Trim21 deficiency in mice increases HCC carcinogenesis in a NASH context and is associated with immune checkpoint upregulation.

The global pandemic of metabolic diseases has increased the incidence of hepatocellular carcinoma (HCC) in the context of non-alcoholic steatohepatitis (NASH). The downregulation of the E3 ubiquitin ligase TRIM21 has been linked to poor prognosis in different cancers including HCC. In order to investigate the role of TRIM21 in liver cancer progression on NASH, Trim21+/+ and Trim21-/- male mice were injected with streptozotocin at the neonatal stage. The hypoinsulinemic mice were then fed with a high-fat high-cholesterol diet (HFHCD) for 4, 8 or 12 weeks. All mice developed NASH which systematically resulted in HCC progression. Interestingly, compared to the Trim21+/+ control mice, liver damage was worsened in Trim21-/- mice, with more HCC nodules found after 12 weeks on HFHCD. Immune population analysis in the spleen and liver revealed a higher proportion of CD4+PD-1+ and CD8+PD-1+ T cells in Trim21-/- mice. The liver and HCC tumors of Trim21-/- mice also exhibited an increase in the number of PD-L1+ and CD68+ PD-L1+ cells. Thus, TRIM21 limits the emergence of HCC nodules in mice with NASH by potentially restricting the expression of PD-1 in lymphocytes and PD-L1 in tumors.

Endogenous IL-33 Accelerates Metacestode Growth during Late-Stage Alveolar Echinococcosis.

During the course of the infectious disease alveolar echinococcosis (AE), the larval stage of Echinococcus multilocularis develops in the liver, where an initial Th1/Th17 immune response may allow its elimination in resistant individuals. In patients susceptible to infection and disease, the Th2 response initiates later, inducing tolerance to the parasite. The role of interleukin 33 (IL-33), an alarmin released during necrosis and known to drive a Th2 immune response, has not yet been described during AE. Wild-type (WT) and IL-33-/- C57BL/6J mice were infected by peritoneal inoculation with E. multilocularis metacestodes and euthanized 4 months later, and their immune response were analyzed. Immunofluorescence staining and IL-33 enzyme-linked immunosorbent assay (ELISA) were also performed on liver samples from human patients with AE. Overall, metacestode lesions were smaller in IL-33-/- mice than in WT mice. IL-33 was detected in periparasitic tissues, but not in mouse or human serum. In infected mice, endogenous IL-33 modified peritoneal macrophage polarization and cytokine profiles. Th2 cytokine concentrations were positively correlated with parasite mass in WT mice, but not in IL-33-/- mice. In human AE patients, IL-33 concentrations were higher in parasitic tissues than in distant liver parenchyma. The main sources of IL-33 were CD31+ endothelial cells of the neovasculature, present within lymphoid periparasitic infiltrates together with FOXP3+ Tregs. In the murine model, periparasitic IL-33 correlated with accelerated parasite growth putatively through the polarization of M2-like macrophages and release of immunosuppressive cytokines IL-10 and transforming growth factor ß1 (TGF-ß1). We concluded that IL-33 is a key alarmin in AE that contributes to the tolerogenic effect of systemic Th2 cytokines. IMPORTANCE Infection with the metacestode stage of Echinococcus multilocularis, known as alveolar echinococcosis, is the most severe cestodosis worldwide. However, less than 1% of exposed individuals, in which the immune system is unable to control the parasite, develop the disease. The factors responsible for this interindividual variability are not fully understood. In this in vivo study comparing wild-type and IL-33-/- infected mice, together with data from human clinical samples, we determined that IL-33, an alarmin released following tissue injury and involved in the pathogenesis of cancer and asthma, accelerates the progression of the disease by modulating the periparasitic microenvironment. This suggests that targeting IL-33 could be of interest for the management of patients with AE, and that IL-33 polymorphisms could be responsible for increased susceptibility to AE.

Deciphering the Role of PIG1 and DHN-Melanin in Scedosporium apiospermum Conidia.

Scedosporium apiospermum is a saprophytic filamentous fungus involved in human infections, of which the virulence factors that contribute to pathogenesis are still poorly characterized. In particular, little is known about the specific role of dihydroxynaphtalene (DHN)-melanin, located on the external layer of the conidia cell wall. We previously identified a transcription factor, PIG1, which may be involved in DHN-melanin biosynthesis. To elucidate the role of PIG1 and DHN-melanin in S. apiospermum, a CRISPR-Cas9-mediated PIG1 deletion was carried out from two parental strains to evaluate its impact on melanin biosynthesis, conidia cell-wall assembly, and resistance to stress, including the ability to survive macrophage engulfment. ΔPIG1 mutants did not produce melanin and showed a disorganized and thinner cell wall, resulting in a lower survival rate when exposed to oxidizing conditions, or high temperature. The absence of melanin increased the exposure of antigenic patterns on the conidia surface. PIG1 regulates the melanization of S. apiospermum conidia, and is involved in the survival to environmental injuries and to the host immune response, that might participate in virulence. Moreover, a transcriptomic analysis was performed to explain the observed aberrant septate conidia morphology and found differentially expressed genes, underlining the pleiotropic function of PIG1.

Alveolar echinococcosis in immunocompromised hosts.

BACKGROUND: Alveolar echinococcosis (AE) results of an infection with the larval stage of Echinococcus multilocularis. It has been increasingly described in individuals with impaired immune responsiveness. OBJECTIVES: This narrative review aims at describing the presentation of AE according to the type of immune impairment, based on retrospective cohorts and case reports. Implications for patient management and future research are proposed accordingly. SOURCES: Targeted search was conducted in PubMed using ((alveolar echinococcosis) OR (multilocularis)) AND ((immunosuppressive) OR (immunodeficiency) OR (AIDS) OR (solid organ transplant) OR (autoimmunity) OR (immune deficiency)). Only publications in English were considered. CONTENT: Seventeen publications were found, including 13 reports of 55 AE in immunocompromised patients (AE/IS) and 4 retrospective studies of 755 AE immunocompetent patients and 115 AE/IS (13%). The cohorts included 9 (1%) solid organ transplantation (SOT) recipients, 2 (0.2%) HIV patients, 41 (4.7%) with chronic inflammatory/autoimmune diseases (I/AID) and 72 (8.3%) with malignancies. SOT, I/AID and malignancies, but not HIV infection, were significantly associated with AE (odds ratios of 10.8, 1.6, 5.9, and 1.3, respectively). Compared to AE immunocompetent patients, AE/IS was associated with earlier diagnosis (PNM stages I-II: 49/85 (58%) vs. 137/348 (39%), p < 0.001), high rate of atypical imaging (24/50 (48%) vs. 106/375 (28%), p < 0.01), and low sensitivity of serology (19/77 (25%) vs. 265/329 (81%), p < 0.001). Unusually extensive or disseminated infections were described in SOT and I/AID patients. IMPLICATIONS: Patients who live in endemic areas should benefit from serology before onset of a long-term immunosuppressive therapy, even if the cost-benefit ratio has to be evaluated. Physicians should explain AE to immunocompromised patients and think about AE when finding a liver lesion. Further research should address gaps in knowledge of AE/IS. Especially, extensive and accurate records of AE cases have to be collected by multinational registries.

Bacteroides fragilis derived metabolites, identified by molecular networking, decrease Salmonella virulence in mice model.

In the gut microbiota, resident bacteria prevent pathogens infection by producing specific metabolites. Among bacteria belonging to phylum Bacteroidota, we have previously shown that Bacteroides fragilis or its cell-free supernatant inhibited in vitro Salmonella Heidelberg translocation. In the present study, we have analyzed this supernatant to identify bioactive molecules after extraction and subsequent fractionation using a semi-preparative reversed-phase Liquid Chromatography High-Resolution Tandem Mass Spectrometry (LC-HRMS/MS). The results indicated that only two fractions (F3 and F4) strongly inhibited S. Heidelberg translocation in a model mimicking the intestinal epithelium. The efficiency of the bioactive fractions was evaluated in BALB/c mice, and the results showed a decrease of S. Heidelberg in Peyer's patches and spleen, associated with a decrease in inflammatory cytokines and neutrophils infiltration. The reduction of the genus Alistipes in mice receiving the fractions could be related to the anti-inflammatory effects of bioactive fractions. Furthermore, these bioactive fractions did not alter the gut microbiota diversity in mice. To further characterize the compounds present in these bioactive fractions, Liquid Chromatography High-Resolution Tandem Mass Spectrometry (LC-HRMS/MS) data were analyzed through molecular networking, highlighting cholic acid (CA) and deoxycholic acid. In vitro, CA had inhibitory activity against the translocation of S. Heidelberg by significantly decreasing the expression of Salmonella virulence genes such as sipA. The bioactive fractions also significantly downregulated the flagellar gene fliC, suggesting the involvement of other active molecules. This study showed the interest to characterize better the metabolites produced by B. fragilis to make them means of fighting pathogenic bacteria by targeting their virulence factor without modifying the gut microbiota.

Receptor-interacting protein kinase-1 ablation in liver parenchymal cells promotes liver fibrosis in murine NASH without affecting other symptoms.

Non-alcoholic steatohepatitis (NASH), a chronic liver disease that emerged in industrialized countries, can further progress into liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the next decade, NASH is predicted to become the leading cause of liver transplantation, the only current interventional therapeutic option. Hepatocyte death, triggered by different death ligands, plays key role in its progression. Previously, we showed that the receptor-interacting protein kinase-1 (RIPK1) in hepatocytes exhibits a protective role in ligand-induced death. Now, to decipher the role of RIPK1 in NASH, Ripk1LPC-KO mice, deficient for RIPK1 only in liver parenchymal cells, and their wild-type littermates (Ripk1fl/fl) were fed for 3, 5, or 12 weeks with high-fat high-cholesterol diet (HFHCD). The main clinical signs of NASH were analyzed to compare the pathophysiological state established in mice. Most of the symptoms evolved similarly whatever the genotype, whether it was the increase in liver to body weight ratio, the steatosis grade or the worsening of liver damage revealed by serum transaminase levels. In parallel, inflammation markers followed the same kinetics with significant equivalent inductions of cytokines (hepatic mRNA levels and blood cytokine concentrations) and a main peak of hepatic infiltration of immune cells at 3 weeks of HFHCD. Despite this identical inflammatory response, more hepatic fibrosis was significantly evidenced at week 12 in Ripk1LPC-KO mice. This coincided with over-induced rates of transcripts of genes implied in fibrosis development (Tgfb1, Tgfbi, Timp1, and Timp2) in Ripk1LPC-KO animals. In conclusion, our results show that RIPK1 in hepatocyte limits the progression of liver fibrosis during NASH.

IL-33/ST2 axis is involved in disease progression in the spleen during Leishmania donovani infection.

BACKGROUND: During infection with Leishmania donovani, parasite control is linked to the systemic Th1 immune response, but in infected organs (liver, spleen and bone marrow), the response differs according to the micro-environment. The pleiomorphic cytokine interleukin-33 (IL-33) exerts various roles during infection, either protective or detrimental. In this study, we explored the role of IL-33 in the outcome of Leishmania infection in the spleen. METHODS: We used several mouse models, on BALB/c and C57BL/6 (B6) backgrounds, infected with L. donovani and sacrificed at 15, 30 or 60 days after infection and characterized mRNA expression of immune markers, immune cell populations, histological response, and parasite loads. RESULTS: During infection IL-33 and ST2 mRNA increased in parallel in the spleen of wild type (wt) animals and paralleled the immunodetection of ST2+ and IL-33+ cells; their expression was twice as high in BALB/c, compared to B6 mice. Mice treated with twice-weekly injections of rIL-33 had higher splenic parasite burdens on D15 (BALB/c) or on D60 (B6). In BALB/c, IL-33 treatment led to immune exhaustion with abolition of Th1 cytokine expression (IFN-γ and IL-12) in the spleen and higher serum levels of Th2 cytokines (IL-4, IL-5 and IL-13). In B6, IL-33 treatment induced the Treg cell pathway with a dramatic increase of FoxP3 mRNA induction and expression on tissue sections. IL-33-KO mice had lower parasite loads and a higher Th1 response than their wt counterparts. CONCLUSIONS: IL-33 appears as a factor of aggravation of the disease in the spleen tissue of mice infected with L. donovani.

Hepatocellular Carcinoma Emergence in Diabetic Mice with Non-Alcoholic Steatohepatitis Depends on Diet and Is Delayed in Liver Exhibiting an Active Immune Response.

The increase of the sedentary lifestyle and high-calorie diet have modified the etiological landscape of hepatocellular carcinoma (HCC), with a recrudescence of non-alcoholic fatty liver disease (NAFLD), especially in Western countries. The purpose of our study was to evaluate the impact of high-fat diet feeding on non-alcoholic steatohepatitis (NASH) establishment and HCC development. Streptozotocin-induced diabetic male mice were fed with high-fat-high-cholesterol diet (HFHCD) or high-fat-high-sugar diet (HFHSD) from 1 to 16 weeks. Even if liver tumors appear regardless of the high-fat diet, two distinct physiopathological patterns were evidenced, with much more severe NASH hallmarks (liver injury, inflammation and fibrosis) in diabetic mice fed with HFHCD. The mild hepatic injury, weak inflammation and fibrosis observed in HFHSD were interestingly associated with earlier emergence of more numerous liver tumors. When activated helper and cytotoxic T cells, detected by flow cytometry, infiltrated the liver of HFHCD-fed diabetic mice, a delay in the appearance of tumor nodules and a limitation of their numbers were observed, suggesting that the immune activities partly controlled tumor emergence. These data highlighted two different mouse models of HCC progression in diabetic mice depending on diet, which could be useful to evaluate new therapeutic approaches for HCC by targeting the immune response.

Developing a rigorous, systematic methodology to identify and categorize elder mistreatment in criminal justice data.

Elder mistreatment is complex, with cases typically requiring integrated responses from social services, medicine, civil law, and criminal justice. Only limited research exists describing elder mistreatment prosecution and its impact. Researchers have not yet examined administrative prosecutorial data to explore mistreatment response, and no standardized analytic approach exists. We developed a rigorous, systematic methodologic approach to identify elder mistreatment cases in prosecutorial data from cases of crimes against victims aged ≥60. To do so, we operationalized elements of the accepted definition of elder mistreatment, including expectation of trust and vulnerability. We also designed an approach to categorize elder mistreatment cases, using the types of charges filed, into: financial exploitation, physical abuse, sexual abuse, verbal/emotional/psychological abuse, and neglect. This standardized methodological approach to identify and categorize elder mistreatment cases in prosecution data is an important preliminary step in analyzing this potentially untapped source of useful information about mistreatment response.

In vitro and in vivo immunomodulatory properties of octyl-ß-D-galactofuranoside during Leishmania donovani infection.

BACKGROUND: The chemotherapeutic arsenal available to treat visceral leishmaniasis is currently limited, in view of many drawbacks such as high cost, toxicity or emerging resistance. New therapeutic strategies are particularly needed to improve the management and the outcome in immunosuppressed patients. The combination of an immunomodulatory drug to a conventional anti-Leishmania treatment is an emerging concept to reverse the immune bias from Th2 to Th1 response to boost healing and prevent relapses. METHODS: Here, immunostimulating and leishmanicidal properties of octyl-ß-D-galactofuranose (Galf) were assessed in human monocyte-derived macrophages (HM) and in a murine model, after challenge with Leishmania donovani promastigotes. We recorded parasite loads and expression of various cytokines and immune effectors in HM and mouse organs (liver, spleen, bone marrow), following treatment with free (Galf) and liposomal (L-Galf) formulations. RESULTS: Both treatments significantly reduced parasite proliferation in HM, as well as liver parasite burden in vivo (Galf, P < 0.05). Consistent with in vitro results, we showed that Galf- and L-Galf-treated mice displayed an enhanced Th1 immune response, particularly in the spleen where pro-inflammatory cytokines TNF-α, IL-1ß and IL-12 were significantly overexpressed compared to control group. The hepatic recruitment of myeloid cells was also favored by L-Galf treatment as evidenced by the five-fold increase of myeloperoxidase (MPO) induction, which was associated with a higher number of MPO-positive cells within granulomas. By contrast, the systemic level of various cytokines such as IL-1ß, IL-6, IL-17A or IL-27 was drastically reduced at the end of treatment. CONCLUSIONS: Overall, these results suggest that Galf could be tested as an adjuvant in combination with current anti-parasitic drugs, to restore an efficient immune response against infection in a model of immunosuppressed mice.

Review of Programs to Combat Elder Mistreatment: Focus on Hospitals and Level of Resources Needed.

BACKGROUND: Elder mistreatment is common and has serious social and medical consequences for victims. Though programs to combat this mistreatment have been developed and implemented for more than three decades, previous systematic literature reviews have found few successful ones. OBJECTIVE: To conduct a more comprehensive examination of programs to improve elder mistreatment identification, intervention, or prevention, including those that had not undergone evaluation. DESIGN: Systematic review. SETTING: Ovid MEDLINE, Ovid EMBASE, Cochrane Library, PsycINFO Elton B. Stephens Co. (EBSCO), AgeLine, CINAHL. MEASUREMENTS: We abstracted key information about each program and categorized programs into 14 types and 9 subtypes. For programs that reported an impact evaluation, we systematically assessed the study quality. We also systematically examined the potential for programs to be successfully implemented in environments with limited resources available. RESULTS: We found 116 articles describing 115 elder mistreatment programs. Of these articles, 43% focused on improving prevention, 50% focused on identification, and 95% focused on intervention, with 66% having multiple foci. The most common types of program were: educational (53%), multidisciplinary team (MDT) (21%), psychoeducation/therapy/counseling (15%), and legal services/support (8%). Of the programs, 13% integrated an acute-care hospital, 43% had high potential to work in low-resource environments, and 57% reported an attempt to evaluate program impact, but only 2% used a high-quality study design. CONCLUSION: Many programs to combat elder mistreatment have been developed and implemented, with the majority focusing on education and MDT development. Though more than half reported evaluation of program impact, few used high-quality study design. Many have the potential to work in low-resource environments. Acute-care hospitals were infrequently integrated into programs.

Depletion of RIPK1 in hepatocytes exacerbates liver damage in fulminant viral hepatitis.

The protein kinase RIPK1 plays a crucial role at the crossroad of stress-induced signaling pathways that affects cell's decision to live or die. The present study aimed to define the role of RIPK1 in hepatocytes during fulminant viral hepatitis, a worldwide syndrome mainly observed in hepatitis B virus (HBV) infected patients. Mice deficient for RIPK1, specifically in liver parenchymal cells (Ripk1LPC-KO) and their wild-type littermates (Ripk1fl/fl), were challenged by either the murine hepatitis virus type 3 (MHV3) or poly I:C, a synthetic analog of double-stranded RNA mimicking viral pathogen-associated molecular pattern. Ripk1LPC-KO mice developed more severe symptoms at early stage of the MHV3-induced fulminant hepatitis. Similarly, administration of poly I:C only triggered increase of systemic transaminases in Ripk1LPC-KO mice, reflecting liver damage through induced apoptosis as illustrated by cleaved-caspase 3 labeling of liver tissue sections. Neutralization of TNF-α or prior depletion of macrophages were able to prevent the appearance of apoptosis of hepatocytes in poly I:C-challenged Ripk1LPC-KO mice. Moreover, poly I:C never induced direct hepatocyte death in primary culture whatever the murine genotype, while it always stimulated an anti-viral response. Our investigations demonstrated that RIPK1 protects hepatocytes from TNF-α secreted from macrophages during viral induced fulminant hepatitis. These data emphasize the potential worsening risks of an HBV infection in people with polymorphism or homozygous amorphic mutations already described for the RIPK1 gene.

The liver as an organ at risk for Toxoplasma transmission during transplantation: myth or reality?

AIM: Toxoplasmosis following liver transplant with donor-recipient mismatch is rare, but is often life-threatening. However, there are no data on the frequency of cyst carriage in the liver, nor consensual chemoprophylaxis guidelines. This study aimed at describing frequency and localisation of Toxoplasma cysts in the liver in a mouse model of chronic infection to predict the risk in liver transplantation. METHODS: Heart, brain and liver lobes of 21 mice chronically infected with Toxoplasma were collected for DNA extraction and amplification of Toxoplasma gondii rep529 sequence by real-time PCR. RESULTS: Parasite DNA was detected in the liver of 19/21 mice (90.5%), with no preferential anatomical localisation, but with higher parasite loads in the papillary process. Parasite loads in the liver were far lower than in brain and heart. The number of infected lobes was inversely correlated to the total liver weight, but was independent of the brain parasite load and of the parasite strain. CONCLUSIONS: The liver is a frequent site of cyst carriage, confirming that transplantation of an organ from a seropositive donor to seronegative recipient is at high risk for acquired toxoplasmosis. Systematic serological screening prior to transplantation and chemoprophylaxis in patients at risk are fully justified.

Criteria to Screen for Traumatic Cervical Spine Instability: A Consensus of Chiropractic Radiologists.

OBJECTIVE: The purpose of this study was to establish consensus on a radiographic definition for cervical instability for routine use in chiropractic patients who sustain trauma to the cervical spine. METHOD: We conducted a modified Delphi study with a panel of chiropractic radiologists. Panelists were asked to rate potential screening criteria for traumatic cervical spine instability when assessing cervical spine radiographs. Items rated as important for inclusion by at least 60% of participants in round 1 were submitted for a second round of voting in round 2. Items rated for inclusion by at least 75% of the participants in round 2 were used to create the consensus-based list of screening criteria. Participants were asked to vote and reach agreement on the final screening criteria list in round 3. RESULTS: Twenty-nine chiropractic radiologists participated in round 1. After 3 rounds of survey, 85% of participants approved the final consensus-based list of criteria for traumatic cervical spine instability screening, including 6 clinical signs and symptoms and 5 radiographic criteria. Participants agreed that the presence of 1 or more of these clinical signs and symptoms and/or 1 or more of the 5 radiographic criteria on routine static radiographic studies suggests cervical instability. CONCLUSION: The consensus-based radiographic definition of traumatic cervical spine instability includes 6 clinical signs and symptoms and 5 radiographic criteria that doctors of chiropractic should apply to their patients who sustain trauma to the cervical spine.

PARP2 deficiency affects invariant-NKT-cell maturation and protects mice from concanavalin A-induced liver injury.

Excessive or persistent inflammation and hepatocyte death are the key triggers of liver diseases. The poly(ADP-ribose) polymerase (PARP) proteins induce cell death and inflammation. Chemical inhibition of PARP activity protects against liver injury during concanavalin A (ConA)-induced hepatitis. In this mice model, ConA activates immune cells, which promote inflammation and induce hepatocyte death, mediated by the activated invariant natural killer T (iNKT) lymphocyte population. We analyzed immune cell populations in the liver and several lymphoid organs, such as the spleen, thymus, and bone marrow in Parp2-deficient mice to better define the role of PARP proteins in liver immunity and inflammation at steady state and during ConA-induced hepatitis. We show that 1) the genetic inactivation of Parp2, but not Parp1, protected mice from ConA hepatitis without deregulating cytokine expression and leucocyte recruitment; 2) cellularity was lower in the thymus, but not in spleen, liver, or bone marrow of Parp2-/- mice; 3) spleen and liver iNKT lymphocytes, as well as thymic T and NKT lymphocytes were reduced in Parp2 knockout mice. In conclusion, our results suggest that the defect of T-lymphocyte maturation in Parp2 knockout mice leads to a systemic reduction of iNKT cells, reducing hepatocyte death during ConA-mediated liver damage, thus protecting the mice from hepatitis.NEW & NOTEWORTHY The genetic inactivation of Parp2, but not Parp1, protects mice from concanavalin A hepatitis. Immune cell populations are lower in the thymus, but not in the spleen, liver, or bone marrow of Parp2-deficient mice compared with wild-type mice. Spleen and liver invariant natural killer T (NKT) lymphocytes, as well as thymic T and NKT lymphocytes, are reduced in Parp2-deficient mice.

Endogenous IL-33 has no effect on the progression of fibrosis during experimental steatohepatitis.

Interleukin (IL)-33 has been recently reported to be strongly pro-fibrogenic in various models of liver disease. Our aim was to study the role of endogenous IL-33 in a diet-induced model of steatohepatitis. IL-33 deficient mice and wild type (WT) littermates received a high-fat diet (HFD), or a standard diet for 12 weeks. The HFD-induced steatohepatitis was associated with an upregulation of IL-33 transcripts and protein. An insulin tolerance test revealed lower systemic insulin sensitivity in IL-33-/-HFD mice than in WT-HFD mice. Nevertheless, IL-33 deficiency did not affect the severity of liver inflammation by histological and transcriptomic analyses, nor the quantity of liver fibrosis. Livers from HFD mice had more myeloid populations, markedly fewer NKT cells and higher proportion of ST2+ Treg cells and ST2+ type 2 innate lymphoid cells (ILC2), all unaffected by IL-33 deficiency. In conclusion, deficiency of endogenous IL-33 does not affect the evolution of experimental diet-induced steatohepatitis towards liver fibrosis.

RIPK1 protects hepatocytes from Kupffer cells-mediated TNF-induced apoptosis in mouse models of PAMP-induced hepatitis.

BACKGROUND & AIMS: The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of pathogen associated molecular patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the receptor interacting protein kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis. METHODS: Hepatitis was induced in mice by independent injections of two different bacterial PAMPs: lipopolysaccharide (LPS) and unmethylated CpG oligodeoxynucleotide (CpG-DNA) motifs. The role of RIPK1 was evaluated by using mice specifically lacking RIPK1 in liver parenchymal cells (Ripk1LPC-KO). Administration of liposome-encapsulated clodronate served to investigate the role of Kupffer cells in the establishment of the disease. Etanercept, a tumor necrosis factor (TNF)-decoy receptor, was used to study the contribution of TNF-α during LPS-mediated liver injury. RESULTS: Whereas RIPK1 deficiency in liver parenchymal cells did not trigger basal hepatolysis, it greatly sensitized hepatocytes to apoptosis and liver damage following a single injection of LPS or CpG-DNA. Importantly, hepatocyte death was prevented by previous macrophage depletion or by TNF inhibition. CONCLUSIONS: Our data highlight the pivotal function of RIPK1 in maintaining liver homeostasis in conditions of macrophage-induced TNF burst in response to PAMPs sensing. LAY SUMMARY: Excessive death of hepatocytes is a characteristic of liver injury. A new programmed cell death pathway has been described involving upstream death ligands such as TNF and downstream kinases such as RIPK1. Here, we show that in the presence of LPS liver induced hepatic injury was due to secretion of TNF by liver macrophages, and that RIPK1 acts as a powerful protector of hepatocyte death. This newly identified pathway in the liver may be helpful in the management of patients to predict their risk of developing acute liver failure.

Are Passive Physical Modalities Effective for the Management of Common Soft Tissue Injuries of the Elbow?: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

OBJECTIVE: To evaluate the effectiveness of passive physical modalities for the management of soft tissue injuries of the elbow. METHODS: We systematically searched MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane Central Register of Controlled Trials from 1990 to 2015. Studies meeting our selection criteria were eligible for critical appraisal. Random pairs of independent reviewers critically appraised eligible studies using the Scottish Intercollegiate Guidelines Network criteria. We included studies with a low risk of bias in our best evidence synthesis. RESULTS: We screened 6618 articles; 21 were eligible for critical appraisal and 9 (reporting on 8 randomized controlled trials) had a low risk of bias. All randomized controlled trials with a low risk of bias focused on lateral epicondylitis. We found that adding transcutaneous electrical nerve stimulation to primary care does not improve the outcome of patients with lateral epicondylitis. We found inconclusive evidence for the effectiveness of: (1) an elbow brace for managing lateral epicondylitis of variable duration; and (2) shockwave therapy or low-level laser therapy for persistent lateral epicondylitis. DISCUSSION: Our review suggests that transcutaneous electrical nerve stimulation provides no added benefit to patients with lateral epicondylitis. The effectiveness of an elbow brace, shockwave therapy, or low-level laser therapy for the treatment of lateral epicondylitis is inconclusive. We found little evidence to inform the use of passive physical modalities for the management of elbow soft tissue injuries.

The Effectiveness of Exercise on Recovery and Clinical Outcomes in Patients With Soft Tissue Injuries of the Hip, Thigh, or Knee: A Systematic Review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

OBJECTIVE: The purpose of this systematic review was to determine the effectiveness of exercise for the management of soft tissue injuries of the hip, thigh, and knee. METHODS: We conducted a systematic review and searched MEDLINE, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials, and CINAHL Plus with Full Text from January 1, 1990, to April 8, 2015, for randomized controlled trials (RCTs), cohort studies, and case-control studies evaluating the effect of exercise on pain intensity, self-rated recovery, functional recovery, health-related quality of life, psychological outcomes, and adverse events. Random pairs of independent reviewers screened titles and abstracts and assessed risk of bias using the Scottish Intercollegiate Guidelines Network criteria. Best evidence synthesis methodology was used. RESULTS: We screened 9494 citations. Eight RCTs were critically appraised, and 3 had low risk of bias and were included in our synthesis. One RCT found statistically significant improvements in pain and function favoring clinic-based progressive combined exercises over a "wait and see" approach for patellofemoral pain syndrome. A second RCT suggests that supervised closed kinetic chain exercises may lead to greater symptom improvement than open chain exercises for patellofemoral pain syndrome. One RCT suggests that clinic-based group exercises may be more effective than multimodal physiotherapy in male athletes with persistent groin pain. CONCLUSION: We found limited high-quality evidence to support the use of exercise for the management of soft tissue injuries of the lower extremity. The evidence suggests that clinic-based exercise programs may benefit patients with patellofemoral pain syndrome and persistent groin pain. Further high-quality research is needed.

The effectiveness of manual therapy for the management of musculoskeletal disorders of the upper and lower extremities: a systematic review by the Ontario Protocol for Traffic Injury Management (OPTIMa) Collaboration.

BACKGROUND: Musculoskeletal disorders (MSDs) of the upper and lower extremities are common in the general population and place a significant burden on the health care system. Manual therapy is recommended by clinical practice guidelines for the management of these injuries; however, there is limited evidence to support its effectiveness. The purpose of our review was to investigate the effectiveness of manual therapy in adults or children with MSDs of the upper or lower extremity. METHODS: Randomized controlled trials (RCTs), cohort studies, and case-control studies evaluating the effectiveness of manual therapy were eligible. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Central Register of Controlled Trials from 1990 to 2015. Paired reviewers screened studies for relevance and critically appraised relevant studies using the Scottish Intercollegiate Guidelines Network criteria. Studies with low risk of bias were synthesized following best-evidence synthesis principles. Where available, we computed mean changes between groups, relative risks and 95 % CI. RESULTS: We screened 6047 articles. Seven RCTs were critically appraised and three had low risk of bias. For adults with nonspecific shoulder pain of variable duration, cervicothoracic spinal manipulation and mobilization in addition to usual care may improve self-perceived recovery compared to usual care alone. For adults with subacromial impingement syndrome of variable duration, neck mobilization in addition to a multimodal shoulder program of care provides no added benefit. Finally, for adults with grade I-II ankle sprains of variable duration, lower extremity mobilization in addition to home exercise and advice provides greater short-term improvements in activities and function over home exercise and advice alone. No studies were included that evaluated the effectiveness of manual therapy in children or for the management of other extremity injuries in adults. CONCLUSIONS: The current evidence on the effectiveness of manual therapy for MSDs of the upper and lower extremities is limited. The available evidence supports the use of manual therapy for non-specific shoulder pain and ankle sprains, but not for subacromial impingement syndrome in adults. Future research is needed to determine the effectiveness of manual therapy and guide clinical practice. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42014009899.