Intractable diarrhea in infancy and molecular analysis: We are beyond the tip of the iceberg.

BACKGROUND: Intractable diarrhea (ID) could be defined as a syndrome of severe chronic diarrhea associated with malnutrition not easily resolved by conventional management. AIMS: To provide an overview on etiology and management of ID patients in Italy in the last 12 years. METHODS: The members of Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) enrolled all ID patients seen between January 1, 2011 and December 31, 2022. RESULTS: 69 children were enrolled (49 M, 20 F; median age at ID onset 9.5 days) from 7 tertiary care pediatric centers. Overall 62 patients had genetic diseases; 3 had infantile Inflammatory Bowel Disease and 1 autoimmune enteropathy in absence of genetic mutations; 2 undefined ID. Defects of intestinal immune-related homeostasis caused ID in 29 patients (42 %). CONCLUSION: ID is a rare but challenging problem, although the potential for diagnosis has improved over time. In particular, molecular analysis allowed to identity genetic defects in 90 % of patients and to detect new genetic mutations responsible for ID. Due to both the challenging diagnosis and the treatment for many of these diseases, the close relationship between immune system and digestive tract should require a close collaboration between pediatric immunologists and gastroenterologists, to optimize epidemiologic surveillance and management of ID.

Biological therapy downregulates the heterodimer S100A8/A9 (calprotectin) expression in psoriatic patients.

The pathophysiology of psoriasis is very complex and involves an interplay between immune cells and keratinocytes. The keratinocyte production of calprotectin (S100A8/A9), induced by the inflammatory psoriatic milieu, may be involved in initiating immune cell invasion, as well as in propagating inflammation. However, the exact role of calprotectin in psoriasis remains unclear. Therapeutic approaches utilizing adalimumab, etanercept and ustekinumab are widely used in psoriatic treatment, but their anti-inflammatory mechanisms are not fully understood. The aim of this study was to investigate, by immunohistochemical analysis, the expression of the heterocomplex S100A8/A9 in lesional skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. Our results showed that S100A8/A9, absent or present at very low level in skin biopsies from healthy subjects, is dramatically upregulated in each epidermal layer from psoriatic patients. Interestingly, calprotectin was mainly localized in keratinocyte nuclei from psoriatic patients, suggesting a role of S100A8/A9 in keratinocyte nuclear function. Furthermore, we have shown that the biological treatment induced a drastic reduction of S100A8/A9 expression in skin biopsies from treated patients, correlating with PASI reduction. Our results suggest that calprotectin may play a crucial role as a significant marker of inflammation in psoriasis, and that its reduction of expression may be considered a favourable prognostic marker in psoriasis.

Barriers against split-dose bowel preparation for colonoscopy.

OBJECTIVE: Although split regimen is associated with higher adenoma detection and is recommended for elective colonoscopy, its adoption remains suboptimal. The identification of patient-related barriers may improve its implementation. Our aim was to assess patients' attitude towards split regimen and patient-related factors associated with its uptake. DESIGN: In a multicentre, prospective study, outpatients undergoing colonoscopy from 8:00 to 14:00 were given written instructions for 4 L polyethylene glycol bowel preparation, offering the choice between split-dose and day-before regimens and emphasising the superiority of split regimen on colonoscopy outcomes. Uptake of split regimen and association with patient-related factors were explored by a 20-item questionnaire. RESULTS: Of the 1447 patients (mean age 59.2±13.5 years, men 54.3%), 61.7% and 38.3% chose a split-dose and day-before regimens, respectively. A linear correlation was observed between time of colonoscopy appointments and split-dose uptake, from 27.3% in 8:00 patients to 96% in 14:00 patients (p<0.001, χ2 for linear trend). At multivariate analysis, colonoscopy appointment before 10:00 (OR 0.14, 95% CI 0.11 to 0.18), travel time to endoscopy service >1 h (OR 0.55, 95% CI 0.38 to 0.79), low education level (OR 0.72, 95% CI 0.54 to 0.96) and female gender (OR 0.74, 95% CI 0.58 to 0.95) were inversely correlated with the uptake of split-dose. Overall, the risk of travel interruption and faecal incontinence was slightly increased in split regimen patients (3.0% vs 1.4% and 1.5% vs 0.9%, respectively; p=NS). Split regimen was an independent predictor of adequate colon cleansing (OR 3.34, 95% CI 2.40 to 4.63) and polyp detection (OR 1.46, 95% CI 1.11 to 1.92). CONCLUSION: Patient attitude towards split regimen is suboptimal, especially for early morning examinations. Interventions to improve patient compliance (ie, policies to reorganise colonoscopy timetable, educational initiatives for patient and healthcare providers) should be considered. TRIAL REGISTRATION NUMBER: NCT02287051; pre-result.

5-HT(1A) and 5-HT(7) receptors differently modulate AMPA receptor-mediated hippocampal synaptic transmission.

We have studied the effects of 5-HT(1A) and 5-HT(7) serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT(1A)/5-HT(7) receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT(1A) receptor agonist 8-OH PIPAT and blocked by the 5-HT(1A) antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT(7) receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT(7) receptors, we used the compound LP-44, which is considered a selective 5-HT(7) agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT(1A) and 5-HT(7) receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT(1A) receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT(7) receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the need for new selective agonists of 5-HT(7) receptors.

Confocal laser endomicroscopy for the detection of mucosal changes in ileal pouch after restorative proctocolectomy.

BACKGROUND: Pouchitis and dysplasia may affect the reservoir after restorative proctocolectomy. AIMS: To assess the suitability of confocal laser endomicroscopy for the in vivo diagnosis of mucosal changes in ileal pouch for ulcerative colitis and familial adenomatous polyposis. METHODS: Standard endoscopy and endomicroscopy were performed in 18 pouches. Confocal images were scored for the presence of villous atrophy, inflammation, ulceration, colonic metaplasia and dysplasia. Targeted biopsies were taken. Endomicroscopic and histological findings were compared. RESULTS: At standard endoscopy, the signs of pouchitis were recorded in 7/18 (38.9%) patients. At endomicroscopy, pathological features were found in 16/18 (88.9%), villous atrophy in 15/18 (83.3%), inflammation in 13/18 (72.2%), ulceration in 3/18 (16.7%), and colonic metaplasia in 12/18 (67.7%). No dysplasia was observed. At histology, abnormalities were present in 17/18 (94.4%): villous atrophy in 15/18 (83.3%), inflammation in 17/18 (94.4%), ulceration in 6/18 (33.3%), colonic metaplasia in 15/18 (83.3%). Morphological changes of the ileal pouch could be predicted with an accuracy of 94.4% (95% CI: 74.2-99.0). The k-value for intra- and interobserver agreement was 0.93 and 0.78, respectively. CONCLUSIONS: Endomicroscopy may be helpful in the evaluation of morphologic changes in ileal pouch. The small size of the population sample requires further studies for the results to be confirmed.

Confocal laser endomicroscopy diagnosis of gastric adenocarcinoma in a patient treated for gastric diffuse large-B-cell lymphoma.

The association between gastric carcinoma and lymphoma is rare. Confocal laser endomicroscopy is a new diagnostic tool that allows the identification of cellular and vascular architecture during endoscopy. This is the first report of an in vivo early gastric carcinoma diagnosis by confocal laser endomicroscopy in a patient successfully treated for a primary gastric diffuse large-B-cell lymphoma.

Long-term endoscopic and clinical follow-up of untreated type 1 gastric neuroendocrine tumours.

BACKGROUND AND AIMS: Type 1 gastric neuroendocrine tumour surveillance and treatment are a matter of debate. Endoscopic, or surgical, resection and chronic somatostatin analog therapy have been proposed. Based on the favourable behaviour of this neoplasm, we performed an endoscopic and clinical follow-up in 11 patients affected by type 1 gastric neuroendocrine tumours, avoiding any specific treatment. METHODS: Between 1994 and 2006, we prospectively recorded the data of 11 untreated patients with type 1 gastric neuroendocrine tumours who underwent an endoscopic and clinical follow-up. All the patients were also evaluated by means of an abdominal computed tomography scan, somatostatin receptor scintigraphy and blood tests. RESULTS: During the follow-up (median 54 months, range 9-136), the endoscopic picture of 4 (36%) out of 11 patients changed in terms of increased number of lesions. In none of the cases were detected any lesions that exceeded 10mm in diameter, and none of the patients demonstrated any evidence of local or distant metastases. CONCLUSIONS: Our data confirm the literature data of the indolent behaviour of type 1 gastric neuroendocrine tumours and suggest that a careful endoscopic follow-up, without any treatment, might represent a reasonable and safe option in selected patients.

Metal stent placement in acute malignant colorectal obstruction.

BACKGROUND: Obstruction is a common complication of advanced colorectal cancer. Stent insertion can reduce the need for emergency surgery and allows chemotherapy to begin immediately. AIMS: To evaluate the technical and clinical success and long-term outcome of stent placement in the management of acute malignant colorectal obstruction. METHODS: From July 2002 to April 2005, 29 self-expanding metal stents were placed in 24 patients (13 men, mean age 67 years, range 36-83). Stents were inserted under endoscopic and fluoroscopic control. Patients were clinically and endoscopically followed up. RESULTS: Twenty-eight out of 29 stents were successfully placed (96.5%) in 23 out of 24 patients with 25 strictures. The clinical success rate was 95.8% (23/24). Two early stent migrations were observed in two patients (8.3%). Late complications developed in eight patients (33.3%) after a median of 3.8 months (range <1-8.6): two migrations and six occlusions. The median survival was 9.8 months (range <1-27). Eleven patients (45.8%) died from progressive disease without any clinical evidence of recurrent obstruction. CONCLUSION: Stent placement is safe and effective. Stent complications are frequent but not life-threatening, and are easy to manage. An improvement in stent design and well-scheduled follow-up are needed in order to prevent such complications.

Is colonoscopy a suitable investigation in the preoperative staging of ovarian cancer patients?

BACKGROUND: During ovarian cancer surgery, colorectal resection may be required. In our institution, preoperative colonoscopy is performed in order to assess visceral involvement. AIMS: The aim of this study was to evaluate the utility of preoperative colonoscopy in ovarian cancer patients and the prevalence of adenomas in this population. PATIENTS: This retrospective study involved 144 consecutive patients with a supposed primary ovarian cancer. METHODS: Mucosal infiltration, bowel wall elasticity and bowel fixation were used to predict colorectal infiltration. Endoscopic and pathological findings were compared. All the polyps observed were removed. RESULTS: Six patients (4.2%) were excluded because of a misdiagnosed colorectal cancer metastatic to the ovary. Eight (6%) patients were considered, at endoscopy, to have a bowel infiltration and eight (6%), an uncertain infiltration. In 116 (88%), no signs of bowel infiltration were observed. The pathological analysis showed that colonoscopy had a low sensitivity (44%) in identifying bowel infiltration. Specificity was 100%, positive predictive value 100% and negative predictive value 92%. The overall accuracy was about 90%. Thirty-six adenomas were removed in 26 (20%) women. CONCLUSIONS: Colonoscopy identifies a not insignificant number of ovarian cancer patients requiring colorectal surgery. An increased prevalence of adenomas was not observed in this population.

Long-term remission in patients with dermatitis herpetiformis on a normal diet.

BACKGROUND: A life-long gluten-free diet is the treatment of choice for dermatitis herpetiformis, which is considered to be coeliac disease of the skin. OBJECTIVES: To investigate the effects on long-term remission of dermatitis herpetiformis in patients who underwent a gluten challenge and subsequently reintroduced dietary gluten. PATIENTS AND METHODS: We studied 38 patients (14 male and 24 female) with biopsy-confirmed dermatitis herpetiformis. They had followed a gluten-free diet for a mean of 8 years, achieving clinical remission and intestinal normalization. The patients were asked to reintroduce gluten in their diet and agreed to undergo skin and intestinal biopsies during the follow-up. RESULTS: Of the 38 patients abandoning a gluten-free diet, 31 reported the onset of rash within an average of 2 months. Seven subjects (three males, mean age 15 years at challenge) experienced no clinical or histological relapses (median follow-up 12 years), and lost IgA immunoglobulin from the skin. The two series of patients differed in terms of age at diagnosis (mean age: 26.6 vs. 6 years), the use of dapsone (one of 31 vs. four of seven) and adherence to the gluten-free diet (strict compliance in 26 of 31 vs. none of seven). CONCLUSIONS: Our data suggest that the ingestion of small doses of gluten in childhood and/or the use of an anti-inflammatory drug may modify the immunological response inducing immune tolerance. We report long-term clinical and histological remissions in seven patients with dermatitis herpetiformis after the reintroduction of dietary gluten.

Serological markers for coeliac disease: is it time to change?

BACKGROUND: Anti-gliadin and anti-endomysium antibodies are useful markers in the screening and follow-up of coeliac disease. The recent finding that tissue transglutaminase is the main auto-antigen of anti-endomysium has led to the discovery of anti-tissue transglutaminase antibodies. AIM: To compare, in a prospective study, the diagnostic accuracy of anti-tissue transglutaminase, anti-gliadin and anti-endomysium antibodies in a large series of adult patients. METHODS: The study involved 80 consecutive subjects undergoing upper gastrointestinal tract endoscopy for suspected coeliac disease (subsequently confirmed in 40 cases), 195 coeliac patients on a gluten-free diet, and 70 patients with different gastrointestinal disor ders and normal duodenal histology. Anti-gliadin, anti-endomysium and anti-tissue transglutaminase antibodies levels were measured using commercial kits. RESULTS: The diagnostic sensitivity and specificity of anti-gliadin, anti-endomysium and anti-tissue transglutaminase antibodies were, respectively, 95% and 89.1%, 100% and 97.3%, and 100% and 98.2%: the agreement between the markers was substantial or almost perfect. In terms of follow-up, the positivity of the markers varied according to the strict adherence to, and duration of the gluten-free diet; the agreement between antiendomysium and anti-tissue transglutaminase antibodies was almost perfect. CONCLUSIONS: Anti-endomysium and anti-tissue transglutaminase antibodies are both highly efficient for routine laboratory screening: the choice of one or the other will depend on the available facilities. However, neither can replace intestinal biopsy for general population screening because, in this case, their respective positive predictive values are only 15.7% and 21.8%. During follow-up, anti-gliadin retain their value as an early predictor of gluten ingestion.

Severe hypopharyngeal dysphagia in a patient on chronic steroid treatment.

A 44-year-old Caucasian male who had been on long-term steroid treatment for an unspecified collagen disease was referred to our Unit because of fever, severe hypopharyngeal dysphagia, night sweats and evidence of marked superior vena cava compression. Extrapulmonary disseminated tuberculosis also involving bone and liver was eventually diagnosed and proven by means of specific polymerase chain reaction assay. Antimycobacterial treatment, which led to a dramatic improvement within two months, was protracted for 18 months until the complete return to normal of both clinical and laboratory findings.