Georgios Kouklakis

Apoptosis, inflammatory bowel disease and carcinogenesis: Overview of international and Greek experiences

Apoptosis is critical for organ development, tissue homeostasis, the elimination of abnormal cells and the maintenance of immune homeostasis by variable regulatory mechanisms. The death of T lymphocytes following their activation involves a series of proteases (caspases), which comprise the central executioners of apoptosis. Abnormal regulation of apoptosis results in disease. T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of the chronic inflammatory process in inflammatory bowel disease with potential tumourigenic effect. The use of antitumour necrosis factor-alpha, anti-interleukin-6R and anti-interleukin-12 antibodies suppresses colitis activity by induction of T-cell apoptosis, thereby having important implications for the design of effective therapeutic strategies in inflammatory bowel diseases. Contrary to international data, the incidence of cancer in Greek patients with inflammatory bowel disease appears to be low. A balance between cell proliferation (Ki-67 overexpression) and apoptosis (Bax protein overexpression) may partly explain the low incidence of cancer development in Greek inflammatory bowel disease patients.

Obestatin/ghrelin ratio: a new activity index in inflammatory bowel diseases.

Background: The aim was to determine obestatin and ghrelin serum levels and their ratio in inflammatory bowel disease (IBD) patients. Methods: We measured the ghrelin and obestatin levels of 31 Crohns disease patients and 22 patients with ulcerative colitis using a radioimmunoassay method. Circulating levels of the 2 hormones and their ratio were correlated with the disease type and activity, disease localization, and treatment. Results: The mean ghrelin value was statistically significantly higher in patients with active disease (402.4 ± 462.6 pg/mL) than in patients in remission (148.2 ± 59.6 pg/mL) P = 0.0290, &agr; = 0.05, whereas obestatin mean values were not (217.4 ± 59.8 pg/mL in active disease and 189.0 ± 46.8 pg/mL in patients with inactive disease P = 0.0607). When we evaluated the obestatin/ghrelin ratio between active and inactive disease, it was found that the ratio in active disease was statistically significantly lower (0.8 ± 0.3) than in patients in remission (1.4 ± 0.3) P < 0.001, &agr; = 0.05. There is also a statistically significantly correlation between obestatin/ghrelin ratio and disease activity (P < 0,001). Conclusions: Ghrelin and obestatin seem to play a significant role in IBD pathogenesis. Further studies are needed to elucidate the role of these hormones as new biological markers of activity of IBD. Inflamm Bowel Dis 2009

Prevalence of Joint Hypermobility and Patterns of Articular Manifestations in Patients with Inflammatory Bowel Disease

Objective. The objective is the investigation of Joint Hypermobility (JH) and the Hypermobility Syndrome (HMS) in patients with inflammatory bowel disease (IBD). Methods. We examined 83 patients with IBD and 67 healthy individuals for the presence of JH. Patients were excluded if they were under 18 or over 50 years of age and if they had other conditions which affect joint mobility. The x2 and the Fisher exact test were used appropriately between study groups. Odds ratios (ORs) for the risk of JH and HMS in IBD groups were calculated. Results. A total of 150 individuals (83 IBD patients and 67 healthy controls) participated in the study. 69 IBD patients, 41 with Crohns Disease (CD) and 28 with ulcerative colitis (UC), were finally eligible. JH was detected in 29 CD patients (70.7%), in 10 UC patients (35.7%), and in 17 healthy control subjects (25.4%). Significant difference was detected on JH in CD patients as compared to UC patients (P = .0063) and controls (P < .0001). The estimated OR for JH was 7.108 (95% CI: 2.98–16.95) in CD and 1.634 (95% CI: 0.63–4.22) in UC patients. HMS was detected in 5 (12.2%) CD and in 1 (3.57%) UC patients. The OR for HMS in CD was 3.75 (95% CI: 0.41–34.007), while 7 (17.1%) CD patients had overlapping symptoms for both HMS and early spondylarthropathy. Conclusions. JH and the HMS are common in CD patients, thus articular manifestations should be carefully interpreted. This implies an involvement of collagen varieties in the pathogenesis of IBD.

Severe eosinophilic infiltration in colonic biopsies predicts patients with ulcerative colitis not responding to medical therapy

Eosinophils are potent proinflammatory cells that are involved in the pathogenesis of ulcerative colitis (UC). We evaluated the infiltration of eosinophils into the lamina propria in patients with active and inactive ulcerative colitis (UC) and investigated its clinical significance, among other variables, in predicting the outcome of medical treatment in active disease.

Endoscopic treatment of a gastrocutaneous fistula using the over-the-scope-clip system: a case report.

The over-the-scope-clip (OTSC; Ovesco Endoscopy GmbH, Tuebingen, Germany) system is a newly designed method for the mechanical compression of large areas in the gastrointestinal tract. So far, indications for OTSC application are hemostasis of primary or postinterventional bleeding, closure of iatrogenic full-thickness or covered perforations. Recently closure of gastrointestinal tract fistulas using this device has been described. A 44-year-old man developed a gastrocutaneous fistula after surgical treatment for a perforated gastric ulcer. We describe the successful endoscopic closure of the fistula using the OTSC system. The patients clinical followup was uneventful. Fistula closure was successfully implemented as it was documented by imaging and endoscopic examinations performed on the 2nd day and 6th week after the application of the clip. Endoscopic application of the OTSC device was safe and effective for the treatment of a gastrocutaneous fistula.

Endoscopic removal of a toothpick perforating the sigmoid colon and causing chronic abdominal pain: a case report

Toothpick ingestion is implicated in gut injuries which may cause severe complications, mimicking diseases causing acute abdomen. However, toothpick ingestion-related perforation may also cause mild, non-specific gastrointestinal symptoms without significant findings or major complications. We describe a young male with chronic postprandial lower abdominal pain caused by a toothpick impaction at the rectosigmoid junction after inadvertent ingestion. The foreign body was detected and successfully removed during flexible sigmoidoscopy. Perforation due to foreign body ingestion must be considered in the differential diagnosis in patients presenting with unexplained symptoms and findings, even when they do not recall any foreign body ingestion.

Spontaneous bowel perforation complicating ventriculoperitoneal shunt: a case report.

Ventriculoperitoneal shunt placement is an effective treatment of hydrocephalus diverting the cerebrospinal fluid into the peritoneal cavity. Unfortunately, the shunt devices have a high incidence of malfunction mainly due to catheter obstruction or infection and are associated with various complications, 25% of which are abdominal. Spontaneous bowel perforation is a rare potentially fatal complication of ventriculoperitoneal shunt occurring anytime, few weeks to several years, after the placement of the ventriculoperitoneal shunt device. A 54-year-old Greek man with spontaneous perforation of sigmoid colon as a complication of distal ventriculoperitoneal shunt migration was treated successfully by antibiotic prophylaxis and abdominal surgery. Clinicians managing patients with ventriculoperitoneal shunt must be familiar with its possible complications and be aware for early recognition of them.

Immunomodulatory Role of Clarithromycin in Acinetobacter baumannii Infection via Formation of Neutrophil Extracellular Traps

ABSTRACT Macrolide antibiotics have been shown to act as immunomodulatory molecules in various immune cells. However, their effect on neutrophils has not been extensively investigated. In this study, we investigated the role of macrolide antibiotics in the generation of neutrophil extracellular traps (NETs). By assessing ex vivo and in vivo NET formation, we demonstrated that clarithromycin is able to induce NET generation both in vitro and in vivo. Clarithromycin utilizes autophagy in order to form NETs, and these NETs are decorated with antimicrobial peptide LL-37. Clarithromycin-induced NETs are able to inhibit Acinetobacter baumannii growth and biofilm formation in an LL-37-dependent manner. Additionally, LL-37 antimicrobial function depends on NET scaffold integrity. Collectively, these data expand the knowledge on the immunomodulatory role of macrolide antibiotics via the generation of LL-37-bearing NETs, which demonstrate LL-37-dependent antimicrobial activity and biofilm inhibition against A. baumannii.

Regulated in development and DNA damage responses 1 (REDD1) links stress with IL-1β–mediated familial Mediterranean fever attack through autophagy-driven neutrophil extracellular traps

Background Familial Mediterranean fever (FMF) is an IL‐1&bgr;–dependent autoinflammatory disease caused by mutations of Mediterranean fever (MEFV) encoding pyrin and characterized by inflammatory attacks induced by physical or psychological stress. Objective We investigated the underlying mechanism that links stress‐induced inflammatory attacks with neutrophil activation and release of IL‐1&bgr;–bearing neutrophil extracellular traps (NETs) in patients with FMF. Methods RNA sequencing was performed in peripheral neutrophils from 3 patients with FMF isolated both during attacks and remission, 8 patients in remission, and 8 healthy subjects. NET formation and proteins were analyzed by using confocal immunofluorescence microscopy, immunoblotting, myeloperoxidase‐DNA complex ELISA, and flow cytometry. Samples from patients with Stills disease and bacterial infections were used also. Results The stress‐related protein regulated in development and DNA damage responses 1 (REDD1) is significantly overexpressed during FMF attacks. Neutrophils from patients with FMF during remission are resistant to autophagy‐mediated NET release, which can be overcome through REDD1 induction. Stress‐related mediators (eg, epinephrine) decrease this threshold, leading to autophagy‐driven NET release, whereas the synchronous inflammatory environment of FMF attack leads to intracellular production of IL‐1&bgr; and its release through NETs. REDD1 in autolysosomes colocalizes with pyrin and nucleotide‐binding domain, leucine‐rich repeat/pyrin domain‐containing 3. Mutated pyrin prohibits this colocalization, leading to higher IL‐1&bgr; levels on NETs. Conclusions This study provides a link between stress and initiation of inflammatory attacks in patients with FMF. REDD1 emerges as a regulator of neutrophil function upstream to pyrin, is involved in NET release and regulation of IL‐1&bgr;, and might constitute an important piece in the IL‐1&bgr;–mediated inflammation puzzle. Graphical abstract Figure. No Caption available.

Esophageal Crohn's disease treated "topically" with swallowed aerosolized budesonide.

Proximal Crohns disease, involving the esophagus, the stomach, the duodenum, and the proximal jejunum, is uncommon. Treatment for proximal Crohns disease is based on data derived from case series than from controlled trials. We present a case of Crohns colitis with concomitant proximal esophagogastroduodenal involvement treated with conventional treatment plus swallowed aerosolized budesonide as a novel adjuvant topical treatment for the esophageal disease, and we review the treatment options for proximal Crohns disease.