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Primary sclerosing cholangitis (PSC) has been suggested as a risk factor for the development of colorectal cancer in ulcerative colitis (UC); however, previous studies of this association have been limited by small numbers of patients with PSC or have been performed retrospectively. This study prospectively evaluates the risk and natural history of colonic tumorigenesis in patients with PSC and UC and compares it with patients with UC without PSC.Twenty patients with PSC and UC and 25 control patients with UC were followed prospectively by colonoscopic surveillance using extensive mucosal biopsy sampling. All control patients with UC had disease extending beyond the sigmoid colon ofor = 8 years' duration; patients with PSC and UC were studied regardless of disease duration.Forty-five percent (9 of 20) of the patients with PSC and UC had dysplasia compared with 16% (4 of 25) of the control patients with UC (Por = 0.002). Prior liver transplantation did not affect the risk of colonic dysplasia. The time course for progression to dysplasia was similar between the patients with PSC and UC and the patients with UC; however, the patients with PSC and UC were five times more likely to develop dysplasia.Patients with PSC and UC represent a subset of patients with UC who are at markedly increased risk for colonic neoplasia and who need close colonoscopic surveillance with extensive biopsy sampling.

The objective of the present study was to determine whether abnormal epithelial DNA content (aneuploidy) in colonic biopsy specimens from ulcerative colitis (UC) patients correlated with and predicted histological progression to dysplasia. Aneuploidy was absent in 20 low-cancer risk patients. In 81 high-cancer risk patients aneuploidy correlated significantly with the severity of histological abnormality (negative, indefinite, dysplasia, or cancer). Statistically our data suggest that many more biopsy specimens than are usually taken are needed to detect focal dysplastic lesions. Prospective study of 25 high risk patients without dysplasia revealed 5 with aneuploidy, all of whom progressed to dysplasia in 1-2.5 years, whereas 19 patients without aneuploidy did not progress to either aneuploidy or dysplasia within 2-9 years. Our data indicate that aneuploidy in mucosal biopsy specimens correlates with histological grade and identifies a subset of patients without dysplasia who are more likely to develop it. It was concluded that more frequent and extensive colonoscopic surveillance of this minority subset of high risk patients and less frequent surveillance in the remaining majority may reduce cost and detect more curable lesions.

Neoplastic progression in patients with chronic ulcerative colitis (UC) is characterized by the development of epithelial dysplasia, which is accompanied by genetic abnormalities that can be detected by flow cytometric and molecular biologic methods. Distribution of and correlation between histologic abnormalities, DNA content, and loss of heterozygosity for a p53 allele (p53 LOH) in the colons of nine UC patients were analyzed. Loss of a p53 allele was found in 85% (22/26) of biopsy specimens classified histologically as carcinoma, 63% (25/40) of biopsy specimens with high grade dysplasia, and 33% (7/21) of biopsy specimens with low grade dysplasia. Loss of heterozygosity for p53 was also found in 9% (5/57) of biopsy specimens indefinite for dysplasia and in 1/18 biopsy specimens negative for dysplasia, showing that this genetic change may occur early in the histological progression towards carcinoma. Aneuploid DNA contents were more common than p53 LOH in regions with negative, indefinite or low grade dysplastic histology; moreover, p53 LOH was detected only in aneuploid cells and not in diploid epithelium. Aneuploidy alone was not as specific a marker for the concomitant presence of dysplasia or carcinoma in a biopsy sample as aneuploidy combined with p53 LOH. These findings show that aneuploidy may precede both p53 LOH and epithelial dysplasia. Two UC patients' colons contained geographically separated clones of cells with different aneuploidies that also showed loss of different p53 alleles, suggesting that neoplasia may arise within different populations of cells in separate areas of the same colon.

To determine whether or not flow-cytometric evidence of aneuploidy and increased G2/tetraploid fractions predispose to neoplastic progression in Barrett's esophagus, 62 patients with Barrett's esophagus were evaluated prospectively for a mean interval of 34 months. Nine of 13 patients who showed aneuploid or increased G2/tetraploid populations in their initial flow-cytometric analysis developed high-grade dysplasia or adenocarcinoma during follow-up, none of the 49 patients without these abnormalities progressed to high-grade dysplasia or cancer ( P

Flow cytometry was used to detect the presence and assess the distribution of aneuploid cell populations in eight proctocolectomy specimens from patients with ulcerative colitis. Mucosal samples were taken according to a systematic protocol for flow cytometry, the surrounding tissue was examined histologically, and the distributions of flow cytometric and histologic abnormalities were "mapped" within each resected colon. Two resection specimens that were negative for dysplasia lacked aneuploid cell populations. Four resection specimens with final case diagnoses of dysplasia or Dukes' stage A carcinoma had 1–5 regions of aneuploidy or increased 4N (G2/ tetraploid) cell populations located in discrete areas of the colon. Two specimens with dysplasia or Dukes' stage C carcinoma each had 14–15 different, often overlapping, regions of aneuploidy or increased 4N (G2/tetraploid) cell populations involving large portions of the colonic mucosa. Analysis of the DNA content of the invasive portion of the tumor from the specimen with a Dukes' stage C carcinoma showed a single aneuploid cell population. The results show that single or multiple aneuploid cell populations are often present in colons resected for ulcerative colitis with dysplasia or early cancer. The distribution of these aneuploid cell populations suggests that each represents a clone of cells that has expanded to occupy a discrete region of colonic mucosa. Additional genetic errors may result in multiple aneuploid cell populations that may be associated with an increased risk of developing cancer. These data, therefore, are consistent with the hypothesis that genomic instability and clonal evolution are associated with the progression to dysplasia and carcinoma in ulcerative colitis. Because flow cytometry can measure aneuploid cell populations in colonoscopic mucosal biopsies, it may prove to be complementary to histology for detecting patients with ulcerative colitis who are at risk for neoplastic progression.

A normal or mildly abnormal fundal gland histology and its well-documented enlarged parietal cell mass. The critical evaluation of gastric biopsy published in this journal 30 years ago was uncertain regarding clinicopathologic correlations in gastritis. Although the two H. pylori gastritides other than DAG involve both antrum and body and become progressively abnormal discovery of the etiologic importance of Helicobacter pylori has greatly advanced our understanding of the pathogenwith time. In DAG, the fundal glands of the body do not become progressively more abnormal with the passage of esis of gastritis, several unsolved problems remain. A critical question is which histological patterns of H. pytime. More than 50 years ago, Robert Hebbel meticulously documented the differences in gastric mucosal hislori–induced gastritis are associated with different types of ulcer and cancer? tology in patients with duodenal compared with gastric ulcer. Most subsequent studies have confirmed Hebbel’s This viewpoint will mainly address the variations in the histological patterns of H. pylori gastritis and their findings, but none are as extensive and well controlled as his classic description. The patterns of H. pylori gastriassociated diseases. Much of the data are not of the quality or quantity to justify final conclusions. Nevertheless, crittis are well described in a preliminary endoscopic study that is outstanding because of the extensive biopsy samical reevaluation may be worth undertaking now because of some new studies relating H. pylori to various types pling and the suitability of the controls. H. pylori–DAG is the pattern of which I am most confident because I of gastritis. Also, there are some observations in the older literature that merit reconsideration. I now believe that have been able to recognize it on blinded review of gastric biopsy specimens in 92% of 311 patients with endoscopithere is evidence for three kinds of HP gastritis: the first associated with duodenal ulcer, the second with gastric cally proven duodenal ulcers. The pangastritis involving the whole stomach, now ulcer and gastric cancer, and the third with neither ulcers nor usually with symptoms. known to be caused by H. pylori, was well described by Correa and Stemmerman and Hayashi. It is referred to The gastritis pattern associated with duodenal ulcer can probably be recognized relatively easily by examining by the acronym MAG for multifocal atrophic gastritis. I three large, well-placed endoscopic biopsy specimens believe that MAG should be subdivided and would be (two from the lesser curvature of the antrum and one better replaced by two new acronyms representing diffrom the mid–greater curvature of the gastric body). The ferent clinicopathologic subsets: nonulcer pangastritis acronym for this type of gastritis is DAG for diffuse (NUP), found in usually asymptomatic H. pylori–infected antral-predominant gastritis. Inflammation of the pyloric individuals without ulcers, and progressive intestinalized glands of the antrum is diffuse and will be of similar pangastritis (PIP), found in patients with non–nonsteroiseverity in both antral biopsy specimens. Although focal dal anti-inflammatory drug (non-NSAID) gastric ulcers intestinal metaplasia may be present in the antrum of and distal gastric cancers. 10%–20% patients with duodenal ulcer, it is less severe The acronym NUP is proposed for the type of gastritis and far less extensive than that seen in patients with seen in more than 90% of usually asymptomatic individgastric ulcer. On the other hand, inflammation of the uals infected with H. pylori who do not have an ulcer. fundal glands is mild or absent in DAG despite histologiThis entity has not been studied extensively because it cally demonstrable H. pylori infection. Intestinal metais difficult to justify endoscopy with extensive biopsy in plasia of the fundal glands is never seen in DAG. Beasymptomatic individuals. However, it has been well cause extensive intestinal metaplasia is the most accepted Abbreviations used in this paper: DAG, diffuse antral-predominant possible precursor of distal gastric cancer, it is not surgastritis; MAG, multifocal atrophic gastritis; NUP, nonulcer pangasprising that the gastric cancer risk is low in patients tritis; PIP, progressive intestinalized pangastritis. with duodenal ulcer disease. Similarly, increased acid q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00 secretion in duodenal ulcer is to be expected with its

Background & Aims: The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of >8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified. Methods: A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma. Results: After direct sequencing of exon 13 and flanking regions of human MSH2 , a germline T to C substitution was shown at the −6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) ( P ≤ 0.04) and in 7 of 80 healthy adult blood donors (9%) ( P ≤ 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it. Conclusions: An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.

Background/Aims: In long-term extensive ulcerative colitis, aneuploidy occurs earlier and loss of heterozygosity for p53 ( p53 LOH) later during histological progression towards carcinoma. This study determined the time of onset of p53 mutation in this progression. Methods: We developed a rapid, sensitive screening assay for p53 mutations at codon 248. The geographic distribution of this p53 mutation was mapped in two fresh colectomy specimens with mutations of codon 248 (1 cancer, 1 dysplasia) and correlated with patterns of clonal expansion, histological progression, and allelic loss. Numerous samples from throughout both colons were analyzed (216 for histology, 142 for DNA content, 104 for mutation, and 41 for p53 LOH). Results: p53 mutation correlated highly with histological grade and was distributed more extensively than p53 LOH. Mutation, but not LOH, was also found in diploid, nondysplastic colonic mucosa adjacent to dysplastic areas. Conclusions: These findings suggest that p53 mutation appears to be an early genetic event that precedes p53 LOH. The very close correlation of p53 mutation with aneuploidy ( P > 0.0001) emphasizes the role of normal p53 at the G 1 checkpoint to help prevent entry of genetically damaged cells into the cell cycle.

Allelic deletions of the p53 gene previously were demonstrated by Southern hybridization to occur in high frequency in sporadic colon carcinomas and in a variety of other human tumors. We have examined the frequency of allelic loss of the p53 gene in carcinoma and dysplasia arising in patients with chronic ulcerative colitis who are heterozygous for the codon 72 polymorphism in exon 4 of the p53 gene. Cells derived from carcinoma and dysplasia specimens from 10 patients who were heterozygous at this locus were sorted by flow cytometry on the basis of DNA content. The p53 exon 4 region was amplified from diploid and aneuploid populations, via a polymerase chain reaction (PCR), and digested with BstUI. Three of three carcinomas, four of six dysplasias, and one patient who was indefinite for dysplasia demonstrated evidence of allelic loss of the p53 gene. Seven of ten cases of sporadic colon carcinoma, analyzed for comparative purposes, exhibited loss of a p53 allele. These results demonstrate that PCR analysis, followed by restriction endonuclease digestion of a polymorphic locus, can provide a rapid, definitive method for analyzing loss of heterozygosity in small numbers of cells from colonic mucosa. Such loss precedes cancer in ulcerative colitis and can be present in its earliest histologically identifiable precursor.

Mutations in the first exon of the c-Ki-ras protooncogene were analyzed in carcinomas and dysplasias from patients with sporadic colon cancer and chronic ulcerative colitis by a combination of histological enrichment, cell sorting, polymerase catalyzed chain reaction, and direct sequencing. In contrast to sporadic colon carcinomas, where 52% (11 of 21) contained mutations in codon 12, only 1 of 28 samples of ulcerative colitis associated carcinoma or dysplasia contained a c-Ki-ras mutation, despite the presence of aneuploid cell populations. These results suggest that a different genetic pathway for tumor progression may exist between sporadic colon carcinoma and carcinomas arising in chronic ulcerative colitis.

The potential value of biopsy surveillance of patients with Barrett's esophagus for dysplasia is diminished by a lack of agreement on the diagnostic criteria for dysplasia. In a preliminary consensus conference, experienced gastrointestinal pathologists from four medical centers agreed on criteria for a five-tiered histologic classification of dysplasia in Barrett's esophagus--negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, and intramucosal carcinoma. Eight morphologists in the four centers tested the criteria for interobserver agreement by examining a set of coded slides that had been chosen to include some especially difficult interpretative problems in all five histologic classifications. Interobserver agreement of 85 and 87% was achieved in successive reviews when the combined group of high-grade dysplasia and intramucosal carcinoma was compared with the combined group of low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia. Comparison of other groups yielded less agreement. For example, negative for dysplasia could be distinguished from all other diagnoses with an interobserver agreement of 72%. We conclude that experienced gastrointestinal morphologists can diagnose high-grade dysplasia and intramucosal carcinoma with a high degree of agreement and thus can detect those patients who may need immediate rebiopsy or esophageal resection. Either further refinement of histologic criteria or alternate diagnostic methods will be needed to achieve the reproducible diagnosis of indefinite changes and low-grade dysplasia. This is important because patients with such changes theoretically merit closer endoscopic surveillance.

Barrett's esophagus develops as a complication of chronic gastroesophageal reflux and predisposes patients to the development of dysplasia and adenocarcinoma of the esophagus. Because light microscopy of dysplasia in Barrett's esophagus shows diminished or absent mucus, we used transmission electron microscopy to compare cytoplasmic organelles required for mucus production in dysplastic and nondysplastic esophageal columnar epithelium. These observations of the rough endoplasmic reticulum, Golgi apparatus, and secretory granules were correlated with histologic interpretations and flow cytometric measurements of abnormalities of DNA content. Ultrastructural abnormalities included depletion and alteration of organelles required for mucus biosynthesis. These abnormalities often were accompanied by cells with markedly distended rough endoplasmic reticulum and massive accumulation of cytoplasmic glycogen aggregates. All 9 patients who had Barrett's dysplasia with or without early adenocarcinoma had ultrastructural abnormalities, as did 3 of 8 patients whose biopsy histology was indefinite for dysplasia. Abnormalities measured by flow cytometry correlated well with the presence of these ultrastructural aberrations. All 9 patients with Barrett's dysplasia with or without early adenocarcinoma had abnormalities observed by electron microscopy and aneuploidy or increased G2ltetraploid fractions measured by flow cytometry. Two of the 3 patients whose biopsies were indefinite for dysplasia and who had ultrastructural abnormalities also had aneuploidy or increased G 2 /tetraploid fractions. Neither ultrastructural nor flow cytometric abnormalities were found in the remaining 5 patients whose biopsies were indefinite for dysplasia, in 19 of 22 patients with Barrett's specialized metaplasia, or in any of the 7 patients with gastroesophageal reflux disease without Barrett's specialized meta plasia. Two of the 22 patients with Barrett's specialized metaplasia had distended rough endoplasmic reticulum in rare cells, and one other had an aneuploid cell population. We conclude that neoplastic progression in Barrett's esophagus is associated with abnormalities of cytoplasmic organelles required for mucus production. With few exceptions, these ultrastructural aberrations correspond to the presence of dysplasia or of aneuploidy or increased G 2 /tetraploid fractions. Electron microscopy and flow cytometry detect abnormalities associated with the development of dysplasia and cancer in Barrett's esophagus that may be biologically significant.

A neodymium YAG (Nd:YAG) laser was evaluated in a dog ulcer model used in the same manner as is recommended for bleeding patients (power 55 W, divergence angle 4 degrees, with CO2 gas-jet assistance). The experiments were performed during sterile laparotomy in heparinized dogs. Bleeding gastric ulcers were photocoagulated until bleeding stopped and then examined histologically 7 days later when depth of tissue injury was maximal. In the first series of experiments, the Nd:YAG laser was compared with the 7-W argon laser in the same dogs. Both lasers stopped bleeding from all experimental ulcers. The 55-W Nd:YAG laser caused full-thickness injury to the gastric wall beneath 11 of the 14 treated ulcers, whereas the 7-W argon laser caused no full-thickness injury beneath 14 treated ulcers. In a second series of experiments, we tried to determine whether varying exposure times with the 55-W Nd:YAG laser would make it less injurious; it did not. In a third series of experiments, the 55-W Nd:YAG laser was tested with and without CO2 gas-jet assistance in order to determine if this would affect the depth of injury; it did not. In the final series of experiments, the wattage of the Nd:YAG laser was varied to see if this would reduce depth of injury; lower wattage did not stop bleeding, and intermediate and higher wattages did stop bleeding but did not reduce depth of injury. We conclude that the 55-W Nd:YAG laser as it is currently used clinically produces deeper tissue damage than the argon laser in our animal model. This damage is not reduced by changes in power, duration of exposure, or the presence of gas-jet assistance.

We have developed a heater probe which can be passed via an endoscope and which can apply pressure and heat simultaneously to a bleeding vessel. A 6.4-mm diameter prototype and a 3.2-mm diameter working model of this device have been tested for efficacy in stopping massive bleeding in experimental canine gastric ulcers. Randomized, internally controlled experiments were carried out at laparotomy in heparinized dogs using standard-sized gastric ulcers made and treated via an ample gastrotomy. In acute experiments the heater probe stopped bleeding from all treated ulcers, whereas all untreated control ulcers continued bleeding. In chronic studies performed at sterile laparotomy the depth of injury produced by heater probe coagulation was systematically evaluated; dogs were killed at intervals from 1 week to 1 month. No perforations occurred, but histological injury was evident extending from the ulcer base to the serosa in 7 of the 18 ulcers treated with the 6.4-mm probe and in 2 of the 30 ulcers treated with the 3.2-mm probe. In a preliminary endoscopic experiment the 3.2-mm probe stopped bleeding in 18 of 19 acute experimental ulcers. Histological evidence of injury extending to the serosa occurred in six instances; no perforations occurred. The efficacy in stopping bleeding with this method is satisfactory, but the depth of injury should be reduced before considering application to human beings.

The value of endoscopic surveillance biopsy for dysplasia and carcinoma in patients with Barrett's esophagus is controversial. One reason is that the available histologic criteria are not adequate to separate patients with lesser degrees of dysplasia or predysplastic changes who are at increased risk for carcinoma and therefore require more frequent surveillance from those patients who are not at increased risk. We used flow cytometry and histology to evaluate 317 biopsy specimens from 64 consecutive patients who were in a cancer surveillance program for Barrett's esophagus and 3 additional patients with adenocarcinoma in Barrett's esophagus. Specimens from 10 patients had aneuploid cells; 9 of these had dysplasia or carcinoma, or both, but 1 patient had only specialized metaplastic epithelium. Twenty specimens ahd G2/tetraploid fractions greater than 6%; all 20 came from patients who had cancer or dysplasia, or were indefinite for dysplasia. All patients with dysplasia or adenocarcinoma had evidence of genomic instability (aneuploidy) or abnormalities of mucosal proliferation by flow cytometry, even when the dysplasia was focal or difficult to recognize histologically. In a small subset of patients with specialized metaplastic epithelium whose specimens were histologically negative or indefinite for dysplasia, the mucosa had aneuploid cell populations or proliferative abnormalities that were otherwise found only in dysplasia or carcinoma. Additional study may prove that this subset of patients merits more frequent endoscopic biopsy surveillance because of an increased risk for developing carcinoma. Because the abnormalities we have detected by flow cytometry correlate well with the conventional histologic diagnoses of dysplasia and carcinoma, they may prove to be a valuable objective adjunct in the diagnosis of dysplasia and carcinoma in Barrett's esophagus.

A single quartz fiber delivery system capable of remotely depositing in excess of 9 watts of continuous laser radiation has been developed and tested. Of particular interest in this development was the achievement of a catheter that can be inserted into the biopsy channel of a conventional flexible endoscope for noninvasive control of gastric bleeding. In animal testing, the prototype device was found capable of producing a large useful area of superficial tissue coagulum, effectively controlling gastric hemorrhage. Future clinical application is highly encouraging.

A previously healthy 67-yr-old man presented with progressive dementia over an 11-mo period. Evaluation revealed evidence of malabsorption. Jejunal biopsy established the diagnosis of Whipple's disease. No other etiology for the patient's dementia was uncovered. Treatment with trim ethoprim-sulfamethoxazole resulted in rapid elimination of Whipple's bacilli from the jejunum and complete reversal of the patient's dementia over a 6-mo period. Significant levels of trimethoprim and sulfamethoxazole were easily quantitated in the cerebrospinal fluid during therapy. There is increasing recognition of progressive neurologic disease in patients with Whipple's disease who were treated with tetracycline. The reversal of presumed central nervous system disease in this case suggests that drugs that penetrate the blood-brain barrier might be preferable for the initial treatment of Whipple's disease.

A practical approach to the interpretation of peroral small intestinal biopsy specimens is presented. Biopsy technique and tissue handling are described. Interpretation of normal and abnormal biopsy specimens is discussed. A practical classification of abnormal small intestinal biopsies is presented and illustrated.

Gastric acid secretion in response to a protein meal and to exogenously administered synthetic human gastrin 17-I was measured in patients with Barrett's esophagus, patients with uncomplicated gastroesophageal reflux, and normal age- and sex-matched controls. Acid secretion, both basally and in response to gastrin 17-I, was significantly greater in patients with Barrett's esophagus compared to normal individuals without reflux. Basal gastrin levels and meal-stimulated levels of the hormone were similar among all three groups. Sensitivity to gastrin, expressed as the concentration causing half-maximal acid secretion, was also similar among the study groups. It is speculated that elevated basal acid production in Barrett's esophagus may contribute to the pathogenesis of the disorder.

Summary A hydraulically operated suction biopsy tube is described which is capable of taking any number of biopsies from any level of the gastrointestinal tract and delivering them externally within seconds of excision while the instrument itself remains in place. These mucosal specimens compare favorably with those obtained by other instruments. Despite a temporary postbiopsy syndrome in onethird of our patients, no major complications have been observed to date.

Seven of 8 patients with hypogammaglobulinemia and gastrointestinal symptoms were infected with Giardia lamblia. This parasite was not detected by multiple stool examinations in 4 of the 7 infected patients but was diagnosed correctly by small intestinal biopsy. Abnormalities of the small intestinal mucosa were found in all 8 patients. Two patients had nodular lymphoid hyperplasia and 3 the flat lesion of hypogammaglobulinemic sprue. The remaining 3 patients had mixed lesions; that is, the lesions varied both in severity of the villus abnormality and in the frequency of lymphoid nodules. All patients lacked plasma cells in the lamina propria. Because of the variation in the severity of the small intestinal abnormalities within individual patients, multiple small bowel biopsies were needed to evaluate the effects of treatment on mucosal morphology. After eradication of Giardia lamblia in 7 patients, the abnormalities in villus structure returned towards normal in all. No change occurred after a course of metronidazole (Flagyl) in the 1 patient who had a severe intestinal lesion but no evidence of giardiasis. Four patients with steatorrhea and giardiasis gained weight and their fecal fat excretion returned to normal. Diarrhea disappeared after treatment in the remaining 3 patients.

Steatorrhea in small intestinal stasis syndrome is often attributed to defective luminal micelle formation secondary to deconjugation of bile salts by excessive numbers of bacteria. The intestinal mucosa is usually presumed to be normal. The pathogenesis of steatorrhea was investigated in 3 patients with stasis syndrome of differing etiologies: (1) multiple jejunal diverticula; (2) scleroderma; and (3) idiopathic intestinal pseudo-obstruction. Although bacterial overgrowth and some deconjugation of bile salts was demonstrated in all 3 of these patients, normal amounts of free fatty acids were solubilized in the aqueous phase of jejunal contents aspirated during a fat meal, indicating normal jejunal micelle formation by the remaining conjugated bile salts. When a sufficient number of jejunal biopsies were taken, patchy abnormalities were revealed by light microscopy in all 3 patients. This histological appearance varied widely in each patient from little or no abnormalities in villus architecture, to severe lesions with virtual absence of villi. Electron microscopy revealed far more extensive intestinal abnormalities than had been suspected by light microscopy. Several defects in mucosal fat absorption were demonstrated by electron microscopic examination of jejunal biopsies taken during a fat meal: (1) decreased numbers of fat particles in absorptive cells; (1) decreased numbers of absorptive cells participating in fat absorption; and (3) impaired transport of chylomicrons out of the absorptive cells into the lamina propria. After antibiotic treatment fat absorption improved by fat balance and there was electron microscopic evidence of chylomicron transport out of the absorptive cells. Nevertheless, other abnormalities by light and electron microscopy remained unchanged after antibiotics. Although the etiology of the jejunal mucosal lesions in these 3 patients remains unclear, our studies suggest that absorptive cell dysfunction rather than defective micelle formation is an important factor in the pathogenesis of their steatorrhea.

Summary A hydraulically operated peroral tube has been developed which delivers individual biopsies externally within seconds of excision. Design considerations and structural details are outlined. A double lumen tube is used to activate the knife and to deliver the biopsy specimen. The knife serves both as the cutting instrument and as the connection valve between the activating channel and the delivery channel. Any number of biopsies may be obtained from any level of the gastrointestinal tract within the limits of the physician's discretion and the patient's tolerance. The rapid delivery of the specimen allows the prompt processing necessary for detailed study of structure and function.

The site of synthesis and some new details of lipoprotein particle transport have been demonstrated within the jejunal mucosa of man. In normal fasting volunteers, lipoprotein particles (88%, 150-650 A diameter) were visualized within the smooth endoplasmic reticulum and Golgi cisternae of absorptive cells covering the tips of jejunal villi. Electron microscopic observations suggested that these particles exited through the sides and bases of absorptive cells by reverse pinocytosis and then passed through the extracellular matrix of the lamina propria to enter lacteal lumina. When these lipid particles were isolated from fasting intestinal biopsies by preparative ultracentrifugation, their size distribution was similar to that of very low density (S(f) 20-400) lipoprotein (VLDL) particles in plasma. After a fatty meal, jejunal absorptive cells and extracts of their homogenates contained lipid particles of VLDL-size as well as chylomicrons of various sizes. The percentage of triglyceride in isolated intestinal lipid particles increased during fat absorption. Our interpretation of these data is that chylomicrons are probably derived from intestinal lipoprotein particles by addition of triglyceride.

Summary Four hundred forty-five rectal suction biopsies from 212 patients were examined in an effort to assess the clinical usefulness of this technique. A method was evolved which provided good specimens. These specimens were then embedded and cut in a uniform fashion to permit microscopic study of properly oriented, serial sections. Histologic categories of normal, equivocal, and abnormal were recognized. Common sources of artifacts were also recognized (1) trauma; (2) too small a specimen; (3) lymphoid nodules; and (4) proximity to the anus. Patients were grouped into clinical categories for analysis:(1) normal; (2) probably normal; (3) edema; (4) colonic polyp; (5) celiac sprue ; (6) infectious colitis; (7) regional enteritis; (8) ulcerative colitis; (9) unclassified diarrhea; and (10) miscellaneous. Some abnormal specimens were obtained in all of the clinical groups except the normal and probably normal. Abnormal findings including crypt abscess were most frequent and most severe in idiopathic and infectious colitis although no specific histologic pattern was invariably associated with this single disease entity. The biopsies were evaluated without knowledge of the clinical facts. A good diagnostic correlation was obtained between careful sigmoidoscopy and biopsy obtained on the same day. Despite the nonspecificity of the abnormalities seen, biopsy was of considerable clinical value as an adjunct to sigmoidoscopy in that objective evidence of early organic disease was often obtained by biopsy when the clinical picture pointed to no more than a functional disturbance.