Longitudinal monocyte Human leukocyte antigen‐DR expression is a prognostic marker in critically ill patients with decompensated liver cirrhosis

Background: Critical illness in cirrhotic patients is associated with a poor prognosis and increased susceptibility to infections. Monocyte HLA‐DR expression is decreased in cirrhotic patients, but its prognostic value has not been investigated prospectively. Methods: Thirty‐eight critically ill patients with decompensated liver cirrhosis were included in this prospective study. On admission to the intensive care unit (ICU), inflammatory parameters (C‐reactive protein, procalcitonin and lipopolysaccharide‐binding protein), interleukin (IL)‐10, interferon (IFN)‐γ serum levels, tumour necrosis factor (TNF)‐αex vivo stimulation (whole blood assay) and HLA‐DR expression on monocytes (FACS analysis) were determined. Immune parameters were furthermore measured every third day until discharge from the ICU or death of the patients. Results: Intensive care unit mortality of the cirrhotic patients was 34.2%. During admission, TNF ex vivo, IFN‐γ and HLA‐DR expression were lower in non‐survivors (all P<0.05), while IL‐10 levels were increased in non‐survivors compared with survivors (P=0.001). However, individual values clearly overlapped between groups. Prospective analysis revealed that monocyte HLA‐DR expression remained stable or increased in survivors, but decreased in non‐survivors (P=0.002). A decrease in HLA‐DR expression between admission and day 3 was strongly associated with decreased IFN‐γ levels and increased ICU mortality (hazard ratio 3.36, P=0.008), mostly owing to late sepsis. This association was independent of the sequential organ failure assessment and model for end‐stage liver disease score. Conclusions: Here we establish the relative HLA‐DR expression (admission/day 3) as a prognostic marker for ICU mortality in critically ill cirrhotic patients. These results may guide the evaluation of immune‐modulating therapies in these patients.     

Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE

The generation of anti-DNA auto-antibodies is characteristic for the human autoimmune condition systemic lupus erythematosus (SLE) and its animal models. However, the contribution of the toll-like receptor (TLR) system of innate immunity receptors and, in particular, TLR9 to this B cell-mediated autoimmune process remains controversial. Here we report that in a novel murine model of SLE, based on hyper-reactive B cell activation mediated by mutant phospholipase Cg2, the genetic deficiency of TLR9 does not protect from spontaneous anti-DNA auto-antibody formation and glomerulonephritis. On the contrary, disease induction is aggravated and additional nucleolar antibody specificity develops in autoimmune TLR9-deficient mice. In vitro studies demonstrate that, in autoimmune-prone mice, dual signaling via the B cell receptor and non-CpG DNA results in synergistic B cell activation in a TLR9-independent manner. These results suggest that engagement of a TLR9-independent DNA activation pathway may promote autoimmunity, while TLR9 signaling can ameliorate SLE-like immune pathology in vivo.     

Genetic prothrombotic risk factors in women with unexplained pregnancy loss

INTRODUCTION: Inherited thrombophilia has been associated with unexplained recurrent pregnancy loss (RPL) and stillbirth. This thrombotic tendency can manifest as thrombotic lesions in the placenta, and may lead to abortion and stillbirth. The aim of our case-control study was to investigate the prevalence of FVL and FII G20210A in women with adverse pregnancy outcome, compared to the prevalence of the same mutations in our health control group. MATERIALS AND METHODS: 102 consecutive women with unexplained pregnancy loss (55 with history of RPL, and 47 with history of stillbirth) were studied for hereditary thrombophilia. The health control group consisted of 217 healthy women from the general population. RESULTS AND CONCLUSIONS: Of the 55 women with recurrent abortions, we found the same prevalence for the FVL and the FII G20210A(9.1%, 5 pts). (p=NS compared to control group). Of the 47 women with stillbirth, 11 (23.4%) had the FVL and 9 (19.1%) had the FII G20210A(p<0.0005 for both mutations). In our experience the prevalence of FVL and the FII G20210Amutations was significantly higher in women with unexplained stillbirth, instead the prevalence of genetic thrombophilia was high but not statistically significant in women with recurrent pregnancy loss.     

Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum

Malaria causes millions of death cases per year. Since Plasmodium falciparum rapidly develops drug resistance, it is of high importance to investigate potential drug targets which may lead to novel rational therapy approaches. Here we report on the interaction of translationally controlled tumor protein of P. falciparum (PfTCTP) with the anti-malarial drug artemisinin. Furthermore, we investigated the crystal structure of PfTCTP. Using mass spectrometry, bioinformatic approaches and surface plasmon resonance spectroscopy, we identified novel binding sites of artemisinin which are in direct neighborhood to amino acids 19–46, 108–134 and 140–163. The regions covered by these residues are known to be functionally important for TCTP function. We conclude that interaction of artemisinin with TCTP may be at least in part explain the antimalarial activity of artemisinin.     

Subclinical CNS Inflammation as Response to a Myelin Antigen in Humanized Mice

Multiple sclerosis is a demyelinating autoimmune disease of the CNS. Its animal model experimental autoimmune encephalomyelitis is commonly induced by active immunization with myelin antigens. To investigate human immune responses against myelin antigens in vivo we established a new subclinical experimental autoimmune encephalomyelitis model in humanized mice. NOD/Scidγc^?/? animals were transferred with peripheral blood mononuclear cells from healthy human donors and immunized with myelin antigens in complete Freund’s adjuvant and antigen-pulsed autologous dendritic cells. Human T cells recovered from these animals reacted specifically to the soluble domain of myelin oligodendrocyte glycoprotein and secreted proinflammatory cytokines. Furthermore, immunized animals developed subclinical CNS inflammation with infiltrating CD4⁺ and CD8⁺ T cells and production of encephalitogenic cytokines. Thus, this model of myelin-induced CNS inflammation by human T cells may allow testing of new human-specific therapeuticals for multiple sclerosis.     

Boswellia serrata has Beneficial Anti‐Inflammatory and Antioxidant Properties in a Model of Experimental Colitis

Ulcerative colitis is an inflammatory disease that involves only the colon and rectum, being characterized by leukocyte infiltrate and superficial ulcers in the intestinal mucosa. To evaluate the anti‐inflammatory and antioxidant effects of extract from the Boswellia serrata plant in an experimental rat model of acute ulcerative colitis induced by the administration of acetic acid (AA). An extract of B. serrata (34.2 mg/kg/day) was administered by oral gavage for 2 days before and after the induction of colitis with 4 mL of 4% AA. The anal sphincter pressure in the colitis group showed a significant decrease compared to that of the control groups (p < 0.001). The analysis of the values of lipid peroxidation (LPO) obtained by substances that react with thiobarbituric acid (TBARS) showed a significantly increased LPO in the colitis group compared to the control groups (p < 0.001). The nitric oxide levels and the expression of inducible nitric oxide synthase (iNOS) showed a significant increase in the colitis group compared to control groups (p < 0.01). Both pretreatment and treatment with B. serrata exhibited significantly reduced lipid peroxidation, nitric oxide and iNOS and showed improvements in tissue injury and anal sphincter pressure in animals with ulcerative colitis. The B. serrata extract has protective anti‐inflammatory and antioxidant effects that inhibit inflammatory mediators in acute experimental colitis. Copyright © 2014 John Wiley & Sons, Ltd.     

A library of strictly linear poly(ethylene glycol)–poly(ethylene imine) diblock copolymers to perform structure–function relationship of non-viral gene carriers

A library of 39 strictly linear poly(ethylene glycol)–poly(ethylene imine) (PEG-PEI) diblock copolymers was synthesized for the delivery of plasmid DNA using PEG of 2, 5, or 10 kDa in combination with linear PEI with a molecular weight (MW) ranging from 1.5 to 10.8 kDa. In contrast to other approaches, the copolymers demonstrated a clear separation between the hydrophilic PEG and the nucleic acid condensing PEI moieties. Hence, the hypothesis was that PEG may not sterically counteract the interaction between the nucleic acid and PEI and that consequently, the copolymers are perfectly suited to build small and stable polyplexes. Analysis of the polyplexes revealed structure–function relationships and the general guideline was that the PEG domain had a greater influence on the physicochemical properties of the polyplexes than PEI. A PEG content higher than 50% led to small (< 150 nm), nearly neutral polyplexes with favorable stability. The transfection efficacy of these polyplexes was significantly reduced compared to the PEI homopolymer, but was restored by the application of the corresponding degradable copolymer, which involved a redox triggerable PEG domain. In conclusion, valuable design criteria for the optimization of gene delivery carriers, which is only possible through the screening of such a large library, were gained.     

A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?

Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N?=?54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level?Cdependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.     

Trends in sociodemographic and health-related indicators in Bangladesh, 1993–2007: will inequities persist?

Objective

To assess levels, trends and gaps between the poorest and the richest in selected health and human development indicators in Bangladesh.

Methods

Data for selected indicators associated with sociodemographic characteristics among ever-married women, contraception use, child vaccination, antenatal care practices and health conditions were extracted from the Bangladesh Demographic and Health Surveys conducted in 1993–94, 1996–1997, 1999–2000, 2004 and 2007. Results for the whole sample and for the poorest and the richest wealth quintiles are presented.

Findings

Positive trends were noted in urbanization, availability of electricity, age at first marriage, use of modern contraception, access to skilled antenatal care, child vaccination, knowledge of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome and overweight and obesity. In contrast, negative trends were seen in factors such as literacy, infant and child mortality, fertility rate, home delivery and malnutrition and underweight. However, changes in these indicators differed between the poorest and richest quintiles. For instance, only the richest quintile experienced rapid urbanization, whereas illiteracy declined more among the poorest. Noteworthy gaps were found in almost all factors. Rich–poor gaps in urbanization, age at marriage, fertility, condom use, home delivery and overweight increased; in contrast, gaps in education, water and sanitation, use of contraception (except condoms) and child vaccination declined.

Conclusion

Persistent inequities in Bangladesh endanger equitable and sustainable human development in the country. Pro-poor development strategies based on the principles of equity and quality should be implemented to narrow existing gaps and further promote holistic and equitable human development.