Systematic review of sub-microscopic P. vivax infections : prevalence and determining factors

Background Sub-microscopic (SM) Plasmodium infections represent transmission reservoirs that could jeopardise malaria elimination goals. A better understanding of the epidemiology of these infections and factors contributing to their occurrence will inform effective elimination strategies. While the epidemiology of SM P. falciparum infections has been documented, that of SM P. vivax infections has not been summarised. The objective of this study is to address this deficiency. Methodology/Principal Findings A systematic search of PubMed was conducted, and results of both light microscopy (LM) and polymerase chain reaction (PCR)-based diagnostic tests for P. vivax from 44 cross-sectional surveys or screening studies of clinical malaria suspects were analysed. Analysis revealed that SM P. vivax is prevalent across different geographic areas with varying transmission intensities. On average, the prevalence of SM P. vivax in cross-sectional surveys was 10.9%, constituting 67.0% of all P. vivax infections detected by PCR. The relative proportion of SM P. vivax is significantly higher than that of the sympatric P. falciparum in these settings. A positive relationship exists between PCR and LM P. vivax prevalence, while there is a negative relationship between the proportion of SM P. vivax and the LM prevalence for P. vivax. Amongst clinical malaria suspects, however, SM P. vivax was not identified. Conclusions/Significance SM P. vivax is prevalent across different geographic areas, particularly areas with relatively low transmission intensity. Diagnostic tools with sensitivity greater than that of LM are required for detecting these infection reservoirs. In contrast, SM P. vivax is not prevalent in clinical malaria suspects, supporting the recommended use of quality LM and rapid diagnostic tests in clinical case management. These findings enable malaria control and elimination programs to estimate the prevalence and proportion of SM P. vivax infections in their settings, and develop appropriate elimination strategies to tackle SM P. vivax to interrupt transmission.

Using upper bounds on attainable discrimination to select discrete valued features

Selection of features that will permit accurate pattern classification is a difficult task. However, if a particular data set is represented by discrete valued features, it becomes possible to determine empirically the contribution that each feature makes to the discrimination between classes. This paper extends the discrimination bound method so that both the maximum and average discrimination expected on unseen test data can be estimated. These estimation techniques are the basis of a backwards elimination algorithm that can be use to rank features in order of their discriminative power. Two problems are used to demonstrate this feature selection process: classification of the Mushroom Database, and a real-world, pregnancy related medical risk prediction task - assessment of risk of perinatal death.

Green-fluorescent protein facilitates rapid in vivo detection of genetically transformed plant cells

Early detection of plant transformation events is necessary for the rapid establishment and optimization of plant transformation protocols. We have assessed modified versions of the green fluorescent protein (GFP) from Aequorea victoria as early reporters of plant transformation using a dissecting fluorescence microscope with appropriate filters. Gfp-expressing cells from four different plant species (sugarcane, maize, lettuce, and tobacco) were readily distinguished, following either Agrobacterium-mediated or particle bombardment-mediated transformation. The identification of gfp-expressing sugarcane cells allowed for the elimination of a high proportion of non-expressing explants and also enabled visual selection of dividing transgenic cells, an early step in the generation of transgenic organisms. The recovery of transgenic cell clusters was streamlined by the ability to visualize gfp-expressing tissues in vitro.

The potential impact of climate change and ultraviolet radiation on vaccine preventable infectious diseases and immunisation service delivery system

Climate change and solar ultraviolet radiation may affect vaccine-preventable infectious diseases (VPID), the human immune response process and the immunization service delivery system. We systematically reviewed the scientific literature and identified 37 relevant publications. Our study shows that climate variability and ultraviolet radiation may potentially affect VPID and the immunization delivery system through modulating vector reproduction and vaccination effectiveness, possibly influencing human immune response systems to the vaccination, and disturbing immunization service delivery. Further research is needed to determine these affects on climate-sensitive VPID and on human immune response to common vaccines. Such research will facilitate the development and delivery of optimal vaccination programs for target populations, to meet the goal of disease control and elimination.

A fast semi-implicit difference method for a nonlinear two-sided space-fractional diffusion equation with variable diffusivity coefficients

In this paper, we derive a new nonlinear two-sided space-fractional diffusion equation with variable coefficients from the fractional Fick’s law. A semi-implicit difference method (SIDM) for this equation is proposed. The stability and convergence of the SIDM are discussed. For the implementation, we develop a fast accurate iterative method for the SIDM by decomposing the dense coefficient matrix into a combination of Toeplitz-like matrices. This fast iterative method significantly reduces the storage requirement of O(n2)O(n2) and computational cost of O(n3)O(n3) down to n and O(nlogn)O(nlogn), where n is the number of grid points. The method retains the same accuracy as the underlying SIDM solved with Gaussian elimination. Finally, some numerical results are shown to verify the accuracy and efficiency of the new method.

The lipophilic opioids: Fentanyl, alfentanil, sufentanil and remifentanil

discusses fentanyl, alfentanil, sufentanil, and remifentanil which are synthetic opioid analgesics with high affinity for the mu opioid receptor. They have been widely adopted in anaesthetic practice for various surgical procedures (e.g. in cardiac surgery) and for long-term analgesia and sedation. Important pharmacokinetic differences between these analgesics have been described, and this chapter addresses how the pharmacokinetic profile of each analgesic is affected by many factors, including patient age, plasma protein content, acid–base balance status, cardiopulmonary bypass, changes in hepatic blood flow, and the co-administration of other drugs which compete for plasma protein carriers and metabolic pathways, although their profile is not significantly affected by renal insufficiency or compensated hepatic dysfunction, which has major clinical implications.

An evaluation of differential reinforcement of other behavior, differential reinforcement of incompatible behavior, and restitution for the management of aggressive behaviors

A 46 year old institutionalized retarded woman was referred for treatment because of frequent verbal abuse and physically aggressive behaviors. A multicomponent behavioral intervention consisting of differential reinforcement of other behaviors, differential reinforcement of incompatible behaviors, and restitution was implemented. A sequential withdrawal design was used in order to evaluate the effects of components of the original intervention, and to provide a measure of response maintenance. Results indicated a marked decrease in verbal abuse and elimination of physical aggression. Verbal abuse recurred when the restitution procedure was withdrawn. The relative efficacy of the different interventions is discussed with respect to the behavioral management of aggression.

Adaptive aneuploidy protects against thiol peroxidase deficiency by increasing respiration via key mitochondrial proteins

Aerobic respiration is a fundamental energy-generating process; however, there is cost associated with living in an oxygen-rich environment, because partially reduced oxygen species can damage cellular components. Organisms evolved enzymes that alleviate this damage and protect the intracellular milieu, most notably thiol peroxidases, which are abundant and conserved enzymes that mediate hydrogen peroxide signaling and act as the first line of defense against oxidants in nearly all living organisms. Deletion of all eight thiol peroxidase genes in yeast (∆8 strain) is not lethal, but results in slow growth and a high mutation rate. Here we characterized mechanisms that allow yeast cells to survive under conditions of thiol peroxidase deficiency. Two independent ∆8 strains increased mitochondrial content, altered mitochondrial distribution, and became dependent on respiration for growth but they were not hypersensitive to H2O2. In addition, both strains independently acquired a second copy of chromosome XI and increased expression of genes encoded by it. Survival of ∆8 cells was dependent on mitochondrial cytochrome-c peroxidase (CCP1) and UTH1, present on chromosome XI. Coexpression of these genes in ∆8 cells led to the elimination of the extra copy of chromosome XI and improved cell growth, whereas deletion of either gene was lethal. Thus, thiol peroxidase deficiency requires dosage compensation of CCP1 and UTH1 via chromosome XI aneuploidy, wherein these proteins support hydroperoxide removal with the reducing equivalents generated by the electron transport chain. To our knowledge, this is the first evidence of adaptive aneuploidy counteracting oxidative stress.

Understanding PK/PD

Pharmacology is the science underpinning dosing, mechanisms of action and effectiveness of drugs. Central to pharmacology, are the studies of pharmacokinetics (PK) and pharmacodynamics (PD). On one hand, PK defines the time-course of drug concentrations in the body and incorporates the broad concepts of drug absorption, distribution, metabolism and elimination. On the other hand, PD describes the relationship between drug concentrations and pharmacological effects. In practice, PK is often referred as “what the body does to the drug” whilst PD as “what the drug does to the body”. Thus, PK/PD describes the relationship between drug dose and pharmacological effects with changes in drug concentrations leading to different pharmacological effects.

Optimized multilayer indium-free electrodes for organic photovoltaics

Flexible multilayer electrodes that combine high transparency, high conductivity, and efficient charge extraction have been deposited, characterised and used as the anode in organic solar cells. The anode consists of an AZO/Ag/AZO stack plus a very thin oxide interlayer whose ionization potential is fine-tuned by manipulating its gap state density to optimise charge transfer with the bulk heterojunction active layer consisting of poly(n-3- hexylthiophene-2,5-diyl) and phenyl-C61-butyric acid methyl ester (P3HT:BC61BM). The deposition method for the stack was compatible with the low temperatures required for polymer substrates. Optimisation of the electrode stack was achieved by modelling the optical and electrical properties of the device and a power conversion efficiency of 2.9% under AM1.5 illumination compared to 3.0% with an ITO-only anode and 3.5% for an ITO:PEDOT electrode. Dark I-V reverse bias characteristics indicate very low densities of occupied buffer states close to the HOMO level of the hole conductor, despite observed ionization potential being high enough. Their elimination should raise efficiency to that with ITO:PEDOT.

Preliminary work on the detection of partial discharges in SF6 under impulse voltages

This paper presents preliminary results of an investigation into the detection of partial discharges on the rise of impulse voltages from a point-to-plane gap in SF6. A parallel RC detection impedance is placed in the earth path of a point. Computer simulations are done to determine the values of R and C that will result in the smallest impulse voltage signal and the largest discharge signal across the detection impedance. These simulations and the experimental work show that the impulse voltage signal can not be sufficiently attenuated during the rise time of the applied voltage impulse using the RC detection impedance alone. An alternative discharge detection method is proposed in which a resonant partial discharge coupler is used. Elimination of noise and the impulse voltage signal can be achieved by shorting the coupler plate to the ground plane in the middle of the disk. However, due to the bandwidth of the measuring equipment and noise from the impulse generator it was not possible to detect discharges on the rising edge of a 1.5s voltage impulse using a coupler shorted in the middle. It was found that for this particular coupler, with no shorting points, and if the rising edge of the voltage impulse is longer than 5us, (10us) PD activity can be detected on the rising edge.

A preconditioned numerical solver for stiff nonlinear reaction-diffusion equations with fractional Laplacians that avoids dense matrices

The numerical solution of fractional partial differential equations poses significant computational challenges in regard to efficiency as a result of the spatial nonlocality of the fractional differential operators. The dense coefficient matrices that arise from spatial discretisation of these operators mean that even one-dimensional problems can be difficult to solve using standard methods on grids comprising thousands of nodes or more. In this work we address this issue of efficiency for one-dimensional, nonlinear space-fractional reaction–diffusion equations with fractional Laplacian operators. We apply variable-order, variable-stepsize backward differentiation formulas in a Jacobian-free Newton–Krylov framework to advance the solution in time. A key advantage of this approach is the elimination of any requirement to form the dense matrix representation of the fractional Laplacian operator. We show how a banded approximation to this matrix, which can be formed and factorised efficiently, can be used as part of an effective preconditioner that accelerates convergence of the Krylov subspace iterative solver. Our approach also captures the full contribution from the nonlinear reaction term in the preconditioner, which is crucial for problems that exhibit stiff reactions. Numerical examples are presented to illustrate the overall effectiveness of the solver.

A Mouse Model of Early-Onset Renal Failure Due to a Xanthine Dehydrogenase Nonsense Mutation

Chronic kidney disease (CKD) is characterized by renal fibrosis that can lead to end-stage renal failure, and studies have supported a strong genetic influence on the risk of developing CKD. However, investigations of the underlying molecular mechanisms are hampered by the lack of suitable hereditary models in animals. We therefore sought to establish hereditary mouse models for CKD and renal fibrosis by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea, and identified a mouse with autosomal recessive renal failure, designated RENF. Three-week old RENF mice were smaller than their littermates, whereas at birth they had been of similar size. RENF mice, at 4-weeks of age, had elevated concentrations of plasma urea and creatinine, indicating renal failure, which was associated with small and irregularly shaped kidneys. Genetic studies using DNA from 10 affected mice and 91 single nucleotide polymorphisms mapped the Renf locus to a 5.8Mbp region on chromosome 17E1.3. DNA sequencing of the xanthine dehydrogenase (Xdh) gene revealed a nonsense mutation at codon 26 that co-segregated with affected RENF mice. The Xdh mutation resulted in loss of hepatic XDH and renal Cyclooxygenase-2 (COX-2) expression. XDH mutations in man cause xanthinuria with undetectable plasma uric acid levels and three RENF mice had plasma uric acid levels below the limit of detection. Histological analysis of RENF kidney sections revealed abnormal arrangement of glomeruli, intratubular casts, cellular infiltration in the interstitial space, and interstitial fibrosis. TUNEL analysis of RENF kidney sections showed extensive apoptosis predominantly affecting the tubules. Thus, we have established a mouse model for autosomal recessive early-onset renal failure due to a nonsense mutation in Xdh that is a model for xanthinuria in man. This mouse model could help to increase our understanding of the molecular mechanisms associated with renal fibrosis and the specific roles of XDH and uric acid. © 2012 Piret et al.

Tissue requirements for establishing long-term CD4+ T cell-mediated immunity following Leishmania donovani infection

Organ-specific immunity is a feature of many infectious diseases, including visceral leishmaniasis caused by Leishmania donovani. Experimental visceral leishmaniasis in genetically susceptible mice is characterized by an acute, resolving infection in the liver and chronic infection in the spleen. CD4+ T cell responses are critical for the establishment and maintenance of hepatic immunity in this disease model, but their role in chronically infected spleens remains unclear. In this study, we show that dendritic cells are critical for CD4+ T cell activation and expansion in all tissue sites examined. We found that FTY720-mediated blockade of T cell trafficking early in infection prevented Ag-specific CD4+ T cells from appearing in lymph nodes, but not the spleen and liver, suggesting that early CD4+ T cell priming does not occur in liver-draining lymph nodes. Extended treatment with FTY720 over the first month of infection increased parasite burdens, although this associated with blockade of lymphocyte egress from secondary lymphoid tissue, as well as with more generalized splenic lymphopenia. Importantly, we demonstrate that CD4+ T cells are required for the establishment and maintenance of antiparasitic immunity in the liver, as well as for immune surveillance and suppression of parasite outgrowth in chronically infected spleens. Finally, although early CD4+ T cell priming appeared to occur most effectively in the spleen, we unexpectedly revealed that protective CD4+ T cell-mediated hepatic immunity could be generated in the complete absence of all secondary lymphoid tissues.

Diabetes in South Asians

Economic, dietary and other lifestyle transitions have been occurring rapidly in most South Asian countries, making their populations more vulnerable to developing Type 2 diabetes and cardiovascular diseases. Recent data show an increasing prevalence of Type 2 diabetes in urban areas as well as in semi-urban and rural areas, inclusive of people belonging to middle and low socio-economic strata. Prime determinants for Type 2 diabetes in South Asians include physical inactivity, imbalanced diets, abdominal obesity, excess hepatic fat and, possibly, adverse perinatal and early life nutrition and intra-country migration. It is reported that Type 2 diabetes affects South Asians a decade earlier and some complications, for example nephropathy, are more prevalent and progressive than in other races. Further, prevalence of pre-diabetes is high, and so is conversion to diabetes, while more than 50% of those who are affected remain undiagnosed. Attitudes, cultural differences and religious and social beliefs pose barriers in effective prevention and management of Type 2 diabetes in South Asians. Inadequate resources, insufficient healthcare budgets, lack of medical reimbursement and socio-economic factors contribute to the cost of diabetes management. The challenge is to develop new translational strategies, which are pragmatic, cost-effective and scalable and can be adopted by the South Asian countries with limited resources. The key areas that need focus are: generation of awareness, prioritizing health care for vulnerable subgroups (children, women, pregnant women and the underprivileged), screening of high-risk groups, maximum coverage of the population with essential medicines, and strengthening primary care. An effective national diabetes control programme in each South Asian country should be formulated, with these issues in mind.