Effector Mechanisms in Low-Dose Streptozotocin-induced Diabetes

The cellular and molecular requirements for β-cell damages in an immune-mediated toxininduced insulin-dependent diabetes mellitus have been studied in the model of multiple low-dose streptozotocin-induced diabetes in rats and mice. It was found that strain-related susceptibility to diabetes induction correlated with a higher level of IL-2, IFN-γ, and TNF-α production, whereas such differences were not observed when IL-1 and NO production by macrophages were analyzed; elimination of immunoregulatory RT6+T cells that increases IFN-γ production, enhances susceptibility to MLD-STZ-induced diabetes; mercury-induced Th-2 cells downregulated the disease; IFN-γ-mediated macrophage activation to produce proinflammatory cytokines rather than NO is an important event in early diabetogenic effects of invading macrophages; inhibition of IL-1 activity downregulates diabetes induction; and generation of NO in β cells appears to be important for diabetogenic effects. Taken together, data indicate that MLD-STZ diabetes is induced by Th-1 lymphocytes that secrete soluble effector molecules that activate macrophages and promote destruction of β cells possibly by both nitric oxide and nonnitric oxide-mediated mechanisms

Eco-design tool to support the use of renewable polymers within packaging applications

Bioplastics derived from renewable polymers such as sugars, starches and cellulose, have attracted significant interest from companies looking to reduce their environmental footprint. New production capacity and improved materials have resulted in their increasing adoption for mainstream consumer products packaging. However questions remain regarding their overall environmental benefits and how the maximum environmental gain can be achieved. These uncertainties highlight the need for a decision support tool to aid the packaging design process. This paper examines the issues surrounding bio-derived polymer use and discusses the development of an eco-design tool to assist in their rapid and efficient adoption

Lack of Apoptosis of Infiltrating Cells as the Mechanism of High Susceptibility to EAE in DA Rats

Dark Agouti (DA) rats are highly susceptible to induction of Th-l-mediated autoimmunity disease, including experimental allergic encephalomyelitis (EAE). In contrast to other susceptible rat strains in which disease is induced only with encephalitogen emulsified in complete Freund's adjuvants (CFA), in DA rats EAE develops after injection of encephalitogen in incomplete Freund's adjuvants (IFA) or Titermax, putative Th-2 directed adjuvant. Lymph node cells derived from immunized DA rats and stimulated in vitro produce significantly more Interferon-γ (IFN-γ) than resistant Albino Oxford (AO) rats. However, cells derived from both strains produce large amounts of IL-10 but not IL-4. Immunized lymph node cells derived from EAE susceptible (AO × DA) F1rats induce clinical signs of disease in sublethally irradiated parental DA but not AO rats. The pathohistology of the target tissue in these recipients clearly demonstrated infiltration of mononuclear cells in both parental strains. However, the number of CD4+ cells was significantly higher and number of apoptotic cells significantly lower in DA rats sacrificed 8 days after passive transfer. We postulate that in addition to higher IFN-γ and TNF-α production, resistance to early apoptosis of the invading cells in the target tissue possibly due to lack of downregulation by TGF-β leads to exceptional susceptibility to EAE in DA rats

Derangements of liver tissue bioenergetics in Concanavalin A-induced hepatitis

BACKGROUND: A novel in vitro system was employed to investigate liver tissue respiration (mitochondrial O(2) consumption) in mice treated with concanavalin A (Con A). This study aimed to investigate hepatocyte bioenergetics in this well-studied hepatitis model. METHODS: C57Bl/6 and C57Bl/6 IFN-γ(−/−) mice were injected intravenously with 12 mg ConA/kg. Liver specimens were collected at various timepoints after injection and analyzed for cellular respiration and caspase activation. Serum was analyzed for interferon-gamma (IFN-γ) and aminotransferases. Fluorescence activated cell sorting analysis was used to determine the phenotype of infiltrating cells, and light and electron microscopy were used to monitor morphological changes. Phosphorescence analyzer that measured dissolved O(2) as function of time was used to evaluate respiration. RESULTS: In sealed vials, O(2) concentrations in solutions containing liver specimen and glucose declined linearly with time, confirming zero-order kinetics of hepatocyte respiration. O(2) consumption was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. Enhanced liver respiration (by ≈68%, p<0.02) was noted 3 hr after ConA treatment, and occurred in conjunction with limited cellular infiltrations around the blood vessels. Diminished respiration (by ≈30%, p=0.005) was noted 12 hr after ConA treatment, and occurred in conjunction with deranged mitochondria, areas of necrosis, and prominent infiltrations with immune cells, most significantly, CD3(+)NKT(+) cells. Increases in intracellular caspase activity and serum IFN-γ and aminotransferase levels were noted 3 hr after ConA treatment and progressed with time. The above-noted changes were less pronounced in C57Bl/6 IFN-γ(−/−) mice treated with ConA. CONCLUSIONS: Based on these results, liver tissue bioenergetics is increased 3 hr after ConA exposure. This effect is driven by the pathogenesis of the disease, in which IFN-γ and other cytokines contribute to. Subsequent declines in liver bioenergetics appear to be a result of necrosis and active caspases targeting the mitochondria within hepatocytes

Opportunities for bio-polymer resource conservation through closed loop recycling

Oil-derived plastics have become well established as a packaging material over the past 75 years due to their many technical and commercial advantages. However, the disposal of plastic packaging waste, a large proportion of which still goes to landfill, continues to raise increasing environmental concerns. Meanwhile, the price of oil continues to rise as demand outstrips supply. In response, biodegradable polymers made from renewable resources have risen to greater prominence, with a variety of materials currently being developed from plant starch, cellulose, sugars and proteins. Whilst the polymer science continues apace, the real ecological impacts and benefits of these materials remain uncertain. Although life cycle assessment (LCA) has been used to provide comparisons with oil-derived plastics, published studies are often limited in scope, allowing the validity of their conclusions to be challenged. The literature appears to support the popular assumption that the end-of-life management of these materials requires little consideration, since their biodegradable properties provide inherent ecological benefits. Opportunities for conserving resources through the recycling of biopolymers are rarely addressed. Through a review of current academic, industrial and commercial progress in the field of biopolymers, a number of LCA case studies are proposed which will address this weakness in existing research, related to the recycling of biopolymers. These, or similar, studies are required to provide a more complete picture of the potential effects of a transition from non-renewable to renewable polymers, thus allowing material selection decisions to be made with greater confidence throughout the packaging supply chain

The Cytotoxicity of Aflatoxin B1 in Human Lymphocytes

Objectives: Aflatoxin B1 (AFB1) is a naturally occurring carcinogenic and immunosuppressive compound. This study was designed to measure its toxic effects on human peripheral blood mononuclear cells (PBMC). Methods: The study recruited 7 healthy volunteers. PBMC were isolated and cellular respiration was monitored using a phosphorescence oxygen analyser. The intracellular caspase activity was measured by the caspase-3 substrate N-acetyl-asp-glu-val-asp-7-amino-4-methylcoumarin. Phosphatidylserine exposure and membrane permeability to propidium iodide (PI) were measured by flow cytometry. Results: Cellular oxygen consumption was inhibited by 2.5 μM and 25 μM of AFB1. Intracellular caspase activity was noted after two hours of incubation with 100 μM of AFB1. The number of Annexin V-positive cells increased as a function of AFB1 concentration and incubation time. At 50 μM, a significant number of cells became necrotic after 24 hours (Annexin V-positive and PI-positive). Conclusion: The results show AFB1 is toxic to human lymphocytes and that its cytotoxicity is mediated by apoptosis and necrosis

Predicting invasive fungal disease due to Candida species in non-neutropenic, critically ill, adult patients in United Kingdom critical care units

Background Given the predominance of invasive fungal disease (IFD) amongst the non-immunocompromised adult critically ill population, the potential benefit of antifungal prophylaxis and the lack of generalisable tools to identify high risk patients, the aim of the current study was to describe the epidemiology of IFD in UK critical care units, and to develop and validate a clinical risk prediction tool to identify non-neutropenic, critically ill adult patients at high risk of IFD who would benefit from antifungal prophylaxis. Methods Data on risk factors for, and outcomes from, IFD were collected for consecutive admissions to adult, general critical care units in the UK participating in the Fungal Infection Risk Evaluation (FIRE) Study. Three risk prediction models were developed to model the risk of subsequent Candida IFD based on information available at three time points: admission to the critical care unit, at the end of 24 h and at the end of calendar day 3 of the critical care unit stay. The final model at each time point was evaluated in the three external validation samples. Results Between July 2009 and April 2011, 60,778 admissions from 96 critical care units were recruited. In total, 359 admissions (0.6 %) were admitted with, or developed, Candida IFD (66 % Candida albicans). At the rate of candidaemia of 3.3 per 1000 admissions, blood was the most common Candida IFD infection site. Of the initial 46 potential variables, the final admission model and the 24-h model both contained seven variables while the end of calendar day 3 model contained five variables. The end of calendar day 3 model performed the best with a c index of 0.709 in the full validation sample. Conclusions Incidence of Candida IFD in UK critical care units in this study was consistent with reports from other European epidemiological studies, but lower than that suggested by previous hospital-wide surveillance in the UK during the 1990s. Risk modeling using classical statistical methods produced relatively simple risk models, and associated clinical decision rules, that provided acceptable discrimination for identifying patients at ‘high risk’ of Candida IFD

Predicting invasive fungal disease due to Candida species in non-neutropenic, critically ill, adult patients in United Kingdom critical care units.

BACKGROUND: Given the predominance of invasive fungal disease (IFD) amongst the non-immunocompromised adult critically ill population, the potential benefit of antifungal prophylaxis and the lack of generalisable tools to identify high risk patients, the aim of the current study was to describe the epidemiology of IFD in UK critical care units, and to develop and validate a clinical risk prediction tool to identify non-neutropenic, critically ill adult patients at high risk of IFD who would benefit from antifungal prophylaxis. METHODS: Data on risk factors for, and outcomes from, IFD were collected for consecutive admissions to adult, general critical care units in the UK participating in the Fungal Infection Risk Evaluation (FIRE) Study. Three risk prediction models were developed to model the risk of subsequent Candida IFD based on information available at three time points: admission to the critical care unit, at the end of 24 h and at the end of calendar day 3 of the critical care unit stay. The final model at each time point was evaluated in the three external validation samples. RESULTS: Between July 2009 and April 2011, 60,778 admissions from 96 critical care units were recruited. In total, 359 admissions (0.6 %) were admitted with, or developed, Candida IFD (66 % Candida albicans). At the rate of candidaemia of 3.3 per 1000 admissions, blood was the most common Candida IFD infection site. Of the initial 46 potential variables, the final admission model and the 24-h model both contained seven variables while the end of calendar day 3 model contained five variables. The end of calendar day 3 model performed the best with a c index of 0.709 in the full validation sample. CONCLUSIONS: Incidence of Candida IFD in UK critical care units in this study was consistent with reports from other European epidemiological studies, but lower than that suggested by previous hospital-wide surveillance in the UK during the 1990s. Risk modeling using classical statistical methods produced relatively simple risk models, and associated clinical decision rules, that provided acceptable discrimination for identifying patients at 'high risk' of Candida IFD. TRIAL REGISTRATION: The FIRE Study was reviewed and approved by the Bolton NHS Research Ethics Committee (reference: 08/H1009/85), the Scotland A Research Ethics Committee (reference: 09/MRE00/76) and the National Information Governance Board (approval number: PIAG 2-10(f)/2005)

The Effects of Learning Orientation and Marketing Programme Planning on Export Performance: Paradoxical Moderating Role of Psychic Distance

Despite extensive research on the effect of organisational learning processes on firm performance, how and when a propensity to learn influences the export performance of small and medium-sized enterprises (SMEs) remains unclear. Using multiple-informant and time-lagged primary data from 242 SMEs in a sub-Saharan African market, this study examines the roles of marketing programme planning and host country psychic distance in linking export learning orientation to export performance. Findings from the study show that increases in both export learning orientation and marketing programme planning are associated with increases in export performance. In addition, the study finds that while increases in psychic distance weaken the effect of export learning orientation on export performance, it strengthens the effect of marketing programme planning on export performance. These findings draw attention to the idea that cognitive distance between home and host country markets may play a paradoxical role in explaining when organisational learning activities may help or hurt exporting SMEs

Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses

Abstract: IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and this is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R. We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3 and ZNF341, genes encoding different components of the IL-6 signalling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.J.E.D.T. is supported by the MRC (RG95376 and MR/L006197/1). KB is supported by the European Research Council (ERC StG 310857) and the Austrian Science Fund (P29951-B30). This work is supported, in part, by the intramural research program of the NIAID, NIH. A.J.T. is supported by the Wellcome Trust (104807/Z/14/Z) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. KGCS is supported by the Medical Research Council (program grant MR/L019027) and is a Wellcome Investigator. M.G. and S.T. are supported in part by Cancer Research UK. RCA and MT are supported by a DOC fellowship of the Austrian Academy of Sciences. This research was made possible through access to the data and findings generated by two pilot studies for the 100,000 Genomes Project. The enrolment for one pilot study was coordinated by the NIHR BioResource (preprint from doi: https://doi.org/10.1101/507244) and the other by Genomics England Limited (GEL), a wholly owned company of the Department of Health in the UK. Over 90% of participants in the pilot studies have been enrolled in the NIHR BioResource. These pilot studies were mainly funded by grants from the National Institute for Health Research (NIHR) in England to the University of Cambridge and GEL, respectively. Additional funding was provided by the BHF, MRC, NHS England, the Wellcome Trust, amongst many other funders. The pilot studies use data provided by patients and their close relatives and collected by the NHS and other healthcare providers as part of their care and support. We thank all volunteers for their participation, and also gratefully acknowledge NIHR Biomedical Research Centres, NIHR BioResource Centres, NHS Trust Hospitals, NHS Blood and Transplant and staff for their contribution. ST is on the scientific advisory board for Ipsen, and is a consultant for Kallyope Inc. The authors declare no competing financial interests