The Role of Personalized Normative Feedback in the Efficacy of Brief Intervention Among Argentinian University Students: A Randomized Controlled Trial.

Background: Personalized Normative Feedback (PNF) aims to modify misperceptions about peer consumption that influence one's drinking. PNF is usually a component in Brief Interventions delivered to university students. Despite this, whether PNF contributes to improving the effect of brief interventions is unclear. Objectives: This randomized controlled trial aimed to determine the role of PNF as an active ingredient in a face-to-face motivational brief intervention. Results: Participants were students from an Argentinian university (n=806; M=20.14; SD=3.17; 63.2% women) who presented at least one binge drinking episode in the last 12 months. Students were randomly assigned to 1) a Brief Intervention, 2) a Brief Intervention with PNF, or 3) an evaluation-only control group. The follow-up was three months later. After controlling sex and age, General Linear Models showed that both the brief intervention and the brief intervention with PNF reduced the quantity and frequency of alcohol consumption, binge drinking, and alcohol problems compared to the control condition. No differences were found between the brief intervention and the brief intervention with PNF. Also, treating eight students with brief intervention and 10 with brief intervention with PNF was necessary to benefit one student. Conclusions: In conclusion, this study demonstrates that brief intervention reduces alcohol consumption among Latin American university students and that PNF might not be an active ingredient of its effectiveness in this population. However, PNF could benefit students with specific characteristics, like those who overestimate their peers' drinking, highlighting the need to study moderators of effectiveness further.

Hip adduction and abduction strength profiles in elite and sub-elite female soccer players according to players level and leg limb-dominance.

BACKGROUND: Understanding the hip adduction and abduction strength in female soccer players is crucial for performance enhancement and injury prevention. This study compares the strength profiles in these muscle groups between elite and sub-elite female soccer players and assesses the impact of leg limb-dominance. METHODS: A descriptive-comparative study was employed. Eighty-two female soccer players were evaluated. Isometric hip-adduction and abduction strength were measured using a handheld dynamometer. RESULTS: Female elite and sub-elite soccer players displayed a mean and standard deviation (SD) on isometric hip-adductor strength for dominant (3.19 Nm/kg ± 0.69 vs. 2.40 Nm/kg ± 0.67) and non-dominant leg (3.32 Nm/kg ± 0.76 versus 2.42 Nm/kg ± 0.70), respectively. For isometric hip-abductor strength in elite and sub-elite players, a mean and SD of dominant (2.86 Nm/kg ± 0.56 vs. 2.07 Nm/kg ± 0.50) and non-dominant (2.80 Nm/kg ± 0.59 vs. 2.04 Nm/kg ± 0.43). In essence, elite players were stronger than sub-elite players on isometric hip-adduction (mean difference [MD] = 0.82 Nm/kg, CI95% = 0.42-1.12) and abduction (MD = 0.83 Nm/kg, CI95% = 0.54- 1.12) both in dominant and non-dominant, leg, whereas no differences existed for hip adduction:abduction ratios between groups and legs. CONCLUSIONS: Elite female athletes exhibited greater strength than sub-elite female players in both hip adduction and abduction, whereas adduction:abduction ratio values did not differ between the two groups or between different legs.

Immune changes over time and survival in patients with cirrhosis treated with non-selective beta-blockers: A prospective longitudinal study.

BACKGROUND: Treatment with non-selective beta-blockers (NSBB) has been associated with anti-inflammatory and anti-cancer effects in patients with cirrhosis. This study aims to analyze the impact of chronic NSBB treatment on immune activation and disease progression in stable outpatients with cirrhosis. METHODS: In this prospective follow-up of 150 patients with cirrhosis, 39 received treatment with NSBB. Blood samples were taken every 6-9 months, and immune and adrenergic variables were measured. Mixed linear models were used to assess the effect of NSBB on these variables over time. Multivariate Cox regression was used to study associations with adverse clinical events (hepatocellular carcinoma, death, or liver transplant). RESULTS: Median follow-up was 1635 days. NSBB treatment was associated with significantly lower levels of IL-6 (ß - 4.7; 95% confidence interval [CI] -6.9, -2.6) throughout the study. During follow-up, 11 patients developed hepatocellular carcinoma, 32 died, and 4 underwent liver transplant. Patients with higher concentrations of IL-10, IL-6 and IFN-γ developed more clinical events. Event-free survival was significantly better in patients treated with NSBB (hazard ratio 0.36, 95% CI 0.18, 0.71) in a multivariate Cox regression adjusted for Child-Pugh-Score, esophageal varices, and platelets. CONCLUSION: Chronic treatment with NSBB in patients with stable cirrhosis gives rise to a different state of immune activation, characterized by lower concentrations of IL-6 over time, and it is associated with a reduced risk of adverse event (death, hepatocellular carcinoma, or transplant), after controlling for disease severity.

Impact of Pain Neuroscience Education Program in Community Physiotherapy Context on Pain Perception and Psychosocial Variables Associated with It in Elderly Persons: A Ranzomized Controlled Trial.

This study investigated the long-term effect (six-months) of a Pain Neuroscience Education (PNE) program on pain perception, quality of life, kinesiophobia and catastrophism in older adults with multimorbidity and chronic pain. Fifty participants (n = 50) were randomly assigned to the pain education therapy group (PET; n = 24) and control group (CG; n = 26). The PET group received six sessions (i.e., once a week, 50 min) about neurophysiology of pain while the CG carried on with their usual life. Perception of pain through the visual analogue scale (VAS), quality of life (EQ-5D questionnaire), kinesiophobia (TSK-11) and catastrophism (PCS) were assessed after six months since the last PNE session. Statistically significant differences on VAS (t(48) = 44, p = 0.01, ES = 0.42 [0.13, 0.65]) was found in favor to PET group. No other statistically significant differences were found. This study found that the application of a PNE intervention in an isolated form was able to significantly reduce pain perception with low effect size in the long-term (six months after intervention) in elderly people with chronic pain.

Road traffic injury risk from alcohol and cannabis use among emergency department patients in Argentina.

Objective: To report the risk from alcohol, cannabis, and their combined use for non-fatal road traffic injuries for drivers, passengers, and pedestrians. Methods: Risk was estimated using the case-crossover method. Participants (N= 306) were injured patients from an emergency department in Mar del Plata, Argentina. Results: Alcohol use (OR= 6.78, CI 95% 3.75-12.25) as well as combined alcohol and cannabis use (OR= 7.05, CI 95% 1.16-42.73) significantly increased the risk of a road traffic injuries. Alcohol use increased the risk in both, women (OR= 8.87, CI 95% 2.69-29.21) and men (OR= 6.16, CI 95% 3.10-12.23); in those >30 years old (OR= 6.01, CI 95% 2.09-17.24) and those <30 years old (OR= 7.15, CI 95% 3.49-14.65). This last group also had an increased risk after combined alcohol and cannabis use (OR= 7.05, CI 95% 1.16-42.75). Both drivers (OR= 6.40, CI 95% 3.23-12.69) and passengers (OR= 13.83, CI 95% 2.87-66.42) had an increased risk after alcohol consumption. Conclusions: To our knowledge, these are the first estimates of the risk of having a road traffic injury after alcohol and cannabis consumption in one of the countries of the Southern Cone (Argentina, Chile, and Uruguay). These results highlight the urgent need to implement and enforce comprehensive alcohol control measures. Furthermore, given the global trend towards legalizing cannabis for recreational use, our results could also inform policymakers to enact or amend impaired driving laws.

Efficacy of Brief Intervention for Alcohol Consumption during Pregnancy in Argentinean Women: A Randomized Controlled Trial.

INTRODUCTION: Although Brief Intervention (BI) has proven to reduce alcohol consumption during pregnancy in high income countries, there is no evidence from the Southern Cone of America. Thus, we conducted a study to assess BI efficacy among Argentinean pregnant women. METHOD AND MATERIALS: We collected data on pregnant women receiving prenatal care at the public health system in Mar del Plata, Argentina. Women with less than 26 weeks of gestation (n = 486) were randomized to brief advice (BA) or BI. Three months later they were re-assessed; women with more than 26 weeks of gestation constituted a screening only control group (SC) (n = 154). Self-reported quantity and frequency of alcohol consumption, frequency of binge drinking, and related problems after three months were used as outcomes. We performed generalized estimating equations and clinical significance analyses. Also, we obtained newborn health indicators from the city's health system database to use as objective outcomes. Women who did not participate in any of the three former conditions were randomly selected to constitute a non-screening control group (NSC) (n = 150). We compared objective outcomes among BI, BA, and NSC groups using the Wilcoxon rank test. RESULTS: In comparison with SC, BI and BA reduced alcohol consumption, without differences between the latter two. Newborns of women who received BI and BA had better health indicators compared with the NSC group. CONCLUSIONS: performing either a BI or BA reduces alcohol consumption among Argentinean pregnant women and might lead to healthier newborns.

Road traffic injury risk from alcohol and cannabis use among emergency department patients in Argentina / Riesgo de lesiones por accidentes de tránsito debido al consumo de alcohol y cannabis en pacientes de urgencias en Argentina / Risco de lesões no trânsito devido ao uso de álcool e cannabis entre pacientes atendidos em um pronto-socorro na Argentina

ABSTRACT Objective. To report the risk from alcohol, cannabis, and their combined use for non-fatal road traffic injuries for drivers, passengers, and pedestrians. Methods. Risk was estimated using the case-crossover method. Participants (N= 306) were injured patients from an emergency department in Mar del Plata, Argentina. Results. Alcohol use (OR= 6.78, CI 95% 3.75-12.25) as well as combined alcohol and cannabis use (OR= 7.05, CI 95% 1.16-42.73) significantly increased the risk of a road traffic injuries. Alcohol use increased the risk in both, women (OR= 8.87, CI 95% 2.69-29.21) and men (OR= 6.16, CI 95% 3.10-12.23); in those >30 years old (OR= 6.01, CI 95% 2.09-17.24) and those <30 years old (OR= 7.15, CI 95% 3.49-14.65). This last group also had an increased risk after combined alcohol and cannabis use (OR= 7.05, CI 95% 1.16-42.75). Both drivers (OR= 6.40, CI 95% 3.23-12.69) and passengers (OR= 13.83, CI 95% 2.87-66.42) had an increased risk after alcohol consumption. Conclusions. To our knowledge, these are the first estimates of the risk of having a road traffic injury after alcohol and cannabis consumption in one of the countries of the Southern Cone (Argentina, Chile, and Uruguay). These results highlight the urgent need to implement and enforce comprehensive alcohol control measures. Furthermore, given the global trend towards legalizing cannabis for recreational use, our results could also inform policymakers to enact or amend impaired driving laws.

RESUMEN Objetivo. Informar sobre el riesgo lesiones por accidentes de tránsito debido al consumo de alcohol, cannabis o su combinación en conductores, pasajeros y peatones. Métodos. Se estimó el riesgo mediante el método de casos cruzados. Los participantes (N = 306) fueron pacientes que habían sufrido lesiones, provenientes de una sala de urgencias en Mar del Plata (Argentina). Resultados. El consumo de alcohol (OR = 6,78, IC95% 3,75-12,25), así como el consumo combinado de alcohol y cannabis (OR = 7,05, IC95% 1,16-42,73) aumentaron significativamente el riesgo de traumatismos por accidentes de tránsito. El consumo de alcohol aumentó el riesgo tanto en mujeres (OR = 8,87, IC95% 2,69-29,21) como en hombres (OR = 6,16, IC95% 3,10-12,23); así como en mayores de 30 años (OR = 6,01, IC95% 2,09-17,24) y en menores de 30 años (OR = 7,15, IC95% 3,49-14,65). Este último grupo también tuvo mayor riesgo tras un consumo combinado de alcohol y cannabis (OR = 7,05, IC95% 1,16-42,75). Tanto los conductores (OR = 6,40, IC95% 3,23-12,69) como los pasajeros (OR = 13,83, IC95% 2,87-66,42) presentaron mayor riesgo después del consumo de alcohol. Conclusiones. Hasta donde sabemos, estas son las primeras estimaciones del riesgo de sufrir lesiones por accidentes de tránsito tras el consumo de alcohol y cannabis en uno de los países del Cono Sur (Argentina, Chile y Uruguay). Estos resultados ponen de relieve la urgente necesidad de aplicar y hacer cumplir medidas integrales de control del alcohol. Además, dada la tendencia mundial hacia la legalización del cannabis para consumo recreativo, nuestros resultados también podrían orientar a los responsables de las políticas para que promulguen o enmienden las leyes sobre la conducción con capacidades alteradas debido al consumo de sustancias.

RESUMO Objetivo. Relatar o risco de lesões não fatais no trânsito atribuível ao álcool, à cannabis e a seu uso combinado para motoristas, passageiros e pedestres. Métodos. O risco foi estimado usando o método clínico cruzado (case-crossover). Os participantes (N=306) eram feridos atendidos em um pronto-socorro em Mar del Plata, Argentina. Resultados. O uso de álcool (OR = 6,78, IC95% 3,75; 12,25) e o uso combinado de álcool e cannabis (OR= 7,05, IC95% 1,16; 42,73) aumentaram significativamente o risco de lesões no trânsito. O uso de álcool aumentou o risco tanto em mulheres (OR = 8,87, IC95% 2,69; 29,21) quanto em homens (OR = 6,16, IC95% 3,10; 12,23); naqueles >30 anos de idade (OR = 6,01, IC95% 2,09; 17,24) e <30 anos de idade (OR = 7,15, IC95% 3,49; 14,65). Esse último grupo também apresentou um risco maior após o uso combinado de álcool e cannabis (OR = 7,05, IC95% 1,16; 42,75). Tanto motoristas (OR = 6,40, IC95% 3,23; 12,69) quanto passageiros (OR = 13,83, IC95% 2,87; 66,42) apresentaram risco maior após o consumo de álcool. Conclusões. Até onde sabemos, estas são as primeiras estimativas do risco de lesões de trânsito após o consumo de álcool e cannabis em um dos países do Cone Sul (Argentina, Chile e Uruguai). Os resultados destacam a necessidade urgente de implementar e aplicar medidas abrangentes de controle do álcool. Além disso, considerando a tendência global de legalização da cannabis para uso recreativo, nossos resultados também poderiam ajudar os formuladores de políticas a decretar ou alterar as leis sobre a condução sob efeito de substâncias psicoativas.

Functionality of beta-adrenergic receptors in patients with cirrhosis treated chronically with non-selective beta-blockers.

BACKGROUND: In patients with cirrhosis, beta-adrenoceptors expressed on peripheral blood mononuclear cells have a reduced response to catecholamine stimulation. This study aimed to determine if chronic treatment with beta-blockers influences these changes. METHODS: Blood samples were collected from patients with cirrhosis treated in outpatient clinics. Differences in cyclic AMP production before and after stimulation of mononuclear cells with epinephrine and/or N-Formylmethionine-leucyl-phenylalanine (fMLP) was used as a marker of beta-adrenoceptors activity in patients treated (N = 19) versus not treated (N = 55) with beta-blockers. In addition, we studied the gene expression of different types of adrenoceptors and possible associations with the activity of beta-adrenoceptors, the serum concentrations of catecholamines and cytokines, and the presence of bacterial antigens such as DNA or gram-negative bacterial endotoxin in patients' blood. RESULTS: The increase in intracellular cAMP concentrations after stimulation of adrenergic receptors with epinephrine was significantly higher in samples from patients treated with beta-blockers. Older patients showed lower responses to epinephrine stimulus, while the response increased linearly with the duration of the beta-blocker treatment. mRNA expression levels of adrenoceptors ß1, ß2, ß3 and α1-A, B and D showed no significant differences according to treatment with beta-blockers. Neither serum cytokines nor catecholamines levels were significantly associated with the intracellular production of cAMP after adrenergic stimulation. CONCLUSION: Chronic treatment with beta-blockers in patients with cirrhosis enables beta-adrenoceptors to respond to catecholamine stimulation irrespective of the degree of systemic adrenergic or immune activations of the patient at the time of sampling.

Increased Th17-Related Cytokine Serum Levels in Patients With Multiple Polyps of Unexplained Origin.

OBJECTIVES: Most patients with multiple colonic polyps do not have a known genetic or hereditary origin. Our aim was to analyze the presence of inflammatory cytokines and levels of glucose, insulin, and C-reactive protein (CRP) in patients with multiple colonic polyps. METHODS: Eighty-three patients with 10 or more adenomatous or serrated polyps and 53 control people with normal colonoscopy were included. Smoking habits were registered, and glucose, CRP, and basal insulin in the serum/blood were measured. Quantification of IL-2, IL-4, IL-6, IL-10, IL-11, IL-17A, and IL-23 cytokine levels in the serum was performed by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Smoking and diabetes were more prevalent in those with colonic polyps than in the control people (67% vs 16%, P = 0.001; 11% vs 2%, P = 0.048). In addition, the cytokine serum levels were higher, i.e., IL-2 (P = 0.001), IL-4 (P = 0.001), IL-6 (P = 0.001), IL-17A (P = 0.001), IL-23 (P = 0.014), and CRP (P = 0.003). Adjusting for sex, smoking, and diabetes in a multivariate analysis, IL-2, IL-4, IL-6, IL-17A, and IL-23 remained independently elevated in cases with multiple polyps. DISCUSSION: These results indicate that immune responses mediated by Th17 cells may be involved in the pathogenesis of multiple colonic polyps.

The Association Between Early Drinking and Dependence Varies by Drinking Context.

Evidence regarding the association between early drinking (ED) and later dependence is controversial. It has been alternately hypothesized that ED either plays a causal role in the development of dependence or that it is an early marker of increased psychosocial vulnerabilities. Despite a clear rationale for delaying youth consumption, it is important to discern this relationship. However, most epidemiological evidence comes from individual studies and high-income countries. If there is a causal link between ED and dependence, an association at the aggregate level would be expected. Furthermore, if the link is due to biological mechanisms, the association should be rather invariable regardless of the drinking context, while if the association is due to psychosocial factors, a wider variability is to be expected. We explored whether the association between ED and dependence varied across countries clustered by their shared contextual drinking characteristics. We used data from 169 countries from the Global Information System on Alcohol and Health of the World Health Organization: ED, alcohol dependence, heavy episodic drinking (HED), actual drinkers, and alcohol policy. To cluster countries by their shared drinking characteristics (prevalences of HED and actual drinkers, and alcohol policy), we used, sequentially, two multivariate data reduction techniques: a multiple correspondence analysis (MCA) and a hierarchic classification. To estimate the association between ED and alcohol dependence, beta regressions were performed, and then adjusted by country income-level and repeated by gender. The results indicated four country clusters: primarily abstainers (class 1), low drinking countries (class 2), high drinking countries (class 3), and very high drinking countries (class 4). Positive relationships between ED and alcohol dependence were found for all the countries in the world and for those in classes 1 and 2. No significant relationships were found for class 3 or class 4. These results were similar for males, but not for females, where no significant relationships were found after adjusting for income level. The association between ED and dependence varies according to the drinking context. Our findings either suggest that the ED-dependence association may be due to individual or environmental vulnerabilities that promote consumption outside cultural norms or that, if there is a causal link between ED and dependence, it is strongly moderated by psychosocial characteristics.

Identification of bacterial DNA in the peripheral blood of patients with active hidradenitis suppurativa.

Bacterial translocation may have a role in the pathogenesis of several inflammatory conditions. A prospective analytical case-control study was designed to assess the presence of bacterial DNA in the peripheral blood of patients with hidradenitis suppurativa (HS). An age- and gender-matched control population was recruited from healthy blood donors. Demographic and HS-related data were also collected. We took fasting blood samples from each participant and determined the presence of bacterial DNA (including bacterial species identification) and levels TNF-α, IL-1ß, and IL-17A. We included 50 patients with HS and 50 healthy controls. Bacterial DNA was present in 17 (34.0%) cases vs. 2 (4.0%) controls (P < 0.001); 14/17 (82.4%) bacterial species identified in HS patients were Gram-negative bacilli, especially Escherichia coli. The presence of bacterial DNA in patients with HS was associated with elevated levels of TNF-α (P < 0.001), IL-1ß (P = 0.01) and IL-17 (P < 0.001); however, it was not associated with disease severity or disease location. BactDNA in the peripheral blood of patients with active HS is more common that in healthy controls, and it is associated with higher levels of proinflammatory cytokines. We hypothesized that BT from the skin/intestinal lumen may play a relevant role in the pathogenesis of HS.

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.

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.

IL26 modulates cytokine response and anti-TNF consumption in Crohn's disease patients with bacterial DNA.

Interleukin IL26 supports killing of microbes and the innate sensing of bacterial-derived DNA (bactDNA). We evaluated the relationship between IL26 serum levels and bactDNA translocation in Crohn's disease (CD). We ran a prospective study on CD patients in remission. IL26 common polymorphisms, serum cytokines and complement protein, amplified-bactDNA, and anti-TNF-α were evaluated. In vitro PBMC analysis was performed. Three hundred and thirteen patients were included (mean CDAI: 83.6 ± 32.8; mean fecal calprotectin: 55.4 ± 35.3 µg/g). A total of 106 patients (33.8%) showed bactDNA and 223 patients (71%) had a varIL26 genotype. BactDNA significantly correlated with increased IL26 levels compared with bactDNA-negative patients. PBMCs from varIL26 patients significantly reduced E. coli killing capacity compared with wtIL26-genotyped patients. The stimulation with a recombinant IL26 protein reduced pro-inflammatory cytokines in response to E. coli in the varIL26 cell supernatants. Serum anti-TNF-α levels in varIL26 vs wtIL26-genotyped patients on biologics were significantly lower in the presence of bactDNA. Cells from varIL26 vs wtIL26-genotyped patients cultured with E. coli DNA and infliximab showed a significant decrease in free anti-TNF-α concentration. A varIL26 genotype was associated with the initiation of anti-TNF-α in CD patients during the 6-month follow-up. IL26 polymorphisms may prevent bactDNA clearance and identify CD patients with a worse inflammatory evolution and response to therapy. KEY MESSAGES: BactDNA translocation in CD is associated with an increased risk of relapse. IL26 is sensitive to bactDNA and modulates the inflammatory response in CD patients. The varIL26 genotype is associated with reduced PMN capacity to kill bacteria. A varIL26 genotype is associated with decreased levels of anti-TNF-α in CD patients. IL26 may help explain the role of bactDNA as a risk factor of flare in CD patients.

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.

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.

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.

Acute effects of dipyrone on renal function in patients with cirrhosis: a randomized controlled trial.

Use of non-steroidal anti-inflammatory drugs in cirrhosis has been associated with impairment of renal function based on its ability to inhibit the renal production of prostaglandins. Renal effects of dipyrone in patients with cirrhosis have not been evaluated. We aimed to assess the renal effect of therapeutic doses of dipyrone used for short periods of time in patients with cirrhosis. Twenty-nine patients with cirrhosis were included in an observer-blind clinical trial. Patients were randomized to receive three times a day oral acetaminophen (500 mg; N = 15) or dipyrone (575 mg; N = 14) for 72 hr. Serum and urine samples were obtained at baseline, 48 and 72 hr, and cystatin C, creatinine, aldosterone, 6-keto-Prostaglandin-F1 alpha and prostaglandin E2 were measured. Cystatin C and creatinine levels remained comparable in patients treated with acetaminophen and dipyrone. Urine and serum prostaglandins concentrations were significantly decreased at 72 hr in patients treated with dipyrone regardless of the status of ascites. One patient with ascites treated with dipyrone required a paracentesis and developed renal insufficiency. We conclude that dipyrone and acetaminophen did not reduce renal function when used for short periods of time (up to 72 hr) in patients with cirrhosis. However, considering that dipyrone lowered renal vasodilator prostaglandins synthesis, acetaminophen appears as the safest choice with respect to kidney function in cirrhosis.

Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis.

BACKGROUND & AIMS: Inflammation is a common event in the pathogenesis of liver cirrhosis. The inflammasome pathway has acquired significant relevance in the pathogenesis of inflammation, but its role in the inflammatory response in patients with decompensated cirrhosis remains unexplored. METHODS: We performed a prospective study in which 44 patients with decompensated cirrhosis and 12 healthy volunteers were included. We isolated macrophages from blood and ascitic fluid and assessed the expression and activation of the inflammasome, its response to priming by bacterial products, and its association with the degree of liver disease. RESULTS: Macrophages from sterile ascitic fluids showed constitutive activation of caspase-1 and a marked increase in the expression of IL-1ß, IL-18, and absent in melanoma 2 (AIM2) when compared to blood macrophages. Pre-stimulation of blood-derived macrophages from cirrhotic patients with bacterial DNA increased the expression of AIM2 and induced a higher AIM2-mediated inflammasome response than priming with other bacterial products such as lipopolysaccharide. By contrast, activation of the AIM2 inflammasome did not require a priming signal in ascitic fluid-derived macrophages, demonstrating the preactivated state of the inflammasome in these cells. Last, higher IL-1ß and IL-18 production by ascitic fluid macrophages correlated with a more advanced Child-Pugh score. CONCLUSIONS: The inflammasome is highly activated in the ascitic fluid of cirrhotic patients, which may explain the exacerbated inflammatory response observed in these patients under non-infected conditions. Clinically, activation of the inflammasome is associated with a higher degree of liver disease.