Addressing health inequalities in Europe: key messages from the Joint Action Health Equity Europe (JAHEE).

Health inequalities within and between Member States of the European Union are widely recognized as a public health problem as they determine a significant share of potentially avoidable mortality and morbidity. After years of growing awareness and increasing action taken, a large gap still exists across Europe in terms of policy responses and governance. With the aim to contribute to achieve greater equity in health outcomes, in 2018 a new Joint Action, JAHEE, (Joint Action Health Equity Europe) was funded by the third EU Health Programme, with the main goal of strengthening cooperation between participating countries and of implementing concrete actions to reduce health inequalities. The partnership led by Italy counted 24 countries, conducting actions in five policy domains: monitoring, governance, healthy living environments, health systems and migration, following a three-step implementation approach. Firstly, specific Policy Frameworks for Action (PFA) collecting the available evidence on what practice should be done in each domain were developed. Second, different Country Assessments (CAs) were completed to check the country's adherence to the recommended practice in each domain. The gap between the expected policy response (PFA) and the present policy response (CA) guided the choice of concrete actions to be implemented in JAHEE, many of which are continuing even after the end of JA. Final recommendations based on the best results achieved during JAHEE were elaborated and agreed jointly with the representatives of the involved Ministries of Health. The JAHEE initiative represented an important opportunity for the participating countries to work jointly, and the results show that almost all have increased their level of action and strengthened their capacities to address health inequalities.

Quality of Life After Operation for End-Stage Achalasia: Pull-Down Heller-Dor Versus Esophagectomy.

BACKGROUND: Therapy for end-stage achalasia is debated, and data on long-term functional results of myotomy and esophagectomy are lacking. We compared quality of life and objective outcomes after pull-down Heller-Dor and esophagectomy. METHODS: The study included 32 patients, aged 57 years (interquartile range [IQR], 49-70 years), who underwent the Heller-Dor operation with verticalization of the distal esophagus in case of first instance treatment or failed surgery caused by insufficient myotomy, and 16 patients, aged 58 years (IQR, 49-67 years; P = .806), who underwent esophagectomy after failed surgery for other causes. Data were extracted from a database designed for prospective clinical research. Postoperative dysphagia, reflux symptoms, and endoscopic esophagitis were graded by semiquantitative scales. Quality of life was assessed with the 36-Item Short Form Health Survey questionnaire. RESULTS: The median follow-up period was 68 months (IQR, 40.43-94.48 months) after pull-down Heller-Dor and 61 months (IQR 43.72-181.43 months) after esophagectomy (P = .598). No statistically significant differences were observed for dysphagia (P = .948), reflux symptoms (P = .186), or esophagitis (P = .253). No statistically significant differences were observed in the domains physical functioning (P = .092), bodily pain (P = .075) or general health (P = .453). Significant differences were observed in favor of pull-down Heller-Dor for the domains role physical (100 vs 100, P = .043), role emotional (100 vs 0, P = .002), vitality (90 vs 55, P< .001), mental health (92 vs 68, P = .002), and social functioning (100 v s75, P = .011). CONCLUSIONS: The pull-down Heller-Dor achieved objective results similar to those of esophagectomy with a better quality of life. This technique may be the first choice for end-stage achalasia in patients with null or low risk for cancer or after recurrent dysphagia caused by insufficient myotomy.

True Short Esophagus in Gastroesophageal Reflux Disease: Old Controversies With New Perspectives.

OBJECTIVE: To explore the true short esophagus (TSE) frequency and long-term results of patients undergoing gastroesophageal reflux disease (GERD) or hiatus hernia (HH) surgery. BACKGROUND: The existence and treatment of TSE during GERD/HH surgery is controversial. Satisfactory long-term results have been achieved with and without surgical techniques dedicated to TSE. METHODS: In 311 consecutive patients undergoing minimally invasive surgery for GERD/HH, the distance between the endoscopically-localized gastroesophageal junction (GEJ) and the apex of the diaphragmatic hiatus after maximal thoracic esophagus mobilization was measured. A standard Nissen fundoplication (SN) was performed in cases with an abdominal length >1.5 cm; in cases of TSE (abdominal length <1.5 cm), a Collis-Nissen (CN) or stomach around the stomach fundoplication (SASF) in elderly patients was performed. The fundoplication superior margin was fixed below the hiatus, but over the GEJ. The patients' symptoms, and radiological and endoscopic data were pre/postoperatively recorded. RESULTS: After intrathoracic esophageal mobilization (median 9 cm), TSE was diagnosed in 31.8% of 311 cases. With a median follow-up of 96 months (309 patients), HH relapse was radiologically diagnosed in 3.2% of patients, with excellent, good, fair, and poor outcomes in 45.6%, 44.3%, 6.2%, and 3.9% of cases, respectively, and no significant differences among SN (68.5%), CN (26.4%), and SASF (5.2%). CONCLUSIONS: TSE was present in 31.8% of patients routinely submitted to GERD/HH surgery. In the presence of TSE, CN and SASF performed according to determined surgical principles may achieve similar satisfactory results. This finding warrants confirmation with a prospective multicenter study.

Health inequalities: a Research Positioning Exercise at the National Institute of Health, Italy.

BACKGROUND: The Italian National Institute of Health (Istituto Superiore di Sanità, ISS) considers health inequalities (HI) an important area of activity. As the scientific and technical body of the Ministry of Health and the National Health Service, ISS may play a key role to reduce HI. In order to enable ISS in addressing the new and crucial HI challenge, a Research Positioning Exercise was designed and implemented. METHODS: The Exercise included: (i) workshop to strengthen the institutional interest in the field of HI; (ii) review and analysis of ISS publications (years 2000-2017) to identify HI research topics; (iii) survey among ISS researchers regarding main research challenges to address HI in the coming years; and (iv) analysis of input on research challenges from HI international experts. RESULTS: The results of this Exercise suggest that the following points should be included in the future ISS agenda planning: (i) themes which ISS should continue working on (e.g. migrants/vulnerable groups); (ii) themes to be improved: (a) relationship between social determinants and mechanism of HI generation and (b) relationship between risk factors exposure and social determinants; and (iii) new themes to be addressed: (a) mechanisms underlying the resilience observed in Italy; (b) new socioeconomic indicators for HI monitoring; and (c) evidence-based policies aimed at reducing HI. CONCLUSION: Findings of this Exercise show that ISS researchers identified relevant areas, addressing inequalities in addressing the health. Because of ISS structural peculiarity that includes multidisciplinary expertise, the ISS could provide a significant contribution to HI research challenges and knowledge gaps.

Environmental Justice in Industrially Contaminated Sites. A Review of Scientific Evidence in the WHO European Region.

In the WHO European Region the topic of contaminated sites is considered a priority among environment and health themes. Communities living in or close to contaminated sites tend to be characterized by a high prevalence of ethnic minorities and by an unfavorable socioeconomic status so rising issues of environmental justice. A structured review was undertaken to describe the contents of original scientific studies analyzing distributive and procedural justice in industrially contaminated sites carried out in the WHO European Region in the period 2010⁻2017. A systematic search of the literature was performed. In total, 14 articles were identified. Wherever assessments on environmental inequalities were carried out, an overburden of socioeconomic deprivation or vulnerability, with very few exemptions, was observed. The combined effects of environmental and socioeconomic pressures on health were rarely addressed. Results show that the studies on environmental and health inequalities and mechanisms of their generation in areas affected by industrially contaminated sites in the WHO European Region are in their early stages, with exemption of UK. Future efforts should be directed to improve study strategies with national and local assessments in order to provide evidence for equity-oriented interventions to reduce environmental exposure and related health risks caused by industrial contamination.

Siewert type I and II oesophageal adenocarcinoma: sensitivity/specificity of computed tomography, positron emission tomography and endoscopic ultrasound for assessment of lymph node metastases in groups of thoracic and abdominal lymph node stations.

OBJECTIVES: In Siewert type I/II oesophageal adenocarcinoma, the sensitivity and specificity of computed tomography (CT), positron emission tomography (PET)-CT and endoscopic ultrasound (EUS) for assessment of the N descriptor in defined groups of lymph nodes were investigated. METHODS: CT, PET/CT, EUS images and the pathological data of 101 oesophageal adenocarcinomas submitted to primary resection were compared. The lymph nodes were identified as (a) right paratracheal/subcarinal/pulmonary ligament; (b) paraoesophageal; (c) paracardial; (d) left gastric artery, lesser curvature; (e) coeliac trunk, hepatic/splenic artery. RESULTS: Of the 2451 lymph nodes identified, 273 (11.1%) were histologically positive. Overall sensitivity, specificity and negative and positive predictive value for detection of lymph nodes metastatic were respectively: CT sensitivity 39%, specificity 86%, negative 58% and positive 74% predictive value; PET/CT sensitivity 30%, specificity 98%, negative 58% and positive 93% predictive value; EUS sensitivity 50%, specificity 81%, negative 72% and positive 62% predictive value. The sensitivity of CT, PET/CT and EUS in the thoracic nodal groups (a) and (b) was, respectively, 58.3%, 7.1% and 87.5% and 33.3%, 20% and 80%. Sensitivity was below 47% for all tests in the abdominal nodal groups. In contrast, specificity (88.6-100%) was super imposable in all nodal groups. The strength of agreement among the 3 imaging techniques was poor (kappa < 0.30) for the thoracic anatomical groups of interest: (a) lower paratracheal/subcarinal/pulmonary ligament and (b) paraoesophageal; it was moderate/good (kappa >0.30) for the abdominal N groups of interest: c, d and e. CONCLUSIONS: The diagnostic performance of CT, PET and EUS for assessing the N descriptor in the paracardial and abdominal stations close to the primary tumour is not satisfactory. EUS can efficiently assess the presence/absence of nodal metastases in the thoracic stations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT03529968.

Incidence and risk factors for the development of epidermoid carcinoma in oesophageal achalasia†.

OBJECTIVES: The risk factors for oesophageal achalasia, a precancerous condition that can lead to epidermoid carcinoma, are unknown. The aim of this study was to determine these factors. METHODS: Beginning in 1973, patients presenting with achalasia from 1955 to 2016 periodically underwent clinical assessment, the barium swallow test (the oesophageal diameter and residual barium column were measured) and endoscopy according to a prospective protocol. We included patients with the minimum follow-up duration of 12 months. RESULTS: Of 681 cases, 583 patients were considered. The median follow-up time was 147.13 months (interquartile range 70.42-257.82 months), and 17 epidermoid carcinomas and 1 carcinosarcoma were diagnosed. After excluding 4 achalasia patients admitted with a cancer diagnosis, the incidence rate of epidermoid carcinomas was 1.61/1000 persons-year, and the cumulative probability of developing cancer at 56.34 years of follow-up was 13%. Risk factors for cancer were a sigmoid oesophagus [risk ratio (RR) = 17.64, 95% confidence interval (CI) 4.13-75.43], duration of achalasia symptoms >280 months (RR = 19.62, 95% CI 4.59-83.80), duration of follow-up >353 months (RR = 5.96, 95% CI 2.50-14.18), oesophageal diameter at diagnosis >71 mm (RR = 21.07, 95% CI 9.29-47.82), residual barium column at diagnosis >23 cm (RR = 24.27, 95% CI 6.93-85.01) and residual barium column at the last follow-up >10 cm (RR = 8.15, 95% CI 2.40-27.62). Conversely, the risk of epidermoid carcinoma was lower when the residual barium swallow decreased by >57% (RR = 0.10, 95% CI 0.03-0.34). CONCLUSIONS: Patients with achalasia carry a substantial risk of developing epidermoid carcinoma. Several factors, such as sigmoid achalasia and dysphagia lasting more than 23 years, are associated with an increased risk of cancer. An effective Heller myotomy may positively influence the carcinogenetic process.

Pharyngo-oesophageal perforation following anterior cervical discectomy and fusion: management and results.

OBJECTIVES: Pharyngo-oesophageal perforation is a rare, life-threatening complication of anterior cervical discectomy and fusion surgery; its management remains poorly defined. We reviewed our experience to understand the treatment of this dreadful complication. METHODS: Data regarding the demographics, clinical course, diagnosis, management and outcomes of 15 cases of pharyngo-oesophageal perforations in 14 patients were collected during the period from 2003 to 2016. RESULTS: Pharyngo-oesophageal perforation occurred at a median of 32 days (range 1 day-102 months) after anterior cervical discectomy and fusion surgery. Clinical manifestations included neck abscesses and cutaneous fistulas (10 cases), cervical swelling (two cases), salivary leakage from cervicotomy (two cases), dysphagia, halitosis and regurgitation (one case). In all cases, conservative management was utilized. Two patients affected by minor external fistulas were successfully managed conservatively. In 13 cases, the following surgery was performed: (i) radical bone debridement, total or partial removal of spine fixation devices, autologous bone graft insertion or plate/cage replacement in one case each; (ii) anatomical suture of the fistula; or (iii) suture line reinforcement with myoplasty (in 11/13 cases). Perforation recurred in three cases. One patient underwent reoperation. The other two patients were treated conservatively At a median follow-up of 82 months (range 1-157 months), all patients exhibited permanent resolution of the perforation. CONCLUSIONS: Patients with minimal leaks in the absence of systemic infection can be managed conservatively. For cases of large fistulas with systemic infection, we recommend partial or total removal of the fixation devices, direct suture of the oesophageal defect and coverage with tissue flaps.

Total Lymphadenectomy and Nodes-Based Prognostic Factors in Surgical Intervention for Esophageal Adenocarcinoma.

BACKGROUND: To evaluate prognostic factors based on the number of resected lymph nodes, we considered 202 patients who underwent radical resection and "total lymphadenectomy" for esophageal adenocarcinoma according to a prospective protocol. METHODS: Fifty-eight tumors surrounded by Barrett's epithelium underwent esophagectomy and esophagogastrostomy, and 144 tumors without Barrett's epithelium underwent esophageal resection at the azygos vein level, total gastrectomy, and Roux-en-Y esophagojejunostomy. All nodes and fat tissue were resected at the following stations: chest 4L and R3, R4, R7, R8, and R9 (TNM seventh edition) and abdomen 1-12 according to the Japanese Classification of Gastric Carcinoma (1998). The nodes were counted, excluding fragments. The correlations between the number of nodes yielded and the ratio of the metastatic lymph nodes/lymph nodes yielded with pT stage, grading measurements, and cancer-specific survival (CSS) were calculated. RESULTS: A total of 6,270 nodes were yielded (interquartile range per patient, 22-38; minimum, 4 nodes; maximum, 61 nodes). In 3 of 21 (14%) stage pT1 cases, less than 10 nodes were counted, in 2 of 27 (8%) stage pT2 cases, less than 20 were counted, and in 73 of 154 (47%) stage pT3-4 cases, less than 30 nodes were counted. The lymph node yield (LNY) and T stage were not correlated (r = 0 .048; p = 0.5). The metastatic lymph nodes to lymph nodes yielded ratio was correlated with pT stage (r = 0.272; p = 0.0001), and G (r = 0.385; p = 0.0001). CSS positively correlated with pT stage (p = 0.02), G (p = 0.001), and metastatic lymph nodes/lymph nodes yielded ratio (p = 0.01) (multivariate analysis). CONCLUSIONS: The total number of lymph nodes to be removed in total and within each T stage indicated as thresholds could not be reached in up to 38.6% of patients. The metastatic lymph nodes/lymph nodes yield ratio not the total LNY, did correlate with cancer-specific survival.

IL-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis.

Although a clear association has been established between IL-33 and inflammatory bowel disease, mechanistic studies to date, primarily using acute murine models of colitis, have yielded contradicting results, demonstrating both pathogenic and protective roles. We used a well-characterized, spontaneous model of inflammatory bowel disease [ie, SAMP1/YitFc (SAMP) mice] to investigate the role of IL-33 during chronic intestinal inflammation. Our results showed marked eosinophil infiltration into the gut mucosa with increased levels of eotaxins and type 2 helper T-cell (Th2) cytokines as disease progressed and became more severe, which could be reversed upon either eosinophil depletion or blockade of IL-33 signaling. Exogenous IL-33 administration recapitulated these effects in ilea of uninflamed (parental) control AKR/J mice. Human data supported these findings, showing colocalization and up-regulation of IL-33 and eosinophils in the colonic mucosa of inflammatory bowel disease patients versus noninflamed controls. Finally, colonization of commensal flora by fecal material transplantation into germ-free SAMP and the presence of the gut microbiome induced IL-33, subsequent eosinophil infiltration, and mounting of Th2 immune responses, leading to exacerbation of chronic intestinal inflammation characteristic of SAMP mice. These data demonstrate a pathogenic role for IL-33-mediated eosinophilia and activation of Th2 immunity in chronic intestinal inflammation that is dependent on the gut microbiome. Targeting IL-33 may represent a novel therapeutic approach to treat patients with inflammatory bowel disease.

Results of left thoracoscopic Collis gastroplasty with laparoscopic Nissen fundoplication for the surgical treatment of true short oesophagus in gastro-oesophageal reflux disease and Type III-IV hiatal hernia.

OBJECTIVES: Controversy exists regarding surgery for true short oesophagus (TSOE). We compared the results of thoracoscopic Collis gastroplasty-laparoscopic Nissen procedure for the treatment of TSOE with the results of standard laparoscopic Nissen fundoplication. METHODS: Between 1995 and 2013, the Collis-Nissen procedure was performed in 65 patients who underwent minimally invasive surgery when the length of the abdominal oesophagus, measured intraoperatively after maximal oesophageal mediastinal mobilization, was ≤1.5 cm. The results of the Collis-Nissen procedure were frequency-matched according to age, sex and period of surgical treatment with those of 65 standard Nissen fundoplication procedures in patients with a length of the abdominal oesophagus >1.5 cm. Postoperative mortality and morbidity were evaluated according to the Accordion classification. The patients underwent a timed clinical-instrumental follow-up that included symptoms assessment, barium swallow and endoscopy. Symptoms, oesophagitis and global results were graded according to semi-quantitative scales. The results were considered to be excellent in the absence of symptoms and oesophagitis, good if symptoms occurred two to four times a month in the absence of oesophagitis, fair if symptoms occurred two to four times a week in the presence of hyperaemia, oedema and/or microscopic oesophagitis and poor if symptoms occurred on a daily basis in the presence of any grade of endoscopic oesophagitis, hiatal hernia of any size or type, or the need for antireflux medical therapy. The follow-up time was calculated from the time of surgery to the last complete follow-up. RESULTS: The postoperative mortality rate was 1.5% for the Collis-Nissen and 0 for the Nissen procedure. The postoperative complication rate was 24% for the Collis-Nissen and 7% for Nissen (P = 0.001) procedure. The complication rate for the Collis-Nissen procedure was 43% in the first 32 cases and 6% in the last 33 cases (P < 0.0001). The median follow-up period was 96 months. The results were: excellent in 27% of Collis-Nissen and 29% of Nissen; good in 64% of Collis-Nissen and 55% of Nissen; fair in 3% of Collis-Nissen and 11% of Nissen and poor in 6% of Collis-Nissen and 5% of Nissen (P = 0.87). CONCLUSIONS: In patients affected by a TSOE, the Collis-Nissen procedure may achieve equally satisfactory results as the standard Nissen procedure in uncomplicated patients. CLINICAL REGISTRATION NUMBER: NCT02288988.

Surgery for Type III-IV hiatal hernia: anatomical recurrence and global results after elective treatment of short oesophagus with open and minimally invasive surgery.

OBJECTIVES: Type III-IV hiatal hernia (HH) is associated with a true short oesophagus in more than 50% of cases; dedicated treatment of this condition might be appropriate to reduce the recurrence rate after surgery. A case series of patients receiving surgery for Type III-IV hernia was examined for short oesophagus, and the results were analysed. METHODS: From 1980 to 1994, 60 patients underwent an open surgical approach, and the position of the oesophago-gastric junction was visually localized; from 1995 to 2013, 48 patients underwent a minimally invasive approach, and the oesophago-gastric junction was objectively localized using a laparoscopic-endoscopic method. The patients underwent a timed clinical-instrumental follow-up that included symptoms assessment, barium swallow and endoscopy. The results were considered to be excellent in the absence of symptoms and oesophagitis; good, if symptoms occurred two to four times a month in the absence of oesophagitis; fair, if symptoms occurred two to four times a week in the presence of hyperaemia, oedema and/or microscopic oesophagitis; and poor, if symptoms occurred on a daily basis in the presence of any grade of endoscopic oesophagitis, HH of any size or type, or the need for antireflux medical therapy. The follow-up time was calculated from the time of surgery to the last complete follow-up. RESULTS: Among the open surgery patients, 78% underwent abdominal fundoplication, 10% the Belsey Mark IV procedure, 8% laparotomic Collis-Nissen fundoplication and 3% the Pearson operation. Among the minimally invasive surgery patients, 44% underwent a laparoscopic floppy Nissen procedure and 56% a left thoracoscopic Collis-laparoscopic Nissen procedure. The postoperative mortality and complication rates were 1.6% (1/60) and 15% for open surgery and 4.1% (2/48) and 12.5% for minimally invasive surgery. A total of 105 patients were followed up for a median period of 96 months. Five relapses occurred after open surgery (5/59, 8%) and two after minimally invasive surgery (2/46, 4%). Among the 105 patients, excellent, good, fair and poor outcomes were observed in 38%, 44%, 9% and 9%, respectively. CONCLUSIONS: These data suggested that the selective treatment of short oesophagus in association with a Type III-IV hernia reduced the anatomical recurrence rate and achieved satisfactory outcomes. CLINICALTRIALSGOV ID: NCT01606449.

In vivo inhibition of RIPK2 kinase alleviates inflammatory disease.

The RIPK2 kinase transduces signaling downstream of the intracellular peptidoglycan sensors NOD1 and NOD2 to promote a productive inflammatory response. However, excessive NOD2 signaling has been associated with numerous diseases, including inflammatory bowel disease (IBD), sarcoidosis and inflammatory arthritis, making pharmacologic inhibition of RIPK2 an appealing strategy. In this work, we report the generation, identification, and evaluation of novel RIPK2 specific inhibitors. These compounds potently inhibit the RIPK2 tyrosine kinase activity in in vitro biochemical assays and cellular assays, as well as effectively reduce RIPK2-mediated effects in an in vivo peritonitis model. In conjunction with the development of these inhibitors, we have also defined a panel of genes whose expression is regulated by RIPK2 kinase activity. Such RIPK2 activation markers may serve as a useful tool for predicting settings likely to benefit from RIPK2 inhibition. Using these markers and the FDA-approved RIPK2 inhibitor Gefitinib, we show that pharmacologic RIPK2 inhibition drastically improves disease in a spontaneous model of Crohn Disease-like ileitis. Furthermore, using novel RIPK2-specific inhibitors, we show that cellular recruitment is inhibited in an in vivo peritonitis model. Altogether, the data presented in this work provides a strong rationale for further development and optimization of RIPK2-targeted pharmaceuticals and diagnostics.

Adenocarcinoma in Crohn's disease: the pathologist's experience in a tertiary referral centre of inflammatory bowel disease.

The aim of the present study is to describe the histological and mutational characteristics of a series of both large and small bowel adenocarcinomas in patients with Crohn's disease from a tertiary referral centre of inflammatory bowel disease. Bowel adenocarcinoma was diagnosed in 11 (1.7%) of 660 consecutive patients submitted to surgery for histologically proven Crohn's disease in 5 years. The following data were collected: tumour site, stage and grade, intracellular/extracellular mucin, lymphovascular invasion, immunohistochemistry for keratin 7, keratin 20 and CDX-2, mutation analyses of KRAS, B-RAF, PI3K and microsatellite instability. A strong predominance of male gender was observed (10/11). Four (36.4%) adenocarcinomas arose in the small bowel, five (45.4%) in the anus/rectum, and two (18.2%) in anastomosis. Furthermore, all cases of anorectal adenocarcinoma showed >50% of extracellular mucin, with associated KRAS mutations in three of five. No influence in cancer incidence by infliximab therapy was observed.Our series, one of the largest on the topic with immunomorphological and molecular deepening, showed that bowel adenocarcinomas in Crohn's disease have an aggressive behaviour and a strong predominance of extracellular mucin. In surgical specimens from Crohn's disease patients, mucinous-looking anal fistulas and ileal areas of adhesion/retraction should always be extensively sampled.

Probiotic bacteria regulate intestinal epithelial permeability in experimental ileitis by a TNF-dependent mechanism.

BACKGROUND: We previously showed that the probiotic mixture, VSL#3, prevents the onset of ileitis in SAMP/YitFc (SAMP) mice, and this effect was associated with stimulation of epithelial-derived TNF. The aim of this study was to determine the mechanism(s) of VSL#3-mediated protection on epithelial barrier function and to further investigate the "paradoxical" effects of TNF in preventing SAMP ileitis. METHODS: Permeability was evaluated in SAMP mice prior to the onset of inflammation and during established disease by measuring transepithelial electrical resistance (TEER) on ex vivo-cultured ilea following exposure to VSL#3 conditioned media (CM), TNF or VSL#3-CM + anti-TNF. Tight junction (TJ) proteins were assessed by qRT-PCR, Western blot, and confocal microscopy, and TNFRI/TNFRII expression measured in freshly isolated intestinal epithelial cells (IEC) from SAMP and control AKR mice. RESULTS: Culture with either VSL#3-CM or TNF resulted in decreased ileal paracellular permeability in pre-inflamed SAMP, but not SAMP with established disease, while addition of anti-TNF abrogated these effects. Modulation of the TJ proteins, claudin-2 and occludin, occurred with a significant decrease in claudin-2 and increase in occludin following stimulation with VSL#3-CM or TNF. TNF protein levels increased in supernatants of SAMP ilea incubated with VSL#3-CM compared to vehicle, while IEC-derived TNFR mRNA expression decreased in young, and was elevated in inflamed, SAMP versus AKR mice. CONCLUSIONS: Our data demonstrate that the previously established efficacy of VSL#3 in preventing SAMP ileitis is due to direct innate and homeostatic effects of TNF on the gut epithelium, modulation of the TJ proteins, claudin-2 and occludin, and overall improvement of intestinal permeability.

Glances in Immunology of HIV and HCV Infection.

Since the identification of HIV and HCV much progress has been made in the understanding of their life cycle and interaction with the host immune system. Despite these viruses markedly differ in their virological properties and in their pathogenesis, they share many common features in their immune escape and survival strategy. Both viruses have developed sophisticated ways to subvert and antagonize host innate and adaptive immune responses. In the last years, much effort has been done in the study of the AIDS pathogenesis and in the development of efficient treatment strategies, and a fatal infection has been transformed in a potentially chronic pathology. Much of this knowledge is now being transferred in the HCV research field, especially in the development of new drugs, although a big difference still remains between the outcome of the two infections, being HCV eradicable after treatment, whereas HIV eradication remains at present unachievable due to the establishment of reservoirs. In this review, we present current knowledge on innate and adaptive immune recognition and activation during HIV and HCV mono-infections and evasion strategies. We also discuss the genetic associations between components of the immune system, the course of infection, and the outcome of the therapies.

Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis.

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL-33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by anti-TNF therapy, and may represent a specific biomarker for active UC.

Immunoregulatory effects of HIV-1 Nef protein.

During HIV infection, the perturbation of the adaptive and innate immune responses contributes to the progressive immunosuppression leading to an increased susceptibility to opportunistic infections and neoplastic diseases. Several impairments observed in HIV-infected patients include a gradual loss of CD4(+) T cells, CD8(+) T cell dysfunction, and a decreased number and function of natural killer (NK) cells. Moreover, a functional impairment and variation in the number of DC and B cells were observed during HIV infection. HIV-1 codes for proteins, including the accessory Nef proteins, that interacting with immune cells may contribute to AIDS pathogenesis. Here, we review the recent progress on the immunomodulatory effect of the accessory Nef protein and its role in the pathogenesis of HIV-1 infection. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

Leptin exerts an anti-apoptotic effect on human dendritic cells via the PI3K-Akt signaling pathway.

Leptin is an adipocyte-derived hormone/cytokine that modulates immune responses. It induces functional and morphological changes in human dendritic cells (DCs), licensing them towards Th1 priming and promoting DC survival. Here we found that leptin protects DCs from spontaneous, UVB and H(2)O(2)-induced apoptosis, by triggering the activation of nuclear factor-kappa B (NF-kappaB) and a parallel up-regulation of bcl-2 and bcl-XL gene expression and Akt activation. We found that leptin activates the PI3K-Akt signaling pathway as demonstrated by the suppression of the effect of leptin on DC survival by wortmannin and API-2, which suppress the leptin-induced activation of Akt, NF-kappaB, bcl-2, bcl-XL and protection from apoptosis. These results provide insights on the immunoregulatory function of leptin, supporting a potential application in immunotherapeutic approaches.