not lithium. Replacement of chloride with sulfate or gluconate had little effect. Sodium-stimulated Lhistidine uptake was further stimulated by an outward potassium gradient (inside-negative) in the presence of valinomycin. Sodium-dependent uptake kinetic constants for L-histidine were: Km=0.44 ± 0.18 mM: Vmax = 536 ± 94 nmol/mg/30 s (mean ± SD). 2-(methylamino) isobutyric acid did not inhibite L-histidine uptake. Conversely, L-histidine noncompetitively inhibited sodium-dependent uptake of 2-(methylamino)isobutyric acid and Lcysteine. L-glutamine competitively inhibited sodium-dependent L-histidine uptake. L-histidine uptake was stimulated by preloading the vesicles with either L-histidine or L-glutamine (transstimulation). L-histidine uptake was not sensitive to N-ethylmaleimide treatment but was strongly inhibited by low pH. These findings suggest that L-histidine is transported in the human placenta by a specific sodium-dependent system similar to the “N” system described in rodent hepatocytes. Furthermore, the ready availability of placental tissue may make it a useful resource for studies of human epithelial transport biology.

Selective Fetal Malnutrition: the Effect of in Vivo Ethanol Exposure upon in Vitro Placental Uptake of Amino Acids in the Non-Human Primate

Summary: In vitro uptake (45 and 90 minutes) of amino acids, alpha-amino isobutyric (AIB) and valine (VAL), was measured in six placentae from the nonhuman primate, Macacca fascicularis. Three of the pregnant primates were chronically treated with ethanol before and throughout pregnancy (CHR); one during the last trimester only (LT); and two were controls (C). Compared to the C placentae, the LT placenta had significantly decreased uptake only for AIB at 45 min: 33.4 ± 6.8% reduction (mean ± S.E.) (P < 0.05). In contrast, the CHR placentae demonstrated significantly reduced uptake (P < 0.01) for both amino acids at both time points. Percent reduction at 45 and 90 min: AIB, 35.2 ± 6.5% and 32.6 ± 5.6% and VAL, 38.7 ± 2.9% and 22.1 ± 4.1%. The results indicate that chronic in vivo ethanol exposure impairs the in vitro placental uptake of two actively transported amino acids, using an animal with a placenta almost identical to the human.

Experimental Colitis Impairs Linear Bone Growth Independent of Nutritional Factors

BACKGROUNDnPoor linear growth frequently complicates chronic inflammatory bowel disease in children. Circulating inflammatory mediators may play a role in this growth delay. We evaluated the effect of experimental colitis on bone growth in a nutritionally controlled rat model.nnnMETHODSnExperimental colitis was induced in male Sprague-Dawley rats (125-150 g) by enema with trinitrobenzene sulfonic acid in 50% ethanol on day 1 and 11 of a 14-day protocol. Control animals were pair-fed and all animals received a liquid rat diet (1 kcal/ml). Twenty-four-hour urine, collected on days 2 and 12 and serum samples, collected at death, were analyzed for calcium, zinc, and magnesium. Serum samples from a separate set of animals were studied for serial interleukin-6 levels. Right proximal tibias were processed for growth-plate histomorphometry, in which linear growth is proportional to the heights of the proliferative zone, and terminal hypertrophic chondrocyte, but inversely proportional to the height of the resting zone.nnnRESULTSnHistology confirmed active inflammation in the animals given trinitrobenzene sulfonic acid. Weight gain and both urinary excretion and serum levels of zinc, calcium, and magnesium did not differ between treatment and nontreatment groups. Histologically, there was impaired linear bone growth. The resting zone was greater in the colitis group (94.5 +/- 32.6 microns versus 3.9 +/- 5.4 microns; p < 0.05); the proliferative zone was smaller in the colitis group (123.7 +/- 18.2 microns versus 78.9 +/- 11.2; p < 0.05 micron); the terminal hypertrophic chondrocyte was reduced in the colitis group (19.5 +/- 1.4 microns versus 28.8 +/- 3.6 microns; p < 0.05). At 6 and 24 hours after induction, the level of interleukin-6 was elevated in the colitis group.nnnCONCLUSIONSnExperimental colitis results in a decreased linear bone growth, independent of nutritional intake. Circulating cytokines derived from intestinal inflammation may contribute to the suppression of bone growth.

Hepatitis in children with acquired immune deficiency syndrome

Hepatic morphology and immunocytology were evaluated in 4 children with clinical and immunologic characteristics of the acquired immune deficiency syndrome or acquired immune deficiency syndrome related complex. All 4 children had hepatomegaly and increased serum alanine and aspartate aminotransferase activity. Both lobular and portal changes were noted. Lymphocytic infiltration, piecemeal necrosis, hepatocellular and bile duct damage, sinusoidal cell hyperplasia, and endothelialitis were prominent. Vesicular rosettes in sinusoidal lymphocytes and tubuloreticular structures in sinusoidal endothelial cells were demonstrated by electron microscopy. The lymphocytic infiltrate in both the lobular and portal spaces was characterized by a relative increase of cytotoxic/suppressor (T8) cells. Hepatitis may be a common feature of pediatric acquired immune deficiency syndrome and acquired immune deficiency syndrome-related complex. Although the histopathologic changes are consistent with chronic active hepatitis, the specific pathogenesis remains to be determined.

Linear growth following surgery in children and adolescents with Crohn's disease: Relationship to pubertal status

Studies of the effect of surgery on growth failure in adolescents with Crohns disease have revealed conflicting data. To better determine the role of surgery for growth delay, growth data from 26 patients with Crohns disease with intestinal resections and/or ileostomies were reviewed, 3 of whom had surgery twice. Operations were performed on 14 Tanner Stage I, 1 Tanner II, 1 Tanner III, and 13 Tanner IV or V patients. In the prepubertal group, 13 of the 14 had growth impairment, only one of whom had surgery primarily for that growth failure. One year after operation, 11 of 13 Tanner I growth failure patients experienced an increase in height velocity of 5.38 +/- 1.18 cm/yr (mean +/- SE;P less than 0.01); 9/11 achieved normal height velocity for Tanner I. Two attained their preillness height percentiles at one year follow-up, while 5 patients attained their preillness height percentiles 2.5 to 10 years following surgery. Of the four who failed to achieve normal height velocity, 3 had early recurrence of active disease. The Tanner Stage II and III patients both had growth failure, and both had a growth spurt following surgery. Of those who were Tanner Stage IV or V at the time of surgery, 5 of 13 had growth failure. Following surgery, none had an increase in height velocity. These data suggest that when patients with Crohns disease and growth failure are prepubertal and surgery is performed primarily because of failure of medical therapy and/or other complications, a postoperative growth spurt may be expected within one year.

Cancer family syndrome: marker studies.

Individuals from kindreds with the cancer family syndrome (CFS) have an increased hereditary risk for the development of adenocarcinoma of the colon in childhood and early adulthood. Previous studies have suggested that this high occurrence of adenocarcinoma may be due to a genetic defect in the control of colonic epithelial proliferation. Others have suggested that these families may have an underlying abnormality in immunologic tumor surveillance. We have investigated these possibilities in 15 cancer-free, at-risk individuals (10 children, ages 3-15 yr, and 5 adults) from two unrelated CFS kindreds. Colonic mucosal proliferative activity was studied by in vitro autoradiography after tritiated thymidine labeling in 7 subjects. The mean labeling index (12.7 +/- 0.9%) was comparable to that in controls, as was the distribution of thymidine labeling. Immunologic evaluation revealed depressed lymphocyte culture responses to stimulation by microbial antigens, but not to that by mitogens. Mixed lymphocyte culture responses were depressed in 4 of 8 subjects, but became normal in 2 of these after filtration through a Sephadex G10 column. Natural killer cell cytotoxicity was significantly depressed in 5 of 13 subjects, and borderline normal in another 3 subjects. These data suggest that many cancer-free members of CFS kindreds have a spectrum of in vitro cell-mediated immunologic defects that might interfere in vivo with the recognition or killing of incipient tumor cells.

Maternal ethanol use and selective fetal malnutrition.

Maternal ethanol ingestion may cause fetal injury, particularly impaired somatic and brain growth, by at least two mechanisms: (1) directly, by fetotoxicity from ethanol and/or acetaldehyde; (2) indirectly, by ethanol-induced placental injury and selective fatal malnutrition. There is ample evidence that ethanol and/or acetaldehyde is fetotoxic. In addition, alcoholics are frequently in a state of poor nutrition. However, regardless of maternal nutritional status, ethanol can be placentotoxic, impairing the normal transfer of essential fetal nutrients. Ethanol and/or acetaldehyde has been shown to inhibit placental uptake and/or transfer of amino acids, zinc, and glucose. These effects have been evaluated in animal models and in human tissue. Recent use of the isolated perfused human placental cotyledon has begun to delineate the pathophysiology of ethanol-induced placental injury.

Calcium-Sensitive Uptake of Amino Acids by Human Placental Slices

ABSTRACT. The placenta supplies many nutrients to the fetus, including amino acids by active transport. Although the exact regulatory mechanism is unknown, a few studies have suggested a role for calcium in amino acid transport. Therefore, we examined the relationship between calcium and amino acid uptake by term human placental slices. Calcium depletion of slices significantly reduced uptake of α-aminoisobutyric (AIB), which is actively transported primarily by a sodium-dependent, carrier-mediated mechanism. Impairment of AIB uptake induced by calcium depletion was reversed by repletion with calcium but not with other divalent cations. In contrast, uptake of phenylalanine, which is transported primarily by a sodium-independent mechanism, was not affected by calcium depletion. Uptake of leucine and valine, which accumulate by both sodium-dependent and independent mechanisms, was partially affected by calcium depletion. Verapamil (10 μM), an inhibitor of transmembrane calcium flux, significantly reduced AIB uptake. Trifluoperazine, a calmodulin antagonist, also inhibited AIB uptake. Analysis of AIB uptake kinetic constants for control and calcium-depleted slices showed no change in the diffusion constant, a 37% reduction in Vmax, and a 2-fold increase in Km. The results indicate that calcium may be an important factor in the cellular regulation of active transport of amino acids.

The Liver in Pediatric Gastrointestinal Disease

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.