Potential benefits of using a toolkit developed to aid in the adaptation of HTA reports: a case study considering positron emission tomography (PET) and Hodgkin's disease

<p>Abstract</p> <p>Background</p> <p>The preparation of HTA reports requires a great deal of time, effort and resource, and there is a desire to improve efficiency, avoid duplication of effort and facilitate the transfer of knowledge between countries. This is of particular importance for countries with more limited resources which have less capacity to produce their own reports. The aim of this study was to investigate the extent of duplication of published Health Technology Assessment (HTA) reports, on the same technology, for the same indication; using positron emission tomography (PET) for lung cancer and Hodgkin's disease as a case study. This was done in order to assess the potential usefulness of a toolkit developed to aid in the adaptation of HTA reports from one context or country to another.</p> <p>Methods</p> <p>A systematic search of the National Institute for Health Research (NIHR) CRD HTA database was conducted in June 2008 in order to identify full HTA reports containing information on the use of PET for lung cancer and Hodgkin's disease, written in English, and readily available on the web. The contents of the reports identified were then examined to assess the extent of duplication of content between reports and potential for the use of the toolkit.</p> <p>Results</p> <p>From 132 records of HTA reports about PET, 8 reports were identified as fulfilling all the criteria set, and therefore demonstrating potential duplication of effort. All these reports covered four similar domains, technology use, safety, effectiveness and economic evaluation. Five of the reports also considered organisational aspects.</p> <p>Conclusions</p> <p>There was some duplication of effort in the preparation of HTA reports concerned with the use of PET for lung cancer and Hodgkin's disease. This is an example of where resource could have been conserved and time saved by the use of a toolkit developed to aid in the adaptation of HTA reports from one context to another.</p

Regulation of Respiration and Apoptosis by Cytochrome c Threonine 58 Phosphorylation

Cytochrome c (cytc) is a multifunctional protein, acting as an electron carrier in the electron transport chain (ETC), where it shuttles electrons from bc1 complex to cytochrome c oxidase (COX), and as a trigger of type II apoptosis when released from the mitochondria. We previously showed that cytc is regulated in a highly tissue-specific manner: Cytc isolated from heart, liver, and kidney is phosphorylated on Y97, Y48, and T28, respectively. Here, we have analyzed the effect of a new Cytc phosphorylation site, threonine 58, which we mapped in rat kidney Cytc by mass spectrometry. We generated and overexpressed wild-type, phosphomimetic T58E, and two controls, T58A and T58I cytc; the latter replacement is found in human and testis-specific Cytc. In vitro, COX activity, caspase-3 activity, and heme degradation in the presence of H2o2 were decreased with phosphomimetic Cytc compared to wild-type. Cytc-knockout cells expressing T58E or T58I Cytc showed a reduction in intact cell respiration, mitochondrial membrane potential (∆Ψm), ROS production, and apoptotic activity compared to wild-type. We propose that, under physiological conditions, Cytc is phosphorylated, which controls mitochondrial respiration and apoptosis. Under conditions of stress Cytc phosphorylations are lost leading to maximal respiration rates, ∆Ψm hyperpolarization, ROS production, and apoptosis

Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

Prostate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the functional effects of K53 modification in vitro, K53 was mutated to acetylmimetic glutamine (K53Q), and to arginine (K53R) and isoleucine (K53I) as controls. Cytochrome c oxidase (COX) activity analyzed with purified Cytc variants showed reduced oxygen consumption with acetylmimetic Cytc compared to the non-acetylated Cytc (WT), supporting the Warburg effect. In contrast to WT, K53Q Cytc had significantly lower caspase-3 activity, suggesting that modification of Cytc K53 helps cancer cells evade apoptosis. Cardiolipin peroxidase activity, which is another proapoptotic function of the protein, was lower in acetylmimetic Cytc. Acetylmimetic Cytc also had a higher capacity to scavenge reactive oxygen species (ROS), another pro-survival feature. We discuss our experimental results in light of structural features of K53Q Cytc, which we crystallized at a resolution of 1.31 Å, together with molecular dynamics simulations. In conclusion, we propose that K53 acetylation of Cytc affects two hallmarks of cancer by regulating respiration and apoptosis in prostate cancer xenografts

α-Thalassemia Impairs the Cytoadherence of Plasmodium falciparum-Infected Erythrocytes

α-Thalassemia results from decreased production of α-globin chains that make up part of hemoglobin tetramers (Hb; α(2)β(2)) and affects up to 50% of individuals in some regions of sub-Saharan Africa. Heterozygous (-α/αα) and homozygous (-α/-α) genotypes are associated with reduced risk of severe Plasmodium falciparum malaria, but the mechanism of this protection remains obscure. We hypothesized that α-thalassemia impairs the adherence of parasitized red blood cells (RBCs) to microvascular endothelial cells (MVECs) and monocytes--two interactions that are centrally involved in the pathogenesis of severe disease.We obtained P. falciparum isolates directly from Malian children with malaria and used them to infect αα/αα (normal), -α/αα and -α/-α RBCs. We also used laboratory-adapted P. falciparum clones to infect -/-α RBCs obtained from patients with HbH disease. Following a single cycle of parasite invasion and maturation to the trophozoite stage, we tested the ability of parasitized RBCs to bind MVECs and monocytes. Compared to parasitized αα/αα RBCs, we found that parasitized -α/αα, -α/-α and -/-α RBCs showed, respectively, 22%, 43% and 63% reductions in binding to MVECs and 13%, 33% and 63% reductions in binding to monocytes. α-Thalassemia was associated with abnormal display of P. falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite's main cytoadherence ligand and virulence factor, on the surface of parasitized RBCs.Parasitized α-thalassemic RBCs show PfEMP1 display abnormalities that are reminiscent of those on the surface of parasitized sickle HbS and HbC RBCs. Our data suggest a model of malaria protection in which α-thalassemia ameliorates the pro-inflammatory effects of cytoadherence. Our findings also raise the possibility that other unstable hemoglobins such as HbE and unpaired α-globin chains (in the case of β-thalassemia) protect against life-threatening malaria by a similar mechanism

Examination of the cut-off scores determined by the Ages and Stages Questionnaire in a population-based sample of 6 month-old Norwegian infants

<p>Abstract</p> <p>Background</p> <p>Few population-based samples have previously published performance on the Ages and Stages Questionnaire (ASQ), a recommended screening tool to detect infant developmental delay. The aim of the study was to investigate performance on the ASQ in a population-based sample of 6-month-old infants.</p> <p>Methods</p> <p>In this population-based questionnaire study from Oslo, Norway, the 30 item ASQ 6 month Questionnaire (N = 1053) were included, however without the pictograms, and compared to the Norwegian reference sample (N.ref) (N = 169) and to US cut-off values. Exclusion criteria were maternal non-Scandinavian ethnicity, infant age < 5.0 or > 7.0 months (corrected age), twins, and birth weight < 2.5 kg. Cut-off = 2.5 percentile (equivalent to mean minus 2 standard deviations). Pearson's Chi square and Mann-Whitney U were used to compare items and areas, respectively, with N.ref.</p> <p>Results</p> <p>The reported ASQ scores were lower on all but one of the 10 significantly different items, and in all areas except Personal social, compared to the N.ref sample. The estimated cut-off values for suspected developmental delay (Communication 25, Gross motor 15, Fine motor 18, Problem solving 25 and Personal social 20) were lower than the recommended American (US) values in all areas, and lower than the Norwegian values in two areas. Scores indicating need for further assessment were reached by 13.8% or 20.5% of the infants (missing items scored according to the US or the Norwegian manual), and by 33.8% or 30.3% of the infants using the recommended US or the Norwegian cut-off values, in this population-based sample. The Fine motor area demonstrated a large variability depending on the different cut-off and scoring possibilities. Both among the items excluding pictograms and the items that do not have pictograms, approximately every third item differed significantly compared to the N.ref sample.</p> <p>Conclusion</p> <p>The psychomotor developmental scores were lower than in the reference samples in this study of ASQ 6 month Questionnaire; to our knowledge the first study to be both representative and comparatively large. Approximately every third child with birth weight above 2.5 kg, received scores suggesting further assessment using recommended ASQ cut-off scores.</p

Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies

Purpose of Review Dairy products contain both beneficial and harmful nutrients in relation to cardiometabolic diseases. Here, we provide the latest scientific evidence regarding the relationship between dairy products and cardiometabolic diseases by reviewing the literature and updating meta-analyses of observational studies. Recent Findings We updated our previous meta-analyses of cohort studies on type 2 diabetes, coronary heart disease (CHD), and stroke with nine studies and confirmed previous results. Total dairy and low-fat dairy (per 200 g/d) were inversely associated with a 3–4% lower risk of diabetes. Yogurt was non-linearly inversely associatedwith diabetes (RR = 0.86, 95%CI: 0.83–0.90 at 80 g/ d). Total dairy and milk were not associated with CHD (RR~1.0). An increment of 200 g of daily milk intake was associated with an 8% lower risk of stroke. Summary The latest scientific evidence confirmed neutral or beneficial associations between dairy products and risk of cardiometabolic diseases

Are groups more rational than individuals? A review of interactive decision making in groups

Many decisions are interactive; the outcome of one party depends not only on its decisions or on acts of nature but also on the decisions of others. In the present article, we review the literature on decision making made by groups of the past 25 years. Researchers have compared the strategic behavior of groups and individuals in many games: prisoner's dilemma, dictator, ultimatum, trust, centipede and principal-agent games, among others. Our review suggests that results are quite consistent in revealing that groups behave closer to the game-theoretical assumption of rationality and selfishness than individuals. We conclude by discussing future research avenues in this area

Ablation of Proliferating Cells in the CNS Exacerbates Motor Neuron Disease Caused by Mutant Superoxide Dismutase

Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1G93A transgenic mice were treated intracerebroventicularly (ICV) with the anti-mitotic drug cytosine arabinoside (Ara-C). ICV delivery of Ara-C accelerated disease progression in SOD1G93A mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1G93A transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1β, IL-6, TGF-β and the growth factor IGF-1

Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model

<p>Abstract</p> <p>Background</p> <p>Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models.</p> <p>Methods</p> <p>To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice.</p> <p>Results</p> <p>By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated.</p> <p>Conclusions</p> <p>This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin.</p