Mediation as an alternative dispute resolution: world experience

The present paper is devoted to the application of mediation as an alternative dispute resolution procedure. It defines features of the legal regulation of mediation procedures in different countries and legal systems, such as United States, European Union, China, and Russian Federation. In addition, the main principles of mediation and their implementation in different legal systems are analyzed in this pape

Alcohol Abstinence Does Not Fully Reverse Abnormalities of Mucosal-Associated Invariant T Cells in the Blood of Patients With Alcoholic Hepatitis

OBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities

Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium

The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects’ demographics with their adherence to follow-up appointments were examined. Three hundred eight-seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two-thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two-thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6- and 12-month follow-up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis

IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection.

Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity

Water Microelement Composition Influence on the Efficiency of the Milk Powder Dissolution Process

Drinking water is important in food production. Its indicators have a direct impact on the quality and safety of finished products, the technological equipment efficiency, etc. In most food technologies, involving the use of milk powder, a priori use the process of its preliminary hydration, that is, dissolution or recovery. In this connection, there is a need to generalize the existing theoretical and practical foundations of this process and find ways to further improve them. Analysis of scientific and technical material in this area showed, that a number of scientists proposed various descriptions not only of individual stages, but also of the dissolution process as a whole, and its determining factors were identified, mathematical models were built, making it possible to determine critical areas depending on from the properties of the raw materials and the process, data were obtained on the parameters of the system during the dissolution of dry dairy products.In the article presents the sanitary and hygienic, physicochemical and organoleptic require-ments for drinking water by Russian legislation, international organizations and national standards of a number of countries.Presented a review of widely used and promising water treatment methods.Analyzed data, describing the effect of the microelement water composition on the efficiency of milk powder dissolving process. It is shown, that decrease of water total hardness and dry substances of mass fraction adjustment in the reconstituted milk have a positive effect on the dissolution process efficiency.Was noted the relevance of further researches on the directional formation of water trace ele-ment composition for increasing the efficiency of milk powder dissolving and to obtain re-constituted dairy systems, used in the production of various food products of predicted quality and safety.Drinking water is important in food production. Its indicators have a direct impact on the quality and safety of finished products, the technological equipment efficiency, etc. In most food technologies, involving the use of milk powder, a priori use the process of its preliminary hydration, that is, dissolution or recovery. In this connection, there is a need to generalize the existing theoretical and practical foundations of this process and find ways to further improve them. Analysis of scientific and technical material in this area showed, that a number of scientists proposed various descriptions not only of individual stages, but also of the dissolution process as a whole, and its determining factors were identified, mathematical models were built, making it possible to determine critical areas depending on from the properties of the raw materials and the process, data were obtained on the parameters of the system during the dissolution of dry dairy products.In the article presents the sanitary and hygienic, physicochemical and organoleptic require-ments for drinking water by Russian legislation, international organizations and national standards of a number of countries.Presented a review of widely used and promising water treatment methods.Analyzed data, describing the effect of the microelement water composition on the efficiency of milk powder dissolving process. It is shown, that decrease of water total hardness and dry substances of mass fraction adjustment in the reconstituted milk have a positive effect on the dissolution process efficiency.Was noted the relevance of further researches on the directional formation of water trace ele-ment composition for increasing the efficiency of milk powder dissolving and to obtain re-constituted dairy systems, used in the production of various food products of predicted quality and safety

Acute Alcoholic Hepatitis: Natural History and Predictors of Mortality Using a Multicenter Prospective Study

Objective: To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. Participants and Methods: We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. Results: Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; P<.001), and this association between regular coffee drinking and lower risk of AH persisted after controlling for relevant covariates (odds ratio=0.26; 95% CI, 0.15-0.46). Time-dependent receiver operating characteristic curve analysis revealed that Model for End-Stage Liver Disease; Maddrey Discriminant Function; age, serum bilirubin, international normalized ratio, and serum creatinine; and Child-Pugh scores all provided similar discrimination performance at 30 days (area under the curve=0.73-0.77). Conclusion: Alcoholic hepatitis remains highly fatal, with 1-year mortality of 25%. Regular coffee consumption was associated with lower risk of AH in heavy drinkers

In Mice, Tuberculosis Progression Is Associated with Intensive Inflammatory Response and the Accumulation of Gr-1dim Cells in the Lungs

Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear.To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression.In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation

The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis

Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate (n=18) or severe AH (n=19). These data were compared to heavy drinking controls (HDC) without obvious liver disease (n=19) and non-alcohol consuming controls (NAC, n=20). The data were related to endotoxin levels and markers of monocyte activation. Linear Discriminant Analysis (LDA) Effect Size (LEfSe) analysis, inferred metagenomics and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (p<0.01) and SAH (p<0.001) subjects. Compared to NAC, the relative abundance of phylum Bacteroidetes was significantly decreased in HDC, MAH, and SAH (p<0.001). In contrast, all alcohol consuming groups had enrichment with Fusobacteria; this was greatest for HDC and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (p=0.01). Compared to alcohol consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Also, both HDC and SAH showed activation of type III secretion system which has been linked to gram negative bacterial virulence. Metagenomics in SAH vs NAC predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram positive bacterial growth and biofilm production respectively. In conclusion, heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions

Negative Regulation of Schistosoma japonicum Egg-Induced Liver Fibrosis by Natural Killer Cells

The role of natural killer (NK) cells in infection-induced liver fibrosis remains obscure. In this study, we elucidated the effect of NK cells on Schistosoma japonicum (S. japonicum) egg-induced liver fibrosis. Liver fibrosis was induced by infecting C57BL/6 mice with 18–20 cercariae of S. japonicum. Anti-ASGM1 antibody was used to deplete NK cells. Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I∶C) was used to enhance the activation of NK cells. Results showed that NK cells were accumulated and activated after S. japonicum infection, as evidenced by the elevation of CD69 expression and IFN-γ production. Depletion of NK cells markedly enhanced S. japonicum egg-induced liver fibrosis. Administration of poly I∶C further activated NK cells to produce IFN-γ and attenuated S. japonicum egg-induced liver fibrosis. The observed protective effect of poly I∶C on liver fibrosis was diminished through depletion of NK cells. Disruption of IFN-γ gene enhanced liver fibrosis and partially abolished the suppression of liver fibrosis by poly I∶C. Moreover, expression of retinoic acid early inducible 1 (RAE 1), the NKG2D ligand, was detectable at high levels on activated hepatic stellate cells derived from S. japonicum-infected mice, which made them more susceptible to hepatic NK cell killing. In conclusion, our findings suggest that the activated NK cells in the liver after S. japonicum infection negatively regulate egg-induced liver fibrosis via producing IFN-γ, and killing activated stellate cells