Progression of kidney disease in type 2 diabetes – beyond blood pressure control: an observational study

BACKGROUND: The risk factors for progression of chronic kidney disease (CKD) in type 2 diabetes mellitus (DM) have not been fully elucidated. Although uncontrolled blood pressure (BP) is known to be deleterious, other factors may become more important once BP is treated. METHODS: All patients seen in the outpatient clinics of our hospital between January 1993 and September 2002 with type 2 DM and clinical evidence of CKD were evaluated. Progression of kidney disease was evaluated by rate of decline of glomerular filtration rate (GFR) as estimated from the simplified MDRD formula. Variables associated with progression in univariate analyses were examined by multivariate analysis to determine the factors independently associated with kidney disease progression. RESULTS: 343 patients (mean age 69 years; all male; 77% Caucasian) were studied. Mean BP, glycated hemoglobin, and serum cholesterol during the study period were 138/72 mmHg, 8.1%, and 4.8 mmol/L, respectively. Mean decline of GFR was 4.5 ml min-1 1.73 m(2)-1 yr-1 (range -14 to +32). Low initial serum albumin (p < 0.001), black race (p < 0.001), and degree of proteinuria (p = 0.002), but not blood pressure, glycated hemoglobin, or serum cholesterol, were independently associated with progression. CONCLUSION: In a cohort of diabetic patients with CKD in whom mean BP was < 140/80 mmHg, the potentially remediable factors hypoalbuminemia and proteinuria but not blood pressure were independently associated with progression of kidney disease. Further understanding of the relationship between these factors and kidney disease progression may lead to beneficial therapies in such patients

Punicic Acid a Conjugated Linolenic Acid Inhibits TNFα-Induced Neutrophil Hyperactivation and Protects from Experimental Colon Inflammation in Rats

BACKGROUND:Neutrophils play a major role in inflammation by releasing large amounts of ROS produced by NADPH-oxidase and myeloperoxidase (MPO). The proinflammatory cytokine TNFalpha primes ROS production through phosphorylation of the NADPH-oxidase subunit p47phox on Ser345. Conventional anti-inflammatory therapies remain partially successful and may have side effects. Therefore, regulation of neutrophil activation by natural dietary components represents an alternative therapeutic strategy in inflammatory diseases such as inflammatory bowel diseases. The aim of this study was to assess the effect of punicic acid, a conjugated linolenic fatty acid from pomegranate seed oil on TNFalpha-induced neutrophil hyperactivation in vitro and on colon inflammation in vivo. METHODOLOGY AND PRINCIPAL FINDINGS:We analyzed the effect of punicic acid on TNFalpha-induced neutrophil upregulation of ROS production in vitro and on TNBS-induced rat colon inflammation. Results show that punicic acid inhibited TNFalpha-induced priming of ROS production in vitro while preserving formyl-methionyl-leucyl-phenylalanine (fMLP)-induced response. This effect was mediated by the inhibition of Ser345-p47phox phosphorylation and upstream kinase p38MAPK. Punicic acid also inhibited fMLP- and TNFalpha+fMLP-induced MPO extracellular release from neutrophils. In vivo experiments showed that punicic acid and pomegranate seed oil intake decreased neutrophil-activation and ROS/MPO-mediated tissue damage as measured by F2-isoprostane release and protected rats from TNBS-induced colon inflammation. CONCLUSIONS/SIGNIFICANCE:These data show that punicic acid exerts a potent anti-inflammatory effect through inhibition of TNFalpha-induced priming of NADPH oxidase by targeting the p38MAPKinase/Ser345-p47phox-axis and MPO release. This natural dietary compound may provide a novel alternative therapeutic strategy in inflammatory diseases such as inflammatory bowel diseases

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

2010a) “ICT for Energy Efficiency: Towards Smart Buildings, Manufacturing, Lighting and Grids

ABSTRACT The European Union (EU) has set its specific target of a 20% energy reduction in EU energy consumption by 2020. Achieving this goal will require major breakthroughs in the research and development (R&amp;D) of new technologies. Information and Communication Technologies (ICT) are today pervasive to all industrial and business sectors. They are expected to have a significant impact on energy efficiency in the future. In this paper, the four industrial disciplines of buildings, manufacturing, lighting and power grids are identified to have great potential to deploy ICT to improve their energy efficiency. These four sectors often come together in delivering infrastructures and environments for production, business and living, and together they produce and consume a significant proportion of Europe&apos;s energy. The state-of-the-art ICT for Energy Efficiency (ICT4EE) in these four sectors are discussed with focuses mainly on their available data on the potential impact, potential to improve through research, development and deployment, obstacles impeding the realisation of full potential, and actions which can be taken to accelerate achievement of potential. This leads to an ICT4EE impact assessment model which is needed to identify complementarities and synergies among these four sectors, harmonising common research and technological development (RTD) priorities, and establishing a cross-sectoral community with links to key stakeholders from them. A methodology for impact assessment model of ICT4EE has been designed on the basis of life cycle assessment and causal relationships which come from the currently existing research. The paper concludes that in order to achieve the full potential of ICT4EE, further support of multidisciplinary R&amp;D and innovation demonstrating the potential of ICT based solutions are needed to boost, reinforce, foster and accelerate the deployment of energy efficient solutions in these four industrial domains

Prognostic markers in patients with COVID-19 requiring intensive care support

المخلص: أهداف البحث: هدفت هذه الدراسة إلى تقييم مستويات معلمات الدم والتخثر المختلفة التي تم جمعها في نقاط زمنية مختلفة للتنبؤ بمضاعفات أو نتائج مرضى كوفيد-19 الذين تم إدخالهم في وحدة العناية المركزة. طرق البحث: أجرينا دراسة استطلاعية متعددة المراكز في أقسام وحدة العناية المركزة، وأدرج 118 مريضا من كوفيد-19 تم قبولهم في وحدة العناية المركزة. تم جمع البيانات السريرية وعينات الدم من اختبارات الدم الروتينية واختبارات التخثر عند الدخول، وفي الأيام 3 و 7 و 14. كانت مقاييس النتائج الرئيسية هي متطلبات التدفق العالي للأكسجين، والتخثر، والوفيات لمدة 30 يوما. النتائج: كان متوسط مدة الإقامة في وحدة العناية المركزة لمرضى عينة الدراسة 15.70 + 19 يوما بمتوسط 9. وقد تطول بشكل ملحوظ في المرضى المتعافين بمتوسط 28.20 + 29.90 يوما والمرضى الذين يعانون من تجلط الدم 34.40 + 39.60 يوما. تلقى ما مجموعه 113 (95.70٪) مريضا منع تخثر وقائي عند الدخول بأنظمة مختلفة، ومع ذلك، لوحظ تجلط الدم في أربعة (3.90٪) مرضى، لكن لم يمت أي منهم. كان هناك اتجاه تصاعدي في نتيجة الجلطات الدموية الوريدية بمرور الوقت من متوسط 5.10 + 2 في اليوم صفر إلى متوسط 6.40 + 2.80 في اليوم 14. ارتبطت درجة التخثر المنتشر داخل الأوعية بشكل كبير مع تجلط الدم. كان لدى 41.20 ٪ من المرضى في وحدة العناية المركزة درجة تخثر منتشر داخل الأوعية ≥4، وكان لدى 11.40 ٪ أقل من 4. ارتبط معدل الوفيات بشكل سلبي مع المرضى الذين عولجوا مع أوكسجين عالي التدفق، 9 (10.80٪)، وارتبط بشكل إيجابي مع المرضى الذين يستخدمون جهاز التنفس الصناعي، 16 (27.50٪). ارتبطت الزيادة في عدد خلايا الدم البيضاء (نسبة خطر التوزيع الفرعي: 0.91؛ فاصل الثقة 95٪: 0.80-1) وعدد العدلات (نسبة خطر التوزيع الفرعي: 1؛ فاصل الثقة 95٪: 1.01-1.05) بزيادة شدة المرض جنبا إلى جنب مع زيادة مستويات دي-دايمرز (نسبة مخاطر التوزيع الفرعي: 1.60 ؛ فاصل الثقة 95٪: 1.10-2.5). الاستنتاجات: تعد مستويات دي-دايمر ومستويات التخثر المنتشر داخل الأوعية علامات تنبؤية قد تتنبأ بشدة المرض لدى مرضى كوفيد-19. Abstract: Objectives: Several hematological and immunological markers, particularly neutrophil count, predict the severity of COVID-19. This study aimed at assessing hematological and coagulation parameters at different time points, to predict the complications or outcomes of patients with COVID-19 admitted to the intensive care unit (ICU). Methods: We conducted a prospective observational multicenter study in ICU departments. A total of 118 patients with COVID-19 admitted to the ICU were included. Clinical data and blood samples from routine hematology and coagulation tests were collected at admission, and on days 3, 7, and 14. The main outcome measures were high-flow-O2 requirement, thrombosis, and 30-day mortality. Results: The venous thromboembolism score increased from a mean of 5.10 ± 2 on day 0 to 6.40 ± 2.80 on day 14 (P = 0.0002). The disseminated intravascular coagulation (DIC) score significantly correlated with thrombosis (P = 0.031). A total of 41.20% of patients in the ICU had a DIC score ≥4, and 11.40% had a score <4. Mortality was negatively associated with patients on high-flow O2, 9 patients (10.80%) (P = 0.040), and positively associated with patients receiving ventilation, 16 patients (27.50%) (P < 0.001). An increase in white blood cell count (subdistribution hazard ratio (SHR): 0.91; 95% CI: 0.80–1) and neutrophil count (SHR: 1; 95% CI: 1.01–1.05) was associated with greater disease severity and D-dimer level (SHR: 1.60; 95% CI: 1.10–2.5). Conclusion: The venous thromboembolism score was significantly higher for patients who died than those who recovered. Furthermore, mechanical ventilation was associated with high mortality, whereas the risk of thrombosis and ICU admission correlated with high D-dimer values and DIC scores. Therefore, D-dimer levels and DIC scores are prognostic markers that may predict disease severity in patients with COVID-19

MULTI-DISCIPLINARY STRATEGIC RESEARCH AGENDA FOR ICT-ENABLED ENERGY EFFICIENCY

ABSTRACT Information and Communication Technologies (ICTs) are today pervasive to all industrial sectors which are faced with a sustainability paradox in maintaining economic growth while consuming fewer resources. ICTs have proven central to the performance driven development of modern industry in supporting production systems at all levels. Given this pervasiveness ICTs have a unique opportunity to address the sustainability paradox by enabling energy efficient viable operations. However, often the issue is not a lack of technological options, but rather a problem in understanding what choices will have the greatest impact. This paper introduces a multi-disciplinary strategic research agenda (SRA) for ICT-enabled energy efficiency developed by the REViSITE (Roadmap Enabling Vision and Strategy for ICT-enabled Energy Efficiency) EU funded project covering migration pathways from the state of the art to a common vision of ICT for energy efficiency (ICT4EE). These pathways are based on research and technology development (RTD) topics for short, medium and long term delivery in terms of industrial take-up. The developed SRA suggests ICT4EE research priorities for four targeted sectors: building, grids, manufacturing and lighting, since these four sectors often come together in delivering infrastructures and environments for production, service, business and living. It is anticipated that the identified RTD topics will be relevant to many other sectors in which ICTs can contribute to improving energy efficiency

Yield optimisation and molecular characterisation of uncultured CD271+ mesenchymal stem cells in the Reamer Irrigator Aspirator waste bag

Bone reconstruction requires the use of autografts from patients' iliac crest (IC); for large-volume defects bone void fillers and autologous mesenchymal stem cells (MSCs) are often added. The Reamer/Irrigator/Aspirator (RIA) device provides the means of harvesting large amounts of autograft and additionally yields a waste bag containing MSCs, which is currently discarded. The aim of this study was to enumerate and characterise native MSCs from RIA waste bag and compare them to 'gold-standard' donor-matched MSCs from IC bone marrow (BM). IC-BM from age matched trauma patients was used as control. In RIA waste bags the median MSC yield established using a colony-forming fibroblast assay was 314333 (range 5 x 104-1.4 x 106), equivalent to approximately one litre of IC-BM aspirate. CD271+ cells were present at high levels in RIA waste bags, had MSC surface phenotype (CD90+CD73+CD105+CD34>sup>-CD61-CD19-CD31-CD33-) and expressed genes associated with multipotentiality, osteogenesis, adipogenesis and angiogenic support. RIA- CD271+ MSCs were transcriptionally similar to donor-matched IC-CD271+ MSCs (76 % transcripts); with the majority of bone-related and Wnt pathway molecules being expressed at comparable levels. Lower-level expression of MCAM/CD146 and 5/13 hypoxia-related molecules was found in RIA-CD271+ MSCs, potentially reflecting their native residence in a more hypoxic environment of the endosteum and bone cortex. These data suggest that long bones contain very large numbers of MSCs, transcriptionally-similar to IC-BM MSCs; they can be procured by reaming using the RIA device and used, following concentration, as autologous and potentially allogeneic bone repair therapy

Protectin DX, a double lipoxygenase product of DHA, inhibits both ROS production in human neutrophils and cyclooxygenase activities.

International audienceNeutrophils play a major role in inflammation by releasing large amounts of reactive oxygen species (ROS) produced by NADPH oxidase (NOX) and myeloperoxidase (MPO). This ROS overproduction is mediated by phosphorylation of the NOX subunits in an uncontrolled manner. Therefore, targeting neutrophil subunits would represent a promising strategy to moderate NOX activity, lower ROS, and other inflammatory agents, such as cytokines and leukotrienes, produced by neutrophils. For this purpose, we investigated the effects of protectin DX (PDX)-a docosahexaenoic acid di-hydroxylated product which inhibits blood platelet aggregation-on neutrophil activation in vitro. We found that PDX decreases ROS production, inhibits NOX activation and MPO release from neutrophils. We also confirm, that PDX is an anti-aggregatory and anti-inflammatory agent by inhibiting both cyclooxygenase-1 and -2 (COX-1 and COX-2, E.C. 1.14.99.1) as well as COX-2 in lipopolysaccharides-treated human neutrophils. However, PDX has no effect on the 5-lipoxygenase pathway that produces the chemotactic agent leukotriene B4 (LTB4). Taken together, our results suggest that PDX could be a protective agent against neutrophil invasion in chronic inflammatory diseases