Vascular disease in HIV/AIDS patients

Objectives. An ongoing prospective clinical survey to determine the spectrum of vascular disease in HIV/AIDS patients and the risk factors affecting clinical outcome in order to formulate a management protocol for future use. Methods. Comprehensive screening for risk factors for vascular disease as well as HIV/AIDS-related conditions. Disease pattern and presentation are noted and patients treated accordingly. Vascular emergencies are managed regardless of HIV status because this information is usually not available at the time of presentation. Elective management is based on immune status and risk stratification. Results. 42 patients tested positive for HIV. The majority of patients presented with occlusive disease (57%), followed by anearysms (21%) and vascular trauma (19%). A variety of vascular surgical procedures were performed on 36 patients. There was no surgical mortality and 10 patients developed complications, including 2 amputations and 7 cases of minor wound sepsis. The 3 patients who received preoperative antiretroviral therapy showed a marked reduction in viral count and a significant improvement in CD4 T-cell count. Conclusion. Surgery can be safe and effective in HIV-positive patients provided the necessary precautions are taken to reduce surgical morbidity. (South African Medical Journal: 2002 92(12): 974-977

ENSO dynamics during the Last Glacial Maximum

We present a numerical eigenmode analysis of an intermediate El Nin˜o–Southern Oscillation (ENSO) model which is driven by present-day observed background conditions as well as by simulated background conditions for the Last Glacial Maximum (LGM) about 21,000 years ago. The background conditions are obtained from two LGM simulations which were performed with the National Center for Atmospheric Research climate system model (CSM1.4) and an Earth system model of intermediate complexity (ECBilt-CLIO). Our analysis clearly shows that the leading present-day unstable recharge-discharge mode changes its stability as well as its frequency during LGM conditions. Simulated LGM background conditions were favorable to support large-amplitude self-sustained interannual ENSO variations in the tropical Pacific. Our analysis indicates that off-equatorial climate conditions as well as a shoaling of the thermocline play a crucial role in amplifying the LGM ENSO mode

D16.4: Final Report on Natural Language Processing

This document is a deliverable (D16.4) of the ARIADNE project (“Advanced Research Infrastructure for Archaeological Dataset Networking in Europe”), which is funded under the European Community's Seventh Framework Programme. It presents the final results of the work carried out in Tasks 16.2 “Natural Language Processing (NLP)”. The report presents one of the most important, but traditionally difficult to access resources in archaeology; the largely unpublished reports generated by commercial or “rescue” archaeology, commonly known as “grey literature”, exploring both rule-based and machine learning NLP methods, the use of archaeological thesauri in NLP, and various Information Extraction (IE) methods in their own language

Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines

Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 β- D-glucopyranose-NH-CO-R putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a “consensus scoring” approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants’ values, in vitro, ranged from 5 to 377 µM while two of them were effective at causing inactivation of GP in rat hepatocytes at low µM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors

Modification and preservation of environmental signals in speleothems

Speleothems are primarily studied in order to generate archives of climatic change and results have led to significant advances in identifying and dating major shifts in the climate system. However, the climatological meaning of many speleothem records cannot be interpreted unequivocally; this is particularly so for more subtle shifts and shorter time periods, but the use of multiple proxies and improving understanding of formation mechanisms offers a clear way forward. An explicit description of speleothem records as time series draws attention to the nature and importance of the signal filtering processes by which the weather, the seasons and longer-term climatic and other environmental fluctuations become encoded in speleothems. We distinguish five sources of variation that influence speleothem geochemistry: atmospheric, vegetation/soil, karstic aquifer, primary speleothem crystal growth and secondary alteration and give specific examples of their influence. The direct role of climate diminishes progressively through these five factors. \ud \ud We identify and review a number of processes identified in recent and current work that bear significantly on the conventional interpretation of speleothem records, for example: \ud \ud 1) speleothem geochemistry can vary seasonally and hence a research need is to establish the proportion of growth attributable to different seasons and whether this varies over time. \ud \ud 2) whereas there has traditionally been a focus on monthly mean Ã�´18O data of atmospheric moisture, current work emphasizes the importance of understanding the synoptic processes that lead to characteristic isotope signals, since changing relative abundance of different weather types might 1Corresponding author, fax +44(0)1214145528, E-mail: [email protected] control their variation on the longer-term. \ud \ud 3) the ecosystem and soil zone overlying the cave fundamentally imprint the carbon and trace element signals and can show characteristic variations with time. \ud \ud 4) new modelling on aquifer plumbing allows quantification of the effects of aquifer mixing. \ud \ud 5) recent work has emphasized the importance and seasonal variability of CO2-degassing leading to calcite precipitation upflow of a depositional site on carbon isotope and trace element composition of speleothems. \ud \ud 6) Although much is known about the chemical partitioning between water and stalagmites, variability in relation to crystal growth mechanisms and kinetics is a research frontier. \ud \ud 7) Aragonite is susceptible to conversion to calcite with major loss of chemical information, but the controls on the rate of this process are obscure. \ud \ud Analytical factors are critical to generate high-resolution speleothem records. A variety of methods of trace element analysis are available, but standardization is a common problem with the most rapid methods. New stable isotope data on Irish stalagmite CC3 compares rapid laser-ablation techniques with the conventional analysis of micromilled powders and ion microprobe methods. A high degree of comparability between techniques for Ã�´18O is found on the mm-cm scale, but a previously described high-amplitude oxygen isotope excursion around 8.3 ka is identified as an analytical artefact related to fractionation of the laser-analysis associated with sample cracking. High-frequency variability of not less than 0.5o/oo may be an inherent feature of speleothem Ã�´18O records

Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis

Aims/hypothesis The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKTcells. Methods We measured circulating and psoriatic plaque iNKT cell numbers in two patients with type 2 diabetes and psoriasis before and after commencing GLP-1 analogue therapy. In addition, we investigated the in vitro effects of GLP-1 on iNKT cells and looked for a functional GLP-1 receptor on these cells. Results The Psoriasis Area and Severity Index improved in both patients following 6 weeks of GLP-1 analogue therapy. This was associated with an alteration in iNKT cell number, with an increased number in the circulation and a decreased number in psoriatic plaques. The GLP-1 receptor was expressed on iNKT cells, and GLP-1 induced a dose-dependent inhibition of iNKT cell cytokine secretion, but not cytolytic degranulation in vitro. Conclusions/interpretation The clinical effect observed and the direct interaction between GLP-1 and the immune system raise the possibility of therapeutic applications for GLP-1 in inflammatory conditions such as psoriasis

Innate Immune Responses to Bacterial Ligands in the Peripheral Human Lung – Role of Alveolar Epithelial TLR Expression and Signalling

It is widely believed that the alveolar epithelium is unresponsive to LPS, in the absence of serum, due to low expression of TLR4 and CD14. Furthermore, the responsiveness of the epithelium to TLR-2 ligands is also poorly understood. We hypothesised that human alveolar type I (ATI) and type II (ATII) epithelial cells were responsive to TLR2 and TLR4 ligands (MALP-2 and LPS respectively), expressed the necessary TLRs and co-receptors (CD14 and MD2) and released distinct profiles of cytokines via differential activation of MAP kinases. Primary ATII cells and alveolar macrophages and an immortalised ATI cell line (TT1) elicited CD14 and MD2-dependent responses to LPS which did not require the addition of exogenous soluble CD14. TT1 and primary ATII cells expressed CD14 whereas A549 cells did not, as confirmed by flow cytometry. Following LPS and MALP-2 exposure, macrophages and ATII cells released significant amounts of TNFα, IL-8 and MCP-1 whereas TT1 cells only released IL-8 and MCP-1. P38, ERK and JNK were involved in MALP-2 and LPS-induced cytokine release from all three cell types. However, ERK and JNK were significantly more important than p38 in cytokine release from macrophages whereas all three were similarly involved in LPS-induced mediator release from TT1 cells. In ATII cells, JNK was significantly more important than p38 and ERK in LPS-induced MCP-1 release. MALP-2 and LPS exposure stimulated TLR4 protein expression in all three cell types; significantly more so in ATII cells than macrophages and TT1 cells. In conclusion, this is the first study describing the expression of CD14 on, and TLR2 and 4 signalling in, primary human ATII cells and ATI cells; suggesting that differential activation of MAP kinases, cytokine secretion and TLR4 expression by the alveolar epithelium and macrophages is important in orchestrating a co-ordinated response to inhaled pathogens

Interlaboratory study for coral Sr/Ca and other element/Ca ratio measurements

The Sr/Ca ratio of coral aragonite is used to reconstruct past sea surface temperature (SST). Twentyone laboratories took part in an interlaboratory study of coral Sr/Ca measurements. Results show interlaboratory bias can be significant, and in the extreme case could result in a range in SST estimates of 7°C. However, most of the data fall within a narrower range and the Porites coral reference material JCp- 1 is now characterized well enough to have a certified Sr/Ca value of 8.838 mmol/mol with an expanded uncertainty of 0.089 mmol/mol following International Association of Geoanalysts (IAG) guidelines. This uncertainty, at the 95% confidence level, equates to 1.5°C for SST estimates using Porites, so is approaching fitness for purpose. The comparable median within laboratory error is <0.5°C. This difference in uncertainties illustrates the interlaboratory bias component that should be reduced through the use of reference materials like the JCp-1. There are many potential sources contributing to biases in comparative methods but traces of Sr in Ca standards and uncertainties in reference solution composition can account for half of the combined uncertainty. Consensus values that fulfil the requirements to be certified values were also obtained for Mg/Ca in JCp-1 and for Sr/Ca and Mg/Ca ratios in the JCt-1 giant clam reference material. Reference values with variable fitness for purpose have also been obtained for Li/Ca, B/Ca, Ba/Ca, and U/Ca in both reference materials. In future, studies reporting coral element/Ca data should also report the average value obtained for a reference material such as the JCp-1

Selective DNA-PKcs inhibition extends the therapeutic index of localized radiotherapy and chemotherapy

Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential