How to Improve Training in Descriptive Psychopathology for Psychiatry Residents: A Delphi Study.

PURPOSE: Descriptive psychopathology (DP) is the language of psychiatry and is dedicated to the description of mental symptoms. Despite its core importance, a systematic review identified a series of shortcomings in its training. This Delphi study seeks to provide guidance for better didactic and clinical training in DP. METHOD: The authors used the Delphi method in order to gather, pool, and optimize the knowledgeable opinion of a highly qualified panel of international experts on how to improve DP training. A preliminary phase with open-ended questions was the basis to elaborate a Delphi questionnaire consisting of 14 questions on didactic and clinical training, which was then used in two successive Delphi rounds. Twenty-nine international experts in DP participated throughout the study. RESULTS: A series of hierarchical lists on how to improve DP training were elaborated. Regarding didactic training, the experts valued the contents and educational methods, as well as recommended authors and texts. Regarding clinical training, the experts valued educational methods, desirable characteristics in clinical supervisors, how to improve the supervisors' expertise, useful aspects and facilitating questions for direct supervision, and the suitability of including other evaluators besides the supervisor. In the final survey, 94% of the experts considered that the Delphi method had been effective to obtain and improve their opinions. CONCLUSIONS: Insufficient direct supervision in live interviews was considered the most important problem. A series of general measures were proposed to improve DP training: (i) adapting DP training throughout residency, with introductory and advanced levels; (ii) making DP training compulsory in psychiatry curricula; (iii) assessing residents' DP knowledge and clinical use; and (iv) training the trainers/supervisors in both content (DP) and form (how to train/supervise residents). Within didactic training, epistemology of DP and contemporary and classic authors/texts were the highest rated contents, while supervised discussions based on cases, videos, or readings were the highest rated methods. Within clinical training, 8 aspects of DP that could guide the supervisor were highly rated: mental state examination, dialogue, empathy and understanding, attitude/willingness, knowledge-practice bridge, mental symptom formation, implications for decision-making, and the written report of the encounter.

Impact of Bacterial Translocation on Sarcopenia in Patients with Decompensated Cirrhosis.

Advanced liver disease is associated with a persistent inflammatory state, derived from abnormal bacterial translocation from the gut, which may contribute to the development of sarcopenia in cirrhosis. We aim to document the association of chronic inflammation and bacterial translocation with the presence of sarcopenia in cirrhosis. We prospectively followed cirrhotic patients aged 18-70 years with medically refractory ascites at a single tertiary care center in Toronto, Canada. The baseline data included patient demographic variables, the presence of bacterial DNA in serum/ascitic fluid, systemic inflammatory response syndrome (SIRS) status, and nutritional assessment. Thirty-one patients were enrolled, 18 (58.1%) were sarcopenic, 9 (29%) had bacterial DNA in serum and ascites fluid. The mean MELD score was 11.5 ± 4.0 (6-23). Sarcopenic and non-sarcopenic patients did not differ significantly in their baseline MELD scores, caloric intake, resting energy expenditure, the incidence of bacterial translocation, or SIRS. While sarcopenia was not linked to increased hospital admissions or death, it was strongly associated with increased episodes of acute kidney injury (3 vs. 0, p = 0.05). This pilot study did not demonstrate an association between sarcopenia and SIRS or bacterial translocation. These results should be confirmed in future larger studies, encompassing a greater number of chronic inflammation events and quantifying levels of bacterial DNA.

Bacterial DNA translocation contributes to systemic inflammation and to minor changes in the clinical outcome of liver transplantation.

Bacterial (bact)DNA is an immunogenic product that frequently translocates into the blood in cirrhosis. We evaluated bactDNA clearance in patients undergoing liver transplantation (LT) and its association with inflammation and clinically relevant complications. We prospectively included patients consecutively admitted for LT in a one-year follow-up study. We evaluated bactDNA before and during the first month after LT, quantifying cytokine response at 30 days. One hundred patients were included. BactDNA was present in the blood of twenty-six patients undergoing LT. Twenty-four of these showed bactDNA in the portal vein, matching peripheral blood-identified bactDNA in 18 cases. Thirty-four patients showed bactDNA in blood during the first month after LT. Median TNF-α and IL-6 levels one month after LT were significantly increased in patients with versus without bactDNA. Serum TNF-α at baseline was an independent risk factor for bactDNA translocation during the first month after LT in the multivariate analysis (Odds ratio (OR) 1.14 [1.04 to 1.29], P = 0.015). One-year readmission was independently associated with the presence of bactDNA during the first month after LT (Hazard ratio (HR) 2.75 [1.39 to 5.45], P = 0.004). The presence of bactDNA in the blood of LT recipients was not shown to have any impact on complications such as death, graft rejection, bacterial or CMV infections. The rate of bactDNA translocation persists during the first month after LT and contributes to sustained inflammation. This is associated with an increased rate of readmissions in the one-year clinical outcome after LT.

AIM2 deficiency reduces the development of hepatocellular carcinoma in mice.

Chronic liver inflammation is crucial in the pathogenesis of hepatocellular carcinoma (HCC). Activation of the inflammasome complex is a key inflammatory process that has been associated with different liver diseases, but its role in HCC development remains largely unexplored. Here we analyzed the impact of different inflammasome components, including absent in melanoma 2 (AIM2) and NOD-like receptor family pyrin domain containing 3 (NLRP3), in the development of diethylnitrosamine (DEN)-induced HCC in mice. Genetic inactivation of AIM2, but not NLRP3, reduces liver damage and HCC development in this model. AIM2 deficiency ameliorates inflammasome activation, liver inflammation and proliferative responses during HCC initiation. We also identified that AIM2 is highly expressed in Kupffer cells, and that AIM2-mediated production of IL-1ß by these cells is enhanced after DEN-induced liver damage. Our data indicate that AIM2 promotes inflammation during carcinogenic liver injury and that it contributes to genotoxic HCC development in mice, thereby recognizing AIM2 as a potential therapeutic target in this disease.

Tie and tag: A study of tie strength and tags for photo sharing.

Tie strength and tags have been separately suggested as possible attributes for photo access controls in Social Network Services. However, an evaluation is missing about the benefits/drawbacks of adding one or both of these attributes to the ones already used in access controls for Social Network Services (groups and individuals). In this paper, we describe an experiment with 48 participants using access controls that include tie strength and tags (separately and simultaneously) together with attributes for groups and individuals. We analyze the results using several quantitative and qualitative metrics. We find that users consider these two new attributes useful in defining their sharing policies, and they prefer to employ access controls that consider tags and tie strength jointly. Specifically, users believe that tie strength improves policy understandability and that tags help them define sharing policies faster. However, we also observe that when users employ these two attributes they tend to make more mistakes in terms of the resulting sharing policy. We hypothesize that this could be caused by the lack of experience using tie strength and tags in access controls.

Treatment with non-selective beta-blockers affects the systemic inflammatory response to bacterial DNA in patients with cirrhosis.

BACKGROUND & AIMS: The use of non-selective beta-blockers has been associated with lower rates of infection and reduced infection-associated morbidity in patients with cirrhosis. However, it is unknown if these drugs modify the systemic inflammatory response to circulating bacterial DNA. METHODS: Sixty-three patients with cirrhosis were included during an episode of decompensation by ascites. Thirty of those patients were on beta-blockers. Blood samples were obtained after each patient had been in the supine position for at least 30 minutes in a quiet atmosphere. Bacterial DNA, serum cytokines, nitric oxide, and LPS were determined. Phagocytic and oxidative burst activities were determined in polymorphonuclear cells from the patients. RESULTS: The detection rate of bacterial DNA in the blood was the same (33%) for patients not treated and treated with non-selective beta-blockers. Patients naive to non-selective beta-blockers showed significantly higher serum levels of IL6, IFN-gamma and IL10 in response to the presence of bacterial DNA. Patients treated with non-selective beta-blockers showed higher basal inflammatory activity that did not change with the presence of bacterial DNA. Monocytes and granulocytes from patients treated with non-selective beta-blockers showed a significantly increased phagocytic capacity in the presence of bacterial DNA. CONCLUSIONS: In patients with cirrhosis, chronic treatment with beta-blockers is associated with a higher unstimulated production of serum cytokines and an increased phagocytic activity in the presence of bacterial DNA.

Norfloxacin is more effective than Rifaximin in avoiding bacterial translocation in an animal model of cirrhosis.

BACKGROUND & AIMS: Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. METHODS: Cirrhosis was induced in rats by oral administration of CCl4 . Animals were divided into three groups: only CCl4 (group I, n = 10); CCl4 + Norfloxacin (group II, n = 17) and CCl4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. RESULTS: Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-α levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. CONCLUSION: Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota.

Toll-like receptor polymorphisms compromise the inflammatory response against bacterial antigen translocation in cirrhosis.

Bacterial translocation is associated with clinically relevant complications in cirrhosis. We evaluated the effect of toll-like receptor polymorphisms in the soluble response against these episodes. Consecutive patients with cirrhosis and ascitic fluid were distributed by TLR2 rs4696480, TLR4 rs4986790, and TLR9 rs187084 single-nucleotide polymorphisms. Lipoteichoic acid, lipopolyssaccharide, bacterial-DNA, pro-inflammatory cytokines and nitric oxide levels were quantified in serum samples. In vitro response against specific ligands in variant TLR genotypes was evaluated. One hundred and fourteen patients were included. Variant TLR-2, TLR-4 and TLR-9 SNP genotypes were associated with significantly increased serum levels of LTA, LPS and bacterial-DNA. TNF-α, IL-6 and nitric oxide serum levels were significantly decreased in all variant TLR genotyped patients. Cytokine levels were significantly less upregulated in response to specific TLR-ligands in patients with all variant vs wildtype TLR genotypes. Although in vitro gene expression levels of all wildtype and variant TLRs were similar, MyD88 and NFkB were significantly downregulated in cells from TLR-variant genotyped patients in response to their ligands. Variant TLR genotypes are associated with an increased circulating antigen burden and a decreased proinflammatory response in cirrhosis. This immunodeficiency may facilitate bacteria-related complications in cirrhosis and enhance TLR targeting for its management.

The expression and activation of the AIM2 inflammasome correlates with inflammation and disease severity in patients with acute pancreatitis.

BACKGROUND: Acute pancreatitis is an inflammatory disorder of the pancreas that is responsible for significant morbidity and mortality. The inflammasome pathway has acquired significant relevance in the pathogenesis of many inflammatory disorders, but its role in patients with acute pancreatitis still awaits clarification. METHODS: We performed a prospective study in which 27 patients with acute pancreatitis and 16 healthy controls were included. We isolated peripheral blood mononuclear cells (PBMCs) and we assessed the expression and activation of different inflammasomes as well as their association with the clinical course of the disease. RESULTS: Our results show that PBMCs from patients with acute pancreatitis have elevated expression of several components of the inflammasome complex, including the inflammasome-forming receptor absent in melanoma 2 (AIM2), early during the onset of the disease. Activation of the AIM2 or NLRP3 inflammasomes in PBMCs from patients with acute pancreatitis results in exacerbated IL-1ß and IL-18 production compared with PBMCs from healthy controls. Furthermore, both AIM2 mRNA expression and AIM2-mediated production of IL-1ß by PBMCs correlated with increased systemic inflammation in these patients. Last, AIM2 expression was further increased in those patients that developed transient or persistent organ failure (moderate or severe acute pancreatitis). CONCLUSIONS: Our data demonstrates that AIM2 inflammasome expression and activation is increased early during the course of acute pancreatitis, and suggests that AIM2 activation may affect systemic inflammation and organ failure in these patients.

Norm Monitoring Under Partial Action Observability.

In the context of using norms for controlling multiagent systems, a vitally important question that has not yet been addressed in the literature is the development of mechanisms for monitoring norm compliance under partial action observability. This paper proposes the reconstruction of unobserved actions to tackle this problem. In particular, we formalize the problem of reconstructing unobserved actions, and propose an information model and algorithms for monitoring norms under partial action observability using two different processes for reconstructing unobserved actions. Our evaluation shows that reconstructing unobserved actions increases significantly the number of norm violations and fulfilments detected.

Lactulose reduces bacterial DNA translocation, which worsens neurocognitive shape in cirrhotic patients with minimal hepatic encephalopathy.

BACKGROUND & AIMS: Minimal hepatic encephalopathy is associated with poor prognosis and mortality in patients with cirrhosis. We aimed at investigating whether bacterial-DNA translocation affects hyperammonaemia and neurocognitive scores in patients with mHE according to the use of lactulose. METHODS: Observational study including 72 mHE cirrhotic patients, as defined by a psychometric hepatic encephalopathy score (PHES)<-4 and/or a critical flicker frequency (CFF)<39 Hz. Bacterial-DNA, serum ammonia, pro-inflammatory cytokines and nitric oxide levels were evaluated. A second cohort of 40 lactulose-untreated patients were evaluated before and 6-month after lactulose administration (30-60 mL/d). RESULTS: In the first cohort, bacterial-DNA rate was significantly higher in patients without lactulose (39% vs 23%, P=.03). Serum ammonia and inflammatory markers were significantly increased in patients with bacterial-DNA, regardless the use of lactulose, and correlated with the amount of amplified bacterial-DNA. Neurocognitive scores were significantly worse in bacterial-DNA positive vs negative patients (PHES -7.6±1.1 vs -5.5±1.0; CFF 32.5±2.6 vs 36.2±2.8, P=.01). Lactulose was associated with improved neurocognitive scores in patients without bacterial-DNA. Serum ammonia levels inversely correlated with neurocognitive scores in patients with bacterial-DNA (PHES r=-.84; CFF r=-.72, P=.001). In the second cohort, lactulose reduced bacterial-DNA translocation (36%-16%, P=.02). Neurocognitive scores were significantly improved in bacterial-DNA positive patients who cleared bacterial-DNA during the period on lactulose. Serum ammonia levels correlated with both neurocognitive scores in patients with bacterial-DNA, either before or after lactulose. CONCLUSION: Bacterial-DNA translocation worsens neurocognitive scores in mHE patients and it is reduced by lactulose, enhancing the relevance of controlling bacterial antigen translocation in these patients.

Selective intestinal decontamination with norfloxacin enhances a regulatory T cell-mediated inflammatory control mechanism in cirrhosis.

BACKGROUND & AIMS: Norfloxacin exerts immunomodulatory effects in cirrhosis beyond its bactericidal activity. We aimed at identifying the role of regulatory T (Treg) cells in the norfloxacin mechanism that compensates the inflammatory environment in cirrhosis. PATIENTS & METHODS: Consecutively admitted patients with cirrhosis and ascitic fluid (AF) with: spontaneous bacterial peritonitis (SBP), non-infected AF, and norfloxacin as secondary SBP prophylaxis (SID group). Tregs were defined by flow-cytometry as CD4+ CD25+ FoxP3+ cells. Dendritic cells (DCs) were purified for co-stimulatory signalling evaluation and norfloxacin and IL-10 levels were measured in serum. Wildtype and recombination activating gene 1 (Rag1)-deficient mice with CCl4 -induced cirrhosis were used for adoptive-transfer experiments using naïve CD4+ T cells and Tregs. RESULTS: Eighty-four patients were included. Treg percentage was significantly increased in SID patients compared with SBP or non-infected AF patients. A positive correlation was observed between Tregs and serum norfloxacin and IL-10 levels. DCs from SID patients showed a significantly decreased expression of CD80 and CD86 compared with SBP and non-infected AF patients and correlated with norfloxacin levels. Modulation of co-stimulatory signalling by norfloxacin was not detected in Rag1-deficient mice and Rag1-deficient mice reconstituted with naïve T-cells. However, reconstitution with naïve T-cells and Tregs was associated with significantly downregulated CD80 and CD86 expression in the presence of norfloxacin. Norfloxacin immunomodulatory effect on IL-2 and IFN-gamma reduction and on the increase of IL-10 was significantly achieved only when the Tregs were restored in Rag1-deficient mice. CONCLUSIONS: These results provide a plausible mechanism for the immunomodulatory effects of norfloxacin in cirrhosis beyond its bactericidal effect.

Grade of soluble inflammatory response is mainly affected by circulating bacterial DNA concentrations in cirrhosis.

BACKGROUND & AIMS: Patients with decompensated cirrhosis show a marked innate immune response that shows a wide variability. The reasons for this fact have not been previously evaluated. This investigation was undertaken to study factors influencing the immune response intensity in both serum and ascitic fluid in patients with cirrhosis and ascites with presence of bactDNA. METHODS: 77 patients with cirrhosis and presence of bactDNA fragments in blood and ascitic fluid were included. Identification of bactDNA was evaluated by 16SrRNA gene PCR followed by nucleotide sequencing and by species-specific PCR. Concentration of amplified bacterial-DNA, bacteria identification, LPS, TNF-alpha, IFN-gamma, Interleukin 12 and nitric oxide in serum and ascitic fluid were evaluated as factors related to intensity of the immune response. RESULTS: Serum and AF levels of bactDNA, TNF-α, IFN-γ and nitric oxide concentration were higher in patients with presence of bactDNA from gram negative bacteria. Serum TNF-α levels showed a significant correlation with concentrations of bactDNA (r = 0.88; P = 0.001) and LPS (r = 0.28; P = 0.016). Serum nitric oxide levels were also significantly correlated with concentrations of bactDNA (r = 0.761; P = 0.001) but not with LPS levels. Levels of INF-γ and IL-12 were not significantly correlated with either bactDNA nor LPS levels. Plasmatic concentration of bactDNA was the most accurately correlated factor with the inflammatory response (ancova model included only levels of bactDNA (r(2) = 0.87, P = 0.047 for TNF-α; r(2) = 0.45, P = 0.03 for NOx). CONCLUSIONS: Bacterial-DNA concentration is the most influencing variable associated with serum TNF-α and nitric oxide response.

Gut Bacterial DNA Translocation is an Independent Risk Factor of Flare at Short Term in Patients With Crohn's Disease.

OBJECTIVES: We aimed at evaluating bacterial DNA (bactDNA) presence in blood of Crohn's disease (CD) patients in remission as an independent risk factor of flare at 6 months. METHODS: This is a prospective, multicenter study on CD patients with Crohn's disease activity index (CDAI)<150. The primary end point was time-to-relapse as evaluated by CDAI>150 in the following 6 months. BactDNA in blood, the nucleotide-binding oligomerization domain containing 2 (NOD2) genotype, and serum cytokine levels were determined at baseline. RESULTS: A total of 288 patients were included. BactDNA was detected in 98 patients (34.0%). A variant-NOD2 genotype was identified in 114 patients (39.6%). Forty patients (14%) relapsed during follow-up. Multivariate survival analysis identified bactDNA as an independent risk factor of flare (hazard ratio (HR) 8.75 (4.02-19.06) 95% confidence interval (CI)). Hospitalization, surgery, switch of treatment, initiation and escalation of anti-tumor necrosis factor (TNF) therapy, steroids initiation, and increased fecal calprotectin levels at 6 months were associated with bactDNA at baseline. A logistic regression analysis showed bactDNA as an independent and significant predictive factor of hospitalization (odds ratio (OR) 11.9 (3.4-42.3); P<0.001), steroids startup (OR 8.5 (2.7-27.1); P<0.001), and switch of treatment (OR 3.5 (1.6-7.7); P=0.002) at 6 months. No relationship was observed between bactDNA and mucosal lesions in patients with colonoscopy at admission. Serum pro-inflammatory cytokines were significantly increased in patients with bactDNA or a variant-NOD2 genotype. The combination of both factors induced decreased anti-TNF-α levels and a higher percentage of patients on intensified anti-TNF therapy. CONCLUSIONS: BactDNA is an independent risk factor of relapse at 6 months in CD patients. BactDNA is also independently associated with an increased risk of hospitalization, switch of treatment, and steroids initiation.

Microbiome and bacterial translocation in cirrhosis. / Microbioma y traslocación bacteriana en la cirrosis.

Qualitative and quantitative changes in gut microbiota play a very important role in cirrhosis. Humans harbour around 100 quintillion gut bacteria, thus representing around 10 times more microbial cells than eukaryotic ones. The gastrointestinal tract is the largest surface area in the body and it is subject to constant exposure to these living microorganisms. The existing symbiosis, proven by the lack of proinflammatory response against commensal bacteria, implies the presence of clearly defined communication lines that contribute to the maintenance of homeostasis of the host. Therefore, alterations of gut flora seem to play a role in the pathogenesis and progress of multiple liver and gastrointestinal diseases. This has made its selective modification into an area of high therapeutic interest. Bacterial translocation is defined as the migration of bacteria or bacterial products from the intestines to the mesenteric lymph nodes. It follows that alteration in gut microbiota have shown importance, at least to some extent, in the pathogenesis of several complications arising from terminal liver disease, such as hepatic encephalopathy, portal hypertension and spontaneous bacterial peritonitis. This review sums up, firstly, how liver disease can alter the common composition of gut microbiota, and secondly, how this alteration contributes to the development of complications in cirrhosis.

Bifidobacterium pseudocatenulatum CECT7765 induces an M2 anti-inflammatory transition in macrophages from patients with cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis show recurrent access of bacterial products into the bloodstream inducing a multi-altered immunological status leading to relevant complications. We aimed at evaluating Bifidobacterium pseudocatenulatum CECT7765 effect on the host's macrophage function. PATIENTS & METHODS: Patients with cirrhosis and ascites were included. Granulocyte-macrophage colony-stimulating factor (GM-CSF) monocyte-derived and ascitic fluid (AF) macrophages were cultured with M-CSF, lipopolysaccharide (LPS) and/or the bifidobacterial strain. Pellets and supernatants were evaluated for gene expression of M1 and M2-related genes and cytokine secretion. Cell surface expression molecules were evaluated by flow cytometry. Kupffer cells from bile duct ligated and CCl4 rats were also evaluated. RESULTS: Experiments were run on GM-CSF blood-derived and AF macrophages from 10 patients with cirrhosis and 10 healthy donors. Different macrophage morphology was observed by optical microscopy in cells stimulated with bifidobacteria vs. LPS. M2-like expression of CD206, CD163 and CD16 was significantly increased in macrophages after stimulation with the bifidobacterial strain vs. LPS. B. pseudocatenulatum CECT7765 was able to significantly change the cytokine secretion pattern of blood-derived and AF macrophages and Kupffer cells from bile duct ligated and CCl4 cirrhotic rats compared to that induced by LPS. B. pseudocatenulatum CECT7765 was also effective in inducing a phenotype transition and a functional change from an M1- to an M2-related gene expression and cytokine secretion pattern in AF macrophages even after LPS-pretreatment. B. pseudocatenulatum CECT7765 did not reduce AF macrophage bacterial killing capacity. CONCLUSION: B. pseudocatenulatum CECT7765 induces a morphologic, phenotypic and functional transition towards an anti-inflammatory profile in GM-CSF monocyte-derived and AF macrophages from patients with cirrhosis that may help in controlling sustained inflammation in decompensated cirrhosis.

Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis.

BACKGROUND: Intestinal homeostasis plays an important role in bacteria-derived complications in cirrhosis. Intestinal lymphocytes are responsible for immune effector functions and can be modulated by certain probiotics. We evaluate the interaction between Bifidobacterium pseudocatenulatum CECT7765 and intestinal lymphocytes in mice with cirrhosis. ANIMALS AND METHODS: Cirrhosis was induced by intragastrical administration of carbon tetrachloride in Balb/C mice. One week prior to laparotomy, animals received B. pseudocatenulatum CECT7765 (10(7), 10(9) or 10(10) cfu/daily) or placebo. Chemokine receptor and cytokine expression were evaluated in intestinal lymphocytes. Gut permeability was studied by FITC-LPS recovery in vivo. Luminal antigens, inflammation and functional markers were evaluated in liver samples. RESULTS: Bifidobacterium pseudocatenulatum CECT7765 decreased the expression of pro-inflammatory chemokine receptors CCR6, CCR9, CXCR3 and CXCR6 in intestinal lymphocytes from cirrhotic mice in a concentration-dependent manner. The bifidobacterial strain induced a shift towards an anti-inflammatory cytokine profile in this cell subset. B. pseudocatenulatum CECT7765-induced inflammatory modulation was TLR2-mediated, as in vitro TLR2 blockade inhibited the reduction of TNF-alpha and its receptors and the increase of IL-10 and IL-10 receptor secretion. The recovery rate of administered fluorescence-labelled endotoxin was significantly and dose-dependently lowered with the bifidobacterial strain. The reduced intestinal permeability was associated with a decreased burden of bacterial antigens in the liver of mice treated with B. pseudocatenulatum CECT7765. Liver function and inflammation were improved with the use of the bifidobacterial strain at the highest dose tested (10(10) cfu). CONCLUSION: Bifidobacterium pseudocatenulatum CECT7765 improves gut homeostasis and prevents gut-derived complications in experimental chronic liver disease.

Immunomodulating effects of antibiotics used in the prophylaxis of bacterial infections in advanced cirrhosis.

The use of norfloxacin either as primary or secondary prophylaxis of bacterial infections in advanced cirrhosis has improved patient's survival. This may be explained not only due to a significant decrease in the number of infections, but also because of a direct immunomodulatory effect. Selective intestinal decontamination with norfloxacin reduces translocation of either viable bacteria or bacteria-driven products from the intestinal lumen. In addition, norfloxacin directly modulates the systemic inflammatory response. The pro-inflammatory cytokine profile secreted by neutrophils from these patients shows a close, significant, and inverse correlation with serum norfloxacin levels. Similar effects have been described with other quinolones in different clinical conditions. Although the underlying mechanisms are not well defined for most of the antibiotics, the pathways triggered for norfloxacin to induce such immunomodulatory effects involve the down-regulation of pro-inflammatory inducible nitric oxide synthase, cyclooxygenase-2, and NF-κB and the up-regulation of heme-oxygenase 1 and IL-10 expression. The knowledge of these immunomodulatory effects, additional to their bactericidal role, improves our comprehension of the interaction between antibiotics and the cellular host response and offer new possibilities for the development of new therapeutic strategies to manage and prevent bacterial infections in cirrhosis.

Use of proton pump inhibitors decrease cellular oxidative burst in patients with decompensated cirrhosis.

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are commonly used antisecretory drugs and have been linked to an increased risk of bacterial infections in cirrhosis. We investigated whether the treatment with PPIs in cirrhosis affects the oxidative burst activity of granulocytes and monocytes and its possible interference with serum norfloxacin (Nflx) levels in these patients. METHODS: 70 patients with cirrhosis and ascitic fluid and 24 healthy controls were included in the study and distributed into groups according to the regular use of PPIs and/or norfloxacin. The blood granulocyte and monocyte's phagocytic activity and oxidative burst were evaluated by flow cytometry. Blood levels of norfloxacin were measured by HPLC and bacterial translocation was evaluated by detection of bacterial DNA in blood. RESULTS: Use of PPIs was associated with a decreased granulocyte and monocyte oxidative burst, but not of phagocytic activity, as compared with patients not receiving PPIs. PPIs use did not affect serum norfloxacin levels in patients. A not significant trend to an increased bacterial DNA translocation was observed in patients receiving PPIs, including patients simultaneously receiving norfloxacin. CONCLUSIONS: PPIs significantly decrease cellular oxidative burst in cirrhosis. This fact may provide a pathogenic explanation to the reported high rates of bacterial infections in this setting, and strongly suggests that PPIs should only be used in patients with cirrhosis when clinically indicated.