Peptide Hp(2-20) accelerates healing of TNBS-induced colitis in the rat.

BACKGROUND AND AIMS: Hp(2-20), a Helicobacter pylori-derived peptide interacting with N-formyl peptide receptors (FPRs), accelerates the healing of gastric injury in rats. Whether Hp(2-20) affects the recovery of inflamed colonic mucosa is unknown. We evaluated whether Hp(2-20) accelerated the healing of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis and explored the mechanism(s) underlying any such effect. METHODS: Fifteen rats underwent rectal administration of Hp(2-20) 250-500 µg/kg/day, or of its control peptide Hp1 for 10 days, following induction of colitis with TNBS. Macroscopic and histological damage was quantified using predetermined injury scores. FPR1, COX-2, TNF-α, TGF-ß, HB-EGF and tissue transglutaminase (t-TG) messenger RNA (mRNA) expression in colonic tissue was determined by quantitative polymerase chain reaction; FPR1, TNF-α and COX-2 protein levels by Western blotting. RESULTS: (1) Hp(2-20) accelerated healing of TNBS-induced colitis compared to controls consistently with the expression of FPRs in colonic mucosa; (2) TNBS upregulated mRNA mucosal expression of COX-2, TNF-α, TGF-ß, HB-EGF and t-TG and (3) this, with the exception of HB-EGF, was significantly counteracted by Hp(2-20). CONCLUSIONS: Hp(2-20), an FPR agonist, accelerates the healing of TNBS-induced colitis in the rat. This effect is associated with a significant reduction in colonic tissue levels of COX-2, TGF-ß, TNF-α and t-TG. We postulate that FPR-dependent pathways may be involved in the repair of inflamed colonic mucosa.

Spontaneous bladder rupture mimicking a jejuno-ileal perforation.

Spontaneous urinary bladder perforation is a very rare disease. The main cause of urinary perforation, indeed, is a damage to the urinary bladder wall by blunt or penetrating trauma. There are only few idiopathic spontaneous rupture of urinary bladder (ISRUB) cases reported in the literature. Pre-operative diagnosis is very difficult due to similar symptoms, laboratory and imaging findings of a gastrointestinal perforation that is usually excluded intraoperatively. Herein we report a case of a 91-year-old man presented to the emergency department with a spontaneous bladder perforation mimicking an ileal perforation.

Role of Formyl Peptide Receptors in Gastrointestinal Healing.

The wound healing and the barrier restoration of the gastrointestinal (GI) mucosa must be continuously ensured to allow homeostasis of the gastrointestinal tract and of all the surrounding tissues. Several lines of the evidence report a key role of innate immunity, and in particular of Pattern Recognition Receptors (PRRs), in controlling the homeostasis of GI tract by sensing commensal and pathogen bacteria, activating the immune response and regulating epithelial repair, thus guaranteeing the morphological and functional recovery of the injured tissue. We will discuss the role of a particular class of PRRs - the Formyl Peptide Receptors - in the homeostasis of GI mucosa. We here report the results of studies that strongly suggest the possibility that the activation of FPRs is crucial in the maintenance of homeostasis of the GI tract and provide indications of the potential clinical relevance of new treatment regimens involving FPR modulation for several GI disorders.

Helicobacter pylori HP(2-20) induces eosinophil activation and accumulation in superficial gastric mucosa and stimulates VEGF-alpha and TGF-beta release by interacting with formyl-peptide receptors.

Eosinophils participate in the immune response against Helicobacter pylori, but little is known about their role in the gastritis associated to the infection. We recently demonstrated that the Hp(2-20) peptide derived from H. pylori accelerates wound healing of gastric mucosa by interacting with N-formyl peptide receptors (FPRs) expressed on gastric epithelial cells. The aim of the present study was to investigate whether eosinophils play a role in the repair of gastric mucosa tissue during H. pylori infection. Immuno-histochemistry and transmission electron microscopy were used to detect eosinophils in gastric mucosal biopsies. Eosinophil re-distribution occurred in the gastric mucosa of H. pylori-infected patients: their density did not change in the deep mucosal layer, whereas it increased in the superficial lamina propria just below the foveolar epithelium; eosinophils entered the epithelium itself as well as the lumen of foveolae located close to the area harboring bacteria, which in turn were also engulfed by eosinophils. The H. pylori-derived peptide Hp(2-20) stimulated eosinophil migration through the engagement of FPR2 and FPR3, and also induced production of VEGF-A and TGF-beta, two key mediators of tissue remodelling. We also demonstrate that Hp(2-20) in vivo induced eosinophil infiltration in rat gastric mucosa after injury brought about by indomethacin. This study suggests that eosinophil infiltrate could modulate the capacity of gastric mucosa to maintain or recover its integrity thereby shedding light on the role of eosinophils in H. pylori infection.

Nutraceuticals for protection and healing of gastrointestinal mucosa.

Natural medicinal products have been used for millennia for the treatment of several ailments. Although many have been superseded by conventional pharmaceutical approaches, there is currently a resurgence in the interest in natural products by the general public and the use of complementary and alternative medicine is increasing rapidly in developed countries. Also, pharmaceutical industries are more and more interested in examining their potential as sources of novel medicinal compounds which may act as growth factor or show immunomodulatory or anti-microbial activity. The subgroup of natural bioactive compounds that bridge the gap between food products and drugs are termed nutraceuticals or functional foods. In contrast with most standard medicinal compounds, nutraceuticals are generally used to prevent rather than to treat disease. Many of the claims for such products are supported by very limited scientific evidence. However, there has recently been a great interest at evaluating the mechanism by which natural products exert their beneficial effects in the gastrointestinal tract. In particular, a major area of interest is for the use of biologically active chemical components of plants, i.e. phytochemicals, in a number of gastrointestinal disorders. While the major focus of phytochemical research has been on cancer prevention, several products of plant origin are being used and/or under study for a variety of other gastrointestinal problems. In this review we discuss the scientific evidence supporting the potential use of nutraceuticals as agents capable to prevent or accelerate healing of gastrointestinal mucosal damage, with a focus on polyphenol extracts obtained from apple.

Myenteric neuronal loss in rats with experimental colitis: role of tissue transglutaminase-induced apoptosis.

BACKGROUND AND AIMS: Transglutaminases are tissue enzymes involved in different neuronal processes including maintenance and signalling. However, their up-regulation elicited by a variety of noxae contributes to neurodegeneration. This study tested the hypothesis that experimental inflammation evoked transglutaminase up-regulation in myenteric neurons and that this event had an impact on neuronal survival. METHODS: Rats with or without trinitro-benzene-sulphonic acid-induced colitis were used. One week after colitis induction, longitudinal muscle-myenteric plexus preparations were obtained from left colon to assess tissue-transglutaminase activity, protein and mRNA expression. Double labelling immunofluorescence using antibodies to neuron-specific enolase and transglutaminase was performed to identify myenteric neurons expressing transglutaminase. Additional sets of experiments evaluated the involvement of transglutaminase in the apoptotic process of cultured myenteric neurons. RESULTS: Compared to controls, rats with colitis showed several tranglutaminase/neuron-specific enolase positive myenteric neurons. Western blot analysis and RT-PCR confirmed that in rats with colitis, the increased neuronal transglutaminase-immunoreactivity was associated with an increased enzyme expression. Similarly, transglutaminase activity was significantly higher than in controls (1100+/-280 m U/g vs. 725+/-119 m U/g, p<0.05). In cultured myenteric neurons incubation with the specific transglutaminase inducer, retinoic acid, significantly increased neuronal apoptosis, whereas the presence of cystamine significantly reduced the number of apoptotic neurons. CONCLUSIONS: Experimental colitis evoked transglutaminase up-regulation and increased activity in myenteric neurons. This mechanism enhances neuronal susceptibility to apoptosis and could contribute to neuropathic changes during gut inflammation.

Bowel sonography in adult celiac disease: diagnostic accuracy and ultrasonographic features.

BACKGROUND: Celiac disease (CD) is a chronic intolerance to gluten, which induces intestinal mucosal lesions in genetically predisposed individuals. Transabdominal bowel sonography (TABS) is a safe and noninvasive procedure that allows to detect intestinal abnormalities in many conditions, but actually is not routinely part of the diagnostic management of CD. AIM: To evaluate the diagnostic accuracy of TABS in CD patients. PATIENTS AND METHODS: Fifty CD patients and 50 dyspeptic subjects (control group) underwent TABS. The presence of fluid-distended small bowel loops with thickened valvulae conniventes and increased peristalsis was considered a TABS sign of CD. All clinical, biochemical, and TABS features were assessed at the diagnosis and revaluated after 1 year of gluten-free diet. RESULTS: TABS signs were present in 66% of CD patients. Sensitivity, specificity, positive and negative predictive value were 66%, 96%, 94%, and 74%, respectively. TABS findings were recorded in 82% of patients with endoscopical markers of CD, in 87.5% of symptomatic patients, and in 61% of patients without symptoms. After 1 year of gluten-free diet TABS was still abnormal in 20% patients, with no correlation with laboratory tests e/o symptoms. CONCLUSIONS: Patients with CD frequently present TABS signs of the disease and operators performing sonography every day have to consider the possibility to suggest CD diagnosis and aTTG determination in these subjects.

Differential expression of multiple transglutaminases in human colon: impaired keratinocyte transglutaminase expression in ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is characterised by refractory inflammatory ulceration and damage to the colon. The mechanisms underlying impaired healing have yet to be defined. As transglutaminase expression resulting in matrix protein cross linking is associated with increased wound healing in a rat model of colitis, we hypothesised that different types of transglutaminase might also play a role in UC. PATIENTS AND METHODS: Endoscopic and histological indices were studied in 26 patients with UC (10 active and 16 inactive) and in 20 normal controls undergoing colonoscopy. Transglutaminase activity was evaluated in plasma (factor XIIIa) by a radioenzymatic method. Factor XIIIa, tissue and keratinocyte transglutaminase protein content, and mRNA expression in the colon were evaluated by western blot analysis and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. Colonic location of transglutaminases and their reaction products, the epsilon-(gamma-glutamyl)lysine bonds, was evaluated by immunohistochemistry using specific monoclonal antibodies. RESULTS: Transglutaminase activity was significantly lower in the plasma of patients with active UC (4.2 (2.4) mU/ml; p<0.05 v controls) than in those with inactive UC and controls (10.6 (2.2) and 12.1 (1.7) mU/ml). As shown by western blot, protein levels of tissue transglutaminase and factor XIIIa were unchanged in active UC compared with inactive disease and controls, while the keratinocyte form was reduced in active UC. Tissue transglutaminase and factor XIIIa immunostaining was strongly present in damaged areas colocalising with isopeptide bonds. In contrast, the keratinocyte form was almost absent in active UC and localised in the upper part of the crypts in normal subjects. RT-PCR showed upregulation of tissue transglutaminase mRNA in active UC (320% compared with controls) while keratinocyte transglutaminase gene expression was downregulated in active UC. CONCLUSIONS: The results of the present study support the concept that, in the damaged colon, transglutaminases are needed in response to chronic injury and underline the key role of these enzymes in mucosal healing.

Apple polyphenol extracts prevent damage to human gastric epithelial cells in vitro and to rat gastric mucosa in vivo.

BACKGROUND: Fresh fruit and vegetables exert multiple biological effects on the gastrointestinal mucosa. AIM: To assess whether apple extracts counteract oxidative or indomethacin induced damage to gastric epithelial cells in vitro and to rat gastric mucosa in vivo. METHODS: Apple extracts were obtained from freeze dried apple flesh of the "Annurca" variety. Cell damage was induced by incubating MKN 28 cells with xanthine-xanthine oxidase or indomethacin and quantitated by MTT. In vivo gastric damage was induced by indomethacin 35 mg/kg. Intracellular antioxidant activity was determined using the (2,2'-azinobis (3-ethylbenzothiazolin-6-sulfonate) method. Malondialdehyde intracellular concentration, an index of lipid peroxidation, was determined by high pressure liquid chromatography with fluorometric detection. RESULTS: (1) Apple extracts decreased xanthine-xanthine oxidase or indomethacin induced injury to gastric epithelial cells by 50%; (2) catechin or chlorogenic acid (the main phenolic components of apple extracts) were equally effective as apple extracts in preventing oxidative injury to gastric cells; and (3) apple extracts (i) caused a fourfold increase in intracellular antioxidant activity, (ii) prevented its decrease induced by xanthine-xanthine oxidase, (iii) counteracted xanthine-xanthine oxidase induced lipid peroxidation, and (iv) decreased indomethacin injury to the rat gastric mucosa by 40%. CONCLUSIONS: Apple extracts prevent exogenous damage to human gastric epithelial cells in vitro and to the rat gastric mucosa in vivo. This effect seems to be associated with the antioxidant activity of apple phenolic compounds. A diet rich in apple antioxidants might exert a beneficial effect in the prevention of gastric diseases related to generation of reactive oxygen species.

Glutathione supplementation improves oxidative damage in experimental colitis.

BACKGROUND: The pathogenesis of inflammatory bowel disease is due, in part, to enhanced free-radical production and reduced antioxidant potential in mucosa cells. AIM: We evaluated in a rat model of trinitrobenzensulphonic acid (TNBS) colitis to see whether parenteral administration of glutathione is able to improve mucosal oxidative damage at onset (study A) and during chronic phases of colitis (study B). METHODS: In study A, the rats were injected with a single dose of glutathione (200 mg/kg, i.p.) or saline (0,2 ml, i.p.) 1 h before colitis induction and killed 1 h later. In study B, rats with induced colitis were treated with daily injection of glutathione (50 mg/kg, i.p.) or saline (0,2 ml, i.p.), and killed at 1, 2, 4 and 8 weeks. We evaluated on mucosal samples the macroscopic and histological damage and the oxidative stress assessed by the mucosal levels of lipoperoxides, malonyldialdehyde, glutathione and cysteine. RESULTS: In study A, colitis induction caused a significant increase to the total histological score (p<0.05), lipoperoxide and malonyldialdehyde levels (p<0.001), but did not affect glutathione and cysteine content. Glutathione pre-treatment decreased both total histological score (p<0.05) and lipoperoxide and malonyldialdehyde values (p<0.001). In study B, the extensive macroscopic and histological colonic damage induced by TNBS was accompanied by a reduction of glutathione and cysteine mucosal levels (p<0.01) and increased lipid peroxidation. Glutathione supplementation significantly improved colonic damage (p<0.01), restored glutathione and cysteine levels, and decreased, and even, if not totally, abolished lipid peroxidation (p<0.001). CONCLUSION: This paper further supports the pathogenic role of the imbalance in oxidant/antioxidant content in inducing mucosal colonic damage.

Up-regulation of heparin binding epidermal growth factor-like growth factor and amphiregulin expression in Helicobacter pylori-infected human gastric mucosa.

BACKGROUND: Host response plays a major role in pathogenesis of Helicobacter pylori-induced gastroduodenal disease including adenocarcinoma of distal stomach. Epidermal growth factor-related growth factors are important modulators of gastric homeostasis in normal and damaged gastrointestinal mucosa. AIM: To evaluate expression of heparin binding epidermal growth factor and amphiregulin in antral mucosa of Helicobacter pylori-infected and non-infected dyspeptic patients and to correlate levels of heparin binding-epidermal growth factor and amphiregulin mRNA with mitogenic activity of gastric epithelial cells. METHODS: A total of 10 Helicobacter pylori-infected and 15 Helicobacter pylori non-infected (10 with and 5 without gastritis) dyspeptic patients were studied. Diagnosis of Helicobacter pylori infection was based on rapid urease test and histology. Heparin binding-epidermal growth factor and amphiregulin mRNA expression in antral mucosa were assessed by reverse transcriptase-polymerase chain reaction. Protein expression and localization of both peptides were determined by immunohistochemistry. Mitogenic activity of antral gastric mucosa was assessed by determination of proliferating cell nuclear antigen labelling index by immunohistochemistry. RESULTS: Heparin binding-epidermal growth factor and amphiregulin mRNA expression increased in Helicobacter pylori-infected vs Helicobacter pylori non-infected patients. Heparin binding-epidermal growth factor and amphiregulin immunostaining was more intense and deeper in gastric gland compartment in infected mucosa than in non-infected mucosa. Increase in heparin binding-epidermal growth factor and amphiregulin mRNA expression significantly correlated with increase in proliferating cell nuclear antigen labelling index. CONCLUSIONS: Helicobacter pylori gastritis is associated with up-regulation of heparin binding-epidermal growth factor and amphiregulin which correlates with increased mitogenic activity of gastric mucosa. Increased heparin binding-epidermal growth factor and amphiregulin expression is postulated to contribute to reparative response of gastric mucosa to Helicobacter pylori infection.

Factor XIII improves gastric stress lesions in rats.

BACKGROUND/AIMS: Tissue transglutaminase has been reported to be involved in the healing of experimental gastric ulcer; nevertheless, other type(s) of transglutaminase could be involved. The present experiments aimed at examining whether plasma transglutaminase (factor XIIIa) contributes to such healing and at evaluating whether factor XIII supplementation improves gastric mucosal lesions. METHODS: The healing effect of 200 U/kg of factor XIII administered intravenously was examined using a water immersion restraint rat model of stress gastric damage. The rats were sacrified 0, 2, 4, and 12 h after stress. The gastric mucosa was examined macroscopically and microscopically, and the transglutaminase activities were assayed in serum and gastric mucosa. Factor XIIIa and tissue transglutaminase protein levels in the gastric mucosa were analyzed by immunoblot. Immunohistochemistry was used to identify the location of tissue transglutaminase, factor XIIIa, and fibronectin in the gastric mucosa. RESULTS: The transglutaminase activity, reduced by stress in the gastric mucosa, increased up to 12 h after stress, peaking at 4 h, when the ulcer index significantly decreased. The serum transglutaminase level was low at all time points. Exogenous administration of factor XIII allowed a faster reduction of the ulcer index that was coincident with an increased transglutaminase activity in the mucosa. Both tissue transglutaminase and factor XIIIa protein levels were reduced by 6 h of stress and increased after factor XIII administration. Immunohistochemistry showed a colocalization of both factor XIIIa and tissue transglutaminase with fibronectin in the extracellular matrix of the damaged area. CONCLUSIONS: Two forms of transglutaminase are involved in the healing of stress-induced gastric erosions, and factor XIII administration allows faster gastric mucosa healing.

Serum transglutaminase correlates with endoscopic and histopathologic grading in patients with ulcerative colitis.

Factor XIIIa, a circulating form of transglutaminase, plays a key role in intestinal mucosal repair. We found that transglutaminase levels are decreased in serum of patients with inflammatory bowel diseases and demonstrated in a rat model of chronic colitis that serum transglutaminase is closely related to the severity of intestinal damage. We aimed, therefore, to correlate serum transglutaminase levels with standard endoscopic and histopathologic grading systems in patients affected by ulcerative colitis (UC). In 249 patients with UC, we assayed serum transglutaminase activity by a radioenzymatic method and measured clinical activity index (CAI) according to modified Rachmilewitz's criteria. In a subset of 82 patients undergoing colonoscopy, endoscopic and histologic indices were studied. Biopsy specimens were also taken from 28 patients to measure myeloperoxidase (MPO) as a marker of mucosa inflammation. Serum transglutaminase levels significantly correlated with the CAI scoring (r = -0.63; P < 0.01); likewise serum transglutaminase showed the best correlation with endoscopic (r = -0.71; P < 0.001) and histologic (r = -0.79; P < 0.001) scores. Myeloperoxidase activity was significantly higher in patients with active UC than those in remission (P < 0.01), showing a significant correlation with serum transglutaminase levels (r = -0.68; P < 0.01). Immunohistochemistry showed factor XIIIa localization in the extracellular matrix of damaged mucosa. In conclusion, these results suggest that transglutaminase assay can be useful in managing UC as a serological, noninvasive indicator of intestinal mucosal status.

A new human chromogranin 'A' immunoradiometric assay for the diagnosis of neuroendocrine tumours.

We investigated whether plasma chromogranin A (CgA), measured by a new immunoradiometric assay, may be a sensitive and specific marker of phaeochromocytoma and of other neuroendocrine tumours. This study involved 121 patients of whom 20 with phaeochromocytoma, 28 with other neuroendocrine tumours (19 gastroenteropancreatic tumors, 3 medullary thyroid and 6 small cell lung carcinomas), 25 with solid nonfunctioning adrenocortical tumours and 48 with essential hypertension. In addition, 130 normal subjects were taken as controls. Plasma catecholamines were measured by using high-performance liquid chromatography, and CgA by a two-site sandwich immunoradiometric assay involving monoclonal antibodies raised against the unprocessed central domain (145-245) of human CgA. Plasma CgA in controls (49.0 +/- 3.1 ng ml(-1), mean +/- SE) and in essential hypertensives (50.8 +/- 3.5 ng ml(-1)) was lower (P< 0.0001) than in adrenocortical tumours (91.8 +/- 13.2 ng ml(-1)), in phaeochromocytomas (254 +/- 49 ng ml(-1)) and in patients with other neuroendocrine tumours (469 +/- 84 ng ml(-1)). Plasma CgA and catecholamines identified 13 and 18 out of 20 phaeochromocytomas with sensitivity of 65% and 90%, respectively. Combined measurement of both markers improved sensitivity up to 100%. In the other neuroendocrine tumours, CgA was abnormal in 23/28 cases (sensitivity 82%) and in 6 it was the only circulating marker of disease. In gastroenteropancreatic tumours, CgA measurement identified all cases (sensitivity 100%). Specificity of CgA in patients with essential hypertension was 98%. In conclusion, CgA determination showed high sensitivity in identifying gastroenteropancreatic tumours and, in association with catecholamines, in detecting patients with phaeochromocytoma. CgA sometimes appeared to be the only circulating marker of disease. Since the specificity of CgA proved to be excellent, this assay may be useful for diagnosis both of functioning and non-functioning neuroendocrine tumours.

Influence of endogenous androgens on carotid wall in postmenopausal women.

OBJECTIVE: There is increasing evidence of a direct association between normal androgen levels and reduced cardiovascular morbidity and mortality in women. After menopause the influence of estrogens declines, whereas that of androgens increases. Therefore, we investigated the effects of androgens on atherosclerosis in postmenopausal women, by using carotid artery intimal-medial thickness as a marker of vascular damage. DESIGN: Blood pressure, body mass index, waist-to-hip ratio, serum dehydroepiandrosterone sulfate, androstenedione, total and free testosterone, estrone, insulin, lipid profile, and glucose were evaluated in 44 women in stable physiological menopause. All subjects underwent carotid ultrasound (Biosound 2000 II s.a. high-resolution unit). RESULTS: Spearman correlation coefficients indicated that serum androstenedione and free testosterone were negatively associated with several carotid intimal-medial thickness measures with correlation coefficients (r) ranging from 0.477 to 0.397 (p < 0.01-0.04). Moreover, age-adjusted androstenedione and free testosterone highest tertiles showed intimal-medial thickness values significantly (p < 0.03-0.05) lower than the other tertiles. There was a favorable association between hormones and the most important cardiovascular risk factors. This association, however, did not reach statistical significance. Stepwise multiple regression analysis showed that the inverse relationships between the hormones (androstenedione and free testosterone) and several intimal-medial thickness measures were maintained (F: 4.15-6.07, p < 0.05-0.02) after adjustment for major cardiovascular risk factors. CONCLUSIONS: Our data demonstrate that in postmenopausal women endogenous steroid precursors and androgens are inversely related to carotid intimal-medial thickness, an established marker of atherosclerosis. In addition, these hormones show favorable associations with cardiovascular risk factors. Therefore, our study suggests that, after menopause, normal androgen levels may benefit the carotid artery wall.

Recombinant factor XIII improves established experimental colitis in rats.

Factor XIII (FXIII) is the plasma-borne transglutaminase involved in fibrin clot stabilization and wound healing. FXIII levels in the plasma of patients with inflammatory bowel diseases are lower than normal and there is a significant inverse correlation of FXIII levels with clinical severity. Moreover, uncontrolled studies report beneficial effects of FXIII supplementation in patients resistant to conventional therapies. We investigated the effects of intravenous recombinant FXIII (rFXIII) treatment in experimentally induced rat colitis to verify that FXIII was the active agent in plasma FXIII concentrates and to better understand the potential therapeutic use of this protein. Colitis was induced by instillation of 12% 2.4,6-trinitrobenzenesulfonic acid (TNBS) in 50% ethanol into the colon of male Wistar rats. Rats were treated with 0.65 mg/kg rFXIII or vehicle (intravenously) daily for 10 days. Treatment was started either immediately after TNBS/EtOH instillation (to evaluate effects on developing lesions) or seven days later (to evaluate effects on established lesions). In both cases rats were killed either immediately after the end of treatment (to evaluate immediate effects) or 17 days later (to evaluate long-lasting effects). The effects of rFXIII were compared to positive (5-amino-2-hydroxybenzoic acid) control over a 35-day time course. The severity of lesions was determined by colon weight and macroscopic and histologic scores. Transglutaminase activity was measured in both colon tissue and serum. rFXIII treatment reduced lesion severity significantly not only in developing but also in established lesions. Improvements in healing persisted at least 18 days after treatment was discontinued. Serum and tissue transglutaminase levels were restored by rFXIII treatment. In conclusion, pure rFXIII is as effective as plasma FXIII concentrates in a rat model of experimental colitis. In addition, rFXIII significantly improves the healing of preexisting lesions, a characteristic useful in treatment of human inflammatory bowel diseases.

Endogenous androgens and carotid intimal-medial thickness in women.

The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and post-menopausal females, we evaluated the relationship between serum androgen levels and both carotid artery intimal-medial thickness (IMT) and major cardiovascular risk factors. In addition to evaluation of blood pressure, body mass index, and waist-to-hip ratio, serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), total testosterone (TTS), free testosterone (FTS), insulin, cholesterol (total and high density lipoproteins), triglycerides, and glucose were measured. All women underwent carotid ultrasonography. Spearman correlation coefficients showed that serum DHEA-S and A levels were negatively related (P < 0.03-0.0004) to several IMT measures. Higher tertiles of DHEA-S, A, and FTS corresponded to significantly lower measures of carotid thickness. DHEA-S, and all androgens were inversely related to age (P < 0.03 or less), showing no unfavorable association with major cardiovascular risk factors. In contrast, serum DHEA-S was negatively associated with WHR (P < 0.02), while A was negatively associated with body mass index (P < 0.02). Stepwise multiple regression analysis indicated that A and FTS showed an inverse association with IMT measures (P < 0.05-0.001). In conclusion, our data indicate that in women serum DHEA-S and androgens decline with age and that normal hormonal levels are not associated with major cardiovascular risk factors. They also show that higher DHEA-S and androgen concentrations are related to lower carotid wall thickness; for A this association is independent of cardiovascular risk factors. Our results suggest that, in the physiological range, DHEA-S and androgens in women are correlated with lower risk of carotid artery atherosclerosis.

Short-chain fatty acid in the human colon. Relation to inflammatory bowel diseases and colon cancer.

Short chain fatty acids (SCFAs) are the end products of anaerobic bacteria break down of carbohydrates in the large bowel. This process, namely fermentation, is an important function of the large bowel; SCFAs, mainly acetate, propionate and butyrate account for approximately 80% of the colonic anion concentration and are produced in nearly constant molar ratio 60:25:15. Among their various properties, SCFAs are readily absorbed by intestinal mucosa, are relatively high in caloric content, are metabolized by colonocytes and epatocytes, stimulate sodium and water absorption in the colon and are trophic to the intestinal mucosa. While the fermentative production of SCFAs has been acknowledged as a principal mechanism of intestinal digestion in ruminants, the interest in the effects of SCFAs production on the human organism has been raising in the last ten years. SCFAs are of major importance in understanding the physiological function of dietary fibers and their possible role in intestinal neoplasia. SCFAs production and absorption are closely related to the nourishment of colonic mucosa, its production from dietary carbohydrates is a mechanism whereby considerable amounts of calories can be produced in short-bowel patients with remaining colonic function and kept on an appropriate dietary regimen. SCFAs enemas or oral probiotics are a new and promising treatment for ulcerative colitis. The effects have been attributed to the oxidation of SCFAs in the colonocytes and to the ability of butyrate to induce enzymes (i.e. transglutaminase) promoting mucosal restitution. Evidence is mounting regarding the effects of butyrate on various cell functions the significance of which needs further considerations. Up until now, attention has been related especially to cancer prophylaxis and treatment. This article briefly reviews the role of SCFAs, particularly butyrate, in intestinal mucosal growth and potential clinical applications in inflammatory and neoplastic processes of the large bowel.

Utility of plasma dehydroepiandrosterone sulphate determination in adrenal incidentalomas.

To evaluate whether low DHEA-S levels are predictors of cortical origin, benignity and hormonal activity in incidentally detected adrenal masses, thirty-five patients with adrenal incidentalomas were studied. All patients were operated on and the diagnosis was histologically confirmed. Basal endocrine workup included plasma determination of cortisol before and after dexamethasone (1 mg overnight), plasma ACTH (08:00 h), 17-OH-progesterone, testosterone and potassium, standing plasma renin activity and aldosterone, supine and standing plasma noradrenaline and adrenaline. If necessary, we performed dexamethasone suppression tests at low (2 mg) and high (8 mg) doses, or the loperamide test (16 mg os) for evaluation of glucocorticoid activity and the glucagon test (1 mg i.v.) for exploring adrenal medulla function. Plasma DHEA-S was measured in all patients and the results were compared to those obtained in controls matched for age, sex and menopausal status. Suppression of DHEA-S was found in 11 out of 35 patients (31.5%). However, this hormonal finding occurred in 50% of the extracortical adrenal lesions, while in proven cortical adenomas (no. = 19) it was detected in only 5 patients (26.3%). Sensitivity, specificity, diagnostic accuracy and positive predictive value of low DHEA-S in indicating a cortical origin of the mass were 0.27, 0.0, 0.25, and 0.80. In malignancies (no. = 6) low DHEA-S levels were found in 1 out of 2 metastases and never in cortical carcinomas. Sensitivity, specificity, diagnostic accuracy and positive predictive value of low DHEA-S in indicating a benign form were 0.34, 0.83, 0.42, and 0.91. Six out of 19 patients with cortical adenomas showed signs of hypothalamic-pituitary adrenal (HPA)-axis dysfunction. Low DHEA-S levels were found in 50% of adenomas with HPA-axis abnormality and in 15.3% of adenomas without hormonal activity. Sensitivity, specificity, diagnostic accuracy, and positive predictive value of low DHEA-S levels in indicating hormonal activity of the mass were 0.50, 0.84, 0.73, and 0.60. Our data indicate that the association between low DHEA-S levels and adrenal incidentalomas is frequent. Low DHEA-S appears to be a poor predictor of hormonal activity with low sensitivity and specificity in respect of cortical origin and benignity of the mass. In conclusion, our results show that DHEA-S measurement does not offer relevant clinical information in the management of adrenal incidentalomas.

Esophageal impairment in adult celiac disease with steatorrhea.

OBJECTIVE: A high prevalence of reflux esophagitis in celiac children and gut motor disorders in adult patients have been described. The aim of this study is to investigate the prevalence of esophageal symptoms and the esophageal motility pattern in adult celiac patients before and after gluten-free diet. METHODS: In 22 consecutive adult celiac patients, before and after gluten-free diet, and in controls we calculated an esophageal symptom score regarding heartburn, regurgitation, dysphagia, and chest pain, and performed esophageal manometry using a constantly perfused multilumen catheter. RESULTS: Patients were divided into two groups: with and without steatorrhea. Before gluten-free diet, the prevalence of esophageal symptoms was 45.5 % in all patients, but was significantly higher in patients with steatorrhea than in those without and in 44 control subjects (80% vs 16.7% and 27%, p < 0.05). Lower esophageal sphincter pressure was 17.5+/-5.3 in all patients, but was significantly lower in patients with steatorrhea than in patients without steatorrhea and 11 controls subjects (13.1+/-4.1 vs 21.0+/-2.9 and 20.7+/-3.7 mm Hg (mean+/-SD, p < 0.05). After the diet, the prevalence of esophageal symptoms diminished in all patients (9% vs 45.4%, p < 0.05) and lower esophageal sphincter pressure, measured in 13 patients, increased (19.0+/-3.7 vs 15.7+/-5.3 mm Hg, p < 0.05). CONCLUSION: Adult celiac patients with steatorrhea present a higher prevalence of esophageal symptoms and a lowered lower esophageal sphincter pressure compared with celiac patients without steatorrhea and control subjects, but these phenomena can be reverted to control levels by gluten-free diet.