Biomedical subjects

L Knutson

Publications and source records attributed to L Knutson.

At least 37 records · Page 2Linked to original sources

PubMed1995

Mucosal synthesis and release of prostaglandin E2 from activated eosinophils and macrophages in ulcerative colitis.

OBJECTIVE: To study the synthesis and release of prostaglandin E2 (PGE2) in diseased and healthy areas of the colon in ulcerative colitis/proctitis (UC) patients. METHODS: Perfusate fluid from rectal and sigmoid segments in patients with UC was analyzed for PGE2, eosinophil cationic protein, myeloperoxidase, and tumor necrosis factor-alpha concentrations. To further elucidate the cell-specific origin of mucosal PGE2 synthesis, double immunofluorescence staining as well as imaging analysis using antibodies reactive with prostaglandin H-synthase and cell-specific antigens were used on surgical colonic specimens from patients with active UC and from controls. RESULTS: The concentrations of PGE2 were, on average, 10-fold higher in perfusates from diseased areas in patients with UC than in perfusates from healthy areas in patients and controls. The PGE2 values correlated well with the released concentrations of eosinophil cationic protein, myeloperoxidase, and tumor necrosis factor-alpha. In the tissue specimens, there was a prominent colocalization in the expression of prostaglandin H-synthase on the one hand and CD 68 (a macrophage marker) and EG1/EG2 (eosinophil cationic protein markers) on the other hand, in both UC patients and controls. This did not apply to prostaglandin H-synthase and antibodies against B and T lymphocytes, neutrophils, or epithelial cells. CONCLUSION: The increased PGE2 production found in the inflamed mucosa in active UC may be caused by a fraction of activated eosinophils and macrophages.

Adult↗

PubMed1994

[Segmental intestinal perfusion. A "new" technique for human studies].

Intestinal release of inflammatory mediators and permeation of macromolecules were studied in patients suffering from Crohn's disease, celiac disease and food intolerance with the use of a system for segmental intestinal perfusion. Drug absorption and ion and bicarbonate transport were also studied in healthy subjects. Patients with Crohn's disease of the distal ileum revealed an increased release of inflammatory agents into the lumen of the proximal jejunum. Luminal provocation with different antigens in cases of celiac disease and food intolerance not only activated cells in the intestinal mucosa but also increased the leakage from plasma and lymph. Studies of drug absorption elucidated the kinetics of drug transport from intestine to plasma, and basal neurologic effects on ion and bicarbonate transport were determined.

Celiac Disease↗

PubMed1994

Increased jejunal secretory IgA and IgM in ankylosing spondylitis: normalization after treatment with sulfasalazine.

OBJECTIVE: To investigate the intestinal immune system in patients with ankylosing spondylitis (AS) and the influence of sulfasalazine treatment. METHODS: Total IgA, secretory IgA and IgM and secretory component were determined in jejunal perfusion fluid in 19 patients with AS before and after 3 months' treatment with sulfasalazine and compared with 18 healthy control subjects. Serum immunoglobulins and inflammatory activity were measured with standard methods and compared with a clinical scoring of disease activity. RESULTS: Total IgA, secretory IgA, IgM and secretory component were significantly increased in the lavage fluid when compared with healthy controls. Treatment with sulfasalazine normalized these alterations. CONCLUSION: Our findings demonstrate that the intestinal immune system is activated in AS and that such activation can be influenced by treatment. This observation supports the idea that antigenic stimulation in the gut is a possible causative event in AS.

Adult↗

PubMed1993

Endogenous dopamine and duodenal bicarbonate secretion in humans.

BACKGROUND: Catechol-O-methyltransferase (COMT) inhibition prevents tissue degradation of catecholamines including dopamine. This study was undertaken to investigate the effect of intraluminal nitecapone, a peripherally acting COMT inhibitor, on duodenal mucosal bicarbonate secretion in humans and to compare the effect with that of the prostaglandin E1 analogue misoprostol. METHODS: The duodenal bulb was isolated by means of a three-balloon six-channel tube as previously described. Basal bicarbonate secretion and secretion after intraluminal administration of 30 and 150 mg nitecapone were determined in 11 healthy subjects. In 7 of these subjects, effects of intraluminal administration of 30 and 150 micrograms of misoprostol were studied in a second experiment. RESULTS: Even the lower dose of misoprostol increased duodenal bicarbonate secretion from 121 +/- 12 to 221 +/- 36 and the lower dose of nitecapone from 149 +/- 18 to 277 +/- 48 microEq.cm-1 x h-1, respectively (P < 0.05). With 150 micrograms of misoprostol or 150 mg of nitecapone there was a further increase in secretion to 296 +/- 33 (P < 0.01) and 421 +/- 36 (P < 0.001) microEq.cm-1 x h-1, respectively. The rise in bicarbonate secretion in response to nitecapone was associated with some increase in the release of prostaglandin E2 to the luminal perfusate. CONCLUSIONS: It seems likely that peripheral COMT inhibition increases duodenal mucosal bicarbonate secretion and protection by inhibition of mucosal degradation of dopamine, an increase similar in magnitude to that obtained by a prostaglandin E1 analogue.

Adult↗

PubMed1993

Intestinal reactivity in allergic and nonallergic patients: an approach to determine the complexity of the mucosal reaction.

BACKGROUND: To determine whether inflammatory markers and mediators were released in response to different intestinal antigens, studies were performed in atopic patients allergic to birch, patients allergic to psyllium powder (ispaghula), and patients intolerant to milk. METHODS: Allergy to birch and psyllium powder was documented by the presence of circulating IgE antibodies and positive skin tests. Patients intolerant to milk had negative outcomes of radioallergosorbent tests and skin tests but positive results of double-blind, placebo-controlled tests. Challenge of the intestine with different antigens was achieved by perfusion of a jejunal segment occluded between balloons. Basal and antigen-activated release of mast cell/basophil and eosinophil products and of substances emanating from the plasma and interstitial fluid was compared in perfusate fluid from patients (n = 8) and matched healthy controls (n = 8). RESULTS: Perfusate levels of albumin and hyaluronan (previous name hyaluronic acid) were increased threefold to fivefold by antigen in all patients, but not in controls. Eosinophilic cationic protein increased in patients but also in ispaghula controls. Histamine was released in response to milk, but not in patients allergic to birch or ispaghula. Prostaglandin E2 increased in milk- and birch-sensitive patients. In response to ispaghula, however, it was released in both patients and controls. CONCLUSIONS: We conclude that subclinical intestinal challenge with antigen induces an increase in the appearance rate of albumin and hyaluronan in the intestinal lumen both in atopic patients (with target organs such as the lungs or nose and eyes) and in patients with intestinal intolerance to milk. These changes in permeation are similar to those reported from other organs such as the lung. They may reflect a common response in early phase I reactions that are either IgE-mediated or occur in response to food antigens without any obvious involvement of an IgE-mediated mechanism. Subclinical provocation with intestinal antigens should prove useful for further elucidation of mechanisms underlying intestinal mucosal reactions to exogenous stimuli.

Antigens↗

PubMed1993

The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man.

1. A new method for perfusing a 10 cm segment of jejunum in humans has been used in seven subjects to study the effect of the amino acid L-leucine (40 mM) on the intestinal absorption of levodopa (2.5 mM). The tube contains six channels and has two inflatable balloons, which enable a perfusion of a closed and defined segment of the proximal small intestine. 2. L-leucine decreased the intestinal absorption of levodopa from 40 +/- 19 to 21 +/- 15% but was without effect on the absorption of antipyrine, benserazide and D-glucose. 3. We confirm that levodopa is absorbed by the active transport system normally responsible for the absorption of large neutral amino acids (LNAA) in humans. Oral absorption by passive diffusion, probably by the paracellular route, might also occur for levodopa in the proximal part of the small intestine.

Adult↗

PubMed1992

Jejunal secretion of secretory immunoglobulins and gliadin antibodies in celiac disease.

The aim of this study was to determine the secretion of secretory immunoglobulins and gliadin antibodies in the small bowel in celiac disease. Twenty-four patients were investigated by perfusion of a defined jejunal segment. Four of the patients studied had a serum IgA deficiency and had no measurable amounts of secretory IgA in the perfusion fluid. The other patients demonstrated a significant increase in the jejunal concentration of secretory IgA (median 28.5 mg/liter) compared with healthy controls (median 16 mg/liter, N = 16) and of IgM, celiac (median 12.3 mg/liter) compared to healthy controls (median 6.8 mg/liter, N = 16). Jejunal IgA gliadin antibodies were detected in all patients except those with an IgA deficiency. All patients had jejunal IgM gliadin antibodies, but none of the patients had measurable jejunal IgG gliadin antibodies. A positive correlation was detected between serum and jejunal IgA gliadin antibody levels in the celiac patients, (P less than 0.01). Calculation of the ratio between gliadin antibodies and total levels of IgA and IgM in serum and jejunal perfusate demonstrated that the jejunal synthesis of gliadin antibodies of IgA and IgM type is both more pronounced and persistent than the systemic humoral immune response to gliadin.

Adult↗

PubMed1992

Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man.

Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (+/- SD) fraction of phenazone absorbed calculated from perfusion data was 51 +/- 12% (3 ml/min), 64 +/- 19% (3 ml/min), and 42 +/- 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 +/- 16%, 51 +/- 19%, and 38 +/- 26%, respectively. The effective permeability of phenazone was 5.3 +/- 2.5, 11 +/- 6.8, and 11 +/- 12 (x 10(4) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Increased luminal release of hyaluronan in uninvolved jejunum in active Crohn's disease but not in inactive disease or in relatives.

Recently obtained data suggest that there is a subclinic inflammatory activity in the apparently uninvolved intestinal mucosa in Crohn's disease (CD). As CD is characterized by an activation of connective tissue and fibrosis, we investigated the extent to which hyaluronan (HA), an essential component of the connective tissue, was released into the lumen of an isolated jejunal segment in CD patients and in relatives. Patients with active CD of the terminal ileum (CD activity index, CDAI, > 150; n = 14), patients with CD in remission (CDAI < 150 n = 10), first-degree relatives of the CD patients (n = 21) and healthy controls (n = 43) were orally intubated with a catheter allowing occlusion and perfusion of a segment of the proximal jejunum. The jejunal fluid concentration of HA was 65 +/- 45 micrograms/l in patients with active CD in the terminal ileum, significantly higher than the value for 43 healthy controls (42 +/- 23 micrograms/l; p < 0.05), and the corresponding values for patients in remission (42 +/- 23 micrograms/l) and for first-degree relatives of the CD patients (53 +/- 52 micrograms/l), were not increased compared to the control group. To localize HA in the tissue, small bowel biopsies were taken during surgery from patients with CD and from controls and affinity stained for HA. There was an intense staining for HA in the lamina propria of the villi, both in biopsies from patients with CD and from controls, but no staining in the epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

A technique for segmental rectal and colonic perfusion in humans.

To enable a better characterization of pathophysiologic processes in colon and rectum, we have developed a perfusion technique for collection of soluble substances and cells from standardized intestinal segments. A tube with balloons attached to its outer wall was endoscopically introduced into the rectum and sigmoid colon, and its position ascertained fluoroscopically. The balloons delimited two segments, one in the sigmoid colon and one in the rectum. The segments were simultaneously perfused by a buffer at 37 degrees C. After a 30-min rinsing period, perfusate and cells were collected at 20-min intervals. Of 51 attempted perfusions, 45 were successfully completed. Recovered volumes equaled those infused. Leakage from the proximal intestine to the segments was negligible. In 18 healthy volunteers, the mean perfusate concentration from the rectal segment was 57.5 (27.5-120.2) mg/L for albumin, 1.3 (1.0-1.7) micrograms/L for eosinophil cationic protein, 5.1 (2.8-9.5) ng/L for prostaglandin E2, and 61.7 (41.7-89.1) micrograms/L for hyaluronan, and all values were lower in the sigmoid segment. Steady state conditions were achieved from the second perfusion period. The perfusate contained 4-80 x 10(4) cells, more than 95% of which were epithelial cells. The technique is safe, has a good subject compliance, and seems to be a valuable tool in investigations on quantitative release of soluble substances and cells in, e.g., colorectal inflammation.

Adult↗

PubMed1991

Prefrontal sulcal prominence is inversely related to response to clozapine in schizophrenia.

The object of this study was to determine if brain computed tomography (CT) scan measures are related to treatment response to clozapine, an atypical antipsychotic drug that is effective in some therapy-resistant schizophrenic patients. Thirty-four therapy-resistant patients were evaluated with the Brief Psychiatric Rating Scale (BPRS) before and after 6 weeks of treatment with clozapine. The patients were classified into Nonresponders, Moderate Responders, and Good Responders based on the percent change in BPRS. Comparison of these groups on prefrontal sulcal prominence (PSP) indicated a statistically significant linear trend, with nonresponders having the highest, moderate responders an intermediate degree, and good responders the least PSP. There were no linear trends for the ventricular-brain ratio (VBR), and no quadratic trends for either brain measure. A similar linear trend relating PSP to four of five BPRS subscales, including both positive and negative symptoms, was observed. The relationship between PSP and treatment response was also assessed with multiple linear regression, and PSP significantly contributed to prediction of BPRS at 6 weeks. The results are discussed with regards to the hypothesis that the effect of clozapine on psychopathology depends on prefrontal cortical function.

Adolescent↗

PubMed1991

Cell recovery during segmental intestinal perfusion in healthy subjects and patients with Crohn's disease.

The recovery of cells arising from small intestinal mucosa alone was studied during continuous perfusion of a closed segment of jejunum. The perfusion technique minimised the contamination of the perfused segment with, for example, proteolytic enzymes from pancreas, allowing recovery of viable cells. The use of hyaluronidase in the perfusion fluid increased the recovery of cells fivefold, the median recovery being 8 x 10(6) cells. The cells were analysed with monoclonal antibodies and flow cytometry. Nearly all cells (98-99%) recovered during perfusion of healthy control subjects and patients with Crohn's disease were epithelial cells. The jejunal cells expressed HLA-DR in similar proportions--around 30%--in patients and control subjects. The ratio between CD4+ and CD8+ lymphocytes was similar (0.2) in control subjects and patients with inactive Crohn's disease but decreased (0.03) in patients with active Crohn's disease in the ileum.

Adult↗

PubMed1990

Enhanced local production of complement components in the small intestines of patients with Crohn's disease.

There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum. The mean (+/- SEM) jejunal-fluid C4 concentration was 2.0 +/- 0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7 +/- 0.1 mg per liter; P less than 0.001). The mean C3 concentration was 1.0 +/- 0.1 mg per liter in the patients and 0.7 +/- 0.1 mg per liter in the controls (P less than 0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid:serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due to at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4). We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages.

Adolescent↗

PubMed1990

The jejunal secretion of histamine is increased in active Crohn's disease.

Previous studies of mast-cell density and histamine content in biopsy specimens in patients with Crohn's disease have yielded conflicting results. In this in vivo study we have measured the jejunal secretion rate of histamine in patients with Crohn's disease (n = 15) of the terminal small bowel and in healthy controls (n = 24). The secretion studies were performed using a recently developed segmental jejunal perfusion system with a two-balloon, six-channel small tube. The histamine secretion rate was 152 +/- 29 (SEM) ng/cm small intestine per h in patients with Crohn's disease, which meant a significant increase (p less than 0.01) compared with the secretion rate in controls (71 +/- 11 ng/cm per h). Moreover, the secretion of histamine was related to the disease activity. Patients with active disease (n = 8) (i.e., Crohn's disease activity index greater than 150) had a mean histamine secretion rate of 193 +/- 47 ng/cm per h, while patients with inactive disease (Crohn's disease activity index less than 150) had a secretion rate not significantly increased compared with controls (105 +/- 24 ng/cm per h). The present data indicate increased mast-cell involvement of the small intestine in active Crohn's disease of the distal ileum. This finding might reflect the systemic nature of the disease process.

Adult↗

PubMed1990

Gliadin challenge-induced jejunal prostaglandin E2 secretion in celiac disease.

Jejunal prostaglandin E2 secretion in patients with adult celiac disease was studied under basal conditions and after local gliadin challenge. A newly developed tube system with occluding balloons was used to perfuse a jejunal segment. After an initial basal perfusion period of 40 minutes, an average of 12 mg +/- 3 (SEM) of crude gliadin was administered into the perfused segment. Perfusion continued for an additional 100 minutes and prostaglandin E2 was determined in the effluent with a radiometric method. Patients with histologically active celiac disease (n = 7) had higher basal jejunal secretion of prostaglandin E2, 523 +/- 229 pg.cm-1.h-1 (mean +/- SEM), than both celiac patients with normalized small bowel mucosa (n = 6), 160 +/- 44 pg.cm-1.h-1, and healthy controls (n = 18), 184 +/- 38 pg.cm-1.h-1, (P less than 0.05). After gliadin challenge of the jejunal segment, a significant increase (P less than 0.05) in prostaglandin E2 secretion was noted in patients with celiac disease (n = 10). The individual maximum increase was on average fivefold and occurred 60-100 minutes after gliadin administration. In healthy controls (n = 5), no alteration in prostaglandin E2 secretion was detected after gliadin challenge. Enhanced jejunal prostaglandin 2 synthesis may be involved in the pathophysiological processes initiated by gliadin in patients with celiac disease.

Adult↗

PubMed1990

Signs of increased leakage over the jejunal mucosa during gliadin challenge of patients with coeliac disease.

Intestinal secretion rates of albumin, hyaluronan, and beta 2-microglobulin (beta 2-micro) were determined under basal conditions and after gliadin challenge of coeliac patients and healthy controls by the use of a jejunal perfusion technique. A new tube system was used where a jejunal segment is isolated between balloons and then perfused with a balanced salt solution. Under basal conditions the secretion rate of albumin was similar in the patients and controls while the secretion rate of the glycosaminoglycan hyaluronan, a high molecular weight connective tissue component, was increased more than two times in coeliac patients. Beta 2-micro was secreted in on average three-fold rates in coeliacs compared with controls. All three substances were secreted at a higher rate in patients with active disease than in those with inactive disease defined by morphological damage in small bowel biopsies. The concentrations in jejunal perfusion fluids relative to serum levels in the coeliac patients were for albumin 0.0007, beta 2-micro 0.10, and for hyaluronan 1.94. Challenge with a single dose of gliadin into the jejunal segment gave within 60 min a significant, about two-fold, increase of the secretion rates of all three measured substances. The appearance of hyaluronan could reflect a gliadin induced mucosal oedema with an enhanced leakage from the interstitial/lymph fluid, rich in this glycosaminoglycan. The observed parallel increases in the jejunal secretion of albumin and beta 2-micro after gliadin challenge are best explained by a similar mechanism.

Adult↗

PubMed1989

Challenge with gliadin induces eosinophil and mast cell activation in the jejunum of patients with celiac disease.

PURPOSE: The aim of this study was to clarify the role of eosinophils and mast cells in the small bowel in celiac disease. PATIENTS AND METHODS: Patients with celiac disease (n = 10) were investigated by perfusion of a closed jejunal segment. The concentrations of certain granule constituents from eosinophils, eosinophil cationic protein (ECP), and from mast cells/basophils, histamine, were measured and the jejunal secretion rates of these cellular markers were calculated. RESULTS: Compared with findings in healthy control subjects (n = 14), increased secretion rates were observed under basal conditions in patients with histopathologically active celiac disease. Gliadin, administered by perfusion to the jejunal segment, induced a fourfold increase in ECP secretion and a twofold increase of histamine secretion in patients with celiac disease (n = 7), but did not influence the secretion rates of these substances in healthy controls (n = 3). The secretion rate of ECP started to increase 20 minutes after challenge of the perfused segment with gliadin and reached maximum levels 40 minutes later. The secretion rate of histamine started to increase 40 minutes after gliadin administration. Concurrently with these inflammatory events, the secretion of albumin was doubled as a sign of increased mucosal leakage. CONCLUSION: These data indicate that eosinophils and mast cells are both involved in the early gliadin-induced reactions of the small intestine, and suggest that these cells are effector cells participating in the celiac lesion of the mucosa.

Adult↗

PubMed1989

Carbonic anhydrase in the normal rat stomach and duodenum and after treatment with omeprazole and ranitidine.

A low pH in the lumen of the stomach and duodenum stimulates gastroduodenal mucosal secretion of bicarbonate, particularly in the duodenum. Long-term deprivation of this acid stimulus might affect the ability of the mucosa to secrete bicarbonate, with a consequent decrease in mucosal protection against the acid. This could occur by 'down-regulation' of carbonic anhydrase (CA) activity in the bicarbonate-transporting cells. Levels of CA activity and amounts of CA isoenzymes in rat gastric and duodenal mucosa were determined by biochemical assay and histochemical and immunohistochemical staining. Control animals and animals pre-treated for 4-6 weeks with the histamine H2-receptor antagonist ranitidine (600 mg kg-1 daily) or the H+,K+-ATPase inhibitor omeprazole (28 mg kg-1 daily) were examined. Both drugs are potent inhibitors of gastric secretion of acid. Both gastric and duodenal mucosal total CA activity and the distribution of isoenzymes were very similar in control animals and animals treated with these drugs. In the stomach, CA II was found in the surface epithelial and parietal cells. In the duodenum both CA I and CA II were observed. The staining for CA I was restricted to a small number of villus cells which looked like ordinary duodenal enterocytes. CA II in the duodenum was found in all villus cells, except the goblet cells. The staining decreased gradually from the top to the bottom of the villi and was absent in the crypts. Duodenal bicarbonate secretion is dependent on mucosal CA activity, and the distribution of CA II thus suggests that this alkaline secretion is of villous rather than cryptal origin.

Animals↗