Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial.

Therapy for Crohn's disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed-dose, delayed-release 6-mercaptopurine (DR-6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR-6MP in patients with moderately severe CD compared to systemically delivered 6-mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12-week, double-blind controlled trial. The primary end-point was the percentage of subjects with clinical remission [Crohn's Disease Activity Index (CDAI) < 150] or clinical response (100-point CDAI reduction). Twenty-six (56·5%) and 13 (54·2%) subjects from the DR-6MP and Purinethol cohorts, respectively, completed the study. DR-6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR-6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR-6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR-6MP group. DR-6MP led to a decrease of CD62(+) expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR-6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug-induced leucopenia in the DR-6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR-6MP. Non-absorbable DR-6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.

Circulating cell-free DNA: a promising marker of regional lymphonode metastasis in breast cancer patients.

PURPOSE: We undertook the current study with untreated breast cancer to (1) role the variations in the plasma levels of cfDNA and the size distribution in early stage, (2) determine the frequency in plasma of methylation of three candidate genes, RASSF1A, MAL, and SFRP1, and (3) to determine whether detection of cfDNA variations and methylation changes in plasma might have specific clinical utility. METHODS AND MATERIALS: Thirty-nine patients woman patients (median age 64 years; range, 36-90 years) who underwent surgery for primary BR and 49 healthy females' subjects (control group without any breast lesion) were evaluated. The cfDNA levels were analyzed using quantitative real-time polymerase chain reaction of ß-globin. Based on the ALU repeats, the cfDNA was considered as either total (fragments of 115 bp, ALU115) or tumoral (fragments of 247 bp, ALU247). The association between the levels of the ALU247, ALU115 repeat, and ALU 247/115and the pathologic tumor characteristics was analyzed. Used methylight qPCR method, cfDNA from plasma samples of healthy donors and patients with breast cancer were evaluated for the diagnotic value of the methylation status of three genes (RASSF1A, MAL, SFRP1) frequently methylated in breast cancer. RESULTS: The baseline levels of cfDNA were significantly higher in the patients with cancer, and the level of ALU247 was the most accurate circulating cfDNA marker in discriminating the cancer from non-cancer subjects. A high statistical significance was found by considering the T stage and patients with regional LN metastasis positive cancers showed significantly higher cfDNA level of ALU247. Moreover, patients with methylation of at least one of the gene under investigate showed a higher quantity of cfDNA ALU115 (p< 0.0001) and ALU247 level (p< 0.0001). CONCLUSIONS: We observed that necrosis could be a potential source of circulating tumour-specific cfDNA ALU247; and that cfDNA ALU247 and methylated cfDNA (RASSF1A, MAL and SFRP1) are both a phenotypic feature of tumour biology.

Separate cavity margins excision as a complement to conservative breast cancer surgery.

BACKGROUND: Positive lumpectomy margins (LM) usually mandate re-excision. However, approximately half of these patients have no residual tumour in the re-excision specimen. The aim of this study was to investigate if separate cavity margin (CM) excision can safely reduce the need of re-operation. METHODS: Rate of re-operation for margin involvement and incidence of residual tumour in the re-excision specimen were retrospectively evaluated in 237 patients (group A) who underwent lumpectomy alone, and in 271 patients (group B) treated by lumpectomy and CM excision. Patients with positive LM (group A) or CM (group B) underwent re-excision. RESULTS: In the group A, 50/237 patients (21.1%) had LM+ and underwent re-excision. In the group B, 74/271 patients (27.3%) had LM+, but tumour was found within the CM specimen in 46 patients (17.0%), 24 LM+ and 22 LM-, and reached the CM cut edge in only 15 (5.5%), who finally underwent re-excision. Residual tumour was found in the re-excision specimen in 28/50 patients (56.0%) of the group A and in 7/15 patients (46.7%) of the group B. CONCLUSIONS: Separate CM excision strongly decreases the rate of re-operation for involved margin. However, the finding of various combinations of LM and CM status and the evidence that CM excision does not improve the positive predictive value of margin involvement suggest prudent conclusions. Only long term follow up of patients treated according to the CM status can exclude that the reduced rate of re-operations allowed by this procedure would expose to an increased risk of local recurrence.

Cost effectiveness of mass screening for coeliac disease is determined by time-delay to diagnosis and quality of life on a gluten-free diet.

BACKGROUND: Coeliac disease is frequently diagnosed after a long delay resulting in increased morbidity and mortality. AIMS: To define the parameters which have the highest impact on the cost-effectiveness of mass screening for coeliac disease. METHODS: A Markov model examined a coeliac disease screening programme of the healthy young-adult general population compared with a no-screening strategy. The main outcome measures were quality adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Effects of variables were examined using sensitivity analyses. RESULTS: The screening strategy resulted in a gain of 0.0027 QALYs. The ICER of screening vs. no-screening strategy was US$48,960/QALYs. The variables with the largest impact on cost effectiveness were: the time delay from symptom onset to diagnosis, the utility of adherence to a gluten-free diet (GFD) and the prevalence of coeliac disease. Screening would be cost-effective if the time delay to diagnosis is longer than 6 years and utility of GFD adherence is greater than 0.978. CONCLUSIONS: Our model suggests that mass screening for coeliac disease of the young-adult general population is associated with improved QALYs and is a cost effectiveness strategy. Shortening of the time-delay to diagnosis by heightened awareness of health-care professionals may be a valid alternative to screening.

Relationships between hypoglycaemia and gastric emptying abnormalities in insulin-treated diabetic patients.

We hypothesize that hypoglycaemia in insulin-treated diabetic patients may result from gastric emptying abnormalities causing insulin and food absorption mismatching. We tested gastric emptying in insulin-treated diabetic patients with unexplained hypoglycaemia and without dyspepsia and in diabetic patients without hypoglycaemia, prospectively. Thirty-one diabetic patients with unexplained hypoglycaemic events within 2 h of insulin injection and 18 insulin-treated diabetic patients without hypoglycaemic events underwent gastric emptying breath tests, glycaemic control and autonomic nerve function. Gastric emptying tests were abnormal in 26 (83.9%) and in four (22.2%) patients with and without hypoglycaemia, respectively (P < 0.001). Gastric emptying was significantly slower in hypoglycaemic diabetic patients (t1/2 139.9 +/- 74.1 vs 77.8 +/- 23.3 and t(lag) 95.8 +/- 80.3 vs 32.84 +/- 16.95 min, P < 0.001 for both comparisons; t-tests). A significant association between hypoglycaemic patients and abnormal values of t1/2 and t(lag) was found (P < 0.001). Gastric emptying abnormalities were more frequent in hypoglycaemic patients. We suggest gastric emptying tests for diabetic patients with unexplained hypoglycaemic events.

Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease.

BACKGROUND AND AIMS: Several antibodies have been reported in the sera of patients with Crohn's disease (CD) and ulcerative colitis (UC). The most commonly described are anti-Saccharomyces cerevisiae mannan antibodies (ASCA) in CD and perinuclear antineutrophil cytoplasm antibodies (pANCA) in UC. Familial clustering of these antibodies has been described, suggesting they might be genetic markers. Our aim was to investigate the presence of these antibodies before the emergence of overt clinical manifestations. METHODS: Since 1980, the Israeli Defense Force (IDF) Medical Corps Serum Repository has stored serum samples obtained systematically from 5% of all recruits on enlistment, and from the same population on discharge from compulsory military service. We evaluated serum samples obtained from 32 subjects with CD and eight with UC before they were clinically diagnosed, along with samples from matched controls. RESULTS: ASCA were present in 10/32 (31.3%) CD patients before clinical diagnosis compared with 0/95 (0%) controls (p<0.001). None of the eight patients with serum samples available before diagnosis of UC were ASCA positive. ASCA was positive in 54.5% of patients after diagnosis of CD. The mean interval between ASCA detection and diagnosis was 38 months. In 90% of patients, antibodies were detected in the first available serum sample; therefore, measurements of the average time from the presence of ASCA to diagnosis may be even longer. pANCA were present in 2/8 (25%) patients with available sera before the diagnosis of UC. None of their 24 matched controls were positive (p = 0.014). CONCLUSIONS: ASCA and pANCA may predict development of inflammatory bowel disease years before the disease is clinically diagnosed.

Safety and tolerability of antagonist anti-human CD40 Mab ch5D12 in patients with moderate to severe Crohn's disease.

BACKGROUND: The ligation of CD40 by CD154 is a critical step in the interaction between APC and T cells. In animals, antagonizing CD40L-CD40 has been shown to reduce the severity of several autoimmune and inflammatory disorders, including experimental colitis. AIM: To investigate tolerability and safety of an antagonist chimeric monoclonal anti-human CD40 antibody (ch5D12) for treatment of Crohn's disease. METHOD: ch5D12 was administrated to 18 patients with moderate to severe Crohn's disease in a single dose, open-label dose-escalation phase I/IIa study. RESULTS: ch5D12 plasma concentrations increased dose-dependently after infusion. Two patients developed an anti-ch5D12 antibody response. Overall response and remission rates were 72 and 22%, respectively with no evidence for a dose-response effect. Treatment with ch5D12 reduced microscopic disease activity and intensity of the lamina propria cell infiltrate, but did not alter percentages of circulating T and B cells. ch5D12 was well tolerated, although some patients experienced headache, muscle aches, or joint pains, which may have been related to the study drug. CONCLUSIONS: Antagonizing CD154-CD40 interactions with ch5D12 is a promising therapeutic approach for remission induction in Crohn's disease.

Complicated endoscopic pediatric procedures using deep sedation and general anesthesia are safe in the endoscopy suite.

BACKGROUND: Complicated upper and lower endoscopic procedures of the gastrointestinal tract are performed in children for a variety of diagnostic and therapeutic reasons. Unlike adult patients, who receive conscious sedation, children usually require deep sedation (DS) or general anesthesia (GA). The aim of this study is to assess the safety parameters of complicated endoscopic procedures under DS or GA performed in children in the endoscopy suite rather than in the operating theatre. METHODS: Between May 1997 and December 2002, 296 patients (mean age 4.5 years, range 3 weeks to 16 years), defined as ASA I-III, underwent either DS or GA for endoscopic foreign body extraction, endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous endoscopic gastrostomy (PEG) insertion. ASA physical status I was found in 15%, II in 57% and III in 28%. The pathologies included neuromuscular diseases, genetic syndromes, nesidioblastosis, biliary atresia, hematologic, respiratory (cystic fibrosis) and cardiac disorders. Propofol was the drug of choice (63%) followed by a combination of propofol and midazolam (16%). RESULTS: Transient desaturation (O2 saturation <90%) was the only complication recorded in 21/296 (7.09%) patients. Only two patients with severe respiratory underlying disease were hospitalized for follow-up for a 24-h period. CONCLUSIONS: The use of DS and GA for complicated endoscopies in a moderately high-risk pediatric population was found to be safe. The very low complication rate found in this study suggests that complicated pediatric patients can be managed successfully outside the operating theatre, provided that all the safety criteria for ambulatory DS or anesthesia are present.

Topical capsaicin--a novel and effective treatment for idiopathic intractable pruritus ani: a randomised, placebo controlled, crossover study.

PURPOSE: Pruritus ani is a common and embarrassing proctological condition which can be very difficult to treat. We report the results of a double blind placebo controlled study of treatment with capsaicin. METHODS: Firstly, a pilot open study was carried out on five patients to establish which of two doses was the most acceptable by comparing effectiveness and side effects. Secondly, a double blind, placebo controlled, crossover study of topical capsaicin was performed. This study involved two four week treatment phases separated by a one week washout phase. Forty four patients were randomised to receive locally either active capsaicin (0.006%) or placebo (menthol 1%) ointment over a four week period (22 patients per group). After four weeks of treatment and a one week washout period, the placebo group began to receive capsaicin while the treated group received placebo (menthol 1%) for another four weeks. At the end of the controlled study, responders from both groups continued with capsaicin treatment in an open labelled manner. RESULTS: Thirty one of 44 patients experienced relief during capsaicin treatment periods and did not respond to menthol; all patients not responding to capsaicin also failed on menthol (p<0.0001). In 13 patients, treatment with capsaicin was unsuccessful: eight patients did not respond to capsaicin treatment, one responded equally to capsaicin and placebo, and four others dropped out because of side effects. During the follow up period (mean 10.9 (SD 5.8) months), 29 "responders" needed a mean application of capsaicin every day (1.6 (SD 1.2); range 0.5-7 days) to remain symptom free (or nearly symptom free). CONCLUSION: Capsaicin is a new, safe, and highly effective treatment for severe intractable idiopathic pruritus ani.

Complicaciones de la Colangiopancreatografia retrogada endoscopica / Complications of endoscopic retrograde cholangiopancreatography

INTRODUCTION: Endoscopic sphincterotomy (ES) is commonly used to remove bile-duct stones and to treat other problems. We prospectively investigated complications and mortality of endoscopic retrograde cholangiopancreatography (ERCP). 2. PATIENTS AND METHODS: Between june 6, 1998 and june 6, 1999 553 ERCP were performed in our centers. Inclusion criteria for protocol were: ERCP indication, complete follow-up and informed consent. We prospectively studied complications of ECRP in consecutive patients treated at 2 institutions (San Martin Hospital, La Plata, Argentina and Hadassah University Hospital, Jerusalem, Israel). The follow-up was done during 365 days with a clinical examination, laboratory test and ultrasonography to determine the possible complications. 3. RESULTS: Of 553 ERCP, 43 had a complications; including pancreatitis in 16 cases, cholangitis in 12, hemorrhage in 5, perforation in 3 and miscellaneous in 7. 3-1) ES frequency: 241 patients (pts). 3-2) Follow-up: 365 days in 504 pts. 3-3) Sex and age: women 274 pts, men 230 pts. Age range 1 month to 90 year old. 3-4) Final diagnoses: choledocholitiasis (38.8%), strictures (18%), pancreatic cancer (4.3%), ampullary cancer (2.3%) and normal ERCP (24.4%). 4. CONCLUSIONS: The rate of complications after ES can vary in different circumstances and is primarily related to the indication for the procedure and to endoscopic technique. Our percentage of complications (7.53%) coincide with consulted studies. Today, diagnostic ERCP has been challenged by magnetic resonance cholangiography (MRC). MRC provides images of the billary and pancreatic ducts that are nearly equal to those of ERCP without the procedural risk associated.

Complicaciones de la Colangiopancreatografia retrogada endoscopica / Complications of endoscopic retrograde cholangiopancreatography

INTRODUCTION: Endoscopic sphincterotomy (ES) is commonly used to remove bile-duct stones and to treat other problems. We prospectively investigated complications and mortality of endoscopic retrograde cholangiopancreatography (ERCP). 2. PATIENTS AND METHODS: Between june 6, 1998 and june 6, 1999 553 ERCP were performed in our centers. Inclusion criteria for protocol were: ERCP indication, complete follow-up and informed consent. We prospectively studied complications of ECRP in consecutive patients treated at 2 institutions (San Martin Hospital, La Plata, Argentina and Hadassah University Hospital, Jerusalem, Israel). The follow-up was done during 365 days with a clinical examination, laboratory test and ultrasonography to determine the possible complications. 3. RESULTS: Of 553 ERCP, 43 had a complications; including pancreatitis in 16 cases, cholangitis in 12, hemorrhage in 5, perforation in 3 and miscellaneous in 7. 3-1) ES frequency: 241 patients (pts). 3-2) Follow-up: 365 days in 504 pts. 3-3) Sex and age: women 274 pts, men 230 pts. Age range 1 month to 90 year old. 3-4) Final diagnoses: choledocholitiasis (38.8%), strictures (18%), pancreatic cancer (4.3%), ampullary cancer (2.3%) and normal ERCP (24.4%). 4. CONCLUSIONS: The rate of complications after ES can vary in different circumstances and is primarily related to the indication for the procedure and to endoscopic technique. Our percentage of complications (7.53%) coincide with consulted studies. Today, diagnostic ERCP has been challenged by magnetic resonance cholangiography (MRC). MRC provides images of the billary and pancreatic ducts that are nearly equal to those of ERCP without the procedural risk associated. (AU)

[Cholangiocarcinoma in primary sclerosing cholangitis: "chronicle of a death foretold"?].

Primary sclerosing cholangitis (PSC), a condition usually associated with inflammatory bowel disease, is a chronic inflammatory state of the biliary tract characterized by fibrotic strictures of intrahepatic and extrahepatic bile ducts. Between 5-15% of patients with PSC will develop cholangiocarcinoma. The diagnosis of cholangiocarcinoma in patients with PSC is difficult, as it is often impossible to distinguish benign PSC-related strictures from lesions associated with cholangiocarcinoma. Consequently, most patients are diagnosed with advanced disease and have a dismal prognosis at the time of diagnosis. The importance of characterizing patients with PSC who have an increased risk of developing cholangiocarcinoma and of developing means for early detection of this disease cannot be over-emphasized. Detection of cholangiocarcinoma in asymptomatic patients is additionally important, as this condition is considered a contraindication for liver transplantation. We describe a patient with longstanding Crohn's disease and PSC who developed cholangiocarcinoma, and review the literature regarding risk factors for cholangiocarcinoma, early detection of cholangiocarcinoma and the significance of existing cholangiocarcinoma in the context of liver transplantation.

[Complications of endoscopic retrograde cholangiopancreatography]. / Complicaciones de la colangiopancreatografía retrógada endoscópica.

INTRODUCTION: Endoscopic sphincterotomy (ES) is commonly used to remove bile-duct stones and to treat other problems. We prospectively investigated complications and mortality of endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: Between june 6, 1998 and june 6, 1999 553 ERCP were performed in our centers. Inclusion criteria for protocol were: ERCP indication, complete follow-up and informed consent. We prospectively studied complications of ECRP in consecutive patients treated at 2 institutions (San Martin Hospital, La Plata, Argentina and Hadassah University Hospital, Jerusalem, Israel). The follow-up was done during 365 days with a clinical examination, laboratory test and ultrasonography to determine the possible complications. RESULTS: Of 553 ERCP, 43 had a complications; including pancreatitis in 16 cases, cholangitis in 12, hemorrhage in 5, perforation in 3 and miscellaneous in 7. 3-1) ES frequency: 241 patients (pts). 3-2) FOLLOW-UP: 365 days in 504 pts. 3-3) Sex and age: women 274 pts, men 230 pts. Age range 1 month to 90 year old. 3-4) Final diagnoses: choledocholitiasis (38.8%), strictures (18%), pancreatic cancer (4.3%), ampullary cancer (2.3%) and normal ERCP (24.4%). CONCLUSIONS: The rate of complications after ES can vary in different circumstances and is primarily related to the indication for the procedure and to endoscopic technique. Our percentage of complications (7.53%) coincide with consulted studies. Today, diagnostic ERCP has been challenged by magnetic resonance cholangiography (MRC). MRC provides images of the billary and pancreatic ducts that are nearly equal to those of ERCP without the procedural risk associated.

Complicaciones de la colangiopancreatografía retrógada endoscópica. / [Complications of endoscopic retrograde cholangiopancreatography]

1. INTRODUCTION: Endoscopic sphincterotomy (ES) is commonly used to remove bile-duct stones and to treat other problems. We prospectively investigated complications and mortality of endoscopic retrograde cholangiopancreatography (ERCP). 2. PATIENTS AND METHODS: Between june 6, 1998 and june 6, 1999 553 ERCP were performed in our centers. Inclusion criteria for protocol were: ERCP indication, complete follow-up and informed consent. We prospectively studied complications of ECRP in consecutive patients treated at 2 institutions (San Martin Hospital, La Plata, Argentina and Hadassah University Hospital, Jerusalem, Israel). The follow-up was done during 365 days with a clinical examination, laboratory test and ultrasonography to determine the possible complications. 3. RESULTS: Of 553 ERCP, 43 had a complications; including pancreatitis in 16 cases, cholangitis in 12, hemorrhage in 5, perforation in 3 and miscellaneous in 7. 3-1) ES frequency: 241 patients (pts). 3-2) Follow-up: 365 days in 504 pts. 3-3) Sex and age: women 274 pts, men 230 pts. Age range 1 month to 90 year old. 3-4) Final diagnoses: choledocholitiasis (38.8

), strictures (18

), pancreatic cancer (4.3

), ampullary cancer (2.3

) and normal ERCP (24.4

). 4. CONCLUSIONS: The rate of complications after ES can vary in different circumstances and is primarily related to the indication for the procedure and to endoscopic technique. Our percentage of complications (7.53

) coincide with consulted studies. Today, diagnostic ERCP has been challenged by magnetic resonance cholangiography (MRC). MRC provides images of the billary and pancreatic ducts that are nearly equal to those of ERCP without the procedural risk associated.

The neurogenetics of mucolipidosis type IV.

BACKGROUND: Mucolipidosis type IV (MLIV) is an autosomal recessive disease caused by mutations in the MCOLN1 gene that codes for mucolipin, a member of the transient receptor potential (TRP) gene family. OBJECTIVE: To comprehensively characterize the clinical and genetic abnormalities of MLIV. METHODS: Twenty-eight patients with MLIV, aged 2 to 25 years, were studied. Ten returned for follow-up every 1 to 2 years for up to 5 years. Standard clinical, neuroimaging, neurophysiologic, and genetic techniques were used. RESULTS: All patients had varying degrees of corneal clouding, with progressive optic atrophy and retinal dystrophy. Twenty-three patients had severe motor and mental impairment. Motor function deteriorated in three patients and remained stable in the rest. All had a constitutive achlorhydria with elevated plasma gastrin level, and 12 had iron deficiency or anemia. Head MRI showed consistent characteristic findings of a thin corpus callosum and remained unchanged during the follow-up period. Prominent abnormalities of speech, hand usage, and swallowing were also noted. Mutations in the MCOLN1 gene were present in all patients. Correlation of the genotype with the neurologic handicap and corpus callosum dysplasia was found. CONCLUSIONS: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.

Wheat grass juice in the treatment of active distal ulcerative colitis: a randomized double-blind placebo-controlled trial.

BACKGROUND: The use of wheat grass (Triticum aestivum) juice for treatment of various gastrointestinal and other conditions had been suggested by its proponents for more than 30 years, but was never clinically assessed in a controlled trial. A preliminary unpublished pilot study suggested efficacy of wheat grass juice in the treatment of ulcerative colitis (UC). METHODS: A randomized, double-blind, placebo-controlled study. One gastroenterology unit in a tertiary hospital and three study coordinating centers in three major cities in Israel. Twenty-three patients diagnosed clinically and sigmoidoscopically with active distal UC were randomly allocated to receive either 100 cc of wheat grass juice, or a matching placebo, daily for 1 month. Efficacy of treatment was assessed by a 4-fold disease activity index that included rectal bleeding and number of bowel movements as determined from patient diary records, a sigmoidoscopic evaluation, and global assessment by a physician. RESULTS: Twenty-one patients completed the study, and full information was available on 19 of them. Treatment with wheat grass juice was associated with significant reductions in the overall disease activity index (P=0.031) and in the severity of rectal bleeding (P = 0.025). No serious side effects were found. Fresh extract of wheat grass demonstrated a prominent tracing in cyclic voltammetry methodology, presumably corresponding to four groups of compounds that exhibit anti-oxidative properties. CONCLUSION: Wheat grass juice appeared effective and safe as a single or adjuvant treatment of active distal UC.

Mast cells involvement in the inflammation and fibrosis development of the TNBS-induced rat model of colitis.

BACKGROUND: Mast cells have been implicated in chronic inflammatory conditions resulting in fibrosis, such as Crohn disease. However, a link between inflammation, fibrosis and mast cells has not been demonstrated in human or animal intestinal diseases. This work was undertaken to analyze whether mast cells play a role in inflammation and fibrosis in the TNBS-induced rat colitis. METHODS: Rats were rectally instilled 2,4,6,-trinitrobenzene sulfonic acid in ethanol, and immediately or 4 days later injected daily i.p. with nedocromil sodium, a mast cell stabilizer, compound 48/80, a mast cell activator, or saline. Rats were sacrificed 5 days post-TNBS, or on day 21. Intestinal inflammation and fibrosis were assessed by gross and histopathological evaluation. Colonic mast cell numbers (toluidine blue) and collagen (type I mRNA expression) were evaluated. Mast cell sonicate was added to rat colon fibroblasts. Fibroblast proliferation (3H-thymidine), collagen synthesis (3H-proline) and contractile activity (tridimensional collagen lattice contraction) were then assessed. RESULTS: Nedocromil reduced inflammation and fibrosis possibly by decreasing mast cell numbers and activation and consequent collagen production. Compound 48/80 slightly enhanced the severity of the disease by activating mast cells. Mast cells increased fibroblast proliferation, collagen production and contractile activity. CONCLUSIONS: Mast cells are involved in the gastrointestinal tract inflammation and fibrosis of the TNBS-colitis rats.

Substance P in rectal mucosa of children with chronic constipation.

Substance P content was determined by radioimmunoassay in rectal mucosa of 17 children with idiopathic constipation and 9 with normal bowel movements who were used as controls. In children with chronic idiopathic constipation, rectal mucosa substance P levels were lower than levels in the control group: 47.6 +/- 11 vs. 79.4 +/- 11 pg/mg net weight respectively (differences not statistically significant). Substance P levels in rectal mucosa of children with soiling (11/17) did not differ from those of chronically constipated children without soiling (46.0 +/- 16 vs. 50.5 +/- 19 pg/mg net weight). In children with constipation, substance P levels did not correlate either with age or duration of symptoms. Substance P levels in normal controls were similar to levels previously observed in non-constipated adults, whereas levels in constipated children were intermediate between levels observed in healthy subjects and levels in adults with chronic constipation. These findings may point to a motility derangement as a possible factor in the pathogenesis of chronic constipation in childhood.