Immunochemical studies in four cases of alpha chain disease.

Studies of a number of properties of the pathological gammaA-proteins in the first four cases of the recently recognized alpha-chain disease demonstrate that, as in gamma-heavy-chain disease, the abnormal protein is devoid of light chains and represents a portion of the alpha-heavy chain related to the Fc-fragment. In two patients, serum electrophoresis showed a broad abnormal band, whereas in the two others the pathological protein was not noticeable on the electrophoretic pattern. The diagnosis of alpha-chain disease can be established without purification of the protein by immuno-electrophoresis and gel diffusion experiments using selected antisera to gammaA and a reference alpha-chain disease protein. All four proteins belonged to the alpha1-subclass, displayed electrophoretic heterogeneity, and showed a strong tendency to polymerize. The polymers occurred in vivo and were held together both by disulfide bonds and by strong noncovalent forces. Two of the three purified proteins had a very high carbohydrate content. The abnormal protein was always found in concentrated urines in variable but generally low amounts. It was not detected in parotid saliva but was present in significant amounts in jejunal fluid of all four patients. The alpha-chain disease protein was shown to be associated with the secretory piece in external secretions of two patients. The clinicopathological features were strikingly similar in the four patients. All patients were affected with a neoplastic and mostly plasmacytic proliferation involving primarily the whole length of the small intestine and the mesenteric nodes and all exhibited a severe malabsorption syndrome. While Israeli authors have emphasized the frequency of this type of abdominal lymphoma in young Arabs and non-Ashkenazi Jews, two of our patients were Kabyles, one a Syrian Arab, and one an Eurasian. Cellular studies showed that the pathological protein was synthesized by the proliferating cells in the lymphoid tissue of the digestive tract and in the mesenteric nodes, and that there was no detectable light-chain synthesis at the intracellular level.

Influence of chronic lactulose ingestion on the colonic metabolism of lactulose in man (an in vivo study).

The effects of a chronic load of nonabsorbable sugars on intracolonic bacterial metabolism of carbohydrates and on H2 breath excretion are disputed. However, most of the discussion relies on indirect evidence or on results of in vitro studies. Thus, we attempted to assess directly and in vivo the effects on intracolonic metabolism of lactulose of a chronic oral load of this nonabsorbable disaccharide. 20 g of lactulose was given orally twice daily during 8 d to eight normal volunteers. In all, breath H2 concentration was measured on days 1 and 8 after ingestion of the morning lactulose dose. In four subjects, stools were collected during 2 d at the beginning and at the end of the lactulose maintenance period to measure fecal pH and daily outputs of carbohydrates and beta-galactosidase. The four other subjects were intubated on days 1 and 8 to measure the pH and the concentrations of carbohydrates, lactic acid, and volatile fatty acids (VFA) in the distal ileum and cecal contents. Moreover, 14C-lactulose was added to cold lactulose and 14CO2 breath outputs determined. Pulmonary H2 excretion fell from day 1 to day 8 (P less than 0.05), whereas 14CO2 excretion increased (P less than 0.01). Fecal water pH, lactic acid, and VFA concentrations did not vary between the two stool collection periods. 24-h fecal weight, fecal water, and carbohydrate outputs showed a trend to decrease between days 1 and 2 and days 7-8, whereas beta-galactosidase activity rose markedly (P less than 0.01). No significant variations were observed for all parameters measured in ileal fluid. In the cecum, areas under the concentration curves decreased from day 1 to day 8 for lactulose, galactose, and fructose (P less than 0.01), while an increase was found for lactic acid (P less than 0.001), acetic acid (P less than 0.0001), and total VFA (P less than 0.001). Cecal fluid pH dropped faster (P less than 0.05) and to a lower level (P less than 0.05) on day 8 than on day 1. These data clearly show that a chronic load of a nonabsorbable sugar induces changes in colonic bacterial metabolic pathways resulting in a better efficiency of the flora to digest the carbohydrate.

Secretion of immunoglobulins and plasma proteins from the jejunal mucosa. Transport rate and origin of polymeric immunoglobulin A.

Parameters of secretion of IgA and several other plasma proteins from the jejunal mucosa were investigated in 11 individuals who had a normal distribution of Ig-containing cells in the lamina propria and in one patient who was totally deficient in jejunal IgA and IgM plasmacytes. Jejunal samples were collected during segmental gut perfusion. The following results were obtained: (a) The secretion of polymeric IgA (p-IgA, mean equals 217 micrograms/40 cm per min) exceeded those of albumin (132 micrograms), IgG (35 micrograms), and monomeric IgA (m-IgA, 15 micrograms, or 6.4% of total IgA). About 35% of IgA was IgA2 in the jejunal secretion, compared with approximately 23% in serum. This closely corresponds to the 35 and 24% of IgA2 plasmocytes in jejunal mucosa and peripheral lymph nodes, respectively. (b) For each protein, a relative coefficient of excretion (RCE) was calculated (jejunum to serum concentration ratio expressed relative to that of albumin). RCEs of 1.41 for orosomucoid, 1.0 for albumin, 0.83 for IgG, and 0.74 for IgE and, in the deficient patient, of 0.64 for m-IgA and 0.016 for IgM were obtained. This was inversely related to the molecular weight of these proteins and indicated their predominantly passive transport into the jejunum. However, in normal individuals, the RCE of transferrin (approximately 1.11 greater than 1, P greater than 0.05), alpha 2-macro globulin (approximately 0.77), m-IgA (approximately 1.98), and p-IgA (approximately 218) exceeded the value expected from simple seepage from plasma, thus pointing to an additional role of either local gut synthesis and/or active transepithelial transport. (c) Approximately 98% of p-IgA, approximately 99% of IgM, and approximately 68% of m-IgA in jejunal secretions were derived from local production in the gut wall, as determined by 125I-p-IgA specific activities and/or by comparison between the RCE values of the deficient patient to the values of controls. Therefore, the jejunal production of p-IgA (approximately 312 mg/d per 40 cm vs. approximately 54 mg/d from bile) contributes the majority of upper intestinal IgA in humans. The active transport of plasma p-IgA across the intestinal mucosa (approximately 0.08 mg/40 cm per kg per d) contributes less than 2% of the total amount of p-IgA (4.5 mg/kg per d) that is cleared daily from plasma.

Potential of using lactic acid bacteria for therapy and immunomodulation in man.

There is in 1993 no proven medical indication of lactic acid bacteria (LAB) for therapy or immunomodulation in man. However, within the bulk of publications, rigorous trials have now opened rational fields of research on beneficial effects of LAB. These include lactose digestion, cholesterol metabolism, diarrheal disorders, prophylaxis of intestinal or urogenital infections, immunomodulation or even oral vaccination. We try here to analyse these studies, considering LAB as pharmacological agents, and conclude that pursuit of research could be promising for ecological therapy of mucosal diseases, and for development of original and flexible vectors for targeting in the gastrointestinal tract.

Effect of the energy density of a solid-liquid meal on gastric emptying and satiety.

The effect of the energy density of a meal on gastric emptying and satiety was assessed in nine volunteers. They ingested, in randomized order, a diluted (2671 kJ/L, 950 mL) and a concentrated (7452 kJ/L, 350 mL) test meal of 2500 kJ each (80% as solids). Half-emptying times of solids and liquids were not significantly different for the diluted and concentrated meal (solids: 145 +/- 18 and 156 +/- 16 min, respectively; liquids: 76 +/- 10 and 84 +/- 10 min, respectively), and consequently, pyloric outputs of energy were identical. Neither the intensity and duration of satiety, nor the amount of energy ingested, ad libitum, 6 h after the test meal, were significantly affected by energy density of the food ingested. Both the intensity and duration of satiety correlated significantly with the gastric emptying time for solids (r = 0.60 and 0.67, respectively, P < 0.01). These results show that satiety depends on gastric emptying of energy and is not affected by the energy density of food intake.

Tolerance and absorption of lactose from milk and yogurt during short-bowel syndrome in humans.

This study aimed to compare the absorption and tolerance of 20-g lactose loads as milk and yogurt in 17 patients with short-bowel syndrome with either a terminal jejunostomy (group A, n = 6) or a jejunocolic anastomosis (group B, n = 11). Records and measurements during the 8 h after the meals included fecal weight, symptoms, lactose and hexose flow rates in stomal effluents (group A), and breath-hydrogen excretion (group B). In group A lactose was better absorbed in the form of yogurt than in the form of milk (mean +/- SE: 76 +/- 6% vs 50 +/- 9%, P < 0.05), whereas no significant difference could be detected by using the breath-hydrogen test in group B. The excellent tolerance to 20 g lactose from milk and yogurt suggests that lactose should not be excluded from the diet of these subjects.

Can diarrhea induced by lactulose be reduced by prolonged ingestion of lactulose?

Twelve healthy volunteers were studied for two test periods, at the beginning of which they ingested a diarrheogenic load (60 g) of lactulose in 350 mL water with 10 g polyethylene glycol 4000 (PEG); the two periods were separated by a lactulose feeding period of 8 d, during which a nondiarrheogenic load (20 g) of lactulose was taken twice daily. The transit time and flow rates of water and lactulose in the distal ileum of four subjects were not different before and after the lactulose feeding period. In the other eight subjects, stool weight and frequency, fecal pH, and fecal outputs of carbohydrates and osmotic moieties after the ingestion of 60 g lactulose dropped significantly (P < 0.05) after the lactulose feeding period, whereas the orofecal transit time and fecal concentrations of beta-galactosidase and lactic acid increased (P < 0.05). We conclude that changes in colonic function induced by prolonged exposure to a nondiarrheogenic amount of lactulose mitigate the severity of the diarrhea because of the larger dose of lactulose.

Starch absorption by healthy man evaluated by lactulose hydrogen breath test.

The amounts of hydrogen produced from starch and lactulose were compared to assess the accuracy of the hydrogen breath test with lactulose as standard to quantify starch malabsorption. The mean amounts of hydrogen produced from starch and lactulose were not different in fecal homogenates and in breath excretion after carbohydrate infusions into the cecum. Known amounts of starch infused into the cecum of 18 subjects were compared with amounts calculated from the total excess excretion of hydrogen in breath computed in relation to hydrogen production after the ingestion of 10 g lactulose; calculated amounts were 3.6 +/- 1.0, 9.9 +/- 1.3, and 22.0 +/- 3.4 g for the infusion of 5, 10, and 25 g of starch, respectively. The lactulose hydrogen breath test based on total excess hydrogen volume provides a valid measurement of the mean amount of starch metabolized in the colon in a group of subjects. However, large individual variations preclude its use in a given subject.

Effect of colonic fermentation on respiratory gas exchanges measured in the postabsorptive state.

To assess the effect of colonic fermentation on respiratory gas exchanges, six methane-nonproducing healthy volunteers ingested in the postabsorptive state 1 wk apart either 90 mL lactulose syrup containing 60 g lactulose, 4 g lactose, and 7 g galactose or the same solution but without lactulose (control solution). Six patients with short bowel and remnant colon (SBS) also ingested 90 mL lactulose syrup. Carbon dioxide production (VCO2), oxygen consumption (VO2), respiratory quotient (RQ), and hydrogen excreted in breath were measured basally and for 4 h after the ingestion of solutions. In healthy volunteers within 4 h after ingestion of the control solution, VCO2 and the RQ decreased whereas VO2 remained unchanged. In contrast, in healthy volunteers and patients with SBS, VCO2 and the RQ increased after lactulose ingestion, whereas VO2 did not change. The increase in VCO2 appeared to be accounted for mainly by bacterial production of carbon dioxide and was significantly related to breath-hydrogen concentration (r = 0.56, P < 0.02 for healthy subjects; r = 0.59, P < 0.01 for SBS subjects). A breath-hydrogen test should be performed in conjunction with indirect calorimetry to determine whether colonic fermentation is taking place and, if so, to correct appropriately the VCO2 value in calorimetric equations.

Survival of bifidobacteria ingested via fermented milk during their passage through the human small intestine: an in vivo study using intestinal perfusion.

The ability of a strain of Bifidobacterium sp to survive passage through the upper gastrointestinal tract when ingested in fermented milk was investigated in six fasting healthy adults by using in vivo ileal perfusion. After ingestion of 10.0 +/- 0.5 log10 bifidobacteria in 400 g fermented milk, ileal flow of bifidobacteria increased significantly and reached a maximum of 8.8 +/- 0.2 log10 bifidobacteria/h 1.7 +/- 0.4 h after ingestion of fermented milk. The average number of bifidobacteria recovered from the terminal ileum during the 8 h after fermented-milk ingestion was 9.0 +/- 0.1 log10 and constituted 23.5 +/- 10.4% of the number ingested. These results indicate that in healthy adults Bifidobacterium sp survive transit through the gastrointestinal tract when ingested in fermented milk. Further studies are needed to investigate the behavior of these exogenous bacteria in the colonic lumen and to explore their effects on the physiology of the human gastrointestinal tract.

Effects of milk viscosity on gastric emptying and lactose intolerance in lactose maldigesters.

The possibility of delaying gastric emptying and improving lactose digestion and tolerance by increasing milk viscosity was studied in 13 lactose maldigesters who ingested three test milks with different viscosities (range: 33-1892 mPa.s) in random order at intervals of 1 wk. Each test portion was 500 mL and provided approximately equal to 1900 kJ and 18 g lactose. The different viscosities were obtained by adding varying proportions of rice starch and maltodextrin to a basic milk formula. A combined [13C]glycine-hydrogen breath test was used to measure gastric emptying and lactose digestion simultaneously. Participants reported their gastrointestinal symptoms by using a four-grade scale. Mean (+/- SEM) gastric-emptying half times were 78 +/- 5.7 min for low-viscosity milk (30 mPa.s), 86 +/- 5.0 min for moderate-viscosity milk (80 mPa.s), and 78 +/- 4.5 min for high-viscosity milk (1.9.10(3) mPa.s). Mean orocecal transit times (180 +/- 24, 163 +/- 23, and 180 +/- 24 min, respectively) were not significantly different. There were no milk-dependent differences in breath-hydrogen excretion or in the severity of gastrointestinal symptoms. The milks were well tolerated; > 50% of the subjects reported nondisturbing symptoms or none. We conclude that gastric emptying, orocecal transit time, and lactose digestion and tolerance were not affected by altering milk viscosity. This may have been due to the high energy content of the test milks, which in itself led to slow gastric emptying.

Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidophilus and Bifidobacterium bifidum on metabolic activities of the colonic flora in humans.

Nine healthy volunteers were studied before, during, and after ingesting a fermented dairy product containing Lactobacillus acidophilus, Bifidobacterium bifidum, and mesophilic cultures (Streptococcus lactis and S cremoris) for 3 wk. Hydrogen and methane productions and fecal beta-galactosidase and beta-glucosidase activities were measured as indicators of fermentation capacity of the colonic flora. Fecal concentrations of nitroreductase, azoreductase, and beta-glucuronidase, which may be implicated in colonic carcinogenesis, were also assessed. Hydrogen and methane productions, fecal beta-galactosidase, beta-glucuronidase, and azoreductase activities did not change over three 3-wk periods whereas fecal beta-glucosidase activity increased (42 +/- 6, 91 +/- 12, and 40 +/- 6 IU/g N, P less than 0.01) and nitroreductase decreased (0.87 +/- 0.13, 0.54 +/- 0.11, and 0.57 +/- 0.08 IU/g N, P less than 0.05).

Gastrointestinal effects and energy value of polydextrose in healthy nonobese men.

We studied seven healthy volunteers before and during acute (PD1) and chronic (PD2) ingestion of 30 g polydextrose (PD)/d. The energy value of PD was assessed after [U-14C]PD was added to the 10-g morning dose of PD during PD1 and at the end of PD2. Thirty-one +/- five percent (mean +/- SD) (PD1) and 29 +/- 4% (PD2) of the dose appeared in breath within 48 h. A small fraction of the ingested radioactivity was recovered in urine (4 +/- 1%) and excreted in flatus (< or = 1%) and in feces as volatile fatty acids (VFAs) (< 1%) and bacteria (3-4%); the remaining radioactivity in stools, 33 +/- 3% (PD1) and 32 +/- 4% (PD2), was assumed to be intact PD. Breath excretion of the label was 49 +/- 5% after intracolonic infusion of [U-14C] acetate. The energy value of PD, calculated by means of Miller and Wolin's stoichiometric equation of colonic fermentation, was similar during PD1 and PD2: 4.0 and 6.1 kJ/g, respectively, when breath 14CO2 and VFA production from PD were used for calculation.

Metabolic effects of digestible and partially indigestible cornstarch: a study in the absorptive and postabsorptive periods in healthy humans.

To compare the effects of digestible (pregelatinized) and partially indigestible (retrograded) cornstarches on some metabolic indexes, we studied eight healthy volunteers during two periods separated by 1 wk. In each period, fasting volunteers consumed at 0800 the test meal containing either the digestible or partially indigestible cornstarch; blood and breath were sampled in the absorptive period for 8 h. To study its late effects, the same test meal as that served at 0800 was given again at 2200, and blood and breath were sampled for 3 h in the postabsorptive period the next morning, i.e., 10 h after ingestion of the test meal. In the absorptive period, blood glucose and insulin were significantly higher after ingestion of digestible cornstarch than after partially indigestible cornstarch. In the postabsorptive period concentrations of blood glucose, insulin, and fatty acids were not significantly different, whereas concentrations of blood acetate, breath hydrogen, methane, and 13CO2, and the respiratory quotient and satiety were significantly higher (P < 0.05) and concentrations of blood glycerol significantly lower (P < 0.05) after ingestion of partially indigestible cornstarch than after digestible cornstarch. We conclude that in healthy humans, digestion of partially indigestible cornstarch is slow in the small intestine and its colonic fermentation continues 10-13 h after its ingestion. Compared with pregelatinized cornstarch, the shift in starch digestion induced by retrogradation leads to a reduction in glycemic and insulinemic responses in the absorptive period and in lipolysis in the postabsorptive.

Small-intestinal digestion of partially resistant cornstarch in healthy subjects.

The aims of this study were to measure the amount of starch from partially resistant starches (retrograded and complexed high-amylose cornstarches) escaping small-intestinal digestion in healthy humans by use of an intubation method and to compare these data with data obtained by indirect in vitro methods. Experiments were carried out in vivo in 6 healthy humans by using ileal intubation and stool analysis and in vitro by using 3 different methods for analyzing resistant starch. In intubated subjects, 51 +/- 2% of the retrograded and 21 +/- 2% of the complexed starch was delivered to the ileum and was fermented almost completely in the colon. In vitro estimates of the absorption of resistant starch were much lower. We conclude that technologically modified starches may substantially increase the amount of carbohydrate available for colonic fermentation in humans, but that in vitro measurements of resistant starch are inaccurate for predicting malabsorption in healthy humans.

Casein peptide release and passage to the blood in humans during digestion of milk or yogurt.

In adult humans, after milk or yogurt ingestion, many peptides derived from alpha s1-, beta- or kappa-caseins were detected in stomach, including the kappa-caseinoglycopeptide, an inhibitor of platelet aggregation. Smaller peptides derived from casein and lactoferrin were recovered from duodenum. Two long peptides, the kappa-caseinoglycopeptide and the N-terminal peptide of alpha s1-casein, were absorbed and detected in plasma. These results support the concept that food-born peptides could have physiological activities in man.

Neutrophil and eosinophil involvement of the small bowel in patients with celiac disease and Crohn's disease: studies on the secretion rate and immunohistochemical localization of granulocyte granule constituents.

PURPOSE: The concentrations of myeloperoxidase (MPO), a neutrophil granule constituent, and eosinophil cationic protein (ECP), a specific eosinophil granule protein, were measured in jejunal perfusion fluid in an attempt to elucidate the neutrophil and eosinophil involvement of the small bowel in health and disease. PATIENTS AND METHODS: The control group consisted of 14 males and two females. Ten patients (seven males and three females) with Crohn's disease and seven patients (two males and five females) with celiac disease were also studied; in addition, one patient with relapsing giardiasis, one patient with giardiasis and complete absence of plasma cells in small intestinal lamina propria, and one patient with selective IgA deficiency and no IgA plasma cells in duodeno-jejunal lamina propria were evaluated. Segmental perfusion of the jejunum was performed according to a previously described method. MPO and ECP were measured by radioimmunoassays. RESULTS: In healthy control subjects, the concentrations of both granule proteins were in a narrow range and much higher than would have been anticipated from passive leakage from circulating blood. In patients with celiac disease, the perfusion fluid concentrations of MPO and ECP were on average 3.5 and eight times, respectively, higher than the values seen in the controls. The jejunal segment perfused in patients with Crohn's disease was endoscopically and histologically normal. The perfusion fluid concentrations of MPO and ECP were increased 3.5 and two times, respectively, compared with that in the control subjects. Both patient groups and the control group had similar perfusion fluid concentrations of albumin. Data on MPO and ECP expressed as jejunal secretion rates gave the same differences between patients and controls as just described for the jejunal fluid concentrations. Immunohistochemical studies of jejunal biopsy specimens from another group of patients with celiac disease demonstrated a prominent extracellular deposit of ECP in the lamina propria of the atrophic intestinal mucosa, whereas the release of neutrophil constituents (cathepsin G, MPO) was scarce. In Crohn's disease, an extracellular degranulation of ECP and, to a lesser extent, of cathepsin G was observed in relation to ulcerations only. CONCLUSION: Data obtained indicate that the local release of neutrophil and eosinophil granule components is enhanced in the jejunal tissue from patients with celiac sprue and Crohn's disease. The prominent extracellular deposit of eosinophil granule constituents with cytotoxic properties at the site of inflammatory intestinal lesions in celiac sprue might reflect a pathophysiologic mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)

Diffuse follicular lymphoid hyperplasia of the small intestine without primary immunoglobulin deficiency.

Three cases of follicular lymphoid hyperplasia extending to the whole length of small intestine are reported in three young adult patients of low economic status. The disease was revealed by chronic diarrhea with malabsorption and/or protein-losing enteropathy. In one patient, all transitional patterns were found between the hyperplastic follicles and a small intestinal multicentric centrocytic-centroblastic lymphoma. No abnormalities in humoral or cellular immunity were found in the three patients. In particular, serum immunoglobulins (except IgG in one case) and plasma cell populations of small intestinal lamina propria were normal. Diffuse follicular lymphoid hyperplasia of the small intestine in the absence of primary immunoglobulin deficiency appears to be a rare condition associated with (or leading to) intestinal malignant lymphoma in most cases. Patients usually belong to the same populations as those suffering from alpha-chain disease.

Methotrexate for the treatment of refractory Crohn's disease.

BACKGROUND: Previous studies suggested that methotrexate has beneficial effects in patients with Crohn's disease. We report our experience with this agent in patients with chronic active Crohn's disease who previously failed to improve with conventional treatment, including azathioprine in most cases. METHODS: Between June 1988 and June 1992, 39 patients with refractory Crohn's disease were treated with methotrexate. In patients with active disease, clinical remission was defined by a Harvey-Bradshaw index of less than 4. For patients also taking corticosteroids, the dates of remission and complete steroid withdrawal were recorded. For patients who achieved clinical remission, and those in clinical remission when methotrexate was started, the relapse rate on methotrexate therapy was noted. RESULTS: In the 37 patients with active disease at methotrexate initiation, the probability of remission was 72% at 3 months. The probability of remission and steroid withdrawal was 42% at 12 months. In patients on clinical remission, the probability of relapse on methotrexate was 58% at 12 months. Twenty-two patients experienced side-effects, but these only warranted methotrexate discontinuation in four cases. CONCLUSIONS: Methotrexate appears effective in most patients with refractory Crohn's disease and its short-term toxicity is acceptable, but the long-term benefit seems more limited.

Short report: treatment of gastric ulcer with lansoprazole or ranitidine: a multicentre clinical trial.

We studied the effectiveness of lansoprazole and ranitidine in promoting gastric ulcer healing in a multicentre double-blind trial, by comparing the proportion of healed ulcers after 4 and 8 weeks of treatment. One hundred and fifty-eight patients were randomly given either ranitidine (150 mg each morning and at bedtime) or lansoprazole (30 mg each morning and placebo at bedtime). One hundred and twenty-eight patients completed the trial (62 taking lansoprazole, 66 taking ranitidine). Fifty-one (80%) of those treated with lansoprazole and forty-two (62%) of those treated with ranitidine had healed ulcers at 4 weeks (P < 0.05). Sixty-one (98%) patients who received lansoprazole and 57 (86%) who received ranitidine had healed ulcers at 8 weeks (P < 0.05). The observed differences were not significant in the intention-to-treat analysis. No serious adverse event was reported with lansoprazole.