Adjuvant Arthroscopy Does Not Improve the Functional Outcome of Volar Locking Plate for Distal Radius Fractures: A Randomized Clinical Trial.

PURPOSE: To evaluate the outcomes of adding arthroscopy to osteosynthesis of distal radius fractures (DRF) with volar locking plate (VLP), by Patient-Rated Wrist Evaluation (PRWE) 1 year after surgery. METHODS: In total, 186 functionally independent adult patients who met the inclusion criteria (DRF and a clinical decision for surgery with a VLP) were randomized to arthroscopic assistance or not. Primary outcome was PRWE questionnaire results 1 year after surgery. For the main variable, PRWE, we obtained the minimal clinically important difference based on a distribution-based method. Secondary outcomes included Disabilities of the Arm, Shoulder and Hand and 12-Item Short Form Health Survey questionnaires, range of motion, strength, radiographic measures, and presence of joint step-offs by computed tomography. Data were collected preoperatively and at +1 and +4 weeks, +3 and +6 months, and +1 year after surgery. Complications were recorded throughout the study. RESULTS: In total, 180 patients (mean age: 59.0 ± 14.9 years; 76% women) were analyzed by modified intention to treat. A total of 82% of the fractures were intra-articular (AO type C). No significant difference between arthroscopic (AG) and control (CG) groups in median PRWE was found at +1 year (median AG: 5.0, median CG: 7.5, difference in medians 2.5; 95% confidence interval [CI] -2.0, 7.0, P = .328). The proportion of patients who exceeded the minimal clinically important difference of 12.81 points in the AG and CG was 86.4% vs 85.1%, P = .819, respectively. Percentage of associated injuries and step-offs reduction maneuvers was greater with arthroscopy (mean differences: 17.1 95% CI -0.1, 26.1, P < .001) and 17.4 (95% CI 5.0, 29.7, P = .007). The difference in percentage of residual joint step-offs at the postsurgical computed tomography in radioulnar, radioscaphoid, and radiolunate joints was not significant (P = .990, P = .538, and P = .063). Complications were similar between groups (16.9% vs 20.9%, P = .842). CONCLUSIONS: Adjuvant arthroscopy did not significantly improve PRWE score +1 year after surgery for DRF with VLP, although the statistical power of the study is below the initially estimated to detect the expected difference. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Testing a vaccine candidate against Hepatitis C virus designed by combinatorial optimization.

This paper presents a new procedure for vaccine design against highly variable viruses such as Hepatitis C. The procedure uses an optimization algorithm to design vaccines that maximize the coverage of epitopes across different virus variants. Weighted epitopes based on the success ratio of immunological assays are used to prioritize the selection of epitopes for vaccine design. The procedure was successfully applied to design DC vaccines loaded with two HCV peptides, STG and DYP, which were shown to be safe, immunogenic, and able to induce significant levels of anti-viral cytokines, peptide-specific cellular immune responses and IgG antibodies. The procedure could potentially be applied to other highly variable viruses that currently lack effective vaccines.

Diversity of immune responses in children highly exposed to SARS-CoV-2.

Background: Children are less susceptible than adults to symptomatic COVID-19 infection, but very few studies addressed their underlying cause. Moreover, very few studies analyzed why children highly exposed to the virus remain uninfected. Methods: We analyzed the serum levels of ACE2, angiotensin II, anti-spike and anti-N antibodies, cytokine profiles, and virus neutralization in a cohort of children at high risk of viral exposure, cohabiting with infected close relatives during the lockdown in Spain. Results: We analyzed 40 children who were highly exposed to the virus since they lived with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected relatives during the lockdown for several months without taking preventive measures. Of those, 26 reported mild or very mild symptoms. The induced immune response to the virus was analyzed 3 months after the household infection. Surprisingly, only 15 children had IgG anti-S (IgG+) determined by a sensitive method indicative of a past infection. The rest, negative for IgG anti-N or S in various tests, could be further subdivided, according to IgM antibodies, into those having IgM anti-S and IgM anti-N (IgG-IgMhigh) and those having only IgM anti-N (IgG-IgMlow). Interestingly, those two subgroups of children with IgM antibodies have strikingly different patterns of cytokines. The IgMhigh group had significantly higher IFN-α2 and IFN-γ levels as well as IL-10 and GM-CSF than the IgMlow group. In contrast, the IgMlow group had low levels of ACE2 in the serum. Both groups have a weaker but significant capacity to neutralize the virus in the serum than the IgG+ group. Two children were negative in all immunological antibody tests. Conclusions: A significant proportion of children highly exposed to SARS-CoV-2 did not develop a classical adaptive immune response, defined by the production of IgG, despite being in close contact with infected relatives. A large proportion of those children show immunological signs compatible with innate immune responses (as secretion of natural antibodies and cytokines), and others displayed very low levels of the viral receptor ACE2 that may have protected them from the virus spreading in the body despite high and constant viral exposure.

Integrative and Collaborative Approach in the Chronic Management of Obesity in Primary and Tertiary Care Setting: Vall Hebron-SAP Muntanya Healthcare Route.

INTRODUCTION: In the context of obesity pandemic, the health care providers involved in the primary care should have a significant role. Several guidelines for the management of obesity in primary care were proposed recently. In general lines, these guidelines include recommendation on the baseline assessment, therapy, and algorithm for referral to specialized obesity clinic and follow-up. Nevertheless, at present, there is no guideline or protocol that continuously and bidirectionally links the two settings: primary care and specialized obesity clinic. METHODS: We present a model of continuous, bilateral, and integrative interaction between primary care units and reference tertiary care setting in the chronic management of obesity that is already implemented in a public health system. RESULTS: The novelty of our algorithm is that incorporates the support and continuous communication with the specialized obesity clinic of the tertiary care setting from the beginning in the management of a patient with obesity, in a bidirectional manner. CONCLUSION: This kind of bidirectional and continuous collaboration will help engage health care providers in the management of obesity, optimize efforts, shorten the time until proper intervention, personalize the approach and, finally, save costs for the health system.

Association Between Hounsfield Units in Preoperative Wrist Computed Tomography Scans and Outcomes After Wrist Fracture Surgery.

Purpose: This work aims to evaluate the hypothesis that the value of Hounsfield units (HU), as a marker of bone density, in preoperative wrist computed tomography (CT) scans correlates with the functional outcomes as measured by patient reported outcomes (PROs) after distal radius fracture surgery with volar locking plate fixation. Methods: Of a database of 92 wrist fractures operated on in our hospital between 2011 and 2020, with a preoperative CT scan performed, we selected the cases with a minimum follow-up period of 12 months. After applying the exclusion criteria, the final cohort comprised 64 patients. Three measurements of HU were performed in correlative coronal sections of the capitate bone. PROs were determined using two functional questionnaires (DASH and PRWE) and one quality of life questionnaire (SF-12). The statistical relationship between PROs and the HU measurements obtained via a CT scan was analyzed. Results: Patients were classified into two groups, osteoporotic (OST) or non-osteoporotic (non-OST), according to the optimal cut-off value of 323 HU selected using a ROC curve. The median DASH questionnaire score in the OST group was significantly higher (1.7 vs 10.0, p = 0.003). Conclusion: HU values in preoperative wrist CT scans may help to identify osteoporotic bone in patients prior to wrist fracture surgery and lead to an improved surgical indication and treatment strategy. Level of Evidence: Level of evidence: Prognostic III.

ACE2 Serum Levels as Predictor of Infectability and Outcome in COVID-19.

Background: COVID-19 can generate a broad spectrum of severity and symptoms. Many studies analysed the determinants of severity but not among some types of symptoms. More importantly, very few studies analysed patients highly exposed to the virus that nonetheless remain uninfected. Methods: We analysed serum levels of ACE2, Angiotensin II and anti-Spike antibodies in 2 different cohorts at high risk of viral exposure, highly exposed but uninfected subjects, either high risk health care workers or persons cohabiting with infected close relatives and seropositive patients with symptoms. We tested the ability of the sera of these subjects to neutralize lentivirus pseudotyped with the Spike-protein. Results: We found that the serum levels of ACE2 are significantly higher in highly exposed but uninfected subjects. Moreover, sera from this seronegative persons can neutralize SARS-CoV-2 infection in cellular assays more strongly that sera from non-exposed negative controls eventhough they do not have anti-CoV-2 IgG antibodies suggesting that high levels of ACE2 in serum may somewhat protect against an active infection without generating a conventional antibody response. Finally, we show that among patients with symptoms, ACE2 levels were significantly higher in infected patients who developed cutaneous as compared with respiratory symptoms and ACE2 was also higher in those with milder symptoms. Conclusions: These findings suggest that soluble ACE2 could be used as a potential biomarker to predict SARS-CoV-2 infection risk and to discriminate COVID-19 disease subtypes.

Suspected Brown Recluse Spider Envenomation: Missed Diagnosis and Delayed Treatment of Loxoscelism: A Case Report.

CASE: We report the case of a previously healthy 51-year-old man who presented to our hospital after worsening clinical appearance of his left ring finger, despite antibiotics and previous surgical drainage for suspected abscess at an outside institution 3 weeks ago. He was admitted to our hospital for surgical debridement and decompression. After suspicion of cutaneous loxoscelism based on the clinical record and corticosteroid administration, the patient presented a favorable evolution. CONCLUSION: Cutaneous loxoscelism caused by a spider bite is present in Europe, mainly in the Mediterranean area, and should be considered in cases of skin infections which do not respond to antibiotics.

Retrospective Cohort Noninferiority Analysis of Barrier Cream in Preventing Pressure Injuries.

OBJECTIVE: To assess the effectiveness of a dimethicone- and zinc-based barrier cream compared with hyperoxygenated fatty acids in preventing pressure injuries (PIs) in patients at high or very high risk. METHODS: Researchers conducted a retrospective noninferiority study in an inpatient acute care hospital in Spain that included hospitalized patients in nonsurgical departments with impaired mobility. RESULTS: The study authors reviewed 522 patients in a control group (hyperoxygenated fatty acids) and an experimental group (barrier cream) over a period of 7 days. The incidence of PI was 31% in the control group and 31.1% in the experimental group. The hazard ratio for developing PI was 0.84 (confidence interval, 0.61-1.17; P = .32) in the experimental group compared with the control group, meeting the criteria for noninferiority. The Kaplan-Meier estimator indicated no statistically significant difference between groups (log-rank = 0.654). CONCLUSIONS: Dimethicone- and zinc-based barrier cream was not inferior to hyperoxygenated fatty acids in preventing PIs in hospitalized patients at high or very high risk of developing them during their hospital stay.

Intestinal Immune Dysregulation Driven by Dysbiosis Promotes Barrier Disruption and Bacterial Translocation in Rats With Cirrhosis.

In cirrhosis, intestinal dysbiosis, intestinal barrier impairment, and systemic immune system abnormalities lead to gut bacterial translocation (GBT) and bacterial infection. However, intestinal immune system dysfunction and its contribution to barrier damage are poorly understood. This study correlates immune system dysregulation in the intestines of rats at different stages of CCl4 -induced cirrhosis with barrier function and pathogenic microbiota. The following variables were addressed in the small intestine: intraepithelial lymphocyte (IEL) and lamina propria lymphocyte (LPL) activation status and cytokine production (flow cytometry), cytokine mRNA and protein expression (quantitative real-time PCR and immunofluorescence), microbiota composition of ileum content (16S recombinant DNA massive sequencing), permeability (fecal albumin loss), and epithelial junctions (immunohistochemistry and immunofluorescence). The intestinal mucosa in rats with cirrhosis showed a proinflammatory pattern of immune dysregulation in IELs and LPLs, which featured the expansion of activated lymphocytes, switch to a T helper 1 (Th1) regulatory pattern, and Th17 reduction. In rats with cirrhosis with ascites, this state was associated with epithelial junction protein disruption, fecal albumin loss, and GBT. Direct correlations (P < 0.01) were observed between elevated interferon gamma (IFNγ)-expressing T cytotoxic LPLs and fecal albumin and between inflammatory taxa abundance and IFNγ-producing immune cells in the ileum. Bowel decontamination led to redistributed microbiota composition, reduced proinflammatory activation of mucosal immune cells, normalized fecal albumin levels, and diminished GBT; but there were no modifications in Th17 depletion. Conclusion: The intestinal mucosa of rats with cirrhosis acquires a proinflammatory profile of immune dysregulation that parallels the severity of cirrhosis; this impaired intestinal immune response is driven by gut dysbiosis and leads to disrupted barrier function, promoting GBT.

The firing frequency of spontaneous action potentials and their corresponding evoked exocytosis are increased in chromaffin cells of CCl4 -induced cirrhotic rats with respect to control rats.

High catecolamine plasma levels because of sympathetic nervous system over-activity contribute to cirrhosis progression. The aim of this study was to investigate whether chromaffin cells of the adrenal gland might potentiate the deleterious effect exerted by this over-activity. Electrophysiological patch-clamp and amperometric experiments with carbon-fibre electrodes were conducted in single chromaffin cells of control and CCl4 -induced cirrhotic rats. The spontaneous action potential firing frequency was increased in chromaffin cells of cirrhotic rats with respect to control rats. The exocytosis evoked by that firing was also increased. However, exocytosis elicited by ACh did not vary between control and cirrhotic rats. Exocytosis triggered by depolarizing pulses was also unchanged. Amperometric recordings confirmed the lack of increased catecholamine charge released in cirrhosis after ACh or depolarization stimuli. However, the amperometric spikes exhibited faster kinetics of release. The overall Ca2+ entry through voltage-dependent Ca2+ channels (VDCC), or in particular through Cav1 channels, did not vary between chromaffin cells of control and cirrhotic rats. The inhibition of VDCC by methionine-enkephaline or ATP was not either altered, but it was increased by adrenaline in cells of cirrhotic rats. When a cocktail composed by the three neurotransmitters was tested in order to approach a situation closer to the physiological condition, the inhibition of VDCC was similar between both types of cells. In summary, chromaffin cells of the adrenal gland might contribute to exacerbate the sympathetic nervous system over-activity in cirrhosis because of an increased exocytosis elicited by an enhanced spontaneous electrical activity.

[Correlation between pneumoperitoneum and surgical findings and morbidity and mortality in newborns with necrotising enterocolitis]. / Correlación entre el neumoperitoneo y los hallazgos quirúrgicos y morbimortalidad en recién nacidos con enterocolitis necrosante.

INTRODUCTION: Surgical intervention in necrotising enterocolitis (NEC) is correct when there is intestinal gangrene. This is evident when gangrene produces perforation and pneumoperitoneum, with this being the only universally accepted radiological indication for the surgical intervention of NEC. OBJECTIVE: To perform an analysis on patients with surgically managed NEC, including determining how the decision to intervene is reached, the outcomes, and if patients with perforation had a pneumoperitoneum. METHODS: Retrospective review of neonates with surgical NEC over a period of 10years (2006-2015). An analysis was made of pre-surgical x-ray findings, which were compared with surgical ones, in addition to the morbidity and mortality, depending on the presence (N+) or absence (N-) of pneumoperitoneum. An evaluation was also made of the interobserver concordance with a paediatric radiologist blinded to the clinical reason using the kappa agreement index. RESULTS: A total of 53 neonates were included in the study. Surgical treatment was indicated after observing pneumoperitoneum in 36%. In the remaining neonates, the surgical decision was made after noting a clinical and metabolic deterioration with classical x-ray findings. Intestinal perforation was observed in 39% of the N- neonates. There were no statistical differences between either group on analysing the excised intestinal length, days of intubation, starting of enteral nutrition, and the mortality rate. Comparisons in terms of duration of symptoms and total hospital stay were statistically significant (7 vs. 2 days, P=.008; 127 vs. 79 days, P=.003, respectively), with both being more favourable in the N+ group. These differences remained when the groups were adjusted by birthweight. CONCLUSIONS: Surgical indication has to be done on an ensemble of clinical and radiological evidence, as 39% of the neonates in the N- groups were perforated. In our study, the presence of a pneumoperitoneum did not correlate with a worse prognosis.

Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.

BACKGROUND & AIMS: In advanced cirrhosis, gut bacterial translocation is the consequence of intestinal barrier disruption and leads to bacterial infection. Bile acid abnormalities in cirrhosis could play a role in the integrity of the intestinal barrier and the control of microbiota, mainly through the farnesoid X receptor. We investigated the long-term effects of the farnesoid X receptor agonist, obeticholic acid, on gut bacterial translocation, intestinal microbiota composition, barrier integrity and inflammation in rats with CCl4-induced cirrhosis with ascites. METHODS: Cirrhotic rats received a 2-week course of obeticholic acid or vehicle starting once ascites developed. We then determined: bacterial translocation by mesenteric lymph node culture, ileum expression of antimicrobial peptides and tight junction proteins by qPCR, fecal albumin loss, enteric bacterial load and microbiota composition by qPCR and pyrosequencing of ileum mucosa-attached contents, and intestinal inflammation by cytometry of the inflammatory infiltrate. RESULTS: Obeticholic acid reduced bacterial translocation from 78.3% to 33.3% (p<0.01) and upregulated the expression of the farnesoid X receptor-associated gene small heterodimer partner. Treatment improved ileum expression of antimicrobial peptides, angiogenin-1 and alpha-5-defensin, tight junction proteins zonulin-1 and occludin, and reduced fecal albumin loss and liver fibrosis. Enteric bacterial load normalized, and the distinctive mucosal microbiota of cirrhosis was reduced. Gut immune cell infiltration was reduced and inflammatory cytokine and Toll-like receptor 4 expression normalized. CONCLUSIONS: In ascitic cirrhotic rats, obeticholic acid reduces gut bacterial translocation via several complementary mechanisms at the intestinal level. This agent could be used as an alternative to antibiotics to prevent bacterial infection in cirrhosis.

Defective thymopoiesis and poor peripheral homeostatic replenishment of T-helper cells cause T-cell lymphopenia in cirrhosis.

BACKGROUND & AIMS: Depletion of circulating CD4(+) T-helper (Th) lymphocytes, especially naive Th cells, is common in cirrhosis. Little is known about the pathogenetic mechanisms involved in Th-cell depletion in cirrhosis. We investigated the mechanisms involved in circulating Th-cell lymphopenia in cirrhosis. METHODS: Circulating naive and memory Th cells were analyzed by flow cytometry in 60 patients with cirrhosis and 40 sex- and age-matched healthy controls. Thymopoiesis, apoptosis, cell activation, and proliferation were assessed through CD31, annexin-V, HLA-DR and Ki-67 expression, respectively. Lipopolysaccharide (LPS)-binding protein (LBP) and spleen size were measured as indicators of bacterial translocation and splenic pooling, respectively. RESULTS: Compared to controls, patients showed reduced numbers of Th cells involving a greater depletion of the naive than memory Th-cell compartment (2.7- vs. 1.5-fold, respectively). Recent thymic emigrants were diminished (p < 0.01), and each patient had a lower number of CD31(+) naive Th cells than the matched-control. Spontaneous and induced apoptosis (Annexin-V(+)) of Th cells was increased in patients. Activated (HLA-DR(+)) and proliferating (Ki-67(+)) memory Th cells were increased in patients (p < 0.01), and they directly correlated with plasma LBP (p < 0.05) and negatively with naive Th cells (p < 0.01), respectively. Naive Th cells were inversely correlated (p < 0.01) with their frequencies of apoptosis and of activated memory Th cells, LBP, and spleen size. On multivariate analysis, defective thymic generation of naive Th cells, increased memory Th-cell activation, and splenomegaly were independently associated with Th-cell depletion. CONCLUSIONS: Th-cell immunodeficiency in cirrhosis is explained by a universal defect in thymopoiesis exacerbated by splenic pooling and activation-driven cell-death induced by bacterial translocation.

Interaction between intestinal dendritic cells and bacteria translocated from the gut in rats with cirrhosis.

UNLABELLED: Cirrhosis with ascites is associated with a high rate of gut bacterial translocation (GBT) and spontaneous bacterial infections of enteric origin. We addressed the activation state and role of intestinal dendritic cells (DCs) in experimental ascitic cirrhosis and their relationship with GBT. Cirrhosis with ascites was CCl(4) induced in rats. To examine their activation state and functions, DCs (CD103(+) RT1B(+) CD3(-) CD45RA(-) ) were isolated from the intestinal lamina propria and mesenteric lymph nodes (MLNs), and the following parameters were determined by flow cytometry: surface antigen expression; spontaneous or lipopolysaccharide-stimulated tumor necrosis factor alpha (TNF-α) production; and in vitro capacity to phagocytose latex beads and to migrate toward the chemokine (C-C motif) ligand 21. GBT was defined as the growth of bacteria in MLNs culture. Bacterial DNA (Bact-DNA) in MLNs was identified by polymerase chain reaction. In rats with Bact-DNA in MLNs without GBT, intestinal and MLNs CD103(+) -DCs showed features of activation, expansion of the proinflammatory CD4(+) -DC subpopulation, augmented TNF-α production, and increased phagocytic and migratory capacities. In contrast, in rats with GBT, CD103(+) -DCs showed the absence of an activated phenotype, lowered TNF-α production, and relatively deficient phagocytosis and migration capacities. The CD103(+) -DC of rats without Bact-DNA in MLNs or GBT were similar to controls. In cirrhotic rats, bowel decontamination with antibiotics eliminated Bact-DNA in MLNs and GBT, normalized the activation state and functions of CD103(+) -DCs, and increased their TNF-α production. CONCLUSION: In experimental cirrhosis with ascites, continuous pressure of gut bacteria shapes the phenotypic and functional profile of intestinal DCs to produce effects that range from their activation and enhanced functions to their exhaustion and tolerance.

Loss of surface antigens is a conserved feature of apoptotic lymphocytes from several mammalian species.

Human lymphocytes lose the expression of lineage antigens (LAgs) along apoptosis. Our aim was to extent our previous studies of LAg loss to rodent species, quantifying LAg expression on apoptotic murine lymphocytes using flow cytometry to measure alterations in cell permeability, phosphatidylserine exposure and caspase activation of CD3, CD5, CD4, CD8, CD19 and CD28 LAgs in highly purified lymphocyte populations. We found loss of expression by apoptotic cells of all LAgs studied in the three species analyzed except for CD3 antigen in mouse. We also found an early, rapid and dramatic reduction in the expression of CD28 by early apoptotic cells. We found several homologies across the three species in the kinetic of loss of several LAgs such as CD5, CD4 and CD28. These data suggest that the loss of expression of LAgs by apoptotic lymphocytes is a common and conserved feature of lymphocytes undergoing apoptosis in several mammalian species.

Critical role of the liver in the induction of systemic inflammation in rats with preascitic cirrhosis.

UNLABELLED: Systemic activation of the inflammatory immune system contributes to the progression of cirrhosis with ascites. Immune cells become activated after interacting at the mesenteric lymph nodes (MLNs) with bacteria translocated from the gut, and thereafter reach the bloodstream through recirculation. It is unknown whether systemic activation of the immune system is present in pre-ascitic cirrhosis, in which gut bacterial translocation has not been described. The purpose of this study was to determine whether systemic activation of the immune system initiates in rats with compensated carbon tetrachloride (CCl(4))-induced cirrhosis, and if so to establish the activation site of immune cells. We studied the activation status of immune cells in peripheral blood, MLNs, and hepatic lymph nodes (HLNs). Systemic inflammation was present in rats with cirrhosis, as shown by expansion (P < 0.01) of circulating total and inflammatory monocytes and recently activated CD134(+) T helper (T(h)) cells. The same populations of cells were increased (P < 0.01) in MLNs and HLNs. Bacterial translocation was absent in rats with cirrhosis or control rats, but bacterial DNA fragments were present in the MLNs of 54% of rats with cirrhosis. The liver was the source of activated immune cells present in the blood, as shown by the direct correlation between activated T(h) cells in the blood and HLNs, but not in MLNs, and the normalization by gut decontamination with antibiotics of activated cells in MLNs, but not in the blood or HLNs. CONCLUSION: In experimental cirrhosis, systemic activation of the immune system occurs before ascites development and is driven by recirculation of cells activated in HLNs. In addition, in compensated cirrhosis, bacterial DNA fragments reach the MLNs, where they elicit a local inflammatory response.

The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis.

BACKGROUND: An inflammatory immune system response ensues in the liver and in the systemic circulation in cirrhosis, where it contributes to hepatic fibrosis and peripheral vasodilation. Modulation of the inflammatory response without increasing susceptibility to infection is a therapeutic target in cirrhosis. AM3 is a low-toxicity biological response modifier with regulatory effects on innate and adaptative immunity, and the ability to normalise the production of tumour necrosis factor alpha (TNFalpha). AIMS: This was an experimental study to investigate the effects of oral AM3 on the systemic and hepatic inflammatory response, liver fibrosis and on the haemodynamic abnormalities of portal hypertension in rats with biliary cirrhosis. DESIGN: Bile-duct ligated rats received a 3-week oral course of AM3 or placebo. RESULTS: In cirrhotic rats, AM3 blunted the inflammatory switch of circulating and intrahepatic monocytes and T-cells to TNFalpha and interferon gamma (IFNgamma) production, respectively. AM3 modified the intrahepatic polarisation pattern of the regulatory cytokines, decreasing the mRNA expression of transforming growth factor beta1 (TGFbeta1), interleukin 4 (IL4), and IFNgamma, and increasing that of IL10. Total and IFNgamma-producing natural killer (NK) cells were lowered by AM3 in the peripheral blood and liver of cirrhotic rats. The immunomodulatory effects of AM3 led to reduced hepatic fibrogenesis in cirrhotic rats, as shown by decreased area of liver fibrosis, hydroxyproline content and mRNA expression of procollagen alpha1(I). Besides, AM3 lowered portal pressure and systemic hyperaemia. CONCLUSIONS: The biological response modifier AM3 reverses the concurrent inflammatory immune system activation in peripheral blood and liver of experimental established cirrhosis, which results in reductions of hepatic fibrosis, portal pressure and peripheral vasodilation.