Long-Term Natural History of Autoimmune Gastritis: Results From a Prospective Monocentric Series.

INTRODUCTION: The natural history of autoimmune gastritis (AIG) has been poorly described. In this study, we report the long-term natural history and clinical clustering of the full spectrum of AIG, from the potential to the complicated stage. METHODS: Prospective single-center study conducted in a tertiary referral center. Patients with AIG at any stage (0 = potential; 1 = early; 2 = florid; 3 = severe; and 4 = complicated) were enrolled (January 2000-December 2022). The histopathological evolution, the clinical presentation, and the correlates of evolution of potential AIG were assessed. RESULTS: Four hundred ninety-eight patients with AIG (mean age 56.7 ± 15.2 years, F:M ratio 2.5:1) were included, of whom 93 experienced potential AIG. The maximum disease duration was 27 years (median 18, interquartile range 14-23), while the overall median follow-up was 52 months (interquartile range 12-95). Age was significantly lower in stage 0 compared with that in the other stages. Accidental histologic evidence and hematologic findings were the most common clusters of diagnosis. The overall median rate of progression was 7.29 per 100 persons/yr (95% confidence interval [CI] 6.19-8.59), while the stage-specific rates of progression were 10.85 (stage 0; 95% CI 7.75-15.18), 14.83 (stages 1-2; 95% CI 11.89-18.49), and 2.68 (stage 3; 95% CI 1.88-3.84). Newly onset neoplastic complications at follow-up occurred in 41/483 patients (8.5%; 23 neuroendocrine tumors and 18 epithelial dysplasia). No cases of adenocarcinoma were noticed. Male sex was associated with a greater likelihood of evolving from potential AIG to overt AIG. DISCUSSION: AIG is a progressive disorder, with a virtually absent risk of gastric adenocarcinoma. Patients with potential AIG should be monitored because they carry a high risk of evolving into overt AIG.

Distinguishing features of autoimmune gastritis depending on previous H. pylori infection or positivity to anti-parietal cell antibodies: results from the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO).

OBJECTIVES: To describe the clinical features and the risk of developing gastric tumors in patients with autoimmune gastritis (AIG). METHODS: This was a retrospective, longitudinal, multicenter study conducted at eight Italian tertiary referral centers. We retrieved clinical data from all histologically proven AIG patients. Differences between H. pylori-exposed vs H. pylori-naïve, and anti-parietal cell antibody (PCA)-positive vs PCA-negative patients were investigated. The rate of gastric adenocarcinoma and type 1 gastric neuroendocrine neoplasm (gNEN) was assessed. A multivariable model for factors associated to gNEN was fitted. RESULTS: 1598 patients with AIG (median age 58 years, IQR 46-68; F:M ratio 2.7:1) were included. H. pylori-naïve patients were more likely to have a first-degree family history of AIG (14.7% vs 8.9%; p=0.012), type 1 diabetes mellitus (4.9% vs 2.3%; p=0.025), and pernicious anemia (30.9% vs 21.1%; p=0.003). PCA-positive patients had significantly more associated autoimmune diseases (59.0% vs 42.9%; p<0.001) and were more likely to have been diagnosed by a case-finding strategy (15.3% vs 2.6%; p<0.001). Overall, 15 cases (0.9%) of gastric adenocarcinoma and 153 cases (9.6%) of gNEN occurred, with a global rate of 0.12 (95% CI 0.07-0.20) and 1.22 (95% CI 1.03-1.42) per 100 person/year, respectively. Having a vitamin B12/iron deficiency manifestation at AIG diagnosis was associated with an 16.44 (95% CI 9.94-27.20 p<0.001) hazard ratio of gNEN. CONCLUSIONS: The "pure" AIG pattern has typical features of an autoimmune disease and seems to be unrelated to H. pylori. In a tertiary referral setting, the risk of developing overt gastric adenocarcinoma is low, while patients with vitamin B12 deficiency complications at onset may benefit from a more intense endoscopic follow-up for early gNEN detection.

Resilience is associated with frailty and older age in hospitalised patients.

BACKGROUND: Little is known about resilience in an internal medicine setting. We aimed to assess the relationship between resilience and frailty and other clinical and sociodemographic characteristics in a cohort of prospectively enrolled hospitalised patients. METHODS: In 2017-2019, we consecutively enrolled patients in our internal medicine wards. We selected all patients who filled in the 25-item Connor-Davidson resilience scale (CD-RISC). Mean resilience was evaluated according to baseline demographic (i.e., age, sex, marital and socioeconomic status) and clinical (i.e., Cumulative Illness Rating Scale [CIRS], Edmonton Frail Scale [EFS], Barthel index, Short Blessed test, length of stay [LOS]) data. A multivariable analysis for assessing factors affecting resilience was fitted. RESULTS: Overall, 143 patients (median age 69 years, interquartile range 52-79, 74 females) were included. Resilience was significantly lower in frail (p = 0.010), elderly (p = 0.021), dependent (p = 0.032), and more clinically (p = 0.028) and cognitively compromised patients (p = 0.028), and in those with a low educational status (p = 0.032). No relation between resilience and LOS was noticed (p = 0.597). Frail patients were significantly older (p < 0.001), had a greater disease burden as measured by CIRS comorbidity (p < 0.001) and severity indexes (p < 0.001), were more dependent (p < 0.001), more cognitively impaired (p < 0.001), and displayed a lower educational level (p = 0.011) compared to non-frail patients. At multivariable analysis, frailty (p = 0.022) and dependency (p = 0.031; according to the Barthel index) were associated with lower resilience in the age groups 18-64 and ≥ 65 years, respectively. CONCLUSIONS: Low resilience was associated with frailty and dependency with an age-dependent fashion. Studies assessing the impact of this finding on important health outcomes are needed. TRIAL REGISTRATION: Clinical Complexity in Internal Medicine Wards. San MAtteo Complexity Study (SMAC); NCT03439410 . Registered 01/11/2017.

Impaired Quality of Life in Patients with Autoimmune Atrophic Gastritis.

BACKGROUND: Autoimmune atrophic gastritis (AAG) leads to vitamin B12 deficiency that may manifest with neuropsychiatric disorders, such as emotional instability, cognitive deficits, depression, and personality changes. AIMS: To evaluate the quality of life (QoL) in patients with AAG and the interplay between QoL, psychopathological symptoms, and demographic factors. METHODS: This is an observational, cross-sectional study including 102 patients with AAG (mean age 62 ± 13 years), 100 with functional gastrointestinal disorders (mean age 38.3 ± 17 years), 100 with other chronic organic gastrointestinal diseases (mean age 50.9 ± 21.4 years), and 100 healthy controls (mean age 37.5 ± 18.9 years). The 36-Item Short Form Health Survey questionnaire (SF-36) and the General Health Questionnaire-12 were administered. The results of the scales were compared among the study groups. Linear regression analyses were fitted to identify independent predictors of QoL in AAG patients. RESULTS: QoL was significantly different among the four groups in all subdomains. In particular, the AAG group was significantly (P < 0.01) more impaired than the functional gastrointestinal disorder group in the physical functioning and it was significantly more impaired than the control group in all the quality of life subdomains with exception of vitality. Vitamin B12 serum level was a significant (P < 0.04) independent predictor of physical functioning. CONCLUSIONS: Patients with AAG have a decreased QoL compared to healthy controls, but in line with that of patients with organic gastrointestinal disorders. Physical component is responsible for worsening QoL. Vitamin B12 supplementation may positively affect patient's perception of body functioning.

Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity.

OBJECTIVE: Non-coeliac gluten sensitivity (NCGS) is characterised by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods, in the absence of coeliac disease (CD) and wheat allergy. No biomarkers are available to diagnose NCGS and the gold standard double-blind placebo-controlled gluten challenge is clinically impractical. The aim of our work was to investigate the role of serum zonulin as a diagnostic biomarker of NCGS and to develop a diagnostic algorithm. DESIGN: In a multicentre study, we enrolled 86 patients with either self-reported or double-blind confirmed NCGS, 59 patients with diarrhoea-predominant IBS (IBS-D), 15 patients with CD and 25 asymptomatic controls (AC). Zonulin serum levels were assessed and the associated diagnostic power calculated. Clinical and symptomatic data were recorded. The effect of diet on zonulin levels was evaluated in a subgroup of patients with NCGS. RESULTS: Compared with ACs, the NCGS, irrespective of modality of diagnosis, and patients with CD had significantly increased levels of zonulin, as did both NCGS and patients with CD compared with participants with IBS-D. Self-reported NCGS showed increased zonulin levels compared with double-blind confirmed and not-confirmed NCGS. Six-month wheat avoidance significantly reduced zonulin levels only in HLA-DQ2/8-positive participants with NCGS. The diagnostic accuracy of zonulin levels in distinguishing NCGS from IBS-D was 81%. After exclusion of CD, a diagnostic algorithm combining zonulin levels, symptoms and gender improved the accuracy to 89%. CONCLUSION: Zonulin can be considered a diagnostic biomarker in NCGS and combined with demographic and clinical data differentiates NCGS from IBS-D with high accuracy. Wheat withdrawal was associated with a reduction in zonulin levels only in NCGS carrying HLA genotype.

Prevalence and pathophysiology of post-prandial migraine in patients with functional dyspepsia.

BACKGROUND: Migraine is a condition frequently associated with gastrointestinal disorders. Previous reports have shown the relationship between irritable bowel syndrome and migraine, but no data are yet available in patients with functional dyspepsia. We therefore evaluated whether alteration of gastric sensorimotor activity may be related to migraine. METHODS: Sixty patients affected by functional dyspepsia, 38 with postprandial distress syndrome and 22 with epigastric pain syndrome were enrolled in a cohort study. Presence and severity of dyspeptic symptoms, migraine presence and severity, gastric sensitivity thresholds during fasting and postprandial period, gastric accommodation and gastric emptying time were evaluated. RESULTS: In epigastric pain syndrome, 12/22 (54%) patients suffered from migraine and this condition was never correlated with meal ingestion. In postprandial distress syndrome patients, 29/38 (76%) suffered from migraine, in 26/29 (89%) its onset was considered as meal-related, and migraine severity was significantly correlated with postprandial modification of the gastric discomfort threshold (r = -0.73; p < 0.001). In patients with postprandial distress syndrome, in the subgroup with moderate to severe migraine, the severity of fullness and early satiation was significantly higher than in patients with mild or absent migraine. In patients with moderate to severe migraine, gastric accommodation, sensitivity thresholds and gastric emptying time were similar to patients with mild or no migraine. CONCLUSIONS: In patients with functional dyspepsia and postprandial symptoms, migraine is a very frequent comorbidity. On clinical grounds, it is associated with an increased severity of fullness and early satiation and, on pathophysiological grounds, it seems correlated with postprandial hypersensitivity.

Two cases of monomorphic epitheliotropic intestinal T-cell lymphoma associated with coeliac disease.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an aggressive type of intestinal lymphoma which affects individuals without evidence of enteropathy. In this single-centre case series, we describe the first two cases of MEITL in Caucasian patients suffering from histologically-proven coeliac disease (CD). Original medical records were retrieved and anonymised. All biopsy and surgical MEITL specimens were reviewed by three haematopathologists. Two patients aged 63- and 55-year old at CD diagnosis, subsequently developed a MEITL. MEITL always involved the ileum and was multifocal. Both patients died from complications after surgery, including gastrointestinal bleeding, septic shock and multiorgan failure, with a mean survival since MEITL diagnosis of 15.5 ± 16.3 months. In one case, array-CGH revealed a large deletion on chromosome nine between 9p13.1 and 9p24.1, and a recurrent chromosome gain at 9q33-q34. Our cases indicate that a subset of MEITL may arise in Caucasian patients suffering from CD. The clinical, pathological and molecular features of these cases show a partial overlap with enteropathy-associated T-cell lymphoma.

The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy.

OBJECTIVES: Common variable immunodeficiency (CVID) is a primary humoral immunodeficiency characterised by reduced serum levels of immunoglobulins, recurrent infections, autoimmune phenomena and lymphoproliferative disorders. Gastrointestinal symptoms are very common in these patients and a coeliac-like villous atrophy was described in some of them. Since mortality in CVID is much higher than in the general population, our aim was to evaluate mortality rates and clinical predictors of survival in patients with both CVID and duodenal villous atrophy. PATIENTS AND METHODS: Sex, date of diagnosis of villous atrophy, HLA genomic typing, date of death/last follow-up, type of complication were retrospectively collected from medical files. Univariate analysis for each predictor was conducted and Kaplan-Meier curves were generated to evaluate survival. RESULTS: Twenty-three patients were enrolled (9 females, mean age at diagnosis of villous atrophy 38 ± 13 years) and 8 of them died after a median time of 96 months (25th-75th 60-120 months) corresponding to a mortality rate of 3.9 per 100 person-years (95% CI 1.9-7.7). Mortality was higher in men compared to women (60 vs. 11/1000 person-years), although not statistically significant. Causes of death included onco-haematological disorders and infections. CONCLUSIONS: Although based on a small cohort, our results confirm that patients with CVID and villous atrophy are burdened by a very high mortality mainly due to onco-immunological disorders and infections. Strict follow-up is required in these patients.

Prognostic Evaluations Tailored to Specific Gastric Neuroendocrine Neoplasms: Analysis Of 200 Cases with Extended Follow-Up.

BACKGROUND: Gastric neuroendocrine neoplasms (NENs) are very heterogeneous, ranging from mostly indolent, atrophic gastritis-associated, type I neuroendocrine tumors (NETs), through highly malignant, poorly differentiated neuroendocrine carcinomas (pdNECs), to sporadic type III NETs with intermediate prognosis, and various rare tumor types. Histologic differentiation, proliferative grade, size, level of gastric wall invasion, and local or distant metastases are used as prognostic markers. However, their value remains to be tailored to specific gastric NENs. METHODS: Series of type I NETs (n = 123 cases), type III NETs (n = 34 cases), and pdNECs (n = 43 cases) were retrospectively collected from four pathology centers specializing in endocrine pathology. All cases were characterized clinically and histopathologically. During follow-up (median 93 months) data were recorded to assess disease-specific patient survival. RESULTS: Type I NETs, type III NETs, and pdNECs differed markedly in terms of tumor size, grade, invasive and metastatic power, as well as patient outcome. Size was used to stratify type I NETs into subgroups with significantly different invasive and metastatic behavior. All 70 type I NETs < 0.5 cm (micro-NETs) were uneventful. Ki67-based grading proved efficient for the prognostic stratification of type III NETs; however, grade 2 (G2) was not associated with tumor behavior in type I NETs. Although G3 NETs (2 type I and 9 type III) had a very poor prognosis, it was found that patient survival was longer with type III G3 NETs compared to pdNECs. CONCLUSIONS: Given the marked, tumor type-related behavior differences, evaluation of gastric NEN prognostic parameters should be tailored to the type of neoplastic disease.

Old and New Lymphocyte Players in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic intestinal inflammatory disorder characterized by diffuse accumulation of lymphocytes in the gut mucosa as a consequence of over-expression of endothelial adhesion molecules. The infiltrating lymphocytes have been identified as subsets of T cells, including T helper (Th)1 cells, Th17 cells, and regulatory T cells. The function of these lymphocyte subpopulations in the development of IBD is well-known, since they produce a number of pro-inflammatory cytokines, such as interferon-γ and interleukin-17A, which in turn activate mucosal proteases, thus leading to the development of intestinal lesions, i.e., ulcers, fistulas, abscesses, and strictures. However, the immune mechanisms underlying IBD are not yet fully understood, and knowledge about the function of newly discovered lymphocytes, including Th9 cells, innate lymphoid cells, mucosal-associated invariant T cells, and natural killer T cells, might add new pieces to the complex puzzle of IBD pathogenesis. This review summarizes the recent advances in the understanding of the role of mucosal lymphocytes in chronic intestinal inflammation and deals with the therapeutic potential of lymphocyte-targeting drugs in IBD patients.

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease.

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases.

Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. Stem Cells 2016;34:1474-1486.

What is the best therapy for Whipple's disease? Our point of view.

Although Whipple's disease (WD) has been treated with antibiotics since the early 50s, the best antibiotics and the duration of the therapy have not yet been established. We consider here the pro and cons of the two most commonly used therapies, ceftriaxone followed by trimethoprim-sulfamethoxazole (TMP-SMZ) and hydroxychloroquine in combination with doxycycline. The therapy based on ceftriaxone and TMP-SMZ is efficient in the vast majority of patients for the first few years. However, since reinfections or reactivations can occur, a life-long prophylaxis is necessary and doxycycline is nowadays the best option. We thus propose a therapy based on merging these to therapies together, ceftriaxone, and TMP-SMZ for the first year(s) and then life-long prophylaxis with doxycycline.

Detection of Active Epstein-Barr Virus Infection in Duodenal Mucosa of Patients With Refractory Celiac Disease.

Refractory celiac disease is characterized by mucosal damage in patients with celiac disease despite a gluten-free diet. Little is known about the mechanisms that cause persistent intestinal inflammation in these patients. We performed a case-control study of 17 consecutive patients diagnosed with refractory celiac disease from 2001 through 2014 (median age, 51 y; 10 women) and 24 patients with uncomplicated celiac disease (controls) to determine whether refractory disease is associated with infection by lymphotropic oncogenic viruses. We performed real-time PCR analyses of duodenal biopsy samples from all patients to detect Epstein-Barr virus (EBV), human herpesvirus-8, and human T-cell lymphotropic virus-I, -II, or -III. We used in situ hybridization and immunohistochemical analyses to identify infected cells and viral proteins. We did not detect human herpesvirus-8 or human T-cell lymphotropic viruses in any of the biopsy specimens. However, 12 of 17 (70.5%) biopsy specimens from patients with refractory celiac disease were positive for EBV, compared with 4 of 24 (16.6%) biopsy specimens from controls (P < .001). EBV was detected in inflammatory cells and enterocytes. An analysis of latency- and replication-associated proteins confirmed active infection. Further studies are needed to determine whether EBV infection contributes to the pathogenesis of refractory celiac disease and enteropathy-associated T-cell lymphoma.

Breath Methane Excretion Is not An Accurate Marker of Colonic Methane Production in Irritable Bowel Syndrome.

OBJECTIVES: The role of colonic methane production in functional bowel disorders is still uncertain. In small samples of irritable bowel syndrome (IBS) patients, it was shown that methane breath excretion correlates with clinical presentation and delayed gastrointestinal transit time. The aim of this study was to evaluate the relationship between intestinal production and breath excretion of CH4 and to correlate CH4 production with the presence and the severity of symptoms, in a large cohort of IBS patients and in a group of healthy volunteers. METHODS: A group of 103 IBS patients and a group of 28 healthy volunteers were enrolled. The presence and severity of symptoms and gastrointestinal transit were evaluated in all subjects, who underwent breath H2/CH4 measurement for 7 h after lactulose to identify breath excretors of these gases; H2 and CH4 were also measured in rectal samples to identify colonic producers. Cumulative H2 and CH4 excretion and production were evaluated by the area under the time-concentration curve calculation (AUC). RESULTS: In IBS patients, CH4 was detected in rectal samples in 48 patients (47%), but only 27 of them (26% of the 103 enrolled patients) excreted this gas with breath. In CH4 producers, the prevalence and severity of symptoms and gastrointestinal transit time were not significantly different with respect to non-producers. IBS subtypes were homogeneously represented in CH4 producers and in non-producers. Healthy volunteers, compared with IBS patients, showed a significantly lower prevalence of CH4 excretion, whereas no difference was found in the prevalence of colonic CH4 production; moreover, in healthy volunteers compared with IBS, CH4 breath excretion and CH4 production were not different in quantitative terms. CONCLUSION: Our data show that colonic CH4 production is not associated with clinical presentation in IBS patients and does not correlate with symptom severity or with gastrointestinal transit time. Clinical inferences based on breath CH4 excretion should undergo an in-depth revision, as this method is not a good marker of CH4 colonic production.

The Circulating Level of Soluble Receptor for Advanced Glycation End Products Displays Different Patterns in Ulcerative Colitis and Crohn's Disease: A Cross-Sectional Study.

BACKGROUND: RAGE is a transmembrane receptor expressed on immune and endothelial cells, whose binding with its ligands, the S100 calgranulins, leads to chronic inflammation. Conversely, its soluble form (sRAGE) plays a protective role by acting as a decoy. We carried out a cross-sectional analysis of the sRAGE and S100A12 serum levels in patients with Crohn's disease (CD) and ulcerative colitis (UC) and searched for a correlation with clinical and biological markers of activity. METHODS: We enrolled 60 CD, 67 UC patients, and 66 controls (all adults). Disease activity was scored through the clinical, endoscopic, and histologic indexes of severity, whilst disease location and behaviour were assessed according to the Montreal classification. In all cases, the levels of serum sRAGE, S100A12, C-reactive protein, and faecal calprotectin were measured. RESULTS: sRAGE levels were significantly lower in UC, both active and inactive, than in controls and CD (817.35, range 437.3-1449; 1211, range 843.7-1618; 1207.5, range 743.15-1875.75; P < 0.05 for both), and inversely correlated with clinical and endoscopic indexes of activity in both IBD groups (P < 0.05 for all) and with the histologic score in the CD group. Moreover, those CD patients with a penetrating behaviour showed a significant reduction in both sRAGE (P = 0.006) and S100A12 (P = 0.034) as compared to those with an inflammatory/stricturing pattern. Although S100A12 levels were not found up-regulated, a negative correlation appeared evident with the clinical (r = -0.38) and endoscopic (r = -0.32) indexes of activity in UC and CD, respectively. CONCLUSION: These data suggest a different role for RAGE in CD and UC, and a potential use of sRAGE as a new biomarker.

Autologous human cytomegalovirus-specific cytotoxic T cells as rescue therapy for ulcerative enteritis in primary immunodeficiency.

PURPOSE: Patients affected by primary immunodeficiency usually undergo a wide range of infections, including reactivation of latent ones. Here we report two cases suffering from late-onset combined immunodeficiency in which ulcerative enteritis due to human Cytomegalovirus caused a life-threatening malabsorption syndrome. METHODS: The assessment of the viral load was carried out on both blood and mucosal samples by quantitative real-time polymerase chain reaction assay. The generation of autologous virus-specific cytotoxic T cell lines was performed according to Good Manufacturing Practice protocol after peripheral blood mononuclear cells were collected through a single leukapheresis. RESULTS: In both patients, the viral load resulted negligible in peripheral blood, but very high in mucosal specimens (range 1.064 - 1.031.692 copies/10(5) cells). After two rounds of antiviral therapy proved unsuccessful, the generation of virus-specific cytotoxic T cell lines was carried out despite severe lymphopenia, and their infusion resulted safe and durably effective in healing intestinal ulcerations and resetting the viral load. CONCLUSIONS: Virus-specific cellular therapy was useful in reconstituting specific immunity and treating severe human Cytomegalovirus-related enteritis in patients with primary immunodeficiency.

Preserved antibody levels and loss of memory B cells against pneumococcus and tetanus after splenectomy: tailoring better vaccination strategies.

Splenectomized patients are exposed to an increased risk of septicemia caused by encapsulated bacteria. Defense against infection is ensured by preformed serum antibodies produced by long-lived plasma cells and by memory B cells that secrete immunoglobulin in response to specific antigenic stimuli. Studying a group of asplenic individuals (57 adults and 21 children) without additional immunologic defects, we found that spleen removal does not alter serum anti-pneumococcal polysaccharide (PnPS) IgG concentration, but reduces the number of PnPS-specific memory B cells, of both IgM and IgG isotypes. The number of specific memory B cells was low in splenectomized adults and children that had received the PnPS vaccine either before or after splenectomy. Seven children were given the 13-valent pneumococcal conjugated vaccine after splenectomy. In this group, the number of PnPS-specific IgG memory B cells was similar to that of eusplenic children, suggesting that pneumococcal conjugated vaccine administered after splenectomy is able to restore the pool of anti-PnPS IgG memory B cells. Our data further elucidate the crucial role of the spleen in the immunological response to infections caused by encapsulated bacteria and suggest that glycoconjugated vaccines may be the most suitable choice to generate IgG-mediated protection in these patients.

Fasting and postprandial gastric sensorimotor activity in functional dyspepsia: postprandial distress vs. epigastric pain syndrome.

OBJECTIVES: Little information is available on the mechanisms responsible for dyspeptic symptoms in postprandial distress syndrome (PDS), characterized by the presence of prevalently meal-related early satiation and fullness, and the epigastric pain syndrome (EPS), characterized by the prominent symptom of epigastric pain, generally not meal related. In a group of PDS patients, the presence of hypersensitivity to gastric distension in both fasting and postprandial phases was described as the main pathophysiological mechanism; on the contrary, we have no information on the pathophysiology of EPS. METHODS: Sixty Helicobacter pylori (HP)-negative, irritable bowel syndrome (IBS)-negative, and gastroesophageal reflux disease (GERD)-negative patients with functional dyspepsia according to Rome III criteria underwent symptom, anxiety, depression, and somatization evaluation, gastric barostat test, and gastric emptying time evaluation for solids. Fifteen age- and sex-matched healthy volunteers (HVs) were also enrolled as a control group. RESULTS: In PDS patients, the prevalence of both fasting and postprandial hypersensitivity was higher than in EPS patients, and the extent of postprandial reduction of discomfort threshold was significantly correlated with symptom severity. In EPS patients, gastric volume at fasting discomfort threshold and fasting compliance were significantly lower than in PDS patients. Gastric emptying time and gastric accommodation were similar between the two dyspeptic groups. Dyspeptic patients showed a higher prevalence of psychiatric disorders than HVs, but the prevalence was similar between PDS and EPS patients. CONCLUSIONS: Fasting and postprandial hypersensitivity characterize PDS patients and a reduction of gastric compliance is present in EPS patients. However, the pathophysiology of EPS appears more complex than PDS and further studies are needed to analyze central processing and integration of afferent pathways in order to clarify the role of the central nervous system in this condition.