Biomedical subjects
Publications and source records attributed to W A Walker.
Massive gallbladder wall thickening in association with hepatitis was diagnosed in a 13-year-old hemophiliac boy. The gallbladder returned to normal with improvement of clinical symptoms, illustrating the nonsurgical nature of this problem in pediatrics.
We investigated the transfer of bovine serum 125I-albumin (125I-BSA), bovine 125I-gamma-globulin (125I-BGG), 125I-ovalbumin (125I-OVA), and 125I-beta-lactoglobulin (125I-BLG) from the blood into the milk of lactating mice. Equal amounts (by weight) of the radiolabeled proteins were injected intravenously into mice 1 wk postpartum. Total radioactivity, trichloroacetic acid-precipitable radioactivity, and specifically immunoprecipitable radioactivity were measured in serum, mammary gland homogenate, and milk. Clearance of immunoreactive OVA (iOVA) and iBLG from the circulation was more rapid than iBSA and iBGG. The radioactivity in mammary tissue associated with BSA and BGG was greater than 70% immunoprecipitable throughout the 4-h test interval; 125I-OVA and 125I-BLG were less than 12% precipitable 1 and 4 h after injection. In milk obtained at 4 h, there was an approximately 10-fold greater accumulation of iBSA or iBGG than of iOVA or iBLG. These experiments demonstrate that protein antigens differ in their ability to transfer from maternal circulation into milk. The transfer into milk appeared to be in proportion to persistence of the antigens in the maternal circulation.
In this review, I have attempted to summarize the research done in a poorly understood area of gastroenterology, namely the role of the intestine in handling luminal antigens. The mature gut retains the capacity to absorb antigens by an energy-dependent, pinocytotic mechanism similar to that described for the transport of gamma-globulins in certain mammalian species in the neonatal state. The vast majority of adults show no ill effects as a result of this physiological phenomenon due to mucosal barrier function. However, when the barrier is disrupted and increased (pathological) quantities of toxic or antigenic macromolecules gain access to the body because of a derangement in the intraluminal digestive process or a defect in the mucosal barrier, antigen handling may be altered and result in either local intestinal or systemic disease. Finally, speculative concepts suggesting that clinical disease states may be associated with altered mucosal permeability have been discussed.
A capillary processor and aliquoter has been designed and fabricated that is capable of accepting aliquots of whole blood and automatically processing them into discrete aliquots of plasma. The device consists of two disks, each of which contains 16 individual capillaries and a processing rotor. One disk accepts larger capillaries that hold approximately 100 microL of whole blood each. The second disk accepts 2.54-cm-long precision capillaries of various internal diameters, which provide exact sample volumes from 1 to 10 microL. The processing rotor contains 16 individual compartments and chambers to accept both disks. Applying centrifugal force transfers the aliquots of whole blood into their respective compartments, where they are separated into cellular and plasma fractions. As the rotor speed is slowly decreased, an aliquot of plasma is withdrawn by capillary action into each measuring capillary. The disk containing the 16 measured aliquots of plasma is then removed and placed into a modified rotor for conventional centrifugal analysis. This device can entrain and deliver microliter volumes of liquids with precision and accuracy (1-2%) near that of mechanical pipettes. Assays of the separated plasma aliquots also have acceptable precision (e.g., CVs approximately 3% for measurements of serum enzymes).
Explore the source record for details and available documents.
125I-BSA injected intravenously into lactating mice persisted in the circulation for 4 h, entered the mammary gland, and was transferred to the neonate via the milk. When injected with anti-BSA antibodies, it was rapidly cleared from the circulation. Although animals receiving anti-BSA antibodies transferred more radioactivity to the neonate via the milk, the radioactivity was not TCA-precipitable or bound to staphylococcal protein A, nor was it immunoreactive. These findings suggest that circulating maternal antibody can limit the transfer of specific protein antigen from mother to newborn.
An important component of bacterial infection of the gastrointestinal tract, particularly when enterotoxin disruption of gut function occurs, relates to the interaction of the bacterium and toxin with the intestinal surface. Adherence or attachment of bacteria lead to colonization and toxic/invasive diarrhoeal states. The purpose of this review is to consider the intestinal mucosal barrier as a deterrent to microbial/toxin attachment, particularly emphasizing the mucosal surface itself, which includes the mucus coat and microvillous membrane. Consequences of mucosal barrier deficiency, particularly the incomplete development of the mucosal barrier, result in bacterially induced diarrhoeal states such as toxigenic diarrhoea and necrotizing enterocolitis. To illustrate the importance of the mucosal barrier as a factor in controlling the external environment containing bacteria and bacterial toxins, recent research in our laboratory on the development of the mucosal barrier is presented. This compares mucosal surface functional control of antigen/toxin attachment and penetration with mucosal surface compositional changes. Finally, evidence of a preliminary nature will be provided to suggest that modifications of the underdeveloped mucosal barrier of the immature intestine by the ingestion of breast milk may act to prevent pathological interactions between the gut and microbes/toxins.
Internal sphincterotomy is thought by most surgeons to have minimal complications. We retrospectively reviewed 306 patients following internal sphincterotomy to determine the incidence of any complications. Major complications (requiring reoperation) caused by fistula, bleeding, abscess, or unhealed wounds occurred in ten patients (3 percent). Minor complications caused by pruritus, persistent wound, pain, bleeding, abscess, discharge, urgency, impaction, or defects of continence occurred in 110 patients (36 percent). Complications were lowest for closed sphincterotomy (20 percent) and highest for open sphincterotomy alone (55 percent). All patients were cured of anal fissure or stenosis. Long-term follow-up (average 4.3 years) revealed a 22 percent incidence of persistent minor complications. Defects in continence caused 15 percent of total long-term morbidity. Minor complications occur frequently after internal sphincterotomy for anal fissure and stenosis. Closed sphincterotomy has the lowest complication rate. Long-term minor defects in continence occur in a significant number of patients.
This article focuses on intolerance to food proteins, discussing the definition and history of food intolerance, the basics of gastrointestinal mucosal immunity, specific food antigens, pathogenesis, clinical manifestations, as well as diagnosis, therapy, and prevention.
Explore the source record for details and available documents.
The postoperative growth rates achieved in eight early pubertal adolescent males with Crohn's disease undergoing surgery for obstructive complications is reported as a function of the use of 1 month's preoperative central venous alimentation. All patients had ileal strictures with ileocolitis, bone ages less than 13, Tanner stages 1 or 2, and growth velocities below the 3rd percentile for age. During a 3-year follow-up, those receiving preoperative venous alimentation demonstrated greater oral caloric intake (significant for 1 year) and greater postoperative growth velocity (significant for 2 years) in comparison to those patients who did not receive preoperative venous alimentation. There was no significant difference between the two groups of patients in postoperative weight gain, sexual development, and 3-year disease control.
When studying mucosal barrier function of developing animals, we noted that intestinal microvillus membranes (MVM) of newborn animals differ in their fluidity and binding characteristics to lectins compared with adult MVM. To further investigate these differences and determine whether maturation of the microvillus surface could be accelerated in utero, pregnant rats were given intraperitoneal cortisone beginning on the 17th day of gestation. Control and cortisone-treated animals were allowed to deliver normally, and the small intestines from newborns were used to isolate MVM. Microvillus membrane surface characteristics were evaluated by employing an 125I-labeled fucose-specific lectin, Ulex europeus (UEA). Changes in MVM proteins were monitored by disaccharidase activities and sodium dodecyl sulfate-polyacrylamide electrophoresis. MVM fluidity was accessed using a 5-doxyl stearic acid label and electron-spin-resonance spectroscopy. Results from these studies indicate that the birth weights of newborn rats exposed to cortisone in utero were significantly reduced; sucrase activity was prematurely induced and specific activities of lactase and maltase were enhanced in the intestines of the cortisone-treated newborns as contrasted with control animals. Furthermore, binding of 125I-UEA to MVM was greatly increased in treated animals. MVM fluidity decreased (P less than 0.001) compared with control animals and resembled the structural characteristics of more mature MVM. These results suggest that cortisone exposure in utero accelerate maturation of the microvillus surface of enterocytes.
The everted gut sac technique was used to study adaptive changes in small intestinal handling and uptake of radiolabeled bovine serum albumin and ovalbumin during lactation in rats. Binding and uptake of both proteins by the gut sacs of lactating animals were significantly less, compared to controls (p less than 0.001, after 30 min of incubation). This change was reversible after lactation ceased. The differences could not be explained by oral immunization since there were no specific antibodies found in sera, mucosal extracts, or breast milk; prior exposure to the protein did not alter the observed differences. No differences in mucosal breakdown of bovine serum albumin could be demonstrated by precipitation with trichloroacetic acid (10%); an increase in breakdown of ovalbumin in the lactating animals was shown under the same conditions. The injection of prolactin produced differences in bovine serum albumin binding and uptake similar to the ones observed in the lactating group (p less than 0.01, after 30 min of incubation, compared to solvent-injected controls). Since food protein antigen binding, breakdown and uptake are functions of the local intestinal host defense, these findings suggest that there are adaptive changes of the gut mucosal barrier during lactation which decrease the transfer of dietary antigens from mother to infant. The adaptation of the maternal intestinal host defense was shown to be influenced by prolactin.
The compromised human newborn frequently presents with overwhelming feeding problems which lead to inadequate intake. These problems may affect the development of the small intestine, especially mucosal barrier function, leading to increased infections and susceptibility to allergens. To study this, an animal model was established using neonatal rabbits deprived of nutrients from birth until 72 h. Mucosal barrier function was compared in deprived and control (naturally fed 72-h-old animals) rabbits by measuring immunoreactive bovine serum albumin in serum 4 h after intragastric infusion of crystalline bovine serum albumin (200 mg/100 g body weight). Trypsin activity was measured in rinse fluid obtained from the small intestine. Representative sections of jejunum from control and experimental animals were formalin fixed and stained with hematoxylin and eosin for morphologic comparison. Following the bovine serum albumin feeding, a significantly increased serum immunoreactive bovine serum albumin and significantly decreased trypsin-like activity of the small intestinal rinse fluid was noted in starved animals compared to controls. In addition, the enterocytes of malnourished animals were more cuboidal and contained fewer and smaller supranuclear granules on microscopic examination than the enterocytes of controls. This study suggests that short-term starvation in newborns affects mucosal barrier function. Acute starvation may place newborns at increased risk for infections and allergic disease.
Stimuli originating in the small intestine enhance gastric acid secretion, an effect termed the intestinal phase of gastric secretion. A humoral agent, enterooxyntin (EO) may mediate this effect. Mechanical distension of an ex vivo-perfused segment of canine jejunum caused the release of EO measured by cytochemical quantification of hydroxyl ion production (HIP) in guinea pig gastric oxyntic cells, an index of acid secretion. The H2 receptor antagonist, cimetidine (10(-5) M), and diamine oxidase, which hydrolyzes endogenous histamine, reduced HIP by 60% and 48%, respectively. Atropine (10(-5) M), the muscarinic cholinergic antagonist, reduced HIP by 75%. EO-induced HIP was also inhibited partially by the Ca2+ antagonist EGTA (10(-6) M) and by blockade of calcium channels with LaCl3 (10(-6) M). EO does not appear to operate through any single pathway. EO may be a single substance, different from gastrin, or a mixture of substances that have stimulatory effects on the oxyntic cell. Its action on the oxyntic cell is apparently mediated by both histaminergic and cholinergic pathways. Since neither cimetidine nor atropine completely inhibited EO-induced HIP, a direct effect of EO on the oxyntic cell seems likely and appears to depend on Ca2+. Isolation and purification of EO will be necessary to better assess the potency, efficacy, and the detailed cellular mechanisms of EO action.
An important adaptation of the gastrointestinal tract to the extrauterine environment is its development of a mucosal barrier against the penetration of proteins and protein fragments. To combat the potential danger of invasion across the mucosal barrier the newborn infant must develop within the lumen and on the luminal mucosal surface an elaborate system of defense mechanisms which act to control and maintain the epithelium as an impermeable barrier to the uptake of macromolecular antigens. As a result of a delay in the maturation of the mucosal barrier, newborn infants are particularly vulnerable to pathologic penetration by harmful intraluminal substances. The consequences of altered defense are susceptibility to infection and the potential for hypersensitivity reactions and the formation of immune complexes. With these reactions comes the potential for developing life-threatening diseases such as necrotizing enterocolitis, sepsis, and hepatitis. Fortunately, "nature" has provided a means for passively protecting the "vulnerable" newborn against the dangers of a deficient intestinal defense system, namely human milk. It is now increasingly apparent that human milk contains not only antibodies and viable leukocytes but many other substances that can interfere with bacterial colonization and prevent antigen penetration.
We have attempted, in this discussion, to summarize the processes and evidence for absorption of antigenic macromolecules in both animals and humans, comparing the infant to the adult. The mature gut retains the capacity to absorb macromolecules by an energy-dependent pinocytotic mechanism similar to that described for the transport of immunoglobulins and other enteric antigens in certain mammalian species in the neonatal state. The vast majority of adults show no ill effects as a result of this physiologic phenomenon. However, when increased (pathologic) quantities of antigenic macro-molecules gain access to the body because of a derangement in the intraluminal digestive process, or because of a defect in the mucosal barrier, both of which are present in the immature intestine, macromolecular absorption may be altered and result in either local intestinal or systemic disorders.
Enteric administration of soluble or particulate antigens to unprimed animals has been repeatedly demonstrated to blunt or abrogate the cellular and humoral immune response to parenteral immunization. We tested the effect of administering bovine serum albumin by gavage or in the drinking water on the serum antigen-binding activity of rats primed by previous immunization with bovine serum albumin and alum. In some animals, this treatment served initially to boost the systemic humoral response; prolonged treatment led to a reduction in antigen-binding activity at a faster rate than was observed in sham-fed controls. In all rats treated with enteric antigen, the booster response to a second parenteral immunization was reduced or absent. Example of the use of enteric antigen in treatment of patients are cited. On the basis of our findings in rats and those of other investigators who studied mice, as well as the results obtained in patients, it is suggested that further exploration of the enteric approach to treating actively immunized subjects appears warranted.