Search

In this work we fit an epidemiological model SEIAQR (Susceptible - Exposed - Infectious - Asymptomatic - Quarantined - Removed) to the data of the first COVID-19 outbreak in Rio de Janeiro, Brazil. Particular emphasis is given to the unreported rate, that is, the proportion of infected individuals that is not detected by the health system. The evaluation of the parameters of the model is based on a combination of error-weighted least squares method and appropriate B-splines. The structural and practical identifiability is analyzed to support the feasibility and robustness of the parameters’ estimation. We use the bootstrap method to quantify the uncertainty of the estimates. For the outbreak of March-July 2020 in Rio de Janeiro, we estimate about 90% of unreported cases, with a 95% confidence interval (85%, 93%).

Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.

In contrast to the former notion of a sterile womb, sequencing techniques have proven a bacterial colonization of the uterus. However, timing of microbiota analysis regarding possible intra-cycle variations as well as specific alterations in patients with recurrent miscarriage (RM) or recurrent implantation failure (RIF) remain unknown. In total, n = 20 RM-, n = 20 RIF-patients and n = 10 healthy controls were included in this prospective study. In every subject, uterine flushing was performed during follicular, ovulatory and luteal phase. Bacterial DNA was isolated and 16S amplicon sequencing analysis of the V3-V4 region was carried out. Diversity measures were compared between samples from the disease groups and the control group separately for each timepoint of the menstrual cycle and over time. In the control group a significant decrease of species richness and evenness was shown around ovulation which remained at this lower level during the luteal phase (Shannon index), indicating a more uniform distribution of microbiota (p 0.05). This loss of diversity during the menstrual cycle was not apparent in RIF and RM patients. A higher similarity was seen in taxonomic distribution between RM and RIF patients compared to the control group. Longitudinal dynamics included increases in Firmicutes (controls and RM only) and a concomitant loss of Proteobacteria in controls that was not present in RIF and RM. We demonstrate longitudinal intra-cycle-dependent changes in the endometrial microbiota of healthy controls. An increased diversity in both patient groups could be the cause or consequence of a micro-environment that is more prone to pregnancy failures.

Background: In recent months numerous health care professional acquired COVID-19 at the workplace resulting in significant shortages in medical and nursing staff. We investigated how prior COVID-19 affects SARS-CoV-2 vaccination and how such knowledge could facilitate frugal vaccination strategies. Methods: In a cohort of 41 healthcare professionals with (n=14) and without (n=27) previous SARS-CoV-2 infection, we assessed the immune status before, during and after vaccination with BNT162b2. The humoral immune response was assessed by receptor binding domain ELISA and different SARS-CoV-2 neutralisation assays using wildtype and pseudo-typed viruses. T cell immunity against SARS-CoV-2 surface and nucleocapsid peptides were studied using interferon g release assays and intracellular flow cytometry. Vaccine-related side effects were captured. Findings: Prior COVID-19 resulted in improved vaccine responses both in the B and T cell compartment. In vaccine recipients with prior COVID-19, the first vaccine dose induced high antibody concentrations comparable to seronegative vaccine recipients after two injections. This translated into more efficient neutralisation of virus particles, even more pronounced than expected from the RBD ELISA results. Furthermore, T cell responses were stronger in convalescents and particularly strong against the SARS-CoV-2 nucleocapsid protein. Interpretation: Herein, we corroborate recent findings suggesting that in convalescents a single vaccine dose may be sufficient to boost adequate protection against SARS-CoV-2. New spike mutated virus variants render the highly conserved nucleocapsid protein – eliciting strong SARS-CoV-2 specific T cell immunity – an interesting additional vaccine target. Funding: Christian Doppler Research Association, Johannes Kepler University Linz Declaration of Interests: TRK and MF are employees of Baxter AG, Vienna, Austria, now part of the Takeda group of companies and have Takeda stock interest. All other authors declare no competing interests. Ethics Approval Statement: This study was approved by the ethics committee of the Johannes Kepler University Linz (EC-No. 1322/2020) and informed consent was obtained from all study subjects.

Ground motion record selection methodologies are commonly developed to ensure that the input excitation used in response history analyses embodies essential conditions such as spectral compatibility, hazard and intensity measure consistency, seismological and site-specific criteria, always performing in a computationally efficient manner. A methodology utilizing genetic algorithms is revisited here, expanded to select multi-component ground motions and satisfying the typically required selection objectives of earthquake engineering applications, while ensuring increased efficiency. Multi-objective optimization is performed, claimed to be superior in delivering robust results that account for spectral compatibility in first and second order statistics (mean and standard deviation) in a wide range of spectral values, as well as satisfying seismological and site-specific criteria. A unique contribution is the ability to include probability distribution targets in specific ordinates of the spectrum, on top of the mean and standard deviation, allowing for more refined ground motion sets that can be used to reduce the number of records required in response history analyses. Additionally, a novel benchmarking process to assess the efficiency of ground motion record methodologies is introduced here, in terms of providing sets that are globally-optimal solutions to the optimization problem. Through this benchmarking algorithm, the proposed methodology appears to be impeccable in extracting the best possible ground motion sets.

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of inflammation, ischemia, infection, and kidney damage. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased LCN2 synthesis. While LCN2 in the intestinal tract regulates the composition of the gut microbiota and shows anti-inflammatory activities, it also exhibits proinflammatory activities in other experimental settings. In animal models of metabolic inflammation, type 2 diabetes mellitus (T2DM), or nonalcoholic steatohepatitis (NASH), increased LCN2 expression favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines. A better understanding of this crucial marker of innate immunity might pave the way for targeting this pathway in future therapies.

In this article we propose a compartmental model for the dynamics of Coronavirus Disease 2019 (COVID-19). We take into account the presence of asymptomatic infections and the main policies that have been adopted so far to contain the epidemic: isolation (or social distancing) of a portion of the population, quarantine for confirmed cases and testing. We model isolation by separating the population in two groups: one composed by key-workers that keep working during the pandemic and have a usual contact rate, and a second group consisting of people that are enforced/recommended to stay at home. We refer to quarantine as strict isolation, and it is applied to confirmed infected cases.In the proposed model, the proportion of people in isolation, the level of contact reduction and the testing rate are control parameters that can vary in time, representing policies that evolve in different stages. We obtain an explicit expression for the basic reproduction numberin terms of the parameters of the disease and of the control policies. In this way we can quantify the effect that isolation and testing have in the evolution of the epidemic. We present a series of simulations to illustrate different realistic scenarios. From the expression ofand the simulations we conclude that isolation (social distancing) and testing among asymptomatic cases are fundamental actions to control the epidemic, and the stricter these measures are and the sooner they are implemented, the more lives can be saved. Additionally, we show that people that remain in isolation significantly reduce their probability of contagion, so risk groups should be recommended to maintain a low contact rate during the course of the epidemic.

This paper addresses the prediction of the median peak floor acceleration (PFA) demand of elastic structures subjected to seismic excitation by means of an adapted response spectrum method. Modal combination is based on a complete quadratic combination (CQC) rule. In contrast to previous studies, in the present contribution closed form solutions for the correlation coefficients and peak factors entering the CQC rule are derived using concepts of normal stationary random vibration theory. A ground motion set, which matches the design response spectrum for a specific site and a target dispersion, is used to define the stochastic base excitation. The response spectrum method is tested for various planar and spatial generic high-rise structures subjected to this particular ground motion set. A comparison of the outcomes with the results of computationally more expensive response history analyses shows the applicability and accuracy of the proposed simplified method.

Background & Aims Alcoholic steatohepatitis (ASH) is characterised by neutrophil infiltration that contributes to hepatic injury and disease. Lipocalin-2 (LCN2) was originally identified as siderophore binding peptide in neutrophils, which exerted tissue protective effects in several disease models. Here we investigate the role of LCN2 in the pathogenesis of alcohol-induced liver injury. Methods We compared hepatic LCN2 expression in ASH patients, alcoholic cirrhosis patients without evidence of ASH and patients with non-alcoholic fatty liver disease (NAFLD; i.e. simple steatosis). To mechanistically dissect LCN2 function in alcohol-induced liver injury, we subjected wild-type (WT) and Lcn2 -deficient ( Lcn2 −/− ) mice to the Lieber-DeCarli diet containing 5% ethanol (EtOH) or isocaloric maltose. Adoptive transfer experiments were performed to track neutrophil migration. Furthermore, we tested the effect of antibody-mediated LCN2 neutralisation in an acute model of ethanol-induced hepatic injury. Results Patients with ASH exhibited increased hepatic LCN2 immunoreactivity compared to patients with alcoholic cirrhosis or simple steatosis, which mainly localised to neutrophils. Similarly, ethanol-fed mice exhibited increased LCN2 expression that mainly localised to leukocytes and especially neutrophils. Lcn2 −/− mice were protected from alcoholic liver disease (ALD) as demonstrated by reduced neutrophil infiltration, liver injury and hepatic steatosis compared to WT controls. Adoptive transfers revealed that neutrophil-derived LCN2 critically determines hepatic neutrophil immigration and persistence during chronic alcohol exposure. Antibody-mediated neutralisation of LCN2 protected from hepatic injury and neutrophilic infiltration after acute alcohol challenge. Conclusions LCN2 drives ethanol-induced neutrophilic inflammation and propagates the development of ALD. Despite a critical role for LCN2 in immunity and infection, pharmacological neutralisation of LCN2 might be of promise in ALD.

High mucosal and fecal concentrations of the antimicrobial siderophore-binding peptide Lipocalin-2 (Lcn2) are observed in inflammatory bowel disease. However, Lcn2 function in chronic intestinal inflammation remains unclear. Here, we demonstrate that Lcn2 protects from early-onset colitis and spontaneous emergence of right-sided colonic tumors resulting from IL-10 deficiency. Exacerbated inflammation in Lcn2(-/-)/Il10(-/-) mice is driven by IL-6, which also controls tumorigenesis. Lcn2(-/-)/Il10(-/-) mice exhibit profound alterations in gut microbial composition, which contributes to inflammation and tumorigenesis, as demonstrated by the transmissibility of the phenotype and protection conferred by antibiotics. Specifically, facultative pathogenic Alistipes spp. utilize enterobactin as iron source, bloom in Lcn2(-/-)/Il10(-/-) mice, and are sufficient to induce colitis and right-sided tumors when transferred into Il10(-/-) mice. Our results demonstrate that Lcn2 protects against intestinal inflammation and tumorigenesis associated with alterations in the microbiota.

Quantitative Holocene temperature reconstructions for Southern Hemisphere terrestrial environments are still restricted to few records, and multi-proxy methods are rarely applied to the same system. Here, we test the applicability and comparability of temperature reconstructions inferred from different methodological approaches. We combined sedimentary cellulose and diatom oxygen isotope data from Lake Pupuke (North Island New Zealand) to derive a record of lake water temperatures. This record is complemented with mean annual air temperatures derived from the branched GDGT index MBT measured on the same sedimentary record. The datasets of both reconstructions show little temperature variation for the period 1320–7110 cal. BP. The exceptions are a warmer period culminating between 1700 and 1600 cal. BP reflected in both proxies and centennial-scale intervals with cooler water temperatures at 3380 and 2750 cal. BP recorded in the oxygen-isotope-based temperature reconstruction but not in the MBT-inferred air temperature estimates. We suggest that variations in lake circulation are the likely reason for deviations between temperature reconstructed from different proxies.

Summary Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By combining data from a GWAS screening in >100,000 individuals of European ancestry, mediator lipidomics, and functional validation studies in mice, we identify the AA metabolome as an important regulator of cholesterol homeostasis. Pharmacological modulation of AA metabolism by aspirin induced hepatic generation of leukotrienes (LTs) and lipoxins (LXs), thereby increasing hepatic expression of the bile salt export pump Abcb11. Induction of Abcb11 translated in enhanced reverse cholesterol transport, one key function of HDL. Further characterization of the bioactive AA-derivatives identified LX mimetics to lower plasma LDL-C. Our results define the AA metabolome as conserved regulator of cholesterol metabolism, and identify AA derivatives as promising therapeutics to treat cardiovascular disease in humans., Graphical Abstract, Highlights • GWAS identifies ALOX5 to associate with plasma cholesterol and HDL-C in humans • Aspirin promotes reverse cholesterol transport (RCT) via Abcb11 • Lipoxins and leukotrienes regulate expression of Abcb11 • Lipoxin mimetics increase hepatic LDLr thereby lowering LDL-C, Omega-6 polyunsaturated fatty acids, including arachidonic acid (AA), have beneficial cardiovascular effects. Demetz et al. show that Alox5, a key enzyme of the AA pathway, regulates cholesterol in humans. Modulation of the AA pathways genetically or pharmacologically, with aspirin or bioactive AA-mimetics influences cholesterol metabolism including reverse cholesterol transport.

This paper pursued to evaluate the residents' evaluation on the smart sustainable city and the sense of community. The study analyzed interviews with 392 citizens from five neighboring cities from a micro-region in southern Brazil. Factorial analysis and linear regression were applied. The investigation recognized three factors for smart sustainable cities evaluation: public services and facilities; material well-being, and environmental well-being. Linear regression reveals that residents' satisfaction with the city is predicated on the material well-being, public services and facilities, environmental well-being, and sense of community, which explain 40.2% of satisfaction with the city. Considering a smart sustainable city viewpoint, the study accomplishes that: (i) policies should be projected from the neighborhood standpoint, due to the facility of understanding shared values (ii) sense of community should be included in policies for smart sustainable city; (iii) the design of neighborhoods and cities should prioritize social interactions, with the view to build social capital and facilitate policies implementation. By integrating the smartness to sustainability approaches in the city context, this study intends to contribute to a major discussion on sustainable development, with special attention to residents' evaluation. Finally, the paper offers pertinent outcomes for urban planners and social researchers, by finding factors that influence the sense of community and residents’ evaluation on their city and by offering elements for academic, political and debates.

Background & Aims Severe obesity is associated with a state of chronic inflammation. Sirtuins (SIRT) are a family of conserved enzymes which are able to affect many metabolic and inflammatory pathways thereby potentially improving health and increasing lifespan. Methods We investigated the effect of weight loss on subcutaneous adipose tissue and liver mRNA and immunohistochemical expression of SIRT1, SIRT3, and SIRT6. Twenty-nine severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB) were studied. Tissue samples were collected before and 6months after LAGB surgery. Tissue mRNA expression levels of SIRT1 , SIRT3 , and SIRT6 were correlated with clinical, biochemical, and histological parameters. In vitro , we studied sirtuin expression in native and stimulated monocytes, adipocytes, and hepatocytes. Results SIRT1 , SIRT3 , and SIRT6 mRNA expression was higher in the subcutaneous adipose tissue than in the liver. Weight loss resulted in a significant induction of SIRT1, SIRT3, and SIRT6 expression in the subcutaneous adipose tissue. In the liver, a significant increase after weight loss was observed, particularly for SIRT3 and SIRT6 mRNA expression; immunohistochemically, SIRT1 and SIRT3 expression was upregulated. Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3, and SIRT6 expression in human monocytes. The same stimuli suppressed total sirtuin deacetylase activity again, mainly in monocytes and less in adipocytes and hepatocytes. Conclusions The relative abundance of adipose tissue mRNA expression of certain sirtuins exceeds its expression in the liver. Extensive weight loss increases sirtuin expression significantly both in adipose tissue and liver, probably as a consequence of reduced inflammation.

In their recent paper, Hong et al. (2010 ; Anti-phase oscillation of Asian monsoons during the Younger Dryas period: Evidence from peat cellulose δ 13 C of Hani, Northeast China, Palaeogeography, Palaeoclimatology, Palaeoecology 297, 214–222) discuss bulk peat sample cellulose δ 13 C data from a fen in northeast China as a proxy for East Asian summer monsoon intensity during the Late Glacial period. Based on their own results, cited papers, and an extensive re-interpretation of sedimentological and palynological data from nearby Lake Sihailongwan, Hong et al. (2010) construct a hypothesis of contrasting moisture conditions in northern and southern China, with wet conditions in the north during the Younger Dryas period and an anti-phase behaviour of Indian- and East Asian summer monsoon intensity. However, we do not approve of the re-interpretation of our Lake Sihailongwan data by Hong et al. (2010) and must strongly reject it. We show here that neither the Hong et al. (2010) fen data, nor the Lake Sihailongwan data or any other cited data allow for the sound assumption of an intensified East Asian summer monsoon in northeastern China during the Younger Dryas. The Late Glacial variability of the fen data found by Hong et al. (2010) can be easily explained by changes in the plant assemblage down core and thus by the composition of the peat. Furthermore, the use of bulk peat cellulose δ 13 C data as a precipitation proxy remains unproven for that area. Hence, there is no basis for a model contrasting Indian and East Asian summer monsoons during that period.

Summary Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-α and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-κB p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-α and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO-EPOR interaction decreases the production of NF-κB-inducible immune mediators, thus limiting tissue damage and ameliorating disease severity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases., Highlights ► Erythropoietin inhibits NF-κB activation ► EPO impairs Salmonella clearance ► Neutralization of endogenous EPO promotes Salmonella elimination ► In chemically induced colitis, EPO ameliorates diseases severity

Chronic inflammation affects bone metabolism and is commonly associated with the presence of osteoporosis. Bone loss is directed by various immune mediators such as the pro-inflammatory cytokines tumour necrosis factor-alpha, interleukin 1-beta or interferon-gamma. Pre-B cell colony enhancing factor (PBEF)/nicotinamide phosphoribosyl transferase (NAMPT)/visfatin is a pleiotropic mediator acting as growth factor, cytokine and enzyme involved in energy and nicotinamide adenine dinucleotide (NAD) metabolism. PBEF/NAMPT/visfatin has been recently demonstrated to exert several pro-inflammatory functions. We studied serum levels of PBEF/NAMPT/visfatin in patients with inflammatory bowel diseases (IBD) and their relation with bone mineral density (BMD). Furthermore, we were interested whether PBEF/NAMPT/visfatin affects osteoclastogenesis and involved mediators. PBEF/NAMPT/visfatin serum levels were increased in patients with IBD, correlated positively with disease activity and negatively with BMD, especially in the lumbar spine. Osteoclast precursor cells were generated from peripheral blood mononuclear cells after stimulation with various growth factors such as macrophage colony-stimulating factor (M-CSF) and soluble ligand of receptor activator of nuclear factor kappa B (RANK). In these in vitro studies, PBEF/NAMPT/visfatin suppressed osteoclastogenesis and inhibited the differentiation of osteoclast precursors into tartrate-resistant acid phosphatase positive multinucleated cells. These effects were paralleled by the suppression of the osteoclast typical markers RANK, nuclear factor of activated T-cells c1 (NFATc1) and cathepsin-K. This is the first report demonstrating a potential role for this important cytokine/enzyme in inflammation-related bone disease.

Background/Aims Adipocytokines play a key role in the pathophysiology of non-alcoholic fatty liver diseases (NAFLD). Whereas adiponectin has mainly anti-inflammatory functions, leptin, resistin and pre-B cell enhancing factor (PBEF)/Nampt/visfatin are considered as mainly pro-inflammatory mediators regulating metabolic and immune processes. Methods We prospectively examined the effect of weight loss on systemic levels and/or hepatic expression of adiponectin/adiponectin receptors, leptin/leptin receptors, resistin and PBEF/Nampt/visfatin. Severely obese patients underwent laparoscopic adjustable gastric banding (LABG) and serum samples ( n =30) were collected before, and after 6 and 12 months. Paired liver biopsies (before and 6 months after LABG) were obtained from 18 patients. Results Bariatric surgery improved insulin resistance, abnormal liver function tests and liver histology. Pronounced weight loss after 6 and 12 months was accompanied by a significant increase in serum adiponectin levels whereas both leptin and PBEF/Nampt/visfatin levels decreased. Resistin serum levels increased after 6 months but fell below baseline values after 12 months. Liver mRNA expression of adiponectin increased slightly after 6 months whereas leptin mRNA expression did not change. Interestingly, weight loss resulted in a significant decrease of hepatic mRNA expression of resistin, PBEF/Nampt/visfatin and both leptin receptor isoforms while expression of type 1 and 2 adiponectin receptor was not affected. Liver immunohistochemistry performed on index and follow-up liver biopsies revealed an increase in adiponectin staining, showed no effect on resistin/leptin positivity, and demonstrated a decrease in PBEF/Nampt/visfatin immunoreactivity. Conclusions Weight loss after LABG surgery drives the adipocytokine milieu towards a more anti-inflammatory direction both systemically and in the liver.

To investigate the potential of stable isotopes of Sphagnum peat deposits for palaeoclimate research and to inform sampling strategies, we present results from a study of selected Sphagnum plant constituents. We report a combined stable carbon and oxygen isotope record of cellulose separately extracted from Sphagnum branches and stem sections manually sampled from a ∼ 4000 year old peat, deposited in a small dry maar crater located in the Westeifel Volcanic Field, Germany. We have determined the species composition of each individual sample of Sphagnum branches to address the sensitivity of the stable isotope records to potential changes in Sphagnum assemblages. The youngest approximately 3000 years old peat section consists of scarcely decomposed Sphagnum plant material. From the bog's surface to a depth of ∼ 60 cm the predominant species is Sphagnum magellanicum . Between ∼ 60 and ∼ 550 cm the peat predominantly consists of Sphagnum capillifolium var. rubellum . At greater depths the decomposition status increases, species identification is, however, solely achievable if the record under examination consists of moderately decomposed peat. The stable carbon and oxygen isotope values of cellulose from Sphagnum stem sections are significantly lighter than those of the branches. Both isotopic offsets between the different plant compounds exhibit a strong degree of correlation, are statistically highly significant and observable down-core. The stable carbon isotope offset averages to 1.5‰, however, presumably decreases with increasing age of the plant material. In contrast, the averaged oxygen isotope offset of 0.9‰ is consistent in time. Our results imply that if no differentiation into Sphagnum branches and stem sections prior to stable isotope analyses is possible, erroneous interpretations of the isotope records are likely, since down-core changes in the ratio of branches to stem sections in the peat profile are most likely. This also implies that the removal of all non- Sphagnum plants or plant fragments is insufficient to retrieve stable isotope signals from peat deposits exclusively reflecting palaeo-environmental conditions. Even isotopic records from bulk Sphagnum cellulose comprise of two different signals: firstly, an environmental signal based on the plant response to external controls. This signal is, however, masked by a second plant physiological signal originating from the isotopic offset between branches and stem sections.

Non-alcoholic fatty liver disease (NAFLD), the major cause of abnormal liver function in the western world, is often associated with obesity and diabetes. In obese individuals, fat accumulation in the abdominal region affects both lipid and glucose metabolism, and a liver loaded with fat is insulin resistant. Insulin resistance (IR) is often associated with chronic low-grade inflammation, and numerous mediators released from immune cells and adipocytes contribute to development of IR. Recent results showing an important role for these mediators in NAFLD are providing us with a better understanding of this highly prevalent disease with implications for novel therapy development. This review highlights new aspects in development of liver steatosis and the relevance of various cytokines and adipocytokines in NAFLD.

The type I interferons interferon alpha (IFNalpha) and IFNbeta are the first line of defense potently induced upon viral infection, and at the same time are immunomodulatory cytokines bridging innate and adaptive immunity. T cells secreting interleukin-17 (IL-17) have recently been identified to regulate neutrophil-mediated inflammation, and have been implicated in the pathogenesis of experimental colitis and human inflammatory bowel disease, and are considered to regulate the inflammatory response in these models. We therefore hypothesized that type I IFNs as sentinels of viral infection might counteract the development of Th17 cells. We studied the effects of IFNalpha on IL-17 mRNA and protein expression in human peripheral blood mononuclear cells (PBMC) and during differentiation of human and murine naïve T cells into Th17 cells. In patients with ulcerative colitis (UC) treated systemically with IFNalpha, we studied colonic expression of IL-17 before and 4 weeks after therapy. IFNalpha potently suppressed IL-17 production in PBMC both at the mRNA and protein level. Th17 differentiation of human and murine naïve T cells was markedly suppressed in the presence of IFNalpha. UC patients exhibited increased IL-17 expression in colonic tissue biopsies compared to healthy controls, which was down-regulated during IFNalpha therapy. IL-17 expression in colonic tissue correlated with clinical remission in these patients. Our data suggest that IFNalpha down-regulates IL-17 expression and Th17 differentiation in vitro and in vivo. As a corollary, these effects might play a role in the mode of action of type I IFNs in the treatment of various diseases.

Portal fibrosis and linkage is a key feature of progressive disease in nonalcoholic steatohepatitis (NASH), but not simple steatosis. It is underappreciated and poorly understood. Fatty liver has impaired regeneration that induces a secondary replicative pathway using bipotential, periportal, hepatic progenitor cells (HPCs). We propose that activation of this pathway, with increased cell injury in NASH, also induces a periportal ductular reaction (DR) that could produce a profibrogenic stimulus.Biopsy specimens from 107 patients with nonalcoholic fatty liver disease and 11 controls were immunostained with cytokeratin-7 to quantify the DR and HPCs, and with p21 to assess hepatocyte replicative arrest. These results were correlated with clinicopathologic variables.Patients with nonalcoholic fatty liver disease had expansion of HPCs, with a strong association between HPCs and the DR (r(s) = 0.582, P.0001). In those with NASH (n = 69) there was an increased DR compared with simple steatosis, which correlated with the stage of fibrosis (r(s) = 0.510, P.0001). The DR increased with the grade of NASH activity (r(s) = 0.478, P.0001), grade of portal inflammation (r(s) = 0.445, P.0001), and extent of hepatocyte replicative arrest (r(s) = 0.446, P.0001). Replicative arrest was in turn associated with insulin resistance (r(s) = 0.450, P.0001) and NASH activity (r(s) = 0.452, P.0001). By multivariate analysis, the extent of DR (odds ratio [OR] = 17.9, P = .016), hepatocyte ballooning (OR = 8.1, P.0001), and portal inflammation (OR = 3.3, P = .005) were associated independently with fibrosis.These findings suggest that an altered replication pathway in active NASH promotes a periportal DR, which in turn may provoke progressive periportal fibrogenesis.

BACKGROUND/AIMS: Recent reports suggest that the adipose tissue and adipokines are potent modulators of inflammation. However, there is only scarce knowledge on the functional role and regulation of endogenous adiponectin in non-fat tissues such as the liver under conditions of acute inflammation. METHODS: In the present study, we investigated adiponectin expression in healthy murine liver tissue and under inflammatory conditions in vivo. RESULTS: Adiponectin mRNA was readily detectable in healthy liver tissue and further increased in ConA-mediated acute liver failure. Adiponectin protein expression was mainly found in hepatic endothelial cells. In vitro adiponectin mRNA expression was detectable in several cell types, including primary hepatic sinusoidal endothelial cells, stellate cells, and macrophages. Mice pretreated with adiponectin before ConA administration developed reduced hepatic injury as shown by decreased release of transaminases and reduced hepatocellular apoptotis. Of note, TNF-alpha levels were not affected by adiponectin, whereas IL-10 production was increased. Neutralisation of IL-10 diminished the protective effect of adiponectin. CONCLUSIONS: Adiponectin expression is up-regulated in ConA-mediated acute liver failure. Therefore, adiponectin might play a role in the control and limitation of inflammation in the liver. Moreover, our data suggest a role for IL-10 in adiponectin-mediated hepatoprotection.

The supremum metric D between fuzzy subsets of a metric space is the supremum of the Hausdorff distances of the corresponding level sets. In this paper some new criteria of compactness with respect to the distance D are given; they concern arbitrary fuzzy sets (see Theorem 7 ), fuzzy sets having no proper local maximum points (see Theorem 12 ) and, finally, fuzzy sets with convex sendograph (see Theorem 13 ). In order to compare results with a previous characterization of compactness of Diamond–Kloeden, the criteria will be expressed by equi-(left/right)-continuity. In the proofs a first author's purely topological criterion of D-compactness and a variational convergence (called Γ -convergence) which was introduced by De Giorgi and Franzoni, are fundamental.

A new technique has been developed for the determination of the oxygen isotope composition from biogenic silica. The iHTR method (inductive high temperature carbon reduction) is based on the reduction of silica by carbon with temperatures of up to 1830°C (maximum T 2200°C) to produce carbon monoxide for isotope analysis. Basically, samples of silica are mixed with graphite and filled into a sample holder made of a glassy carbon rod. The rod is introduced into a glassy carbon cylinder liner closed at the top which itself is enclosed by a double-walled glass vessel. The glassy carbon rod is inductively heated under vacuum to the temperature needed for quantitative conversion of the particular silica material to CO. The most critical process of dehydration (in the case of opal) and reduction to CO is routinely achieved in the iHTR device. Weakly bound oxygen and oxygen-containing contaminants, like hydroxyl groups, as well as remaining minor organic constituents are volatilized stepwise under high vacuum at temperatures of 850°C and 1050°C without isotopic exchange before the reduction of the silica. After completion of dehydration, the temperature is raised to the value needed for silica reduction. For both biogenic silica and quartz a temperature of 1550°C was found to be adequate. The technical design with a standard preparation routine and various test experiments is presented proving the reliability and capability of the new iHTR method, especially with respect to fresh diatom materials and diatom opal. The amount of sample material necessary at present is ∼1.5 mg of silica and the reproducibility achieved for natural samples is better than ±0.15‰. Replicate analysis of the quartz standard NBS28 resulted in a δ 18 O value of 9.62‰ ± 0.11‰ (n = 17).