Local and global aspects of biological motion perception in children born at very low birth weight.

Biological motion perception can be assessed using a variety of tasks. In the present study, 8- to 11-year-old children born prematurely at very low birth weight (<1500 g) and matched, full-term controls completed tasks that required the extraction of local motion cues, the ability to perceptually group these cues to extract information about body structure, and the ability to carry out higher order processes required for action recognition and person identification. Preterm children exhibited difficulties in all 4 aspects of biological motion perception. However, intercorrelations between test scores were weak in both full-term and preterm children--a finding that supports the view that these processes are relatively independent. Preterm children also displayed more autistic-like traits than full-term peers. In preterm (but not full-term) children, these traits were negatively correlated with performance in the task requiring structure-from-motion processing, r(30) = -.36, p < .05), but positively correlated with the ability to extract identity, r(30) = .45, p < .05). These findings extend previous reports of vulnerability in systems involved in processing dynamic cues in preterm children and suggest that a core deficit in social perception/cognition may contribute to the development of the social and behavioral difficulties even in members of this population who are functioning within the normal range intellectually. The results could inform the development of screening, diagnostic, and intervention tools.

Addressing human variability in risk assessment--the robustness of the intraspecies uncertainty factor.

Addressing human variability and sensitive subpopulations is one of the challenges of risk assessment and is an important aspect of the Food Quality Protection Act, the law passed in 1996 that regulates food use pesticides in the United States. The intraspecies uncertainty factor is intended to address differences in susceptibility within the human population. This paper examines the history and scientific basis for the intraspecies uncertainty factor. Our best source of knowledge about human variability in the response to chemicals comes from clinical trials of pharmaceuticals. This large body of data allows both qualitative and quantitative characterization of variability in pharmacokinetic and pharmacodynamic parameters in the general population and in subgroups such as children. The preponderance of evidence in the areas of pharmacodynamics and pharmacokinetics supports the routine use of an intraspecies uncertainty factor in the range of 1-10 as being protective of greater than 99% of the human population. The intraspecies uncertainty factor is highly protective of various subpopulations, including infants and children.

Common mechanism of toxicity: a case study of organophosphorus pesticides.

The Food Quality Protection Act of 1996 (FQPA) requires the EPA to consider "available information concerning the cumulative effects of such residues and other substances that have a common mechanism of toxicity ... in establishing, modifying, leaving in effect, or revoking a tolerance for a pesticide chemical residue." This directive raises a number of scientific questions to be answered before the FQPA can be implemented. Among these questions is: What constitutes a common mechanism of toxicity? The ILSI Risk Science Institute (RSI) convened a group of experts to examine this and other scientific questions using the organophosphorus (OP) pesticides as the case study. OP pesticides share some characteristics attributed to compounds that act by a common mechanism, but produce a variety of clinical signs of toxicity not identical for all OP pesticides. The Working Group generated a testable hypothesis, anticholinesterase OP pesticides act by a common mechanism of toxicity, and generated alternative hypotheses that, if true, would cause rejection of the initial hypothesis and provide criteria for subgrouping OP compounds. Some of the alternative hypotheses were rejected outright and the rest were not supported by adequate data. The Working Group concluded that OP pesticides act by a common mechanism of toxicity if they inhibit acetylcholinesterase by phosphorylation and elicit any spectrum of cholinergic effects. An approach similar to that developed for OP pesticides could be used to determine if other classes or groups of pesticides that share structural and toxicological characteristics act by a common mechanism of toxicity or by distinct mechanisms.

A 2-year comparison study of Crl:CD BR and Hsd:Sprague-Dawley SD rats.

In this 2-year study, the suitability of the Hsd:Sprague-Dawley SD (SD) as a replacement for the Crl:CD BR (CD) rat was assessed by comparing survival rates, palpable mass incidence, body weights, food consumption, clinical laboratory parameters, and necropsy and histopathology observations. At week 104, survival rates in the CD and SD males were 29 and 49%, respectively. Corresponding survival rates in females were 44 and 63%. The total numbers of animals with palpable masses and animals with neoplasms were similar in the CD and SD rats; however, the total numbers of palpable masses and neoplasms were higher in the CD rats. The incidence of corneal lesions was higher in the SD rats, whereas the incidence of lenticular opacities was higher in the CD rats. Body weights, food and water consumption, and organ weights were significantly lower in the SD rats. In contrast, food intake per kilogram of body weight was slightly higher in the SD rats. Numerous differences in clinical laboratory parameters between the CD and SD rats were observed. Some of these were consistent with the increased prevalence of kidney disease and secondary sequelae in the SD rats. Taken together, the better survival, smaller size, and lower food consumption of the SD rat may make it a better model for chronic bioassays. However, the increased propensity for spontaneous renal disease may limit the utility of the SD rat for studying nephrotoxic compounds.

Comparison of Periotest values of integrated implants with and without healing abutments: a pilot study.

The role of the Periotest in the clinical evaluation of osseointegration has been well documented. Some clinicians have used the initial Periotest values at second-stage surgery as a baseline to measure changes in integration at the bone-implant interface over time. The purpose of this pilot study was to compare Periotest values made with and without healing abutments in place. A statistically significant difference was found between the Periotest values that were recorded with and without healing abutments, with the values without the healing abutments being more negative and suggestive of greater osseointegration.

Distribution of somatostatin-14 and somatostatin-28 gastrointestinal-pancreatic cells of rats and humans.

Somatostatin-14 and somatostatin-28 are biologically active peptides derived from the posttranslational cleavage of prosomatostatin. Because both peptides are found in variable concentrations in the gastrointestinal (GI) tract and pancreas, it has been contended that somatostatin-28 is either an intermediate in the processing to somatostatin-14 or a terminal product derived from prosomatostatin. To address this question, two antisera were used to recognize epitopes in two regions of somatostatin-14; one with high specificity for somatostatin-14 and the other interacting with prosomatostatin, somatostatin-28, and somatostatin-14. Distribution of these peptides was measured in extracts of pancreas and mucosa and submucosa/muscularis from the rat and human GI mucosal biopsies; the antisera were used to immunostain cells in these tissues. Extracts of human and rat intestinal mucosa contained both somatostatin-28 and somatostatin-14. By immunocytochemistry, D cells in stomach and pancreas and neural processes in the intestine, extending into the mucosal villi adjacent to endocrine cells, stained with both antisera indicating the presence of somatostatin-14, prosomatostatin, and possibly somatostatin-28. In contrast, endocrine cells in the gut reacting with antisera against somatostatin-28 did not immunostain with somatostatin-14-specific antisera. Thus, these data suggest that somatostatin-28 is the terminal peptide processed from prosomatostatin in intestinal mucosal cells, whereas somatostatin-14 is the major final product in gastric and pancreatic D cells and neurons. The localization of somatostatin-28 and somatostatin-14 in different cells in the pancreas and GI tract implies that they serve different functions.

Morphological consequences of bisacodyl on normal human rectal mucosa: effect of a prostaglandin E1 analog on mucosal injury.

Bisacodyl causes acute injury to the human rectal mucosa. Our objectives were to test whether pretreating the human rectum with an enema of 400 micrograms of a prostaglandin E1 analog (misoprostol) would ameliorate the mucosal injury provoked by an enema of 10 mg of bisacodyl, and to follow the evolution of the bisacodyl-induced injury in normal volunteers. Mucosal biopsies were taken 10 cm from the anus with an endoscopic forceps through a straight sigmoidoscope. Histological sections were interpreted blindly. In a preliminary experiment without bisacodyl, biopsies obtained from six subjects after misoprostol administration were indistinguishable from those taken from another six subjects after enemas of saline. In a parallel treatment experiment involving 30 subjects, all subjects sustained injury to the superficial epithelium and upper third of the crypt within 30 min after bisacodyl. Pretreatment with misoprostol also failed to prevent deeper injury to the lower third of colonic crypts. In a cross-over trial, a subset of four volunteers had biopsies at five different intervals after an enema of bisacodyl or saline. For up to 30 hours after bisacodyl, there was histological evidence of mild inflammation. Bisacodyl-induced colitis might confound the assessment of patients with suspected inflammatory bowel disease.

Beneficial effects of glucose polymer and an H2-receptor blocker in a patient with a proximal ileostomy.

A patient with an ileocolectomy and proximal ileostomy for Crohn's disease had severe diarrhea and steatorrhea. An oral electrolyte solution containing glucose polymer was shown to improve water and electrolyte absorption. Ileal contents were abnormally acidic. Therapy with an H2-receptor blocker raised ileal pH, improved the efficiency of fat absorption, and promoted a gain in body weight.

Misoprostol reduces gastroduodenal injury from one week of aspirin: an endoscopic study.

Misoprostol is a synthetic prostaglandin E1 analogue that inhibits gastric acid production and may augment mucosal defense. A double-blind trial examined the effect of misoprostol on the endoscopic appearance of gastroduodenum at the end of 1 wk of aspirin ingestion. One hundred thirty healthy subjects were randomized to take either 50, 100, or 200 micrograms of misoprostol, or placebo along with 975 mg of aspirin four times daily. Fewer subjects developed acute endoscopic gastric ulcers in the group taking any dose of misoprostol compared with the placebo group (1% vs. 43%). No subject taking the 100- or 200-micrograms dose of misoprostol developed an acute endoscopic duodenal ulcer compared with 13% of subjects taking placebo (p less than 0.05). Significantly fewer subjects developed gastric erosions and significantly fewer subjects developed duodenal erosions in each of the three groups taking misoprostol compared with the placebo group (p less than 0.01). There were fewer subjects with a gastric erosion (p less than 0.05) and fewer subjects with a duodenal erosion (p less than 0.05) in the group taking the 200-micrograms dose compared with the group taking the 50-micrograms dose of misoprostol. Gastrointestinal symptoms causing a modification in usual activities were infrequent but there was significantly more diarrhea in the 200-micrograms misoprostol group. There was no correlation between endoscopic scores and symptoms in any group. We conclude that misoprostol can protect the normal gastroduodenum from acute ulceration and reduce the chance of erosion after 1 wk of aspirin ingestion.

Absorption of triglyceride by human small intestine: dose-response relationships.

Healthy subjects with ileostomies (ileostomates) were fed six breakfasts of 5-100 g linseed oil. This lipid source was chosen so that linolenic acid could be used as a fatty acid probe. Phenol red was included in the meal so that mouth-to-stoma transit could be measured as the t 1/2 of phenol red. Ileostomy effluent was collected over 24 h and the dose of lipid ingested was related to lipid output and to intestinal transit time. The coefficient of variation for mouth-to-stoma transit was less than 12%. The slopes of the least-square lines relating lipid ingested to lipid output and to mouth-to-stoma transit time were positive and significantly different (p less than 0.05) from 0. The ileostomate's small intestine absorbed linolenic acid with 98% efficiency. A delay in mouth-to-ileum transit, associated with increasing lipid loads, is one obvious mechanism that maintains the intestine's absorptive efficiency.

Comparison of human jejunal and ileal fat absorption by electron microscopy.

Morphologic and physiologic experiments in rodents have demonstrated differences between jejunal and ileal fat absorption. Compared with the rat jejunum, absorbed lipid particles within rat ileal absorptive cells are larger and exit at a slower rate. To evaluate the relevance of these observations to humans, we studied jejunal and ileal ultrastructure in 3 volunteers, each of whom had an intact small intestine and an ileostomy postcolectomy for ulcerative colitis. Proximal jejunal biopsy specimens were obtained via a hydraulic tube after an overnight fast and again after a 20-min intrajejunal lipid infusion. On a separate day, terminal ileal biopsy specimens were taken via the stoma with a small steerable suction biopsy tube after an overnight fast and again after a 20-min intraileal infusion of the same lipid mixture. One volunteer underwent biopsy after a 60-min ileal infusion of a digested meal of higher lipid content. Electron microscopy of fasting human jejunal absorptive cells revealed obvious smooth endoplasmic reticulum in the extreme apical region beneath the terminal web; very low density lipoprotein particles were observed within smooth endoplasmic reticulum and Golgi cisternae. In contrast, fasting human ileal absorptive cells contained less apical smooth endoplasmic reticulum and fewer or no very low density lipoprotein particles. After the 20-min infusion of lower-lipid content, human jejunal and ileal absorptive cells were indistinguishable because they contained fat particles of the same size and number within smooth endoplasmic reticulum, Golgi cisternae, and extracellular spaces. After the 60-min ileal infusion of higher-lipid content, human ileal absorptive cells appeared to be the same as those of the human jejunum after similar lipid infusions. Our observations of the ultrastructural similarity in human jejunal and ileal absorptive cells after lipid infusions contrasts with those in rodents and may reflect species-specific differences in mechanisms of fat absorption.

Reduction of endoscopically assessed acute aspirin-induced gastric mucosal injury with cimetidine.

We studied the influence of cimetidine on the gastroscopically visible effects of a single 1296-mg dose of aspirin. An initial dose-response study in 48 subjects showed that 200- and 400-mg doses of cimetidine conferred a sufficient reduction in gastric mucosal injury to warrant further study. A second study showed that coadministration of a single 200- or 400-mg cimetidine tablet with the aspirin conferred the same degree of injury reduction as when cimetidine was given before the aspirin. Reduction in mucosal injury by a 200-mg cimetidine tablet, coadministered with four aspirin tablets, was then compared to placebo in a double-blind trial. A reduction of mucosal injury was observed in 14 of 20 (70%) subjects receiving cimetidine and 0 of 10 subjects receiving placebo (P less than 0.001). Two hundred milligrams of cimetidine is therefore a rational dose for further studies of the reduction of chronic aspirin-induced gastric mucosal injury.

Gastric protection by misoprostol against 1,300 mg of aspirin. An endoscopic dose-response study.

Misoprostol at a dose of 200 micrograms inhibits gastric acid secretion and protects the gastric mucosa against the injurious effects of a single 1,300-mg dose of aspirin. The purpose of this study was to determine whether lower subantisecretory doses of misoprostol protect the gastric mucosa in this single-dose aspirin model. Protection was defined as no more than 10 hemorrhagic spots and no more than two hemorrhagic streaks. A total of 140 men participated in the two phases of the study. In the first phase, groups of 10 subjects each received placebo or misoprostol in doses of 200 micrograms, 100 micrograms, 50 micrograms, or 25 micrograms in a double-blind design. All misoprostol doses protected 50 to 70 percent of subjects as compared with 20 percent of subjects in the placebo group. To expand the number of observations, 90 additional subjects in groups of 30 each were evaluated after receiving misoprostol 50 micrograms or 25 micrograms or placebo. Misoprostol 50 micrograms protected 14 of 30 subjects (47 percent), 25 micrograms protected 11 of 30 (37 percent), and placebo protected six of 30 (20 percent). The dose-response trend was statistically significant (p less than 0.05). It is concluded that misoprostol protects the gastric mucosa against a single 1,300-mg dose of aspirin and that there is a significant dose-response relationship.

Gastric protection by misoprostol against 1300 mg of aspirin. An endoscopic study.

Misoprostol, a synthetic prostaglandin E1 analog, is being evaluated in the treatment of peptic ulcer. It has been reported to have both antisecretory and cytoprotective properties. In this placebo-controlled, double-blind study, pretreatment with 200-micrograms doses of misoprostol was evaluated in the prevention of gastric injury caused by aspirin. Five oral doses of misoprostol or placebo were administered over 24 hr followed by a single oral 1296-mg dose of aspirin 30 min after the fifth dose of test agent. Two hours later the gastric mucosa was examined with a small-caliber fiberendoscope. Protection was defined as no more than 10 petechiae and no more than two hemorrhagic streaks in the gastric mucosa. Twenty of 30 (67%) subjects who received misoprostol was protected, whereas only one of 30 (3%) subjects receiving placebo was protected. The difference between the effects of misoprostol and placebo was highly significant (P less than 0.001). We concluded that five 200-micrograms doses of misoprostol given over 24 hr protects the gastric mucosa from the injurious effect of a single dose of aspirin.

Effect of oral dioctyl sodium sulfosuccinate on intake-output studies of human small and large intestine.

Dioctyl sodium sulfosuccinate (DSS) is an anionic detergent that is used widely as a laxative and promoted as a stool softener. Although many anecdotal reports attest to the laxative and stool softening efficacy of DSS, no controlled trials have been performed to document the effect of DSS on small or large bowel function in humans. We have compared, therefore, the effects of 100 mg of DSS three times daily (the maximum recommended dose) with placebo in a randomized, single blind, crossover study in two groups of subjects. First, 6 healthy ileostomates were studied while they ate a constant diet for 8 days. Dioctyl sodium sulfosuccinate administered for 4 days did not increase the daily ileal output of carbohydrate, total fatty acids, bile acids, nitrogen, or water. Cholesterol excretion was decreased while taking DSS (p less than 0.05). Second, 6 healthy volunteers were studied while eating a constant diet of 20 g of fiber plus 30 radiopaque markers daily so that mean daily transit time could be measured. After equilibration, a 7-day collection of stool was weighed and lyophylized to measure fecal water. Dioctyl sodium sulfosuccinate had no effect on stool weight, stool frequency, stool water, or mean transit time. We conclude that 300 mg/day of DSS does not increase ileal or colonic output of solids or water in healthy human subjects.

Absorption of starch by healthy ileostomates: effect of transit time and of carbohydrate load.

Recently, breath hydrogen studies and intubation techniques have indicated that in excess of 10% of starch in normal foods may be malabsorbed in the small intestine and enter the colon. We evaluated starch absorption in healthy subjects with ileostomy. First, unabsorbed starch was quantified in ileostomy effluent from six ileostomates who ingested constant diets of wheat and potato starch for four days. Daily unabsorbed starch ranged from 1.3% to 5.0% of total ingested starch. Second, starch from a radiolabeled solid meal containing 50 g potato starch was measured under control conditions and after altering transit time with either loperamide, or magnesium citrate. Loperamide significantly decreased the amount of unabsorbed starch in all six ileostomates (p less than 0.05), while magnesium citrate significantly increased starch malabsorption in all six subjects (p less than 0.05). Third, starch absorption was measured after single solid meals containing 25, 50, 75, and 100 g potato starch. There was a linear relationship between starch input and output. Mean output expressed as a percent of input remained constant. We conclude that the degree of starch malabsorption by the small intestine of ileostomates may be less than that estimated by indirect methods in intact humans. The amount of unabsorbed starch is directly related to the quantity ingested and to the small intestinal transit time.

Absorption of carbohydrate-electrolyte solutions in rat duodenojejunum. Implications for the composition of oral electrolyte solutions in man.

Commonly used oral electrolyte solutions are based on glucose, or sucrose, and 90 mM Na+. We had been disappointed with the ability of such solutions to improve Na+ absorption in patients with extensive resection of distal small bowel. Therefore, we tested the effect on net Na+ and water transport of combinations of different carbohydrates (glucose, sucrose, and glucose polymers) and NaCl in the rat duodenojejunum. Absorption was measured under steady-state conditions in unanesthetized animals which were infused with a different combination every hour for up to 5 hr. Of the various combinations, 10 mM glucose polymer (equivalent to 56 mmol of glucose as glucose oligosaccharides), or 60 mM glucose promoted net Na+ absorption from 120 mM NaCl and 20 mM KCl, but the glucose polymer infusate promoted more rapid water absorption than did the infusate containing glucose. The infusate of 10 mM glucose polymer in saline was initially hypotonic (276 mosmol/kg), but it became isotonic (298 mosmol/kg) as the glucose polymer was hydrolyzed during its passage through the duodenojejunum. In contrast, an infusate of 60 mM sucrose with 120 mM NaCl and 20 mM KCl remained hypertonic (320 mosmol/kg), and it did not promote water and Na+ absorption by the duodenojejunum. The efficacy of 10 mM glucose polymer with 120 mM NaCl should be tested in patients with short-bowel syndrome due to distal bowel resection.

Prevention of acute aspirin-induced gastric mucosal injury by 15-R-15 methyl prostaglandin E2: an endoscopic study.

The deleterious effects of aspirin on gastric mucosa have been well documented in experimental and clinical studies. Prostaglandins offer a potential method by which this injury may be prevented. In these studies, we developed a single-dose endoscopic assay system of aspirin-induced gastric mucosal injury in normal volunteers. With this system, 27 of 30 volunteers (90%) demonstrated severe mucosal injury after ingestion of aspirin. Subsequently, we evaluated whether pretreatment with 15-R-15 methyl prostaglandin E2 prevented severe injury after ingestion of aspirin. Following an initial dose-response study, a double-blind crossover trial was performed using pretreatment with placebo or with 10-micrograms doses of 15-R-15 methyl prostaglandin E2 for 24 h before treatment with aspirin. The results of this trial indicate that prostaglandin pretreatment significantly prevented the occurrence of endoscopically visible severe gastric mucosal injury after single-dose aspirin administration.