Safety and efficacy of a feed additive consisting of a dried extract from the leaves of Ginkgo biloba L. (G. biloba dry extract) for use in cats and dogs (C.I.A.M.).
Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of a dried extract prepared from the leaves of Ginkgo biloba L. (G. biloba dry extract) when used as a sensory additive in feed for cats and dogs. G. biloba dry extract is specified to contain at least 24% flavonol glycosides, at least 6% terpene lactones and less than 5 ppm ginkgolic acids. Since uncertainty remains concerning the nature of up to 75% of the extract, the additive is not sufficiently characterised to allow an assessment based on the individual components. In view of the indication of potential carcinogenicity from the results of studies by the National Toxicology Program of the USA, obtained with a G. biloba extract comparable with the additive under assessment, the FEEDAP Panel concludes that the additive cannot be considered safe for cats and dogs. In the absence of data, no conclusions can be drawn on the safety for the user. In the absence of evidence that the extract acts as a flavour in animal feed or has an effect on palatability, the FEEDAP Panel was unable to conclude on the efficacy of the additive.


NovoHMM: a hidden Markov model for de novo peptide sequencing.
De novo sequencing of peptides poses one of the most challenging tasks in data analysis for proteome research. In this paper, a generative hidden Markov model (HMM) of mass spectra for de novo peptide sequencing which constitutes a novel view on how to solve this problem in a Bayesian framework is proposed. Further extensions of the model structure to a graphical model and a factorial HMM to substantially improve the peptide identification results are demonstrated. Inference with the graphical model for de novo peptide sequencing estimates posterior probabilities for amino acids rather than scores for single symbols in the sequence. Our model outperforms state-of-the-art methods for de novo peptide sequencing on a large test set of spectra.


Human IMR-32 neuroblastoma cells as a model cell line in Alzheimer's disease research.
The present study investigated expression and processing of amyloid precursor protein by neuronally differentiated IMR-32 neuroblastoma cells. APP mRNA in these cells was found to consist of approximately 58% APP695, 38% APP751, and < 4% APP770. APP-immunoreactive bands detected in western blots of cellular protein extracts were only detected by anti-APP antibodies to peptides with strong homology to APLP2, suggesting that these bands represent APP-like proteins and not APP itself. This result suggests that previous studies claiming immunodetection of cellular forms of APP may have to be re-evaluated. Four main species of C-terminal truncated, secreted APP were detected in blots of protein extracts from medium conditioned by these cells. The immunoreactive profile of these bands suggested a cleavage site N-terminal to the Lys16-Leu17 bond of alpha-secretase. This, together with differences in number and molecular mass of APP-immunoreactive bands between secreted APP from IMR-32 cells and that from the commonly used PC-12 cells, suggests differences in APP processing between these two neuronally differentiated cell lines. In theory, IMR-32 cells being of human neuronal origin may be a more appropriate cell line to study APP-processing in relation to Alzheimer's disease than the rat phaeochromocytoma PC-12 cell line. Therefore, these detected differences warrant further investigation. Additionally IMR-32 cells under certain tissue culture conditions can form intracellular fibrillary material that reacts with anti-PHF specific antibodies. Neuronally differentiated IMR-32 cells could therefore be used as a model system to investigate possible interactions between APP-processing and PHF formation.


Defective erythropoiesis in bone marrow is a mechanism of anemia in children with cancer.
Evaluation of the mechanism of anemia in cancer patients might help to select patients for the more efficient use of erythropoietin (EPO, a growth factor for erythroid precursor cells). For this, we investigated whether the production of EPO responds to anemia and the bone marrow responds to EPO appropriately, and whether chronic inflammation is inhibitory to erythropoiesis in anemic cancer children. Serum levels of EPO, soluble transferrin receptor (sTfR), tumor necrosis factor (TNF)-alpha, and erythrocyte sedimentation rate (ESR) in anemic cancer children were measured by enzyme-linked immunosorbent assay and then the correlation coefficients between those parameters and hemoglobin (Hb) were determined. Both in leukemia and in solid tumor patients, there were significant inverse correlations between Hb and EPO (leukemia: tau=-0.547, p<0.0001; solid tumor: tau=-0.591, p<0.0001), and between sTfR and EPO (leukemia: tau=-0.223, p<0.05; solid tumor: tau=-0.401, p<0.05). In contrast, sTfR showed a correlation with Hb in leukemia (tau=0.216, p<0.05) but not in solid tumor patients. sTfR was suppressed in 53% of anemic episodes of leukemia and 78% of those of solid tumor patients. Our results suggest that in cancer children, the EPO production is not defective and chronic inflammation is not inhibitory to erythropoiesis. Rather, the defective erythropoiesis itself is thought to be responsible for the anemia.


A mucoadhesive in situ gel delivery system for paclitaxel.
MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer and colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX) and mucoadhesives for sustained and targeted delivery of anticancer drugs. The delivery system consisted of chitosan and glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence and absence of Tween 80 at drug loads of 0.18%, 0.30%, and 0.54% (wt/wt), in Sorensen's phosphate buffer (pH 7.4) at 37 degrees C. Different mucin-producing cell lines (Calu-3>Caco-2) were selected for PTX transport studies. Transport of PTX from solution and gel delivery system was performed in side by side diffusion chambers from apical to basal (A-B) and basal to apical (B-A) directions. In vitro release studies revealed that within 4 hours, only 7.61% +/- 0.19%, 12.0% +/- 0.98%, 31.7% +/- 0.40% of PTX were released from 0.18%, 0.30%, and 0.54% drug-loaded gel formulation, respectively, in absence of Tween 80. However, in presence of surfactant (0.05% wt/vol) in the dissolution medium, percentages of PTX released were 28.1% +/- 4.35%, 44.2% +/- 6.35%, and 97.1% +/- 1.22%, respectively. Paclitaxel has shown a polarized transport in all the cell monolayers with B-A transport 2 to 4 times higher than in the A-B direction. The highest mucin-producing cell line (Calu-3) has shown the lowest percentage of PTX transport from gels as compared with Caco-2 cells. Transport of PTX from mucoadhesive gels was shown to be influenced by the mucin-producing capability of cell.


[Testicular autotransplant and laparoscopic orchiectomy in a case of bilateral adult cryptorchism].
B.L. a 27 year old bilaterally cryptorchid patient underwent right testicular autotransplantation in the presence of a quite normal testis. After one year the patency of microsurgical anastomosis was confirmed by means Doppler flowmetry and scrotal echography demonstrated the presence into the scrotum of a testis provided of a normal echogenicity. Left laparoscopic orchiectomy was planned. A small semilunar skin incision was made just below the rime of the umbilicus. Veress needle was introduced: as soon as the needle pierced the parietal peritoneum, its spring mechanism was released allowing the sharp needle point to retract leaving only the blunt tip protruding. Carbon dioxide gas was insufflated through the side part of the Veress needle until adequate abdominal distension was achieved. After having removed the Veress needle, the laparoscope on its sharp-pointed trocar was introduced into the peritoneal cavity and left testis was easily localized. Four trocars were introduced up to proceed to laparoscopic orchiectomy. The patient was discharged two days after. In our opinion in the presence of a bilateral cryptorchism in the adult, is better to plan a monolateral autotransplantation. After having verified the long-term result of microsurgery we can decide if a contralateral orchiectomy has to be planned.


Optically nonlinear energy transfer in light-harvesting dendrimers.
Dendrimeric polymers are the subject of intense research activity geared towards their implementation in nanodevice applications such as energy harvesting systems, organic light-emitting diodes, photosensitizers, low-threshold lasers, and quantum logic elements, etc. A recent development in this area has been the construction of dendrimers specifically designed to exhibit novel forms of optical nonlinearity, exploiting the unique properties of these materials at high levels of photon flux. Starting from a thorough treatment of the underlying theory based on the principles of molecular quantum electrodynamics, it is possible to identify and characterize several optically nonlinear mechanisms for directed energy transfer and energy pooling in multichromophore dendrimers. Such mechanisms fall into two classes: first, those where two-photon absorption by individual donors is followed by transfer of the net energy to an acceptor; second, those where the excitation of two electronically distinct but neighboring donor groups is followed by a collective migration of their energy to a suitable acceptor. Each transfer process is subject to minor dissipative losses. In this paper we describe in detail the balance of factors and the constraints that determines the favored mechanism, which include the excitation statistics, structure of the energy levels, laser coherence factors, chromophore selection rules and architecture, possibilities for the formation of delocalized excitons, spectral overlap, and the overall distribution of donors and acceptors. Furthermore, it transpires that quantum interference between different mechanisms can play an important role. Thus, as the relative importance of each mechanism determines the relevant nanophotonic characteristics, the results reported here afford the means for optimizing highly efficient light-harvesting dendrimer devices.


ICU survivors' utilisation of diaries post discharge: a qualitative descriptive study.
A growing body of evidence has confirmed that intensive care unit survivors encounter myriad of physical and psychological complications during their recovery. The incidence of psychological morbidity in intensive care survivors is increasingly being recognised. The causes of psychological morbidity are multi-factorial but may be associated with a complete lack of, or delusional recall of events in intensive care. Intensive care unit diaries are an initiative designed to enable survivors to help restore factual memories and differentiate those from delusional. To explore survivors' and family members' perceptions and utilisation of diaries following discharge from hospital. A single centre qualitative descriptive study was undertaken in a general intensive care unit in Western Australia. Participants were surveyed 3, 6 and 12 months following discharge from hospital. Eighteen participants completed one or more surveys. Many of the participants who completed the surveys read their diaries but few made entries in them following discharge. Reading the diaries evoked mixed emotions for these participants; however they still viewed the diaries as a positive initiative in their recovery. Diaries enabled survivors to fill the memory gaps, make sense of their experience and reinforced the human connection when they were immersed in a technological environment. Use of patient diaries was received positively by the participants in this study. Diaries are a simple, cost effective initiative which enabled survivors to piece together the time they had lost, concreted their experience in reality and enabled them to retain a connection with their loved ones whilst immersed in a technological environment.


Clustered Multi-Task Learning Via Alternating Structure Optimization.
Multi-task learning (MTL) learns multiple related tasks simultaneously to improve generalization performance. Alternating structure optimization (ASO) is a popular MTL method that learns a shared low-dimensional predictive structure on hypothesis spaces from multiple related tasks. It has been applied successfully in many real world applications. As an alternative MTL approach, clustered multi-task learning (CMTL) assumes that multiple tasks follow a clustered structure, i.e., tasks are partitioned into a set of groups where tasks in the same group are similar to each other, and that such a clustered structure is unknown a priori. The objectives in ASO and CMTL differ in how multiple tasks are related. Interestingly, we show in this paper the equivalence relationship between ASO and CMTL, providing significant new insights into ASO and CMTL as well as their inherent relationship. The CMTL formulation is non-convex, and we adopt a convex relaxation to the CMTL formulation. We further establish the equivalence relationship between the proposed convex relaxation of CMTL and an existing convex relaxation of ASO, and show that the proposed convex CMTL formulation is significantly more efficient especially for high-dimensional data. In addition, we present three algorithms for solving the convex CMTL formulation. We report experimental results on benchmark datasets to demonstrate the efficiency of the proposed algorithms.


Agent-based model of genotype editing.
Evolutionary algorithms rarely deal with ontogenetic, non-inherited alteration of genetic information because they are based on a direct genotype-phenotype mapping. In contrast, several processes have been discovered in nature which alter genetic information encoded in DNA before it is translated into amino-acid chains. Ontogenetically altered genetic information is not inherited but extensively used in regulation and development of phenotypes, giving organisms the ability to, in a sense, re-program their genotypes according to environmental cues. An example of post-transcriptional alteration of gene-encoding sequences is the process of RNA Editing. Here we introduce a novel Agent-based model of genotype editing and a computational study of its evolutionary performance in static and dynamic environments. This model builds on our previous Genetic Algorithm with Editing, but presents a fundamentally novel architecture in which coding and non-coding genetic components are allowed to co-evolve. Our goals are: (1) to study the role of RNA Editing regulation in the evolutionary process, (2) to understand how genotype editing leads to a different, and novel evolutionary search algorithm, and (3) the conditions under which genotype editing improves the optimization performance of traditional evolutionary algorithms. We show that genotype editing allows evolving agents to perform better in several classes of fitness functions, both in static and dynamic environments. We also present evidence that the indirect genotype/phenotype mapping resulting from genotype editing leads to a better exploration/exploitation compromise of the search process. Therefore, we show that our biologically-inspired model of genotype editing can be used to both facilitate understanding of the evolutionary role of RNA regulation based on genotype editing in biology, and advance the current state of research in Evolutionary Computation.


Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome.
Recently, differences in the levels of various chemokines and cytokines were reported in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as compared with controls. Moreover, the analyte profile differed between chronic ME/CFS patients of long duration versus patients with disease of less than 3years. In the current study, we measured the plasma levels of 34 cytokines, chemokines and growth factors in 100 chronic ME/CFS patients of long duration and in 79 gender and age-matched controls. We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients. All three biomarkers were significantly correlated in a multivariate cluster analysis. In addition, we identified significant reductions in the concentrations of fractalkine (CX3CL1) and monokine-induced-by-IFN-γ (MIG; CXCL9) along with increases in the concentrations of eotaxin 2 (CCL24) in ME/CFS patients. Our data recapitulates previous data from another USA ME/CFS cohort in which circulating levels of IL-7 were reduced. Also, a reduced level of VEGF-A was reported previously in sera of patients with Gulf War Illness as well as in cerebral spinal fluid samples from a different cohort of USA ME/CFS patients. To our knowledge, we are the first to test for levels of IL-16 in ME/CFS patients. In combination with previous data, our work suggests that the clustered reduction of IL-7, IL-16 and VEGF-A may have physiological relevance to ME/CFS disease. This profile is ME/CFS-specific since measurement of the same analytes present in chronic infectious and autoimmune liver diseases, where persistent fatigue is also a major symptom, failed to demonstrate the same changes. Further studies of other ME/CFS and overlapping disease cohorts are warranted in future.


Practical limitations to a positive deviance approach for identifying dietary patterns compatible with the reduction of cancer risk.
The positive deviance (PD) approach seeks to devise and promote health-promoting practices identified within the most successful member of a society. The World Cancer Research Fund and the American Institute for Cancer Research (WCRF/AICR) recommendations indicate the need for specific dietary behaviours, which may be considered impractical. Thus, it is important to demonstrate ways in which these dietary practices have been achieved from concordant individuals. The present study aimed to assess the feasibility of constructing healthy eating guides in four international settings. Adult participants from the Netherlands (n = 1052), Scotland (n = 849), Mexico (n = 790) and Guatemala (n = 873) enrolled in an international diet survey project. Participants with inadequate diets and current smokers were excluded from the analysis. Concordance with selected WCRF/AICR individual guideline components related to diet and lifestyle were evaluated. A selection of participants was made towards making a set of 14 rotating menus for a cancer-prevention healthy-eating guide. Overall concordance with the WCRF/AICR recommendations was low in all four nations and no participants with an ideal behaviour were found. The selection of candidates for constructing 14 daily menus for a single national guide identified 51, 13 and 12 individuals concordant with 11 of 14 WCRF/AICR recommendation components in Guatemala, Scotland and Mexico, respectively, and 24 individuals concordant with eight of 14 WCRF/AICR components in the Netherlands. The basis for PD guidance for developing dietary recommendations for cancer prevention was strong across all social classes in Guatemala, marginal for Mexico and Scotland, and effectively impossible for the Netherlands.


Brain MRI atrophy quantification in MS: From methods to clinical application.
Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years.


Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial.
Evidence suggests that low vitamin D status may increase the risk of cancer. To determine if dietary supplementation with vitamin D3 and calcium reduces the risk of cancer among older women. A 4-year, double-blind, placebo-controlled, population-based randomized clinical trial in 31 rural counties (June 24, 2009, to August 26, 2015-the final date of follow-up). A total of 2303 healthy postmenopausal women 55 years or older were randomized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. The treatment group (vitamin D3 + calcium group) received 2000 IU/d of vitamin D3 and 1500 mg/d of calcium; the placebo group received identical placebos. The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Among 2303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2064 (90%) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, -0.06% to 3.46%]; P = .06). Kaplan-Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D3 + calcium group and 2 in the placebo group). Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. clinicaltrials.gov Identifier: NCT01052051.


Enzymatically activated emulsions stabilised by interfacial nanofibre networks.
We report on-demand formation of emulsions stabilised by interfacial nanoscale networks. These are formed through biocatalytic dephosphorylation and self-assembly of Fmoc(9-fluorenylmethoxycarbonyl)dipeptide amphiphiles in aqueous/organic mixtures. This is achieved by using alkaline phosphatase which transforms surfactant-like phosphorylated precursors into self-assembling aromatic peptide amphiphiles (Fmoc-tyrosine-leucine, Fmoc-YL) that form nanofibrous networks. In biphasic organic/aqueous systems, these networks form preferentially at the interface thus providing a means of emulsion stabilisation. We demonstrate on-demand emulsification by enzyme addition, even after storage of the biphasic mixture for several weeks. Experimental (Fluorescence, FTIR spectroscopy, fluorescence microscopy, electron microscopy, atomic force microscopy) and computational techniques (atomistic molecular dynamics) are used to characterise the interfacial self-assembly process.


Religious differentials in postfamine marriage patterns, Northern Ireland, 1840-1915. I. Demographic and isonymy analysis.
During the Irish famine of 1846-1851 there were an estimated 1.0 million excess deaths, the migration of 1.3 million persons, and 300,000 averted births. To assess the influence of population changes at the local level in Ulster, decennial census records were analyzed for the Barony of Upper Ards, County Down, from 1841 to 1911. Data on marriages contracted in the four Roman Catholic, five Presbyterian, and eight Episcopalian congregations also were abstracted from civil parish registers for the period 1840-1915 and were used to calculate levels of random and nonrandom inbreeding through time by isonymy analysis. In the prefamine census of 1841 the total population of the Upper Ards was 16,964. From 1841 to 1911 population numbers decreased by 44.5%, with a consistent surplus of females in all parishes throughout the study period. Both population density and the number of persons per dwelling declined at equivalent rates, resulting in increasingly dispersed patterns of settlement. There was a marked overall increase in nonrandom inbreeding (Fn) in the immediate postfamine period, which was sustained throughout the nineteenth century before declining during 1900-1915. However, significant heterogeneity was observed in the Fn values calculated, both between and within each of the three main religious denominations, indicating differential local responses to marriage partner choice in the postfamine years. The observed changes are not compatible with a simple model of reduction in mate availability under conditions of population decline. Instead, they can most convincingly be explained in terms of a specific population response to the subsistence crisis initiated by the famine.


A survey of plant and algal genomes and transcriptomes reveals new insights into the evolution and function of the cellulose synthase superfamily.
Enzymes of the cellulose synthase (CesA) family and CesA-like (Csl) families are responsible for the synthesis of celluloses and hemicelluloses, and thus are of great interest to bioenergy research. We studied the occurrences and phylogenies of CesA/Csl families in diverse plants and algae by comprehensive data mining of 82 genomes and transcriptomes. We found that 1) charophytic green algae (CGA) have orthologous genes in CesA, CslC and CslD families; 2) liverwort genes are found in the CesA, CslA, CslC and CslD families; 3) The fern Pteridium aquilinum not only has orthologs in these conserved families but also in the CslB, CslH and CslE families; 4) basal angiosperms, e.g. Aristolochia fimbriata, have orthologs in these families too; 5) gymnosperms have genes forming clusters ancestral to CslB/H and to CslE/J/G respectively; 6) CslG is found in switchgrass and basal angiosperms; 7) CslJ is widely present in dicots and monocots; 8) CesA subfamilies have already diversified in ferns. We speculate that: (i) ferns and horsetails might both have CslH enzymes, responsible for the synthesis of mixed-linkage glucans and (ii) CslD and similar genes might be responsible for the synthesis of mannans in CGA. Our findings led to a more detailed model of cell wall evolution and suggested that gene loss played an important role in the evolution of Csl families. We also demonstrated the usefulness of transcriptome data in the study of plant cell wall evolution and diversity.


Cloning, function, and localization of human, canine, and Drosophila ZIP10 (SLC39A10), a Zn2+ transporter.
Zinc (Zn2+) is the second most abundant trace element, but is considered a micronutrient, as it is a cofactor for many enzymes and transcription factors. Whereas Zn2+ deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn2+ is nephrotoxic. As for other ions and solutes, Zn2+ is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins. ZIP10 is reported to be localized at the apical membrane of renal proximal tubules in rats, where it is believed to play a role in Zn2+ import. Renal regulation of Zn2+ is of particular interest in light of growing evidence that Zn2+ may play a role in kidney stone formation. The objective of this study was to show that ZIP10 homologs transport Zn2+, as well as ZIP10, kidney localization across species. We cloned ZIP10 from dog, human, and Drosophila ( CG10006), tested clones for Zn2+ uptake in Xenopus oocytes and localized the protein in renal structures. CG10006, rather than foi (fear-of-intimacy, CG6817) is the primary ZIP10 homolog found in Drosophila Malpighian tubules. The ZIP10 antibody recognizes recombinant dog, human, and Drosophila ZIP10 proteins. Immunohistochemistry reveals that ZIP10 in higher mammals is found not only in the proximal tubule, but also in the collecting duct system. These ZIP10 proteins show Zn2+ transport. Together, these studies reveal ZIP10 kidney localization, a role in renal Zn2+ transport, and indicates that CG10006 is a Drosophila homolog of ZIP10.


Space bandwidth-efficient realizations of linear systems.
One can obtain either exact realizations or useful approximations of linear systems or matrix-vector products that arise in many different applications by implementing them in the form of multistage or multichannel fractional Fourier-domain filters, resulting in space-bandwidth-efficient systems with acceptable decreases in accuracy. Varying the number and the configuration of filters enables one to trade off between accuracy and efficiency in a flexible manner. The proposed scheme constitutes a systematic way of exploiting the regularity or structure of a given linear system or matrix, even when that structure is not readily apparent.


WAVELET-BASED GENETIC ASSOCIATION ANALYSIS OF FUNCTIONAL PHENOTYPES ARISING FROM HIGH-THROUGHPUT SEQUENCING ASSAYS.
Understanding how genetic variants influence cellular-level processes is an important step toward understanding how they influence important organismal-level traits, or "phenotypes," including human disease susceptibility. To this end, scientists are undertaking large-scale genetic association studies that aim to identify genetic variants associated with molecular and cellular phenotypes, such as gene expression, transcription factor binding, or chromatin accessibility. These studies use high-throughput sequencing assays (e.g., RNA-seq, ChIP-seq, DNase-seq) to obtain high-resolution data on how the traits vary along the genome in each sample. However, typical association analyses fail to exploit these high-resolution measurements, instead aggregating the data at coarser resolutions, such as genes, or windows of fixed length. Here we develop and apply statistical methods that better exploit the high-resolution data. The key idea is to treat the sequence data as measuring an underlying "function" that varies along the genome, and then, building on wavelet-based methods for functional data analysis, test for association between genetic variants and the underlying function. Applying these methods to identify genetic variants associated with chromatin accessibility (dsQTLs), we find that they identify substantially more associations than a simpler window-based analysis, and in total we identify 772 novel dsQTLs not identified by the original analysis.


Towards a multidimensional healthy ageing phenotype.
There is great interest in developing tools to measure healthy ageing and to identify early stages of health impairment, which may guide the implementation of interventions to prevent or delay the development of disease, disability, and mortality. Here, we review the most recent developments directed to operationalize, and test, definitions of healthy ageing. There is lack of consensus about how to define healthy ageing and, unsurprisingly, diversity in the instruments for its measurement. However, progress is being made in describing and in devising tools to capture the healthy ageing phenotype. Attempts to measure healthy ageing have relied primarily on cross-sectional data collected in older people. More recent studies have assessed the healthy ageing phenotype using markers of multiple functional domains and have used longitudinal data to model the dynamics and trajectories of healthy ageing. Given the complexity of the ageing process, no single measure is able to predict the ageing trajectory. Current attempts to operationalize the healthy ageing phenotype have relied on markers and data from earlier cohort studies and are limited by the tools used to collect data in those studies. Such data are often unsuitable to detect early subtle declines in function and/or are inappropriate for use in younger old adults. Future studies employing more objective and novel markers of healthy ageing are likely to offer opportunities to define and operationalize the healthy ageing phenotype.


Climate and Pest-Driven Geographic Shifts in Global Coffee Production: Implications for Forest Cover, Biodiversity and Carbon Storage.
Coffee is highly sensitive to temperature and rainfall, making its cultivation vulnerable to geographic shifts in response to a changing climate. This could lead to the establishment of coffee plantations in new areas and potential conflicts with other land covers including natural forest, with consequent implications for biodiversity and ecosystem services. We project areas suitable for future coffee cultivation based on several climate scenarios and expected responses of the coffee berry borer, a principle pest of coffee crops. We show that the global climatically-suitable area will suffer marked shifts from some current major centres of cultivation. Most areas will be suited to Robusta coffee, demand for which could be met without incurring forest encroachment. The cultivation of Arabica, which represents 70% of consumed coffee, can also be accommodated in the future, but only by incurring some natural forest loss. This has corresponding implications for carbon storage, and is likely to affect areas currently designated as priority areas for biodiversity. Where Arabica coffee does encroach on natural forests, we project average local losses of 35% of threatened vertebrate species. The interaction of climate and coffee berry borer greatly influences projected outcomes.


Common Lung Microbiome Identified among Mechanically Ventilated Surgical Patients.
The examination of the pulmonary microbiome in patients with non-chronic disease states has not been extensively examined. Traditional culture based screening methods are often unable to identify bacteria from bronchoalveolar lavage samples. The advancement of next-generation sequencing technologies allows for a culture-independent molecular based analysis to determine the microbial composition in the lung of this patient population. For this study, the Ion Torrent PGM system was used to assess the microbial complexity of culture negative bronchoalveolar lavage samples. A group of samples were identified that all displayed high diversity and similar relative abundance of bacteria. This group consisted of Hydrogenophaga, unclassified Bacteroidetes, Pedobacter, Thauera, and Acinetobacter. These bacteria may be representative of a common non-pathogenic pulmonary microbiome associated within this population of patients.


Purification of the 300K intermediate filament-associated protein and its in vitro recombination with intermediate filaments.
IFAP-300K is a 300,000-mol-wt intermediate filament-associated protein previously identified in the baby hamster kidney fibroblastic cell line (BHK-21) by a monoclonal antibody (Yang H.-Y., N. Lieska, A. E. Goldman, and R. D. Goldman, 1985, J. Cell Biol., 100: 620-631). In the present study, this molecule was purified from the high salt/detergent-insoluble cytoskeletal preparation of these cells. Gel filtration on Sephacryl S-400 in the presence of 7.2 M urea allowed separation of the high molecular weight fraction from the structural intermediate filament (IF) subunits desmin and vimentin, designated 54K and 55K, respectively, and other low molecular weight polypeptides. DE-52 cellulose chromatography of the high molecular weight fraction using a linear NaCl gradient in 8 M urea yielded a pure 300,000-mol-wt species which was confirmed to be IFAP-300K by immunological and peptide mapping criteria. Two-dimensional PAGE of native BHK IF preparations followed by immunoblot analysis demonstrated the inability of the IFAP-300K-immunoreactive material to enter the first dimensional gel except as a 200,000-mol-wt doublet which presumably represented a major proteolytic derivative of IFAP-300K. The molecule's pl of 5.35, as determined by chromatofocusing, and its amino acid composition were extremely similar to those of BHK cell vimentin/desmin despite their non-identity. Ultrastructurally, IFAP-300K preparations in low salt buffers existed as particles composed of one or two elliptical units measuring 16 X 20 nm. In physiological salt buffers, the predominant entities were large, elongated aggregates of the elliptical units, which were able to be decorated by using the immunogold technique with monoclonal anti-IFAP-300K. Compared with the morphology of homopolymer vimentin IF, in vitro recombination studies using column-purified vimentin and IFAP-300K demonstrated the additional presence of aggregates similar in appearance to IFAP-300K at points of contact between IFs. Antibody decoration and immunogold labeling of these recombined preparations using rabbit antidesmin/vimentin and monoclonal anti-IFAP-300K confirmed the identity of the inter-filament, amorphous material as IFAP-300K. The presence of IFAP-300K at many points of intersection and lateral contact between IFs, as well as at apparent inter-filament "bridges," in these recombined specimens was identical to that seen both in situ and in native IF preparations. No such co-sedimentation was found in vitro between actin and IFAP-300K. No effects of IFAP-300K upon the kinetics of IF polymerization were detected by turbidimetric measurements.


Measurement of atmospheric neutrino flux consistent with tau neutrino appearance.
A search for the appearance of tau neutrinos from nu(mu) <--> nu(tau) oscillations in the atmospheric neutrinos has been performed using 1489.2 days of atmospheric neutrino data from the Super-Kamiokande-I experiment. A best fit tau neutrino appearance signal of 138+/-48(stat)-32(+15)(syst) events is obtained with an expectation of 78+/-26(syst). The hypothesis of no tau neutrino appearance is disfavored by 2.4 sigma.


Prenatal cocaine exposure alters potassium-evoked dopamine release dynamics in rat striatum.
The emerging profile for the effects of prenatal cocaine exposure presents two prominent features in the exposed offspring: cognitive/attention deficits and an age-associated trend toward motor/tone abnormalities up to 2 years of age. One candidate mechanism underlying these clinical features is long-lasting alterations to dopamine (DA) neuron function. However, the impact of prenatal cocaine exposure on DA release in dopaminergic terminal fields in vivo in mature offspring is poorly understood. Long-Evans female rats were implanted with an i.v. access port, bred, and given saline or cocaine-HCl (3 mg/kg/ml) for gestational days (GD) 8-14 (1x/day), GD 15-21 (2x/day), or GD 8-21 (1x/day-GD 8-14, 2x/day-GD 15-21). Using in vivo high-speed chronoamperometric recordings, potassium-stimulated DA release was measured in striatum of anesthetized male offspring 90-150 days after birth. There was a trend toward increased potassium-evoked DA signal amplitudes in offspring exposed to cocaine at any time period examined. In offspring exposed to cocaine during GD 8-21 and GD 15-21, but not at GD 8-14, there were significant decreases in the clearance capacity of the potassium-evoked DA signal compared with control offspring. The time required to clear 80% of the evoked DA signal (T(80)) in striatum for DA was significantly prolonged (approximately 150% of control) and this effect was further increased in the mean-evoked DA concentration range for these two groups. We also measured total dopamine transporter (DAT) and tyrosine hydroxylase protein levels in these offspring by blot immunolabeling and found a small, but significant, decrease in DAT protein in striatum from offspring exposed at GD 8-21 and GD 15-21. Collectively, these data demonstrate that prenatal cocaine exposure during dopamine neuron neurogenesis has long-lasting effects on DA neuron function lasting into early adulthood which may be related in part to steady state DAT protein levels. These molecular events may be associated with established cognitive deficits and perhaps the trends seen in altered motor behavior.


Contribution of central neuropathy to postural instability in IDDM patients with peripheral neuropathy.
To evaluate the contribution of central neuropathy on postural impairment observed in diabetic patients with peripheral neuropathy. Central sensory and motor nervous propagation, nerve conduction velocity, and static posturography were assessed in the following age-matched subjects: 7 IDDM patients with peripheral neuropathy (group DN), 18 IDDM patients without peripheral neuropathy (group D), and 31 control subjects (group C). Somatosensory-evoked potentials (SEPs) during tibial nerve stimulation were recorded, and the spine-to-scalp sensory central conduction time (SCCT) was evaluated. Motor-evoked potentials (MEPs) were recorded from leg muscles during magnetic transcranial brain stimulation, and the scalp-to-spine motor central conduction time (MCCT) was evaluated. The following posturographic parameters were calculated from the statokinesigram: trace length, trace surface, velocity of body sway with its standard deviation, and VFY (a parameter derived from the velocity variance and the anteroposterior mean position of the body). SCCT was significantly higher in the DN group than in the C and D groups (P < 0.001). MCCT was similar in all groups. Posturographic parameters were all significantly impaired in the DN group (P < 0.01). While posturographic parameters showed a direct relationship with some parameters of peripheral nerve conduction, no correlations were observed with SEP and MEP central conduction time. These results were also confirmed by logistic regression, which indicates peripheral neuropathy as the only implicating factor in postural instability (odds ratio 0.22, 95% CI 0.07-0.75) after data reduction by means of factor analysis. Although diabetic patients with peripheral neuropathy show a delay in central sensory conduction, postural instability may be fully explained by the presence of peripheral neuropathy.


Mode-locked laser cavities with a single prism for dispersion compensation.
We demonstrate the use of a single prism for adjustable dispersion compensation in a mode-locked laser cavity, instead of the standard approach with a prism pair. A simple model based on the prism-pair configuration is presented to determine the group-velocity dispersion by use of ray optics to trace the wavelength-dependent optical axes through the cavity. We experimentally demonstrated this concept with a passively mode-locked diode-pumped Nd:glass laser producing 200-fs pulses with a 200-mW average output power, using only one intracavity prism. The advantages of such a cavity design are simple alignment, reduced loss, and lossless wavelength tunability This technique can be generalized to other angularly dispersive elements such as prismatic output couplers.


Kir2.1 encodes the inward rectifier potassium channel in rat arterial smooth muscle cells.
1. The molecular nature of the strong inward rectifier K+ channel in vascular smooth muscle was explored by using isolated cell RT-PCR, cDNA cloning and expression techniques. 2. RT-PCR of RNA from single smooth muscle cells of rat cerebral (basilar), coronary and mesenteric arteries revealed transcripts for Kir2.1. Transcripts for Kir2.2 and Kir2.3 were not found. 3. Quantitative PCR analysis revealed significant differences in transcript levels of Kir2.1 between the different vascular preparations (n = 3; P < 0.05). A two-fold difference was detected between Kir2.1 mRNA and beta-actin mRNA in coronary arteries when compared with relative levels measured in mesenteric and basilar preparations. 4. Kir2.1 was cloned from rat mesenteric vascular smooth muscle cells and expressed in Xenopus oocytes. Currents were strongly inwardly rectifying and selective for K+. 5. The effect of extracellular Ba2+, Ca2+, Mg2+ and Cs2+ ions on cloned Kir2.1 channels expressed in Xenopus oocytes was examined. Ba2+ and Cs+ block were steeply voltage dependent, whereas block by external Ca2+ and Mg2+ exhibited little voltage dependence. The apparent half-block constants and voltage dependences for Ba2+, Cs+, Ca2+ and Mg2+ were very similar for inward rectifier K+ currents from native cells and cloned Kir2.1 channels expressed in oocytes. 6. Molecular studies demonstrate that Kir2.1 is the only member of the Kir2 channel subfamily present in vascular arterial smooth muscle cells. Expression of cloned Kir2.1 in Xenopus oocytes resulted in inward rectifier K+ currents that strongly resemble those that are observed in native vascular arterial smooth muscle cells. We conclude that Kir2.1 encodes for inward rectifier K+ channels in arterial smooth muscle.


Sino-orbital aspergillosis in acquired immunodeficiency syndrome.
To describe the clinical features, causes, imaging characteristics, treatment, and outcome of patients with the acquired immunodeficiency syndrome (AIDS) and sino-orbital aspergillosis. Records of 5 patients were reviewed. Results of imaging and histopathologic examinations and clinical courses of the patients were studied. There were 3 women and 2 men (mean age, 34.0 years). All had received a diagnosis of AIDS, and mean CD4+ cell count was 0.014 x 10(9)/L (14 cells/mm3). Computed tomographic scanning exhibited heterogeneous, enhancing sino-orbital soft tissue lesions with bony erosion, and magnetic resonance imaging disclosed soft tissue masses hypointense on T1- and T2-weighted images. The infection involved 1 or more paranasal sinuses, with extension into the right orbit in 3 patients and into the left orbit in 2. Patients were treated with aggressive surgical debridement and intravenous antifungal agents. In addition, local irrigation of amphotericin B was performed in 3 patients. Aspergillus fumigatus was found to be the cause in all 5 patients. Intracranial extension developed in 4 patients, and all subsequently died. The 2 longest surviving patients were the only ones being treated with protease inhibitors. Three patients had a history of frequent marijuana smoking. Sino-orbital aspergillosis is a progressive, relentless, and usually fatal opportunistic infection of advanced AIDS. Patients are first seen with long-standing headache and proptosis with minimal external inflammatory signs. Marijuana smoking may increase the risk for development of sino-orbital aspergillosis in these patients. Aggressive surgical and medical treatment, combined with newer combination therapies using protease inhibitors, may improve the longevity of these patients.


Impact of preventing exacerbations on deterioration of health status in COPD.
Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St George's Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent (<1.65 exacerbations x yr(-1)) and frequent (>1.65 exacerbations x yr(-1)). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.


Nutrient limitation and stoichiometry of carnivorous plants.
The cost-benefit model for the evolution of carnivorous plants posits a trade-off between photosynthetic costs associated with carnivorous structures and photosynthetic benefits accrued through additional nutrient acquisition. The model predicts that carnivory is expected to evolve if its marginal benefits exceed its marginal costs. Further, the model predicts that when nutrients are scarce but neither light nor water is limiting, carnivorous plants should have an energetic advantage in competition with non-carnivorous plants. Since the publication of the cost-benefit model over 20 years ago, marginal photosynthetic costs of carnivory have been demonstrated but marginal photosynthetic benefits have not. A review of published data and results of ongoing research show that nitrogen, phosphorus, and potassium often (co-)limit growth of carnivorous plants and that photosynthetic nutrient use efficiency is 20 - 50 % of that of non-carnivorous plants. Assessments of stoichiometric relationships among limiting nutrients, scaling of leaf mass with photosynthesis and nutrient content, and photosynthetic nutrient use efficiency all suggest that carnivorous plants are at an energetic disadvantage relative to non-carnivorous plants in similar habitats. Overall, current data support some of the predictions of the cost-benefit model, fail to support others, and still others remain untested and merit future research. Rather than being an optimal solution to an adaptive problem, botanical carnivory may represent a set of limited responses constrained by both phylogenetic history and environmental stress.


The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis.
Curcumin and quercetin are antioxidant molecules with anti-proliferative, anti-inflammatory and immunosuppressive activities. The objective of this study was to investigate the inhibitory activity of these agents using four assays of inflammatory aspects of arthritis. Crystal-induced neutrophil activation was measured by luminol-dependent chemiluminescence. Synoviocyte proliferation was measured by an MTS assay using HIG-82 rabbit synoviocytes in cell culture. Chondrocyte (cultured primary cells) expression of the matrix metalloproteinases collagenase and stromelysin was measured by Northern Blot analysis. Angiogenesis was measured using the chorioallantoic membrane of the chick embryo. Both agents inhibited neutrophil activation, synoviocyte proliferation and angiogenesis. Curcumin strongly inhibited collagenase and stromelysin expression at micromolar concentrations whereas quercetin had no effect in this assay. These studies suggest that curcumin and to a lesser extent quercetin may offer therapeutic potential for the treatment of crystal-induced arthritis or rheumatoid arthritis.


Detection of Helicobacter pylori in paraffin-embedded gastric biopsy specimens by in situ hybridization.
Helicobacter pylori is the causative agent of chronic gastritis, peptic ulcers, and is also associated with gastric cancer. Eradication of H pylori infection has proven to be difficult to confirm. The authors developed a nonradioactive in situ hybridization method for detection of H pylori and compared it with conventional methods for diagnosis of the infection. Reverse transcription followed by polymerase chain reaction (PCR) with two 22-base primers was used to amplify a 520 base pair (bp) segment of 16S rRNA from H pylori. The PCR product was labeled with digoxigenin and used as a probe. Specificity of the probe was tested by dot blot hybridization against DNA from 30 different strains of related and unrelated bacteria. Specificity of in situ hybridization assay was proven by the lack of hybridization on sections with gram negative and positive bacteria other than H pylori, with an unrelated probe, without probe, and after RNase treatment. A random sample of 15 biopsy specimens was blindly studied by in situ hybridization method and the results were compared with those of culture and conventional histology. Comparison of in situ hybridization and conventional histology showed agreement in all 15 specimens (5 negative and 10 positive). Between culture and in situ hybridization there was agreement in 13 cases (8 positive, 5 negative). Two cases were negative by culture but positive by in situ hybridization and histology. Nonradioactive in situ hybridization provides a sensitive and specific method for detection of H pylori infection. It should be particularly useful for confirmation of infection in cases equivocal with other methods, and potentially useful in post-treatment evaluation.


The ipsilateral human motor cortex can functionally compensate for acute contralateral motor cortex dysfunction.
What promotes motor recovery from stroke? To date, studies of recovery from stroke have shown alterations in function in various cortical areas, including the contralesional (unaffected) motor cortex (M1). However, whether these changes contribute to recovery or are mere epiphenomena remains unclear. We therefore sought evidence that the ipsilateral M1 can compensate for dysfunction of the contralateral M1. We recorded the change in force production during a finger-tapping task in response to acute disruption of M1 function by repetitive transcranial magnetic stimulation (rTMS). Neither control (occipital) nor ipsilateral M1 rTMS lead to a change in tapping force. RTMS over contralateral M1 had a short-lived effect and induced changes in ipsilateral M1 excitability around the time that these behavioral effects abated, consistent with delayed compensation by the ipsilateral M1. Simultaneous bilateral M1 stimulation, designed to prevent compensation by the ipsilateral M1, had a large and prolonged effect on tapping force. This is the first demonstration that the ipsilateral primary motor cortex is capable of functionally significant compensation for focal contralateral cortical dysfunction in the adult human and provides a rational basis for interventional treatments aimed at promoting functional compensation in unaffected cortical areas after stroke.


Long-Term Outcomes of Indirect Bypass for 629 Children With Moyamoya Disease: Longitudinal and Cross-Sectional Analysis.
Background and Purpose- In pediatric moyamoya disease, there are few reports on the efficacy of surgical intervention for stroke prevention. We evaluated the long-term outcomes of indirect bypass surgery on a relatively large number of children with moyamoya disease in a single center. Methods- From August 1988 to December 2012, 772 children underwent indirect bypass surgery. This study included 629 patients who were followed up for >5 years, excluding patients with moyamoya syndrome. The mean clinical follow-up duration was 12 years (range, 5-29 years). Cross-sectional analysis was performed based on either Karnofsky Performance Scale or Lansky Play Performance Scale to evaluate overall clinical outcomes and factors associated with unfavorable outcomes. To analyze the longitudinal effect of surgery, the annual risk of symptomatic infarction or hemorrhage on the operated hemisphere after indirect bypass surgery was calculated with a person-year method, and the event-free survival rate was evaluated using the Kaplan-Meier method. Results- The overall clinical outcome was favorable in 95% of the patients. The annual risks of symptomatic infarction and hemorrhage on the operated hemispheres were 0.08% and 0.04%, respectively. Furthermore, the 10-year event-free survival rates for symptomatic infarction and hemorrhage were 99.2% and 99.8%. Conclusions- Indirect bypass surgery could provide satisfactory long-term improvement in overall clinical outcome and prevention of recurrent stroke in children with moyamoya disease.


Interaction of the chemoreflex and the pulmonary inflation reflex in the regulation of coronary circulation in conscious dogs.
The interaction of chemoreflex and pulmonary inflation reflex control of the coronary circulation was examined in conscious dogs by comparing the responses to chemoreflex stimulation (intracarotid injection of nicotine) when ventilation was allowed to increase with those when ventilation was controlled. The responses were also compared with those elicited by both forced mechanical and spontaneous hyperinflation. When the heart rate was constant, intracarotidly administered nicotine induced an increase in the depth of respiration followed closely by an increase in late diastolic coronary flow from 48 +/- 2 to 106 +/- 8 ml/min and a reduction in late diastolic coronary resistance from 1.62 +/- 0.08 to 0.78 +/- 0.06 mm Hg/ml min-1. After beta-receptor and cholinergic blockade, a similar coronary dilation in response to nicotine occurred only when ventilation was allowed to increase. However, when ventilation was controlled, intracarotidly administered nicotine increased coronary resistance after combined beta-receptor and cholinergic blockade. The reflex coronary dilation was not observed after carotid sinus nerve section or after alpha-receptor blockade. Thus, nicotine stimulation of the carotid chemoreflex results in a striking coronary dilation that has two components. The minor component involves a chemoreflex with its efferent pathway in tthe vagi. The major component of coronary dilation follows an increase in the depth of respiration, and its efferent component appears to involve withdrawal of alpha-adrenergic constrictor tone. An almost identical period of reflex coronary dilation followed either forced mechanical or spontaneous hyperinflation in the conscious dog.


Elevated E2F1 inhibits transcription of the androgen receptor in metastatic hormone-resistant prostate cancer.
Activation of E2F transcription factors, through disruption of the retinoblastoma (Rb) tumor-suppressor gene, is a key event in the development of many human cancers. Previously, we showed that homozygous deletion of Rb in a prostate tissue recombination model exhibits increased E2F activity, activation of E2F-target genes, and increased susceptibility to hormonal carcinogenesis. In this study, we examined the expression of E2F1 in 667 prostate tissue cores and compared it with the expression of the androgen receptor (AR), a marker of prostate epithelial differentiation, using tissue microarray analysis. We show that E2F1 expression is low in benign and localized prostate cancer, modestly elevated in metastatic lymph nodes from hormone-naïve patients, and significantly elevated in metastatic tissues from hormone-resistant prostate cancer patients (P = 0.0006). In contrast, strong AR expression was detected in benign prostate (83%), localized prostate cancer (100%), and lymph node metastasis (80%), but decreased to 40% in metastatic hormone-resistant prostate cancer (P = 0.004). Semiquantitative reverse transcription-PCR analysis showed elevated E2F1 mRNA levels and increased levels of the E2F-target genes dihyrofolate reductase and proliferating cell nuclear antigen in metastatic hormone-independent prostate cancer cases compared with benign tissues. To identify a role of E2F1 in hormone-independent prostate cancer, we examined whether E2F1 can regulate AR expression. We show that exogenous expression of E2F1 significantly inhibited AR mRNA and AR protein levels in prostate epithelial cells. E2F1 also inhibited an AR promoter-luciferase construct that was dependent on the transactivation domain of E2F1. Furthermore, using chromatin immunoprecipitation assays, we show that E2F1 and the pocket protein family members p107 and p130 bind to the AR promoter in vivo. Taken together, these results show that elevated E2F1, through its ability to repress AR transcription, may contribute to the progression of hormone-independent prostate cancer.


Regulatory Peptide Nesfatin-1 and its Relationship with Metabolic Syndrome.
Metabolic syndrome is associated with a group of conditions abdominal obesity, high triglyceride levels, reduction in low-density lipoprotein, increased blood pressure, and increased fasting blood glucose. Hence, it poses a risk for type 2 diabetes and cardiovascular diseases. The prevalence of metabolic syndrome increases with age. Nesfatin-1, which affects different systems, has recently been discovered as a regulatory peptide molecule. With the discovery of nesfatin-1, it has been reported to inhibit the intake of nutrients and have significant regulatory effects on energy metabolism. As nesfatin-1 is present in both central and peripheral tissues, it is thought to have many functions. In addition to its suppressive effect on food intake, nesfatin-1 has also been reported to have an effect on the blood glucose level for regulating cardiac functions and affecting obesity by providing weight loss. Considering the effects of nesfatin-1, it may be associated with metabolic syndrome.


Unified single-cell analysis of testis gene regulation and pathology in five mouse strains.
To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyze a novel 57,600 cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. By jointly analyzing mutant and wild-type cells we decomposed our data into 46 components that identify novel meiotic gene-regulatory programs, mutant-specific pathological processes, and technical effects, and provide a framework for imputation. We identify, de novo, DNA sequence motifs associated with individual components that define temporally varying modes of gene expression control. Analysis of SDA components also led us to identify a rare population of macrophages within the seminiferous tubules of Mlh3-/- and Hormad1-/- mice, an area typically associated with immune privilege.


Developing a "clinical presentation" curriculum at the University of Calgary.
Currently, medical curricula are structured according to disciplines, body systems, or clinical problems. Beginning in 1988, the faculty of the University of Calgary Faculty of Medicine (U of C) carefully evaluated the advantages and disadvantages of each of these models in seeking to revise their school's curriculum. However, all three models fell short of a curricular structure based on current knowledge and principles of adult learning, clinical problem solving, community demands, and curriculum management. By 1991, the U of C had formulated a strategic plan for a revised curriculum structure based on the way patients present to physicians, and implementation of this plan has begun. In creating the new curriculum, 120 clinical presentations (e.g., "loss of consciousness/syncope") were defined and each was assigned to an individual or small group of faculty for development based on faculty expertise and interest. Terminal objectives (i.e., "what to do") were defined for each presentation to describe the appropriate clinical behaviors of a graduating physician. Experts developed schemes that outlined how they differentiated one cause (i.e., disease category) from another. The underlying enabling objectives (i.e., knowledge, skills, and attitudes) for reaching the terminal objectives for each clinical presentation were assigned as departmental responsibilities. A new administrative structure evolved in which there is a partnership between a centralized multidisciplinary curriculum committee and the departments. This new competency-based, clinical presentation curriculum is expected to significantly enhance students' development of clinical problem-solving skills and affirms the premise that prudent, continuous updating is essential for improving the quality of medical education.


Development of an updated PCR assay for detection of African swine fever virus.
Due to the current unavailability of vaccines or treatments for African swine fever (ASF), which is caused by African swine fever virus (ASFV), rapid and reliable detection of the virus is essential for timely implementation of emergency control measures and differentiation of ASF from other swine diseases with similar clinical presentations. Here, an improved PCR assay was developed and evaluated for sensitive and universal detection of ASFV. Primers specific for ASFV were designed based on the highly conserved region of the vp72 gene sequences of all ASFV strains available in GenBank, and the PCR assay was established and compared with two OIE-validated PCR tests. The analytic detection limit of the PCR assay was 60 DNA copies per reaction. No amplification signal was observed for several other porcine viruses. The novel PCR assay was more sensitive than two OIE-validated PCR assays when testing 14 strains of ASFV representing four genotypes (I, V, VIII and IX) from diverse geographical areas. A total of 62 clinical swine blood samples collected from Uganda were examined by the novel PCR, giving a high agreement (59/62) with a superior sensitive universal probe library-based real-time PCR. Eight out of 62 samples tested positive, and three samples with higher Ct values (39.15, 38.39 and 37.41) in the real-time PCR were negative for ASFV in the novel PCR. In contrast, one (with a Ct value of 29.75 by the real-time PCR) and two (with Ct values of 29.75 and 33.12) ASFV-positive samples were not identified by the two OIE-validated PCR assays, respectively. Taken together, these data show that the novel PCR assay is specific, sensitive, and applicable for molecular diagnosis and surveillance of ASF.


The pathogens and curative effects analysis of perianal abscess of infants under 3 months.
Zhu Y, Xu F. The pathogens and curative effects analysis of perianal abscess of infants under 3 months. Turk J Pediatr 2019; 61: 40-43. In order to guide clinical treatment for perianal abscess of young infants, the characteristics of pathogens and curative effects analysis were conducted. Bacterial culture results, antibiotics susceptibility tests and curative effects of abscess incision were retrospectively analyzed in 66 cases of perianal abscess of infants under 3 months. There were 48 cases of Klebsiella pneumoniae, 7 cases of Staphylococcus, 6 cases of Escherichia coli, 5 cases of Proteus in the pathogen culture results. Klebsiella pneumoniae, the predominant pathogen, was susceptible to most antibiotics, especially to imipenem, cefoperazonesulbactam and amikacin with low drug resistance rates. However, high drug resistance rates were found to ampicillin and nitrofurantion. After abscess incision, the complication rate of anal fistula was 6.6% in infants under 3 months and 60.3% in the adult group. There was significant difference P<0.01. In conclusion, Klebsiella pneumoniae was the most common pathogen in perianal abscess of infants under 3 months and was commonly resistant to ampicillin and nitrofurantion. Since perianal abscess of infants under 3 months is a self-limited disorder, simple surgical intervention and synchronous sensitive antibiotic administration are suggested as the optimal management.


A comparison of the effects of citalopram and moclobemide on resting brain perfusion in social anxiety disorder.
The serotonin specific reuptake inhibitor (SSRI) citalopram and the reversible mono-amine oxidase-A inhibitor (RIMA) moclobemide have both been used successfully for the treatment of social anxiety disorder (SAD). In this study we investigate the effects of these compounds on resting brain function using single photon emission computed tomography (SPECT). Subjects meeting DSM-IV criteria for SAD underwent regional cerebral blood flow (rCBF) SPECT using Tc-HMPAO at baseline and after 8 weeks of treatment with either citalopram or moclobemide. Using statistical parametric mapping brain SPECT studies were analysed to determine the effects of treatment on rCBF, to compare the effects of citalopram and moclobemide, and to detect correlations between changes in rCBF and clinical response. Subjects received citalopram (n=17) or moclobemide (n=14) as therapy. Subjects in both treatment groups demonstrated a significant improvement of SAD symptoms as measured by the Liebowitz Social Anxiety Scale total score. All subjects demonstrated a decrease in rCBF in the insulae post therapy. Subjects receiving citalopram had decreased superior cingulate rCBF after therapy compared to those receiving moclobemide. Both SSRI's and RIMA's decreased rCBF in the insulae during treatment of SAD; an effect that may be consistent with the role of these regions in processing internal somatic cues evoked by emotional stimuli. Citalopram had a greater effect on superior cingulate perfusion, an effect that is consistent with evidence of high levels of 5-HT transporters in this region.


A comparative clinico-pathological study of single dose ROM in paucibacillary leprosy patients with 1-3 skin lesions.
A controlled clinical and histopathological study was carried out to compare the efficacy of a combination of rifampicin 600 mg plus ofloxacin 400 mg plus minocycline 100 mg (ROM) administered as a single dose with that of standard WHO/MDT-PB six months' regimen with regard to resolution of lesion clinically and histopathologically. Skin biopsy was performed at the intake and at 6 months. The study subjects were 32 previously untreated, smear-negative patients, without nerve trunk involvement and having 1-3 skin lesions. The results were analyzed for mean clinical score for marked, moderate and no improvement and mean histopathological score was graded as active, resolving and complete resolution, according to granuloma fraction at the end of 6 months. Marked clinical improvement was seen in 25% and 12%, moderate improvement in 50% and 56% patients treated with ROM and standard regimens respectively. Histopathologically, activity was seen in 62.5% and 43.7% and resolution of granuloma in 25% and 31.2% in the ROM and standard regimens respectively. Both the regimens were equally efficacious in the reduction of clinical score and granuloma fraction. No adverse drug reactions or reversal reactions were seen during the study period in both the groups.


Holographic grating formation in a colloidal suspension of silver nanoparticles.
Holographic gratings are recorded in colloidal suspensions of silver nanoparticles by utilizing interfering nanosecond pulses. The diffraction efficiency is measured with continuous-wave light. An instantaneous response together with a transient grating are observed: the nanoparticles absorb the pump light and heat up. Heat is transferred to the solvent, and a delayed thermal grating appears. The final decay time constant of this grating depends quadratically on the period length and has a typical value of 1 micros for grating spacings of several micrometers.


Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation.
The inherent variability of conformational diseases is demonstrated by two families with different mutations of the same conserved aminoacid in antithrombin. Threonine 85 underlies the opening of the main beta-sheet of the molecule and its replacement, by the polar lysine, in antithrombin Wobble, resulted in a plasma deficiency of antithrombin with an uncharacteristically severe onset of thrombosis at 10 years of age, whereas the replacement of the same residue by a nonpolar methionine, antithrombin Wibble, gave near-normal levels of plasma antithrombin and more typical adult thromboembolic disease. Isolated antithrombin Wibble had a decreased thermal stability (Tm 56.2, normal 57.6 degreesC) but was fully stabilized by the heparin pentasaccharide (Tm 71.8, normal 71.0 degreesC), indicating that the prime abnormality is a laxity in the transition of the main sheet of the molecule from the 5- to 6-stranded form, as was confirmed by the ready conversion of antithrombin Wibble to the 6-stranded latent form on incubation. That this transition can occur in vivo was shown by the finding of nearly 10% of the proband's plasma antithrombin in the latent form and also, surprisingly, of small but definitive amounts of latent antithrombin in normal plasma. The latent transition will be predictably accelerated not only by gross mutations, as with antithrombin Wobble, to give severe episodic thrombosis, but also by milder mutations, as with antithrombin Wibble, to trigger thrombosis in the presence of other predisposing factors, including the conformational stress imposed by the raised body temperatures of fevers. Both antithrombin variants had an exceptional (25-fold) increase in heparin affinity and this, together with an increased inhibitory activity against factor Xa, provides evidence of the direct linkage of A-sheet opening to the conformational basis of heparin binding and activation.


SU-E-J-47: Evaluation of the Mismatches Between DRR's and Port Films for IMRT Fields.
To quantify the frequency and magnitude of mismatches between the MLC shape on the DRR created by the Pinnacle planning system and the corresponding port film MLC shape generated by the Mosaiq record-and-verify system for IMRT fields. A retrospective review was made of the most recent 60 patients to receive IMRT at our clinic. The MLC shape on the DRR created by the Philips Pinnacle planning system for each treatment field was reviewed (573 fields total) and compared with the MLC shape of the port film image, which was generated by the Mosaiq treatment planning system. Of the 60 patients studied, 20 had at least one leaf mismatched between the MLC shape on the DRR and port film (142 of the 573 fields). Of the affected cases, on average 59% of the fields had a mismatch. The affected fields had an average of 6.7 leaves mismatched with a mean discrepancy of 27mm. The average maximum discrepancy for each affected patient was 69mm. Discrepancies were most common for head and neck cancers. The MLC shape Mosaiq generates for the port film is the CIAO, or Complete Irradiated Area Outline, which is the area that is actually treated. The Pinnacle DRR displays the maximum leafmotion, which can be different for larger fields in which the MLC leaves abut within the collimator jaw opening. The discrepancy can create substantially different MLC shapes. The problem can be solved by not filming the MLC shape and only using the films for isocenter placement; however, displaying the area receiving treatment can be a useful safety check, possibly preventing a treatment error. The persons assessing the films must be aware of this issue and evaluate the films carefully.


Two contrasting papers stimulate a commentary on the origins of tumour immunology, current cancer immunotherapies, and the future potential for cancer immunotherapy.
Two early papers expressing conflicting views on the occurrence of effective immune attack against cancers stimulate an analysis of the gradual development of an understanding of tumour biology. This understanding has led to the development of the strikingly effective check point blocking and CART anti-cancer immunotherapies, and the promise of more widely applicable therapies based on T cell attracting genetically engineered monoclonal antibodies.


Handedness, clumsiness and developmental language disorders.
Hand preference and relative hand skill were assessed in 83 8 1/2-year-olds who had first been enrolled in a longitudinal study of specific language impairment at 4 years of age. There was no evidence that hand preference or relative skill of the two hands differed from normal in this population, although skill of both hands was poor in children with persisting language difficulties.


School Achievement, IQ, and Risk of Alcohol Use Disorder: A Prospective, Co-Relative Analysis in a Swedish National Cohort.
Most studies suggest that poor cognitive functioning in adolescence increases risk of alcohol use disorders (AUDs). We seek to clarify the causes of this association. In Swedish individuals born from 1972 to 1990 in whom cognitive functioning was assessed by school achievement at age 16 years (males and females, N = 1,796,048) and by IQ at ages 18-20 (males, N = 554,644), we examined the hazard ratio (HR) for AUD ascertained from public registries. We examined and modeled risk of AUD in cousins, full siblings, and monozygotic twin pairs discordant for school achievement and IQ scores. In males and females, HRs for AUD per standard deviation of increasing school achievement equaled 0.47 (95% CI [0.46, 0.47]) and 0.52 (95% CI [0.51, 0.53]), respectively. In males, the HR for AUD per standard deviation of increasing IQ was 0.54 (95% CI [0.53, 0.55]). Excluding onsets of AUD within 5 years of the cognitive evaluation did not weaken the association, nor did controlling for alcohol intake and problems at IQ assessment. The HRs for AUD in relative pairs were higher than those observed in the population but significantly less than unity. We predicted the following HRs for AUD in discordant monozygotic twins for school achievement in males and females and for IQ in males: 0.66 (95% CI [0.62, 0.70]), 0.67 (95% CI [0.62, 0.73]), and 0.72 (95% CI [0.65, 0.79]), respectively. Cognitive ability in adolescence, assessed by two different measures, strongly predicts risk of AUD. This association cannot be explained by early symptoms of AUD impairing performance. Co-relative analyses suggest that this association arises partly from familial confounding and partly from a causal impact of low cognitive ability on AUD risk.


Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.
Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Genetic variants associated with primary open-angle glaucoma. Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.


Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses.
Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration 0·69 [95% CI 0·59-0·80]; p<0·0001) and non-significant inverse associations for stroke (0·85 [0·70-1·02], p=0·09) and coronary heart disease (0·89 [0·76-1·04]; p=0·14). A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D concentrations and all-cause mortality up to around 40 nmol/L. Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies. British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.


Cancer survival disparities by health insurance status.
Previous studies found that uninsured and Medicaid insured cancer patients have poorer outcomes than cancer patients with private insurance. We examined the association between health insurance status and survival of New Jersey patients 18-64 diagnosed with seven common cancers during 1999-2004. Hazard ratios (HRs) with 95% confidence intervals for 5-year cause-specific survival were calculated from Cox proportional hazards regression models; health insurance status was the primary predictor with adjustment for other significant factors in univariate chi-square or Kaplan-Meier survival log-rank tests. Two diagnosis periods by health insurance status were compared using Kaplan-Meier survival log-rank tests. For breast, colorectal, lung, non-Hodgkin lymphoma (NHL), and prostate cancer, uninsured and Medicaid insured patients had significantly higher risks of death than privately insured patients. For bladder cancer, uninsured patients had a significantly higher risk of death than privately insured patients. Survival improved between the two diagnosis periods for privately insured patients with breast, colorectal, or lung cancer and NHL, for Medicaid insured patients with NHL, and not at all for uninsured patients. Survival from cancer appears to be related to a complex set of demographic and clinical factors of which insurance status is a part. While ensuring that everyone has adequate health insurance is an important step, additional measures must be taken to address cancer survival disparities.


The hsSsu72 phosphatase is a cohesin-binding protein that regulates the resolution of sister chromatid arm cohesion.
Cohesin is a multiprotein complex that establishes sister chromatid cohesion from S phase until mitosis or meiosis. In vertebrates, sister chromatid cohesion is dissolved in a stepwise manner: most cohesins are removed from the chromosome arms via a process that requires polo-like kinase 1 (Plk1), aurora B and Wapl, whereas a minor amount of cohesin, found preferentially at the centromere, is cleaved by separase following its activation by the anaphase-promoting complex/cyclosome. Here, we report that our budding yeast two-hybrid assay identified hsSsu72 phosphatase as a Rad21-binding protein. Additional experiments revealed that Ssu72 directly interacts with Rad21 and SA2 in vitro and in vivo, and associates with sister chromatids in human cells. Interestingly, depletion or mutational inactivation of Ssu72 phosphatase activity caused the premature resolution of sister chromatid arm cohesion, whereas the overexpression of Ssu72 yielded high resistance to this resolution. Interestingly, it appears that Ssu72 regulates the cohesion of chromosome arms but not centromeres, and acts by counteracting the phosphorylation of SA2. Thus, our study provides important new evidence, suggesting that Ssu72 is a novel cohesin-binding protein capable of regulating cohesion between sister chromatid arms.


In vivo endoscopic mass spectrometry using a moving string sampling probe.
At present, endoscopy relies almost exclusively on optical microscopy and the accurate analysis such as MS interrogation is performed ex situ using biopsy. In this work, a novel probing system is developed to perform in situ and in vivo endoscopic mass spectrometry using a moving string for the sampling and transportation of material. A prototype of a mass spectrometric endoscope is constructed using an industrial endoscope and a commercial mass spectrometer. The sampling system consists of a moving cotton thread driven by motorized pulleys. When the target surface is touched by the sampling probe, the cotton thread "wipes" and transports the adhered sample to the ion source. Depending on the target analytes, desorption electrospray and atmospheric pressure chemical ionization sources are employed interchangeably for the desorption and ionization. The surface under analysis is not subjected to heat, organic solvents, high voltage or charged droplets. In situ endoscopic MS of a living mouse and surface analysis inside a volunteer subject's mouth are demonstrated.


Multilevel modelling of the risk of malaria among children aged under five years in Nigeria.
Malaria is still a major cause of morbidity and mortality among children aged <5 y (U5s). This study assessed individual, household and community risk factors for malaria in Nigerian U5s. Data from the Nigerian Malaria Health Indicator Survey 2015 were pooled for analyses. This comprised a national survey of 329 clusters. Children aged 6-59 mo who were tested for malaria using microscopy were retained. Multilevel logit model accounting for sampling design was used to assess individual, household and community factors associated with malaria parasitaemia. A total of 5742 children were assessed for malaria parasitaemia with an overall prevalence of 27% (95% CI 26 to 28%). Plasmodium falciparum constituted 98% of the Plasmodium species. There was no significant difference in parasitaemia between older children and those aged ≤12 mo. In adjusted analyses, rural living, northwest region, a household size of >7, dependence on river and rainwater as primary water source were associated with higher odds of parasitaemia, while higher wealth index, all U5s who slept under a bed net and dependence on packaged water were associated with lower odds of parasitaemia. Despite sustained investment in malaria control and prevention, a quarter of the overall study population of U5s have malaria. Across the six geopolitical zones, the highest burden was in children living in the poorest rural households.


Policy statement--emergency information forms and emergency preparedness for children with special health care needs.
Children with chronic medical conditions rely on complex management plans for problems that cause them to be at increased risk for suboptimal outcomes in emergency situations. The emergency information form (EIF) is a medical summary that describes medical condition(s), medications, and special health care needs to inform health care providers of a child's special health conditions and needs so that optimal emergency medical care can be provided. This statement describes updates to EIFs, including computerization of the EIF, expanding the potential benefits of the EIF, quality-improvement programs using the EIF, the EIF as a central repository, and facilitating emergency preparedness in disaster management and drills by using the EIF.


Oral delivery of lipophilic drugs: the tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations.
The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug's permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone's absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1:1 = 2311 M(-1)), all experimental models showed that the drug's permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone's permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.


Genetic variants associated with circulating C-reactive protein levels and colorectal cancer survival: Sex-specific and lifestyle factors specific associations.
Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.


History of radiation detriment and its calculation methodology used in ICRP Publication 103.
Over the past decades, the International Commission on Radiological Protection (ICRP) has used radiation detriment, which is a multidimensional concept to quantify the overall harm to health from stochastic effects of low-level radiation exposure of different parts of the body. Each tissue-specific detriment is determined from the nominal tissue-specific risk coefficient, weighted by the severity of the disease in terms of lethality, impact on quality of life and years of life lost. Total detriment is the sum of the detriments for separate tissues and organs. Tissue weighting factors for the calculation of effective dose are based on relative contributions of each tissue to the total detriment. Calculating radiation detriment is a complex process that requires information from various sources and judgements on how to achieve calculations. As such, it is important to document its calculation methodology. To improve the traceability of calculations and form a solid basis for future recommendations, the ICRP Task Group 102 on detriment calculation methodology was established in 2016. As part of its mission, the history of radiation detriment was reviewed, and the process of detriment calculation was detailed. This article summarises that work, aiming to clarify the methodology of detriment calculation currently used by ICRP.


Handling varying amounts of missing data when classifying mental-health risk levels.
One of the main challenges of classifying clinical data is determining how to handle missing features. Most research favours imputing of missing values or neglecting records that include missing data, both of which can degrade accuracy when missing values exceed a certain level. In this research we propose a methodology to handle data sets with a large percentage of missing values and with high variability in which particular data are missing. Feature selection is effected by picking variables sequentially in order of maximum correlation with the dependent variable and minimum correlation with variables already selected. Classification models are generated individually for each test case based on its particular feature set and the matching data values available in the training population. The method was applied to real patients' anonymous mental-health data where the task was to predict the suicide risk judgement clinicians would give for each patient's data, with eleven possible outcome classes: zero to ten, representing no risk to maximum risk. The results compare favourably with alternative methods and have the advantage of ensuring explanations of risk are based only on the data given, not imputed data. This is important for clinical decision support systems using human expertise for modelling and explaining predictions.