TNF-α Producing Innate Lymphoid Cells (ILCs) Are Increased in Active Celiac Disease and Contribute to Promote Intestinal Atrophy in Mice.

Innate lymphoid cells (ILCs) are an emerging family of innate hematopoietic cells producing inflammatory cytokines and involved in the pathogenesis of several immune-mediated diseases. The aim of this study was to characterize the tissue distribution of ILCs in celiac disease (CD), a gluten-driven enteropathy, and analyze their role in gut tissue damage. ILC subpopulations were analyzed in lamina propria mononuclear cells (LPMCs) isolated from duodenal biopsies of CD patients and healthy controls (CTR) and jejunal specimens of patients undergoing gastro-intestinal bypass by flow cytometry. Cytokines and Toll-like receptors (TLR) were assessed in ILCs either freshly isolated or following incubation of control LPMC with peptidoglycan, poly I:C, or CpG, the agonists of TLR2, TLR3, or TLR9 respectively, by flow cytometry. The role of ILCs in gut tissue damage was evaluated in a mouse model of poly I:C-driven small intestine atrophy. Although the percentage of total ILCs did not differ between CD patients and CTR, ILCs producing TNF-α and IFN-γ were more abundant in CD mucosa compared to controls. ILCs expressed TLR2, TLR3 and TLR9 but neither TLR7 nor TLR4. Stimulation of LPMC with poly I:C but not PGN or CpG increased TNF-α and IFN-γ in ILCs. RAG1-deficient mice given poly I:C exhibited increased frequency of TNF-α but not IFN-γ/IL17A-producing ILCs in the gut and depletion of ILCs prevented the poly I:C-driven intestinal damage. Our data indicate that CD-related inflammation is marked by accumulation of ILCs producing TNF-α and IFN-γ in the mucosa. Moreover, ILCs express TLR3 and are functionally able to respond to poly I:C with increased synthesis of TNF-α thus contributing to small intestinal atrophy.

Does the Multidimensional Prognostic Index (MPI), based on a Comprehensive Geriatric Assessment (CGA), predict mortality in cancer patients? Results of a prospective observational trial.

OBJECTIVE: Despite the lack of definitive data on the impact of Comprehensive Geriatric Assessment (CGA) in the geriatric oncology setting, the broad use of any form of CGA is strongly recommended before any treatment decision in elderly cancer patients (ECP); currently there is no consensus about the best format for this geriatric assessment. The aim of this study was to firstly test the Multidimensional Prognostic Index (MPI) in ECP with locally advanced or metastatic disease. MATERIALS AND METHODS: Patients aged ≥70years with inoperable or metastatic solid cancer consecutively admitted to our Program of Geriatric Oncology were assessed by a multidisciplinary team and received a basal CGA to calculate the MPI score. RESULTS: A hundred and sixty patients entered the study. In the Cox's regression model, MPI, CIRS-SI, BSA, GDS, MMSE, chemotherapy and a diagnosis of primary lung cancer were associated with mortality at 6 and 12months. The ROC curves confirmed the prognostic value of MPI, with the best discriminatory power for mortality at both 6 and 12months. CONCLUSION: The present study is the first to indicate that the MPI retains its prognostic value even in elderly cancer patients with advanced stage of disease. The CIRS-SI and the GDS may potentiate the prognostic value of MPI.

Role of 0.4% glyceryl trinitrate ointment after haemorrhoidectomy: results of a prospective randomised study.

INTRODUCTION: Conventional haemorrhoidectomy (CH) is well known to cause significant post-operative pain and delayed return to daily activities. Both surgical wounds and sphincterial apparatus spasms are likely responsible for the pain. In this study, we evaluated the role of glyceryl trinitrate ointment (GTN) in reducing post-operative pain, ameliorating wound healing and recovery after CH. PATIENTS AND METHODS: Between 01/08 and 12/11, 203 patients with symptomatic haemorrhoids were enrolled in the study and received (103 patients) or not (100 patients) 0.4 % GTN ointment for 6 weeks after surgery. Pain was assessed using a 10-cm linear visual analogue scale (VAS). Data on post-operative pain, wound secretion and bleeding, return to normal activities and complications were recorded. Data were analysed using Fisher's exact and Mann-Whitney tests. RESULTS: GTN-treated group experienced significantly less pain during the first week after surgery (p < 0.0001). This difference was more evident starting from post-operative day 4 (p < 0.0001). A significant higher percentage of untreated patients experienced severe pain (mean VAS score > 7) (10 % vs 31 %). There were significant differences in terms of secretion time (p = 0.0052) and bleeding time (p = 0.02) in favor of GTN. In addition, the duration of itching was less in the GTN group (p = 0.0145). Patients treated with GTN were able to an early return to daily activities compared to untreated (p < 0.0001). Fifteen GTN-treated patients (14.6 %) discontinued the application because of local discomfort and headache. CONCLUSIONS: GTN ointment enhances significantly post-operative recovery, reducing pain in terms of duration and intensity. This effect might be secondary to a faster wound healing expressed by reduced secretion, bleeding and itching time.

Nonerosive gastroesophageal reflux disease and mild degree of esophagitis: comparison of symptoms endoscopic, manometric and pH-metric patterns.

BACKGROUND: Our aim in the present study was to compare patients presenting with gastroesophageal reflux disease in the presence or absence of mild-grade esophagitis (grade I or II according to the Savary-Miller classification). METHODS: Between 2005 and 2007, 215 patients with gastroesophageal reflux disease (67 with reflux associated with grade I or II esophagitis and 148 without esophagitis) were evaluated at the Department of Surgery, University Hospital Tor Vergata, Rome, and were included in the present study. The evaluations consisted of clinical interviews, endoscopy of the high digestive tract, esophageal manometry and pH monitoring. RESULTS: There was no significant difference between the two groups with regard to age, sex or symptoms. The incidence of heartburn associated with noncardiac chest pain was greater in the esophagitis group than in the dysphagia group. The incidence of hiatal hernia was similar in both groups. Although the motor pattern was similar in both groups, the length of the abdominal esophagus was greater in patients without esophagitis (1.6 cm vs 1.1 cm; P < 0.05). The reflux pattern was nearly identical in both groups. CONCLUSIONS: Gastroesophageal reflux without esophagitis must be regarded not as a milder form of the disease but as part of a single disease. Furthermore, these patients often demonstrate lower rates of symptom improvement after antireflux treatment in comparison with patients with erosive esophagitis. Therefore, further trials to assess the treatment algorithm for these patients are warranted.

Laparoscopic ventral rectopexy for internal rectal prolapse using biological mesh: postoperative and short-term functional results.

BACKGROUND: Laparoscopic ventral mesh rectopexy is a novel procedure to correct internal and external rectal prolapse. Several authors have shown that this approach is safe and improves obstructive defaecation symptoms and faecal incontinence, without inducing new-onset constipation, possible after posterior rectopexy. Over the last decade, as for other procedures, biological meshes are used to correct pelvic floor disorders. Literature data are scant. In this study, we present our experience with this procedure using biological mesh. PATIENTS AND METHODS: Prospectively collected data on laparoscopic ventral mesh rectopexy for internal rectal prolapse were analysed. All patients underwent preoperative evaluation with defaecating proctography and/or pelvic dynamic MRI, full colonoscopy, anal physiology studies and endo-anal ultrasound. End-points were to evaluate surgical complications and functional results of this technique such as changes in bowel function (Wexner Constipation Score and Faecal Incontinence Severity Index) at 3 and 6 months. Analysis was performed using Mann-Whitney U test for unpaired data and Wilcoxon signed rank test for paired data (two-sided p test). RESULTS: Thirty-four consecutive patients underwent laparoscopic ventral mesh rectopexy (median age 59, range 25-78 years, mean follow-up was 12 months). Twenty-eight patients (82%) had a constipation score ≥ 5, while 14 (41%) a FISI score ≥ 10. Nine patients (26%) had mixed obstructed defaecation and faecal incontinence. One patient required conversion to open (3%). Median length of stay was 2 days. Overall complication rate was 23.5%. Preoperative constipation (median Wexner score 15) and faecal incontinence (median FISI score 12) improved significantly at 3 months (Wexner 5, FISI 5, both p < 0.001). Two patients experienced prolapse persistence or recurrence. No patients had function worsening or complained of sexual dysfunction. CONCLUSIONS: Laparoscopic ventral mesh rectopexy using biological mesh for internal rectal prolapse is safe and effective in ameliorating symptoms of obstructed defaecation and faecal incontinence.

Prevalence of defaecatory disorders in morbidly obese patients before and after bariatric surgery.

BACKGROUND: The prevalence of obesity is increasing worldwide and has lately reached epidemic proportions in western countries. Several epidemiological studies have consistently shown that both overweight and obesity are important risk factors for the development of various functional defaecatory disorders (DDs), including faecal incontinence and constipation. However, data on their prevalence as well as effectiveness of bariatric surgery on their correction are scant. The primary objective of this study was to estimate the effect of morbid obesity on DDs in a cohort of patients listed for bariatric surgery. We also evaluated preliminary results of the effects of sleeve gastrectomy on these disorders. PATIENTS AND METHODS: A questionnaire-based study was proposed to morbidly obese patients having bariatric surgery. Data included demographics, past medical, surgical and obstetrics histories, as well as obesity related co-morbidities. Wexner Constipation Score (WCS) and the Faecal Incontinence Severity Index (FISI) questionnaires were used to evaluate constipation and incontinence. For the purpose of this study, we considered clinically relevant a WCS ≥5 and a FISI score ≥10. The same questionnaires were completed at 3 and 6 months follow-up after surgery. RESULTS: A total of 139 patients accepted the study and 68 underwent sleeve gastrectomy and fully satisfied our inclusion criteria with a minimum follow-up of 6 months. Overall, mean body mass index (BMI) at listing was 47 ± 7 kg/m(2) (range 35-67 kg/m(2)). Mean WCS was 4.1 ± 4 (range 0-17), while mean FISI score (expressed as mean±standard deviation) was 9.5 ± 9 (range 0-38). Overall, 58.9% of the patients reported DDs according to the above-mentioned scores. Twenty-eight patients (20%) had WCS ≥5. Thirty-five patients (25%) had a FISI ≥10 while 19 patients (13.7%) reported combined abnormal scores. Overall, DDs were more evident with the increase of obesity grade: Mean BMI decreased significantly from 47 ± 7 to 36 ± 6 and to 29 ± 4 kg/m(2) respectively at 3 and 6 months after surgery (p < 0.0001). According to the BMI decrease, the mean WCS decreased from 3.7 ± 3 to 3.1 ± 4 and to 1.6 ± 3 respectively at 3 and 6 months (p = 0.02). Similarly, the FISI score decreased from 10 ± 8 to 3 ± 4 and to 1 ± 2 respectively at 3 and 6 months (p = 0.0001). CONCLUSIONS: Defaecatory disorders are common in morbidly obese patients. The risk of DDs increases with BMI. Bariatric surgery reduces DDs, mainly faecal incontinence, and these findings correlated with BMI reduction.

Surgery for fistula-in-ano in a specialist colorectal unit: a critical appraisal.

BACKGROUND: Several techniques have been described for the management of fistula-in-ano, but all carry their own risks of recurrence and incontinence. We conducted a prospective study to assess type of presentation, treatment strategy and outcome over a 5-year period. METHODS: Between 1st January 2005 and 31st March 2011,247 patients presenting with anal fistulas were treated at the University Hospital Tor Vergata and were included in the present prospective study. Mean age was 47 years (range 16-76 years); minimum follow-up period was 6 months (mean 40, range 6-74 months).Patients were treated using 4 operative approaches: fistulotomy, fistulectomy, seton placement and rectal advancement flap. Data analyzed included: age, gender, type of fistula, operative intervention, healing rate, postoperative complications, reinterventions and recurrence. RESULTS: Etiologies of fistulas were cryptoglandular (n = 218), Crohn's disease (n = 26) and Ulcerative Colitis (n = 3). Fistulae were classified as simple -intersphincteric 57 (23%), low transphincteric 28 (11%) and complex -high transphicteric 122 (49%), suprasphincteric 2 (0.8%), extrasphinteric 2 (0.8%), recto-vaginal 7 (2.8%) Crohn 26 (10%) and UC 3 (1.2%).The most common surgical procedure was the placement of seton (62%), usually applied in case of complex fistulae and Crohn's patients.Eighty-five patients (34%) underwent fistulotomy, mainly for intersphincteric and mid/low transphincteric tracts. Crohn's patients were submitted to placement of one or more loose setons.The main treatment successfully eradicated the primary fistula tract in 151/247 patients (61%). Three cases of major incontinence (1.3%) were detected during the follow-up period; Furthermore, three patients complained minor incontinence that was successfully treated by biofeedback and permacol injection into the internal anal sphincter. CONCLUSIONS: This prospective audit demonstrates an high proportion of complex anal fistulae treated by seton placement that was the most common surgical technique adopted to treat our patients as a first line. Nevertheless, a good outcome was achieved in the majority of patients with a limited rate of faecal incontinence (6/247 = 2.4%). New technologies provide promising alternatives to traditional methods of management particularly in case of complex fistulas. There is, however, a real need for high-quality randomized control trials to evaluate the different surgical and non surgical treatment options.

Ets1 is required for p53 transcriptional activity in UV-induced apoptosis in embryonic stem cells.

Embryonic stem (ES) cells contain a p53-dependent apoptosis mechanism to avoid the continued proliferation and differentiation of damaged cells. We show that mouse ES cells lacking Ets1 are deficient in their ability to undergo UV-induced apoptosis, similar to p53 null ES cells. In Ets1(-/-) ES cells, UV induction of the p53 regulated genes mdm2, perp, cyclin G and bax was decreased both at mRNA and protein levels. While p53 protein levels were unaltered in Ets1(-/-) cells, its ability to transactivate genes such as mdm2 and cyclin G was reduced. Furthermore, electrophoretic mobility shift assays and immunoprecipitations demonstrated that the presence of Ets1 was necessary for a CBP/p53 complex to be formed. Chromatin immunoprecipitations demonstrated that Ets1 was required for the formation of a stable p53-DNA complex under physiological conditions and activation of histone acetyltransferase activity. These data demonstrate that Ets1 is an essential component of a UV-responsive p53 transcriptional activation complex in ES cells and suggests that Ets1 may contribute to the specificity of p53-dependent gene transactivation in distinct cellular compartments.