Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia.

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.

Possible association between nonsynonymous polymorphisms of the anaplastic lymphoma kinase (ALK) gene and schizophrenia in a Japanese population.

We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.

Adenovirus-mediated gene delivery of interleukin-10, but not transforming growth factor beta, ameliorates the induction of Graves' hyperthyroidism in BALB/c mice.

Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) are well known anti-inflammatory cytokines. We have studied the effect of adenovirus-mediated IL-10 and TGF-beta gene delivery on the induction of Graves' hyperthyroidism in our mouse model that involves repeated injections of adenovirus expressing the thyrotropin receptor A subunit (AdTSHR). We first constructed adenoviruses encoding the two cytokines (AdIL10 and AdTGF(beta)) and confirmed expression by in vitro infection of COS cells. Susceptible BALB/c mice were injected twice with AdTSHR alone or together with AdIL10 or AdTGF(beta), and bled two weeks after the second immunization. Significantly elevated serum thyroxine levels were seen in 26% of mice immunized with AdTSHR and AdIL10 versus 61% with AdTSHR alone. Levels of thyroid stimulating antibody, but not nonstimulating antibody, were also decreased, and TSHR-specific splenocyte secretion of interferon-gamma in recall assays was impaired in mice treated with AdIL10. In contrast, AdTGF(beta) had little effect on hyperthyroidism. Overall, our findings demonstrate that gene delivery of IL-10, but not TGF-beta, suppresses the induction of Graves' hyperthyroidism in a mouse model. However, the effect of IL-10 is less powerful than we observed previously with T helper type 2-inducers including adenovirus expressing IL-4, Shistosoma mansoni infection or alpha-galactosylceramide.

TSH receptor-adenovirus-induced Graves' hyperthyroidism is attenuated in both interferon-gamma and interleukin-4 knockout mice; implications for the Th1/Th2 paradigm.

The role of the Th1/Th2 balance in the pathogenesis of murine Graves' hyperthyroidism is controversial. In BALB/c mice injected with adenovirus expressing TSH receptor (TSHR-adeno model), we found that suppression of TSHR-specific Th1 immune responses by exogenous interleukin-4 (IL-4), alpha-galactosylceramide or helminth (Schistosoma mansoni) infection was associated with inhibition of hyperthyroidism, indicating the critical role for Th1 cytokines. In contrast, BALB/c IL-4 knockout (KO), but not interferon-gamma (IFN-gamma) KO mice failed to develop Graves' hyperthyroidism when injected with TSHR-expressing M12 B lymphoma cells (TSHR-M12 model), suggesting the importance of Th2 cytokine IL-4. To reconcile differences in these two models, we used IL-4 KO and IFN-gamma KO BALB/c mice in the TSHR-adeno model. Unlike wild-type (wt) BALB/c mice in which 60% developed hyperthyroidism, only 13 and 7% of IL-4 KO and IFN-gamma KO mice, respectively, became hyperthyroid. Thyroid stimulating antibodies were positive in most hyperthyroid mice. TSHR antibody titres determined by TSH binding inhibition and ELISA were comparable in all three groups. IgG1 and IgG2a TSHR antibody titres were similar in IFN-gamma KO and wt mice, whereas IgG1 TSHR antibody titres and TSHR-specific splenocyte IFN-gamma secretion were lower in IL-4 KO than in IFN-gamma KO and wt mice, respectively. Our results clearly implicate both IFN-gamma and IL-4 in development of hyperthyroidism in the TSHR-adeno model. These data, together with the previous report, also indicate different cytokine requirements in these two Graves' models, with IFN-gamma being more important in the TSHR-adeno than the TSHR-M12 model. Moreover, our previous and present observations indicate a difference in the role of exogenous versus endogenous IL-4 in TSHR-adenovirus induced Graves' hyperthyroidism.

Medium-chain fatty acids stimulate interleukin-8 production in Caco-2 cells with different mechanisms from long-chain fatty acids.

BACKGROUND AND AIM: It has been suggested that dietary fat exacerbates intestinal inflammation. We investigated the effect of fatty acids on interleukin (IL)-8 production in a human intestinal epithelial cell line (Caco-2). METHODS: The cells were cultured as monolayers on microporous membranes in culture inserts. Oleic acid (OA), capric acid (CA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were applied to the apical compartment of Caco-2 cell monolayers. The concentration of IL-8 in the basolateral medium was measured by using enzyme-linked immunosorbent assay, and the expression of IL-8 mRNA was measured by using competitive reverse transcription--polymerase chain reaction. Protein kinase C inhibitors (GF109203X and calphostin C) and H-7 (a protein kinase inhibitor) were used to study the mechanisms by which IL-8 production is stimulated. RESULTS: Both OA and CA enhanced IL-8 production (approximately fivefold), whereas DHA and EPA did not. Both OA and CA also enhanced IL-1-induced IL-8 production. The onset of OA-induced IL-8 production was delayed compared with that of CA-induced IL-8 production. Both OA and CA enhanced IL-8 mRNA expression (approximately fivefold) after 6 and 3 h, respectively. The protein kinase inhibitor (H-7) reduced both OA- and CA-induced IL-8 production by 88.0 and 85.9%, respectively. The protein kinase C inhibitors (GF109203X and calphostin C) reduced OA-induced IL-8 production by 29.3 and 54.5%, respectively, but showed no effect on CA-induced IL-8 production. CONCLUSIONS: These findings suggest that not only OA but also CA stimulates IL-8 production in intestinal epithelial cells, and the mechanisms of action differ between OA and CA.

Heteromeric association creates a P2Y-like adenosine receptor.

Adenosine and its endogenous precursor ATP are main components of the purinergic system that modulates cellular and tissue functions via specific adenosine and ATP receptors (P1 and P2 receptors), respectively. Although adenosine inhibits excitability and ATP functions as an excitatory transmitter in the central nervous system, little is known about the ability of P1 and P2 receptors to form new functional structures such as a heteromer to control the complex purinergic cascade. Here we have shown that G(i/o) protein-coupled A1 adenosine receptor (A1R) and Gq protein-coupled P2Y1 receptor (P2Y1R) coimmunoprecipitate in cotransfected HEK293T cells, suggesting the oligomeric association between distinct G protein-coupled P1 and P2 receptors. A1R and P2Y2 receptor, but not A1R and dopamine D2 receptor, also were found to coimmunoprecipitate in cotransfected cells. A1R agonist and antagonist binding to cell membranes were reduced by coexpression of A1R and P2Y1R, whereas a potent P2Y1R agonist adenosine 5'-O-(2-thiotriphosphate) (ADPbetaS) revealed a significant potency to A1R binding only in the cotransfected cell membranes. Moreover, the A1R/P2Y1R coexpressed cells showed an ADPbetaS-dependent reduction of forskolin-evoked cAMP accumulation that was sensitive to pertussis toxin and A1R antagonist, indicating that ADPbetaS binds A1R and inhibits adenylyl cyclase activity via G(i/o) proteins. Also, a high degree of A1R and P2Y1R colocalization was demonstrated in cotransfected cells by double immunofluorescence experiments with confocal laser microscopy. These results suggest that oligomeric association of A1R with P2Y1R generates A1R with P2Y1R-like agonistic pharmacology and provides a molecular mechanism for an increased diversity of purine signaling.

Comparison of tests for fecal lactoferrin and fecal occult blood for colorectal diseases: a prospective pilot study.

OBJECTIVE: This prospective pilot study was conducted to compare the usefulness of measuring fecal lactoferrin (Lf) to that of fecal occult blood (FOB) test for detection of colorectal diseases. PATIENTS AND METHODS: The subjects were 351 patients who underwent colonoscopy. A fecal sample was obtained on the day before colonoscopy. Fecal Lf was measured by enzyme-linked immunosorbent assay. The FOB test was performed by combined assay (latex agglutination) of hemoglobin and transferrin. RESULTS: The specificities of the fecal Lf and FOB tests were the same (88.7%). For patients with colorectal cancer (13), colorectal polyp (69), ulcerative colitis (18), Crohn's disease (13), non-specific colitis (8), internal hemorrhoids (60), colon diverticulum (27), and miscellaneous diseases of the colon (10), the rates of positivity for fecal Lf were 7/13, 14/69, 12/18, 7/13, 4/8, 22/60, 8/27, and 6/10, respectively. The corresponding rates for FOB were 8/13, 12/69, 11/18, 4/13, 4/8, 9/60, 2/27, and 1/10. For patients with internal hemorrhoids, the rate of positivity for fecal Lf was significantly higher than that for FOB. In other disease groups, there was no significant difference in the rate of positivity between fecal Lf and FOB. CONCLUSION: These findings suggest that measurement of fecal Lf is as useful as FOB in detecting colorectal diseases.

Accuracy of detection of colorectal neoplasia using an immunochemical occult blood test in symptomatic referred patients: comparison of retrospective and prospective studies.

OBJECTIVE: In this study the sensitivity and specificity of immunochemical tests for colorectal neoplasia were evaluated in retrospective and prospective studies. METHODS: Four types of fecal blood tests--a chemical test (Hemoccult II) and three different immunochemical tests including a test which detects hemoglobin and transferrin- were performed in the retrospective study. In the prospective study the test for hemoglobin and transferrin was used for all patients that underwent total colonoscopy. PATIENTS: One hundred seven patients with colorectal neoplasia, 57 with gastroduodenal bleeding, and 62 with normal digestive tracts were examined retrospectively. One thousand two hundred and ninety-eight nonspecifically symptomatic patients whose endoscopic examination was negative for hemorrhagic lesions in the upper digestive tract were examined prospectively. RESULTS: In the retrospective study, sensitivities for the detection of colorectal cancers and adenomas with diameters > or =10 mm using the tests which detect hemoglobin and transferrin were 98% and 89%, respectively. These were the highest sensitivity among the four tests. The specificity of this test was 97%, which was higher than that of the Hemoccult II test. In the prospective study, the sensitivities of the tests for hemoglobin and transferrin for the detection of colorectal cancers and adenomas with diameters > or =10 mm were 79% and 33%, respectively. The specificity was 95%. CONCLUSIONS: The test for hemoglobin and transferrin showed the highest sensitivity and specificity for colorectal neoplasia in the retrospective study. The sensitivity and specificity of this test were not so high in the prospective study, but they may be clinically applicable in the evaluation of patients with various nonspecific symptoms.

Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis.

Cytokines such as IL-1, tumour necrosis factor-alpha (TNF-alpha), IL-6 and IL-8 are increased in inflamed colonic mucosa after administration of mouse DSS. Nuclear factor kappaB (NF-kappaB) is a transcription factor which regulates the expression of these cytokine genes. The effect of intracolonically administered NF-kappaB (p65) antisense phosphorothioate oligonucleotide was examined in mouse DSS-induced colitis using drinking water containing 5% DSS. When antisense oligonucleotide was given on day 0, the disease activity index (DAI) representing clinical symptoms improved and the histological score decreased; furthermore, IL-1, IL-6, and TNF-alpha concentrations in rectal mucosa were lower compared with the control group. Clinical and histological improvement was also observed when antisense oligonucleotide was begun on day 2 but not on day 7. In addition, the distribution of antisense oligonucleotides was investigated by confocal laser microscopy. In colonic mucosa, oligonucleotides were predominantly localized to cells in the lamina propria, but also in the epithelium. Western blot analysis using homogenized rectal mucosa showed the decreased expression of NF-kappaB p65 in the antisense oligonucleotide-treated group, although it was increased in the colitis group. These results suggest that intracolonic administration of NF-kappaB antisense oligonucleotide may be effective in ulcerative colitis.

Neural correlates of memory organization deficits in schizophrenia. A single photon emission computed tomography study with 99mTc-ethyl-cysteinate dimer during a verbal learning task.

Regional cerebral blood flow (rCBF) during a verbal learning task was measured using 99mTc-ethyl-cysteinate dimer and single photon emission computed tomography in 10 patients with schizophrenia and nine normal controls. Verbal repetition was used as a control task. The schizophrenic patients showed failure to spontaneously utilize implicit category information to learn the word lists. In the normal controls, rCBF in the left inferior frontal and left anterior cingulate regions was significantly increased during the verbal learning task, compared with the verbal repetition task. In contrast, there was no significant frontal lobe activation by the verbal learning in the schizophrenic patients. The patients had lower rCBF during the verbal learning task than the controls in the bilateral inferior frontal, left anterior cingulate, right superior frontal, and bilateral middle frontal regions. Activation in the left inferior frontal region was significantly positively correlated with categorical clustering in the task in the controls, but no such correlation was found in the patients. These results indicate that memory organization deficits in schizophrenia may be related to dysfunction in the prefrontal areas, especially in the left inferior frontal region.

Acquired ileal diverticulum: an unusual bleeding source.

Acquired ileal diverticulum is an uncommon condition and diagnosis is often difficult when bleeding occurs from this source. Here we describe two cases of ileal diverticulum with massive bleeding. Both patients presented with anal bleeding, but upper and lower gastrointestinal endoscopy did not reveal the source. Selective visceral angiography finally detected bleeding lesions in the terminal ileum. Surgical resection was performed in both patients, confirming that the bleeding arose from diverticula less than 1 cm in size. In patients with obscure gastrointestinal bleeding, an ileal diverticulum should be considered, and selective visceral angiography should be performed for precise diagnosis.

Fecal eosinophil granule-derived proteins reflect disease activity in inflammatory bowel disease.

OBJECTIVES: The aims of this study were: 1) to examine whether the fecal levels of eosinophil granule-derived proteins reflect disease activity in inflammatory bowel disease (IBD); and 2) to examine the extracellular release of these proteins from eosinophils and their stability in feces by an in vitro study. METHODS: We investigated 42 patients with ulcerative colitis (UC), 37 patients with Crohn's disease (CD), and 29 control subjects. The stool samples were collected at 4 degrees C over 48 h and were homogenized. The fecal levels of eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured by radioimmunoassay. Fecal Hb (Hb), alpha1-antitrypsin (AT), and lactoferrin (Lf) were also measured by ELISA. RESULTS: Fecal ECP and EPX concentrations were significantly increased in both active UC and active CD compared to inactive UC and inactive CD, respectively. Fecal EPX concentration correlated with the fecal Hb, AT, and Lf concentrations more closely than fecal ECP concentration. Even in the inactive stage, CD patients who relapsed within the following 3 months showed higher fecal ECP and EPX concentrations compared to the patients who did not. EPX was released extracellularly more efficiently than ECP (18.6% vs 6.3%, after incubation for 15 min at 25 degrees C). EPX was more stable in the feces than ECP. CONCLUSIONS: The measurement of eosinophil granule-derived proteins in feces is useful for evaluating disease activity and predicting relapse in patients with IBD. EPX may be more suitable than ECP as a fecal eosinophil marker.

Antineutrophil cytoplasmic antibodies in Japanese patients with inflammatory bowel disease: prevalence and recognition of putative antigens.

OBJECTIVE: Our aim was to investigate the prevalence of antineutrophil cytoplasmic antibodies (ANCA) in Japanese patients with ulcerative colitis (UC) and Crohn's disease (CD), and the putative antigens recognized by perinuclear staining pattern ANCA (p-ANCA)-positive sera. METHODS: Sera from UC (n = 52) and CD (n = 43) patients, and from healthy controls (n = 74) were studied. The indirect immunofluorescence (IIF) method was used for the detection of ANCA and its binding pattern. p-ANCA-positive sera were studied further for putative antigens. ELISAs using lactoferrin (Lf), myeloperoxidase (MPO), and cathepsin G (Cat G) as antigens were performed. RESULTS: ANCA was positive in 40 of the 52 (76.9%) UC (p-ANCA in 33) and in 32 of the 43 (74.4%) CD (p-ANCA in 31) patients. UC and CD patients showed significantly higher titers of p-ANCA than controls; however, no significant difference was observed between UC and CD. In UC, 23, 17, and nine of the 33 patients with p-ANCA-positive sera showed reactivity with Lf, MPO, and Cat-G, respectively. In CD, 21, 20, and 11 of the 31 patients with p-ANCA-positive sera showed reactivity with Lf, MPO, and Cat-G, respectively. Fourteen of the UC and six of the CD patients showed reactivity with two different antigens, and seven of the UC and 11 of the CD patients showed reactivity with all three antigens. The presence of anti-Lf and anti-MPO antibodies was further confirmed by Western blotting. CONCLUSIONS: ANCA is useful in distinguishing patients with IBD from normal subjects but is not sufficient for the differential diagnosis of CD and UC. p-ANCA reactivity might be derived from the recognition of heterogeneous neutrophil-associated antigens.

Bile acids inhibit tumour necrosis factor alpha-induced interleukin-8 production in human colon epithelial cells.

To clarify the regulatory mechanism of the production of various inflammatory mediators by intestinal epithelial cells, the effect of bile acids (tauroursodeoxycholate, TUDC; taurochenodeoxycholate, TCDC; and taurocholate, TC) on the cytokine-induced production of interleukin (IL)-8 in a human colon epithelial cell line (HT-29) was examined. HT-29 cells were incubated for 24 h in a culture medium containing tumour necrosis factor alpha (TNF alpha; 1 ng/mL) and/or interleukin (IL)-1beta (1 ng/mL) in the presence or absence of bile acids. The IL-8 concentration in the medium was measured by an enzyme-linked immunosorbent assay. The binding assay of TNF alpha was performed using [125I]-TNF alpha (100 pmol/L). Interleukin-8 production during incubation with TNF alpha was markedly reduced in the presence of 0.5 and 1 mmol/LTUDC, 0.5 and 1 mmol/LTCDC and 0.5 and 1 mmol/LTC, by 56, 85, 86, 91, 37 and 70%, respectively. The IL-8 production during incubation with IL-1beta was not significantly reduced in the presence of these bile acids. The specific binding of TNF alpha to cells was inhibited 33, 47, and 14% by 1 mmol/LTUDC, TCDC and TC, respectively. These findings suggest that bile acids inhibit TNF alpha-induced IL-8 production by the colonic cells. The suppression may be partly due to inhibition of TNF alpha binding to the cells by bile acids.

Cyclosporine A inhibits interleukin-8 production in a human colon epithelial cell line (HT-29).

Intestinal epithelial cells produce various inflammatory mediators. However, the way in which immunosuppressive agents influence the production of these mediators by intestinal epithelial cells is not understood. The effects of cyclosporine A (CsA), tacrolimus (FK506), and dexamethasone (DEX) on cytokine-induced production of interleukin (IL)-8 in a human colonic cancer cell line (HT-29) were examined. HT-29 cells were stimulated with either IL-1 beta or tumor necrosis factor alpha (TNF alpha) together with CsA, FK506, or DEX. The presence of IL-8 protein was detected by enzyme-linked immunosorbent assay, and the expression of IL-8 messenger RNA (mRNA) by reversetranscription polymerase chain reaction. CsA (1, 5, and 10ng/ml) significantly reduced IL-1 beta-induced IL-8 production (by 32%, 41%, and 48%, respectively), and reduced TNF alpha-induced IL-8 production (by 21%, 42%, and 50%, respectively). FK506 or DEX had no effect on IL-1 beta- or TNF alpha-induced IL-8 production. The expression of IL-8 mRNA was also inhibited by CsA. These findings suggest that CsA may influence the production of inflammatory mediators in colonic cells in a different manner from FK506 and DEX.

Expression of neurofilament proteins in proliferating C2C12 mouse skeletal muscle cells.

Expression of neurofilament proteins, NF140K, NF68K, and NF200K, in C2C12 mouse skeletal muscle cells was studied. Immunofluorescence and immunoblot analyses revealed that NF140K was expressed in proliferating C2C12 cells and its localization was similar to desmin, a muscle-specific intermediate filament protein. NF140K became undetectable in C2C12 cells as muscle cell differentiation proceeded. Reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analyses confirmed the expression of NF140K, NF68K, and NF200K in proliferating C2C12 cells. Sequences of the RT-PCR products of NF140K and NF68K were identical to that of authentic mouse NF140K and NF68K, respectively. The NF140K and NF68K mRNA were down-regulated during myogenesis in contrast to the up-regulation of mRNA encoding troponin-T. Furthermore, subcloned C2C12 cells, which express NF140K at a higher level, exhibited retarded myogenesis, i.e., delayed onset of myosin heavy chain synthesis and myoblast fusion. These results suggest that neurofilament proteins may play an inhibitory role in commitment of muscle cell differentiation. The presence of neurofilament proteins in skeletal muscle cells indicates that desmin, vimentin, and neurofilament proteins can be expressed in a single muscle cell.

Fecal lactoferrin as a marker for disease activity in inflammatory bowel disease: comparison with other neutrophil-derived proteins.

OBJECTIVES: 1) To investigate which neutrophil-derived proteins in feces most accurately reflect disease activity in inflammatory bowel disease. 2) To examine the extracellular release of these proteins by activated neutrophils and their stability in feces by in vitro study. METHODS: We studied 41 patients (91 samples) with ulcerative colitis (UC), 34 patients (105 samples) with Crohn's disease (CD), and 25 control subjects. Fecal levels of lactoferrin (Lf), polymorphonuclear neutrophil elastase (PMN-E), myeloperoxidase (MPO), and lysozyme (Lys) were measured by ELISA. We also measured fecal hemoglobin (Hb) and alpha 1-antitrypsin (alpha 1-AT), useful markers of disease activity in UC and CD, respectively. For the in vitro study, blood samples were stimulated with phorbol myristate acetate or latex beads. For the assessment of stability, homogenized stool samples were stored at 4 degrees C, 25 degrees C, and 37 degrees C for various periods. RESULTS: 1) Fecal Lf, PMN-E, MPO, and Lys concentrations were significantly increased in the active phase of the disease compared to the inactive phase in both UC and CD. 2) Fecal Lf, PMN-E, MPO, and Lys concentrations correlated significantly with fecal Hb concentration in UC, whereas fecal Lf, PMN-E, and MPO concentrations correlated significantly with alpha 1-AT concentration in CD. In UC, fecal Lf, PMN-E, MPO, and Lys concentrations were high in 15, 9, 14, and 14 samples, respectively, of 25 samples with normal Hb concentration. In CD, fecal Lf, PMN-E, and MPO concentrations were high in 19, 10, and 16 samples, respectively, of 30 samples with normal alpha 1-AT concentration. 3) The extracellular release of Lf was the most efficient and this molecule was the most stable in feces. CONCLUSIONS: Both our clinical and our in vitro studies suggested that Lf is the most suitable of these proteins to use as neutrophil-derived fecal marker of inflammation for clinical application.

The forms and the levels of fecal PMN-elastase in patients with colorectal diseases.

OBJECTIVES: To compare the form of polymorphonuclear leukocyte (PMN)-elastase in feces with that in plasma and to investigate the usefulness of measuring fecal PMN-elastase levels in patients with colorectal diseases. METHODS: We examined PMN-elastase complexed with alpha 1-antitrypsin (alpha 1-AT), chymotrypsin, and alpha 2-macroglobulin by ELISA in feces and plasma. Fecal levels of total PMN-elastase were determined in patients with colonic polyp (N = 19), colonic cancer (N = 20), ulcerative colitis (UC; N = 36), colonic Crohn's disease (CD; N = 26), and in control subjects (N = 20). RESULTS: Most PMN-elastase was not complexed with alpha 1-AT, chymotrypsin, or alpha 2-macroglobulin in feces, whereas most plasma PMN-elastase was complexed with alpha 1-AT. Fecal concentrations and daily fecal excretion of PMN-elastase were significantly increased in patients with active UC (medians 54.8 micrograms/g, 15.14 mg/day) and active CD (41.5 micrograms/g, 10.24 mg/day) compared to those values in control subjects (0.6 micrograms/g, 0.11 mg/day) and in patients with colonic cancer (2.5 micrograms/g, 0.33 mg/day). In inactive UC and CD, these values (3.4 micrograms/g, 0.52 mg/day and 5.2 micrograms/g, 0.59 mg/day, respectively) were significantly lower than in active UC and CD, respectively. In UC, all patients whose rectal biopsies showed infiltration of PMN had high fecal PMN-elastase levels. CONCLUSIONS: Our results suggest that the measurement of fecal PMN-elastase concentrations are useful for monitoring the disease activity of UC and CD, especially when evaluating whether intestinal inflammation has disappeared completely.

Intestinal protein loss and bleeding assessed by fecal hemoglobin, transferrin, albumin, and alpha-1-antitrypsin levels in patients with colorectal diseases.

Four fecal proteins (hemoglobin, transferrin, albumin, and alpha 1-antitrypsin) were measured by enzyme-linked immunosorbent assay (ELISA) in patients with colorectal diseases. Levels of all 4 proteins were significantly increased in patients with colonic cancer and ulcerative colitis (UC) compared to levels in control subjects, while fecal alpha 1-antitrypsin was particularly elevated in colonic Crohn's disease (CD). That is, the fecal protein pattern of CD was distinct from those of colonic polyps, colonic cancer, and UC. To investigate whether levels of these fecal proteins reflect disease activity in UC and CD, comparative evaluation of fecal proteins in the active and inactive phases was performed. In UC, differences in the fecal concentrations of all 4 proteins were significant between the active and inactive phases of the disease. In CD, however, the difference in alpha 1-antitrypsin concentration was significant. Our results suggest that measurements of these 4 fecal proteins would be useful in the screening of colorectal diseases. In addition, these markers can also be used as indicators of disease activity in inflammatory bowel diseases.