A spatiotemporal Data Envelopment Analysis (S-T DEA) approach:the need to assess evolving units

One of the major challenges in measuring efficiency in terms of resources and outcomes is the assessment of the evolution of units over time. Although Data Envelopment Analysis (DEA) has been applied for time series datasets, DEA models, by construction, form the reference set for inefficient units (lambda values) based on their distance from the efficient frontier, that is, in a spatial manner. However, when dealing with temporal datasets, the proximity in time between units should also be taken into account, since it reflects the structural resemblance among time periods of a unit that evolves. In this paper, we propose a two-stage spatiotemporal DEA approach, which captures both the spatial and temporal dimension through a multi-objective programming model. In the first stage, DEA is solved iteratively extracting for each unit only previous DMUs as peers in its reference set. In the second stage, the lambda values derived from the first stage are fed to a Multiobjective Mixed Integer Linear Programming model, which filters peers in the reference set based on weights assigned to the spatial and temporal dimension. The approach is demonstrated on a real-world example drawn from software development

Negative Effect of Smoking on the Performance of the QuantiFERON TB Gold in Tube Test.

False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively. Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results. Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02). Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status

Kaposi's Sarcoma-Associated Herpesvirus ORF57 Protein Binds and Protects a Nuclear Noncoding RNA from Cellular RNA Decay Pathways

The control of RNA stability is a key determinant in cellular gene expression. The stability of any transcript is modulated through the activity of cis- or trans-acting regulatory factors as well as cellular quality control systems that ensure the integrity of a transcript. As a result, invading viral pathogens must be able to subvert cellular RNA decay pathways capable of destroying viral transcripts. Here we report that the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 protein binds to a unique KSHV polyadenylated nuclear RNA, called PAN RNA, and protects it from degradation by cellular factors. ORF57 increases PAN RNA levels and its effects are greatest on unstable alleles of PAN RNA. Kinetic analysis of transcription pulse assays shows that ORF57 protects PAN RNA from a rapid cellular RNA decay process, but ORF57 has little effect on transcription or PAN RNA localization based on chromatin immunoprecipitation and in situ hybridization experiments, respectively. Using a UV cross-linking technique, we further demonstrate that ORF57 binds PAN RNA directly in living cells and we show that binding correlates with function. In addition, we define an ORF57-responsive element (ORE) that is necessary for ORF57 binding to PAN RNA and sufficient to confer ORF57-response to a heterologous intronless β-globin mRNA, but not its spliced counterparts. We conclude that ORF57 binds to viral transcripts in the nucleus and protects them from a cellular RNA decay pathway. We propose that KSHV ORF57 protein functions to enhance the nuclear stability of intronless viral transcripts by protecting them from a cellular RNA quality control pathway

Several domains from VAR2CSA can induce Plasmodium falciparum adhesion-blocking antibodies

<p>Abstract</p> <p>Background</p> <p>Malaria caused by <it>Plasmodium falciparum </it>can result in several different syndromes with severe clinical consequences for the about 200 million individuals infected each year. During pregnancy, women living in endemic areas become susceptible to malaria due to lack of antibodies against a unique <it>P. falciparum </it>membrane protein, named VAR2CSA. This antigen is not expressed in childhood infections, since it binds chondroitin sulphate A (CSA) expressed on the intervillous space in the placenta. A vaccine appears possible because women acquire protective antibodies hindering sequestration in the placenta as a function of parity. A challenge for vaccine development is to design small constructs of this large antigen, which can induce broadly protective antibodies. It has previously been shown that one domain of VAR2CSA, DBL4-FCR3, induces parasite adhesion-blocking antibodies. In this study, it is demonstrated that other domains of VAR2CSA also can induce antibodies with inhibitory activity.</p> <p>Methods</p> <p>All VAR2CSA domains from the 3D7 and HB3 parasites were produced in <it>Baculovirus</it>-transfected insect cells. Groups of three rats per protein were immunized and anti-sera were tested for surface reactivity against infected erythrocytes expressing FCR3 VAR2CSA and for the ability to inhibit FCR3CSA parasite adhesion to CSA. The fine specificity of the immune sera was analysed by VAR2CSA peptide arrays.</p> <p>Results</p> <p>Inhibitory antibodies were induced by immunization with DBL3-HB3 T1 and DBL1-3D7. However, unlike the previously characterised DBL4-FCR3 response the inhibitory response against DBL1-3D7 and DBL3-HB3 T1 was poorly reproduced in the second rounds of immunizations.</p> <p>Conclusion</p> <p>It is possible to induce parasite adhesion-blocking antibodies when immunizing with a number of different VAR2CSA domains. This indicates that the CSA binding site in VAR2CSA is comprised of epitopes from different domains.</p

Assessment of fatigue in chronic disease: a bibliographic study of fatigue measurement scales

A large number of fatigue scales exist and there is no consensus on which fatigue measuring scales that are most appropriate for use in assessment of fatigue in different diseases. We aimed to describe the use of fatigue scales in studies of disease-related fatigue during the last three decades. We searched databases from 1975 to 2004 for original studies reporting on disease-related fatigue and extracted information on method used to assess fatigue, diseases under study and year of publication. A total of 2285 papers reported measures of fatigue in chronic non-acute diseases of which 80% were published during the last decade. We identified 252 different ways to measure fatigue, of which 150 were use only once. Multi-symptom scales (n = 156) were used in 670 studies, while 71 scales specifically designed to measure fatigue were applied in 416 studies. The majority of these studies used scales with a multidimensional approach to fatigue, and most studies used scales that were disease-specific or only applied to few different diseases. Research in disease-related fatigue has increased exponentially during the last three decades, even if we adjust for the general increase in publishing activity. The number of scales has also increased and the majority of scales were developed for specific diseases. There is need for measure instruments with different sizes and dimensionality, and due to ceiling and floor effects, the same scale may not be useful for patients with different severity of fatigue. However, since fatigue is an unspecific symptom there should not be need for adopting disease specific fatigue scales for each individual disease. There may be differences in characteristics of fatigue between diseases and generic measurement instruments may facilitate documentation of such differences, which may be of clinical importance

Defining the molecular basis of interaction between R3 receptor-type protein tyrosine phosphatases and VE-cadherin

Receptor-type protein tyrosine phosphatases (RPTPs) of the R3 subgroup play key roles in the immune, vascular and nervous systems. They are characterised by a large ectodomain comprising multiple FNIII-like repeats, a transmembrane domain, and a single intracellular phosphatase domain. The functional role of the extracellular region has not been clearly defined and potential roles in ligand interaction, di-merization, and regulation of cell-cell contacts have been reported. Here bimolecular fluorescence complementation (BiFC) in live cells was used to examine the molecular basis for the interaction of VE-PTP with VE-cadherin, two proteins involved in endothelial cell contact and maintenance of vascu-lar integrity. The potential of other R3-PTPs to interact with VE-cadherin was also explored using this method. Quantitative BiFC analysis, using a VE-PTP construct expressing only the ectodomain and transmembrane domain, revealed a specific interaction with VE-cadherin, when compared with con-trols. Controls were sialophorin, an unrelated membrane protein with a large ectodomain, and a mem-brane anchored C-terminal Venus-YFP fragment, lacking both ectodomain and transmembrane do-mains. Truncation of the first 16 FNIII-like repeats from the ectodomain of VE-PTP indicated that re-moval of this region is not sufficient to disrupt the interaction with VE-cadherin, although it occurs predominantly in an intracellular location. A construct with a deletion of only the 17th domain of VE-PTP was, in contrast to previous studies, still able to interact with VE-cadherin, although this also was predominantly intracellular. Other members of the R3-PTP family (DEP-1, GLEPP1 and SAP-1) also exhibited the potential to interact with VE-cadherin. The direct interaction of DEP-1 with VE-cadherin is likely to be of physiological relevance since both proteins are expressed in endothelial cells. Together the data presented in the study suggest a role for both the ectodomain and transmembrane domain of R3-PTPs in interaction with VE-cadherin

Application of Direct Renin Inhibition to Chronic Kidney Disease

Chronic kidney disease has serious implications with a high risk for progressive loss of renal function, increased cardiovascular events as well as a substantial financial burden. The renin-angiotensin-aldosterone system (RAAS) is activated in chronic kidney disease, especially in diabetes and hypertension, which are the leading causes of chronic kidney disease. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease the rate of progression of diabetic and non-diabetic nephropathy and are recommended therapy for chronic kidney disease. Key clinical trials supporting the use of ACE inhibitors and ARBs in chronic kidney disease are discussed. Recent developments in our understanding of RAAS biology and the use of direct renin inhibition are reviewed in the context of their potential impact on the prevention and management of chronic kidney disease. Despite the clinical success of ACE inhibitors and ARBs the rates of mortality and progression to renal failure remain high in these patient populations. ACE inhibitor or ARB monotherapy, in doses commonly used in clinical practice does not result in complete suppression of the RAAS. Aliskiren, a direct renin inhibitor, offers a novel approach to inhibit the RAAS in chronic kidney disease. High dose ARB therapy or combination therapies with ACE inhibitors and ARBs have shown beneficial effects on surrogate markers of chronic kidney disease. Early data based on urinary protein excretion rates as a surrogate marker for renal function suggest a possibly novel role for aliskiren alone or in combination with ARBs in chronic kidney disease

Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families

<p>Abstract</p> <p>Background</p> <p>Currently known susceptibility genes such as <it>BRCA1 </it>and <it>BRCA2 </it>explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, <it>RNF8, UBC13 </it>and <it>MMS2 </it>were considered plausible candidate genes for susceptibility to breast cancer.</p> <p>Methods</p> <p>The entire coding region and splice junctions of <it>RNF8, UBC13 </it>and <it>MMS2 </it>genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing.</p> <p>Results</p> <p>Mutation analysis revealed several changes in <it>RNF8 </it>and <it>UBC13</it>, whereas no aberrations were observed in <it>MMS2</it>. None of the found sequence changes appeared to associate with breast cancer susceptibility.</p> <p>Conclusions</p> <p>The present data suggest that mutations in <it>RNF8, UBC13 </it>and <it>MMS2 </it>genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.</p

In vivo and in vitro assessment of pathways involved in contrast media-induced renal cells apoptosis

Contrast-induced nephropathy accounts for >10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay and represents a powerful predictor of poor early and late outcome. Mechanisms of contrast-induced nephropathy are not completely understood. In vitro data suggests that contrast media (CM) induces a direct toxic effect on renal tubular cells through the activation of the intrinsic apoptotic pathway. It is unclear whether this effect has a role in the clinical setting. In this work, we evaluated the effects of CM both in vivo and in vitro. By analyzing urine samples obtained from patients who experienced contrast-induced acute kidney injury (CI-AKI), we verified, by western blot and immunohistochemistry, that CM induces tubular renal cells apoptosis. Furthermore, in cultured cells, CM caused a dose–response increase in reactive oxygen species (ROS) production, which triggered Jun N-terminal kinases (JNK1/2) and p38 stress kinases marked activation and thus apoptosis. Inhibition of JNK1/2 and p38 by different approaches (i.e. pharmacological antagonists and transfection of kinase-death mutants of the upstream p38 and JNK kinases) prevented CM-induced apoptosis. Interestingly, N-acetylcysteine inhibited ROS production, and thus stress kinases and apoptosis activation. Therefore, we conclude that CM-induced tubular renal cells apoptosis represents a key mechanism of CI-AKI

High-resolution regional gravity field recovery from Poisson wavelets using heterogeneous observational techniques

2016-2017 > Academic research: refereed > Publication in refereed journal201804_a bcmaVersion of RecordPublishe